I I CS Health Care Guideline: Diagnosis and Management of Type …a... · 2010-09-21 · • the...
Transcript of I I CS Health Care Guideline: Diagnosis and Management of Type …a... · 2010-09-21 · • the...
Health Care Guideline:
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults
Thirteenth Edition May 2009
I ICSI NSTITUTE FOR C LINICAL S YSTEMS I MPROVEMENT
The information contained in this ICSI Health Care Guideline is intended primarily for health profes-sionals and the following expert audiences:
• physicians, nurses, and other health care professional and provider organizations;
• health plans, health systems, health care organizations, hospitals and integrated health care delivery systems;
• health care teaching institutions;
• health care information technology departments;
• medical specialty and professional societies;
• researchers;
• federal, state and local government health care policy makers and specialists; and
• employee benefit managers.
This ICSI Health Care Guideline should not be construed as medical advice or medical opinion related to any specific facts or circumstances. If you are not one of the expert audiences listed above you are urged to consult a health care professional regarding your own situation and any specific medical questions you may have. In addition, you should seek assistance from a health care professional in interpreting this ICSI Health Care Guideline and applying it in your individual case.
This ICSI Health Care Guideline is designed to assist clinicians by providing an analytical framework for the evaluation and treatment of patients, and is not intended either to replace a clinician's judgment or to establish a protocol for all patients with a particular condition. An ICSI Health Care Guideline rarely will establish the only approach to a problem.
Copies of this ICSI Health Care Guideline may be distributed by any organization to the organization's employees but, except as provided below, may not be distributed outside of the organization without the prior written consent of the Institute for Clinical Systems Improvement, Inc. If the organization is a legally constituted medical group, the ICSI Health Care Guideline may be used by the medical group in any of the following ways:
• copies may be provided to anyone involved in the medical group's process for developing and implementing clinical guidelines;
• the ICSI Health Care Guideline may be adopted or adapted for use within the medical group only, provided that ICSI receives appropriate attribution on all written or electronic documents; and
• copies may be provided to patients and the clinicians who manage their care, if the ICSI Health Care Guideline is incorporated into the medical group's clinical guideline program.
All other copyright rights in this ICSI Health Care Guideline are reserved by the Institute for Clinical Systems Improvement. The Institute for Clinical Systems Improvement assumes no liability for any adaptations or revisions or modifications made to this ICSI Health Care Guideline.
Health Care Guideline:
Diagnosis and Management of Type 2 Diabetes Mellitus in AdultsI ICS
I NSTITUTE FOR C LINICAL S YSTEMS I MPROVEMENT A = Annotation
www.icsi.org
Copyright © 2009 by Institute for Clinical Systems Improvement 1
Should patient be hospitalized?
6
A
Treatment goals for patients without cardiovascular disease:• Consider statin, unless contraindicated• LDL < 100 mg/dL• Blood pressure control (BP < 130/80)• Aspirin/antiplatelet medication optional• Smoking status: tobacco cessation if indicated
Recommend education andself-management:• Nutrition therapy• Physical activity• Weight management• Education for self-management• Foot care• Community resources
10
A
See Ongoing Management
algorithm
yes
no
Initial stabilization for outpatients requiring
immediate insulintreatment
9
A
Treatment goals not met:• Modify treatment based on appropriate related guideline• See Glycemic Control and Blood Pressure Control algorithms and/or• Consider referral to diabetes health team or specialists• Assess patient adherence• Evaluate for depression
16
Diagnostic testing for diabetes
1
A
Inpatient diabetes management
yes
Does patientneed outpatient
stabilization?
8
Are treatment goals met?
15
A
yes
17
A
Evaluation of patients with
elevated glucose
2
A
Diagnosis of type 2 diabetes
Diagnosis of prediabetes
Treatment to prevent or delay the progression to
diabetes
534
A A A
7
A
no
no
A
Complex patient factors to consider:• Known cardiovascular disease or high cardiovascular risk• Inability to recognize and treat hypoglycemia; history of severe hypoglycemia requiring assistance• Inability to comply with standard goals, such as polypharmacy issues• Limited life expectancy or estimated survival of less than 10 years• Cognitive impairment• Extensive comorbid conditions
11a
Set personalized A1c goal = A1c < 7% or individualize
to a goal < 8% based on factors in 11a
11
A
Treatment goals for patients with cardiovascular disease:• Consider statin, unless contraindicated• LDL < 70 mg/dL• Blood pressure control (BP < 130/80)• Aspirin/antiplatelet medication• Smoking status: tobacco cessation if indicated
14
A
A
no yes
Does patient have known cardiovascular
disease?
12
13
Thirteenth EditionMay 2009
Institute for Clinical Systems Improvement
www.icsi.org
2
Glycemic Control Algorithm
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Thirteenth Edition/May 2009
A = Annotation
Glycemic Control algorithm
18
A
Pharmacologic agent(s) – which is
best?
19
A
Prescribe insulin therapy
insulin See OngoingManagement algorithm
20
Prescribe non-insulin agents
• Titrate to goal
22
A
non-insulin
Glycemic control achieved?
23
See OngoingManagement algorithm
yes
Intensify therapy• Start insulin alone or insulin + other agent(s)
no
25
A
A
21
24
Institute for Clinical Systems Improvement
www.icsi.org
3
Blood Pressure Control Algorithm
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Thirteenth Edition/May 2009
A = Annotation
Blood Pressure Control algorithm
26
A
Is systolic blood pressure
> 130 mmHg?
27
A
Treat systolic blood pressure to< 130 mmHg. While ACE inhibitors
and ARBs are preferred first-line therapy, two or more agents (to
include thiazide diuretics) may be required
28
A
yes
Is diastolic blood pressure
< 80 mmHg?
29
A
no
Treat diastolic blood pressure to < 80 mmHg
no
A
31
See Ongoing Management algorithm
yes
See Ongoing Management algorithm
30
32
Institute for Clinical Systems Improvement
www.icsi.org
4
Ongoing Management Algorithm
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Thirteenth Edition/May 2009
A = Annotation
Ongoing management and follow-up of people with
diabetes
33
A
Maintain treatment goals: • Nutrition • Exercise • Monitor A1c every 3-6 months - Review blood glucose at each visit - Ask about hypoglycemia • Monitor lipid profile yearly • Monitor BP each visit • Ask about aspirin use • Ask about alcohol and tobacco use
34
A
Annual assessment of complications: • Targeted annual history and physical exam • Specialist dilated eye exam • Renal assessment • Comprehensive foot exam with risk assessment • Cardiovascular and cerebrovascular complication assessment • Special considerations
35
A
Treatment and referral for complications: • Nephropathy • Neuropathy • Retinopathy • Cardiovascular and cerebrovascular disease • Peripheral vascular disease
36
A
Are goals continuing to be
met?
37
no
yes
Treatment goals not met: • Modify treatment based on appropriate guidelines and/or • See Glycemic Control and Blood Pressure Control algorithms, and/or • Consider referral to diabetes health team or specialists • Assess patient adherence • Evaluate for depression
38
Institute for Clinical Systems Improvement
www.icsi.org
5
Table of Contents
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Thirteenth Edition/May 2009
Work Group LeadersBruce Redmon, MDDivision of EndocrinologyUniversity of MinnesotaJoAnn Sperl-Hillen, MD Internal Medicine, HealthPartners Medical GroupWork Group MembersEndocrinologyRichard Bergenstal, MDPark NicolletSteve Smith, MDMayo ClinicFamily MedicineGreg Frane, MDNorthwest Family PhysiciansPatrick O'Connor, MDHealthPartners Medical GroupTodd Wade, MDMayo ClinicHealth EducationJulie Roberts, MS, RD, CDE HealthPartners Medical GroupInternal MedicineEugene Ollila, MDAllina Medical ClinicNursingPenny Louise Flavin, APRNOlmsted Medical CenterCarol Manchester, MSN, APRNFairview Health ServicesPharmacySarah Merbach, BS, RPhOlmsted Medical CenterVyvy Vo, PharmDHealthPartners Medical GroupFacilitatorMelissa Marshall, MBAICSI
Algorithms and Annotations ....................................................................................... 1-57Algorithm (Main) ................................................................................................................1Algorithm (Glycemic Control) ........................................................................................... 2Algorithm (Blood Pressure Control) .................................................................................. 3Algorithm (Ongoing Management) .................................................................................... 4Foreword
Scope and Target Population ......................................................................................... 6Clinical Highlights and Recommendations .................................................................. 6Priority Aims .............................................................................................................. 6-7Key Implementation Recommendations .................................................................... 7-8Related ICSI Scientific Documents .............................................................................. 8Disclosure of Potential Conflict of Interest ................................................................... 9Introduction to ICSI Document Development .............................................................. 9Description of Evidence Grading................................................................................ 10
Definitions .........................................................................................................................11Annotations ................................................................................................................. 12-55
Annotations (Main) ................................................................................................ 12-34Annotations (Glycemic Control)............................................................................ 34-47Annotations (Blood Pressure Control) ................................................................... 47-49Annotations (Ongoing Management) .................................................................... 49-55
Appendices .................................................................................................................. 56-57Appendix A – Treatment of Diabetic Nephropathy .....................................................56Appendix B – Using a Semmes-Weinstein Monofilament to Screen the Diabetic Foot for Peripheral Sensory Neuropathy ..................................................57
Supporting Evidence.................................................................................................. 58-101Brief Description of Evidence Grading ............................................................................ 59References ...................................................................................................................60-69Conclusion Grading Worksheets ...............................................................................70-101
Conclusion Grading Worksheet A – Annotation #4 (Prediabetes) ......................... 70-78Conclusion Grading Worksheet B – Annotation #11 (A1c) ................................... 79-85Conclusion Grading Worksheet C – Annotations #13, 14 (Statin Use) ................. 86-92Conclusion Grading Worksheet D – Annotations #13, 14, 27, 29 (Goals for Blood Pressure)......................................................................................93Conclusion Grading Worksheet E – Annotations #13, 14 (Aspirin Use) ............... 94-99Conclusion Grading Worksheet F – Annotations #28, 36 (Treatment with ACE Inhibitors or ARBs) ...........................................................100Conclusion Grading Worksheet G – Annotations #28, 36 (Thiazide Diuretics) ..............................................................................................101
Support for Implementation ................................................................................. 102-114Priority Aims and Suggested Measures ................................................................... 103-105Key Implementation Recommendations ................................................................. 106-107Knowledge Resources .................................................................................................... 107Resources Available................................................................................................. 108-114
Institute for Clinical Systems Improvement
www.icsi.org
6
Foreword
Scope and Target PopulationTo provide a comprehensive approach to the diagnosis and management of prediabetes and type 2 diabetes mellitus in adults age 18 and older. Management will include nutrition therapy, physical activity, self-man-agement strategies, and pharmacologic therapy recommendations, as well as the prevention and diagnosis of diabetes-associated complications and risk factors.
The diagnosis of gestational diabetes or the management of diabetes in patients who are pregnant is excluded from the scope of this guideline. Oral agents do not have Food and Drug Administration approval for use in pregnancy. The glucose goals are different in pregnancy and require more aggressive treatment.
Please refer to the ICSI Routine Prenatal guideline for information relating to gestational diabetes.
The diagnosis and management of type 1 diabetes is not included in this guideline.
Clinical Highlights and Recommendations• Education and self-management support is necessary for people with diabetes to manage their disease.
(Annotation #10)
• Focus on cardiovascular risk reduction (blood pressure control, low-density lipoprotein cholesterol control and statin use, aspirin use and tobacco cessation). (Annotations #11, 13, 14)
• A1c levels should be individualized to the patient. (Annotation #11)
• Aggressive blood pressure control is just as important as glycemic control. Systolic blood pressure level should be the major factor for detection, evaluation and treatment of hypertension. The use of two or more blood pressure lowering agents is often required to meet blood pressure goal. (Annotations #13, 14)
• Prevent microvascular complications through annual or biannual eye exams, foot risk assessments and foot care counseling, and annual screening for proteinuria. (Annotation #35)
• Initial therapy with lifestyle treatment and metformin is advised unless contraindicated. (Annotations #4, 10)
Priority AimsA multifactorial intervention targeting hyperglycemia and cardiovascular risk factors in individuals with diabetes is most effective. Both individual measures of diabetes care as well as comprehensive measures of performance on broader sets of measures are recommended. A randomized controlled trial has shown a 50% reduction in major cardiovascular events through a multifactorial intervention targeting hypergly-cemia, hypertension, dyslipidemia, microalbuminuria, aspirin and ACE inhibitor use in individuals with microalbuminuria (Gaede, 2003 [A]).
Goals for A1c, low-density lipoprotein, and other diabetes measures should be personalized, and lower goals for A1c and low-density lipoprotein than those included here in the priority aims and measures may be clinically justified in some adults with type 2 diabetes. However, efforts to achieve lower A1c below 7% may increase risk of mortality, weight gain, hypoglycemia and other adverse effects in many patients with type 2 diabetes. Therefore, the aims and measures listed here are selected carefully in the interests of patient safety.
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
7
1. Diabetes Optimal Care Measures: Maximize the percentage of adult patients, ages 18-75 with type 2 diabetes mellitus, who in a defined period of time achieve any of the possible measures of established control.
2. Diabetes Optimal Care Comprehensive Measure Set: Maximize the percentage of adult patients ages 18-75 with type 2 diabetes mellitus, who in a one-year period of time achieved the identified measures of care.
3. Diabetes Process of Care Measure Set: Maximize the percentage of adult patients ages 18-75 with type 2 diabetes mellitus for whom recommended screening procedures are done.
4. High-Risk Population Measures: The purpose of this aim is to identify and focus on a higher risk population by decreasing the percentage of adult patients, ages 18-75 with type 2 diabetes mellitus, with poorly controlled glucose and cardiovascular risk factors (clinical strategies that target high-risk populations may be more viable with limited resources).
Key Implementation RecommendationsThe implementation of type 2 diabetes mellitus clinical guidelines at medical groups and clinics is a complex and challenging task. However, a number of key processes have been shown to accelerate effective clinical guideline implementation and care improvement (Sperl-Hillen, 2005 [D]). These overlapping care elements can be categorized at the medical group and provider levels:
• Essential Elements at the Medical Group Level:
- Leadership. Medical group leaders must communicate the need for change in clinical practice patterns and consistently identify improvement priorities.
- Resources. Resources adequate to the task at hand will be needed to assure the success of a change effort. Resources may include staff time, money and provision of tools (such as elec-tronic medical records) to support care improvement.
- Select Specific Improvement Goals and Measures. For most chronic diseases, including diabetes, the most efficient improvement strategy is to focus on a limited number of specific improvement goals. These may be based on observed gaps in care, potential clinical impact, cost considerations or other criteria (O'Connor, 2005a [R]). In type 2 diabetes, focusing on glycemic control, lipid control and blood pressure control is a strategy that has been shown to be effective in preventing up to 53% of heart attacks and strokes, the leading drivers of excess mortality and costs in adults with diabetes (Gaede, 2003 [A]).
- Accountability. Accountability within the medical group is a management responsibility, but external accountability may also play an important enhancing role to motivate sustained efforts to implement guidelines and improve care. Examples of external accountability include participation in shared learning activities (such as Institute for Healthcare Improvement or ICSI and its Action Groups), or public reporting of results (such as in pay-for-performance or the Minnesota Community Measures Project).
- Prepared Practiced Teams. The medical group may need to foster the development of prepared practice teams that are designed to meet the many challenges of delivering high-quality chronic disease care.
• Essential Elements at the Clinic Level:
- Develop "Smart" Patient Registries. These are registries that are designed to identify, automatically monitor, and prioritize patients with diabetes based on their risk, current level of control, and possibly patient readiness-to-change.
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Foreword Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
8
- Assure "Value-Added" Visits. These are office visits or other patient encounters (by phone, e-mail, etc.) that include intensification of treatment if the patient has not yet reached his/her evidence-based clinical goals. Failure of providers and patients to intensify treatment when indicated (referred to as "clinical inertia") is a key obstacle to better diabetes care (O'Connor, 2003 [R]; O'Connor, 2005a [R]; O'Connor, 2005b [R]). HSR editorial. Previsit planning and best practice prompts may help to increase the efficiency of patient visits and remind providers of needed tests and care.
- Develop "Active Outreach." These are strategies to reach patients with chronic disease who have not returned for follow-up or for other selected elements of care. Outreach strategies that enhance the likeliness of a future provider encounter that addresses one of the barriers to patient activation (discussed below) may be more effective. Simple reporting of lab test results or care suggestions through the mail may be ineffective at addressing these barriers.
- Emphasize "Patient Activation" Strategies. These may include diabetes education and other actions designed to sustain engagement of patients with their diabetes care. Many patients with diabetes either (a) do not really believe they have diabetes, or (b) do not really believe that diabetes is a serious disease, or (c) lack motivation for behavioral change, or (d) do not believe that recommended treatments will make a difference to their own outcomes. For care to be effective, these issues must be addressed for many patients (O'Connor, 1997 [D]).
Related ICSI Scientific DocumentsGuidelines
• Hypertension Diagnosis and Treatment
• Lipid Management in Adults
• Major Depression in Adults in Primary Care
• Preventive Services for Adults
• Prevention and Management of Obesity (Mature Adolescents and Adults)
• Primary Prevention of Chronic Disease Risk Factors
• Stable Coronary Artery Disease
Order Sets
• Subcutaneous Insulin Management Order Set
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Foreword Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
9
Disclosure of Potential Conflict of InterestICSI has adopted a policy of transparency, disclosing potential conflict and competing interests of all indi-viduals who participate in the development, revision and approval of ICSI documents (guidelines, order sets and protocols). This applies to all work groups (guidelines, order sets and protocols) and committees (Committee on Evidence-Based Practice, Cardiovascular Steering Committee, Women's Health Steering Committee, Preventive & Health Maintenance Steering Committee and Respiratory Steering Committee).
Participants must disclose any potential conflict and competing interests they or their dependents (spouse, dependent children, or others claimed as dependents) may have with any organization with commercial, proprietary, or political interests relevant to the topics covered by ICSI documents. Such disclosures will be shared with all individuals who prepare, review and approve ICSI documents.
Richard Bergenstal, MD has stock in Merck through a family inheritance. Dr. Bergenstal participates in clinical research and/or serves on a scientific advisory board for Amylin, Merck, Pfizer, ResMed, Valeritas, Eli Lilly, Novo Nordisk, Sanofi-Aventis, MannKind, Intuity, Roche, LifeScan, Abbott, Bayer and Medtronic. All compensation goes directly to the non-profit Park Nicollet Institute. Dr. Bergenstal is an officer within the American Diabetes Association.
Carol Manchester, MSN, APRN received speakers' fees or honorarium from Sanofi-Aventis and Pfizer.
Patrick O'Connor, MD receives research or grant funding from HealthPartners Research Foundation; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute for Health; National Heart, Lung, and Blood Institute; Robert Wood Johnson Foundation, Agency for Healthcare Research and Quality; Centers for Disease Control; Minnesota Department of Health, University of Minnesota. Dr. O'Connor received speakers' fees or honorarium from Merck.
Bruce Redmon, MD is contracted with Ingenix and receives research or grant funds from Mannkind Corp.
Steve Smith, MD is a member of the national board of directors for the American Diabetes Association.
JoAnn Sperl-Hillen, MD receives research support from National Heart, Lung, and Blood Institute; National Institute of Diabetes and Digestive and Kidney Diseases; and Merck.
No other work group members have potential conflicts of interest to disclose.
Introduction to ICSI Document DevelopmentThis document was developed and/or revised by a multidisciplinary work group utilizing a defined process for literature search and review, document development and revision as well as obtaining input from and responding to ICSI members.
For a description of ICSI's development and revision process, please see the Development and Revision Process for Guidelines, Order Sets and Protocols at http://www.icsi.org.
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Foreword Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
10
Evidence Grading SystemA. Primary Reports of New Data Collection:
Class A: Randomized, controlled trial
Class B: Cohort study
Class C: Non-randomized trial with concurrent or historical controls Case-control study Study of sensitivity and specificity of a diagnostic test Population-based descriptive study
Class D: Cross-sectional study Case series Case report
B. Reports that Synthesize or Reflect upon Collections of Primary Reports:
Class M: Meta-analysis Systematic review Decision analysis Cost-effectiveness analysis
Class R: Consensus statement Consensus report Narrative review
Class X: Medical opinion
Citations are listed in the guideline utilizing the format of (Author, YYYY [report class]). A full explanation of ICSI's Evidence Grading System can be found at http://www.icsi.org.
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Foreword Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
11
DefinitionsPrediabetes: Hyperglycemia not sufficient to meet the diagnostic criteria for diabetes. Formerly catego-rized as either impaired fasting glucose (IFG) or impaired glucose tolerance (IGT), depending on whether it is identified through a fasting plasma glucose test or oral glucose tolerance test. Diagnosis of prediabetes is based on:
• Fasting plasma glucose of 100 mg/dL to 125 mg/dL
• Oral glucose tolerance test – two-hour plasma glucose of 140 mg/dL to 199 mg/dL
Type 2 Diabetes Mellitus: Diabetes that results from a progressive insulin secretory defect on the back-ground of insulin resistance. The diagnosis of type 2 diabetes is based on:
• Symptoms of diabetes and a casual plasma glucose of greater than or equal to 200 mg/dL
- Casual is defined as any time of day without regard to time since last meal.
- The classic symptoms of diabetes include polyuria, polydipsia and unexplained weight loss, excessive hunger, fatigue or wounds that are slow to heal or frequent skin infections.
• Fasting plasma glucose of greater than or equal to 126 mg/dL on two occasions
- Fasting is defined as no caloric intake for at least eight hours.
• Oral glucose tolerance test – two-hour plasma glucose of 200 mg/dL
- The oral glucose tolerance test should be performed as described by the World Health Organi-zation, using a glucose load containing the equivalent of 75-g anhydrous glucose dissolved in water.
- Verified by repeat test on a separate occasion.
(American Diabetes Association, 2007a [R])
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Foreword Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
12
Algorithm Annotations
1. Diagnostic Testing for DiabetesPrediabetes is now the term recommended for patients with impaired glucose tolerance or impaired fasting glucose. Type 2 diabetes is frequently not diagnosed until complications appear, and approximately one-third of all people with diabetes may be undiagnosed (American Diabetes Association, 2007c [R]).
Possible tests to assess for diabetes include a fasting plasma glucose or an oral glucose tolerance test. A fasting blood glucose is the preferred test for screening for diabetes (American Diabetes Association, 2007c [R]).
Patients presenting with symptoms of diabetes should be tested.
Risk factors for diabetes include:
• Risk factors for athrosclerosis: smoking, hypertension, dyslipidemia.
• Age, race/ethnicity, family history of diabetes, prior history of diabetes, physical inactivity, cardio-vascular disease, cerebral vascular disease, hyperlipidemia, overweight/obese (as defined by body mass index), low high-density lipoprotein, high triglycerides, polycystic ovarian syndrome.
• Gestation history of an infant weighing more than nine pounds, toxemia, stillbirth or previous diagnosis of gestational diabetes.
Testing patients with hypertension, blood pressure over 130/80, dyslipidemia or heart disease are also recommended.
See the ICSI Hypertension Diagnosis and Treatment guideline, the ICSI Lipid Management in Adults guideline, the ICSI Preventive Services in Adults guideline, the Prevention and Management of Obesity (Mature Adolescents and Adults) guideline, and the Stable Coronary Artery Disease guideline for more information.
2. Evaluation of Patients with Elevated GlucoseEvaluation may be completed in one or more visits over a reasonably short period of time. Clinical judg-ment is needed to determine the urgency of completing the evaluation.
History (American Diabetes Association, 2007c [R])
• Symptoms
• Eating habits, weight history
• Physical activity
• Prior or current infections, particularly skin, foot, dental and genitourinary
• Symptoms and treatment of chronic complications associated with diabetes: eye, heart, kidney, nerve, genitourinary (including sexual function), peripheral vascular and cerebrovascular (these may be present at diagnosis)
• Current medications including over-the-counter medications, dietary supplements and alternative therapies with a focus on medications known to induce diabetes-type states (e.g., steroids, atypical antipsychotics)
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
13
• Psychosocial, cultural and economic factors that might influence the management of diabetes
• Alcohol/drug use
Physical examination (American Diabetes Association, 2007c [R])
• Weight, height, body mass index (BMI), blood pressure
• Cardiovascular system: heart, blood pressure, peripheral vascular including pulses and bruits (abdominal, carotid, femoral)
• Feet: nails, web spaces, ulcers, pulses, calluses, structural deformities, protective sensation and shoes
• Other examinations as guided by the patient's symptoms and/or concerns:
- Skin: infections or diseases such as acanthosis nigricans, xanthomia
- Neurological symptoms: sensory state of hands and feet, muscle wasting, deep tendon reflexes
- Mental health: screen for depression and/or anxiety
- Referral to an eye specialist to assess optic health
- Referral to a dentist to assess oral health
Laboratory evaluation
• Fasting plasma glucose or random plasma glucose
• A1c (not required for prediabetes)
• Fasting lipid profile: total cholesterol, high-density lipoprotein (HDL cholesterol), low-density lipoprotein (LDL cholesterol) and triglycerides
• Serum creatinine and liver function test alanine aminotransferase (ALT) or aspartate aminotrans-ferase (AST)
• Urine: ketones, glucose, protein, microalbuminuria, and culture if microscopic is abnormal or symptoms of infection present
Urine microalbumin tests can identify patients with early diabetic nephropathy when intervention may be most effective in delaying or preventing end-stage renal disease. Single tests for urinary microalbumin and urinary creatinine can accurately detect urinary microalbumin excretion.
For more information, see Annotation #35, "Annual Assessment of Complications" (American Diabetes Association, 2004d [R]; Nelson, 1991 [B]).
Increased urinary microalbumin is a predictor of increased cardiovascular mortality (American Diabetes Association, 2007c [R]).
3. Diagnosis of Prediabetes• Fasting plasma glucose of 100 mg/dL to 125 mg/dL
• Oral glucose tolerance test two-hour plasma glucose: 140 mg/dL to 199 mg/dL
(American Diabetes Association, 2007c [R])
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Algorithm Annotations Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
14
4. Treatment to Prevent or Delay the Progression to DiabetesPatients who are identified with prediabetes should be referred for education and lifestyle interventions. Health care providers should follow up with patients diagnosed with prediabetes on an annual basis to monitor their progress and review treatment goals (American Diabetes Association, 2007c [R]).
Intensive lifestyle change or programs have been proven effective in delaying or preventing the onset of diabetes by about 50%. Effective lifestyle changes include setting achievable goals, obtaining weight loss when needed (ideally at least 5% total body weight), and increasing physical activity (Tuomilehto, 2001 [A]).
• Lifestyle modifications, such as nutrition, exercise and even modest weight loss, are recommended for prevention or delayed progression of patients with prediabetes.
• Pharmacotherapy, such as metformin, are effective in some patients with prediabetes.
• There are concerns that the recent modification of the definition of impaired fasting glucose by the American Diabetes Association has low specificity and low positive predictive value compared to the WHO definition.
[Conclusion Grade II: See Conclusion Grading Worksheet A – Annotation #4 (Prediabetes)]
The following initial approaches are recommended for people with prediabetes:
• Intensive lifestyle behavioral change including a nutrition and activity plan by a registered dietitian, health educator or other qualified health professional. Ongoing support of behavioral change is necessary.
• Cardiovascular risk reduction appropriate to the needs of the individual
Patients who respond to lifestyle interventions:
• Annual follow-up and reassessment of risks for developing diabetes (American Diabetes Associa-tion, 2004g [R]; Chiasson, 2002 [A]; Eriksson, 1999 [R]; Heart Outcomes Prevention Evaluation Study Investigators, 2002 [A]; Kelley, 2002 [A]; Miles, 2002 [A])
Patients who are high risk and not responding to lifestyle interventions:
• Intensify education and counseling on lifestyle interventions.
• There is some evidence of prevention of diabetes through pharmacotherapy with biguanides and alpha glycosidase inhibitors (Diabetes Prevention Program Research Group, 2002 [A]; Gillies, 2007 [M]). Rosiglitazone has been shown to prevent diabetes, but the risk of congestive heart failure was increased (DREAM Trial Investigators, 2006 [A]). Lifestyle change remains the preferred method to prevent diabetes (Diabetes Prevention Program Research Group, 2002 [A]; Gillies, 2007 [M]).
5. Diagnosis of Type 2 DiabetesDiagnosis of type 2 diabetes (American Diabetes Association, 2007a [R]):
• Fasting plasma glucose greater than or equal to 126 mg/dL on two separate occasions.
• Casual plasma glucose greater than or equal to 200 mg/dL plus typical symptoms of diabetes.
• In the absence of unequivocal hyperglycemia associated with acute metabolic decompensation, the results should be confirmed by repeat testing on a different day.
• At the present time A1c should not be used to diagnose diabetes.
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Algorithm Annotations Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
15
History
• Details of previous treatment programs, including diabetes education
• Current treatment of diabetes, including medications, nutrition, physical activity patterns and results of glucose monitoring
• Frequency, severity and cause of acute complications such as hypoglycemia, hyperglycemia and non-ketotic hyperosmolar coma
6. Should Patient Be Hospitalized?Inpatient care may be appropriate in the following situations (American Diabetes Association, 2004d [R]):
• Elderly patients with infection or illness, weight loss, dehydration, polyuria or polydipsia
• Life-threatening acute metabolic complications of diabetes:
- Hyperglycemic hyperosmolar state with impaired mental status, elevated plasma osmolaity that includes plasma glucose greater than 600 mg/dL
- Diabetic ketoacidosis with a plasma glucose greater than 250 mg/dL, arterial pH less than 7.30 and serum bicarbonate level less than 15 mEq/L and the presence of moderate ketonuria and/or ketonemia
- Hypoglycemia with neuroglycopenia that includes blood glucose less than 50 mg/dL and treat-ment has not resulted in prompt recovery, coma, seizures or altered behavior
• Uncontrolled insulin-requiring diabetes during pregnancy
• Surgery, infection, steroids – if these conditions cause significant hyperglycemia and rapid initiation of rigorous insulin is needed
7. Inpatient Diabetes ManagementHospitalized inpatients with diabetes suffer increased morbidity, mortality, length of stay, and other related hospital costs compared to non-hyperglycemic inpatients. These negative outcomes are observed more frequently in hospitalized patients with newly discovered hyperglycemia. Hyperglycemia is an independent marker of inpatient mortality in patients with undiagnosed diabetes (Umpierrez, 2002 [B]).
Hyperglycemia has been associated with increased infection rates and poorer short-term and long-term outcomes in critically ill patients in the intensive care unit, post-myocardial infarction, and post-surgical settings. Studies support that aggressive glucose management in medical and surgical patients can improve outcomes (van den Berghe, 2001 [A]).
The following are recommended in the inpatient setting (Clement, 2004 [R]):
• Intensive insulin therapy with intravenous insulin in critically ill patients (van den Berghe, 2001 [R])
• Use of scheduled insulin, with basal coverage (improves glucose control compared to sliding scale coverage alone)
• For insulin-deficient patients, despite reductions or the absence of caloric intake, basal insulin must be provided to prevent diabetic ketoacidosis
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Algorithm Annotations Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
16
• Target preprandial plasma glucose levels are 90-130 mg/dL (American Diabetes Association, 2004b [R]; Clement, 2004 [R]; Garber, 2004 [R])
• If measured, the target postprandial plasma glucose is less than 180 mg/dL (American Diabetes Association, 2004b [R]; Clement, 2004 [R]; Garber, 2004 [R])
• Establishing a multidisciplinary team that sets and implements institutional guidelines, protocols and standardized order sets for the hospital results in reduced hypoglycemic and hyperglycemic events
Other considerations include (Clement, 2004 [R]):
• For patients who are alert and demonstrate accurate insulin self-administration and glucose moni-toring, insulin self-management should be allowed as an adjunct to standard nurse-delivered diabetes management.
• Patients with no prior history of diabetes who are found to have hyperglycemia (random fasting blood glucose greater than 125 mg/dL or random glucose of 200 mg/dL or more) during hospitaliza-tion should have follow-up testing for diabetes within one month of hospital discharge (Umpierrz, 2002 [B]).
Please see ICSI's Subcutaneous Insulin Management order set for additional information regarding inpatient glucose management.
8. Does Patient Need Outpatient Stabilization?Indications for immediate insulin treatment in type 2 diabetes mellitus (Clements, 1987 [A]; Nathan, 2006 [R])
• Severe symptoms, marked weight loss, polyuria, polydypsia
- Fasting plasma glucose greater than 300 mg/dL fasting, or
- Random glucose over 350 mg/dL, or
- A1c over 10%, or
- Presence of ketonuria
Insulin therapy may not be permanent once patient is stabilized.
9. Initial Stabilization for Outpatients Requiring Immediate Insulin TreatmentIf the patient presents and is considered stable enough for outpatient care but meets indications noted above for starting insulin, the work group offers several acceptable ways of initiating insulin:
• One example is to calculate the total daily dose of insulin at 0.3 units/kg and start bedtime glargine at 50% of the total dose, splitting the remaining 50% with short-acting insulin before meals.
• Another example is to start an oral agent while simultaneously initiating glargine at a dose of approximately 0.1 units/kg.
• A third example is to calculate the total daily dose of insulin at 0.3 units/kg and use premixed insulin with 2/3 the dose in the a.m. and 1/3 in the p.m.
At presentation, all patients should be instructed on glucose monitoring, hypoglycemia recognition and treatment, and how/when to contact health care support. Patients should check glucose frequently when
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Algorithm Annotations Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
17
insulin is initiated. Patients should receive daily phone or visit contact for at least three days and have 24-hour emergency phone support if needed.
Patients should be referred for nutrition and diabetes education and be seen in a timely way after diagnosis, e.g., within one to seven days.
Insulin therapy may not be permanent, particularly if oral agents are added or if, at presentation, the patient is in metabolic stress such as infections, acute metabolic complications, recent surgery (Peters, 1996 [D]). As the metabolic stress resolves, the insulin dose requirements may rapidly fall.
For the occasional unstable patient with type 2 diabetes, maximal doses of oral hypoglycemic agents may afford an approach to the patient who is psychologically resistant to or refuses insulin initiation.
10. Recommend Education and Self-ManagementNutrition TherapyMedical nutrition therapy for diabetes emphasizes improving metabolic outcomes by modifying nutrient intake and lifestyle. Major goals are to attain and maintain in the normal or as close to normal range as is safely possible glucose, blood pressure and lipid/lipoprotein levels. These prevent or slow the development of the chronic complications of diabetes (American Diabetes Association, 2008 [R]).
The priority for nutrition therapy for type 2 diabetes is to implement lifestyle strategies that will reduce hyperglycemia and hypertension and improve dyslipidemias (American Dietetic Association, 2008 [R]; American Diabetes Association, 2008 [R]). Because many individuals are insulin resistant and overweight or obese, nutrition therapy often begins with strategies that reduce energy intake and increase energy expen-diture through physical activity. Many individuals may have already tried unsuccessfully to lose weight and it is important to note that lifestyle strategies, independent of weight loss, can improve glucose control and risk factors for cardiovascular disease.
Moderate weight loss (5% of body weight) is associated with decreased insulin resistance, improved measures of glycemic and lipidemia, and reduced blood pressure. The optimal macronutrient distribution of weight loss diets has not been established (American Diabetes Association, 2008 [R]).
Low carbohydrate diets, restricting total carbohydrate to less than 130 g/day, are not recommended in the management of diabetes.
Appropriate nutrition therapy will be developed collaboratively with the person who has diabetes. Instruc-tion may require a provider with expertise in medical nutrition therapy, and instruction may be obtained through individual or group consultation (Franz, 1995a [A]). It is important that physicians understand the general principles of medical nutrition therapy and support them for patients with diabetes. In most people, nutrition recommendations are similar to those of the general population. Medical nutrition therapy is a Medicare Part B-covered benefit.
• Evaluate the patient's current eating habits and modify as needed. Recommend:
- Working together toward gradual, realistic and culturally appropriate lifestyle change goals.
- Maintaining the pleasure of eating by limiting only food choices indicated by scientific evidence.
- Healthful food choices: foods containing carbohydrates from whole grains, fruits, vegetables, legumes and low-fat milk should be included in a healthy eating plan.
- Reducing total caloric intake by moderating food/beverage and limiting total fat intake.
- Distributing carbohydrates evenly throughout the day to smaller meals and snacks.
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Algorithm Annotations Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
18
- Monitoring carbohydrates remains a key strategy in achieving glycemic control, whether by carbo-hydrate counting, exchanges or experience-based estimation (American Diabetes Association, 2008 [R]).
- If one chooses to drink alcohol and has not been cautioned against it, limit intake to one drink per day for women and two drinks per day for men, according to USDA guidelines. A drink is defined as 12 oz. of regular beer, 5 oz. of wine, or 1.5 oz. of 80-proof distilled spirits. To reduce the risk of hypoglycemia, alcohol should be consumed with food.
• Individualize the nutrition prescription based on the nutrition assessment and treatment goals of each patient. For example, if the patient has been eating 45% of calories from fat, lowering fat to even 40% can be helpful.
Carbohydrate (American Diabetes Association, 2009 [R])
• Both the quantity and the type or source of carbohydrate in food influences post-prandial glucose levels.
• For individuals with diabetes, the use of glycemic index and glycemic load may provide a modest additional benefit for glycemic control over that observed when total carbohydrate is considered alone.
• Sucrose (e.g., table sugar) and sucrose-containing foods do not need to be restricted. However, they should be substituted for other carbohydrate sources, or if added, covered with insulin or other glucose-lowering medication. They should be eaten within the context of a healthy diet and avoid excess energy intake.
• Added fructose as a sweetening agent is not recommended as it may adversely affect plasma lipids. Naturally occurring fructose in fruits, vegetables and other foods does not need to be avoided.
• The use of sugar alcohols, such as sorbitol or manitol in small amounts, appears to be safe; however, they may cause gastrointestinal side effects. When calculating carbohydrate content of foods containing sugar alcohols, subtract half of sugar alcohol grams from total carbohydrate grams (American Diabetes Association, 2008 [R]).
• Sugar alcohols and non-nutritive sweeteners are safe when consumed within the acceptable daily intake levels established by the Food and Drug Administration.
• Encourage consuming a wide variety of fiber-containing foods such as legumes, fiber-rich cereals, fruits, vegetables and whole grain products to achieve fiber intake goals of 14 g/1,000 calories.
Protein (American Diabetes Association, 2007b [R]; American Diabetes Association, 2008 [R])
• 15%-20% of the total calories. Avoid protein intakes of greater than 20% of total daily energy. The long-term effects of consuming more than 20% of energy as protein on the development of nephropathy have not been determined. High-protein diets are not recommended as a method of weight loss at this time.
• Reduction of protein intake to 0.8-1 gm/kg in individuals with diabetes in the earlier stages of chronic kidney disease and to 0.8 gm/kg in the later stages of chronic kidney disease is recommended and may improve measures of renal function (urine albumin excretion rate, glomerular filtration rate).
• Protein does not increase plasma glucose concentrations but does increase serum insulin responses, and thus protein should not be used to treat acute or prevent nighttime hypoglycemia.
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Algorithm Annotations Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
19
Fat (American Diabetes Association, 2007b [R]; American Diabetes Association, 2008 [R])
• Patients with normal weight and lipids: continue maintaining healthy weight and lipids that include less than or equal to 30% calories from fat, less than 7% saturated fats, limit of trans fats, and less than 200 mg cholesterol (Klein, 2004 [R]).
• Weight control: balance lower fat and caloric consumption with regular physical activity of 30 minutes most days.
• Patients with elevated cholesterol and low-density lipoprotein cholesterol: implement National Cholesterol Education Program-Therapeutic Lifestyle recommendations. Program-Therapeutic Lifestyle diet: reduce saturated fat to less than 7% calories and cholesterol to less than 200 mg, consider increased soluble fiber intake (10-25 g/day) and plant stanols/sterols (2 g/day), and mini-mize trans fat intake.
• Two or more servings of fish per week (with the exception of commercially fried fish fillets) provide omega-3 fatty acids and are recommended.
• Patients with elevated triglycerides: improve glucose control, encourage weight loss, increase physical activity, moderate carbohydrate intake and limit dietary saturated fat and trans fat. Increase consumption of omega-3 fatty acids from fish or supplements, which has been shown to reduce adverse cardiovascular outcomes (Wang, 2006 [M]).
Sodium (American Diabetes Association, 2007b [R])
• Medical nutrition therapy for hypertension control focuses on weight reduction and recommended sodium intakes of 2,300 mg/day for normotensive and hypertensive individuals and a sodium intake less than 2,000 mg/day for patients with diabetes and symptomatic heart failure. Additional recom-mendations include consuming five to nine servings of fruits and vegetables daily, and two to four daily servings of low-fat dairy products rich in calcium, magnesium and potassium.
Supplements (American Diabetes Association, 2009 [R])
• Routine supplementation with antioxidants, such as vitamins E and C and carotene, is not advised because of lack of evidence of efficacy and concern related to long-term safety.
• Benefit from chromium supplementation in people with diabetes or obesity has not been conclusively demonstrated and, therefore, cannot be recommended.
Physical activity and behavior modification are important components of weight loss programs and are most helpful in maintenance of weight loss.
Structured programs that emphasize lifestyle changes including education, reduced energy and fat intake (approximately 30% of total energy), regular physical activity and frequent participant contact are neces-sary to produce long-term weight loss of 5%-7% of starting weight. Lifestyle change should be the primary approach to weight loss (American Diabetes Association, 2007b [R]).
When usual measures to promote weight loss are unsuccessful in severely obese individuals with comorbidi-ties, there may be a role for adjunctive pharmacotherapy or surgical procedures.
There is some evidence that pharmacotherapy for weight loss may offer short-term benefit for a subset of patients with type 2 diabetes (Hollander, 1998 [A]; Kelley, 2002 [A]; Miles, 2002 [A]). The studies, however, were of relatively weak design, and pharmacotherapy for weight loss cannot be recommended for most patients with type 2 diabetes.
Patients should be provided with ongoing nutrition self-management and care support (American Diabetes Association, 2007b [R]).
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Algorithm Annotations Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
20
Physical ActivityPeople with diabetes should peform at least 150 minutes a week of moderate intensity activity (50%-70% maximum heart rate), and strengthening exercises three times a week unless contraindicated.
The positive benefits of physical activity include improved blood pressure values, improved lipid profile, improved cardiac status, increased insulin sensitivity, more effective weight management and improved glycemic control, and it helps in the management of depressive symptoms. Because the positive effects of increased physical activity diminish within days of the cessation of exercise, regular activity is recom-mended (Bourn, 1994 [D]).
Recent studies indicate that cumulative daily physical activity may be almost as beneficial as continuous physical exertion (De Buske, 1990 [A]; Hardman, 1999 [R]). The major emphasis is to gradually increase level of physical activity either by increasing duration or frequency.
Epidemiological studies suggest that regular aerobic physical activity is beneficial for the treatment of type 2 diabetes mellitus (American Diabetes Association, 2004e [R]; Helmrich, 1991 [C]).
Reinforce the ongoing need and benefits of physical activity at each visit, offering support and advice on ways to incorporate 30 minutes of physical activity into most days of the week (Pate, 1995 [R]).
Results of self-monitoring glucose can be useful in preventing hypoglycemia and adjusting medications, medical nutrition therapy and physical activity.
Hypoglycemia is a risk in individuals who participate in physical activity and are taking insulin, sulfonylu-reas and/or meglitinides. Depending on the level of physical activity, the medication dosage or the amount of carbohydrate ingested, hypoglycemia can occur. For patients on these drug classes and pre-exercise glucose monitor results are less than 100 mg/dL, additional carbohydrate should be ingested for prevention of hypoglycemia (American Diabetes Association, 2008 [R]).
Strategies for initiation of increased physical activity
• Start by incorporating 10 minutes of increased activity into each day
- Use stairs instead of elevator.
- Park car away from building entrance and walk.
- Walk to do errands.
• Overcome barriers
- Self-monitor activity performed using pedometer, time record and/or journal.
- Be consistent.
- Have alternative activities for inclement weather.
- Find enjoyable activities.
- Be active at the time of day that is best for the individual.
- Doing a physical activity with a partner and/or being accountable to someone regarding your progress greatly improves the ability to be successful (American Diabetes Association, 2008 [R]).
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Algorithm Annotations Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
21
Medical evaluation to assess safety of exercise program
• Assess physical condition and limitations of the patient.
• Assess for cardiovascular disease. Atypical symptoms and painless ischemia are more common in patients with diabetes (Janard-Delenne, 1999 [D]).
• Cardiac stress testing: there is no evidence that stress testing is routinely necessary in asymptomatic people before beginning a moderate-intensity exercise program such as walking.
• Cardiac stress testing should be considered for the previously sedentary individual at moderate to high-risk for cardiovascular disease or other patients who are clinically indicated who want to undertake vigorous aerobic exercise that exceeds the demands of everyday living (American Diabetes Association, 2007c [R]).
• Assess glucose control.
• Assess knowledge of physical activity in relation to glucose control.
• When making a referral, make other health care providers aware of limitations for exercise.
Physical activity can be intermittent or cumulative (DeBuske, 1990 [A]; Hardman, 1999 [R]; Pate, 1995 [R].
Weight ManagementWhen usual measures to promote weight loss are unsuccessful in severely obese individuals with comorbidi-ties, there may be a role for adjunctive pharmacotherapy or surgical procedures.
There is some evidence that pharmacotherapy for weight loss may offer short-term benefit for a subset of patients with type 2 diabetes (Hollander, 1998 [A]; Kelley, 2002 [A]; Miles, 2002 [A]). The studies, however, were of relatively weak design, and pharmacotherapy for weight loss cannot be recommended for most patients with type 2 diabetes.
Bariatric surgery has recently been discussed as an option for some individuals with type 2 diabetes who have a body mass index of 35 kg/m2 or more. Bariatric surgery can result in marked improvements in glycemia; however, the long-term benefits and risks need to be studied further (American Diabetes Associa-tion, 2007b [R]).
Weight loss is also an important goal because it improves insulin resistance, glycemic control, blood pressure and lipid profiles. Moderate weight loss (5% of body weight) can improve fasting blood glucose in many overweight or obese persons (Pastors, 2002 [R]). Low-carbohydrate diets, restricting total carbohydrate to less than 130 g/day, are not recommended in the management of diabetes.
There is considerable interest in low-carbohydrate diets for weight loss; however, the long-term effects of these diets are unknown and although such diets produce short-term weight loss, maintenance of weight loss is similar to that of low-fat diets, and impact on cardiovascular disease risk profile is uncertain (American Diabetes Association, 2007b [R]).
Low-carbohydrate diets, restricting total carbohydrate to less than 130 g/day, are not recommended in the management of diabetes. For weight loss, either low-carbohydrate or low-fat calorie-restricted diets may be effective in the short-term (up to one year) (Standards of Medical Care in Diabetes, 2009 [R]).
Further research is needed to determine the long-term efficacy and safety of low-carbohydrate diets (Klein, 2004 [R]).
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Algorithm Annotations Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
22
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Algorithm Annotations Thirteenth Edition/May 2009
A recent meta-analysis showed at six months, low-carbohydrate diets were associated; with greater improve-ments in triglyceride and high-density lipoprotein cholesterol than low-fat diets, however, low-density lipoprotein cholesterol was significantly higher in low-carbohydrate diets (Nordmann, 2006 [M]). For patients on low-carbohydrate diets, monitor lipid profiles, renal function and protein intake (in those with nephropathy), and adjust hypoglycemic therapy as needed (American Diabetes Association Standards of Medical Care in Diabetes, 2009 [R]).
Please see the Prevention and Management of Obesity (Mature Adolescents and Adults) guideline for more information.
Appropriate nutrition therapy will be developed collaboratively with the person who has diabetes. Instruc-tion may require a provider with expertise in medical nutrition therapy, and instruction may be obtained through individual or group consultation (Franz, 1995a [A]; Franz, 1995b [M]; Franz, 2002 [R]). It is important that physicians understand the general principles of medical nutrition therapy and support them for patients with diabetes. In most people, nutrition recommendations are similar to those of the general population. Medical nutrition therapy is a Medicare Part B-covered benefit.
Education for Self-ManagementAdequate self-management support for patients requires integration of available self-management educa-tion and support resources into routine care. Usually appropriate education may require the expertise of the diabetes educator. This instruction can be obtained through individual or group consultation (Franz, 1995a [A]; Franz, 1995b [M]; Franz, 2002 [R]). Medicare reimbursement for diabetes self-management training requires this service be provided by an education program that has achieved recognition by the American Diabetes Association or American Association of Diabetes Educators; the staff in such a program are multidisciplinary and include at least a registered dietician and an registered nurse with experiential preparation in education and diabetes management (Mensing, 2007 [R]). A number of studies involving a clinical pharmacist in programs with cardiac risk factors in select patients with diabetes have proven to be effective (Cioffi, 2004 [D]). Providers should be aware of culturally appropriate educational and community resources to support persons with diabetes and their families.
An education plan should be identified based on the needs of the individual and referral made to either an internal or external education resource. Periodic reassessment of educational goals is recommended (Lorig, 2001 [D]; Mensing, 2007 [R]).
See the Support for Implementation Section for a list of American Diabetes Association-recognized educa-tion programs available.
Components of self-management include:
• Description of the diabetes disease process and treatment options
• Goal-setting to promote health, and problem-solving for daily living
• Preventing, detecting and treating acute complications
• Preventing (through risk reduction behavior), detecting and adhering to treatments for chronic complications
• Self-monitoring blood glucose, ketones (when appropriate), and using results to improve control
• Incorporation of appropriate nutrition management (Barnard, 1994 [C])
• Incorporation of physical activity into lifestyle (Barnard, 1994 [C])
• Utilizing medications (if applicable) to maximize therapeutic effectiveness
Institute for Clinical Systems Improvement
www.icsi.org
23
• Awareness of culturally appropriate community resources/support for persons with diabetes mellitus and their families and ability to access community resources
• Psychosocial adjustment of diabetes to daily life
• Promotion of preconception care, counseling and management during pregnancy, if applicable
Foot CareEducation should be tailored to patient's current knowledge, individual needs and risk factors. Patients should be aware of their risk factors and appropriate measures to avoid complications (American Diabetes Association, 2004f [R]; Mayfield, 1998 [R]). See Annotation #35, "Annual Assessment of Complications, Comprehensive Foot Exam with Risk Assessment."
Education should cover:
• Inspect feet daily for cuts, bruises, bleeding, redness and nail problems.
• Wash feet daily and dry thoroughly including between the toes.
• Do not soak feet unless specified by a health care provider.
• Be careful of hot water.
• Use of lotions, creams or moisturizer is acceptable, but do not use between the toes.
• Do not walk barefoot.
• Check shoes each day for objects that may have fallen inside, excessive wear or areas that may cause irritation.
• Avoid injuries from cutting toenails; avoid self-cutting calluses or corns.
• When to seek care
Community ResourcesThere is some evidence for the effectiveness of community-based diabetes self-management education and support. These programs may complement the care and education that are routinely part of standard medical practice, and may enhance a patient's ability to self-manage diabetes. The Task Force on Community Preventive Services, supported by the Centers for Disease Control and Prevention, recommends diabetes self-management education in community gathering places.
11. Set Personalized A1c Goal = A1c Less Than 7% or Individualized to a Goal Less Than 8% Based on Factors in 11aKey Points:
• Individual A1c and other treatment goals should be based on the risks and benefits for each patient. Set personalized A1c goal less than 7% or individualize to goal less than 8% based on complex patient factors.
A1c target in type 2 diabetes is aimed at reducing microvascular complications while not increasing risk of morbidity or mortality.
• All patients with type 2 diabetes should aim to achieve an A1c less then 8%. This will reduce microvasuclar disease and not increase risk substantially.
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Algorithm Annotations Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
24
• Most (many) patients with type 2 diabetes may derive additional benefit in reduction of microva-suclar disease by reaching a target A1c less than 7% (and not increase risks as long as the target is not A1c less than 6%).
[Conclusion Grade II: See Conclusion Grading Worksheet B – Annotation #11 (A1c)]
The work group defines high cardiovascular risk as the patient having two other cardiovascular risks (obesity, hypertension, dyslipidemia, smoking and proteinura). Alternative approachs to calculate cardiovascular risk include the Framingham equation, Archimedes and UKPDS.
The physician and patient should discuss and document specific treatment goals and develop a plan to achieve all desired goals. A multifactorial approach to diabetes care that includes emphasis on blood pressure, lipids, glucose, aspirin use, and non-use of tobacco will maximize health outcomes far more than a strategy that is limited to just one or two of these clinical domains (American Diabetes Association, 2009 [R]; Duckworth, 2009 [A]; Gaede, 2008 [A]; Holman, 2008 [A]).
For patients with type 2 diabetes and the following factors, an A1c goal of less than 8% may be more appro-priate than an A1c goal of less than 7% (Action to Control Cardiovascular Risk in Diabetes Study Group, The, 2008 [A]; ADVANCE Collaborative Group, The, 2008 [A]; Duckworth, 2009 [A]).
• Known cardiovascular disease or high risk cardiovascular risk.
• Inability to recognize and treat hypoglycemia, history of severe hypoglycemia requiring assis-tance.
• Inability to comply with standard goals, such a polypharmacy issues.
• Limited life expectancy or estimated survival of less than 10 years.
• Cognitive impairment.
• Extensive comorbid conditions such as renal failure, liver failure and end-stage disease complica-tions.
The benefits of a multifactorial approach to diabetes care are supported by the results of the Steno 2 Study of 160 patients with type 2 diabetes and microalbuminuria. Multifactorial interventions achieved a 50% reduction in mortality and significant reduction in microvascular complications five years after ending a 7.8-year multifactorial intervention that achieved A1c of 7.8%, low-density lipoprotein 83 mg/dL, blood pressure 131/73, compared to a conventional group that achieved A1c 9%, low-density lipoprotein 126 mg/dL and blood pressure 146/78 (Gaede, 2008 [A]). Results of this study are consistent with the need for reasonable blood sugar control with emphasis on blood pressure and lipid management.
Recently reported clinical trials have evaluated the impact of A1c less than 7% on macrovascular and microvascular complications of type 2 diabetes. These studies, the Action to Control Cardiovascular Risk in Diabetes (ACCORD), the Action in Diabetes and Vascular Disease: Preferax and Diamcron Modified Release Controlled Evaluation (ADVANCE), and VADT Trials, are the first that have ever achieved and maintained A1c less than 7% in their intensive treatment patients. A more detailed description of these trials is included in Conclusion Grading Worksheet B – Annotation #11 (A1c).
In the ACCORD Trial, excess mortality in the intensive group (A1c mean 6.4% vs. standard group A1c 7.5%) forced the safety board to discontinue the intensive treatment arm earlier than planned (Action to Control Cardiovascular Risk in Diabetes Study Group, The, 2008 [A]). There was one excess death for every 90 patients in the intensive group over a 3.5-year period of time. In the ADVANCE trial, intensive group patients achieved A1c 6.5% (vs. 7.5% in standard group) but had no reduction in cardiovascular complications or events. In the VADT trial, intensive group patients achieved A1c of 6.9% but had no significant reduction in cardiovascular events or microvascular complications compared to standard group patients who achieved
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Algorithm Annotations Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
25
A1c 8.4%. However, the VADT Trial was underpowered for its main hypothesis tests (Duckworth, 2009 [A]). In the ADVANCE trial, intensive group patients had less progression to proteinuria (one less patient advancing to proteinuria for every 100 people in the intensive group over a five-year period of time), but no fewer eye complications in the intensive group than in the standard group. ACCORD has not yet analyzed impact of A1c control on microvascular complications.
Recent follow-up data from the United Kingdom Prospective Diabetes Study of newly diagnosed patients with type 2 diabetes confirm major macrovascular and microvascular benefits of achieving A1c in the 7.1% to 7.3% range, vs. A1c of about 8% in the comparison groups (Holman, 2008 [A]). The United Kingdom Prospective Diabetes Study main trial included 3,867 newly diagnosed type 2 diabetes patients and showed over a 10-year period a 25% decrease in microvascular outcomes with a policy using insulin and sulfony-lureas that achieved a median A1c of 7.1%, compared to 7.9%. A subgroup of obese patients (n=1,704) treated with metformin and achieving a median A1c of 7.3% showed greater advantages over conventional treatment: a 32% reduction of diabetes-related end points (P=0.002), a 42% reduction of diabetes-related deaths (P=0.017), and a 36% reduction of all-cause mortality (P=0.011) (UK Prospective Diabetes Study Group, 1998b [A]; United Kingdom Prospective Diabetes Study Group, 1998d [A]).
Epidemiological studies supported the recommendation for intensive glycemic control to A1c below 7% to reduce microvascular and macrovascular disease, but the benefits have not been consistently demonstrated in randomized control trials. It is possible that some aspect of the medications used to achieve low A1c values in the ACCORD, ADVANCE and VADT trials offset the anticipated benefits. Of available glucose-lowering medications, only metformin and human insulins have been thoroughly vetted for long-term safety (Goldfine, 2008 [R]; Inzucchi, 2002 [M]; Selvin, 2008 [M]). Many recent reports have questioned the safety of rosiglitazone, which was widely used in ACCORD (Nissen, 2007 [M]; Winkelmayer, 2008 [B]). Furthermore, the microvascular benefits in recent trials (ADVANCE, VADT) have been fewer than in older trials, perhaps because of better background blood pressure and low-density lipoprotein control in recent trials.
Glycosylated hemoglobin assays provide an accurate indication of long-term glycemic control. A1c is formed by the continuous non-enzymatic glycosylation of hemoglobin throughout the lifespan of an eryth-rocyte. This assay yields an accurate measure of time-averaged blood glucose during the previous six to eight weeks.
There are various methodologies (e.g., HbA, A1c, glycated hemoglobin) for this assay. At present, there are no established criteria for use as a diagnostic test. Clinically it can assist in determining duration and severity of hyperglycemia and can help guide treatment.
Eating, physical activity or acute metabolic stress do not influence the A1c test. The test can be done at any time of day and does not require fasting.
Glucose should also be used to assess level of glycemic control, in addition to A1c. It is appropriate to determine need for medication changes based on blood glucose whenever this information is available.
• Self-monitoring blood glucose
Major clinical trials assessing the impact of glycemic control on diabetes complications have included self-monitoring blood glucose (SMBG) as part of multifactorial interventions, suggesting that self-monitoring blood glucose is a component of effective therapy (American Diabetes Association, 2007c [R]). However, there have been few large published studies done specifically to assess the link between self-monitoring blood glucose and A1c levels. The following table gives ranges of self-monitored glucose readings that would be expected for patients with the corresponding A1c levels.
Self-monitoring blood glucose allows patients to evaluate their individual response to therapy and assess whether glucose targets are being achieved. Results of self-monitoring blood glucose can be useful in
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Algorithm Annotations Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
26
preventing hypoglycemia and adjusting medications, medical nutrition therapy and physical activity (American Diabetes Association, 1994 [R]).
The frequency and timing of self-monitoring blood glucose should be dictated by the particular needs and goals of the individual patient. Patients with type 2 diabetes on insulin typically need to perform self-monitoring blood glucose more frequently than those not using insulin, particularly if using glucose readings to guide mealtime insulin dosing. It is recommended that patients using multiple insulin injec-tions perform self-monitoring blood glucose three or more times daily (American Diabetes Association, 2007c [R]). The optimal frequency and timing of self-monitoring blood glucose for patients with type 2 diabetes on oral agent therapy are not known but should be sufficient to facilitate reaching glucose goals. Self-monitoring blood glucose should be performed more frequently when adding or modifying therapy; two-hour postprandial glucose testing is useful in some patients. The role of self-monitoring blood glucose in stable diet-treated patients with type 2 diabetes is not known.
Because the accuracy of self-monitoring blood glucose is instrumental and user dependent, it is important for health care providers to evaluate each patient's monitoring technique. In addition, optimal use of self-monitoring blood glucose requires proper interpretation of the data. Patients should be taught how to use the data to adjust food intake, exercise or pharmacological therapy to achieve specific glycemic goals.
Examples of self-monitoring glucose goals, frequency and timing are (American Diabetes Association, 2007c [R]):
• Target preprandial plasma glucose values to a goal of 70-130 mg/dL for an A1c goal less than 7%. Target blood glucose readings could be higher or lower depending on individualized A1c goal.
• Average two-hour post-prandial plasma glucose values less than 140-180 mg/dL.
• Two-hour postmeal plasma blood glucoses can be helpful for adjusting mealtime medications. The target range for postmeal glucoses is controversial at this time, but a reasonable two-hour postprandial target is within 40 mg/dL higher than the preprandial reading.
• Average bedtime plasma glucose values are less than 120 mg/dL with a goal of 110-150 mg/dL.
• Bedtime glucose goals vary dependent on the patient's treatment program, risks for hypogly-cemia, and time after last meal.
• More than half of the plasma blood glucose readings should fall in the desired goal range.
Table 1. Ranges of self-monitored blood glucose values for various A1c goals
A1c Target Average Mean
Fasting Blood
Glucose*
Average Mean Post-
Prandial Blood
Glucose
Estimated Average
Blood Glucose**
< 6% < 100 < 140 126
7% 90-130 < 180 154
8% 120-160 < 210 182
9% 160-190 < 240 211
* It is not recommended to target fasting glucose values below 70 mg/dl.
** This average figures weigh both fasting and post-prandial blood glucose readings from continuous
glucose monitors or from 7-point daily testing.
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Algorithm Annotations Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
27
Table 1 was developed by the diabetes work group based on data currently available from studies of frequently monitored glucose values and will be modified if necessary as further studies become available.
13. Treatment Goals for Patients without Cardiovascular DiseaseKey Points:
• A major focus of diabetes care is to achieve the following treatment goals: use of statins in all adult type 2 diabetes patients if tolerated; statins should be titrated to achieve low-density lipoprotein cholesterol of less than 100 mg/dL without coronary artery disease, blood pressure less than 130/80 mmHg. Set personalized A1c goal = A1c less than 7% or individualized to goal of less than 8% based on risk factors. Daily aspirin use is optional for primary prevention of cardiovascular events.
• Consider statin, unless contraindicated
For patients with type 2 diabetes mellitus, consider the use of a statin. Randomized controlled trials, including a number of large trials, and observational data consistently show a benefit of statin therapy for patients with type 2 diabetes. Some studies also report that statin therapy was well tolerated in these patients. However, none of these studies was able to assess long-term effects of statin treat-ment/use. [Conclusion Grade I: See Conclusion Grading Worksheet C – Annotations #13, 14 (Statin Use)]. Evidence (Colhoun, 2004 [A]; Heart Protection Collaborative Study Group, 2002 [A]) and Adult Treatment Panel III consensus guidelines (Grundy, 2004 [R]) suggest that statins are beneficial for high-risk patients ages 40-80 years with a 10-year risk of cardiovascular event of more than 20%, even with baseline untreated low-density lipoprotein of less than 100 mg/dL. There is an online and a Palm format-downloadable cardiovascular risk calculator that is used in assessing 10-year risk of cardiovascular disease used in the Adult Treatment Panel III guideline report and this guideline on lipid management (Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, 2001 [R]). The links are:
Online calculator: http://hin.nhlbi.nih.gov/atpiii/calculator.asp?usertype=prof
Palm format (downloadable): http://hin.nhlbi.nih.gov/atpiii/riskcalc.htm.
[Conclusion Grade I: See Conclusion Grading Worksheet C – Annotations #13, 14 (Statin Use)] (Colhoun, 2004 [A]; Heart Protection Collaborative Study Group, 2002 [A]; Howard, 2008 [A]; Malmström, 2009 [A]; Newman, 2008 [A]; Robins, 2001 [A]; Settergren, 2008 [A])
• LDL less than 100 mg/dL
The low-density lipoprotein cholesterol goal for people with diabetes mellitus without coronary artery disease is less than 100 mg/dL.
Intensify statin or lipid-lowering medications to meet low-density lipoprotein cholesterol goals (LaRosa, 2005 [A]).
Three pathways to improve lipids are:
• Medical nutrition therapy
• Increased physical exercise
• Pharmacotherapy
Beneficial effects of statins on cardiovascular risk reduction may go beyond their effects on lipid levels. Diabetes is considered a coronary artery disease equivalent.
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Algorithm Annotations Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
28
There currently is little evidence for safety and efficacy of combination therapy with statins and other lipid drugs. National Institutes of Health-sponsored randomized controlled studies are currently underway to determine whether adding fibrates or niacin to statin therapy will lower the risk of cardiovascular events for patients with diabetes. ACCORD (fibrate plus statins in diabetes patients) results will be reported in early 2010, and AIM-HIGH (niacin plus statin) will be reported circa 2012.
Seventy to seventy-five percent of adult patients with diabetes die of macrovascular disease, specifically coronary, carotid and/or peripheral vascular disease. Dyslipidemia is a known risk factor for macrovas-cular disease. Patients with diabetes develop more atherosclerosis than patients without diabetes with the same quantitative lipoprotein profiles. In most diabetes patients, use of a statin can reduce major vascular events (HPS [A] 4S diabetes substantially (Pyorola, 1997 [A]).
High triglycerides and low high-density lipoprotein cholesterol levels are independent risk factors for cardiovascular disease in the patient with diabetes (American Diabetes Association, 2007c [R]). Indi-viduals with elevated triglycerides have significant cardiovascular risk reduction with the use of fibrates (Robins, 2001 [A]) or statins (Heart Protection Collaborative Study Group, 2003 [A]). While a number of studies support favorable changes in lipid profiles with niacin alone, randomized controlled trials considering hard cardiovascular outcomes are still underway (AIM-HIGH).
• Goals for blood pressure control: blood pressure less than 130/80 mmHg, emphasis on systolic blood pressure control (American Diabetes Association, 2007c [R]; Chobanian, 2003 [R])
Uncontrolled hypertension is a major cardiovascular risk factor that also accelerates the progression of diabetic nephropathy (Morrish, 1991 [B]). When hypertension is identified, it should be aggressively treated to achieve a target blood pressure of less than 130/80 mmHg. In many patients with diabetes, two or three or more antihypertensive agents may be needed to achieve this goal. The use of generic combination tablets (such as ACE plus calcium-channel blocker, or else beta-blocker plus diuretic) can reduce the complexity of the regimen and out-of-pocket costs. See the Blood Pressure Control algorithm.
For patients with type 2 diabetes mellitus, the systolic blood pressure goal is less than 130 mmHg and the diastolic blood pressure goal is less than 80 mmHg. [Conclusion Grade II: See Conclusion Grading Worksheet D – Annotations #13, 14, 27, 29 (Goals for Blood Pressure)] (Hansson, 1998 [A]; UK Prospective Diabetes Study [A], 1998c; UK Prospective Diabetes Study, 1998e [A]). ADVANCE trial BP results, also showed major benefits of SBP of 134 mmHg in patients with type 2 diabetes.
• Aspirin/antiplatelet medication optional (Bhatt, 2002 [A])
Patients with type 2 diabetes are at a significantly increased risk for development of heart disease (American Diabetes Association, 2007c [R]). There is insufficient evidence to support aspirin use in the primary prevention of cardiovascular events in patients with type 2 diabetes, although there is no evidence of significant harm. However, there is sufficient evidence to support the use of aspirin for secondary prevention of cardiovascular events in patients with type 2 diabetes. [Conclusion Grade I: See Conclusion Grading Worksheet E – Annotations #13, 14 (Aspirin Use)]. Some recent trials of aspirin use in diabetes have shown less benefit than older trials (perhaps due to better background A1c, blood pressure, and low-density lipoprotein control and lower smoking rates in recent trials) (Belch, 2008 [A]; Ogawa, 2008 [A]). There are significant limitations identified in these studies, and more definitive studies would be helpful. [Conclusion Grade I: See Conclusion Grading Worksheet E – Annotations #13, 14 (Aspirin Use)]. Therefore, based on current evidence, low-dose aspirin is considered optional for primary prevention.
On September 8, 2006, the Food and Drug Administration issued a Safety Information and Adverse Event Report regarding the concomitant use of aspirin and ibuprofen. With occasional use of ibuprofen, there is likely to be minimal risk from any attenuation of the antiplatelet effect of low-dose aspirin, because
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Algorithm Annotations Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
29
of the long-lasting effect of aspirin on platelets. Recommendations include taking immediate-release aspirin (not enteric-coated) 30 minutes or longer prior to taking ibuprofen (400 mg). If ibuprofen is taken first, aspirin should not be taken for at least eight hours after ingestion of ibuprofen.
• Goals for tobacco use-smoking cessation, if indicated
Tobacco smoking increases risk of macrovascular complications about 4%-400% in adult with type 2 diabetes and also increases risk of macrovascular complications. Although only about 14% of adult with diabetes in Minnesota are current smokers, in these patients, smoking cessation is very likely to be the single most beneficial intervention that is available, and should be emphasized by providers as described below.
- Identify and document tobacco use status.
- Treat every tobacco user. If the patient is unwilling, the clinician should implement motivational treatments.
- Individual, group and telephone counseling are effective, and their effectiveness increases with treatment intensity.
- Practical counseling (problem-solving/skills training and social support delivered as part of the treatment) are especially effective counseling strategies and should be implemented by clinicians.
- Numerous effective medications are available.
- The combination of counseling and medication is more effective than either alone. Therefore, clini-cians should encourage all individuals making a quit attempt to use both.
- Telephone quit line counseling is effective. Therefore, clinicians and health care delivery systems should ensure patient access to quit lines and promote their use.
- Tobacco dependence treatments are both clinically effective and cost effective. Effective interven-tions require coordinated interventions. Just as the clinician must intervene with the patient, so must the health care administrator, insurer and purchaser foster and support tobacco intervention as an integral element of health care delivery.
Numerous effective pharmacotherapies for smoking cessation now exist. Except in the presence of contrain-dications, these may be used with all patients attempting to quit smoking. Please see the ICSI Preventive Services in Adults guideline for additional information.
Tobacco telephone quit lines: HHS National Quit line (1-800-QUITNOW) or 1-800-784-8669; other local quit lines may be available.
14. Treatment Goals for Patients with Cardiovascular DiseaseKey Points:
• A major goal of diabetes care is to achieve the following treatment goals: use of statins in all adult type 2 diabetes patients if tolerated; statins should be titrated to achieve low-density lipoprotein cholesterol of less than 70 mg/dL with coronary artery disease, blood pressure less than 130/80 mmHg. Set personalized A1c goal = A1c less than 7% or individualized to goal of less than 8% based on risk factors. Daily aspirin use is recommended in patients with cardiovascular disease.
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Algorithm Annotations Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
30
• Consider statin, unless contraindicated
For patients with type 2 diabetes mellitus, consider the use of a statin. Randomized controlled trials, including a number of large trials, and observational data consistently show a benefit of statin therapy for patients with type 2 diabetes. Some studies also reported that statin therapy was well tolerated in these patients. However, none of these studies was able to assess long-term effects of statin treatment/use. [Conclusion Grade I: See Conclusion Grading Worksheet C – Annotations #13, 14 (Statin Use)] (Colhoun, 2004 [A]; Heart Protection Collaborative Study Group, 2002 [A]; Howard, 2008 [A]; Malm-ström, 2009 [A]; Newman, 2008 [A]; Robins, 2001 [A]; Settergren, 2008 [A])
• LDL less than 70 mg/dL
The low-density lipoprotein cholesterol goal for people with diabetes mellitus with coronary artery disease is less than 70 mg/dL.
Intensify statin or lipid-lowering medications to meet low-density lipoprotein cholesterol goals (LaRosa, 2005 [A]).
Use of moderate- to high-dose statins or other low-density lipoprotein cholesterol-lowering medications as needed to achieve a low-density lipoprotein cholesterol value less than 70 mg/dL is recommended for patients with coronary heart disease (Cannon, 2004 [A]; Pyorala, 1997 [A]).
Three pathways to improve lipids are:
• Medical nutrition therapy
• Increased physical exercise
• Pharmacotherapy
There currently is no evidence for safety and efficacy of combination therapy with statins and other lipid drugs. National Institutes of Health-sponsored randomized controlled studies are currently underway to determine whether adding fibrates or niacin to statin therapy will lower the risk of cardiovascular events for patients with diabetes.
Seventy to seventy-five percent of adult patients with diabetes die of macrovascular disease, specifically coronary, carotid and/or peripheral vascular disease. Dyslipidemia is a known risk factor for macrovas-cular disease. Patients with diabetes develop more atherosclerosis than patients without diabetes with the same quantitative lipoprotein profiles. In most diabetes patients, use of a statin can reduce major vascular events (HPS [A] 4S diabetes substantially (Pyorola, 1997 [A]).
High triglycerides and low high-density lipoprotein cholesterol levels are independent risk factors for cardiovascular disease in the patient with diabetes (American Diabetes Association, 2007c [R]). Indi-viduals with elevated triglycerides have significant cardiovascular risk reduction with the use of fibrates (Robins, 2001 [A]) or statins (Heart Protection Collaborative Study Group, 2003 [A]). While a number of studies support favorable changes in lipid profiles with niacin alone, randomized controlled trials considering hard cardiovascular outcomes are still underway (AIM-HIGH).
• Goals for blood pressure control: blood pressure less than 130/80 mmHg, emphasis on systolic blood pressure control (American Diabetes Association, 2007c [R]; Chobanian, 2003 [R])
Uncontrolled hypertension is a major cardiovascular risk factor that also accelerates the progression of diabetic nephropathy (Morrish, 1991 [B]). When hypertension is identified, it should be aggressively treated to achieve a target blood pressure of less than 130/80 mmHg. In many diabetes patients, two or three or more antihypertensive agents may be needed to achieve this goal. The use of generic combina-tion tablets (such as ACE plus calcium-channel blocker, or else beta-blocker plus diuretic) can reduce the complexity of the regimen and out-of-pocket costs. See the Blood Pressure Control algorithm.
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Algorithm Annotations Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
31
For patients with type 2 diabetes mellitus, the systolic blood pressure goal is less than 130 mmHg and the diastolic blood pressure goal is less than 80 mmHg. [Conclusion Grade II: See Conclusion Grading Worksheet D – Annotations #13, 14, 27, 29 (Goals for Blood Pressure)] (Hansson, 1998 [A]; UK Prospective Diabetes Study [A], 1998c; UK Prospective Diabetes Study, 1998e [A]).
• Aspirin/antiplatelet medication use unless contraindicated (Bhatt, 2002 [A])
There is insufficient evidence to support aspirin use in the primary prevention of cardiovascular events in patients with type 2 diabetes, although there is no evidence of significant harm. However, there is sufficient evidence to support the use of aspirin for secondary prevention of cardiovascular events in patients with type 2 diabetes. [Conclusion Grade I: See Conclusion Grading Worksheet E – Annota-tions #13, 14 (Aspirin Use)]
If aspirin is contraindicated, consider use of clopidogrel or ticlopidine. For more information, please refer to the ICSI Stable Coronary Artery Disease guideline and the Antithrombotic Therapy Supplement.
On September 8, 2006, the Food and Drug Administration issued a Safety Information and Adverse Event Report regarding the concomitant use of aspirin and ibuprofen. Health care professionals should counsel patients about the appropriate timing of ibuprofen dosing if they are taking aspirin for cardiopro-tective effects. With occasional use of ibuprofen, there is likely to be minimal risk from any attenuation of the antiplatelet effect of low-dose aspirin, because of the long-lasting effect of aspirin on platelets. Recommendations include taking immediate-release aspirin (not enteric-coated) 30 minutes or longer prior to taking ibuprofen (400 mg). If ibuprofen is taken first, aspirin should not be taken for at least eight hours after ingestion of ibuprofen.
For more information, please refer to the information listed on the Food and Drug Administration's Web site for a complete copy of the alert and cited references.
http://www.fda.gov/medwatch/safety/2006/safety06.htm#aspirin.
• Goals for tobacco use-smoking cessation, if indicated
Tobacco smoking increases risk of macrovascular complications about 4%-400% in adult with type 2 diabetes, and also increases risk of macrovascular complications. Although only about 14% of adult with diabetes in Minnesota are current smokers, in these patients, smoking cessation is very likely to be the single most beneficial intervention that is available, and should be emphasized by providers as described below.
- Identify and document tobacco use status.
- Treat every tobacco user. If the patient is unwilling, the clinician should implement motivational treatments.
- Individual, group and telephone counseling are effective, and their effectiveness increases with treatment intensity.
- Practical counseling (problem-solving/skills training and social support delivered as part of the treatment) are especially effective counseling strategies and should be implemented by clinicians.
- Numerous effective medications are available.
- The combination of counseling and medication is more effective than either alone. Therefore, clini-cians should encourage all individuals making a quit attempt to use both.
- Telephone quit line counseling is effective. Therefore, clinicians and health care delivery systems should ensure patient access to quit lines and promote their use.
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Algorithm Annotations Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
32
- Tobacco dependence treatments are both clinically effective and cost effective. Effective interven-tions require coordinated interventions. Just as the clinician must intervene with the patient, so must the health care administrator, insurer and purchaser foster and support tobacco intervention as an integral element of health care delivery.
15. Are Treatment Goals Met?Major long-term goals of care in type 2 diabetes are cardiovascular disease prevention (see the Blood Pres-sure Control algorithm) and achieving optimal glycemic control (see Glycemic Control algorithm).
Setting initial goals that are achievable, however modest they may be, may encourage patients to take further steps along the way to the more ambitious long-term goals.
Goals and progress toward agreed-upon goals should be briefly reviewed at each office visit for diabetes. Adjustment of goals will likely be required over time, and patient involvement in this process can increase levels of patient involvement in care, give patients a greater sense of control of their diabetes, and allow flexibility in management of diabetes during periods of high stress or major life transitions.
16. Treatment Goals Not MetModify Treatment Based on Appropriate Related Guideline
• Prevention and Management of Obesity (Mature Adolescents and Adults)
• Hypertension Diagnosis and Treatment
• Lipid Management in Adults
• Major Depression in Adults in Primary Care
See Glycemic Control and Blood Pressure Control Algorithms
Consider Referral to Diabetes Care Team or Specialists• Assess patient adherence
Non-adherence with medications can limit the success of therapy and help to explain why a patient is not achieving treatment goals. To screen for non-adherence, clinicians can ask patients open-ended, non-threatening questions at each office visit. The assessment should include probes for factors that can contribute to non-adherence (fear of adverse reactions, misunderstanding of chronic disease treatment, depression, cognitive impairment, complex dosing regimens, or financial constraints).
• Assess the patient's knowledge of his/her condition and his/her expectations for treatment.
• Assess the patient's medication administration process.
• Assess the patient's barriers to adherence.
Interventions to enhance medication adherence should be directed at risk factors or causes of non-adherence. Interventions may include simplifying the medication regimen, using reminder systems, involving family or caregivers in care, involving multiple disciplines in team care, providing written and verbal medication instructions, setting collaborative goals with patients, and providing education about medications (including potential adverse effects) and about diabetes in general (Nichols-English, 2000 [R]).
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Algorithm Annotations Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
33
• Evaluate for depression
There is a substantial increase in the prevalence of depression among people with diabetes as compared to the general adult population (Anderson, 2001 [M]). Self-administered or professionally administered instruments (such as the PHQ-9) are useful adjuncts to the clinical interview in the identification of depression. Depression impacts the ability of a person with diabetes to achieve blood glucose control, which in turn impacts the rate of development of diabetes complications (DeGroot, 2001 [M]; Lustman, 2001 [R]).
Identification and management of depression is an important aspect of diabetes care. Self-administered or professionally administered instruments, such as PHQ-9, are useful adjuncts to the clinical interview in the identification of depression. The ICSI Major Depression in Adults in Primary Care guideline provides more suggestions for the identification and mangement of depression. Intervention studies have demonstrated that when depression is treated, both quality of life and glycemic control improve. Counseling may be effective, especially among those who are having difficulty adjusting to the diag-nosis of diabetes or are having difficulty living with diabetes. Pharmacotherapy for depression is also effective.
• Diabetes care team
Assure the patient has an adequate care team.
Diabetes educator
Consultation with a diabetes educator is suggested if the patient is having difficulty adhering to a nutri-tion, exercise and medication regimen and the patient is having difficulty adhering to, or accurately completing, blood glucose monitoring or may need answers to some questions.
Every primary care physician must develop a relationship with a diabetes education program to provide other options for management. The American Diabetes Association publishes a list of recognized educational programs in each state. These programs may be staffed with endocrinologists or primary care providers plus diabetes educators including dietitians, nurses and other health care providers who are Certified Diabetes Educators or have didactic and experiential expertise in diabetes care and educa-tion.
Endocrinologist/nephrologist
Most type 2 diabetes management can be managed by a primary care physician with periodic consultation as needed by an endocrinologist.
Consultation with a specialist is suggested if persistent proteinuria, worsening microalbuminuria and elevation in serum creatinine or blood urea nitrogen, or hypertension unresponsive to treatment is seen. For additional discussion, see Annotation #36, "Treatment and Referral for Complications, Nephropathy."
Endocrinologist/neurologist
Consultation with a specialist is suggested if neuropathy progresses and becomes disabling.
Endocrinologist/cardiologist/hypertension specialist
Consultation with a specialist is suggested if blood pressure is refractory to treatment, the patient has marked associated postural hypotension or symptoms of coronary artery disease.
Foot care specialist
A consultation with a specialist is suggested if the patient is unable to care properly for his/her own feet, needs prescriptive footwear and/or more serious problems such as foot deformities (e.g., Charcot deformity), infected lesions, and ulcers, deformed nails or thick calluses are present.
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Algorithm Annotations Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
34
Vascular Specialist/Surgeon
Consider referral if patient has symptoms of peripheral vascular disease such as loss of pulses and/or clau-dication.
Glycemic Control Algorithm Annotations
18. Glycemic Control AlgorithmMedical nutrition therapy may be all that is required to treat diabetes, especially for the patient with early mild symptomatic disease. Medical nutrition therapy should be maintained throughout the course of the disease, even as pharmacologic agents are used. Oral agent medications are generally used if medical nutri-tion therapy alone does not succeed in obtaining patients' goals within a reasonable time frame, usually no longer than two to three months. Metformin plus lifestyle treatment is also a reasonable initial therapy at the time of diagnosis, given the low risk of hypoglycemia and the benefits of metformin shown in both prediabetes and diabetes (Nathan, 2006 [R]).
At the time of diagnosis, if patients have severe symptomatic disease, insulin should be initiated. With appropriate educational support and care, the risks of insulin may not differ from many oral agents. In some circumstances when glucose intolerance is significant and the patient is unwilling to consider insulin or it is not felt to be appropriate, the initiation of combinations of oral agents can be appropriate. Insulin is indicated when there is a failure to achieve treatment goals with oral agents.
It is important to remember that patients can move both ways on the Glycemic Control algorithm, e.g., they can move off of specific pharmacologic therapies as lifestyle changes are made that improve glycemic control. Diabetes is a progressive disease, however, and the use of pharmacologic agents will likely become necessary in the majority of patients, even if they are able to follow through with nutrition and physical activity recommendations (Turner, 1999 [A]).
19. Pharmacologic Agent(s) – Which Is Best?Key Points:
• Age and weight of the patient, as well as presence of renal dysfunction, cardiopulmonary comorbidities and hepatic disease must be considered when choosing pharmacologic agents.
Only general guidelines can be given when deciding about which pharmacologic agent will be best for a specific patient. While each patient presents with unique circumstances, the work group offers the following clinical circumstances to consider.
Age of PatientIt is important to recognize that risks of medications are often increased with advancing age, but this does not justify the withholding of medications that may reduce the symptoms of polyuria, nocturia and frequent visits to the bathroom that may place the patient at risk of hip fracture or falls.
With age, decline in renal function is often not reflected in a measurable change in serum creatinine because of an accompanying decline in muscle mass. Because of this, metformin should be used with caution in elderly patients (over age 80).
Decline in ventricular function and risks for volume overload can be occult in the elderly and may become clinically apparent with the use of thiazolidinediones.
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Algorithm Annotations Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
35
In select circumstances, because of the risks of hypoglycemia, variable diet habits and renal clearance and function, it may be safer to consider initial low-dose, short-acting sulfonylurea (e.g., glipizide or repaglinide/nateglinide when a meal is eaten).
Weight of the PatientType 2 diabetes is often associated with insulin resistance and weight gain. Metformin, acarobose, exenatide, sitagliptin and human amylin are more often associated with weight loss or weight maintenance. Due to its weight benefits as well as general tolerability, lower cost and proven benefits in UK Prospective Diabetes Study Group, metformin is recommended for most diabetes patients with type 2 diabetes unless contrain-dicated. Insulin and thiazolidinediones may be associated with weight gain (United Kingdom Prospective Diabetes Study Group, 1998b [A]).
Renal DysfunctionRenal dysfunction increases the risk for hypoglycemia, in particular with the use of oral hypoglycemic agents.
Metformin and alpha glucosidase inhibitors should not be used.
Thiazolidinediones may be considered, but the potential risks of fluid retention and increased risk of cardiac events need to considered.
Short-acting oral agents glipizide, glimepiride (in which serum levels have been noted to decrease in mild renal failure), repaglinide or nateglinide may be preferred if an oral agent is felt to be necessary in the face of renal dysfunction.
Insulin may be the safest when serum creatinine is greater than 1.8 mg or creatinine clearance is less than 60 mL/min.
Cardiopulmonary ComorbiditiesMetformin should be used with caution for patients with conditions that predispose them to risk of hypoxia such as congestive heart failure, chronic obstructive pulmonary disease or obstructive sleep apnea. Metformin should be promptly discontinued in situations of cardiovascular collapse from acute congestive heart failure, acute myocardial infarction or any other cause.
Patients started on thiazolidinediones should be instructed to report signs of lower extremity swelling, rapid weight gain, and shortness of breath. Risk of thiazolidinediones needs to be discussed and documented before using in patients with cardiovascular risks. Please see the thiazolidinediones warning for more information.
Short-acting sulfonylurea (e.g., glipizide), repaglinide/nateglinide, and the cautious use of long-acting sulfonylureas agents or insulin may be safest.
Hepatic DiseaseHepatic disease or insufficiency increases the risks of lactic acidosis and hypoglycemia and influences the metabolism of many oral medications.
Metformin and thiazolidinediones should not be used if alanine aminotransferase (ALT) is 2.5-3 times normal upper limits.
First-generation sulfonylureas, glipizide and glyburide have some component of hepatic metabolism and should be used with caution because of the risks of hypoglycemia. Insulin would be considered safest.
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Algorithm Annotations Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
36
20. Prescribe Insulin Therapy• Insulin programs should be individualized based on the patient's lifestyle, treatment goals and self-
monitoring blood glucose. Many patients can be taught to interpret self-monitoring blood glucose results and adjust insulin doses (American Diabetes Association, 2004c [R]).
• Total dose ranges from 5 units/day to several hundred units/day.
• Average insulin doses are 0.6-0.8 units/kg of body weight per day.
• Obese patients often require doses equal to or exceeding 1.2 units/kg.
• Meal times and snacks should be consistent. Synchronize insulin with food intake patterns.
Time Course of Action of Insulin Preparations
Insulin Preparations Onset of
Action
Peak Action Duration of
Action
Cost
Short-Acting Regular 30 min. 2-5 hours 5-8 hours $$
Rapid-Acting Lispro
Aspart
Glulisine
15 min.
15 min.
15 min.
30-90 min.
1-3 hours
50-100 min.
2-4 hours
3-5 hours
5 hours
$$$$
$$$$
$$$$
Intermediate-
Acting
NPH 1-3 hours 6-12 hours 16-24 hours $$$
Long-Acting Detemir
Glargine
1 hour
1 hour
**
**
Up to 24 hours
24 hours
$$$$
$$$$
Mixtures Humalog® mix (75/25) or Humalog® mix (50/50)
Novolog® mix (70/30)
NPH and Regular
(70/30; 50/50)
15 min.
15 min.
30 min.
30-240 min.
60-240 min.
2-12 hours
16-24 hours
16-24 hours
16-24 hours
$$$$
$$$$
$$$
Source: Compiled from pdr.net
Cost is based on average wholesale price (AWP) of 30-day supply or one vial of injectible
drug.
Cost Indicators:
$ = $0 - $20
$$ = $21 - $40
$$$ = $41 - $60
$$$$ = $61 - $100
$$$$$ = $101 - $500
$$$$$$ = greater than $500
Note: Lente and Ultralente are no longer being manufactured and have been removed from this table.
• This table summarizes the typical time course of action of various insulin preparations. These values are highly variable among individuals. Even in a given patient, these values vary depending
on the site and depth of injection, skin temperature and exercise.
• No pronounced peak: small amounts of insulin are slowly released resulting in a relatively constant concentration/time profile over 24 hours.
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Algorithm Annotations Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
37
• Rapid-acting insulin should not be taken more than 15 minutes before meals in contrast to regular insulin, which should ideally be taken at least 30 minutes before a meal to better match the insulin peak action with postmeal hyperglycemia.
• Patients who are testing their glucose before meals and adjusting insulin doses to match meals may find rapid-acting insulin to be more effective, although generally studies have not shown an improvement in A1c when compared to regular insulin taken according to package insert (30-45 minutes preprandial).
• Effective use of rapid-acting insulin usually requires the addition of basal intermediate or long-acting insulin.
• There are several devices available on the market for the administration of insulin (e.g., insulin pump, insulin pen).
• Insulin pump therapy may be helpful for patients who are interested in more intensified management of blood glucose and want more flexibility, or if pregnancy is desired. Candidates for pump therapy should be evaluated by an endocrinologist or diabetes specialist to assess patient understanding, self-care knowledge including medical nutrition therapy, responsibility and commitment. Insulin pump therapy is more commonly used in type 1 patients, but is also being used by some type 2 patients.
• Please note the work group left the brand names for Humalog® and Novolog® in the table. The generic mix is as follows:
- Humalog mix: lispro protamine suspension/lispro injection
- Novolog mix: aspart protamine suspension/aspart injection
• Every facility needs to evaluate insulin safety per their specific situation.
22. Prescribe Non-Insulin AgentsPlease consult the manufacturer's product labeling insert for full prescribing information.
If not contraindicated, metformin is the preferred initial oral agent for type 2 diabetes due to low cost, low risk of hypoglycemia and side effects, and lack of associated weight gain. If metformin is contraindicated, sulfonylureas and glitazones are acceptable secondary choices for oral agents. Sulfonylureas have the advantage of being relatively inexpensive, and glitazones are contraindicated in congestive heart failure (Nathan, 2006 [R]).
For the following tables, cost is based on average wholesale price (AWP) of 30-day supply. Cost Indica-tors:
$ = $0 - $20$$ = $21 - $40$$$ = $41 - $60$$$$ = $61 - $100$$$$$ = $101 - $500$$$$$$ = greater than $500
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Algorithm Annotations Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
38
Metformin
Drug Name (Trade Name)
Usual starting
dose
Usual maximum clinically effective dose
per day
Maximum dose per day
Cost
Metformin (regular release)
500 mg daily or twice daily
1,000 mg twice daily 2,550 mg daily or
850 mg three times a day
$$*
Metformin (extended release)
500 mg daily with evening meal
2,000 mg daily or 1,000 mg twice daily
2,000 mg daily or 1,000 mg twice daily
$$
EFFICACY
• The A1c lowering commonly achieved with metformin is 1.5%-2.0%.
• Absorption and bioavailability of metformin (extended release) 2,000 mg daily is similar to that of metformin 1,000 mg twice daily. Costs favor the use of metformin for patients who can manage twice-daily dosing.
• The major effect may be reducing hepatic glucose production.
Metformin is indicated for treatment of type 2 diabetes as monotherapy or in combination with sulfonylureas or insulin.
SAFETY
• Metformin is contraindicated in patients with known hypersensitivity, renal disease, congestive heart failure (treated with medications), acute or chronic metabolic acidosis (including diabetic ketoacidosis).
• Do not use metformin in renal disease (creatinine greater than or equal to 1.5 mg/dL in men, creatinine greater than or equal to 1.4 mg/dL in women) because of possible lactic acidosis. In patients over age 80, check a creatinine clearance and use with caution. Even temporary reductions in renal function (e.g., pyelography or angiography) can cause lactic acidosis.
• Do not use for patients with COPD, severe hepatic disease or alcoholism.
• Side effects may be transient and can include metallic taste, diarrhea, nausea and anorexia.
• The use of metformin in pregnancy or lactation is not recommended.
• As monotherapy, metformin does not cause hypoglycemia.
• Intramuscular contrast studies with indicated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin. Therefore, metformin should be temporarily discontinued at the time or prior to any such study and withheld for 48 hours subsequent to the procedure. Reinstitute only after renal function has been reevaluated and found to be normal.
Source: Compiled from pdr.net
* Average wholesale price indicates a cost of $$; however, regionally this product is available for $.
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Algorithm Annotations Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
39
Second-Generation Sulfonylureas
Drug Name
(Trade
Name)
Duration Usual
starting
dose
Usual
start
dose
for
elderly
Usual
maximum
clinically
effective
dose
Maximum
dose per
day
Cost
Glimepiride 24 hr. 1-2 mg/d 1-2
mg/d
4 mg/d 8 mg/d $
Glipizide (regular
release)
10-24 hr. 5 mg/d 2.5 mg/d
10 mg twice daily
40 mg/d $
Glipizide
(extended release)
24 hr. 5 mg/d 5 mg/d 10 mg/d 20 mg/d $
Glyburide
(regular release)
18-24 hr. 2.5 mg-5
mg/d
1.25
mg/d
5 mg twice
daily
20 mg/d $
Glyburide
(micronized)
18-24 hr. 1.5-3
mg/d
0.75
mg/d
6 mg twice
daily
12 mg/d $
EFFICACY
• The A1c lowering commonly achieved with sulfonylureas is 1.5%-2.0%.
• The dose should be increased every one to two weeks until satisfactory glycemic control or the maximum dose is reached.
• There are no major differences between sulfonylureas with respect to effectiveness in
controlling hyperglycemia. Switching from one to another is rarely beneficial in improving hyperglycemia.
SAFETY
• These agents are contraindicated in diabetic ketoacidosis and in patients with known hypersensitivity to sulfonylureas.
• There are rare cross-sensitivities for patients with sulfa allergies.
• These agents should be used with caution for patients with hepatic or renal disease.
• Glipizide/or glimepiride may be relatively safer than glyburide patients with mild renal impairment.
• Hypoglycemia risk increases with impaired renal function. Glimepiride may cause less hypoglycemia in these circumstances.
• Glyburide has the highest rate of hypoglycemia of the sulfonylureas listed.
Source: Compiled from pdr.net
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Algorithm Annotations Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
40
Alpha Glucosidase Inhibitors
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Algorithm Annotations Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
41
Dipeptidyl Peptidase-4 (DPP-4) Inhibitor
Source: Compiled from pdr.net
Drug Name (Trade name)
Usual starting
dose
Usual maximum clinically
effective dose
Maximum dose per day
Cost
Sitagliptin 100 mg once daily
100 mg once daily 100 mg once daily $$$$$
EFFICACY
• Slows the inactivation of incretins, hormones that are normally released in the gut throughout the day and increased after meals. Incretins increase insulin release from pancreatic beta cells, and lower glucagon secretion from pancreatic alpha cells.
• Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
• The A1c lowering commonly achieved with sitagliptin is 0.6-0.8 mg/dL. • Sitagliptin is indicated for monotherapy and as combination therapy (metformin,
glimepiride, glimepiride plus metformin, or a TZD). • Sitagliptin has not been studied in combination with insulin. • Can be taken with or without food.
SAFETY
• Dosage adjustment is recommended in patients with moderate or severe renal insufficiency and in patients with ESRD. Assessment of renal function is recommended prior to initiating sitagliptin and periodically thereafter.
o Moderate renal disease (start 50 mg once daily): CrCl ! 30 to < 50 mL/min; ~Serum Cr levels [mg/dL] – Men: > 1.7– " 3.0; Women: > 1.5 - " 2.5
o Severe and ESRD (start 25 mg once daily): CrCl < 30 mL/min: ~Serum Cr levels [mg/dL] – Men: > 3.0; Women: > 2.5; or on dialysis
• When used with a sulfonylurea, a lower dose of sulfonylurea may be required to reduce the risk of hypoglycemia.
• Side effects reported in more than 5% of patients and more often than placebo were nasopharyngitis, upper respiratory tract infections, and headache.
• Safety and effectiveness of sitagliptin in children under 18 years have not been established.
• There are no adequate and well-controlled studies in pregnant women. • Hypoglycemia was similar to placebo (1.2% versus 0.9%).
• Studies addressing long-term safety are not available.
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Algorithm Annotations Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
42
Meglitinides (Short-Acting Secretagogues)
Drug Name (Trade Name)
Usual starting dose Maximum dose per day Cost
Repaglinide 0.5 mg/meal with A1c less than 8% or no previous treatment
1 or 2 mg/meal with A1c greater than 8% or on other oral agent
4 mg/meal or 16 mg/day $$$$$
Nateglinide 60-120 mg three times a day before meals
120 mg/meal/day $$$$$
EFFICACY
• The average A1c lowering commonly achieved is 0.5%.
• The mechanism of action of these agents is to stimulate insulin secretion (similar to sulfonylureas).
• These agents have a short duration of action, one to four hours.
• These agents are usually taken 15 minutes before meals (range of 0-30 minutes).
• These agents are indicated for use in combination with metformin or TZDs.
SAFETY
• The major side effect of these agents is hypoglycemia, but the incidence may be less common than with sulfonylureas.
• Skip the dose if the meal is not eaten.
• Doses of nateglinide should be adjusted for hepatic impairment.
• Administration of gemfibrozil significantly increases repaglinide blood levels, which may lead to hypoglycemia. Avoid concomitant use of gemfibrozil and repaglinide.
Source: Compiled from pdr.net
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Algorithm Annotations Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
43
Glucagon-like Peptide 1 (GLP-1) Agonist:
Drug Name (Trade Name)
Indications Onset of action
Peak action
Duration of action
Usual starting dose
Maximum dose per day
Cost
Exenatide injection
Type 2 0-10 min. 2.1 hrs.
6-10 hrs. 5 mcg subcutaneous twice daily
10 mcg subcutaneous twice daily after one month
$$$$$
Mechanism of Action
• Stimulates glucose-dependent release of insulin and suppresses glucagons levels.
1. Modulation of gastric emptying 2. Prevention of the postprandial rise in plasma glucagons 3. Satiety leading to decreased caloric intake and potential weight loss
EFFICACY
• Intended for people with type 2 diabetes who are on oral medication but not achieving good blood sugar control. Offers an alternative option before starting insulin.
• Must be administered within the 60-minutes before the morning and evening meals. It should not be administered after a meal.
• When this agent is added to sulfonylurea therapy, a reduction in the dose of sulfonylurea may be needed to reduce the risk of hypoglycemia.
• Advantages over insulin are yet unclear, since like insulin, it must be injected twice daily. • Improves A1c by an average of 0.9% and lowers postprandial glucose.
SAFETY
• Contraindicated in patients with known hypersensitivity to this product or any of its components. • Is not a substitute for insulin in insulin-requiring patients. • Should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. • Not recommended for use in patients with ESRD or severe renal impairment (CrCl less than 30 mL/min). • Not recommended in patients with severe gastrointestinal disease because its use is commonly associated with
gastrointestinal adverse effects, including nausea, vomiting and diarrhea. • Caution in patients receiving oral medications that require rapid gastrointestinal absorption. • For oral medications that are dependent on threshold concentrations for efficacy, such as contraceptives and
antibiotics, patients should be advised to take those drugs at least one hour before exenatide injection. • Weight loss is often associated with use of this agent, especially when used concomitantly with metformin. • Exenatide use has been associated with reports of pancreatitis, although a causal relationship has not to this point
been established.
Source: Compiled from pdr.net
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Algorithm Annotations Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
44
Synthetic Analog of Human Amylin
Drug Name (Trade Name)
Indications Onset of
action
Peak action
Duration of action
Usual starting dose
Maximum dose per day
Cost
Pramlintide acetate injection
Type 1 and 2 diabetes
15-30 min.
20-27 min.
3-4 hrs. Type 2 : 60 mcg subcutaneous/meals
Type 2 : 120 mcg subcutaneous
$$$$$
Mechanism of Action
• Acting as an amylinomimetic agent has the following effects: 1. Modulation of gastric emptying 2. Prevention of the postprandial rise in plasma glucagons 3. Satiety leading to decreased caloric intake and potential weight loss
EFFICACY
• Indicated as an adjunct treatment in patients with type 1 or type 2 diabetes who use mealtime insulin therapy and who have failed to achieve desired glucose control despite optimal insulin therapy, and it is used with or without a sulfonylurea and/or metformin.
• May decreases A1c by an average of 0.4% and may observe weight loss of less than 1 kg at six months.
• Must be administered immediately prior to each major meal.
• Reduce preprandial, rapid-acting or short-acting insulin dosages, including fixed-mix insulins by 50%.
• The agent may be considered in highly motivated patients willing to add two to four injections and more frequent glucose monitoring to their regimen.
SAFETY
• Contraindicated in patients with a known hypersensitivity to any of its components, including metacresol.
• Should only be considered in patients with insulin-using type 2 or type 1 diabetes who have failed to achieve adequate glycemic control despite individualized insulin management and are receiving ongoing care under the guidance of a health care professional skilled in the use of insulin and supported by the services of diabetes educator(s).
• Before initiation of therapy, A1c, recent glucose monitoring data, history of insulin-induced hypoglycemia, current insulin regimen, and body weights should be reviewed.
• Patients meeting any of the following criteria should not be considered for pramlintide therapy: - Poor adherence with current insulin regimen - Poor adherence with prescribed self-blood glucose monitoring - A1c greater than 9% - Recurrent severe hypoglycemia requiring assistance during the past six months - Presence of hypoglycemia unawareness - Confirmed diagnosis of gastroparesis - Require the use of drugs that stimulate gastrointestinal motility - Require the use of drugs that slow the intestinal absorption of nutrients - Pediatric patients
• Primlintide alone does not cause hypoglycemia (without the concomitant administration of insulin). However, when it is co-administered with insulin therapy, there is an increase risk of insulin-induced severe hypoglycemia. Therefore, prescribe frequent pre- and postmeal glucose monitoring combined with an initial 50% reduction in premeal doses of short-acting insulin when starting pramlintide to reduce the occurrence of hypoglycemia.
• Its use is commonly associated with gastrointestinal adverse effects, including nausea, anorexia and vomiting.
• When the rapid onset of a concomitant orally administered agent is a critical determinant of effectiveness, the agent should be administered at least one hour prior to two hours after primlintide injection.
• This product and insulin should always be administered as separate injections and never be mixed. Mixing will alter the pharmacokinetics parameters of primlintide.
Source: Compiled from pdr.net
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Algorithm Annotations Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
45
Thiazolidinediones (TZDs)
Drug Name (Trade Name)
Usual starting dose Maximum dose per day Cost
Pioglitazone 15 or 30 mg once daily 45 mg daily $$$$$
Rosiglitazone 2 mg daily or twice daily 4 mg twice daily or 8 mg daily $$$$$
EFFICACY
• The A1c lowering commonly achieved with thiazolidinediones is 1.0%-1.5%.
• TZDs improve insulin action in peripheral tissues, particularly muscle.
• Both pioglitazone and rosiglitazone are indicated for combination therapy with sulfonylureas, metformin.
• Both LDL and HDL cholesterol concentrations may increase slightly.
• Rosiglitazone may increase cardiovascular events and is not recommended.
• When a thiazolidinedione is used, pioglitazone is preferred due to concerns about rosiglitazone cardiovascular safety in observational analysis.
SAFETY
• Thiazolidinediones are contraindicated in patients with known hypersensitivity. Their use in pregnancy and lactation is not recommended.
• TZDs alone, or in combination with other antidiabetic agents including insulin, can cause fluid retention, which may lead to heart failure. Do not use in patients with moderate to severe heart failure (NYHA Class III and IV cardiac status).
• Side effects may include moderate weight gain, edema and mild anemia, all due, at least in part, to fluid retention.
• As monotherapy, TZDs do not cause hypoglycemia.
• Measure ALT at baseline and periodically thereafter.
• Administration of gemfibrozil increases plasma levels of rosiglitazone. Decreases in the dose of rosiglitazone may be needed when gemfibrozil is added.
• Meta-analysis showed rosiglitazone may be associated with an increase in the risk of myocardial infarction and death from cardiovascular causes.
• Pioglitazone may not have the same cardiovascular concerns as rosiglitazone (Dormandy, 2005 [R])
• Macular edema has been reported in postmarketing experience in some diabetic patients who were taking thiazolidinedione.
• The risk of fracture should be considered in the care of patients, especially female patients, treated with thiazolidinedione.
• Physicians and patients should have an informed discussion around the risks of rosiglitazone.
Source: Compiled from pdr.net and FDA Warning 11/19/2007.
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Algorithm Annotations Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
46
Combination Products
Combination type
Fixed dose combination (mg)
Usual start dose (mg) Maximum dose per day
Cost
Sulfonylurea + metformin
Glipizide/metformin
2.5/250, 2.5/500, 5/500
As initial treatment:
2.5/250 daily
As second-line treatment:
2.5/500 or 5/500 twice daily
As initial treatment: 10 mg/2,000 mg
As second-line treatment: 20 mg/2,000 mg
$$
Sulfonylurea + metformin
Glyburide/metformin
1.25/250, 2.5/500, 5/500
As initial treatment:
1.25/250 daily or twice daily
As second-line treatment:
2.5/500 or 5/500 twice daily
20 mg/2,000 mg
$$
TZD + metformin
Pioglitazone/ metformin
15/500, 15/850
Not recommended as initial treatment; one tab PO daily or twice daily if on metformin monotherapy; 15 mg/500 mg by mouth twice daily or 15 mg/850 mg by mouth daily if on pioglitazone monotherapy
45 mg/ 2,550 mg/day
$$$$
TZD + metformin
Rosiglitazone/ metformin 1/500, 2/500, 4/500, 2/1,000, 4/1,000
Not recommended as initial treatment
8 mg/2,000 mg $$$$
TZD + sulfonylureas
Pioglitazone/glimerpiride 30/2, 30/4
Not recommended as initial treatment; 30/2 or 30/4 by mouth daily
45 mg/ 8 mg/day
$$$$$
TZD + sulfonylureas
Rosiglitzone/ glimerpiride
4/1, 4/2, 4/4
Not recommended as initial treatment; 4/1 or 4/2 by mouth daily
8 mg/4 mg/day
$$$$$
DDP-IV inhibitor + metformin
Sitaglipton/metformin 50/500, 50/1,000
As adjunct for patients in adequately controlled on metformin monotherapy: 50 mg sitaglipton plus current dose of metformin twice daily
100 mg/2,000 mg/day
$$$$$
Source: Compiled from pdr.net
25. Intensify TherapyIf treatment goals are not met on oral agents, or if oral agents are contraindicated, then it is necessary to begin insulin either alone or as an adjunct to oral therapy. There are many regimens that have been studied and are efficacious (Aviles-Santa, 1999 [A]; Relimpio, 1998 [A]; Yki-Järvinen, 1999 [A]; Zimmerman, 1998 [R]). The following are some commonly used regimens.
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Algorithm Annotations Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
47
Insulin as an adjunct to oral therapy:
• A once-daily (often at bedtime) dose of NPH, detemir or glargine insulin is added to metformin or thiazolidinediones. The recommended starting dose of basal insulin is often 0.1 U/kg, based on body weight. The basal insulin should be increased by two units every three days that blood glucoses in the a.m. remain above target. While adusting the basal insulin dose, the blood glucose should be monitored twice daily to three times daily to monitor glucose values and prevent hypoglycemic episodes. If patient is also on a sulfonylurea, it may be discontinued or reduced when insulin is added.
• A once-daily (often at bedtime) dose of insulin (as above) is added to sulfonylurea. The dose of the sulfonylurea may be reduced (approximately 50%) when insulin is added. The basal insulin should be increased by two units every three days that blood glucoses in the a.m. remain above target. While adjusting the basal insulin dose, the blood glucose should be monitored twice daily to three times daily to monitor glucose values and prevent hypoglycemic episodes. It must be noted that glargine or detemir may be dosed in the a.m. or p.m. Morning dosing may prevent nighttime hypoglycemic episodes and may also provide for improved blood glucose control.
Insulin alone:
• Twice-daily insulin regimen is established with progression to increased frequency of insulin administration as necessary to achieve treatment goals or to add flexibility to a patient's meal and activity schedules. Multiple dose insulin with rapid-acting and basal insulin therapy may offer patients with active lifestyles the greatest flexibility.
• One method of starting multidose insulin is to use a total daily dose of .2-.4 units/kg and prescribe half the dose as glargine once a day (morning or bedtime) and the other half as rapid acting insulin with meals (split appropriately according to the patient's frequency and pattern of meal sizes and/or carbohydrate consumption).
Oral agents as an adjunct to insulin therapy:
• Metformin may be helpful as an adjunct for patients who require large doses of insulin (e.g., greater than 100 units/day).
Blood Pressure Control Algorithm Annotations
26. Blood Pressure Control AlgorthimControl of blood pressure is at least as important as glycemic control for people with type 2 diabetes in reducing the risk of complications (Alder, 2000 [B]; Estacio, 2000 [A]).
SHEP, Syst-Eur and HOT trials all showed a greater absolute benefit from antihypertensive therapy in people with diabetes than in hypertensive people without diabetes (Hansson, 1998 [A]; SHEP Cooperative Research Group, 1991 [A]; Tuomilehto, 1999 [A]).
27. Is Systolic Blood Pressure Greater Than or Equal to 130 mmHg?For patients with type 2 diabetes mellitus, the systolic blood pressure goal is less than 130 mmHg and the diastolic blood pressure goal is less than 80 mmHg [Conclusion Grade II: See Conclusion Grading Work-sheet D – Annotations #13, 14, 27, 29 (Goals for Blood Pressure)] (Hansson, 1998 [A]; United Kingdom Prospective Diabetes Study [A], 1998c; UK Prospective Diabetes Study, 1998e [A]).
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Algorithm Annotations Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
48
A report from the UK Prospective Diabetes Study Group study showed an inverse relationship between systolic blood pressure and the aggregate end point for any complication related to diabetes (United Kingdom Prospective Diabetes Study Group (UKPDS), 1998e [R]. The lowest risk occurred at a systolic blood pres-sure below 120 mmHg.
The goal for patients with renal insufficiency and urinary protein excretion greater than 1-2 g/day should be less than 120/75 mmHg (American Diabetes Association, 2004c [R]).
28. Treat Systolic Blood Pressure to Less Than 130 mmHg. While ACE Inhibitors and ARBs Are Preferred First-Line Therapy, Two or More Agents (to Include Thiazide Diuretics) May Be RequiredNon-pharmacologic and pharmacologic methods are recommended at blood pressures greater than or equal to 130/80 mmHg. The initial focus of treatment should be the systolic blood pressure.
For patients with type 2 diabetes mellitus, ACE inhibitors or ARBs can reduce progression of micro- and macrovascular complications. [Conclusion Grade I: See Conclusion Grading Worksheet F – Annotations #28, 36 (Treatment with ACE Inhibitors or ARBs)] (HOPE Investigators, 2000a [A]; Lewis, 2001 [A]).
While ACE inhibitors and ARBs are preferred first-line therapy, two or more agents (to include thiazide diuretics) may be required. For patients with type 2 diabetes mellitus, thiazide diuretics in the treatment of hypertension can reduce cardiovascular events, particularly heart failure. [Conclusion Grade I: See Conclu-sion Grading Worksheet G – Annotations #28, 36 (Thiazide Diuretics)] (ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group, 2002 [A]; Wing, 2003 [B]). The possible advantages to ACE inhibitors include renal protection, decreased insulin resistance, lack of adverse effect on lipids, and decreased cardiovascular risk.
In ALLHAT, chlorthalidone, at doses of 12.5 to 25 mg daily, was superior to other treatments at reducing cardiovascular events in both diabetic and non-diabetic patients.
Treatment of isolated systolic hypertension, as well as combined systolic and diastolic hypertension, in both young and elderly people protects against major cardiovascular diseases. Drug treatment should be initiated if systolic blood pressure is greater than or equal to 130 mmHg (Bakris, 2000 [R]).
Thiazide diuretics used in the treatment of hypertension can reduce cardiovascular events, especially heart failure, for patients with type 2 diabetes (Alkaharouf, 1993 [D]; American Diabetes Association, 2007c [R]; Chobanian, 2003 [R]; HOPE Investigators, 2000a [A]; Lewis, 1993 [A]).
29. Is Diastolic Blood Pressure Less Than 80 mmHg?For patients with type 2 diabetes mellitus, the systolic blood pressure goal is less than 130 mmHg and the diastolic blood pressure goal is less than 80 mmHg [Conclusion Grade II: See Conclusion Grading Work-sheet D – Annotations #13, 14, 27, 29 (Goals for Blood Pressure)] (Hansson, 1998 [A]; United Kingdom Prospective Diabetes Study [UKPDS] Group, 1998c [A]; United Kingdom Prospective Diabetes Study [UKPDS] Group, 1998e [A]).
The HOT trial provides evidence that a target diastolic blood pressure less than 80 mmHg has a cardioprotective effect in people with diabetes. This study reported that in the diabetic subgroup (n=1,501) major cardiovascular events were reduced by greater than 51% (p=0.005) in those randomized to a diastolic blood pressure goal of less than 80 mmHg compared to less than 90 mmHg. The HOT study has been criticized by some because this was a post hoc analysis of a subgroup of patients in the study and the number of events is relatively small. Nevertheless, results are consistent with United Kingdom Prospective Diabetes Study. United Kingdom Prospective Diabetes Study achieved an average diastolic blood pressure of 82 mmHg in the tightly controlled
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Algorithm Annotations Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
49
group (vs. 87 mmHg in the less tightly controlled group). The more tightly controlled group had diabetes related end points reduced by 24% (p=0.005) and death by 32% (p=.019) (United Kingdom Prospective Diabetes Study Group, 1998b [A]).
31. Treat Diastolic Blood Pressure to Less Than 80 mmHgCombinations of medications are often required to achieve goals. Thirty percent of patients in the tight blood pressure arm of the United Kingdom Prospective Diabetes Study with goal less than 150/85 mmHg required three or more antihypertensive medications to achieve the mean 144/82 mmHg. Findings from the ALLHAT study suggest that thiazide diuretics be considered as part of a multidrug regimen (United Kingdom Prospecitve Diabetes Study [UKPDS] Group, 1998a [M]; ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group, 2002 [A]).
Ongoing Management Algorithm Annotations
33. Ongoing Management and Follow-Up of People with DiabetesIn studies of general population groups, coronary artery disease deaths have been substantially reduced by the treatment of hypertension, hypercholesterolemia and smoking. Lipid treatment has also been shown to be of benefit in diabetes. Therefore, risk factor reduction is prudent for patients with diabetes (American Diabetes Association, 2007c [R]; Hansson, 1998 [A]).
• Frequency of visits depends on blood glucose control, changes in the treatment regimen, and presence of complications of diabetes or other medical conditions.
• Patients starting or having a major change in their treatment program (such as initiating insulin therapy) may need to be in contact with their care provider as often as daily until glucose control is achieved, the risk of hypoglycemia is low, and the patient is competent to conduct the treatment program.
• Contact with the patient after a major modification of the treatment plan (such as introducing a new medication) should not be delayed greater than one week.
• Regular visits should be scheduled for insulin-treated patients at least quarterly and for other patients at least semiannually. More frequent visits may be necessary if treatment goals are not achieved.
• Cardiovascular disease is the primary cause of morbidity and mortality in people with type 2 diabetes. The risk of coronary artery disease is approximately doubled in men and quadrupled in women with diabetes.
• At each encounter, ask if the patient has experienced symptoms of hypoglycemia or low blood glucose, and educate the patient on appropriate recognition, prevention and management.
• If the patient has a history of severe hypoglycemia (assistance of another person was needed to treat a low glucose) or has developed hypoglycemia unawareness, evaluate the treatment goals for appropriate safety.
34. Maintain Treatment Goals• Nutrition/physical activity: work with individual patients regularly to set realistic goals.
• Monitor A1c every three to six months. In insulin-treated patients and non-insulin-treated patients with poor metabolic control, quarterly A1c may assist management.
- Review blood glucose at all patient encounters. Reinforce blood glucose targets with patients and educate regarding hypoglycemia.
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Algorithm Annotations Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
50
• Monitor lipid profile yearly (total cholesterol, triglycerides, high-density lipoprotein-cholesterol and low-density lipoprotein-cholesterol): treat to achieve recommended goals (see Annotation #13, "Treat-ment Goals for Patients Without Cardiovascular Disease"). If lipid goals are consistently met, patient is in metabolic control, has stable clinical conditions, and has not had a change in medication, an annual lipid profile is not mandatory.
Diabetes is a major risk factor for coronary artery disease, and many patients with diabetes also have lipid disorders (American Diabetes Association, 2004a [R]). Thus, control of dyslipidemia in diabetes is important because evidence shows that correcting lipid disorders reduces the rate of coronary artery disease events.
• Monitor blood pressure each visit and control hypertension to recommended levels. See the Blood Pressure Control algorithm.
• Ask about aspirin use and recommend aspirin use in patients age 40 and over unless contraindicated (American Diabetes Association, 2007c [R]).
• Ask about alcohol and tobacco use and assist with cessation if indicated.
35. Annual Assessment of ComplicationsTargeted Annual History and Physical Exam • The history should assess (American Diabetes Association, 2007c [R]):
- Results of self-monitoring blood glucose – validate results at least once a year (e.g., check patient's glucose meter against an office random capillary glucose)
- Adjustments by the patient of the therapeutic regimen
- Frequency, causes and severity of both hyperglycemia and hypoglycemia
- Problems with adherence to therapeutic regimen
- Symptoms suggesting development or progression of the complications of diabetes
- Current prescribed medications, over-the-counter medications, dietary supplements and alternative therapies
- Documentation of eye care specialist exam results
- Alcohol/drug use patterns
• Assess for symptoms of depression
- Lab assessment of liver function and/or creatinine to assess ongoing acceptability of medication usage
• The targeted physical exam should assess:
- Weight, body mass index
- Blood pressure
- Cardiovascular – evaluation of preexisting problems
- Feet (nails, web spaces, calluses, ulcers, structural deformities, protective sensation and shoes)
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Algorithm Annotations Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
51
Specialist Dilated Eye ExamA dilated eye examination for diabetic eye disease performed by an ophthalomologist or optomostrist is recommended annually for patients with type 2 diabetes mellitus (American Diabetes Association, 2007c [R]). Less frequent exams (every two to three years) may be considered in the setting of a normal eye exam.
Renal AssessmentUrinary albumin excretion should be tested annually by a microalbuminuria method. There are racial/ethnic variability with regard to the prevalence of end-stage renal disease with Native Americans, Latinos (especially Mexican Americans), and African Americans having higher rates than non-Hispanic whites with type 2 diabetes (American Diabetes Association, 2004d [R]). If albuminuria is above normal, serum creati-nine should be measured. Screening for microalbuminuria can be performed by three methods (American Diabetes Association, 2004d [R]; Nelson, 1991 [B]; Bennett, 1995 [R]):
• Measurement of the albumin-to-creatinine ratio in a random, spot collection. This is easiest to perform, generally accurate and therefore is the preferred screening method.
• 24-hour collection with creatinine, allowing for simultaneous measurement of creatinine clear-ance
• Timed (four-hour or overnight) collection
Some factors can artificially increase the levels of albumin in the urine and should be avoided at the time of the urine collection; these factors include blood in the urine, prolonged heavy exercise, fever, congestive heart failure, uncontrolled diabetes, severe hypertension, urinary tract infection and vaginal fluid contami-nation of specimen.
If the dipstick or urine analysis test is negative for protein, then a more sensitive early screening test is indicated. A qualitative urinary microalbumin screen can be used to detect urinary microalbumin. If the qualitative test is positive, a quantitative test must be performed.
A microalbumin screening test should be done each year on patients with type 2 diabetes. If positive (exceeds 30 mg/gm), it should be repeated twice in the next three months.
If two out of three of these screening microalbuminuria tests are positive, the individual has microalbuminuria, and interventions should be considered. A negative finding should be followed annually; a positive finding should be followed periodically to see if the interventions are effective in diminishing the albuminuria (Bennett, 1995 [R]; Hannah, 1999 [R]; Mogensen, 1996 [R]; National Institutes of Health, 1993 [R]).
See Appendix A, "Treatment of Diabetic Nephropathy."
Comprehensive Foot Exam with Risk Assessment Patients with one or more risk factors for foot complications should be educated about their risk factors and appropriate measures taken to avoid complications. Measures may include self-management education, more intensive follow-up, and/or referral to appropriate specialist (American Diabetes Association, 2007c [R]; Mayfield, 1998 [R]).
Risk factors for foot complications include:
• Loss of protective sensation. Protective sensation can be assessed using either a 5.07 Semmes-Weinstein monofilament for light touch or by testing vibration using a 128-Hz tuning fork at the dorsum of the interphalangeal joint of the great toe, or both. Patients with reduced or absent sensa-tion with either of these tests should be educated about their risk and the need for proper foot care to prevent foot complications. See Appendix B, "Using a Semmes-Weinstein Monofilament to Screen the Diabetic Foot for Peripheral Sensory Neuropathy."
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Algorithm Annotations Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
52
• Peripheral vascular disease (absent pedal pulse, history of claudication or ischemic skin changes)
• Structural deformities (bunion, hammertoes, Charcot deformity, limited joint mobility or prior amputation)
• Skin disorders (nail deformity, callus, fissure, tinea or ulceration)
• Footwear (excessively worn, ill-fitting or inappropriate shoes)
Cardiovascular and Cerebrovascular Complication Assessment• History of cardiovascular symptoms such as chest pain, vascular claudication, TIA
• Cardiac and carotid exams
• Evaluate cardiovascular status before advising increased intensity of exercise (American Diabetes Association, 2004e [R]; Sigal, 2004 [R]).
Special Considerations • Influenza vaccine every year
• Pneumococcal vaccine – consider repeating the immunization for those at risk of losing immunity after five years including:
- Nephrotic syndrome
- Chronic renal disease
- Other immunocompromised states
• There is evidence that ACE inhibitors and ARBs are beneficial in reducing cardiovascular morbidity and mortality in acute MI, congestive heart failure and type 2 diabetes patients at high risk for cardio-vascular disease; they are also beneficial in improving renal outcomes in diabetes. Results of the HOPE (Heart Outcomes Prevention Evaluation) study strongly support the use of ACE inhibitors for patients with diabetes who are at high risk for cardiovascular disease. In the Second Australian National Blood Pressure Study (ANblood pressure2), the use of ACE inhibitors in older patients was associated with better cardiovascular outcomes, despite similar reductions in blood pressure from diuretics. Confirming studies would be helpful to strengthen this recommendation or to generalize recommendations to all patients with diabetes (HOPE Investigators [A], 2000a; Wing, 2003 [A]).
• Vitamin E has no apparent effect on cardiovascular outcomes (HOPE Investigators, 2000b [A]).
• Osteoporosis: Type 2 diabetes does not appear to be a risk factor for decreased bone mineral density; nonetheless, some studies have found an increased fracture risk for people with type 2 diabetes (Schwartz, 2001 [B]). Hypoglycemic episodes, decreased visual acuity secondary to retinopathy, and altered balance and postural control secondary to peripheral and autonomic neuropathy can all increase the risk of falls and fracture.
In the absence of diabetes specific osteoporosis screening guidelines, it is reasonable to follow general osteoporosis screening recommendations for people with diabetes. See the ICSI Diagnosis and Treat-ment of Osteoporosis guideline for more information.
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Algorithm Annotations Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
53
36. Treatment and Referral for ComplicationsNephropathy
In type 2 diabetes, albuminuria may be present at the time of diagnosis in about 10% of patients, and another 10% later develop it. Progression to renal failure is less certain in type 2 patients than in type 1 patients and appears to be modulated by genetic and other factors.
Patients with clinical nephropathy almost always have retinopathy and coronary artery disease.
Numerous interventions are appropriate at different stages of renal function in order to prevent or slow the progression of renal disease and associated cardiovascular disease and include (American Diabetes Asso-ciation, 2004d [R]:
• Glucose Control – Improved glucose control at any stage of renal function reduces renal disease progression. See the Glycemic Control algorithm.
• For patients with type 2 diabetes mellitus, ACE inhibitors or ARBs can reduce progression of micro- and macrovascular complications. [Conclusion Grade I: See Conclusion Grading Worksheet F – Annotations #28, 36 (Treatment with ACE Inhibitors or ARBs)] (HOPE Investigators, 2000a [A]; Lewis, 2001 [A]). These agents appear effective even in normotensive microalbuminuric indi-viduals. This class of drugs must not be used in pregnancy. Within one week of initiation, check for elevations in potassium and creatinine levels and monitor for cough.
• Hypertension Control – Although ACE inhibitors and ARBs seem to have special renal protective properties beyond their antihypertensive effect, any effort to optimize blood pressure will help the kidneys. When significant microalbumin or overt nephropathy are present, there may be a tendency to retain sodium. In this case, a loop diuretic added to the antihypertensive regimen is often helpful. A goal blood pressure of less than 130/80 mmHg is recommended (American Diabetes Association, 2007c [R]). See the Blood Pressure Control algorithm.
For patients with type 2 diabetes, thiazide diuretics in the treatment of hypertension can reduce cardiovascular events, particularly heart failure. [Conclusion Grade I: See Conclusion Grading Worksheet G – Annotations #28, 36 (Thiazide Diuretics)] (ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group, 2002 [A]; Wing, 2003 [B]).
In ALLHAT, chlorthalidone, at doses of 12.5-25 mg daily, was superior to other treatments at reducing cardiovascular events in both diabetic and non-diabetic patients.
• Cardiovascular Risk Factor Intervention – Dyslipidemia is often present with microalbuminuria and should be treated aggressively. Dyslipidemia may be an independent risk factor for progression of renal disease. Smoking is associated with the onset and progression of microalbuminuria.
• Restriction of dietary protein has been shown to slow progression of overt nephropathy (macroalbu-minuria), and there may be some benefit in dietary protein reduction in microalbuminuric patients. In these circumstances, protein intake should be reduced to the adult recommended daily allowance of 0.8-1.0 g/kg body weight per day with microalbuminuria present, and 0.8 gm/kg body weight per day with macroalbuminuria present (American Diabetes Association, 2007b [R]).
Treatment for microalbuminuria includes aggressive blood pressure control, glycemic control, ACE inhibitor or ARB use, and aggressive cardiovascular risk factor screening and management. Strongly consider referral to nephrology any patients with a creatinine greater than 1.5 mg, or nephrotic range proteinuria (greater than 3 gm/24 hour). Nephrology interventions often include early patient education as renal disease progresses, review and reinforcement of the medical regimen, and preservation of arm veins for future vascular access. Patients with a creatinine clearance of less than 30 mL/min should be referred to nephrology for discussions of future options and to enhance
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Algorithm Annotations Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
54
the ability to receive a future transplant. These patients also have significant enough renal impair-ment that they also benefit from more intensive nutritional interventions and proper management of anemia and bone disease (American Diabetes Association, 2004d [R]; DeFronza, 1995 [R]; HOPE Investigators, 2000a [A]; Karter, 2002 [B]; Lewis, 1993 [A]; Lewis, 2001 [A]; Ravid, 1993 [A]; Viberti, 1994 [A]).
Neuropathy – Peripheral neuropathy is difficult to prevent and treat. Most patients with type 2 diabetes and peripheral neuropathy have few symptoms but are found on examination to have diminished reflexes and sensation. Sometimes neuropathy can be very painful, especially at night, with "pins-and-needles" numb-ness and tingling in a stocking-and-glove distribution. Absence of reflexes or decreased thermal, vibratory, proprioceptive or pain sensation may be noted on examination and confirm the diagnosis. Good glycemic control should be the first control to symptomatic neuropathy. Treatment with amitriptyline, nortriptyline or trazodone in doses beginning at 25 mg at night and increasing to 75 mg may help some patients. Topical treatment with capsaicin, 0.025% cream three to four times per day, has also shown benefit. Carbamazepine, duloxetine and gabapentin may also improve neuropathic pain. These medications may provide symptomatic relief, but they do not improve the neuropathy (Boulton, 2005 [R]).
Retinopathy – Prevalence of retinopathy is related to the duration of diabetes mellitus. After 20 years of type 2 diabetes mellitus, more than 60% of patients have some degree of retinopathy (Fong, 2004 [R]). Diabetic retinopathy is estimated to be the most frequent cause of new cases of blindness among adults ages 20 to 74 years.
Up to 21% of patients with type 2 diabetes mellitus are found to have retinopathy at the time of diagnosis of diabetes mellitus (Fong, 2004 [R]). Generally retinopathy progresses from mild background abnormalities to preproliferative retinopathy to proliferative retinopathy.
Poor glucose control is associated with progression of retinopathy. High blood pressure is a risk factor for the development of macular edema and is associated with the development of proliferative retinopathy (Fong, 2004 [R]).
Screening for diabetic retinopathy saves vision at a relatively low cost. In fact, screening costs may be less than the costs of disability payments for those who become blind. Laser photocoagulation surgery is effective in preventing visual loss in diabetic retinopathy.
Studies have shown that retinal examinations by physicians who are not eye care specialists are not reliable in detecting retinopathy (American College of Physicians, American Diabetes Association, and American Academy of Ophthalmology, 1992 [R]; Diabetic Retinopathy Study Research Group, The, 1981 [R]; ETDRS Research Group, 1985 [A]; ETDRS Research Group, 1991 [A]; Fong, 2004 [R]; Klein, 1984 [C]; Klein, 1987 [R]).
Treatment includes glycemic and blood pressure control. Periodic screening and dilated eye exams by an eye specialist and early treatment of diabetic retinopathy prevents visual loss (Fong, 2004 [R]). See the Glycemic Control and Blood Pressure Control algorithms.
Cardiovascular and cerebrovascular disease – Treatment includes control of cardiovascular risk factors (hypertension, hyperlipidemia and smoking cessation) and aspirin use. Consider referring patients with known coronary artery disease to cardiology and patients with known carotid disease to surgery.
Heart failure is also common in patients with diabetes. Caution should be used when prescribing spironolac-tone and eplerenone to people with diabetes, especially in combination with ACE inhibitors.
Close monitoring of potassium and renal function is necessary. Thiazolidinediones must also be used with caution in patients with Class I and II congestive heart failure or patients at high risk for congestive heart failure. Close monitoring for fluid retention and signs of congestive heart failure is needed. Thiazolidin-ediones should not be used in Class III and IV congestive heart failure.
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Algorithm Annotations Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
55
For patients with type 2 diabetes mellitus, thiazide diuretics in the treatment of hypertension can reduce cardiovascular events, particularly heart failure. [Conclusion Grade I: See Conclusion Grading Worksheet G – Annotations #29, 36 (Thiazide Diuretics)] (ALLHAT Officers and Coordinators for the ALLHAT Collab-orative Research Group, The, 2002 [A]; Wing, 2003 [A])
Patients with type 2 diabetes have twice the average risk of suffering a stroke (American Diabetes Asso-ciation, 1998 [R]). It is unclear whether good glycemic control reduces this risk. However, treatment of hypertension, smoking and hyperlipidemia reduces the risk of stroke in most persons. See Annotation #14, "Treatment Goals for Patients With Cardiovascular Disease," and the Blood Pressure Control algorithm.
Peripheral vascular disease – Peripheral arterial disease is commonly associated with diabetes (American Diabetes Association, 2007c [R]). As many as 36% of patients with diabetes have lower-extremity peripheral arterial disease based on lower-extremity blood pressure readings. However, a typical history of intermittent claudication or an absent peripheral pulse is less commonly noted.
Peripheral vascular disease in combination with peripheral neuropathy places patients with diabetes at increased risk for non-traumatic amputations of the lower extremity. Peripheral vascular disease may be slowed by smoking cessation and treatment of hypertension and dyslipidemia. See Annotation #14, "Treat-ment Goals for Patients With Cardiovascular Disease," and the Blood Pressure Control algorithm.
Aggressive daily foot care, inspection of the feet at every office visit, early treatment of foot infections, treat-ment of callus, use of moisturizing lotion and proper footwear may forestall problems, including amputation. Vascular surgery may also prevent amputation in some patients with established severe peripheral vascular disease (American Diabetes Association, 2004f [R]).
Proper high-risk foot management is necessary to prevent ulceration and amputation. Consider referral of patients with claudication and/or absent pedal pulses to surgery. See the Glycemic Control and Blood Pressure Control algorithms.
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Algorithm Annotations Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
56
Appendix A – Treatment of Diabetic Nephropathy
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Thirteenth Edition/May 2009
Screen patients with diabetic nephropathy
B1
Dipstick test urine sample• Positive microablumin reaction
B2
Semiquantitative immunoassaytest• Positive correlates well with > 20 mg albumin/24 hr
B3
Quantitative tests• Albumin/creatinine ratio on random urine sample (easiest for patients)• 24-hour urine collection• Time urine collection (4-hour or overnight)• Positive is > 30 mg/24 hr or 30 > mg/g Cr
B4
Positive for microalbumin?
B5
Repeat screen annually
B6
no
Verify all positive tests• Use 2 additional quantitative screening tests• Perform verification tests over next 2-3 months
B7
yes
False positives for urinealbumin may occur secondaryto:• UTI• Fever• Blood in urine• Heart failure• Extreme hypertension• Vaginal fluid contamination• Uncontrolled blood glucose• Prolonged exercise
B5
2 of 3 tests positive for urine
albumin?
B8
no
Definition for microalbuminuriaand macroalbuminuria• Microalbuminuria: > 30 mg/ 24 hr or > 30 mg/g Cr• Macroalbuminuria: > 300 mg/ 24 hr or > 300 mg/g Cr
Macroalbuminuria: Suspect overt nephropathy• Referral to nephrology specialist
B8
Microalbuminuria: Perform periodic 24-hr creatinine clearance and urine protein tests to assess renal function and treatment success• Blood pressure control• ACE inhibitor use• Glycemic control• Lipid/CV risk factor control• Consider referral to nephrology specialist
yes
B9 B10
Institute for Clinical Systems Improvement
www.icsi.org
57
Appendix B – Using a Semmes-Weinstein Monofilament to Screen the Diabetic Foot for Peripheral Sensory Neuropathy
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Thirteenth Edition/May 2009
1) Show the monofilament to the patient and touch it to his/her arm to demonstrate that it does not hurt.2) Use the Semmes-Weinstein 5.07/10 gram monofilament to test sensation at the indicated sites on each foot*.
Avoid applying the monofilament to calluses, ulcers, or scars. A foot exam is not reimbursed my Medicare without monofilament sensation testing in four locations.
3) Hold the monofilament perpendicular to the skin and touch it to the skin using a smooth motion with sufficient force to cause the filament to bend. The test should take about 1-1/2 seconds at each site.
4) Ask the patient to respond "yes" when the filament is felt. If the patient does not respond when you touch a given site on the foot, continue on to another site in a random sequence. When you have completed testing all sites on the foot, retest any site(s) where the patient did not feel the filament.
5) The results of the monofilament testing should be documented in the medical record**. PATIENTS WHO CANNOT FEEL THE MONOFILAMENT AT ANY SITE SHOULD BE CONSIDERED TO BE INSENSATE AND AT INCREASED RISK FOR ULCERATION AND AMPUTATION.
*Testing at the first and fifth metatarsal heads is sufficient. This combination of sites has been shown to detect the insensate foot with reasonable sensitivity (80%) and specificity (86%). Testing the great toes may be of added benefit.**Chart documentation is required for the American Diabetes Association – Provider Recognition Program. An annual diabetic foot examination is also one of the eight diabetes quality improvement project (DQIP) measures adopted by the National Committee for Quality Assurance (NCQA) and the Health Care Financing Administration.
58Copyright © 2009 by Institute for Clinical Systems Improvement
Released in May 2009 for Thirteenth Edition. The next scheduled revision will occur within 12 months.
Contact ICSI at: 8009 34th Avenue South, Suite 1200; Bloomington, MN 55425; (952) 814-7060; (952) 858-9675 (fax)
Online at http://www.ICSI.org
I ICSI NSTITUTE FOR C LINICAL S YSTEMS I MPROVEMENT
Document Drafted Nov 1994 – Apr 1995
First Edition Mar 1996
Second Edition Apr 1997
Third Edition May 1998
Fourth Edition Apr 1999
Fifth Edition Apr 2000
Sixth Edition Oct 2001
Seventh Edition Oct 2002
Eighth Edition Dec 2003
Ninth Edition Dec 2004
Tenth Edition Dec 2005
Eleventh Edition Dec 2006
Twelfth Edition Apr 2008
Thirteenth Edition Begins June 2009
Supporting Evidence:
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults
Original Work Group MembersJanet Davidson, RN, CDENurse ClinicianPark Nicollet ClinicJinnet Fowles, PhDMeasurement AdvisorInstitute for Research and Education HealthSystem MinnesotaMarion Franz, RD, CDEDieteticsInternational Diabetes CenterPatrick O'Connor, MDFamily PracticeHealthPartnersTeresa Pearson, MS, RN, CDEHealth EducationHealthPartners
Greg Angstman, MDFamily Practice, Work Group LeaderMayo ClinicRichard Bergenstal, MDEndocrinologyInternational Diabetes CenterMary BergeneBHCAG RepresentativeHoneywell, Inc.Don Bishop, PhDMinnesota Department of Health RepresentativesMinnesota Dept. of HealthCindy Clark, MSMinnesota Department of Health RepresentativesMinnesota Dept. of Health
Peg Sannes, R PhPharmacyHealthPartnersMary Shelerud, RNFacilitatorMayo ClinicDace Trence, MDEndocrinologyHealthPartnersBruce Zimmerman, MDEndocrinologyMayo Clinic
Institute for Clinical Systems Improvement
www.icsi.org
59
Brief Description of Evidence Grading
Individual research reports are assigned a letter indicating the class of report based on design type: A, B, C, D, M, R, X.
A full explanation of these designators is found in the Foreword of the guideline.
II. CONCLUSION GRADES
Key conclusions (as determined by the work group) are supported by a conclusion grading worksheet that summarizes the important studies pertaining to the conclusion. Individual studies are classed according to the system defined in the Foreword and are assigned a designator of +, -, or ø to reflect the study quality. Conclusion grades are determined by the work group based on the following definitions:
Grade I: The evidence consists of results from studies of strong design for answering the question addressed. The results are both clinically important and consistent with minor exceptions at most. The results are free of any significant doubts about generalizability, bias, and flaws in research design. Studies with negative results have sufficiently large samples to have adequate statistical power.
Grade II: The evidence consists of results from studies of strong design for answering the question addressed, but there is some uncertainty attached to the conclusion because of inconsistencies among the results from the studies or because of minor doubts about generalizability, bias, research design flaws, or adequacy of sample size. Alternatively, the evidence consists solely of results from weaker designs for the question addressed, but the results have been confirmed in separate studies and are consistent with minor exceptions at most.
Grade III: The evidence consists of results from studies of strong design for answering the question addressed, but there is substantial uncertainty attached to the conclusion because of inconsistencies among the results from different studies or because of serious doubts about generalizability, bias, research design flaws, or adequacy of sample size. Alternatively, the evidence consists solely of results from a limited number of studies of weak design for answering the question addressed.
Grade Not Assignable: There is no evidence available that directly supports or refutes the conclusion.
The symbols +, –, ø, and N/A found on the conclusion grading worksheets are used to designate the quality of the primary research reports and systematic reviews:
+ indicates that the report or review has clearly addressed issues of inclusion/exclusion, bias, generaliz-ability, and data collection and analysis;
– indicates that these issues have not been adequately addressed;
ø indicates that the report or review is neither exceptionally strong or exceptionally weak;
N/A indicates that the report is not a primary reference or a systematic review and therefore the quality has not been assessed.
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
60
References
Abraira C, Colwell J, Nuttall F, et al. Cardiovascular events and correlates in the veterans affairs diabetes feasibility trial: veterans affairs cooperative study on glycemic control and complications in type II diabetes. Arch Intern Med 1997;157:181-88. (Class A)
Action to Control Cardiovascular Risk in Diabetes Study Group, The. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545-59. (Class A)
Adler AI, Stratton IM, Neil AW. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36) prospective observational study. BMJ 2000;321:412-19. (Class B)
ADVANCE Collaborative Group, The. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560-72. (Class A)
Alkaharouf J, Nalinikumari K, Corry D, Tuck M. Long term effects of the angiotensive converting enzyme inhibitor captopril on metabolic control in non-insulin dependent diabetes mellitus. Am J Hypertension 1993;6:337-43. (Class D)
ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group, The. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). JAMA 2002;288:2981-97. (Class A)
American College of Physicians, American Diabetes Association, and American Academy of Ophthal-mology. Screening guidelines for diabetic retinopathy. Ann Intern Med 1992;116:683-85. (Class R)
American Diabetes Association. Consensus development conference on the diagnosis of coronary heart disease in people with diabetes. Diabetes Care 1998;21:1551-59. (Class R)
American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2007a;30:S42-S47. (Class R)
American Diabetes Association. Dyslipidemia management in adults with diabetes. Diabetes Care 2004a;27:S68-S71. (Class R)
American Diabetes Association. Hospital admission guidelines for diabetes. Diabetes Care 2004b;27:S103. (Class R)
American Diabetes Association. Insulin administration. Diabetes Care 2004c;27:S106-S109. (Class R)
American Diabetes Association. Nephropathy in diabetes. Diabetes Care 2004d;27:S79-S83. (Class R)
American Diabetes Association. Nutrition recommendations and interventions for diabetes: a position statement of the American Diabetes Association. Diabetes Care 2007b;30:S48-S65. (Class R)
American Diabetes Association. Physical activity/exercise and diabetes. Diabetes Care 2004e;27:S58-S62. (Class R)
American Diabetes Association. Prevention or delay of type 2 diabetes. Diabetes Care 2004g;27:S47-S54. (Class R)
American Diabetes Association. Preventive foot care in diabetes. Diabetes Care 2004f;27:S63-S64. (Class R)
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
61
American Diabetes Association. Self monitoring of blood glucose (consensus statement). Diabetes Care 1994;17:81-86. (Class R)
American Diabetes Association. Standards of medical care in diabetes – 2007. Diabetes Care 2007c;30:S4-S41. (Class R)
American Diabetes Association. Standards of medical care in diabetes – 2008. Diabetes Care 2008;31:S12-S54. (Class R)
American Diabetes Association. Standards of medical care in diabetes – 2009. Diabetes Care 2009;32:S13-S61. (Class R)
Anderson RJ, Freedland KE, Clouse RE, Lustman PJ. The prevalence of comorbid depression in adults with diabetes: a meta-analysis. Diabetes Care 2001;24:1069-78. (Class M)
Avilés-Santa L, Sinding J, Raskin P. Effects of metformin in patients with poorly controlled, insulin-treated type 2 diabetes mellitus. Ann Intern Med 1999;131:182-88. (Class A)
Bakris GL, Williams M, Dworkin L, et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach. Am J Kidney Dis 2000;36: 646-61. (Class R)
Barnard JR, Jung T, Inkeles SB. Diet and exercise in the treatment of NIDDM. Diabetes Care 1994;17:1469-72. (Class C)
Belch J, MacCuish A, Campbell I, et al. The prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease. BMJ 2008. (Class A)
Bennett PH, Haffner S, Kasiske BL, et al. Diabetic renal disease recommendations: screening and management of microalbuminuria in patients with diabetes mellitus: recommendations to the Scientific Advisory Board of the National Kidney Foundation from an ad hoc committee of the Council on Diabetes Mellitus of the National Kidney Foundation. Am J Kidney Dis 1995;25:107-12. (Class R)
Bhatt DL, Marso SP, Hirsch AT, et al. Amplified benefit of clopidogrel versus aspirin in patients with diabetes mellitus. Am J Cardiol 2002;90:625-28. (Class A)
Borch-Johnsen K, Colagiuri S, Balkau B, et al. Creating a pandemic of prediabetes: the proposed new diagnostic criteria for impaired fasting glycaemia. Diabetologia 2004;47:1396-1402. (Class D)
Boulton AJM, Vinik AI, Arezzo JC, et al. Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care 2005;28:956-62. (Class R)
Bourn DM, Mann JI, McSkimming BJ, et al. Impaired glucose tolerance and NIDDM: does a lifestyle intervention program have an effect? Diabetes Care 1994;17:1311-19. (Class D)
California Healthcare Foundation/American Geriatrics Society Panel on Improving Care for Elders with Diabetes. Guidelines for improving the care of the older person with diabetes mellitus. JAGS 2003;51:S265-S280. (Class R)
Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495-504. (Class A)
Catella-Lawson F, Reilly MP, Kapoor SC, et al. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med 2001;345:1809-17. (Class C)
Chiasson JL, Josse RG, Gomis R, et al. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet 2002;359:2072-77. (Class A)
Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure: the JNC 7 report. JAMA 2003;289:2560-72. (Class R)
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults References Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
62
Cioffi ST, Caron MF, Kalus JS, et al. Glycosylated hemoglobin, cardiovascular, and renal outcomes in a pharmacist-managed clinic. Ann Pharmacother 2004;38:771-75. (Class D)
Clement S, Braithwaite SS, Magee MF, et al. Management of diabetes and hyperglycemia in hospitals. Diabetes Care 2004;27:553-91. (Class R)
Clements RS Jr, Bell DSH, Benbarka A, et al. Rapid insulin initiation in non-insulin dependent diabetes mellitus. Am J Med 1987;82:415-20. (Class A)
Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the collaborative atorvastatin diabetes study (CARDS): multicentre randomised placebo-controlled trial. Lancet 2004;364:685-96. (Class A)
DeBusk RF, Stenestrand U, Sheehan M, et al. Training effects of long versus short bouts of exercise in healthy subjects. Am J Cardiol 1990;65:1010-13. (Class A)
DeFronza RA. Diabetic nephropathy: etiologic and therapeutic considerations. Diabetes Reviews 1995;3:510-64. (Class R)
De Groot M, Anderson R, Freedland KE, et al. Association of depression and diabetes complications: a meta-analysis. Psychosom Med 2001;63:619-30. (Class M)
Diabetes Control and Complications Trial Research Group, The. The absence of a glycemic threshold for the development of long-term complications: the perspective of the diabetes control and complica-tions trial. Diabetes 1996;45:1289-98. (Class A)
Diabetes Prevention Program Research Group, The. Prevention of type 2 diabetes with troglitazone in the diabetes prevention program. Diabetes 2005;54:1150-56. (Class A)
Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393-403. (Class A)
Diabetic Retinopathy Study Research Group, The. Photocoagulation treatment of proliferative diabetic retinopathy: clinical application of diabetic retinopathy, (DRS) findings, DRS report number 8. Ophthal-mology 1981;88:583-600. (Class A)
Dormandy JA, Charbonnel B, Eckland DJA, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive study (PROspective pioglitazone clinical trial in macro-vascular events): a randomised controlled trial. Lancet 2005;366:1279-89. (Class R)
DREAM (Diabetes Reduction Assessment with ramipril and rosiglitazone Medication) Trial Investigators, The. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet 2006;368:1096-1105. (Class A)
Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009;360:129-39. (Class A)
Duckworth WC, McCarren M, Abraira C. Glucose control and cardiovascular complications: the VA diabetes trial. Diabetes Care 2001;24:942-45. (Class R)
Eriksson J, Lindstrom J, Valle T, et al. Prevention of type II diabetes in subjects with impaired glucose tolerance: the diabetes prevention study (DPS) in Finland. Diabetologia 1999;42:793-801. (Class R)
ETDRS Investigators. Aspirin effects on mortality and morbidity in patients with diabetes mellitus: ETDRS report 14. JAMA 1992;268:1292-1300. (Class A)
ETDRS Research Group. Early photocoagulation for diabetic retinopathy: ETDRS report number 9. Ophthalmology 1991;98:766-85. (Class A)
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults References Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
63
ETDRS Research Group. Photocoagulation for diabetic macular edema: ETDRS report number 1. Arch Ophthalmol 1985;103:1796-1806. (Class A)
Estacio RO, Jeffers BW, Gifford N, Schrier RW. Effect of blood pressure control on diabetic microvas-cular complications in patients with hypertension and type 2 diabetes. Diabetes Care 2000;23:B54-B64. (Class A)
Evangelista V, De Berardis G, Totani L, et al. Persistent platelet activation in patients with type 2 diabetes treated with low doses of aspirin. J Thromb Haemost 2007;5:2197-2203. (Class C)
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA 2001;285:2486-97. (Class R)
Farag A, Karam J, Nicasio J, McFarlane SI. Prevention of type 2 diabetes: an update. Curr Diabetes Reports 2007;7:200-07. (Class R)
Ferrer-Garceîa JC, Sanchez-Ballester E, Albalat-Galera R, et al. Efficacy of atorvastatin for achieving cholesterol targets after LDL-cholesterol based dose selection in patients with type 2 diabetes. J Cardiovasc Pharmacol Ther 2008;13:183-88. (Class C)
Fleg JL, Mete M, Howard BV, et al. Effect of statins alone versus statins plus ezetimibe on carotid atherosclerosis in type 2 diabetes: the SANDS (Stop Atherosclerosis in Native Diabetics Study) trial. J Am Coll Cardiol 2008;52:2198-205. (Class C)
Fong DS, Aiello L, Gardner TW, et al. Retinopathy in diabetes. Diabetes Care 2004;27:S84-S87. (Class R)
Franz MJ, Bantle JP, Beebe CA, et al. Evidence-based nutrition principles and recommendations for the treatment and prevention of diabetes and related complications. Diabetes Care 2002;25:148-98. (Class R)
Franz MJ, Monk A, Barry B, et al. Effectiveness of medical nutrition therapy provided by dietitians in the management of non-insulin-dependent diabetes mellitus: a randomized, controlled clinical trial. J Am Diet Assoc 1995a;95:1009-17. (Class A)
Franz MJ, Splett PL, Monk A, et al. Cost-effectiveness of medical nutrition therapy provided by dieti-tians for persons with non-insulin-dependent diabetes mellitus. J Am Diet Assoc 1995b;95:1018-24. (Class M)
Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med 2008;358:580-91. (Class A)
Gaede P, Vedel P, Larsen N, et al. Multifactoral intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003;348:383-93. (Class A)
Garber AJ, Moghissi ES, Bransome Jr ED, et al. American college of endocrinology position statement on inpatient diabetes and metabolic control. Endocr Pract 2004;10:77-82. (Class R)
Garg A. Lipid-lowering therapy and macrovascular disease in diabetes mellitus. Diabetes 1992;41(Suppl 2):111-15. (Class R)
Gilles CL, Abrams KR, Lambert PC, et al. Pharmacological and lifestyle interventions to prevent or delay type 2 diabetes in people with impaired glucose tolerance: systematic review and meta-analysis. BMJ 2007;334:299. (Class M)
Goldfine AB. Assessing the cardiovascular safety of diabetes therapies. N Engl J Med 2008;359:1092-95. (Class R)
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults References Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
64
Grundy SM, Cleeman JI, Bairey Merz CN, et al. Implications of recent clinical trials for the national cholesterol education program adult treatment panel III guidelines. Circulation 2004;110:227-39. (Class R)
Haffner SM, Lehto S, Ronnemaa T, et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998;339:229-34. (Class C)
Hannah R, Levin N, London R, et al, eds. Renal disease in the managed care setting: selection and monitoring of outcome criteria. Am J Kidney Dis 1999;33(Suppl 1):S1-S23. (Class R)
Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the hypertension optimal treatment (HOT) randomised trial. Lancet 1998;361:1755-62. (Class A)
Hardman AE. Accumulation of physical activity for health gains: what is the evidence? Br J Sports Med 1999;33:87-92. (Class R)
Harpaz D, Gottlieb S, Graff E, et al. Effects of aspirin treatment on survival in non-insulin-dependent diabetic patients with coronary artery disease. Am J Med 1998;105:494-99. (Class B)
Heart Outcomes Prevention Evaluation Study Investigators, The. Effects of an angiotensin-converting – enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2002;342:145-53. (Class A)
Heart Protection Study Collaborative Group. MRC/BHF heart protection study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360:7-22. (Class A)
Heart Protection Study Collaborative Group. MRC/BHF heart protection study of cholesterol-lowering with simvastatin in 5,963 people with diabetes: a randomised placebo-controlled trial. Lancet 2003;361:2005-16. (Class A)
Helmrich SP, Ragland DR, Leung RW, et al. Physical activity and reduced occurrence of non-insulin-dependent diabetes mellitus. N Engl J Med 1991;325:147-52. (Class C)
Hollander PA, Elbein SC, Hirsch IB, et al. Role of orlistat in the treatment of obese patients with type 2 diabetes. Diabetes Care 1998;21:1288-93. (Class A)
Holman RR, Paul SK, Bethel MA, et al. Long-term follow-up after tight control of blood pressure in type 2 diabetes. N Engl J Med 2008;359:1565-76. (Class A)
HOPE Investigators, The. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet 2000a;355:253-59. (Class A)
HOPE Investigators, The. Vitamin E supplementation and cardiovascular events in high-risk patients. N Engl J Med 2000b;342:154-60. (Class A)
Howard BV, Roman MJ, Devereux RB, et al. Effect of lower targets for blood pressure and LDL cholesterol on atherosclerosis in diabetes: the SANDS randomized trial. JAMA 2008;299:1678-89. (Class A)
Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes: scientific review. JAMA 2002;287:360-72. (Class M)
Janand-Delenne B, Savin B, Habib G, et al. Silent myocardial ischemia in patients with diabetes: who to screen. Diabetes Care 1999;22:1396-1400. (Class D)
Karter AJ, Ferrara A, Liu JY, et al. Ethnic disparities in diabetic complications in an insured population. JAMA 2002;287:2519-27. (Class B)
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults References Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
65
Kelley DE, Bray GA, Pi-Sunyer FX, et al. Clinical efficacy of orlistat therapy in overweight and obese patients with insulin-treated type 2 diabetes. Diabetes Care 2002;25:1033-41. (Class A)
Kim SG, Ryu OH, Kim HY, et al. Effect of rosiglitazone on plasma adiponectin levels and arterial stiffness in subjects with prediabetes or non-diabetic metabolic syndrome. Eur J Endocrinol 2006;154:433-40. (Class A)
Klein R, Klein BEK, Moss SE, et al. The Wisconsin epidemiologic study of diabetic retinopathy. III. Prevalence and risk of diabetic retinopathy when age at diagnosis is 30 or more years. Arch Ophthalmol 1984;102:527-32. (Class C)
Klein R, Moss SE, Klein BEK. New management concepts for timely diagnosis of diabetic retinopathy treatable by photocoagulation. Diabetes Care 1987;10:633-38. (Class R)
Klein S, Sheard NF, Pi-Sunyer X, et al. Weight management through lifestyle modification for the prevention and management of type 2 diabetes: rationale and strategies: a statement of the American Diabetes Association, the North American association for the study of obesity, and the American society for clinical nutrition. Diabetes Care 2004;27:2067-73. (Class R)
Knopp RH, d'Emden M, Smilde JG, Pocock SJ. Efficacy and safety of atorvastatin in the prevention of cardiovascular end points in subjects with type 2 diabetes: the atorvastatin study for prevention of coronary heart disease endpoints in non-insulin-dependent diabetes mellitus (ASPEN). Diabetes Care 2006;29:1478-85. (Class A)
LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005;352:1425-35. (Class A)
Leiter LA, Martineau P, de Teresa E, et al. How to reach LDL targets quickly in patients with diabetes or metabolic syndrome. J Fam Pract 2008;57:661-68. (Class C)
Lewis EJ, Hunsicker LG, Bain RP, et al. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med 1993;329:1456-62. (Class A)
Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antago-nist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345:851-60. (Class A)
Li G, Zhang P, Wang J, et al. The long-term effect of lifestyle interventions to prevent diabetes in the China Da Qing diabetes prevention study: a 20-year follow-up study. Lancet 2008;371:1783-89. (Class A)
Lindström J, Ilanne-Parikka P, Peltonen M, et al. Sustained reduction in the incidence of type 2 diabetes by lifestyle intervention: follow-up of the Finnish diabetes prevention study. Lancet 2006;368:1673-79. (Class A)
Lorig KR, Ritter P, Stewart AL, et al. Chronic disease self-management program: 2-year health status and health care utilization outcomes. Med Care 2001;39:1217-23. (Class D)
Lustman PJ, Gavard JA. Psychosocial aspects of diabetes in adult populations. In Diabetes in America, 2nd Ed. 507-18. On-line reference, accessed July, 2001 at http://diabetes-in-america.s-3.com/ (Class R)
Malmström RE, Settergren M, Böhm F, et al. No effect of lipid lowering on platelet activity in patients with coronary artery disease and type 2 diabetes or impaired glucose tolerance. Thromb Haemost 2009;101:157-64. (Class A)
Mayfield JA, Reiber GE, Sanders LJ, et al. Preventive foot care in people with diabetes. Diabetes Care 1998;21:2161-77. (Class R)
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults References Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
66
McFarlane SI. Diabetes prevention between RAAS inhibition and PPAR-gamma stimulation: the diabetes reduction assessment with ramipril and rosiglitazone medication (DREAM) trial. J Cardiometab Syndr 2007;2:149-50. (Class A)
Medical Letter® on Drugs and Therapeutics, The. Rosiglitazone for type 2 diabetes mellitus. 1999;41. (Class R)
Mensing C, Boucher J, Cypress M, et al. National standards for diabetes self-management education. Diabetes Care 2007;30:S96-S103. (Class R)
Miles JM, Leiter L, Hollander P, et al. Effect of orlistat in overweight and obese patients with type 2 diabetes treated with metformin. Diabetes Care 2002;25:1123-28. (Class A)
Mogensen CE, Keane WF, Bennett PH, et al. Prevention of diabetic renal disease with special refer-ence to microalbuminuria. Lancet 1996;346:1080-84. (Class R)
Morrish NJ, Stevens LK, Fuller JH, et al. Risk factors for macrovascular disease in diabetes mellitus: the London follow-up to the WHO multinational study of vascular disease in diabetes. Diabetologia 1991;34:590-94. (Class B)
Nathan DM, Buse JB, Davidson MB, et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2006;29:1963-72. (Class R)
National Institutes of Health. Morbidity and mortality of dialysis (consensus statement, online). 1993;11:1-33. (Class R)
Nelson RG, Knowler WC, Pettitt DJ, et al. Assessment of risk of overt nephropathy in diabetic patients from albumin excretion in untimed urine specimens. Arch Intern Med 1991;151:1761-65. (Class B)
Newman CB, Szarek M, Colhoun HM, et al. The safety and tolerability of atorvastatin 10 mg in the collab-orative atorvastatin diabetes study (CARDS). Diabetes Vasc Dis Res 2008;5:177-83. (Class A)
Nichols-English G, Poirier S. Optimizing adherence to pharmaceutical care plans. J Am Pharm Assoc 2000;40:475-83. (Class R)
Niemi M, Backman JT, Neuvonen M, Neuvonen PJ. Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics and pharmacodynamics of repaglinide: potentially hazardous interaction between gemfibrozil and repaglinide. Diabetologia 2003;46:347-51. (Class A)
Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardio-vascular causes. N Engl J Med 2007;356:2457-71. (Class M)
Nolan T, Berwick DM. All-or-none measurement raises the bar on performance. JAMA 2008;295: 1168-70. (Class R)
Norris SL, Zhang X, Avenell A, et al. Long-term effectiveness of weight-loss interventions in adults with pre-diabetes: a review. Am J Prev Med 2005;28:126-39. (Class M)
O'Connor PJ. Commentary – improving diabetes care by combating clinical inertia. Health Serv Res 2005b;40:1854-61. (Class R)
O'Connor PJ. Overcome clinical inertia to control systolic blood pressure. Arch Intern Med 2003;163:2677-78. (Class R)
O'Connor PJ, Crabtree BF, Yanoshik MK. Differences between diabetic patients who do and do not respond to a diabetes care intervention: a qualitative analysis. Fam Med 1997;29:424-28. (Class D)
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults References Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
67
O'Connor PJ, Sperl-Hillen JM, Johnson PE, et al. Advances in patient safety: clinical inertia and outpa-tient medical errors. AHRQ 2005a;2:293-308. (Class R)
Ogawa S, Mori T, Nako K, et al. Reduced albuminuria with sarpogrelate is accompanied by a decrease in monocyte chemoattractant protein-1 levels in type 2 diabetes. Clin J Soc Nephrol 2008;3:362-68. (Class A)
Ohkubo Y, Kishikawa H, Araki E, et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract 1995;28:103-17. (Class A)
Pastors JG, Warshaw H, Daly A, et al. The evidence for the effectiveness of medical nutrition therapy in diabetes management. Diabetes Care 2002;25:608-13. (Class R)
Pate RR, Pratt M, Blair SN, et al. Physical activity and public health: a recommendation from the Centers for Disease Control Prevention and the American College of Sports Medicine. JAMA 1995;273:402-07. (Class R)
Peters AL, Davidson MB. Maximal dose glyburide therapy in markedly symptomatic patients with type 2 diabetes: a new use for an old friend. J Clin Endocrinol Metab 1996;81:2423-27. (Class D)
Physicians' Health Study Research Group. Final report on the aspirin component of the ongoing physi-cians' health study. N Engl J Med 1989;321:129-35. (Class A)
Pyorala K, Pedersen TR, Kjekshus J, et al. Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease: a subgroup analysis of the Scandinavian simvas-tatin survival study (4S). Diabetes Care 1997;20:614-20. (Class A)
Ravid M, Savin H, Jutrin I, et al. Long-term stabilizing effect of angiotensin-converting enzyme inhibi-tion on plasma creatinine and on proteinuria in normotensive type II diabetic patients. Ann Intern Med 1993;118:577-81. (Class A)
Relimpio F, Pumar A, Losada F, et al. Adding metformin versus insulin dose increase in insulin-treated but poorly controlled type 2 diabetes mellitus: an open-label randomized trial. Diabet Med 1998;15:997-1002. (Class A)
Robins SJ, Collins D, Wittes JT, et al. Relation of gemfibrozil treatment and lipid levels with major coronary events: VA-HIT: a randomized controlled trial. JAMA 2001;285:1585-91. (Class A)
Schmidt MI, Duncan BB, Bang H, et al. Identifying individuals at high risk for diabetes: the atheroscle-rosis risk in communities study. Diabetes Care 2005;28:2013-18. (Class C)
Schwartz AV, Sellmeyer DE, Ensrud KE, et al. Older women with diabetes have an increased risk of fracture: a prospective study. J Clin Endocrinol Metab 2001;82:32-38. (Class B)
Selvin E, Bolen S, Yeh HC, et al. Cardiovascular outcomes in trials of oral diabetes medications: a systematic review. Arch Intern Med 2008;168:2070-80. (Class M)
Selvin E, Marinopoulos S, Berkenblit G, et al. Meta-analysis: glycosylated hemoglobin and cardiovas-cular disease in diabetes mellitus. Ann Intern Med 2004;141:421-31. (Class M)
Serebruany VL, Malinin AI, Pokov A, et al. Effects of clopidogrel and aspirin in combination versus aspirin alone on platelet activation and major receptor expression in diabetic patients: the pLavix use for treatment of diabetes (PLUTO-Diabetes) trial. Am Heart J 2008;155:93.e1-7. (Class A)
Settergren M, Böhm F, Ryden L, Pernow J. Cholesterol lowering is more important than pleiotropic effects of statins for endothelial function in patients with dyslycaemia and coronary artery disease. Eur Heart J 2008;29:1753-60. (Class A)
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults References Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
68
Sever PS, Poulter NR, Dahlöf B, et al. Reduction in cardiovascular events with atorvastatin in 2,532 patients with type 2 diabetes: Anglo-Scandinavian Cardiac Outcomes Trial – lipid-lowering arm (ASCOT-LLA). Diabetes Care 2005;28:1151-57. (Class A)
SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: final results of the systolic hypertension in the elderly program. JAMA 1991;265:3255-64. (Class A)
Shepard J, Barter P, Carmena R, et al. Effect of lowering LDL cholesterol substantially below currently recommended levels in patients with coronary heart disease and diabetes: the treating to new targets (TNT) study. Diabetes Care 2006;29:1220-26. (Class A)
Sigal RJ, Kenny GP, Wasserman DH, Castaneda-Sceppa C. Physical activity/exercise and type 2 diabetes. Diabetes Care 2004;27:2518-39. (Class R)
Sirois C, Poirier P, Moisan J, Grégoire JP. The benefit of aspirin therapy in type 2 diabetes: what is the evidence? Int J Cardiol 2008;129:172-79. (Class M)
Solberg LI, Mosser G, McDonald S. The three faces of performance measurement: improvement, accountability, and research. Jt Comm J Qual Improv 1997;23:135-47 (Class R)
Sperl-Hillen JM, O'Connor JP. Factors driving diabetes care improvement in a large medical group: ten years of progress. Am J Manag Care 2005;11:S177-S185. (Class D)
Tuomilehto J, Lindstrom J, Eriksson JH, et al. Prevention of type 2 diabetes mellitus by changes in life-style among subjects with impaired glucose tolerance. N Engl J Med 2001;344:1343-50. (Class A)
Tuomilehto J, Rastenyte D, Birkenhager WH, et al. Effects of calcium-channel blockade in older patients with diabetes and systolic hypertension. N Engl J Med 1999;340:677-84. (Class A)
Turner R, Cull C, Frighi V, et al. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). JAMA 1999;281:2005-12. (Class A)
Twigg SM, Kamp MC, Davis TM, et al. Prediabetes: a position statement from the Australian diabetes society and Australian diabetes educators association. Med J Aust 2007;186:461-65. (Class R)
UK Prospective Diabetes Study (UKPDS) Group. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000;321:405-12. (Class B)
UK Prospective Diabetes Study (UKPDS) Group. Cost effectiveness analysis of improved blood pres-sure control in hypertensive patients with type 2 diabetes. UKPDS 40. BMJ 1998a;317:720-26. (Class M)
UK Prospective Diabetes Study Group. Effect of intensive blood glucose control with metformin on complications in overweight patients with type 2 diabetes mellitus (UKPDS 34). Lancet 1998b;352:854-64. (Class A)
UK Prospective Diabetes Study (UKPDS) Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. BMJ 1998c;317:713-20. (Class A)
UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998d;352:837-53. (Class A)
UK Prospective Diabetes Study (UKPDS) Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998e;317:703-20. (Class A)
Umpierrez GE, Isaacs SD, Bazargan N, et al. Hyperglycemia: an independent marker of in-hospital mortality in patients with undiagnosed diabetes. J Clin Endocrinol Metab 2002;87:978-82. (Class B)
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults References Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
69
U.S. Department of Health and Human Services. In Treating Tobacco Use and Dependence. June 2000. (Class R)
van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001;345:1359-67. (Class A)
Viberti G, Mogensen CE, Groop LC, et al. Effect of captopril on progression to clinical proteinuria in patients with insulin-dependent diabetes mellitus and microalbuminuria. JAMA 1994;271:275-79. (Class A)
Vijan S, Hofer TP, Hayward RA. Estimated benefits of glycemic control in microvascular complications in type 2 diabetes. Ann Intern Med 1997;127:788-95. (Class D)
Walsh M, Spurling G. Aspirin in type 2 diabetes: is there any evidence base? BMJ 2008;337:1163-65. (Class R)
Wang C, Harris WS, Chung M, et al. n-3 Fatty acids from fish or fish-oil supplements, but not alpha-linolenic acid, benefit cardiovascular disease outcomes in primary- and secondary-prevention studies: a systematic review. Am J Clin Nutr 2006;84:5-17. (Class M)
Wing LMH, Reid CM, Ryan P, et al. A comparison of outcomes with angiotensin-converting-enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med 2003;348:583-92. (Class A)
Winkelmayer WC, Setoguchi S, Levin R, Solomon DH. Comparison of cardiovascular outcomes in elderly patients with diabetes who initiated rosiglitazone vs pioglitazone therapy. Arch Intern Med 2008;168:2368-75. (Class B)
Yki-Järvinen H, Ryysy L, Nikkilä K, et al. Comparison of bedtime insulin regimens in patients with type 2 diabetes mellitus. Ann Intern Med 1999;130:389-96. (Class A)
Zimmerman BR, Hagen MD. An evaluation of new agents in the treatment of type 2 diabetes. J Fam Pract 1998;47(Suppl 1):S37-S43. (Class R)
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults References Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
70
Conclusion Grading Worksheet A – Annotation #4 (Prediabetes)
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Thirteenth Edition/May 2009
Wo
rk
Gro
up
's C
on
clu
sio
n:
•
Lif
esty
le m
od
ific
atio
ns,
su
ch a
s n
utr
itio
n,
exer
cise
an
d e
ven
mo
des
t w
eig
ht
loss
, ar
e re
com
men
ded
fo
r
pre
ven
tio
n o
r d
elay
ed p
rog
ress
ion
of
pat
ien
ts w
ith
pre
dia
bet
es.
•
Ph
arm
aco
ther
apy
, su
ch a
s m
etfo
rmin
, ar
e ef
fect
ive
in s
om
e p
atie
nts
wit
h p
red
iab
etes
.
•
Th
ere
are
con
cern
s th
at t
he
rece
nt
mo
dif
icat
ion
of
the
def
init
ion
of
imp
aire
d f
asti
ng
glu
cose
by
th
e A
mer
ican
Dia
bet
es A
sso
ciat
ion
has
lo
w s
pec
ific
ity
an
d l
ow
po
siti
ve
pre
dic
tiv
e v
alu
e co
mp
are
d t
o t
he
WH
O d
efin
itio
n.
Co
nclu
sio
n G
ra
de:
II
Au
tho
r/
Yea
r
Des
ign
Ty
pe
Cla
ss
Qu
al-
ity
+,–
,ø
Po
pu
lati
on
Stu
die
d/S
amp
le S
ize
Pri
mar
y O
utc
om
e M
eas
ure
(s)/
Res
ult
s (e
.g.,
p-v
alu
e,
con
fid
ence
inte
rval
, re
lati
ve r
isk
, o
dd
s ra
tio
, li
kel
iho
od
rati
o, n
um
ber
need
ed t
o t
reat)
Au
tho
rs' C
on
clu
sio
ns/
Wo
rk G
rou
p's
Co
mm
ents
(ita
liciz
ed)
Bo
rch
-
Joh
nso
n,
et a
l.,
20
04
Ob
serv
a-
tio
nal
,
cro
ss-
sect
ion
al
stu
dy
D
+
Dat
a p
oo
led
fro
m 5
inte
rnati
on
al p
op
ula
tio
n b
ase
d
stu
die
s:
1)
Dan
ish
IN
TE
R9
9
(n=
62
65
ad
ult
s 3
0-
61
y)
DE
TE
CT
-2 S
tud
ies:
2)
Par
is
Pro
spect
ive(
n=
70
34
adu
lts
44
-55
y)
3)
Gin
gd
oa
(Ch
ina)
(n=
18
08
ad
ult
s 3
0-
74
y)
4)
NU
DS
(In
dia
)
(n=
10
03
9 a
du
lts
22
-99
y)
5)
NH
AN
ES
19
88
-
19
94
(n
=3
51
7
adu
lts
40
-74
y)
Pri
mar
y o
bje
cti
ve
was
to
ev
alu
ate
the c
on
seq
uen
ces
of
20
03
Am
eric
an D
iab
etes
Ass
ocia
tio
n e
xp
ert
com
mit
tee r
evis
ion
of
dia
gn
ost
ic c
rite
ria
for
imp
air
ed f
asti
ng
glu
cose
fro
m 6
.1 t
o 5
.6
mm
ol/
l; s
peci
fica
lly
wit
h r
egar
d t
o
1)
the
pre
vale
nce
of
imp
aire
d f
ast
ing
glu
cose
in
fiv
e
dif
fere
nt
cou
ntr
ies,
2)
the
con
cord
ance
betw
een
im
pair
ed f
ast
ing
glu
cose
stat
us
and
im
pair
ed g
luco
se t
ole
ran
ce,
and
3)
Th
e car
dio
vas
cula
r ri
sk p
rofi
le o
f th
ese
gro
up
s.
Th
e p
rop
ose
d c
han
ges
in
dia
gn
ost
ic c
rite
ria
wo
uld
in
cre
ase
the
pre
vale
nce
of
imp
air
ed f
ast
ing
glu
cose
in
Den
mark
fro
m 1
1.8
%
to 3
7.6
%, w
hic
h w
ou
ld i
den
tify
60
% o
f al
l su
bje
cts
wit
h
imp
aire
d g
luco
se t
ole
ran
ce
com
pare
d t
o 2
9.2
% w
ith
th
e o
ld
crit
eria
. H
ow
ever,
am
on
g i
nd
ivid
uals
wit
h t
he
new
im
pai
red
fast
ing
glu
cose
cat
ego
ry, 1
8.5
% w
ou
ld a
lso
hav
e im
pair
ed
glu
cose
to
lera
nce
; fu
rth
erm
ore
, in
div
idu
als
wit
h i
sola
ted
imp
aire
d f
asti
ng
glu
cose
had
lo
wer
insu
lin
lev
els
an
d a
lo
wer
card
iov
asc
ula
r d
isease
ris
k c
om
pare
d w
ith
cu
rren
t W
HO
cri
teri
a.
Dat
a fr
om
DE
TE
CT
-2 a
lso
sh
ow
ed a
n i
ncr
eas
e in
th
e p
rev
ale
nce
of
imp
aire
d f
ast
ing
glu
cose
– t
he
nu
mb
er o
f in
div
idu
als
ages
40-
64
yea
rs w
ith
im
pair
ed f
ast
ing
glu
cose
in
urb
an I
nd
ia, u
rban
Ch
ina,
an
d t
he
US
A w
ou
ld i
ncre
ase
by
78
%, 1
35
% a
nd
19
3%
,
resp
ect
ivel
y, w
ith
th
e n
ew
cri
teri
a co
mp
are
d t
o t
he
old
cri
teri
a.
Th
e au
tho
rs c
on
clu
de
that
a r
evis
ion
of
dia
gn
ost
ic c
rite
ria f
or
imp
aire
d
fast
ing
gly
cem
ia w
ill
incr
eas
e th
e
pre
vale
nce
of
imp
air
ed f
ast
ing
glu
cose
tw
o-
to f
ou
rfo
ld.
Im
pai
red
fast
ing
glu
cose
an
d i
mp
aire
d
glu
cose
to
lera
nce
wil
l re
main
tw
o
dif
fere
nt
cat
ego
ries
of
glu
cose
into
lera
nce.
T
he
new
im
pair
ed
fast
ing
glu
cose
gro
up
wil
l h
ave
a
mo
re f
avo
rab
le c
ard
iov
asc
ula
r ri
sk
pro
file
th
an t
he
gro
up
def
ined
by
WH
O,
and
th
e u
sefu
lness
of
imp
aire
d f
asti
ng
glu
cose
as
a t
arg
et
gro
up
fo
r d
iab
ete
s p
rev
enti
on
may
bec
om
e q
uest
ion
able
.
New
Thi
rteen
th E
ditio
n, M
ay 2
009.
Institute for Clinical Systems Improvement
www.icsi.org
71
Conclusion Grading Worksheet A – Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Annotation #4 (Prediabetes) Thirteenth Edition/May 2009
Au
tho
r/
Yea
r
Des
ign
Ty
pe
Cla
ss
Qu
al-
ity
+,–
,ø
Po
pu
lati
on
Stu
die
d/S
amp
le
Siz
e
Pri
mar
y O
utc
om
e M
eas
ure
(s)/
Res
ult
s (e
.g.,
p-
val
ue,
con
fid
ence
inte
rval
, re
lati
ve r
isk
, o
dd
s
rati
o,
lik
elih
oo
d r
atio
, n
um
ber
nee
ded
to
tre
at)
Au
tho
rs' C
on
clu
sio
ns/
Wo
rk G
rou
p's
Co
mm
ents
(it
ali
cize
d)
Tw
igg
,
et a
l.,
20
07
Po
siti
on
Sta
tem
ent
bas
ed o
n a
syst
emat
ic
rev
iew
of
lite
ratu
re f
rom
the
Au
stra
lian
Dia
bet
es
So
ciety
an
d
Au
stra
lian
Dia
bet
es
Ed
uca
tors
Ass
oci
atio
n
R
+
A r
evie
w o
f p
eer-
rev
iew
ed j
ou
rnal
s
was
co
nd
uct
ed
usi
ng
ME
DL
INE
19
66
-20
05
).
Sea
rch
term
s
incl
ud
ed
pre
dia
bet
es,
glu
cose
into
lera
nce,
IG
T,
IFG
, im
pair
ed
glu
cose
to
lera
nce
,
imp
aire
d f
asti
ng
glu
cose
an
d
imp
aire
d f
asti
ng
gly
cem
ia.
Art
icle
s w
ere
gra
ded
acc
ord
ing
to l
evel
of
evid
ence
.
-Th
e ai
m o
f th
is r
epo
rt w
as t
o d
evel
op
reco
mm
end
atio
ns
for
the
clin
ical
man
agem
ent
of
pre
dia
bet
es
for
ph
ysi
cia
ns
and
all
ied
heal
th c
are
pro
fess
ion
als.
- P
red
iab
etes
is d
efin
ed a
s th
e p
rese
nce
of
imp
air
ed
fast
ing
glu
cose
/gly
cem
ia a
nd
/or
imp
air
ed g
luco
se
tole
ran
ce.
- P
red
iab
etes
affe
cts
abo
ut
16
.4%
of
Au
stra
lian
ad
ult
s.
- P
eop
le w
ith
pre
dia
bete
s are
at
incr
eas
ed r
isk
of
dev
elo
pin
g d
iab
ete
s, ~
3%
-10
% o
f p
eop
le p
er y
ear
wit
h
pre
dia
bet
es
dev
elo
p d
iab
ete
s.
In m
ost
po
pu
lati
on
s
stu
die
s, t
he
rate
s o
f co
nv
ers
ion
fro
m i
mp
aire
d f
asti
ng
glu
cose
or
imp
air
ed g
luco
se t
ole
ran
ce a
re s
imil
ar,
wit
h
imp
aire
d g
luco
se t
ole
ran
ce
hav
ing
gre
ate
r se
nsi
tiv
ity
bu
t le
ss s
peci
fici
ty.
- P
eop
le w
ith
pre
dia
bete
s h
ave a
tw
o t
o t
hre
efo
ld
incr
eas
ed r
isk
of
card
iov
asc
ula
r d
isea
se c
om
par
ed t
o
adu
lts
wh
o h
ave
no
rmal
glu
cose
to
lera
nce.
- S
ever
al r
and
om
ized
, p
rosp
ect
ive s
tud
ies
of
sub
ject
s
wit
h p
red
iab
ete
s h
ave
do
cum
ente
d b
enef
icia
l ef
fect
s o
f
life
sty
le i
nte
rven
tio
ns
in p
rev
enti
ng
ty
pe
2 d
iab
etes
.
Th
e D
iab
ete
s P
rev
enti
on
Pro
gra
m o
bse
rved
a 5
8%
ris
k
red
ucti
on
in
pro
gre
ssio
n t
o d
iab
etes
ev
en t
ho
ug
h
par
ticip
ants
did
not
mee
t w
eig
ht
loss
an
d m
od
era
te
ph
ysi
cal
act
ivit
y g
oals
.
- M
ult
iple
med
icat
ion
s h
ave
been
sh
ow
n t
o r
edu
ce
inci
den
ce
of
dia
bet
es i
n p
eop
le w
ith
pre
dia
bet
es i
n
ran
do
miz
ed,
do
ub
le-b
lin
ded
tri
als.
In
th
e D
iab
ete
s
Pre
ven
tio
n P
rog
ram
, su
bje
cts
all
oca
ted
to
met
form
in
ther
apy
had
a 3
1%
red
uce
d r
isk
of
con
vers
ion
to
dia
bete
s co
mp
are
d w
ith
th
e c
on
tro
l g
rou
p.
Oth
er
dru
gs,
su
ch a
s acar
bo
se a
nd
ro
sig
lita
zon
e, m
ay r
edu
ce
con
ver
sio
n t
o d
iab
etes
as
wel
l as
card
iov
ascu
lar
even
ts,
bu
t th
e re
sult
s n
eed
to
be c
on
firm
ed b
y o
ther
stu
die
s.
- N
o d
ata
ex
ist
to d
efin
e t
he u
tili
ty o
f m
on
ito
rin
g
Hb
Alc
in
pre
dia
bet
ic p
ati
ents
.
- A
sses
smen
t an
d m
anag
em
ent
of
risk
fact
ors
fo
r
card
iov
asc
ula
r d
isease
, su
ch a
s li
pid
an
d b
loo
d
pre
ssu
res
abn
orm
alit
ies,
sh
ou
ld b
e u
nd
erta
ken
.
Alt
ho
ug
h t
her
e h
ave
been
no
tri
als
in
pre
dia
beti
cs,
the
lip
id a
nd
blo
od
pre
ssu
re t
arg
ets
sho
uld
be
equ
ival
ent
to t
ho
se f
or
typ
e 2
dia
bet
es.
- S
ust
ain
ed a
nd
mo
der
ate
weig
ht
loss
in
peo
ple
wit
h p
red
iab
ete
s is
an
im
po
rtan
t p
red
icto
r o
f a
po
siti
ve
ou
tco
me o
f li
fest
yle
in
terv
enti
on
s.
- It
is
reco
mm
end
ed t
hat
a m
inim
um
of
6 m
on
ths
of
life
sty
le i
nte
rven
tio
n b
e tr
iale
d b
efo
re d
rug
ther
apy
is
con
sid
ered
.
- P
racti
cal
hea
lth
car
e d
eliv
ery
of
life
sty
le a
spec
ts
of
dia
bet
es p
rev
enti
on
req
uir
es f
urt
her
stu
dy
.
- P
harm
aco
ther
apy
may
in
vo
lve
metf
orm
in, w
hic
h
app
ears
to
be
mo
re e
ffic
aci
ou
s in
yo
un
ger
(<
60
yea
rs)
and
mo
re o
verw
eig
ht
peo
ple
. O
ther
dru
gs
may
be o
rlis
tat,
aca
rbo
se o
r a t
hia
zoli
din
edio
ne.
- In
th
e a
bse
nce
of
speci
fic
clin
ical
ind
icat
ion
s,
ther
e is
no
need
fo
r ro
uti
nel
y c
on
du
ctin
g t
he
foll
ow
ing
test
s in
pre
dia
bet
ic p
atie
nts
: c
apil
lary
blo
od
glu
cose
measu
rem
ent,
Hb
A1
c, s
eru
m i
nsu
lin
or
pan
cre
ati
c C
-pep
tid
e, t
ests
fo
r is
chem
ic h
eart
dis
ease
, te
sts
for
mic
rov
asc
ula
r co
mp
lica
tio
ns.
- F
oll
ow
-up
tes
tin
g i
n p
red
iab
ete
s re
qu
ires
a f
orm
al
75
g o
ral
glu
cose
to
lera
nce
test
.
[Th
is p
osi
tio
n s
tate
men
t h
as
no
t a
do
pte
d A
meri
can
Dia
bet
es A
sso
cia
tio
n r
ecen
tly
mo
dif
ica
tio
n t
o
imp
air
ed f
ast
ing
glu
cose
def
init
ion
of
5.6
-6.9
mm
ol/
L.
Th
e a
uth
ors
sta
te t
ha
t su
ch a
lo
w
thre
sho
ld g
luco
se l
eve
l m
ay
cau
se t
he i
mp
air
ed
fast
ing
glu
cose
ca
teg
ori
zati
on
to
lo
se s
pec
ific
ity
an
d p
osi
tive
pre
dic
tive
valu
e a
s a
ris
k fa
cto
r fo
r
dia
bet
es.
T
he r
epo
rt u
ses
the
WH
O d
efin
itio
n o
f
!6
.1 m
mo
l/L
an
d <
7.0
mm
ol/
L]
Institute for Clinical Systems Improvement
www.icsi.org
72
Au
tho
r/
Yea
r
Des
ign
Ty
pe
Cla
ss
Qu
al-
ity
+,–
,ø
Po
pu
lati
on
Stu
die
d/S
amp
le
Siz
e
Pri
mar
y O
utc
om
e M
eas
ure
(s)/
Res
ult
s (e
.g.,
p-
val
ue,
con
fid
ence
inte
rval
, re
lati
ve r
isk
, o
dd
s
rati
o,
lik
elih
oo
d r
atio
, n
um
ber
nee
ded
to
tre
at)
Au
tho
rs' C
on
clu
sio
ns/
Wo
rk G
rou
p's
Co
mm
ents
(it
ali
cize
d)
Sch
mid
t,
et a
l.,
20
05
Stu
dy
of
sen
siti
vit
y
and
speci
fici
ty
of
a r
isk
pre
dic
tio
n
fun
ctio
n
C
+
79
15
par
tici
pan
ts f
rom
the
Ath
ero
scle
rosi
s
Ris
k i
n C
om
mu
nit
ies
stu
dy
, st
ud
y s
ub
jects
wer
e fr
ee o
f d
iab
etes
at b
asel
ine (
19
87-
19
89
) an
d f
oll
ow
ed
un
til
19
96
-19
98
.
-Th
e o
bje
cti
ve
of
this
stu
dy
was
to d
eri
ve
risk
fun
ctio
ns
to p
red
ict
dia
bete
s w
ith
eq
ual
or
bet
ter
dia
gn
ost
ic p
rop
erti
es t
han
im
pai
red
glu
cose
tole
ran
ce.
- L
og
isti
c re
gre
ssio
n w
as
use
d i
n a
ran
do
m h
alf
of
the
sam
ple
, th
en e
valu
ate
the r
isk
fu
nct
ion
s in
th
e
oth
er h
alf
of
the
sam
ple
.
- R
ule
s b
ase
d o
n r
isk
fu
nct
ion
s in
clu
din
g l
abo
rato
ry
mea
sure
men
ts p
erf
orm
ed g
enera
lly
bet
ter;
a r
isk
fun
ctio
n b
ased
on
wai
st c
ircu
mfe
ren
ce,
hei
gh
t,
hy
per
ten
sio
n, b
loo
d p
ress
ure
, fa
mil
y h
isto
ry o
f
dia
bete
s, e
thn
icit
y a
nd
ag
e w
as p
erf
orm
ed s
imil
arly
to o
ne
base
d o
n f
asti
ng
glu
cose
(are
a u
nd
er
the
curv
e 0
.71
an
d 0
.74
, re
spec
tiv
ely
, p
=0
.2).
- R
ule
s b
ase
d o
n t
he
pre
sen
ce
of
ele
men
ts o
f th
e
met
abo
lic
syn
dro
me
pro
du
ced
sli
gh
tly
less
desi
rab
le
dia
gn
ost
ic p
rop
erti
es (
23
% l
abel
ed a
s h
igh
ris
k a
nd
50
% o
f fu
ture
case
s id
enti
fied
) th
an r
ule
s b
ase
d o
n
risk
fu
ncti
on
in
clu
din
g l
ipid
s (2
0%
lab
eled
as
hig
h
risk
an
d 5
2%
of
futu
re c
ase
s id
enti
fied
).
Met
abo
lic
syn
dro
me
rule
s h
ad s
lig
htl
y l
ess
sen
siti
vit
y (
2%
)
and
sp
ecif
icit
y (
4%
) co
mp
are
d t
o r
ule
s u
sin
g a
clin
ical
cal
cula
tor
or
web
pag
e.
Ru
les
base
d o
n t
he m
eta
bo
lic s
yn
dro
me
crit
eria
are
reaso
nab
le a
lter
nat
ives
to r
ule
s d
eri
ved
fro
m
the
risk
fu
ncti
on
s.
Kim
, et
al.,
20
06
Ran
do
miz
ed,
con
tro
lled
tria
l
A
- 5
2 m
en a
nd
47
wo
men
age
53
.5±
11
.4 y
ear
s
wit
h p
red
iab
ete
s o
r
no
n-d
iab
etic
met
abo
lic
syn
dro
me
wer
e
enro
lled
an
d
ran
do
miz
ed t
o e
ith
er
4m
g r
osi
gli
tazo
ne
trea
tmen
t g
rou
p o
r
no
n-t
reat
ed c
on
tro
l
gro
up
an
d f
oll
ow
ed
for
12
wee
ks.
At
base
lin
e an
d 1
2-w
eek
fo
llo
w-u
p,
sub
jects
wer
e
giv
en a
75
g o
ral
glu
cose
to
lera
nce
tes
t.
Infl
amm
ato
ry m
ark
ers
th
ou
gh
t to
be
card
iov
asc
ula
r
risk
mark
ers
, p
uls
e-w
ave-
vel
oci
ty (
a m
easu
re o
f
arte
rial
sti
ffn
ess
) an
d a
nth
rop
om
etri
cs
wer
e al
so
mea
sure
d.
Ro
sig
lita
zon
e t
reat
men
t si
gn
ific
antl
y i
ncre
ased
circ
ula
tin
g l
evel
s o
f ad
ipo
nec
tin
an
d d
ecr
eas
ed
lev
els
of
CR
P r
elat
ive
to t
he
con
tro
l g
rou
p. T
he
trea
tmen
t g
rou
p a
lso
had
sig
nif
ican
tly
decr
eas
ed
pu
lse-
wav
e-v
elo
cit
y c
om
pare
d t
o t
he
con
tro
l g
rou
p.
Th
ese
data
su
gg
est
th
at
rosi
gli
tazo
ne
ther
apy
may
hav
e an
an
ti-a
thero
gen
ic a
ffect
in
su
bje
cts
wit
h
pre
dia
bet
es.
[Th
is s
tud
y w
as
no
t co
nd
uct
ed i
n a
do
ub
le-
bli
nd
ed p
laceb
o c
on
tro
lled
fa
shio
n.
It
is p
oss
ible
tha
t th
e ro
sig
lita
zon
e g
rou
p h
ad
mo
re i
nte
nsi
ve
life
styl
e ch
an
ges
th
at
cou
ld h
ave
exa
gg
era
ted
th
e
ben
efic
ial
effe
ct o
f ro
sig
lita
zon
e. A
lso
, it
is
dif
ficu
lt t
o i
mp
oss
ible
to
tea
se a
pa
rt t
he
effe
ct o
f
ph
arm
aco
ther
ap
y a
nd
lif
est
yle
ch
an
ges
in
th
is
stu
dy.]
Conclusion Grading Worksheet A – Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Annotation #4 (Prediabetes) Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
73
Au
tho
r/
Yea
r
Des
ign
Ty
pe
Cla
ss
Qu
al-
ity
+,–
,ø
Po
pu
lati
on
Stu
die
d/S
amp
le
Siz
e
Pri
mar
y O
utc
om
e M
eas
ure
(s)/
Res
ult
s (e
.g.,
p-
val
ue,
con
fid
ence
inte
rval
, re
lati
ve r
isk
, o
dd
s
rati
o,
lik
elih
oo
d r
atio
, n
um
ber
nee
ded
to
tre
at)
Au
tho
rs' C
on
clu
sio
ns/
Wo
rk G
rou
p's
Co
mm
ents
(it
ali
cize
d)
No
rris
,
et a
l.,
20
05
Met
a-
anal
ysi
s
M
+
Lit
eratu
re s
ear
ches
wer
e co
nd
uct
ed u
p
to 2
00
3.
Ran
do
miz
ed
con
tro
lled
tri
als
in
any
lan
gu
age
that
exam
ined
weig
ht
loss
or
weig
ht
con
tro
l w
ith
at
leas
t
on
e d
ieta
ry,
ph
ysi
cal
acti
vit
y o
r
beh
avio
ral
inte
rven
tio
n w
ith
foll
ow
-up
gre
ate
r
than
12
mo
nth
s
wer
e se
lect
ed.
A
met
a-an
aly
sis
was
con
du
cted
an
d
effe
cts
wer
e
com
bin
ed u
sin
g a
ran
do
m e
ffects
mo
del
.
Th
e o
bje
cti
ve
of
this
meta
-an
aly
sis
was
to
asse
ss t
he e
ffect
iven
ess
of
weig
ht-
loss
an
d
wei
gh
t-co
ntr
ol
inte
rven
tio
n f
or
adu
lts
wit
h
pre
dia
bete
s.
A t
ota
l o
f 5
16
8 p
arti
cip
ants
wer
e in
clu
ded
in
po
ole
d a
nal
yse
s. F
oll
ow
-up
ran
ged
fro
m 1
to
10
yea
rs.
Co
mp
ared
to
usu
al
care
, fo
ur
stu
die
s
wit
h a
fo
llo
w-u
p o
f 1
yea
r re
du
ced
weig
ht
by
2.8
kg
(9
5%
CI
1.0
-4.7
) an
d d
ecr
eas
ed b
od
y
mas
s in
dex
by
1.4
kg
/m2 (
0.5
-2.3
).
Wei
gh
t
loss
at
2 y
ear
s w
as 2
.7 k
g (
1.9
-3.4
) fr
om
tw
o
stu
die
s.
Mo
des
t im
pro
vem
ents
wer
e n
ote
d i
n
the
few
stu
die
s th
at
exam
ined
gly
cem
ic
con
tro
l, b
loo
d p
ress
ure
, li
pid
s.
Th
e i
nci
den
ce
of
dia
bete
s w
as s
ign
ific
antl
y l
ow
er i
n t
he
inte
rven
tio
n g
rou
ps
vs.
co
ntr
ols
in
3 o
r 5
stu
die
s th
at
exam
ined
th
is o
utc
om
e a
t 3
to
6
yea
rs f
oll
ow
-up
.
Alt
ho
ug
h t
he
wei
gh
t lo
ss a
mo
un
ts
dem
on
stra
ted
in
th
is r
evie
w w
ere
small
, it
app
ears
th
at e
ven
mo
des
t w
eig
ht
loss
may
hav
e h
eal
th b
enef
its
wit
h r
egar
d t
o
card
iov
asc
ula
r d
iseas
e ri
sk f
act
ors
an
d
dev
elo
pm
ent
of
dia
bete
s.
Conclusion Grading Worksheet A – Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Annotation #4 (Prediabetes) Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
74
Au
tho
r/Y
ear
D
esig
n
Ty
pe
Cla
ss
Qu
al-
ity
+,–
,ø
Po
pu
lati
on
Stu
die
d/S
amp
le
Siz
e
Pri
mar
y O
utc
om
e M
eas
ure
(s)/
Res
ult
s (e
.g.,
p-
val
ue,
con
fid
ence
inte
rval
, re
lati
ve r
isk
, o
dd
s
rati
o,
lik
elih
oo
d r
atio
, n
um
ber
nee
ded
to
tre
at)
Au
tho
rs' C
on
clu
sio
ns/
Wo
rk G
rou
p's
Co
mm
ents
(it
ali
cize
d)
McF
arl
ane,
et
al.,
20
07
Do
ub
le-
bli
nd
,
ran
do
m-
ized
con
tro
lled
tria
l, t
he
DR
EA
M
tria
l
A
- T
he
stu
dy
scre
ened
24
,59
2
per
son
s an
d
ran
do
miz
ed 5
,26
9
in 1
91
sit
es
fro
m
21
co
un
trie
s w
ith
a m
edia
n f
oll
ow
-
up
of
3 y
ear
s.
Pat
ien
ts e
nro
lled
wer
e o
lder
th
an 3
0
yea
rs w
ith
pre
dia
bet
es
def
ined
as
imp
aire
d g
luco
se
tole
ran
ce (
fast
ing
pla
sma g
luco
se
<7
, 2
-ho
ur
pla
sma
glu
cose
7.8
-11
mm
ol/
L)
and
/or
imp
aire
d f
asti
ng
glu
cose
(fa
stin
g
pla
sma g
luco
se
6.1
-6.9
mm
ol/
L).
Th
e p
rim
ary
aim
s o
f th
is s
tud
y w
ere
to
tes
t 1
) d
oes
ram
ipri
l p
rev
ent
dia
bete
s? a
nd
2)
do
es
rosi
gli
tazo
ne
pre
ven
t d
iab
etes?
Pri
mar
y o
utc
om
es
of
the
stu
dy
were
in
cid
ent
dia
bete
s (c
on
firm
ed b
y f
ast
ing
pla
sma
glu
cose
>7
or
2-h
ou
r p
lasm
a g
luco
se >
11
.1 o
r d
iag
no
sis
mad
e b
y a
ph
ysi
cian
or
deat
h.
Sec
on
dary
ou
tco
mes
in
clu
ded
ass
essm
ent
of
the
rate
of
con
vers
ion
to
pre
dia
bete
s to
no
rmo
gly
cem
ia a
s
wel
l as
ev
alu
ati
on
of
ram
ipri
l an
d r
osi
gli
tazo
ne
effe
cts
on
card
iore
nal
even
ts.
Res
ult
s:
Ram
ipri
l at
a d
osa
ge
of
15
mg
/d f
or
3.5
yea
rs d
id n
ot
pre
ven
t d
iab
etes.
H
ow
ever
, ra
mip
ril
was
ass
oci
ated
wit
h a
no
nsi
gn
ific
ant
decre
ase
(9%
)
in n
ew-o
nse
t d
iab
ete
s co
mp
are
d t
o p
laceb
o a
nd
was
asso
cia
ted
wit
h a
sig
nif
ican
t in
creas
e (1
6%
) in
th
e
rate
of
con
ver
sio
n t
o n
orm
og
lycem
ia f
rom
im
pai
red
glu
cose
to
lera
nce
an
d i
mp
air
ed f
ast
ing
glu
cose
.
Ro
sig
lita
zon
e w
as
asso
cia
ted
wit
h a
sig
nif
ican
t
dec
reas
ed (
60
%)
in n
ew o
nse
t d
iab
ete
s co
mp
are
d
wit
h p
laceb
o.
Th
is e
ffect
was
con
sist
ent
acr
oss
ag
e,
sex
an
d r
aci
al/e
thn
ic g
rou
ps.
Ad
dit
ion
all
y,
there
was
a si
gn
ific
ant
incre
ase
(7
1%
) in
co
nv
ersi
on
rat
e to
no
rmo
gly
cem
ia a
mo
ng
th
ose
wit
h i
mp
aire
d g
luco
se
tole
ran
ce a
nd
im
pair
ed f
ast
ing
glu
cose
.
Th
e D
RE
AM
tri
al
did
no
t cle
arl
y d
emo
nst
rate
a
dia
bete
s p
rev
enti
on
eff
ect
wit
h r
amip
ril
and
on
ly
sho
wed
a t
ren
d.
Ho
wev
er,
th
e fi
nd
ing
s co
nfi
rmed
the
ben
efic
ial
eff
ects
of
ram
ipri
l o
n g
luco
se
met
abo
lism
.
Th
e ro
sig
lita
zon
e f
ind
ing
s co
nfi
rm o
ther
fin
din
gs
that
th
e d
rug
red
uces
in
suli
n r
esi
stan
ce
and
pre
serv
es
pan
crea
tic
B-c
ell
fu
nct
ion
. H
ow
ever,
du
e to
liv
er
tox
icit
y,
the a
gen
t th
at w
as
act
ual
ly
test
ed (
tro
gli
tazo
ne)
was
wit
hd
raw
n f
rom
th
e
mar
ket
an
d e
ven
tual
ly r
epla
ced
wit
h m
uch
saf
er
thia
zoli
daz
ides
that
wer
e n
ot
speci
fical
ly t
este
d i
n
ran
do
miz
ed c
on
tro
lled
tri
als
for
dia
bete
s
pre
ven
tio
n.
Th
e au
tho
rs s
ug
ges
t th
at u
se o
f an
AC
E i
nh
ibit
or,
wh
en o
therw
ise i
nd
icate
d, w
ou
ld b
e a
pru
den
t
cho
ice
for
pre
dia
beti
cs b
ecau
se t
hey
are
at
incr
eas
ed r
isk
of
card
iov
asc
ula
r d
isea
se.
[Th
is i
s a
rela
tive
ly l
arg
e tr
ial
of
ph
arm
aco
ther
ap
y to
pre
ven
t d
iab
etes
am
on
g
pre
dia
beti
cs. H
ow
eve
r, t
his
art
icle
wa
s a
bri
ef
rep
ort
an
d d
id n
ot
inclu
de
an
y d
eta
ils
of
the
recr
uit
men
t a
nd
ra
nd
om
iza
tio
n p
roce
ss, n
or
did
it
incl
ud
e a
ny
ba
seli
ne t
ab
les.
In
ad
dit
ion
, th
ere
wer
e n
o c
on
fid
ence
inte
rva
ls p
rese
nte
d f
or
the
po
int
est
ima
tes
giv
en i
n t
he t
ext.
]
Conclusion Grading Worksheet A – Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Annotation #4 (Prediabetes) Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
75
Au
tho
r/
Yea
r
Des
ign
Ty
pe
Cla
ss
Qu
al-
ity
+,–
,ø
Po
pu
lati
on
Stu
die
d/S
amp
le
Siz
e
Pri
mar
y O
utc
om
e M
eas
ure
(s)/
Res
ult
s (e
.g.,
p-v
alu
e,
con
fid
ence
inte
rval
, re
lati
ve r
isk
, o
dd
s ra
tio
,
lik
eli
ho
od
rat
io,
nu
mb
er n
eed
ed t
o t
reat
)
Au
tho
rs' C
on
clu
sio
ns/
Wo
rk G
rou
p's
Co
mm
ents
(it
ali
cize
d)
Far
ag,
et a
l.,
20
07
Nar
rati
ve
rev
iew
R
- A
no
n-
syst
em
ati
c
rev
iew
of
typ
e 2
dia
bete
s
pre
ven
tio
n
rese
arch
,
incl
ud
ing
pre
ven
tio
n
amo
ng
pre
dia
beti
cs.
Th
ere a
re n
o d
eta
ils
of
ho
w a
rtic
les
wer
e se
lect
ed f
or
incl
usi
on
in
th
e re
vie
w.
Ho
wev
er, th
e a
rtic
le c
ov
ers
sev
eral
imp
ort
ant
area
s o
f d
iab
ete
s p
rev
enti
on
:
Pre
dia
bet
ic s
tate
: d
efin
es p
red
iab
etic
s as
imp
air
ed
fast
ing
glu
cose
of
10
0 t
o 1
25
mg
/dL
an
d/o
r im
pai
red
glu
cose
to
lera
nce
wit
h g
luco
se l
evels
of
14
0 t
o 1
99
mg
/dL
2 h
ou
rs a
fter
an
ora
l lo
ad o
f g
luco
se.
Est
imat
es t
hat
40
% o
f p
eop
le w
ith
im
pair
ed g
luco
se
tole
ran
ce
pro
gre
ss t
o d
iab
etes
.
Lif
est
yle
ch
ang
es:
su
mm
ariz
es f
ind
ing
s th
at
weig
ht
loss
, d
iet
and
ex
ercis
e h
ave
been
sh
ow
n s
epar
atel
y
and
in
co
mb
inat
ion
to
be e
ffect
ive i
n d
ecre
asin
g t
he
inci
den
ce
of
typ
e 2
dia
bet
es i
n h
igh
ris
k p
ati
ents
.
Ph
arm
oco
log
ic i
nte
rven
tio
ns:
su
mm
ariz
es
fin
din
gs
for
sev
eral
typ
es o
f d
rug
s.
Insu
lin
sen
siti
zin
g d
rug
s
(met
form
in,
thia
zoli
din
edio
nes
) an
d o
ral
anti
-dia
bet
ic
agen
ts (
glu
cosi
dase
in
hib
ito
rs)
hav
e b
een
sho
wn
to
be
effe
cti
ve
in r
edu
cin
g i
ncid
ence
of
dia
bet
es i
n p
ati
ents
wit
h i
mp
aire
d g
luco
se t
ole
ran
ce o
r ar
e cu
rren
tly
bei
ng
ex
amin
ed i
n o
ng
oin
g t
rial
s (n
ate
gli
nid
ines
).
Oth
er d
rug
s su
ch a
s A
CE
S, st
atin
s an
d f
ibra
tes
hav
e
inco
nsi
sten
t fi
nd
ing
s fo
r d
iab
etes
pre
ven
tio
n.
Th
ere
is n
ot
suff
icie
nt
evid
ence
for
a p
rote
cti
ve
effe
ct
for
dia
bete
s w
ith
weig
ht-
red
ucin
g a
gen
ts, b
ut
ther
e is
evid
ence
of
gre
ate
r su
cce
ss w
ith
weig
ht
loss
.
Su
rger
y:
su
mm
ariz
es s
tud
ies
fro
m S
wed
en a
nd
US
that
ev
alu
ated
su
rgic
al
inte
rven
tio
ns
for
wei
gh
t lo
ss.
Th
e au
tho
rs c
on
clu
de
that
sev
eral
inte
rven
tio
ns
hav
e b
een
sh
ow
n t
o b
e
effe
cti
ve
in p
rev
enti
ng
dia
bet
es,
incl
ud
ing
lif
est
yle
mo
dif
icati
on
s as
wel
l
as a
nti
-dia
bet
ic p
har
mac
oth
erap
y.
Conclusion Grading Worksheet A – Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Annotation #4 (Prediabetes) Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
76
Au
tho
r/Y
ear
D
esig
n
Ty
pe
Cla
ss
Qu
al-
ity
+,–
,ø
Po
pu
lati
on
Stu
die
d/S
amp
le
Siz
e
Pri
mar
y O
utc
om
e M
eas
ure
(s)/
Res
ult
s (e
.g.,
p-
val
ue,
con
fid
ence
inte
rval
, re
lati
ve r
isk
, o
dd
s
rati
o,
lik
elih
oo
d r
atio
, n
um
ber
nee
ded
to
tre
at)
Au
tho
rs' C
on
clu
sio
ns/
Wo
rk G
rou
p's
Co
mm
ents
(it
ali
cize
d)
Tu
om
ileh
to,
et
al.,
20
01
Fin
nis
h
Dia
bet
es
Pre
ven
tio
n
Stu
dy
RC
T
A
+
52
2 m
idd
le-a
ged
,
ov
erw
eig
ht
sub
juct
s
(17
2 m
en a
nd
35
0
wo
men
, m
ean
ag
e 5
5
yea
rs,
mea
n B
MI
31
kg
/m2)
wit
h i
mp
air
ed
glu
cose
wer
e
ran
do
miz
ed t
o e
ith
er
ind
ivid
ual
ized
cou
nse
lin
g a
imed
at
red
ucin
g w
eig
ht
and
tota
l fa
t in
tak
e an
d
incr
eas
ing
ph
ysi
cal
acti
vit
y a
nd
fib
er
inta
kes
(in
terv
enti
on
gro
up
) o
r a
con
tro
l
gro
up
. T
he
mean
du
rati
on
of
foll
ow
-up
was
3.2
year
s.
Th
e p
rim
ary
aim
of
this
stu
dy
was
to
det
erm
ine t
he
feas
ibil
ity
of
a li
fest
yle
in
terv
enti
on
to
del
ay o
r
pre
ven
t in
cid
ence
ty
pe 2
dia
bet
es.
Th
e m
ean
(S
D)
amo
un
t o
f w
eig
ht
lost
betw
een
bas
elin
e an
d t
he
end
of
year
1 w
as 4
.2 (
5.1
) k
g i
n
the
inte
rven
tio
n g
rou
p a
nd
0.8
(3
.7)
kg
in
th
e co
ntr
ol
gro
up
(p
<0
.00
1).
A
fter
tw
o y
ears
, th
e n
et w
eig
ht
loss
was
3.5
(5
.5)
kg
in
th
e in
terv
enti
on
gro
up
an
d
0.8
(5
.5)
kg
in
th
e co
ntr
ol
gro
up
(p
<0
.00
1).
Th
e cu
mu
lati
ve i
ncid
ence
of
dia
bete
s aft
er f
ou
r
yea
rs w
as
11
% (
95
% C
I 6
to
15
%)
in t
he
inte
rven
tio
n g
rou
p a
nd
23
% (
95
% C
I 1
7 t
o 2
9%
) in
the
con
tro
l g
rou
p.
In
th
e tr
ial,
th
e ri
sk o
f d
iab
etes
was
red
uced
by
58
% (
p<
0.0
01
) in
th
e in
terv
enti
on
gro
up
.
Th
e au
tho
rs c
on
clu
de
that
th
e re
du
cti
on
in
inci
den
ce
of
dia
bet
es w
as a
dir
ectl
y a
sso
ciat
ed
wit
h c
han
ges
in l
ifes
tyle
.
[In
tere
stin
gly
, a
chie
vin
g a
rela
tive
ly m
od
est
ph
ysic
al
act
ivit
y g
oa
l o
f 4
hr/
week
wa
s a
sso
cia
ted
wit
h a
sig
nif
ica
nt
red
ucti
on
in
in
cid
ent
dia
bet
es
in s
ub
jects
wh
o d
id n
ot
lose
wei
gh
t.
It i
s p
oss
ible
tha
t a
ny
typ
e o
f p
hys
ica
l a
cti
vity
is
ben
efic
ial.
]
Lin
dst
röm
, et
al.,
20
06
Fin
nis
h
Dia
bet
es
Pre
ven
tio
n
Stu
dy
(fo
llo
w-
up
stu
dy
)
RC
T
A
Ø
25
6 i
nte
rven
tio
n a
nd
25
7 c
on
tro
l ar
tici
pan
ts
wh
o w
ere
stil
l fr
ee
of
dia
bete
s af
ter
the
acti
ve
inte
rven
tio
n
per
iod
of
4 y
ear
s
(Tu
om
ileh
to,
et a
l.,
20
01
) w
ere
furt
her
foll
ow
ed u
p f
or
a
med
ian
of
3 y
ear
s, f
or
a to
tal
med
ian
fo
llo
w-
up
of
7 y
ear
s.
Th
e p
rim
ary
ou
tco
mes
of
this
stu
dy
was
inci
den
t
typ
e 2
dia
bete
s.
Du
rin
g t
he t
ota
l fo
llo
w-u
p,
the i
ncid
ence
of
dia
bete
s
was
4.3
an
d 7
.4 p
er
10
0 p
erso
n y
ear
s in
th
e
inte
rven
tio
n a
nd
co
ntr
ol
gro
up
s, r
esp
ecti
vely
(p=
0.0
00
1),
in
dic
ati
ng a
43
% r
edu
cti
on
in
rel
ativ
e
risk
. T
he
risk
red
uct
ion
was
rela
ted
to
su
cce
ss i
n
ach
iev
ing
th
e in
terv
enti
on
go
als
of
wei
gh
t lo
ss,
red
uced
in
tak
e o
f to
tal
satu
rate
d f
at
and
in
crea
sed
ph
ysi
cal
act
ivit
y a
nd
fib
er i
nta
ke.
Ben
efic
ial
life
sty
le c
han
ges
in t
he
inte
rven
tio
n g
rou
ps
wer
e
sust
ain
ed a
fter
the
dis
con
tin
uat
ion
of
the
inte
rven
tio
n,
and
th
e c
orr
esp
on
din
g i
ncid
ence
rate
s
du
rin
g t
he
po
st f
oll
ow
-up
per
iod
were
4.6
an
d 7
.2
(p=
0.4
01
), i
nd
icat
ing
a 3
6%
red
uct
ion
in
rel
ati
ve
risk
.
Th
e au
tho
rs c
on
clu
de
that
th
e re
sult
s fr
om
th
e
exte
nd
ed f
oll
ow
-up
of
the F
inn
ish
Dia
bete
s
Pre
ven
tio
n S
tud
y s
ho
w t
hat
th
e ef
fect
of
life
sty
le
inte
rven
tio
n o
n d
iab
etes
ris
k d
oes
no
t d
isap
pear
afte
r ac
tiv
ity
lif
esty
le c
ou
nse
lin
g i
s st
op
ped
.
Th
e au
tho
rs a
ckn
ow
led
ge s
om
e li
mit
atio
ns
to t
his
stu
dy
. F
irst
, th
e an
aly
ses
rela
ted
to
th
e p
ost
-
inte
rven
tio
n p
erio
d w
ere
no
t p
art
of
the o
rig
inal
pro
toco
l, a
nd
po
st-h
oc r
esu
lts
sho
uld
be
inte
rpre
ted
wit
h c
auti
on
as
the
foll
ow
-up
was
no
t
con
sid
ered
in
th
e o
rig
inal
sam
ple
siz
e c
alcu
lati
on
.
Sec
on
d,
the
low
dro
p-o
ut
rate
su
gg
ests
a h
igh
ly
hea
lth
co
nsc
iou
s p
op
ula
tio
n, p
rob
ably
mo
re s
o
than
th
e g
ener
al p
op
ula
tio
n.
Conclusion Grading Worksheet A – Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Annotation #4 (Prediabetes) Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
77
Au
tho
r/Y
ear
D
esig
n
Ty
pe
Cla
ss
Qu
al-
ity
+,–
,ø
Po
pu
lati
on
Stu
die
d/S
amp
le
Siz
e
Pri
mar
y O
utc
om
e M
eas
ure
(s)/
Res
ult
s (e
.g.,
p-
val
ue,
con
fid
ence
inte
rval
, re
lati
ve r
isk
, o
dd
s
rati
o,
lik
elih
oo
d r
atio
, n
um
ber
nee
ded
to
tre
at)
Au
tho
rs' C
on
clu
sio
ns/
Wo
rk G
rou
p's
Co
mm
ents
(it
ali
cize
d)
Li,
et
al.,
20
08
Ch
ina
Da
Qin
g
Dia
bete
s
Pre
ven
tio
n
Stu
dy
RC
T
A
- 5
77
ad
ult
s w
ith
imp
air
ed g
luco
se
tole
ran
ce
fro
m 3
3
clin
ics
in C
hin
a
wer
e ra
nd
om
ly
assi
gn
ed t
o e
ith
er a
con
tro
l g
rou
p o
r o
ne
of
3 l
ifes
tyle
inte
rven
tio
n g
rou
ps
(die
t, e
xer
cis
e o
r
die
t p
lus
exer
cise
).
Th
e g
oal
of
the d
iet
inte
rven
tio
n w
as
to
incr
eas
e f
ruit
an
d
veg
etab
le i
nta
ke
and
low
er a
lco
ho
l an
d
sug
ar i
nta
ke.
Th
e
go
al o
f th
e e
xer
cise
inte
rven
tio
n w
as
to
was
to
in
creas
e
leis
ure
tim
e p
hy
sica
l
acti
vit
y.
Th
e in
terv
enti
on
was
co
nd
uct
ed f
or
6
yea
rs w
ith
lon
git
ud
inal
fo
llo
w-
up
fo
r 2
0 y
ears
.
Th
e p
rim
ary
ou
tco
mes
of
this
stu
dy
wer
e
inci
den
t d
iab
etes
, C
VD
in
cid
ence
and
mo
rtali
ty,
and
all
-cau
se m
ort
alit
y i
n t
he
inte
rven
tio
n g
rou
ps
com
bin
ed a
nd
th
e co
ntr
ol
gro
up
.
Co
mp
ared
to
par
tici
pan
ts i
n t
he c
on
tro
l g
rou
p,
tho
se i
n t
he
inte
rven
tio
n g
rou
ps
com
bin
ed h
ad
a 5
1%
lo
wer
in
cid
ence
of
dia
bete
s (H
aza
rd
rati
o 0
.49
[9
5%
CI
0.3
3-0
.73
]) d
uri
ng
th
e 6
-
yea
r in
terv
enti
on
per
iod
an
d 4
2%
lo
wer
(0
.57
,
[0.4
1-0
.81
]) o
ver
th
e 2
0-y
ear
fo
llo
w-u
p p
erio
d
afte
r co
ntr
oll
ing
fo
r ag
e an
d c
lin
ic c
ente
r.
Th
ere w
as n
o s
ign
ific
ant
dif
fere
nce
bet
wee
n
inte
rven
tio
n a
nd
co
ntr
ol
gro
up
s w
ith
reg
ard
to
CV
D e
ven
ts o
r m
ort
alit
y,
or
all-
cau
se m
ort
alit
y
(bu
t w
ere n
ot
po
wer
ed t
o d
etec
t su
ch
dif
fere
nces
).
Res
ult
s fo
r ea
ch i
nte
rven
tio
n a
rm (
die
t alo
ne,
exer
cis
e a
lon
e, d
iet
plu
s ex
erci
se)
wer
e n
ot
pre
sen
ted
.
Th
e au
tho
rs c
on
clu
de
that
th
e re
du
ctio
n i
n
dia
bete
s in
cid
ence
ob
serv
ed d
uri
ng
th
e 6-
yea
r in
terv
enti
on
per
sist
ed f
or
two
dec
ades
.
Th
e au
tho
rs c
ite g
rou
p-b
ased
lif
esty
le
inte
rven
tio
ns
of
6 y
ears
as
pre
ven
tiv
e o
f
dia
bete
s.
Lim
itati
on
s o
f th
is s
tud
y i
ncl
ud
e th
e p
assi
ve
ascer
tain
men
t o
f o
utc
om
es
du
rin
g t
he
po
st-
inte
rven
tio
n p
erio
d. T
his
may
ex
pla
in t
he
ob
serv
ed l
ow
er r
ate
of
incid
ent
dia
bet
es.
Ho
wev
er,
this
bia
s w
as n
ot
syst
emat
ic a
nd
lik
ely
aff
ect
ed b
oth
co
ntr
ol
and
tre
atm
ent
gro
up
s si
mil
arly
.
[Th
ere i
s n
o d
eta
iled
des
crip
tio
n o
f th
e
inte
rven
tio
n –
ho
w i
t w
as
deli
vere
d,
wh
at
wa
s in
clu
ded
. B
eca
use
th
e a
uth
ors
nei
ther
pre
sen
t n
or
dis
cuss
fin
din
gs
for
the
dif
fere
nt
trea
tmen
t a
rms,
it
is i
mp
oss
ible
to
asc
ert
ain
wh
ich
co
mp
on
ents
of
the
life
style
inte
rven
tio
ns
wer
e m
ost
im
po
rta
nt.
Ad
dit
ion
all
y, a
s re
ad
ers,
we
are
un
ab
le t
o
det
erm
ine
wh
at
effe
ct
the
gro
up
dyn
am
ic
mig
ht
ha
ve
ha
d o
n t
he l
ifes
tyle
inte
rven
tio
ns.
]
Conclusion Grading Worksheet A – Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Annotation #4 (Prediabetes) Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
78
Au
tho
r/Y
ear
D
esig
n
Ty
pe
Cla
ss
Qu
al-
ity
+,–
,ø
Po
pu
lati
on
Stu
die
d/S
amp
le
Siz
e
Pri
mar
y O
utc
om
e M
eas
ure
(s)/
Res
ult
s (e
.g.,
p-
val
ue,
con
fid
ence
inte
rval
, re
lati
ve r
isk
, o
dd
s
rati
o,
lik
elih
oo
d r
atio
, n
um
ber
nee
ded
to
tre
at)
Au
tho
rs' C
on
clu
sio
ns/
Wo
rk G
rou
p's
Co
mm
ents
(it
ali
cize
d)
Th
e D
iab
etes
Pre
ven
tio
n
Pro
gra
m
Res
earc
h
Gro
up
(DP
P),
20
05
RC
T
A
Ø
Par
ticip
ants
wer
e
ran
do
mly
ass
ign
ed
to m
etfo
rmin
(n=
58
7),
tro
gli
tazo
ne
(n=
58
5),
do
ub
le
pla
ceb
o (
n=
58
2),
or
inte
nsi
ve l
ifest
yle
inte
rven
tio
n
(n=
58
9).
Th
e p
rim
ary
en
d p
oin
t o
f th
is s
tud
y w
as d
ela
y
or
pre
ven
tio
n o
f ty
pe
2 d
iab
ete
s w
ith
trig
lita
zon
e co
mp
ared
to
oth
er t
reatm
ents
.
Beca
use
of
con
cern
s o
f li
ver
to
xic
ity
, th
e
tro
gli
tazo
ne
arm
was
dis
con
tin
ued
bef
ore
th
e
stu
dy
’s e
nd
. D
uri
ng
th
e m
ean
0.9
year
s o
f
tro
gli
tazo
ne
treat
men
t, t
he d
iab
ete
s in
cid
ence
rate
was
3 c
ases
/10
0,0
00
per
son-y
ears
,
com
par
ed w
ith
12
, 6
.7,
and
5.1
cas
es/1
00
,00
0
per
son
-yea
rs i
n t
he
pla
ceb
o,
met
form
in a
nd
life
sty
le i
nte
rven
tio
n g
rou
ps
(p<
0.0
00
1
tro
gli
tazo
ne
vs.
pla
ceb
o,
p=
0.0
2 t
rig
lita
zon
e
vs.
met
form
in,
p=
0.1
8 t
rog
lita
zon
e v
s.
life
sty
le).
Th
e au
tho
rs b
elie
ve
the
trig
lita
zon
e ef
fect
was
in
par
t d
ue t
o i
mp
rov
ed i
nsu
lin
sen
siti
vit
y w
ith
main
ten
ance
of
insu
lin
secr
etio
n.
Du
rin
g 3
yea
rs a
fter
tri
gli
tazo
ne
wit
hd
raw
al,
the d
iab
etes
in
cid
ence
was
nea
rly
id
enti
cal
to p
lace
bo
gro
up
.
Th
eref
ore
, th
e au
tho
rs c
on
lud
e t
hat
trig
lita
zon
e m
ark
edly
red
uced
th
e in
cid
ence
of
dia
bete
s d
uri
ng
tre
atm
ent,
bu
t th
is a
ctio
n
did
no
t p
ersi
st b
eyo
nd
th
e l
imit
ed p
erio
d o
f
use
.
Th
ere w
as i
nsu
ffic
ien
t d
ata
(o
nly
10
cas
es o
f
dia
bete
s d
uri
ng
33
0 p
erso
n-y
ear
s o
f fo
llo
w-
up
fo
r tr
og
lita
zon
e ar
m)
to e
xam
ine a
ny
effe
cts
acco
rdin
g t
o a
ge,
eth
nic
ity
, B
MI.
Ho
wev
er,
it a
pp
ears
th
at t
rog
lita
zon
e
trea
tmen
t w
as
the
mo
st e
ffecti
ve o
f all
trea
tmen
t ar
ms.
Dia
bete
s
Pre
ven
tio
n
Pro
gra
m
Res
earc
h
Gro
up
, 2
00
2
DP
P
RC
T
A
+
3,2
34
no
nd
iab
etic
per
son
s w
ith
elev
ated
fas
tin
g a
nd
po
st-l
oad
pla
sma
glu
cose
wer
e
ran
do
miz
ed t
o
pla
ceb
o,
metf
orm
in
or
life
sty
le t
her
apy
.
Th
e p
rim
ary
ou
tco
me
of
incid
ent
dia
bete
s.
Th
e av
erag
e fo
llo
w-u
p t
ime
was
2.8
year
s.
Th
e in
cid
ence
of
dia
bet
es w
as 1
1, 7
.8 a
nd
4.8
case
s p
er 1
00
per
son-y
ear
s in
th
e p
lace
bo
,
met
form
in a
nd
lif
est
yle
gro
up
s, r
esp
ecti
vel
y.
Co
mp
ared
to
pla
ceb
o,
the
life
sty
le i
nte
rven
tio
n
red
uce
d t
he i
ncid
ence
of
dia
bete
s b
y 5
8%
(95
% C
I 4
8 t
o 6
6%
), a
nd
th
e m
etf
orm
in
inte
rven
tio
n r
edu
ced
th
e in
cid
ence
of
dia
bet
es
by
31
% (
95
% C
I 1
7 t
o 4
3%
).
In t
his
ran
do
miz
ed t
rial,
bo
th m
etf
orm
in a
nd
life
sty
le c
han
ges
red
uce
d t
he i
nci
den
ce o
f
dia
bete
s co
mp
ared
to
pla
ceb
o i
n p
erso
ns
at
hig
h r
isk
. H
ow
ever
, th
e l
ifes
tyle
in
terv
enti
on
was
sig
nif
ican
tly
mo
re e
ffec
tiv
e th
an
met
form
in.
[In
tere
stin
gly
, th
e l
ifes
tyle
gro
up
lo
st m
ore
weig
ht
com
pa
red
to
th
e m
etf
orm
in a
nd
pla
ceb
o g
rou
ps.
H
ow
eve
r, t
he s
tud
y w
as
no
t
des
ign
ed t
o t
est
th
e r
ela
tive
co
ntr
ibu
tio
ns
of
die
tary
ch
an
ges
, in
crea
sed
ph
ysi
cal
act
ivit
y
an
d w
eig
ht
loss
.]
Conclusion Grading Worksheet A – Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Annotation #4 (Prediabetes) Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
79
Conclusion Grading Worksheet B – Annotation #11 (A1c)
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Thirteenth Edition/May 2009
Work
Gro
up
’s C
on
clu
sion
:
A1c
targ
et i
n t
ype
2 d
iabet
es i
s ai
med
at
reduci
ng m
icro
vas
cula
r co
mpli
cati
ons
whil
e not
incr
easi
ng r
isk o
f m
orb
idit
y o
r m
ort
alit
y.
• A
ll p
atie
nts
wit
h t
ype
2 d
iabet
es s
hould
aim
to a
chie
ve
an A
1c
less
than
8%
. T
his
wil
l re
duce
mic
rovas
ucl
ar d
isea
se a
nd n
ot
incr
ease
ris
k s
ubst
anti
ally
.
• M
ost
(m
any)
pat
ients
wit
h t
ype
2 d
iabet
es m
ay d
eriv
e ad
dit
ional
ben
efit
in r
educt
ion o
f m
icro
vas
ucl
ar d
isea
se b
y r
each
ing a
tar
get
A1c
less
than
7%
and n
ot
incr
ease
ris
ks
as l
ong a
s th
e ta
rget
is
not
A1c
less
than
6%
.
Con
clu
sio
n G
rad
e:
II
Au
tho
r/
Year
Desi
gn
Ty
pe
Cla
ss
Qu
al-
ity
(+,–
,ø)
Po
pu
lati
on
Stu
die
d/S
am
ple
Siz
e P
rim
ary
Ou
tco
me M
easu
re(s
)/R
esu
lts
(e.g
., p
-valu
e, c
on
fiden
ce
inte
rval,
rela
tiv
e r
isk
, od
ds
rati
o,
likeli
ho
od
rati
o,
nu
mb
er n
eed
ed t
o t
reat)
Au
tho
rs' C
on
clu
sio
ns/
Wo
rk G
rou
p's
Co
mm
en
ts
(ita
lici
zed)
Gaed
e
et
al.
,
20
08
Ran
-
do
m-
ized
co
nt-
roll
ed
tria
l
(RC
T)
A
+
-- F
oll
ow
-up
stu
dy
aft
er
co
mp
leti
on
of
inte
rven
tio
nal
stu
dy
(S
ten
o-2
Stu
dy
).
-- 1
60
pati
en
ts (
mean
ag
e 5
5.1
years
at
base
lin
e)
wit
h t
yp
e 2
dia
bete
s an
d
mic
roalb
inu
ria r
an
do
mly
ass
ign
ed t
o
inte
nsi
ve t
hera
py
gro
up
([I
G],
targ
et
Hb
A1
c <
6.5
%, fa
stin
g c
ho
lest
ero
l <
17
5 m
g/d
l, f
ast
ing
tri
gly
ceri
des
< 1
50
mg
/dl,
blo
od
pre
ssu
re <
13
0/8
0 m
m
Hg
, an
d f
ocu
sed
beh
avio
r
mo
dif
icati
on
) an
d a
con
ven
tion
al
(CG
) m
ult
ifacto
rial
treatm
en
t g
rou
p.
-- A
ll p
ati
en
ts r
eceiv
ed
ren
in-
an
gio
ten
sin
sy
stem
blo
ck
ers
and
lo
w-
do
se a
spir
in.
-- 3
pati
en
ts w
ith
dre
w, 2
7 d
ied
du
rin
g
inte
rven
tio
nal
stu
dy
, le
av
ing
13
0 p
ts
for
start
of
foll
ow
-up
stu
dy
.
-- 3
7 d
ied
du
rin
g f
oll
ow
-up
peri
od
,
leav
ing
93
sub
jects
co
mp
leti
ng
foll
ow
-up
stu
dy
.
-- P
rim
ary
en
d p
oin
t in
fo
llo
w-u
p
tria
l w
as
tim
e t
o d
eath
(an
y c
au
se),
wit
h s
eco
nd
ary
en
d p
oin
ts b
ein
g
death
fro
m c
ard
iovasc
ula
r (C
V)
cau
ses,
an
d c
om
po
site
of
CV
dis
ease
ev
en
ts.
-- T
ota
l m
ean
fo
llo
w-u
p t
ime 1
3.3
years
(7
.8 y
ears
in
in
terv
en
tio
nal
stu
dy
an
d 5
.5 y
ears
fo
r o
bse
rvati
on
al
foll
ow
-up
).
-- U
sed
in
ten
tio
n-t
o-t
reat
pri
ncip
le
-- B
oth
gro
up
s si
mil
ar
at
base
lin
e
-- M
easu
red
resu
lts
were
as
foll
ow
s:
BP
(m
ean
sy
sto
lic/d
iast
oli
c m
m H
g):
I
G:
en
d o
f in
terv
en
tio
n:
13
1/7
3;
end
of
foll
ow
-up
: 1
40
/74
C
G:
en
d o
f in
terv
en
tio
n:
14
6/7
8;
en
d o
f fo
llo
w-u
p:
146
/73
H
bA
1c (
mean
%):
IG
: en
d o
f in
terv
en
tio
n:
7.9
;
en
d o
f fo
llo
w-u
p:
7.7
C
G:
en
d o
f in
terv
en
tio
n:
9.0
; en
d o
f fo
llo
w-u
p:
8.0
Fast
ing
to
tal
ch
ole
stero
l (m
ean
mg
/dl)
:
I
G:
en
d o
f in
terv
en
tio
n:
15
9;
en
d o
f fo
llo
w-u
p:
14
7
C
G:
en
d o
f in
terv
en
tio
n:
21
6;
en
d o
f fo
llo
w-u
p:
15
5
Fast
ing
tri
gly
ceri
des
(med
ian
mg
/dl)
:
I
G:
en
d o
f in
terv
enti
on
: 1
15
; en
d o
f fo
llo
w-u
p:
99
C
G:
en
d o
f in
terv
en
tio
n:
15
9;
en
d o
f fo
llo
w-u
p:
14
8
-- D
uri
ng
en
tire
13
.3 y
ears
of
foll
ow
-up
, 2
4 I
G p
ts d
ied
an
d 4
0 C
G p
ts d
ied
(hazard
rati
o [
HR
] 0
.54
; p
=0
.02
)
-- 9
IG
pts
die
d o
f C
V c
au
ses
an
d 1
9 C
G p
ts d
ied
of
CV
cau
ses
(HR
0.4
3;
p=
0.0
4)
-- T
ota
l C
V e
ven
ts:
51
in
IG
, 1
58
in
CG
(H
R 0
.41
; p
<0
.00
1);
n
o e
vid
en
ce o
f
ch
an
ge i
n H
R o
ccu
rred
betw
een
en
d o
f in
terv
en
tion
an
d f
inal
ob
serv
ati
on
al
foll
ow
-up
-- D
iab
eti
c n
ep
hro
path
y d
ev
elo
ped
in
20
IG
pts
an
d 3
7 C
G p
ts (
rela
tiv
e r
isk
[RR
] 0
.44
; p
=0
.00
4)
-- P
rog
ress
ion
of
dia
beti
c r
eti
no
path
y o
ccu
rred
in
41
IG
pts
an
d 5
4 C
G p
ts (
RR
0.5
7;
p=
0.0
1)
-- A
uto
no
mic
neu
rop
ath
y p
rog
ress
ed
in
39
IG
pts
an
d i
n 5
2 C
G p
ts (
RR
0.5
3;
p=
0.0
04
); p
eri
ph
era
l n
eu
rop
ath
y p
rog
ress
ion
was
no
t si
gn
ific
an
tly
dif
fere
nt
betw
een
th
e t
wo
gro
up
s
-- D
iffe
ren
ces
in h
yp
og
lycem
ic e
pis
od
es
were
no
t si
gn
ific
an
t b
etw
een
th
e t
wo
gro
up
s (p
=0
.15
tre
nd
fo
r m
ore
ep
iso
des
in I
G)
- -
Du
rin
g e
nti
re f
oll
ow
-up
peri
od
, d
eath
rate
in
CG
was
50
%;
au
tho
rs s
tate
th
is
un
ders
core
s p
oo
r p
rog
no
sis
wit
ho
ut
inte
nsi
ve t
reatm
en
t.
-- S
tud
y w
as
no
t d
esi
gn
ed
to
sho
w w
hic
h e
lem
en
ts o
f in
ten
siv
e
treatm
en
t co
ntr
ibu
ted
mo
st t
o t
he
CV
ris
k r
ed
ucti
on
.
-- S
ign
ific
an
t d
iffe
ren
ces
in r
isk
facto
rs b
etw
een
th
e t
wo
gro
ups
betw
een
th
e i
nte
rven
tion
ph
ase
an
d f
inal
foll
ow
-up
ten
ded
to
co
nv
erg
e (
all
pts
were
off
ere
d
inte
nsi
ve t
reatm
en
t aft
er
inte
rven
tio
n s
tud
y e
nd
ed
), b
ut
tim
e t
o f
irst
CV
ev
en
ts c
on
tin
ued
to d
iverg
e;
au
tho
rs s
tate
d t
hat
this
pro
vid
ed e
vid
ence t
hat
earl
y
inte
rven
tio
n (
inte
nsi
ve t
reatm
en
t)
co
nti
nu
es t
o s
ho
w b
en
efi
t lo
ng-
term
.
[No
te t
ha
t a
lth
ou
gh
ori
gin
al
Hb
A1
c g
oa
l fo
r in
ten
sive
trea
tmen
t w
as
< 6
.5%
yet
avg
., a
t
en
d o
f fo
llo
w-u
p w
as
7.7
%,
un
ders
cori
ng
th
e d
iffi
cu
lty i
n
att
ain
ing
ag
gre
ssiv
e H
bA
1c
go
als
.]
Upd
ated
Thi
rteen
th E
ditio
n, M
ay 2
009.
Institute for Clinical Systems Improvement
www.icsi.org
80
Conclusion Grading Worksheet B – Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Annotation #11 (A1c) Thirteenth Edition/May 2009
Au
tho
r/Y
ear
D
esig
n
Ty
pe
Cla
ss
Qu
alit
y
(+,–
,ø)
Po
pu
lati
on
Stu
die
d/S
am
ple
Siz
e
Pri
mar
y O
utc
om
e M
eas
ure
(s)/
Res
ult
s
(e.g
., p
-val
ue,
co
nfi
den
ce i
nte
rval,
rela
tiv
e ri
sk,
od
ds
rati
o, li
keli
ho
od
rati
o, n
um
ber
need
ed t
o t
reat)
Au
tho
rs' C
on
clu
sio
ns/
Wo
rk G
rou
p's
Co
mm
ents
(it
ali
cize
d)
Sel
vin
et
al.
,
20
04
Met
a-
anal
ysi
s
M
ø
-- M
eta
-an
aly
sis
of
pro
spec
tiv
e
ob
serv
atio
nal
(co
ho
rt)
stu
die
s
on
th
e as
socia
tio
n b
etw
een
Hb
A1
c le
vels
an
d i
nci
den
t
card
iov
asc
ula
r d
isease
,
incl
ud
ing
fata
l an
d n
on
fata
l
my
oca
rdia
l in
farc
tio
n,
ang
ina
and
isc
hem
ic h
eart
dis
ease
,
cere
bro
vas
cula
r d
iseas
e (f
atal
and
no
nfa
tal
stro
ke),
per
iph
era
l
arte
rial
dis
eas
e, a
nd
a c
om
bin
ed
ou
tco
me
that
incl
ud
es
coro
nary
dis
ease
an
d s
tro
ke
-- T
yp
e 2
dia
bet
es
analy
zed
sep
arat
ely
fro
m t
yp
e 1
-- R
and
om
eff
ect
s m
od
el
use
d
to p
oo
l th
e r
esu
lts
-- T
ota
l o
f 1
7 s
tud
y r
epo
rts
incl
ud
ed,
rep
rese
nti
ng
13
un
iqu
e sa
mp
les
(10
gro
up
s o
f
typ
e 2
dia
beti
cs –
in
clu
ded
UK
PD
S s
tud
ies;
to
tal
n=
74
35
for
10
stu
die
s)
-- A
dju
stm
ent
for
po
ssib
le
con
fou
nd
ing
fact
ors
var
ied
con
sid
erab
ly –
ab
ou
t 5
0%
of
stu
die
s u
sed
au
tom
atic
ste
pw
ise
met
ho
ds
for
det
erm
inin
g
mu
ltiv
aria
te m
od
els;
on
ly 3
stu
die
s si
mu
ltan
eou
sly
ad
just
ed
for
kn
ow
n c
ard
iov
ascu
lar
risk
fact
ors
su
ch a
s ag
e, g
end
er,
lip
id l
evel
s, b
loo
d p
ress
ure
an
d
smo
kin
g
-- P
oo
led
rel
ativ
e r
isk
fo
r to
tal
card
iov
asc
ula
r d
isease
(1
0 i
nd
epen
den
t
dat
ase
ts o
f co
ron
ary
dis
ease
alo
ne, st
rok
e
alo
ne,
and
co
mb
ined
str
ok
e a
nd
co
ron
ary
dis
ease
in
ty
pe
2 d
iab
eti
cs)
was
1.1
8 (
95
%
CI,
1.1
0 t
o 1
.26
) fo
r eac
h 1
% i
ncr
ease
in
Hb
A1
c.
-- F
or
the
5 i
nd
epen
den
t st
ud
ies
of
fata
l
and
no
nfa
tal
coro
nar
y d
isea
se r
isk
, th
e
po
ole
d r
elat
ive
risk
was
1.1
5 (
95
% C
I,
1.0
6 t
o 1
.20
), w
ith
th
e r
elat
ive
risk
fo
r fa
tal
coro
nar
y d
iseas
e b
ein
g 1
.16
(9
5%
CI,
1.0
7
to 1
.26
) fo
r ea
ch 1
% i
ncre
ase
in
Hb
A1
c.
-- F
or
the
3 i
nd
epen
den
t st
ud
ies
that
incl
ud
ed s
tro
ke
risk
ass
essm
ent,
th
e p
oo
led
rela
tiv
e r
isk
was
1.1
7 (
95
% C
I, 1
.09
to
1.2
5)
for
each
1%
in
creas
e in
Hb
A1
c.
-- F
or
the
3 i
nd
epen
den
t st
ud
ies
that
incl
ud
ed p
erip
her
al a
rter
ial
dis
ease
ris
k
asse
ssm
ent,
th
e p
oo
led
rela
tiv
e r
isk
was
1.2
8 (
95
% C
I, 1
.18
to
1.3
9).
-- S
mal
l n
um
ber
of
stu
die
s li
mit
ed t
he
abil
ity
to
asc
ert
ain
im
po
rtan
t so
urc
es
of
het
ero
gen
eit
y a
mo
ng
th
e st
ud
ies.
-- D
ata
anal
ysi
s su
pp
ort
s m
od
era
te i
ncr
eas
e in
card
iov
asc
ula
r ri
sk w
ith
in
cre
asi
ng
Hb
A1
c
lev
els
in
ty
pe
1 a
nd
ty
pe 2
dia
beti
cs.
-- I
n s
om
e st
ud
ies,
ass
oci
atio
n o
f
card
iov
asc
ula
r d
isease
wit
h i
ncre
asi
ng
Hb
A1
c
lev
els
was
in
dep
end
ent
of
oth
er
kn
ow
n
card
iov
asc
ula
r ri
sk f
acto
rs.
-- L
inear
rel
atio
nsh
ip o
f car
dio
vas
cula
r ri
sk t
o
Hb
A1
c le
vels
ass
um
ed i
n s
tud
ies,
bu
t n
ot
clea
r
if t
his
is
act
uall
y t
he
cas
e.
-- F
utu
re R
CT
s n
eed
ed t
hat
sp
ecif
ical
ly a
nsw
er
the
qu
est
ion
of
the
rela
tio
nsh
ip o
f g
lycem
ic
con
tro
l (s
peci
fica
lly
Hb
A1
c le
vels
) to
card
iov
asc
ula
r d
isease
an
d d
isea
se r
isk
.
Institute for Clinical Systems Improvement
www.icsi.org
81
Au
tho
r/Y
ear
D
esig
n
Ty
pe
Cla
ss
Qu
alit
y
(+,–
,ø)
Po
pu
lati
on
Stu
die
d/S
am
ple
Siz
e
Pri
mar
y O
utc
om
e M
eas
ure
(s)/
Res
ult
s
(e.g
., p
-val
ue,
co
nfi
den
ce i
nte
rval,
rela
tiv
e ri
sk,
od
ds
rati
o, li
keli
ho
od
rati
o, n
um
ber
need
ed t
o t
reat)
Au
tho
rs' C
on
clu
sio
ns/
Wo
rk G
rou
p's
Co
mm
ents
(it
ali
cize
d)
Ab
rair
a, e
t al.
,
19
97
RC
T
A
_
-- F
easi
bil
ity
stu
dy
co
mp
arin
g
stan
dar
d v
s. i
nte
nsi
ve
insu
lin
ther
apy
-- 1
53
men
wit
h n
on-i
nsu
lin
dep
end
ent
dia
bet
es (
NID
DM
)
wer
e en
roll
ed,
aver
age a
ge
60
yea
rs,
hav
ing
dia
bete
s fo
r an
avera
ge
of
7.8
year
s, w
ith
po
or
gly
cem
ic c
on
tro
l (m
ean
bas
elin
e
Hb
A1
c >
9%
)
-- A
bo
ve p
ts r
and
om
ized
to
a
stan
dar
d i
nsu
lin
tre
atm
ent
gro
up
(SG
, n
=7
8, 1
mo
rnin
g i
nsu
lin
inje
ctio
n p
er d
ay)
and
an
inte
nsi
ve t
reat
men
t g
rou
p (
IG,
n=
75
, st
epp
ed p
lan
)
-- A
ssess
ed c
ard
iov
asc
ula
r
even
ts (
new
my
oca
rdia
l
infa
rcti
on
s, c
on
ges
tiv
e h
ear
t
fail
ure
, st
rok
e,
amp
uta
tio
ns,
card
iov
asc
ula
r m
ort
ali
ty,
ang
ina/
coro
nary
dis
ease
,
ang
iop
last
y/C
AB
G, T
IAs,
per
iph
era
l v
ascu
lar
dis
eas
e
-- 3
8%
of
pts
had
kn
ow
n p
re-
exis
tin
g C
V d
iseas
e
-- S
amp
le s
ize a
nd
du
rati
on o
f
feas
ibil
ity
tri
al
no
t p
ow
ered
to
dem
on
stra
te a
tre
atm
ent
eff
ect
on
CV
dis
ease
, b
ut
ob
ject
ive
was
to
ass
ess
freq
uen
cy a
nd
typ
es o
f C
V e
nd
po
ints
in
pre
para
tio
n f
or
a lo
ng
er-t
erm
tria
l
-- I
G h
ad m
ean
Hb
A1
c o
f 7
.1%
, 2
.1%
low
er t
han
SG
pts
an
d m
ain
tain
ed th
is
dif
fere
nce
for
the 2
7 m
on
ths
of
foll
ow
-up
(p<
0.0
01
).
-- M
ild
an
d m
od
era
te h
yp
og
lyce
mic
ev
ents
occ
urr
ed m
ore
fre
qu
entl
y i
n t
he
IG (
16
.5
even
ts p
er p
atie
nt
per
year
vs.
1.5
ev
ents
per
pat
ien
t p
er
year
, p
<0
.00
1);
sev
ere
hy
po
gly
cem
ic e
ven
ts w
ere
rare
an
d n
ot
sig
nif
ican
tly
dif
fere
nt
bet
wee
n t
he g
rou
ps.
-- G
rou
ps
wer
e n
ot
sig
nif
ican
tly
dif
fere
nt
in b
ase
lin
e B
MI,
ser
um
TG
lev
els
, to
tal
cho
lest
ero
l/L
DL
/HD
L l
evels
, b
loo
d
pre
ssu
re a
nd
cig
are
tte
smo
kin
g (
bu
t all
4
pip
e sm
ok
ers
wer
e ra
nd
om
ized
in
to t
he I
G
arm
).
-- 6
1 C
V e
ven
ts o
ccu
rred
du
rin
g t
he s
tud
y;
33
occ
urr
ed i
n 2
4 p
ts i
n t
he I
G;
26
ev
ents
occ
urr
ed i
n 1
6 p
ts i
n t
he S
G (
p=
0.1
0);
10
pts
die
d d
uri
ng
th
e st
ud
y (
5 i
n e
ach
gro
up
,
wit
h 3
in
each
gro
up
bei
ng
CV
rel
ated
).
-- M
ult
ivari
ate
anal
ysi
s o
n t
imes
to
CV
even
t sh
ow
ed t
hat
the
on
ly s
ign
ific
ant
pre
dic
tor
vari
able
was
a p
rev
iou
s h
isto
ry
of
CV
dis
ease
(p
=0
.04
); lo
wer
Hb
A1
c
lev
el
was
a b
ord
erl
ine
corr
ela
te w
hen
sub
stit
ute
d f
or
the
trea
tmen
t as
sig
nm
ent
var
iab
le.
-- W
hen
sil
ent
base
lin
e C
V a
bn
orm
alit
ies
wer
e co
mb
ined
wit
h k
no
wn
pre
vio
us
CV
even
ts a
s th
e d
epen
den
t v
aria
ble
, o
nly
th
e
Hb
A1
c le
vel
(lo
wer
lev
el)
rose
to
sig
nif
ican
ce a
s a
pre
dic
tor
of
new
CV
even
ts (
p=
0.0
5).
-- A
uth
ors
sta
te t
hat
inte
nsi
ve
insu
lin
tre
atm
ent
des
ign
ed t
o l
ow
er
Hb
A1
c l
evel
s can
su
stai
n a
clin
ical
ly s
ign
ific
ant
sep
ara
tio
n i
n H
bA
1c
lev
els
wit
ho
ut
incr
easi
ng
BP
, d
ysl
ipid
emia
,
sev
ere
hy
po
gly
cem
ia,
excess
ive
wei
gh
t g
ain
or
hig
h i
nsu
lin
req
uir
emen
t.
-- S
mal
l sa
mp
le s
ize,
sh
ort
-du
rati
on
stu
dy
no
ted
mo
rtali
ty r
ates
near
ly i
den
tical
bet
ween
gro
up
s.
-- C
V h
isto
ry h
ad a
sig
nif
ican
t eff
ect
on
ris
k o
f
new
ev
ents
.
-- B
ord
erli
ne
tren
d t
ow
ard
mo
re C
V e
ven
ts i
n
pat
ien
ts w
ith
lo
wer
Hb
A1
c le
vel
s, b
ut
fin
din
g
nee
ds
cau
tio
us
inte
rpre
tati
on
du
e to
th
e s
ho
rt
len
gth
of
the
stu
dy
; in
suli
n d
ose
its
elf
did
no
t
app
ear
to b
e a
sig
nif
ican
t p
red
icto
r o
f ev
ents
.
-- N
eed
fu
rth
er
pro
spect
ive
stu
dy
befo
re
reco
mm
end
atio
ns
for
NID
DM
tre
atm
ent
can
be
mad
e.
-- A
uth
ors
sta
te t
hat
ben
efit
of
Hb
A1
c le
vels
bel
ow
8%
may
be
rela
tiv
ely
sm
all
.
Conclusion Grading Worksheet B – Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Annotation #11 (A1c) Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
82
Au
tho
r/
Yea
r
Des
ign
Ty
pe
Cla
ss
Qu
al
-ity
(+,–
,ø)
Po
pu
lati
on
Stu
die
d/S
am
ple
Siz
e
Pri
mar
y O
utc
om
e M
eas
ure
(s)/
Res
ult
s (e
.g.,
p-v
alu
e, c
on
fid
ence
inte
rval
, re
lati
ve
risk
,
od
ds
rati
o,
lik
elih
oo
d r
ati
o,
nu
mb
er n
eed
ed
to t
reat)
Au
tho
rs' C
on
clu
sio
ns/
Wo
rk G
rou
p's
Co
mm
ents
(it
ali
cize
d)
Ger
stei
n,
et a
l.,
20
08
(T
he
AC
CO
RD
Wo
rk-
gro
up
)
RC
T
A
+
-10
,25
1 p
atie
nts
wit
h a
med
ian
bas
elin
e A
1c
of
8.1
% w
ho
had
hea
rt d
isea
se o
r ev
iden
ce
of
ath
ero
scle
rosi
s, a
lbu
nie
ria,
hy
per
ten
sio
n,
left
ven
tric
le
hy
per
tro
ph
y o
r tw
o
card
iov
asc
ula
r d
isease
ris
k
fact
ors
- P
art
icip
ants
wer
e ra
nd
om
ized
to r
ecei
ve
eith
er i
nte
nsi
ve
ther
apy
tar
get
ing
red
uct
ion
of
A1
c to
bel
ow
6 o
r st
and
ard
ther
apy
tar
get
ing
A1
c b
etw
een
7.0
-7.9
-In
clu
sio
n/e
xclu
sio
n c
rite
ria
clea
rly
def
ined
-Use
d i
nte
nti
on
to
tre
at
analy
sis
- P
rim
ary
ou
tco
mes
meas
ure
d w
as a
co
mp
osi
te
of
no
n-f
ata
l m
yo
card
ial
infa
rcti
on
, n
on-f
atal
stro
ke,
an
d d
eat
h f
rom
car
dio
vas
cula
r d
iseas
e.
- O
ver
3.5
yea
rs o
f fo
llo
w-u
p,
the
pri
mar
y
ou
tco
me
occu
rred
in
35
2 i
n t
he i
nte
nsi
ve t
hera
py
gro
up
an
d 3
71
in
th
e s
tan
dard
th
erap
y g
rou
p (
RR
0.9
0, 9
5%
CI
0.7
4-1
.04
, p
=0
.16
).
- T
here
were
25
7 d
eat
hs
in t
he
inte
nsi
ve
ther
apy
gro
up
co
mp
ared
to
20
3 d
eath
s in
th
e st
and
ard
ther
apy
gro
up
(R
R =
1.2
2, 9
5%
CI
1.0
1-1
.46
,
p=
0.0
4).
- In
ad
dit
ion
, h
yp
og
lyce
mia
req
uir
ing
att
enti
on
and
weig
ht
gain
in
ex
cess
of
10
kg
occu
rred
mo
re
freq
uen
tly
in
th
e in
ten
siv
e th
erap
y g
rou
p.
- C
om
pare
d t
o s
tan
dar
d t
hera
py
, in
ten
siv
e
ther
apy
led
to
in
cre
ase
d m
ort
alit
y a
nd
did
no
t
sig
nif
ican
tly
red
uce
card
iov
asc
ula
r ev
ents
.
- D
iffe
ren
ces
in m
ort
ali
ty e
mer
ged
1-
2 y
ear
s
afte
r ra
nd
om
izati
on
, w
hic
h m
ay i
nd
icat
e th
at
the
po
ten
tial
ben
efit
s o
f in
ten
siv
e th
erap
y d
o
no
t em
erg
e fo
r se
ver
al y
ear
s, d
uri
ng
wh
ich
tim
e
ther
e is
in
cre
ase
d r
isk
of
mo
rtali
ty.
-Th
e st
and
ard
th
era
py
gro
up
had
few
er v
isit
s
and
use
d f
ewer
dru
gs
in f
ewer
com
bin
ati
on
s;
thu
s, t
he
hig
her
rat
e o
f m
ort
ali
ty i
n t
he
inte
nsi
ve t
her
apy
gro
up
may
be
rela
ted
to
th
e
var
iou
s st
rate
gie
s o
f in
ten
siv
e tr
eatm
ent.
Pat
el,
et
al.,
20
08
(AD
V-
AN
CE
tria
l)
RC
T
A
+
-11
,40
0 p
atie
nts
wit
h t
yp
e 2
dia
bete
s w
ho
wer
e d
iag
no
sed
afte
r ag
e 3
0 o
r w
ere
ov
er
55
and
had
a h
isto
ry
mic
rov
ascu
lar
or
macr
ov
asc
ula
r
dis
ease
or
at l
east
on
e
card
iov
asc
ula
r ri
sk f
acto
r
- R
and
om
ized
to
sta
nd
ard
glu
cose
co
ntr
ol
or
inte
nsi
ve
ther
apy
tar
get
ing
<6
.5%
A1
c
- P
rim
ary
ou
tco
mes
wer
e a
com
po
site
of
mic
rov
ascu
lar
even
ts (
new
or
wo
rsen
ing
nep
hro
pat
hy
, n
eed
fo
r re
nal
rep
lacem
ent
thera
py
,
or
deat
h t
o r
enal
dis
ease
) an
d a
co
mp
osi
te o
f
mac
rov
asc
ula
r ev
ents
(n
on-f
ata
l m
yo
card
ial
infa
rcti
on
, n
on
-fata
l st
rok
e, a
nd
card
iov
asc
ula
r
dis
ease
deat
h).
- O
ver
5 y
ears
of
foll
ow
-up
, A
1c
was
lo
wer
in
the
inte
nsi
ve
ther
apy
gro
up
(6
.5%
) co
mp
ared
to
the
stan
dar
d g
luco
se c
on
tro
l g
rou
p (
7.3
%).
- In
ten
siv
e c
on
tro
l re
du
ced
th
e in
cid
ence
of
com
bin
ed m
icro
- an
d m
acro
vasc
ula
r ev
ents
(18
.1%
vs.
20
.0%
wit
h s
tan
dar
d c
on
tro
l, h
azard
rati
o 0
.90
[0
.82
-0.9
8])
.
- A
red
uct
ion
in
mic
rov
ascu
lar
even
ts w
as
ob
serv
ed i
n t
he
inte
nsi
ve
trea
tmen
t g
rou
p (
9.4
%)
com
par
ed t
o t
he
stan
dar
d c
on
tro
l g
rou
p (
10
.9%
)
wit
h a
hazar
d r
ati
on
of
0.8
6 (
0.7
7-0
.97
).
- N
o r
edu
cti
on
in
macr
ov
ascu
lar
even
ts w
as
ob
serv
ed,
(haza
rd r
atio
0.9
4 [
0.8
4-1
.06
]).
- T
he o
bse
rved
10
% r
ela
tiv
e re
du
cti
on
may
be
du
e to
a r
edu
cti
on
in
wo
rsen
ing
nep
hro
pat
hy
.
- In
th
e A
DV
AN
CE
tri
al,
no
su
bg
rou
p o
f
par
ticip
ants
was
iden
tifi
ed t
o h
ave e
vid
ence
of
an a
dv
erse
eff
ect
of
inte
nsi
ve g
luco
se l
ow
erin
g
on
maj
or
vasc
ula
r o
utc
om
es,
in
clu
din
g a
sub
gro
up
wit
h a
n i
nit
ial
med
ian
A1
c
com
par
able
to
th
e A
CC
OR
D s
tud
y p
op
ula
tio
n.
- In
ten
siv
e t
hera
py
sig
nif
ican
tly
red
uce
d t
he
pri
mary
co
mp
osi
te o
utc
om
e o
f m
ajo
r
mac
rov
asc
ula
r o
r m
icro
vasc
ula
r ev
ents
. T
her
e
was
no
sep
ara
te s
ign
ific
ant
red
uct
ion
in
maj
or
mac
rov
asc
ula
r ev
ents
, alt
ho
ug
h t
his
ben
efi
t
cou
ld n
ot
be r
ule
d o
ut.
Conclusion Grading Worksheet B – Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Annotation #11 (A1c) Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
83
Au
tho
r/
Yea
r
Des
ign
Ty
pe
Cla
ss
Qu
al-
ity
(+
,–
,ø)
Po
pu
lati
on
Stu
die
d/S
amp
le
Siz
e
Pri
mar
y O
utc
om
e M
eas
ure
(s)/
Res
ult
s
(e.g
., p
-val
ue,
co
nfi
den
ce i
nte
rval,
rela
tiv
e ri
sk,
od
ds
rati
o, li
keli
ho
od
rati
o, n
um
ber
need
ed t
o t
reat)
Au
tho
rs' C
on
clu
sio
ns/
Wo
rk G
rou
p's
Co
mm
ents
(it
ali
cize
d)
Bre
tzel
,
et a
l.,
20
08
RC
T
A
+
- 5
15
ran
do
mly
assi
gn
ed t
o i
nsu
lin
lisp
ro o
r in
suli
n
gla
rgin
e
- B
asel
ine
A1
c
bet
wee
n 7
.5%
an
d
10
.5%
, B
MI
35
or
less
- P
rim
ary
en
dp
oin
ts w
ere
chan
ges
in
A1
c
and
blo
od
glu
cose
at
44
week
s fo
llo
w-u
p
- C
han
ges
in A
1c i
n t
he g
larg
ine g
rou
p
wer
e 8
.7 t
o 7
.0 a
nd
8.7
to
6.8
in
lis
pro
gro
up
.
- 5
7%
of
pati
ents
in
th
e g
larg
ine g
rou
p
and
69
% i
n t
he
lisp
ro g
rou
p r
eac
hed
A1
c
bel
ow
7%
.
- F
all
in
mean
fas
tin
g b
loo
d g
luco
se w
as
4.3
in
th
e g
larg
ine
gro
up
an
d -
1.8
in
th
e
lisp
ro g
rou
p (
p <
0.0
00
1).
- In
cid
ence
of
hy
peg
lycem
ic e
ven
ts w
as
less
in
th
e g
larg
ine g
rou
p c
om
pare
d t
o
lisp
ro g
rou
p.
- M
ean
weig
ht
gain
s w
ere
3.0
1 i
n t
he
gla
rgin
e g
rou
p a
nd
3.5
4 i
n t
he
lisp
ro
gro
up
.
- T
he t
wo
tre
atm
ents
were
eq
ual
ly e
ffect
ive
in l
ow
erin
g
A1
c.
[No
te t
ha
t th
is s
tud
y p
rob
ab
ly d
oes
no
t h
ave
lo
ng
en
ou
gh
foll
ow
-up
tim
e to
det
ect
an
y a
dver
se e
ven
ts.
In
ad
dit
ion
,
pa
tien
ts r
ecru
ited
fo
r th
is s
tud
y d
id n
ot
ha
ve e
xis
tin
g
card
iova
scu
lar
dis
ease
or
risk
fa
cto
rs a
t b
ase
lin
e, u
nli
ke
AC
CO
RD
an
d A
DV
AN
CE
pa
tien
ts.]
Conclusion Grading Worksheet B – Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Annotation #11 (A1c) Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
84
Au
tho
r/
Yea
r
Des
ign
Ty
pe
Cla
ss
Qu
al-
ity
(+,–
,ø)
Po
pu
lati
on
Stu
die
d/S
amp
le
Siz
e
Pri
mar
y O
utc
om
e M
eas
ure
(s)/
Res
ult
s
(e.g
., p
-val
ue,
co
nfi
den
ce i
nte
rval,
rela
tiv
e ri
sk,
od
ds
rati
o, li
keli
ho
od
rati
o, n
um
ber
need
ed t
o t
reat)
Au
tho
rs' C
on
clu
sio
ns/
Wo
rk G
rou
p's
Co
mm
ents
(it
ali
cize
d)
Ho
lman
,
et a
l.,
20
08
RC
T
[Th
is i
s a
lo
ng
-
term
fo
llo
w-u
p o
f
pa
rtic
ipa
nts
po
st-
inte
rven
tio
n,
du
rin
g w
hic
h t
ime
pa
rtic
ipa
nts
were
no
t in
terv
ened
on
no
r w
ere
th
ey
enco
ura
ged
to
ma
inta
in t
heir
trea
tmen
t
ass
ign
men
t.]
A
+
- O
ut
of
a tr
ial
of
4,2
09
new
ly
dia
gn
ose
d d
iab
etic
pat
ien
ts r
and
om
ly
assi
gn
ed t
o
con
ven
tio
nal
ther
apy
or
inte
nsi
ve
thera
py
,
3,2
77
wer
e av
aila
ble
for
po
st-t
rial
ob
serv
atio
n.
- D
iffe
ren
ces
in A
1c
du
e to
tre
atm
ent
gro
up
wer
e
dim
inis
hed
by
th
e
end
of
the
1-y
ear
tria
l, a
t th
e s
tart
of
po
st-t
rial
fo
llo
w-u
p
the
med
ian
A1
c w
as
7.9
in
th
e
sulf
on
ylu
rea
trea
tmen
t g
rou
p, 8
.5
in t
he c
om
par
iso
n
gro
up
an
d 8
.4 i
n t
he
met
form
in t
reat
men
t
gro
up
, 8
.9 i
n t
he
com
par
iso
n g
rou
p.
- O
utc
om
es
of
inte
rest
were
an
y d
iab
etes
rela
ted
en
d p
oin
t, d
iab
etes-
rela
ted
dea
th,
dea
th f
rom
an
y c
ause
, M
I, s
tro
ke,
per
iph
eral
vas
cula
r d
isea
se, m
icro
vasc
ula
r d
isease
.
- In
th
e s
ulf
on
ylu
rea
arm
, co
mp
are
d t
o t
he
con
ven
tio
nal
ther
apy
gro
up, th
e R
R (
95
%
CI)
of
dia
bete
s-re
late
d e
nd
pt
0.9
1 (
0.8
3-
0.9
9),
dia
bet
es-
rela
ted
deat
h 0
.83
(0
.73
-
0.9
6),
deat
h f
rom
an
y c
ause
0.8
7 (
0.7
9-
0.9
6),
MI
0.8
5 (
0.7
4-0
.97
), s
tro
ke
0.9
1
(0.7
3-1
.13
), P
VD
0.8
2 (
0.5
6-1
.19
),
mic
rov
ascu
lar
dis
eas
e 0
.76
(0
.64-0
.89
).
- In
th
e m
etf
orm
in a
rm,
com
pare
d t
o t
he
con
ven
tio
nal
ther
apy
gro
up, th
e R
R (
95
%
CI)
of
dia
bete
s-re
late
d e
nd
pt
was
0.7
9
(0.6
6-0
.95
), d
iab
etes
-rel
ated
dea
th 0
.70
(0.5
3-0
.92
), d
eath
fro
m a
ny
cau
se 0
.73
(0.5
9-0
.89
), M
I 0
.67
(0
.51-0
.89
), s
tro
ke
0.8
0 (
0.5
0-1
.27
), P
VD
0.6
3 (
0.3
2-1
.27
),
mic
rov
ascu
lar
dis
eas
e 0
.84
(0
.60-1
.17
).
- B
enef
its
of
inte
nsi
ve t
hera
py
to
co
ntr
ol g
luco
se w
ere
mai
nta
ined
fo
r u
p t
o 1
0 y
ears
aft
er
the
cess
ati
on
of
the
ran
do
miz
ed t
rial.
- In
th
e s
ulf
on
ylu
rea
gro
up, th
e r
edu
cti
on
in
mic
rov
ascu
lar
dis
eas
e ri
sk a
nd
dia
bet
es-r
elat
ed
end
po
int
risk
ob
serv
ed i
n t
he i
nte
nsi
ve
thera
py
gro
up
was
su
stai
ned
th
rou
gh
ou
t th
e p
ost
-tri
al p
erio
d, d
esp
ite
rap
id c
on
ver
gen
ce
of
A1
c v
alu
es a
nd
sim
ilar
use
of
glu
cose
-lo
wer
ing
th
era
pie
s.
In t
he m
etfo
rmin
gro
up
, m
ade
up
of
ov
erw
eig
ht
pat
ien
ts,
risk
red
ucti
on
s fo
r M
I an
d a
ll-c
ause
mo
rtali
ty
wer
e su
stain
ed t
hro
ug
ho
ut
the
po
st-t
rial
peri
od
des
pit
e
sim
ilar
A1
c le
vel
s b
etw
een
tre
atm
ent
and
co
ntr
ol
gro
up
.
[No
te:
Th
is r
epo
rt d
oes
no
t in
dic
ate
wh
at
the
targ
et
A1
c le
vel
s w
ere
fo
r th
e in
terv
enti
on
stu
dy,
no
r w
ha
t
A1
cs w
ere a
chie
ved
wit
h i
nte
nsi
ve t
her
ap
y d
uri
ng
th
e
tria
l.
At
the b
egin
nin
g o
f p
ost
-tri
al
foll
ow
-up
, th
e
med
ian
A1
cs
wer
e a
rou
nd
8.]
[No
te:
Pa
rtic
ipa
nts
were
excl
ud
ed f
rom
th
e st
ud
y i
f
they
ha
d M
I w
ith
in o
ne
yea
r, c
urr
ent
an
gin
a o
r h
eart
fail
ure
, m
ore
th
an
on
e m
ajo
r va
scu
lar
even
t,
ma
lig
na
nt
hyp
ert
ensi
on
, u
nco
rrec
ted
en
do
crin
e
dis
ord
er,
ret
ino
pa
thy
req
uir
e l
ase
r tr
eatm
ent,
ele
vate
d
seru
m c
rea
tin
ine
level
, ke
ton
uri
a.
So
, th
ese
pa
tien
ts
did
no
t h
ave
exi
stin
g v
asc
ula
r d
isea
se o
r ri
sk f
acto
rs,
un
like
AC
CO
RD
an
d A
DV
AN
CE
.]
Conclusion Grading Worksheet B – Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Annotation #11 (A1c) Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
85
Au
tho
r/Y
ear
D
esig
n
Ty
pe
Cla
ss
Qu
alit
y (
+,–
,ø)
Po
pu
lati
on
Stu
die
d/S
amp
le
Siz
e
Pri
mar
y O
utc
om
e M
eas
ure
(s)/
Res
ult
s
(e.g
., p
-val
ue,
co
nfi
den
ce i
nte
rval,
rela
tiv
e ri
sk,
od
ds
rati
o, li
keli
ho
od
rati
o, n
um
ber
need
ed t
o t
reat)
Au
tho
rs' C
on
clu
sio
ns/
Wo
rk G
rou
p's
Co
mm
ents
(it
ali
cize
d)
Du
ckw
ort
h,
et
al.,
20
09
RC
T
A
Ø
1,7
91
mil
itary
vet
era
ns
(mea
n a
ge
60
.4 y
ears
) w
ho
had
a
sub
op
tim
al
resp
on
se
to t
hera
py
fo
r ty
pe
2
dia
bete
s w
ere
ran
do
miz
ed t
o r
ece
ive
eith
er i
nte
nsi
ve
or
stan
dar
d g
luco
se
con
tro
l. F
ort
y p
erc
ent
of
these
pati
ents
had
alre
ady
had
a
card
iov
asc
ula
r ev
ent.
Th
e g
oal
of
the
inte
rven
tio
n w
as
an
abso
lute
red
uct
ion
in
A1
c o
f 1
.5 p
erc
enta
ge
po
ints
.
Pat
ien
ts i
n i
nte
nsi
ve
ther
apy
gro
up
were
star
ted
on
max
imu
m
do
ses,
an
d p
atie
nts
in
the
stan
dar
d t
hera
py
gro
up
wer
e st
arte
d o
n
hal
f th
e m
axim
al
do
ses
of
metf
orm
in
plu
s ro
sig
lita
zon
e (i
f
BM
I >
27
kg
/m2)
or
gli
mep
irid
e p
lus
rosi
gli
tazo
ne
(if
BM
I
< 2
7 k
g/
m2).
Th
e p
rim
ary
en
d p
oin
t in
th
is s
tud
y w
as
tim
e
fro
m r
and
om
izat
ion
to
th
e fi
rst
occu
rren
ce o
f
a m
ajo
r ca
rdio
vasc
ula
r ev
ent,
a c
om
po
site
of
MI,
str
ok
e, d
eat
h f
rom
CV
D c
ause
s,
con
ges
tiv
e h
ear
t fa
ilu
re,
surg
ery
fo
r v
asc
ula
r
dis
ease
, in
op
era
ble
co
ron
ary
dis
ease
or
amp
uta
tio
n.
Aft
er a
med
ian
fo
llo
w-u
p 5
.6 y
ear
s, m
edia
n
A1
c le
vels
were
8.4
% i
n t
he
stan
dar
d t
hera
py
gro
up
an
d 6
.9%
in
th
e i
nte
nsi
ve
thera
py
gro
up
. T
he
pri
mar
y o
utc
om
e o
ccu
rred
in
26
4
of
stan
dard
th
erap
y g
rou
p p
atie
nts
an
d 2
35
of
inte
nsi
ve t
her
apy
gro
up
pat
ien
ts (
Haz
ard
rat
io
= 0
.88
95
% C
I 0
.74
-1.0
5).
T
here
was
also
no
sig
nif
ican
t d
iffe
ren
ce
betw
een
gro
up
s w
ith
reg
ard
to
th
e c
om
po
site
ou
tco
me.
Th
e au
tho
rs c
on
clu
de
that
in
ten
siv
e g
luco
se
con
tro
l in
pat
ien
ts w
ith
po
orl
y c
on
tro
lled
ty
pe 2
dia
bete
s h
ad n
o s
ign
ific
ant
effe
cts
on
th
e r
ates
of
majo
r car
dio
vas
cula
r ev
ents
, d
eat
h o
r
mic
rov
ascu
lar
com
pli
cati
on
s.
An
ob
vio
us
lim
itat
ion
of
this
stu
dy
is
that
the
po
pu
lati
on
was
pre
do
min
antl
y m
en,
so
extr
apo
lati
on
of
thes
e fi
nd
ing
s to
wo
men
sho
uld
be
do
ne
wit
h c
auti
on
. A
dd
itio
nal
ly,
at
the
beg
inn
ing
of
the
stu
dy
(2
00
0-2
00
3),
th
e
avai
lab
ilit
y o
f n
ew d
rug
s w
as
lim
ited
, so
it
rem
ain
s p
oss
ible
th
at
new
er
agen
ts m
ay h
ave
dif
fere
nt
eff
ects
.
Th
e au
tho
rs n
ote
th
at
adv
erse
ev
ents
wer
e m
ore
com
mo
n i
n t
he
inte
nsi
ve
ther
apy
gro
up;
ho
wev
er,
ther
e w
as n
o d
iffe
ren
ce
in C
VD
dea
th
bet
wee
n g
rou
ps.
[No
te:
Wh
ile
the
au
tho
rs s
ug
ges
t th
at
thei
r
resu
lts
are
co
nsi
sten
t w
ith
th
e A
DV
AN
CE
an
d
AC
CO
RD
tri
als
, it
is
no
t a
va
lid
co
mp
ari
son.
Th
eir
fin
din
g t
ha
t th
ere
wa
s n
o d
iffe
ren
ce
in
CV
D d
eath
ra
tes
is l
ikel
y d
ue t
o l
ack
of
po
wer
to d
etect
su
ch d
iffe
ren
ces
(or
lack
there
of)
.]
Conclusion Grading Worksheet B – Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Annotation #11 (A1c) Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
86
Conclusion Grading Worksheet C – Annotations #13, 14 (Statin Use)
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Thirteenth Edition/May 2009
Wo
rk
Gro
up
's C
on
clu
sio
n:
Fo
r p
atie
nts
wit
h t
yp
e 2
dia
bet
es m
elli
tus,
co
nsi
der
th
e u
se o
f a
stat
in.
Ran
do
miz
ed c
on
tro
lled
tr
ials
, in
clu
din
g s
om
e la
rge
tria
ls,
and
ob
serv
atio
nal
dat
a co
nsi
sten
tly
sh
ow
a b
enef
it o
f st
atin
th
erap
y f
or
pati
ents
wit
h t
yp
e 2
d
iab
etes
. S
om
e st
ud
ies
also
rep
ort
ed t
hat
sta
tin
th
erap
y w
as w
ell
tole
rate
d i
n t
hes
e p
atie
nts
. H
ow
ever
, n
on
e o
f th
ese
stu
die
s w
as a
ble
to
ass
ess
lon
g-t
erm
eff
ects
of
stat
in t
reat
men
t/u
se.
Co
nclu
sio
n G
ra
de:
I
Au
tho
r/
Yea
r D
esig
n
Ty
pe
Cla
ss
Qu
al-
ity
+
,–,ø
Po
pu
lati
on
Stu
die
d/S
am
ple
Siz
e P
rim
ary
Ou
tco
me M
eas
ure
(s)/
Res
ult
s (e
.g.,
p-v
alu
e,
con
fid
ence
inte
rval
, re
lati
ve r
isk
, o
dd
s ra
tio
, li
kel
iho
od
ra
tio
, n
um
ber
need
ed t
o t
reat)
Au
tho
rs' C
on
clu
sio
ns/
W
ork
Gro
up
's C
om
men
ts (
ita
lici
zed
)
Co
lho
un
, et
al.
, C
AR
DS
20
04
RC
T
A
+
2,8
38
pat
ien
ts (
age
40-7
5 y
ear
s, 9
4%
C
auca
sio
n a
nd
68
% m
ale
), i
n 1
32
cen
ters
in
th
e U
K/I
rela
nd
Ato
rva
sta
tin
10
mg
vs.
pla
ceb
o
Acu
te c
oro
nar
y e
ven
t H
R 0
.63
(0
.48-0
.83
) S
tro
ke
HR
0.5
2 (
0.3
1-0
.89
)
Dea
th f
rom
an
y c
ause
HR
0.7
3 (
0.5
2-0
.85
)
Ran
do
miz
atio
n w
ith
eq
ual
gro
up
s at
bas
eli
ne a
nd
1%
lo
st t
o f
oll
ow
-up
af-
ter
a m
ean
fo
llo
w-u
p o
f 4
year
s.
An
aly
sis
was
wit
h i
nte
nti
on
to
tre
at,
and
du
rin
g t
he
cou
rse
of
stu
dy
, 9
% o
f p
laceb
o g
rou
p w
as k
no
wn
to
tak
e a
stati
n a
nd
85
% o
f th
e in
terv
enti
on
(ei
-th
er a
torv
asta
tin
or
ano
ther
sta
tin
).
Ov
eral
l fr
equ
ency
of
adv
erse
ev
ents
o
r se
rio
us
adv
erse
ev
ents
did
no
t d
if-
fer
betw
een
tre
atm
ents
. I
n e
ach
g
rou
p, 1
.1%
of
pat
ien
ts r
and
om
ized
h
ad o
ne
or
mo
re s
erio
us
adv
erse
ev
ents
. B
ased
on
pre
- an
d p
ost
-LD
L
val
ues
in
in
terv
enti
on
an
d c
on
tro
l g
rou
p, th
ere d
id n
ot
app
ear
to b
e a
par
ticu
lar
thre
sho
ld l
evel
of
LD
L c
ho
-
lest
ero
l to
red
uce
card
iov
ascu
lar
even
ts.
Ro
bin
s, e
t al
., 2
00
1
RC
T
A
+
2,5
31
men
wit
h c
oro
nar
y h
eart
dis
eas
e
and
lo
w H
DL
-C l
evel
s (a
vg
32
mg
/dL
).
62
0 p
atie
nts
had
dia
bet
es.
Gem
fib
rizo
l 1
,20
0 m
gm
/da
y v
s. p
lace
bo
RR
95
% C
I (4
-46
%)
Pat
ien
ts w
ere r
and
om
ized
wit
h c
on
-ce
ale
d a
llo
cati
on
; th
ey w
ere s
imil
ar a
t b
aseli
ne a
nd
tre
ated
rel
ativ
ely
sim
i-la
rly
th
rou
gh
ou
t th
e tr
ial;
pat
ien
ts,
stu
dy
per
son
nel,
hea
lth
car
e p
rov
ider
s
and
ou
tco
mes
ass
esso
rs w
ere
bli
nd
ed;
inte
nti
on
-to
-tre
at a
naly
sis
was
con
-d
uct
ed;
ther
e w
as t
riv
ial
loss
to
fol-
low
-up
. N
o v
alid
ity
con
cern
s.
Upd
ated
Thi
rteen
th E
ditio
n, M
ay 2
009.
Institute for Clinical Systems Improvement
www.icsi.org
87
Conclusion Grading Worksheet C – Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Annotations #13, 14 (Statin) Thirteenth Edition/May 2009
Au
tho
r/Y
ear
Des
ign
T
yp
e C
lass
Q
ual
-it
y
+,–
,ø
Po
pu
lati
on
Stu
die
d/S
am
ple
Siz
e P
rim
ary
Ou
tco
me M
eas
ure
(s)/
Res
ult
s (e
.g.,
p-v
alu
e,
con
fid
ence
inte
rval
, re
lati
ve r
isk
, o
dd
s ra
tio
, li
kel
iho
od
ra
tio
, n
um
ber
need
ed t
o t
reat)
Au
tho
rs' C
on
clu
sio
ns/
W
ork
Gro
up
's C
om
men
ts (
ita
lici
zed
)
Hea
rt
Pro
tec-
tio
n,
20
02
RC
T
A
+
20
,53
6 p
atie
nts
40
-80
yea
rs (
75
%
mal
es, 3
5%
wit
ho
ut
a p
rio
r h
isto
ry o
f C
AD
, 2
8%
>7
0 y
ear
s o
f ag
e) w
ith
no
n-
fast
ing
LD
L c
ho
l o
f >
3.4
mm
ol/
L (
13
5
mg
m%
). 3
,98
2 p
atie
nts
had
dia
bete
s,
3,9
82
wit
ho
ut
pri
or
hx
of
MI
or
CA
D.
Sim
va
sta
tin
40
mg
m/d
ay
vs.
pla
ceb
o
Maj
or
vas
cula
r ev
ent
Nu
mb
er n
eed
ed t
o t
reat
2
1 9
5%
CI
(14-4
1)
Ran
do
miz
atio
n i
ncl
ud
ed i
nd
ivid
uals
fe
lt n
ot
to h
ave
a cl
ear
cli
nic
al i
nd
ica-
tio
n f
or
the u
se o
f a s
tati
n.
Cen
tral
tele
ph
on
e ra
nd
om
izati
on
(p
resu
med
co
nce
aled
ass
ign
men
t) w
ith
min
imi-
zati
on
alg
ori
thm
to
bal
ance
trea
tmen
t g
rou
ps.
M
ean
du
rati
on
of
foll
ow
-up
w
as 5
yea
rs w
ith
at
leas
t 8
0%
dem
on
-st
rati
ng
co
mp
lian
ce w
ith
use
of
sim
-v
asta
tin
or
pla
ceb
o.
4,0
02
pati
ents
too
k a
no
n-s
tud
y s
tati
n t
o i
ncl
ud
e th
e p
laceb
o a
rm (
aver
age
of
17
% f
or
5
yea
rs).
A
ll p
ati
ents
wer
e ac
cou
nte
d
for
(lo
ss t
o f
oll
ow
-up
0.0
3-0
.33
%)
wit
h i
nte
nti
on
-to
-tre
at
analy
sis.
P
a-ti
ents
, p
rov
ider
s an
d o
utc
om
e as
ses-
sors
wer
e b
lin
ded
to
tre
atm
ent
arm
s,
and
in
terv
enti
on
an
d c
on
tro
l g
rou
p
wer
e si
mil
ar a
t st
art
of
tria
l.
Oth
er
than
th
e in
terv
enti
on
, it
is
no
t p
oss
ible
to
tel
l if
gro
up
s w
ere t
reate
d e
qu
ally
.
Set
ter-
gre
n, et
al.,
20
08
RC
T
A
- 4
3 p
atie
nts
wit
h t
yp
e 2
dia
bete
s o
r im
-p
aire
d g
luco
se t
ole
ran
ce
and
sta
ble
co
ron
ary
art
ery
dis
eas
e w
ere
recr
uit
ed
and
ran
do
miz
ed. P
ati
ents
wh
o w
ere
on
a
stati
n o
r o
ther
lip
id-l
ow
erin
g t
reat
men
t in
th
e p
rev
iou
s 1
2 w
eek
s w
ere
excl
ud
ed.
Pat
ien
ts w
ere r
and
om
ized
to
eit
her
sim
-v
asta
tin
80
mg
/d o
r ez
etim
ibe 1
0 m
g/d
p
lus
sim
vast
atin
10
mg
/d f
or
6 w
eek
s.
4 p
atie
nts
wer
e l
ost
to
fo
llo
w-u
p (
2 f
rom
ea
ch a
rm)
and
on
ly 3
9 w
ere
analy
zed
.
Th
e p
rim
ary
ou
tco
mes
of
this
stu
dy
were
en
do
the-
lia
l fu
nct
ion
mea
sured
by
bra
chia
l a
rtery
flo
w-
med
iate
d v
aso
dil
ati
on
s a
nd
th
e ef
fect
s o
f en
do
theli
n
recep
tor b
lock
ag
e, se
rum
lip
ids,
an
d i
nfl
am
ma
tory
ma
rker
s w
ere
ev
alu
ate
d a
t b
ase
lin
e a
nd
foll
ow
-up
.
Aft
er 6
week
s o
f fo
llo
w-u
p,
LD
L c
ho
lest
ero
l le
vels
dec
reas
ed f
rom
3.1
to
1.5
mm
ol/
L a
nd
3.0
to
1.3
m
mo
l/L
in
th
e s
imv
ast
atin
an
d s
imv
asta
tin
plu
s ez
eti
mib
e g
rou
ps,
res
pecti
vely
(p
=).
T
he
chan
ges
in
fl
ow
med
iate
d d
ilati
on
an
d C
RP
wer
e n
ot
dif
fere
nt
be-
tween
gro
up
s; i
n t
he
enti
re s
tud
y g
rou
p, fl
ow
med
iate
d
dil
ati
on
in
crea
sed
fro
m 4
.3%
to
5.5
%,
and
CR
P d
e-cr
ease
d f
rom
3.1
to
2.3
mg
/L.
Th
e au
tho
rs c
on
clu
de
that
th
e tw
o
trea
tmen
ts d
id n
ot
dif
fer
wit
h r
egar
d
to t
hei
r ef
fect
on
en
do
thel
ial
functi
on
in
pati
ents
wit
h t
yp
e 2
dia
bet
es,
im-
pai
red
glu
cose
to
lera
nce
and
sta
ble
co
ron
ary
art
ery
dis
eas
e.
Th
ey f
urt
her
p
osi
t th
at
in c
on
tras
t to
th
eir
hy
po
the-
sis,
th
e li
pid
-lo
wer
ing
eff
ects
of
stat
-in
s w
ere
mo
re i
mp
ort
ant
for
end
oth
e-li
al f
un
ctio
n a
s o
pp
ose
d t
o t
he
ple
i-o
tro
pic
eff
ect
s o
f st
atin
s.
[No
te:
Th
e i
nve
stig
ato
rs d
id n
ot
ad
-h
ere
to i
nte
nti
on
-to
-tre
at
an
aly
sis
pri
ncip
les.
T
here
wer
e s
om
e p
ote
n-
tia
lly
imp
ort
an
t d
iffe
ren
ces
in A
1c,
asp
irin
use
, a
s w
ell
as
use
of
bet
a-
blo
cker
s a
nd
ca
lciu
m c
ha
nn
el
blo
ck-
ers
bet
wee
n t
rea
tmen
t g
rou
ps
at
ba
se-
lin
e.]
Institute for Clinical Systems Improvement
www.icsi.org
88
Conclusion Grading Worksheet C – Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Annotations #13, 14 (Statin) Thirteenth Edition/May 2009
Au
tho
r/Y
ear
Des
ign
T
yp
e C
lass
Q
ual
-it
y
+,–
,ø
Po
pu
lati
on
Stu
die
d/S
am
ple
Siz
e P
rim
ary
Ou
tco
me M
eas
ure
(s)/
Res
ult
s (e
.g.,
p-v
alu
e,
con
fid
ence
inte
rval
, re
lati
ve r
isk
, o
dd
s ra
tio
, li
kel
iho
od
ra
tio
, n
um
ber
need
ed t
o t
reat)
Au
tho
rs' C
on
clu
sio
ns/
W
ork
Gro
up
's C
om
men
ts (
ita
lici
zed
)
Fle
g,
et
al.,
20
08
D
ata
fro
m t
he
SA
ND
S
tria
l
No
n-
ran
do
m-
ized
tri
al
C
Ø
Sec
on
dar
y a
naly
sis
of
data
fro
m t
he
Sto
p A
ther
osc
lero
sis
in N
ativ
e D
iab
eti
cs
Stu
dy
(S
AN
DS
) T
rial
. A
gg
ress
ively
trea
ted
pati
ents
(n
=6
9)
tak
ing
sta
tin
s p
lus
eze
tim
ibe
wer
e c
om
par
ed t
o a
g-
gre
ssiv
ely
tre
ated
pati
ents
on
sta
tin
s al
on
e (
n=
15
4)
and
no
n-a
gg
ress
ively
tr
eate
d p
ati
ents
(n
=2
04
).
Th
e p
rim
ary
ou
tco
mes
of
this
stu
dy
were
ch
an
ge i
n
L
DL
ch
ole
stero
l a
nd
ca
roti
d i
nti
ma-m
edia
th
ick
-n
ess.
Mea
n L
DL
ch
ole
ster
ol
was
red
uce
d b
y 3
1 m
g/d
L a
nd
3
2 m
g/d
L i
n t
he a
gg
ress
ive
gro
up
rec
eiv
ing
sta
tin
s p
lus
eze
tim
ibe
ver
sus
stati
ns
alo
ne c
om
par
ed w
ith
a
chan
ge
of
1m
g/d
L i
n t
he
no
n-a
gg
ress
ive g
rou
p.
At
36
mo
nth
s fo
llo
w-u
p,
mean
car
oti
d i
nti
ma-
med
ia
reg
ress
ed f
rom
base
lin
e si
mil
arly
in
th
e e
zeti
mib
e (-
0.0
25
mm
) an
d n
on
-ezeti
mib
e (
-0.0
12
mm
) g
rou
ps
wh
ile
it p
rog
ress
ed i
n t
he n
on
-ag
gre
ssiv
e tr
eat
men
t g
rou
p (
0.0
39
).
Th
e au
tho
rs c
on
clu
de
that
am
on
g p
er-
son
s w
ith
ty
pe
2 d
iab
etes
an
d b
asel
ine
LD
L c
ho
lest
ero
l !
10
0 m
g/d
L.
Bo
th
agg
ress
ive
treat
men
t st
rate
gie
s w
ere
effe
cti
ve
at r
edu
cin
g c
aro
tid
in
tim
a-m
edia
th
ick
nes
s.
[No
te:
Th
is s
tud
y u
sed
da
ta f
rom
th
e
SA
ND
S t
ria
l fo
r a
sec
on
da
ry a
na
lysi
s th
at
com
pa
red
gro
up
s w
ith
in t
he
ag
-g
ress
ive
trea
tmen
t a
rm. T
her
efo
re,
the
stu
dy d
esig
n u
sed
fo
r th
is a
na
lysi
s
is n
ot
a r
an
do
miz
ed t
ria
l; r
ath
er,
the
da
ta a
re b
ein
g a
na
lyze
d a
s a
no
n-
ran
do
miz
ed t
ria
l o
r co
ho
rt s
tud
y.]
Fer
rer-
Gar
cia
, et
al.
, 2
00
8
No
n-
ran
do
m-
ized
, u
nco
n-
tro
lled
tr
ial
C
- 2
02
pat
ien
ts w
ith
ty
pe 2
dia
bete
s w
ho
had
no
sta
tin
use
in
th
e p
rio
r 2
4 w
eek
s.
All
met
cri
teri
a f
or
ph
arm
aco
log
ic t
her
-ap
y, acc
ord
ing
to
th
e N
CE
P-A
TP
III
an
d A
DA
cri
teri
a, w
ith
LD
L l
evels
in
ex
cess
of
2.6
mm
ol/
L.
Th
ese p
ati
ents
w
ere
assi
gn
ed t
o r
ece
ive a
dail
y d
osa
ge
of
ato
rvas
tati
n b
ased
on
th
eir
in
itia
l
LD
L c
ho
lest
ero
l le
vels
.
Th
e p
rim
ary
ou
tco
me
of
this
stu
dy
wa
s th
e p
rop
or-
tio
n o
f p
ati
ents
ach
iev
ing
th
e L
DL
ch
ole
stero
l g
oa
l a
fter
24
wee
ks
of
trea
tmen
t.
18
8 p
atie
nts
co
mp
lete
d t
he
stu
dy;
of
tho
se, 6
6.5
%
ach
iev
ed t
he L
DL
ch
ole
ster
ol
targ
et. A
t d
ose
s o
f 1
0,
20
, 4
0 a
nd
80
mg
/day
of
ato
rvas
tati
n,
the
% o
f p
atie
nts
re
ach
ing
go
al
LD
L w
as 7
5%
, 6
7%
, 5
8%
an
d 5
9%
, re
-
spec
tiv
ely
.
Th
e au
tho
rs c
on
clu
de
that
in
div
idu
al-
izin
g t
he
star
tin
g d
ose
of
atorv
ast
atin
ac
cord
ing
to
bas
eli
ne
and
tar
get
LD
L
cho
lest
ero
l le
vel
s all
ow
ed a
hig
h p
ro-
po
rtio
n o
f ty
pe
2 d
iab
ete
s p
atie
nts
to
ac
hie
ve t
he
targ
et
wit
hin
24
wee
ks.
Th
e au
tho
rs n
ote
d t
hat
they
ob
serv
ed
a re
du
cti
on
in
tri
gly
cer
ides,
bu
t n
o
chan
ge
in A
1c.
Th
is s
tud
y d
id n
ot
add
ress
lim
itati
on
s o
f h
avin
g n
o c
on
tro
l g
rou
p.
Th
ey a
lso
did
no
t ex
pla
in w
hy
th
ey d
id n
ot u
se
an i
nte
nti
on
-to
-tre
at
analy
sis
if t
his
is
a tr
ial.
Institute for Clinical Systems Improvement
www.icsi.org
89
Conclusion Grading Worksheet C – Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Annotations #13, 14 (Statin) Thirteenth Edition/May 2009
Au
tho
r/
Yea
r D
esig
n
Ty
pe
Cla
ss
Qu
al-
ity
+
,–,ø
Po
pu
lati
on
Stu
die
d/S
am
ple
Siz
e P
rim
ary
Ou
tco
me M
eas
ure
(s)/
Res
ult
s (e
.g.,
p-v
alu
e,
con
fid
ence
inte
rval
, re
lati
ve r
isk
, o
dd
s ra
tio
, li
kel
iho
od
ra
tio
, n
um
ber
need
ed t
o t
reat)
Au
tho
rs' C
on
clu
sio
ns/
W
ork
Gro
up
's C
om
men
ts (
ita
lici
zed
)
Leit
er,
et
al.,
20
08
T
he
AC
TF
AS
T s
tud
y
No
n-
ran
do
m-
ized
op
en
lab
el
tria
l
C
Ø
2,7
17
hig
h-r
isk
su
bje
cts
, 1
,02
4 o
f w
ho
m
had
dia
bet
es a
nd
1,2
51
had
met
abo
lic
syn
dro
me.
P
ati
ents
had
CH
D o
r C
HD
eq
uiv
ale
nt
at
bas
eli
ne
and
LD
L c
ho
les-
tero
l le
vels
bet
wee
n 1
00
an
d 2
20
m
g/d
L. P
ati
ents
wer
e as
sig
ned
a s
tart
-in
g d
ose
of
arto
vas
tati
n (
10
, 2
90
, 4
0 o
r
80
mg
/day
) b
ased
on
LD
L c
ho
lest
ero
l le
vels
an
d s
tati
n u
se a
t b
aseli
ne.
Th
e p
rim
ary
en
d p
oin
t o
f th
is s
tud
y w
as
the
pro
-p
ort
ion
of
pa
tien
ts w
ho
ach
iev
ed
LD
L c
ho
lest
ero
l g
oa
ls.
Am
on
g p
atie
nts
wit
h d
iab
ete
s, 8
1%
of
sub
ject
s w
ho
w
ere
pre
vio
usl
y n
ot
on
a s
tati
n (
82
%, 8
4%
, 8
2%
an
d
76
% w
ith
10
, 2
0, 4
0 a
nd
80
mg
/day
, re
spec
tiv
ely
)
reac
hed
th
e L
DL
ch
ole
ster
ol
targ
et.
A
mo
ng
pat
ien
ts
wh
o w
ere p
rev
iou
sly
on
a s
tati
n,
60
% o
f su
bje
cts
(6
1%
, 6
8%
an
d 4
7%
wit
h 2
0, 4
0 a
nd
80
mg
/day
, re
-sp
ecti
vely
) re
ach
ed L
DL
ch
ole
ster
ol
targ
et.
Th
e au
tho
rs c
on
clu
de
that
a t
arg
ete
d
do
se o
f ato
rvas
tati
n a
llo
ws
mo
st p
a-ti
ents
wit
h t
yp
e 2
dia
bet
es t
o a
chie
ve
thei
r L
DL
ch
ole
ster
ol
targ
et w
ith
th
e in
itia
l d
ose
or
a si
ng
le t
itra
tio
n w
ith
in
12
wee
ks.
T
he a
uth
ors
fu
rth
er c
on
-cl
ud
e t
hat
hig
her
sta
rtin
g d
ose
s o
f
stati
ns
are
ben
efic
ial
and
well
to
ler-
ated
, b
ut
low
er d
ose
s w
ork
, to
o.
Lim
itati
on
s o
f th
is s
tud
y i
ncl
ud
e th
at
it w
as n
ot
bli
nd
ed.
Ho
war
d,
et a
l.,
20
08
T
he
SA
ND
S
Tri
al
Ran
do
m-
ized
co
n-
tro
lled
tr
ial
A
+
Par
ticip
ants
wer
e 4
99
Am
eric
an I
nd
ian
men
an
d w
om
en a
ged
> 4
0 y
ear
s w
ith
ty
pe
2 d
iab
etes
an
d n
o p
rio
r ca
rdio
vas
-cu
lar
even
ts. F
oll
ow
-up
tim
e w
as
for
3
yea
rs.
Pat
ien
ts w
ere r
and
om
ized
to
ag
gre
ssiv
e
or
stan
dar
d t
reatm
ent
gro
up
s.
Th
e p
rim
ary
ob
ject
ive
of
this
stu
dy
wa
s to
co
mp
are
the
pro
gre
ssio
n o
f su
bcl
inic
al
ath
ero
scle
rosi
s in
a
du
lts
wit
h t
yp
e 2
dia
bet
es t
rea
ted
to
rea
ch a
gg
res
-si
ve t
arg
ets
of
low
-den
sity
LD
L c
ho
lest
ero
l a
nd
b
loo
d p
ress
ure.
Mea
n t
arg
et L
DL
ch
ole
ster
ol
and
sy
sto
lic
blo
od
pre
s-su
re l
evels
wer
e r
eac
hed
an
d m
ain
tain
ed i
n b
oth
gro
up
s.
Mean
(9
5%
co
nfi
den
ce i
nte
rval)
lev
els
for
LD
L c
ho
lest
ero
l at
the
end
of
foll
ow
-up
wer
e 7
2 (
69
-7
5)
and
10
4 (
10
1-1
06
) an
d S
BP
lev
els
wer
e 1
17
(1
15-
11
8)
and
12
9 (
12
8-1
30
) in
th
e ag
gre
ssiv
e v
s. s
tan
dar
d
trea
tmen
t g
rou
ps,
resp
ecti
vel
y.
Fro
m b
asel
ine t
o f
oll
ow
-up
, th
ere
wer
e g
reate
r de-
crea
ses
in c
aro
tid
in
tim
a m
edia
th
ick
nes
s, l
eft
ven
tric
u-
lar
mas
s in
dex
, an
d c
aro
tid
art
eria
l cr
oss
-sec
tio
n i
n t
he
agg
ress
ive
gro
up
co
mp
ared
to
th
e n
on-a
gg
ress
ive
gro
up
.
Ser
iou
s ad
ver
se e
ven
ts r
ela
ted
to
blo
od
pre
ssu
re m
edi-
cati
on
wer
e h
igh
er i
n t
he a
gg
ress
ive g
rou
p (
4 v
s. 1
in
no
n-a
gg
ress
ive g
rou
p).
Car
dio
vas
cula
r ev
ents
did
no
t d
iffe
r si
gn
ific
antl
y
bet
ween
gro
up
s.
Th
e au
tho
rs c
on
clu
de
that
th
e ag
gre
s-
siv
ely
tre
ate
d g
rou
p h
ad a
reg
ress
ion
o
f su
bcl
inic
al
ath
ero
scle
rosi
s (i
nti
ma
med
ia t
hic
kn
ess,
lef
t v
entr
icu
lar
mas
s in
dex
).
At
the
sam
e ti
me,
the
stan
-d
ard
tre
atm
ent
gro
up
had
a w
ors
enin
g
in i
nti
ma m
edia
th
ick
nes
s.
Th
ere w
ere n
o d
iffe
ren
ces
in
cli
nic
al
CV
D o
utc
om
es b
etw
een
gro
up
s, a
nd
th
e p
rog
ress
ion
of
sub
clin
ical
dis
eas
e
in t
he
stan
dar
d t
reatm
ent
gro
up
was
lo
wer
th
an e
xp
ect
ed.
Giv
en t
he l
ack
of
dif
fere
nce
in
CV
D
even
ts a
nd
th
e i
ncr
ease
in
ad
ver
se
even
ts i
n t
he
agg
ress
ive
treat
men
t ar
m,
ther
e is
a p
oss
ibil
ity
th
at
ther
e m
ay n
ot
be f
avo
rab
le l
on
g-t
erm
ou
t-co
mes
.
It s
ho
uld
be
no
ted
th
at
this
stu
dy
fo
-
cuse
d o
n a
sin
gle
eth
nic
gro
up
.
[No
te:
Th
is s
tud
y d
id n
ot
con
tro
l fo
r
con
fou
nd
ing
by
ora
l h
ypo
gly
cem
ic
med
ica
tio
n u
se,
wh
ich
ma
y h
ave
b
iase
d r
esu
lts
aw
ay
fro
m t
he
nu
ll.]
Institute for Clinical Systems Improvement
www.icsi.org
90
Conclusion Grading Worksheet C – Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Annotations #13, 14 (Statin) Thirteenth Edition/May 2009
Au
tho
r/Y
ear
Des
ign
T
yp
e C
lass
Q
ual
-it
y
+,–
,ø
Po
pu
lati
on
Stu
die
d/S
am
ple
Siz
e P
rim
ary
Ou
tco
me M
eas
ure
(s)/
Res
ult
s (e
.g.,
p-v
alu
e,
con
fid
ence
inte
rval
, re
lati
ve r
isk
, o
dd
s ra
tio
, li
kel
iho
od
ra
tio
, n
um
ber
need
ed t
o t
reat)
Au
tho
rs' C
on
clu
sio
ns/
W
ork
Gro
up
's C
om
men
ts (
ita
lici
zed
)
New
-m
an,
et
al.,
20
08
Th
e C
AR
DS
st
ud
y
RC
T
A
+
2,3
38
pat
ien
ts w
ith
ty
pe 2
dia
bete
s an
d
no
his
tory
of
coro
nar
y h
ear
t d
isea
se w
ho
w
ere
enro
lled
in
th
e C
oll
abo
rati
ve
Ato
rvas
tati
n D
iab
etes
Stu
dy
(C
AR
DS
) an
d f
oll
ow
ed f
or
3.9
yea
rs.
P
atie
nts
wer
e r
and
om
ized
to
rec
eiv
e at
orv
asta
tin
10
mg
/day
or
pla
ceb
o i
n a
d
ou
ble
-bli
nd
ed s
tud
y.
Th
e p
rim
ary
ou
tco
me
of
this
stu
dy
wa
s to
ev
alu
ate
th
e sa
fety
an
d t
ole
rab
ilit
y o
f a
torv
ast
ati
n 1
0 m
g/d
ay
w
ith
pla
ceb
o.
Th
e p
erce
nta
ge
of
pati
ents
ex
per
ien
cin
g a
dv
erse
ev
ents
, se
rio
us
adv
erse
ev
ents
, an
d d
isco
nti
nu
ati
on
s d
ue
to a
dv
erse
ev
ents
in
th
e ato
rvas
tati
n v
s. p
laceb
o
gro
up
s w
ere
23
.0%
vs.
25
.4%
, 1
.1%
vs.
1.1
%,
and
2
.9%
vs.
3.4
%,
resp
ecti
vel
y.
T
he
mo
st c
om
mo
n a
dv
erse
ev
ents
wer
e d
igest
ive
sys-
tem
rela
ted
.
Th
e au
tho
rs c
on
clu
de
that
ato
rvas
tati
n
10
mg
/day
was
well
to
lera
ted
in
pa-
tien
ts w
ith
ty
pe
2 d
iab
etes
du
rin
g r
ela
-
tiv
ely
lo
ng
-ter
m t
reatm
ent
(3.9
year
s)
and
th
at
pat
ien
ts w
ith
dia
bete
s b
enef
it
fro
m s
tati
n t
her
apy
.
[No
te:
Th
is s
tud
y w
as
un
ab
le t
o a
s-ce
rta
in l
on
g-t
erm
ou
tco
mes
of
trea
t-m
ent.
]
Mal
m-
stro
m,
et
al.,
20
09
(s
ame
stu
dy
as
Set
ter-
gre
n)
RC
T
A
Ø
32
pat
ien
ts w
ith
ty
pe 2
dia
bete
s o
r im
-p
aire
d g
luco
se t
ole
ran
ce
and
sta
ble
co
ron
ary
art
ery
dis
eas
e r
ece
ived
6
wee
ks
of
trea
tmen
t w
ith
sim
vast
atin
80
mg
/day
or
ezeti
mib
e 1
0 m
g/d
ay p
lus
sin
vas
tati
n 1
0 m
g/d
ay.
Th
e p
rim
ary
ou
tco
mes
of
this
stu
dy
were
LD
L c
ho
-le
ster
ol,
C-r
eact
ive p
rote
in, a
nd
pla
tele
t fu
nct
ion
.
To
tal
and
lo
w-d
ensi
ty L
DL
ch
ole
ster
ol
dec
reas
ed f
rom
3.2
(±
0.6
) to
1.7
(±
0.7
) in
th
e ez
itim
ibe +
sim
vas
tati
n
gro
up
an
d 3
.0 (
±1
.0)
to 1
.4 (
±0
.5)
in t
he
sim
vas
tati
n-
alo
ne g
rou
p.
Nei
ther
tre
atm
ent
affe
cte
d p
late
let
act
ivit
y (
pla
tele
t P
-se
lecti
n e
xp
ress
ion
an
d f
ibri
no
gen
bin
din
g,
AD
P-
ind
uce
d p
late
let
agg
reg
ati
on
).
Th
e au
tho
rs c
on
clu
de
that
pro
no
un
ced
li
pid
-lo
wer
ing
did
no
t in
flu
ence
in
di-
ces
of
pla
tele
t fu
nct
ion
. T
hes
e r
esu
lts
sug
ges
t th
at
nei
ther
th
e l
ipid
-lo
wer
ing
no
r th
e p
leio
tro
pic
eff
ects
of
stati
n
ther
apy
red
uce
d t
he r
eac
tiv
ity
of
pla
tele
t ag
gre
gat
ion
.
Th
is s
tud
y i
s li
mit
ed b
y a
sm
all
nu
m-
ber
of
pati
ents
. A
lso
, th
ere w
ere
som
e b
aseli
ne
dif
fere
nce
s in
clo
pi-
do
gre
l an
d a
spir
in u
se a
nd
gen
der
dis
-tr
ibu
tio
n.
Sev
er,
et
al.,
20
05
A
SC
OT
RC
T
A
+
2,5
32
pat
ien
ts w
ith
dia
bet
es a
t ra
nd
om
i-za
tio
n i
n t
he
AS
CO
T s
tud
y.
Pat
ien
ts
wer
e h
yp
erte
nsi
ve, w
ith
no
his
tory
of
coro
nar
y h
eart
dis
eas
e, b
ut
at
leas
t th
ree
card
iov
asc
ula
r ri
sk f
acto
rs.
R
and
om
ized
to
rece
ive
10
mg
ato
rvas
-ta
tin
or
pla
ceb
o.
Th
e p
rim
ary
ou
tco
me
of
this
stu
dy
wa
s a
co
mp
osi
te
of
tota
l ca
rdio
va
scu
lar o
utc
om
es.
Du
rin
g a
med
ian
fo
llo
w-u
p o
f 3
.3 y
ear
s, c
on
cen
trati
on
of
tota
l an
d L
DL
ch
ole
ster
ol
was
~1
mm
ol/
l lo
wer
in
th
ose
ran
do
miz
ed t
o a
torv
ast
atin
co
mp
ared
wit
h p
la-
ceb
o.
T
her
e w
ere 1
66
maj
or
card
iov
ascu
lar
even
ts (
9.2
%)
in
the
ato
rvast
atin
gro
up
an
d 1
51
(1
1.9
%)
in t
he
pla
ceb
o
gro
up
(H
azar
d r
atio
0.7
7,
95
% c
on
fid
ence
in
terv
al
0.6
1-0
.98
). T
her
e w
ere n
o s
tati
stic
ally
sig
nif
ican
t re
-d
uct
ion
s in
in
div
idu
al c
ard
iov
ascu
lar
end
po
ints
(s
tro
ke,
co
ron
ary
ev
ents
).
Th
e au
tho
rs c
on
clu
de
that
ato
rvas
tati
n
sig
nif
ican
tly
red
uced
th
e ri
sk o
f m
ajo
r ca
rdio
vasc
ula
r ev
ents
an
d p
roce
du
res
amo
ng
dia
beti
c p
ati
ents
wit
h w
ell
-
con
tro
lled
hy
per
ten
sio
n a
nd
wit
ho
ut
a h
isto
ry o
f co
ron
ary
hear
t d
isea
se.
Th
e re
du
ctio
n i
n r
isk
was
sim
ilar
to
th
at
amo
ng
stu
dy
par
ticip
ants
wh
o w
ere
no
t d
iag
no
sed
wit
h d
iab
etes
.
Th
is s
tud
y w
as l
imit
ed b
y r
ela
tiv
ely
sh
ort
fo
llo
w-u
p t
ime;
th
us,
th
e in
ves
-ti
gato
rs w
ere u
nab
le t
o a
ssess
lo
ng-
term
sta
tin
use
in
dia
beti
cs.
Th
is s
tud
y d
id n
ot
asse
ss m
icro
vas
cu-
lar
even
ts.
Institute for Clinical Systems Improvement
www.icsi.org
91
Conclusion Grading Worksheet C – Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Annotations #13, 14 (Statin) Thirteenth Edition/May 2009
Au
tho
r/Y
ear
Des
ign
T
yp
e C
lass
Q
ual
-it
y
+,–
,ø
Po
pu
lati
on
Stu
die
d/S
am
ple
Siz
e P
rim
ary
Ou
tco
me M
eas
ure
(s)/
Res
ult
s (e
.g.,
p-v
alu
e,
con
fid
ence
inte
rval
, re
lati
ve r
isk
, o
dd
s ra
tio
, li
kel
iho
od
ra
tio
, n
um
ber
need
ed t
o t
reat)
Au
tho
rs' C
on
clu
sio
ns/
W
ork
Gro
up
's C
om
men
ts (
ita
lici
zed
)
Kn
op
p,
et a
l.,
20
06
9
Th
e A
SP
EN
st
ud
y
RC
T
A
Ø
2,4
10
su
bje
cts
wer
e ra
nd
om
ly a
ssig
ned
to
rece
ive
10
mg
ato
rvast
atin
or
pla
ceb
o
in a
4-y
ear,
do
ub
le-b
lin
ded
stu
dy
.
Th
e p
rim
ary
en
d p
oin
t o
f th
is s
tud
y w
as
a c
om
pos-
ite
com
pro
mis
ed o
f ca
rd
iov
asc
ula
r d
eath
, n
on
-fa
tal
MI,
no
n-f
ata
l st
rok
e, r
eca
na
liza
tio
n,
coro
na
ry a
r-
tery
by
pa
ss s
urg
ery
, re
susi
cita
ted
ca
rdia
c a
rres
t,
an
d w
ors
enin
g o
r u
nst
ab
le a
ng
ina
. A
t th
e en
d o
f th
e 4-y
ear
stu
dy
, L
DL
ch
ole
ster
ol
was
red
uce
d b
y 3
0.1
% i
n t
he
ato
rvas
tati
n g
rou
p a
nd
1.1
%
in t
he
pla
ceb
o g
rou
p (
p=
0.0
00
1).
C
om
po
site
en
d p
oin
t ra
tes
wer
e 1
3.7
% i
n t
he
ato
rvas
-ta
tin
gro
up
an
d 1
5.0
% i
n t
he p
laceb
o g
rou
p (
Haz
ard
ra
tio
0.9
0, 9
5%
co
nfi
den
ce i
nte
rval
0.7
3-1
.12
).
Th
e au
tho
rs c
on
clu
de
that
th
ere w
ere
no
t si
gn
ific
ant
dif
fere
nces
bet
wee
n
gro
up
s in
co
mp
osi
te e
nd
po
ints
. T
hey
furt
her
ack
no
wle
dg
e th
at t
hes
e r
esu
lts
that
are
in
con
sist
ent
wit
h o
ther
s re
-p
ort
ed i
n t
he
lite
ratu
re m
ay b
e d
ue
to
the
pri
mar
y e
nd p
oin
t d
efin
itio
n
(wh
ich
may
hav
e b
een
in
flat
ed d
ue t
o
incl
usi
on
of
ho
spit
aliz
atio
n f
or
an-
gin
a) o
r p
roto
col
chan
ges
du
e t
o
chan
ges
in
tre
atm
ent
gu
idel
ines
.
Th
us,
beca
use
of
the i
ncr
eas
ed r
isk
of
coro
nar
y h
eart
dis
eas
e a
mo
ng
dia
bet
ic
pat
ien
ts,
they
sh
ou
ld s
till
be t
reate
d t
o
ach
iev
e L
DL
ch
ole
ster
ol
targ
ets
.
Tw
o y
ear
s in
to t
he s
tud
y,
the
stu
dy
p
roto
col
was
alt
ered
to
in
clu
de
pa-
tien
ts w
ith
ou
t p
rio
r M
I o
r in
terv
en-
tio
nal
pro
ced
ure
du
e t
o c
han
ges
in
tr
eatm
ent
gu
ideli
nes
.
Su
bse
qu
ent
trea
tmen
t g
uid
eli
nes
nec
essi
tate
d a
ll
seco
nd
ary
pre
ven
tio
n s
ub
jects
an
d
pri
mar
y p
rev
enti
on
su
bje
cts
wit
h a
p
rim
ary
CV
D e
nd
po
int
to d
isco
n-
tin
ue t
he
stu
dy
med
icati
on
(as
man
-
dat
ed b
y t
he
DS
MB
).
Institute for Clinical Systems Improvement
www.icsi.org
92
Conclusion Grading Worksheet C – Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Annotations #13, 14 (Statin) Thirteenth Edition/May 2009
Au
tho
r/
Yea
r D
esig
n
Ty
pe
Cla
ss
Qu
al-
ity
+
,–,ø
Po
pu
lati
on
Stu
die
d/S
am
ple
Siz
e P
rim
ary
Ou
tco
me M
eas
ure
(s)/
Res
ult
s (e
.g.,
p-v
alu
e,
con
fid
ence
inte
rval
, re
lati
ve r
isk
, o
dd
s ra
tio
, li
kel
iho
od
ra
tio
, n
um
ber
need
ed t
o t
reat)
Au
tho
rs' C
on
clu
sio
ns/
W
ork
Gro
up
's C
om
men
ts (
ita
lici
zed
)
Sh
eph
erd
, et
al.
, 2
00
6
Tre
ati
ng
to
N
ew T
ar-
get
s S
tud
y
(TN
T)
RC
T
A
+
1,5
01
pat
ien
ts w
ith
dia
bet
es a
nd
co
ro-
nar
y h
eart
dis
eas
e, w
ith
LD
L c
ho
lest
ero
l le
vels
<1
30
mg
/dL
wer
e r
and
om
ized
to
a eit
her
ato
rvas
tati
n 1
0 o
r 8
0 m
g/d
ay.
Pat
ien
ts w
ere f
oll
ow
ed f
or
a m
edia
n o
f 4
.9 y
ears
.
Th
e p
rim
ary
en
d p
oin
t o
f th
is s
tud
y w
as
tim
e to
firs
t ca
rdio
va
scu
lar e
ven
t (d
efin
ed a
s d
eath
fro
m
coro
na
ry h
eart
dis
ease
, n
on
-fa
tal
MI,
res
usc
ita
ted
card
iac
arr
est,
or
fata
l o
r n
on
-fa
tal
stro
ke)
.
Th
e m
ean
LD
L c
ho
lest
ero
l le
vel
s at
the e
nd
of
treat
-m
ent
wer
e 9
8.6
mg
/dl
wit
h 1
0 m
g a
torv
ast
atin
an
d
77
.0 m
g/d
l w
ith
80
mg
ato
rvas
tati
n.
A p
rim
ary
ev
ent
occ
urr
ed i
n 1
35
pat
ien
ts o
n 1
0 m
g
com
par
ed w
ith
10
3 p
ati
ents
on
80
mg
(H
aza
rd r
atio
0
.75
, 9
5%
co
nfi
den
ce i
nte
rval
0.5
8-0
.97
).
Th
ere w
ere s
ign
ific
ant
dif
fere
nce
s b
etw
een
gro
up
s in
fa
vo
r o
f ato
rvas
tati
n 8
0 m
g f
or
tim
e to
fir
st c
ere-
bro
vas
cula
r ev
ent
(0.6
9, 9
5%
co
nfi
den
ce
inte
rval
0.4
8-
0.9
8)
and
an
y c
ard
iov
ascu
lar
even
t (0
.85
, 9
5%
co
nfi
-
den
ce i
nte
rval
0.7
3-1
.00
).
Th
e au
tho
rs c
on
clu
de
that
am
on
g p
a-ti
ents
wit
h c
oro
nar
y h
eart
dis
eas
e an
d
dia
bete
s, i
nte
nsi
ve
stati
n t
her
apy
of
80
mg
ato
rvas
tati
n s
ign
fica
ntl
y r
edu
ced
th
e ra
te o
f m
ajo
r car
dio
vasc
ula
r ev
ents
by
25
co
mp
ared
to
10
mg
at
orv
asta
tin
.
Th
e w
ere n
o d
iffe
ren
ces
in r
ate
s o
f ad
ver
se e
ven
ts
betw
een
gro
up
s.
Th
is s
tud
y d
id n
ot
asse
ss m
icro
vas
cu-
lar
even
ts.
Th
is s
tud
y w
as n
ot
po
wer
ed t
o d
ete
ct
dif
fere
nces
in
mo
rtali
ty.
Th
is i
s a
po
st-h
oc
anal
ysi
s o
f a s
ub
po
pu
lati
on
fro
m t
he l
arg
er T
NT
stu
dy
.
[No
te:
In
tere
stin
gly
, th
ere w
as
no
d
iffe
ren
ce
in c
ard
iova
scu
lar
even
ts
bet
ween
pa
tien
ts w
ith
an
d w
ith
ou
t g
oo
d g
lycem
ic c
on
tro
l.]
Institute for Clinical Systems Improvement
www.icsi.org
93
Conclusion Grading Worksheet D – Annotations #13, 14, 27, 29 (Goals for Blood Pressure)
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Thirteenth Edition/May 2009
Work
Gro
up
's C
on
clu
sion
: F
or
pat
ien
ts w
ith
ty
pe
2 d
iab
etes
mel
litu
s, t
he
syst
oli
c b
loo
d p
ress
ure
go
al i
s le
ss t
han
130
mm
Hg
an
d
the
dia
sto
lic
blo
od
pre
ssu
re g
oal
is
less
th
an 8
0 m
mH
g.
Con
clu
sio
n G
rad
e: I
I
Au
tho
r/
Yea
r
Des
ign
Ty
pe
Cla
ss
Qu
al-
ity
+
,–,ø
Po
pu
lati
on
Stu
die
d/S
am
ple
Siz
e P
rim
ary
Ou
tco
me M
eas
ure
(s)/
Res
ult
s (e
.g.,
p-v
alu
e, c
on
-
fid
ence
inte
rval
, re
lati
ve
risk
, o
dd
s ra
tio
, li
keli
ho
od
rat
io,
nu
mb
er n
eed
ed t
o t
reat)
Au
tho
rs' C
on
clu
sio
ns/
Wo
rk G
rou
p's
Co
mm
ents
(it
ali
-ci
zed
)
UK
Pro
-sp
ecti
ve
Dia
bete
s S
tud
y
Gro
up
(U
KP
DS
3
9),
19
98
RC
T
A
ø
-75
8 p
atie
nts
all
oca
ted
to
tig
ht
con
tro
l o
f B
P a
mo
ng
1,1
48
hy
per
ten
siv
e p
atie
nts
w
ith
ty
pe 2
dia
bete
s -4
00
pat
ien
ts t
reate
d w
ith
cap
top
ril
(25-5
0
mg
tw
ice
dai
ly),
35
8 w
ith
ate
no
lol
(50-1
00
m
g t
wic
e d
aily
) -A
ll p
atie
nts
ag
es
48
-60
yea
rs o
f ag
e (m
ean
ag
e o
f tr
eatm
ent
gro
up
s 5
6 y
ears
) -9
-yea
r fo
llo
w-u
p
-go
al o
f B
P <
15
0/8
5 m
m H
g
-Cap
top
ril
and
ate
no
lol
eual
lele
eff
ecti
ve i
n m
ean
BP
re-
du
ctio
n (
14
4/8
4 a
nd
14
3/8
1 m
m H
g, re
spec
tiv
ely
) -R
edu
cti
on
of
risk
of
mac
rov
ascu
lar
end
po
ints
wer
e si
mil
ar i
n t
he
two
gro
up
s (3
1%
an
d 3
7%
sh
ow
ed
det
erio
rati
on
in
reti
no
pat
hy
by
2 g
rad
es;
5%
an
d 9
%
dev
elo
ped
cli
nic
al g
rad
e a
lbu
min
uri
a g
reate
r th
an o
r eq
ual
to
30
0 m
g/l
) -S
imil
ar p
erce
nta
ge o
f p
ati
ents
req
uir
ed 3
or
mo
re a
nti
-h
yp
erte
nsi
ve
treat
men
ts (
27
% a
nd
31
%)
or
dev
elo
ped
h
yp
og
lyce
mic
att
ack
s b
ut
mean
wt
gain
was
gre
ater
in
th
e at
eno
lol
gro
up
(1
.6 k
g v
s 3
.4k
g)
-78
% c
apto
pri
l an
d 6
5%
ate
no
lol
pati
ents
tak
ing
tre
at-
men
t at
last
vis
it (
p<
0.0
00
1)
-Blo
od
pre
ssu
re l
ow
erin
g w
ith
ca
pto
pri
l o
r ate
no
lol
was
sim
i-la
rly
eff
ecti
ve i
n r
edu
cin
g t
he
in-
cid
ence
of
dia
beti
c co
mp
lica
-
tio
ns.
T
his
stu
dy
su
gg
ests
th
at
blo
od
pre
ssu
re r
edu
cti
on
in
its
elf
m
ay b
e m
ore
im
po
rtan
t th
an t
he
trea
tmen
t u
sed
.
UK
Pro
-sp
ecti
ve
Dia
bete
s S
tud
y
Gro
up
(U
KP
DS
3
8),
19
98
RC
T
A
+
-1,1
48
hy
per
ten
siv
e p
atie
nts
wit
h t
yp
e 2
d
iab
ete
s
-75
8 p
atie
nts
all
oca
ted
to
tig
ht
con
tro
l o
f B
P w
ith
go
al
of
<1
50
/85
mm
Hg
(4
00
pa-
tien
ts t
reate
d w
ith
cap
top
ril
[25-5
0 m
g
twic
e d
ail
y],
35
8 w
ith
ate
no
lol
[50-1
00
mg
tw
ice d
ail
y])
an
d 3
90
pat
ien
ts a
llo
cate
d t
o
less
tig
ht
con
tro
l o
f B
P w
ith
go
al
of
<1
80
/10
5 m
m H
g
-All
pat
ien
ts a
ges
48
-60
yea
rs o
f ag
e (m
ean
ag
e o
f tr
eatm
ent
gro
up
s 5
6 y
ears
) -8
.4-y
ear
foll
ow
-up
-Mean
BP
was
sig
nif
ican
tly
red
uce
d i
n t
he t
igh
t B
P
gro
up
(1
44
/82
Hg
mm
) as
co
mp
ared
to
th
e le
ss-t
igh
t B
P
gro
up
(an
d 1
54
/87
mm
Hg
, p
<0
.00
01
) -R
edu
cti
on
s o
f ri
sk i
n t
he t
igh
t B
P g
rou
p a
s co
mp
ared
to
th
e le
ss t
igh
t B
P g
rou
p w
ere
24
% i
n d
iab
ete
s-re
late
d e
nd
p
oin
ts (
95
CI
8%
to
38
%,
p=
0.0
04
6),
32
% i
n d
eat
hs
re-
late
d t
o d
iab
ete
s (9
5C
I 6
% t
o 5
1%
, p
=0
.01
9),
44
% i
n
stro
kes
(9
5C
I 1
1%
to
65
%,
p=
0.0
13
), 3
7%
in
mic
rov
as-
cula
r en
d p
oin
ts (
95
CI
11
% t
o 5
6%
, p
=0
.00
92
)
-Tig
ht
BP
gro
up
had
a 3
4%
red
ucti
on
in
ris
k o
f p
rop
or-
tio
n w
ith
dete
rio
rati
on
in
reti
no
path
y b
y 2
gra
des
(9
9C
I 1
1%
to
50
%,
p=
0.0
00
4),
an
d a
47
% r
edu
ced
ris
k f
or
de-
teri
ora
tio
n i
n v
isu
al a
cuit
y (
99
CI
7%
to
70
%, p
=0
.00
4)
-Tig
ht
blo
od
pre
ssu
re c
on
tro
l in
p
atie
nts
wit
h h
yp
erte
nsi
on
an
d
typ
e 2
dia
bet
es a
chie
ved
a c
lin
i-ca
lly
im
po
rtan
t re
du
cti
on
in
th
e
risk
of
deat
hs
rela
ted
to
dia
bet
es,
com
pli
cat
ion
s re
late
d t
o d
iab
etes
, p
rog
ress
ion
of
dia
beti
c re
tin
op
a-th
y,
and
dete
rio
rati
on
in
vis
ual
ac
uit
y.
Han
sso
n e
t al
., 1
99
8
Hy
per
ten
-si
on
Op
ti-
mal
Tre
at-
men
t
(HO
T)
Tri
al
RC
T
A
ø
-1,5
10
pat
ien
ts w
ith
dia
bet
es (
amo
ng
1
8,7
90
to
tal
pat
ien
ts w
ith
hy
per
ten
sio
n
and
dia
sto
lic
BP
10
0-1
15
mm
HG
in
tri
al)
-All
pat
ien
ts a
ges
50
-80
yea
rs o
f ag
e
-Pat
ien
ts r
and
om
ly a
ssig
ned
a t
arg
et
dia
-st
oli
c B
P o
f le
ss t
han
or
equ
al
to 9
0 m
m
Hg
, 8
5 m
m H
g,
or
80
mm
Hg
-All
pat
ien
ts r
ecei
ved
felo
dip
ine
for
hy
per
-te
nsi
on
-A
CE
in
hib
ito
rs o
r B
-blo
cker
s w
ere
use
d
to t
reat
to g
iven
tar
get
dia
sto
lic B
P
-3-
to 8
-yea
r fo
llo
w-u
p
-Fo
r p
atie
nts
wit
h d
iab
etes
, th
e b
loo
d p
ress
ure
in
terv
en-
tio
n l
ed t
o a
sig
nif
ican
t re
du
cti
on
(5
1%
) in
nu
mb
er o
f m
ajo
r car
dio
vas
cula
r ev
ents
(4
5 e
ven
ts i
n 9
0 m
m H
G
gro
up
, 3
4 i
n 8
5 m
m H
G g
rou
p, an
d 2
2 i
n 8
0 m
m H
G
gro
up
; p
=0
.00
5 f
or
tren
d)
and
car
dio
vas
cula
r m
ort
alit
ies
(21
, 2
1 a
nd
7;
p=
0.0
16
) -F
or
pat
ien
ts w
ith
dia
bet
es,
the
blo
od
pre
ssu
re i
nte
rven
-
tio
n r
edu
ced
to
tal
mo
rtal
ity
(3
0, 2
9, 1
7 e
ven
ts),
MIs
(1
4,
8, 7
) an
d s
tro
ke (
17
, 1
3, 1
2),
bu
t n
on
e w
as
stati
stic
ally
si
gn
ific
ant
-In
ten
siv
e lo
wer
ing
of
BP
in
dia
-b
etes
pati
ents
wit
h h
yp
erte
nsi
on
w
as a
sso
cia
ted
wit
h a
sig
nif
i-ca
ntl
y 5
1%
lo
wer
rat
e o
f ca
rdio
-v
ascu
lar
even
ts.
Upd
ated
Thi
rteen
th E
ditio
n, M
ay 2
009.
Institute for Clinical Systems Improvement
www.icsi.org
94
Conclusion Grading Worksheet E – Annotations #13, 14 (Aspirin Use)
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Thirteenth Edition/May 2009
Upd
ated
Thi
rteen
th E
ditio
n, M
ay 2
009.
Wo
rk G
rou
p's
Co
ncl
usi
on
:
Th
ere
is i
nsu
ffic
ien
t ev
iden
ce t
o s
up
po
rt a
spir
in u
se i
n t
he
pri
mar
y p
rev
enti
on
of
card
iov
ascu
lar
even
ts i
n p
atie
nts
wit
h t
yp
e 2
dia
bet
es,
alth
ou
gh
th
ere
is n
o e
vid
ence
of
sig
nif
ican
t h
arm
. H
ow
ever
, th
ere
is s
uff
icie
nt
evid
ence
to
su
pp
ort
th
e u
se o
f as
pir
in
for
seco
nd
ary
pre
ven
tio
n o
f ca
rdio
vas
cula
r ev
ents
in
pat
ien
ts w
ith
ty
pe
2 d
iab
etes
.
Co
nclu
sio
n G
ra
de:
I
Au
tho
r/Y
ear
D
esig
n
Ty
pe
Cla
ss
Qu
al-
ity
+
,–,ø
Po
pu
lati
on
Stu
die
d/S
am
ple
Siz
e P
rim
ary
Ou
tco
me M
eas
ure
(s)/
Res
ult
s (e
.g.,
p
-val
ue,
co
nfi
den
ce
inte
rval
, re
lati
ve
risk
, o
dd
s ra
tio
, li
kel
iho
od
rati
o,
nu
mb
er n
eed
ed
to t
reat)
Au
tho
rs' C
on
clu
sio
ns/
W
ork
Gro
up
's C
om
men
ts (
ita
lici
zed
)
Ear
ly T
reat-
men
t D
ia-
bet
ic R
eti-
no
pat
hy
S
tud
y
(ET
DR
S)
Rep
ort
14
, 1
99
2
RC
T
A
ø
-3,7
11
pat
ien
ts w
ith
dia
bet
es m
ell
itu
s (3
1%
ty
pe 1
, 3
1%
ty
pe
2,
and
39
% t
yp
e 1
o
r 2
) ra
nd
om
ized
to
rece
ive a
spir
in o
r p
la-
ceb
o (
65
0 m
g t
wic
e d
ail
y)
-All
pat
ien
ts a
ges
18-7
0 y
ears
of
age
-5-y
ear
foll
ow
-up
-RR
fo
r to
tal
mo
rtal
ity
was
0.9
1 (
99C
I 0
.75
-1
.11
, p
=N
S)
ov
erall
an
d 0
.92
in
ty
pe 2
p
atie
nts
(9
9C
I 0
.69
-1.2
3, p
=N
S)
trea
ted
vs.
p
laceb
o p
ati
ents
-M
yo
car
dia
l in
farc
tio
n r
ate
s w
ere
9.1
% w
ith
as
pir
in a
nd
12
.3%
wit
h p
laceb
o (
RR
0.8
3,
p=
0.0
4)
ov
erall
-T
he
NN
T t
o p
rev
ent
on
e M
I in
5 y
ears
wit
h
asp
irin
was
31
pati
ents
-Asp
irin
use
may
red
uce
th
e ri
sk o
f m
yo
-ca
rdia
l in
farc
tio
n i
n a
du
lts
wit
h d
iab
etes
bu
t d
id n
ot
red
uce
to
tal
mo
rtali
ty o
r C
V m
ort
al-
ity
rat
es.
-Th
ere
was
no
ev
iden
ce
of
har
mfu
l ef
fect
s o
f as
pir
in.
-Th
e E
TD
RS
res
ult
s su
pp
ort
use
of
asp
irin
in
per
son
s w
ith
dia
bete
s at
incr
ease
d r
isk
of
card
iov
asc
ula
r d
iseas
e.
Han
sso
n e
t al
., 1
99
8
Hy
per
ten
sio
n
Op
tim
al
Tre
atm
ent
(HO
T)
Tri
al
RC
T
A
ø
-1,5
10
pat
ien
ts w
ith
dia
bet
es (
amo
ng
1
8,7
90
to
tal
pat
ien
ts w
ith
hy
per
ten
sio
n
and
dia
sto
lic
BP
10
0-1
15
mm
HG
in
tri
al)
-All
pat
ien
ts a
ges
50-8
0 y
ears
of
age
-P
atie
nts
ran
do
mly
ass
ign
ed a
tar
get
dia
-st
oli
c B
P o
f le
ss t
han
or
equ
al
to 9
0 m
m
Hg
, 8
5 m
m H
g,
or
80
mm
Hg
-All
stu
dy
su
bje
cts
wer
e ra
nd
om
ized
to
re
ceiv
e a
spir
in 7
5 m
g/d
ay o
r p
laceb
o
-3 t
o 8
-yea
r fo
llo
w-u
p
-Fo
r al
l p
atie
nts
, as
pir
in u
se s
ign
ific
antl
y r
e-d
uce
d c
ard
iov
asc
ula
r ev
ents
15
% (
p=
0.0
3)
and
red
uced
MI
rate
s 3
6%
(p
=0
.00
2)
bu
t d
id
no
t re
du
ce
mo
rtali
ty
-Th
e re
lati
ve
ben
efit
of
asp
irin
to
th
ose
wit
h
dia
bete
s w
as
“ab
ou
t th
e s
ame”
as
in t
he
wh
ole
tri
al p
op
ula
tio
n
-Use
of
asp
irin
in
dia
bete
s an
d i
n n
on-
dia
bete
s p
ati
ents
sig
nif
ican
tly
red
uced
MIs
(3
6%
) an
d c
ard
iov
ascu
lar
even
ts (
15
%)
bu
t d
id n
ot
sig
nif
ican
tly
red
uce
mo
rtal
ity
. -A
spir
in u
se (
75
mg
/day
) ap
pear
s to
ben
efit
d
iab
ete
s p
ati
ents
wit
h h
yp
erte
nsi
on
, ev
en
tho
se i
n w
ho
m b
loo
d p
ress
ure
is
ver
y w
ell
con
tro
lled
.
Har
paz
, et
al.,
19
98
Co
ho
rt
B
+
-2,3
68
NID
DM
ad
ult
s w
ith
CH
D a
nd
8,5
86
no
n-N
IDD
M a
du
lts
wit
h C
HD
-M
ean
fo
llo
w-u
p 5
.1 y
ears
-5
2%
of
NID
DM
pat
ien
ts r
epo
rted
no
A
SA
use
-All
-cau
se m
ort
ali
ty w
as 1
8.4
% i
n N
IDD
M
AS
A u
sers
an
d 2
6.2
% i
n N
IDD
M A
SA
no
n-
use
rs (
p <
0.0
01
) -C
ard
iac m
ort
ali
ty w
as 1
0.9
% i
n
NID
DM
A
SA
use
rs a
nd
15
.9%
in
NID
DM
AS
A n
on-
use
rs (
p <
0.0
01
) -B
oth
sig
nif
ican
t d
iffe
ren
ces
per
sist
ed a
fter
ad
just
men
t fo
r p
oss
ible
co
nfo
un
der
s
-Tre
atm
ent
wit
h A
SA
was
ass
ocia
ted
wit
h a
sig
nif
ican
t re
du
ctio
n i
n c
ard
iac a
nd
to
tal
mo
rtali
ty a
mo
ng
NID
DM
ad
ult
s w
ith
CH
D.
-Th
e ab
solu
te b
enef
it o
f as
pir
in w
as g
reate
r in
dia
bete
s v
ersu
s n
on-d
iab
ete
s ad
ult
s.
Ph
ysi
cia
n’s
Hea
lth
Stu
dy
R
esea
rch
G
rou
p, 1
98
9
RC
T
A
ø
-Pri
mar
y p
rev
enti
on
of
MI
in s
ub
gro
up
of
53
3 p
hy
sici
ans
wit
h d
iab
etes
(am
on
g
22
,07
1 t
ota
l p
arti
cip
ants
) -P
atie
nts
ran
do
miz
ed t
o e
ith
er 3
25
mg
A
SA
/day
or
pla
ceb
o
-Mean
fo
llo
w-u
p 5
year
s
-Ov
eral
l, 4
4%
red
uct
ion
in
MI
(p<
0.0
00
01
)
in t
ho
se w
ho
to
ok
AS
A
-In
dia
bete
s su
bg
rou
p, 4
.0%
had
MI
in A
SA
g
rou
p (
11
/27
5)
and
10
.1%
had
MI
in n
on-
AS
A g
rou
p (
p=
0.2
2, N
S)
-Rela
tiv
e ri
sk o
f M
I in
AS
A g
rou
p w
as 0
.60
in
en
tire
co
ho
rt,
and
0.3
9 i
n d
iab
ete
s
-Asp
irin
red
uce
d M
I ra
te i
n o
ver
all
stu
dy
.
-Ben
efit
s in
DM
gro
up
ap
pea
r to
be
at l
east
as
gre
at a
s in
no
n-D
M g
rou
p.
-Th
e n
on
-sig
nif
ica
nt
dif
fere
nce
s in
DM
g
rou
p w
ere
like
ly d
ue t
o s
ma
ll s
am
ple
siz
e a
nd
in
suff
icie
nt
po
wer.
Institute for Clinical Systems Improvement
www.icsi.org
95
Conclusion Grading Worksheet E – Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Annotations #13, 14 (Aspirin Use) Thirteenth Edition/May 2009
Au
tho
r/Y
ear
Des
ign
T
yp
e C
lass
Q
ual
-it
y
+,–
,ø
Po
pu
lati
on
Stu
die
d/S
am
ple
Siz
e P
rim
ary
Ou
tco
me M
eas
ure
(s)/
Res
ult
s (e
.g.,
p
-val
ue,
co
nfi
den
ce
inte
rval
, re
lati
ve
risk
, o
dd
s ra
tio
, li
kel
iho
od
rati
o,
nu
mb
er n
eed
ed
to t
reat)
Au
tho
rs' C
on
clu
sio
ns/
W
ork
Gro
up
's C
om
men
ts (
ita
lici
zed
)
Og
awa,
et a
l.,
20
08
RC
T
A
+
2,5
39
pat
ien
ts w
ith
ty
pe 2
dia
bete
s fr
ee
of
ath
ero
scle
roti
c d
isea
se r
ecru
ited
fro
m 1
63
in
-
stit
uti
on
s th
rou
gh
ou
t Ja
pan
. P
ati
ents
wer
e
ran
do
miz
ed t
o 8
1 o
r 1
00
mg
asp
irin
per
day
or
no
n-a
spir
in g
rou
p (
JPA
D s
tud
y).
Tri
al
was
con
du
cted
fro
m 2
00
2-2
00
6.
Med
ian
fo
llo
w-u
p t
ime
was
4.3
7 y
ears
.
Th
e p
rim
ary
ou
tco
me
was
ath
ero
scle
roti
c
even
ts,
inclu
din
g f
ata
l an
d n
on
-fat
al
isch
emic
hea
rt d
iseas
e, fa
tal
and
no
n-f
ata
l
stro
ke,
an
d p
erip
her
al
arte
rial
dis
ease
.
Haz
ard
rati
os:
(9
5%
co
nfi
den
ce
inte
rval
s)
All
ath
ero
scle
roti
c ev
ents
: 0
.80
(0
.58
-1.1
0)
Co
ron
ary
an
d c
ereb
rov
ascu
lar
mo
rtal
ity
:
0.1
0 (
0.0
1-0
.79
)
CH
D e
ven
ts (
fata
l an
d n
on-f
atal)
: 0
.81
(0
.49
-
1.3
3)
No
n-f
atal
MI:
1.3
4 (
0.5
7-3
.19
)
Un
stab
le a
ng
ina:
0.4
0 (
0.1
3-1
.29
)
Sta
ble
an
gin
a: 1
.10
(0
.49-2
.50
)
Cer
ebro
vas
cula
r d
iseas
e (f
ata
l an
d n
on-
fata
l):
0.8
4 (
0.5
3-1
.32
)
Fat
al s
tro
ke:
0.2
0 (
0.2
4-1
.74
)
No
n-f
atal
stro
ke
isch
emic
: 0
.93
(0
.52-1
.66
)
No
n-f
atal
stro
ke
hem
orr
hag
ic:
1.6
8 (
0.4
0-
7.0
4)
Tra
nsi
ent
isch
em
ic a
ttack
: 0
.63
(0
.21-1
.93
)
PA
D:
0.6
4 (
0.2
5-1
.65
)
Th
e au
tho
rs c
on
clu
de
that
low
-do
se a
spir
in
use
do
es n
ot
red
uce
car
dio
vas
cula
r ev
ents
in p
ati
ents
wit
h t
yp
e 2
dia
bet
es.
Th
is s
tud
y f
aced
tw
o i
mp
ort
ant
lim
itati
on
s:
1)
th
e s
tud
y d
esig
n w
as
no
t b
lin
ded
be-
cau
se l
aw i
n J
apan
do
es n
ot
allo
w d
octo
rs
to d
isp
ense
pla
ceb
o;
and
2)
the
ath
ero
scle
-
roti
c e
ven
t ra
te w
as l
ow
er t
han
an
tici
pat
ed
and
as
a r
esu
lt,
the
JPA
D t
rial
was
no
t
po
wer
ed t
o d
emo
nst
rate
th
at a
spir
in h
ad a
sig
nif
ican
t ef
fect
on
red
ucin
g t
ota
l at
her
o-
scle
roti
c e
ven
ts.
Ho
wev
er,
the
auth
ors
ad
e-
qu
ately
ack
no
wle
dg
e th
ese
lim
itati
on
s.
Ad
dit
ion
ally
, th
ey i
nd
icate
th
at t
he
resu
lts
sho
uld
be
tak
en i
nto
th
e co
nte
xt
of
low
ath
ero
scle
roti
c d
isea
se r
ates
in
Jap
an.
Institute for Clinical Systems Improvement
www.icsi.org
96
Au
tho
r/Y
ear
Des
ign
T
yp
e C
lass
Q
ual
-it
y
+,–
,ø
Po
pu
lati
on
Stu
die
d/S
am
ple
Siz
e P
rim
ary
Ou
tco
me M
eas
ure
(s)/
Res
ult
s (e
.g.,
p
-val
ue,
co
nfi
den
ce
inte
rval
, re
lati
ve
risk
, o
dd
s ra
tio
, li
kel
iho
od
rati
o,
nu
mb
er n
eed
ed
to t
reat)
Au
tho
rs' C
on
clu
sio
ns/
W
ork
Gro
up
's C
om
men
ts (
ita
lici
zed
)
Belc
h, et
al.,
20
08
RC
T
A
+
1,2
76
ad
ult
s ag
ed 4
0 o
r m
ore
yea
rs w
ith
ty
pe
1 o
r ty
pe 2
dia
bete
s an
d a
nk
le b
rach
ial
pre
s-
sure
in
dex
of
0.9
9 o
r le
ss b
ut
no
sy
mp
tom
atic
CV
D.
Pat
ien
ts w
ere r
and
om
ized
to
10
0 m
g
asp
irin
per
day
plu
s an
tio
xid
ant
cap
sule
(n=
32
0),
pla
ceb
o t
able
t p
lus
anti
ox
idan
ts c
ap-
sule
(n
=3
20
), o
r p
laceb
o t
able
t p
lus
pla
ceb
o
cap
sule
(n
=3
18
).
Th
e m
edia
n l
eng
th o
f fo
llo
w-u
p w
as
6.7
yea
rs
and
fo
r th
ose
wit
h a
fin
al
foll
ow
-up
in
20
06
,
foll
ow
-up
ran
ged
fro
m 4
.5 t
o 8
.6 y
ear
s, r
e-
sult
ing
in
a t
ota
l 8
.12
7 p
erso
n-y
ears
of
ob
serv
atio
n.
Th
ere w
ere
two
pri
mar
y o
utc
om
e m
easu
res:
1)
a co
mp
osi
te o
f d
eat
h f
rom
CH
D o
r st
rok
e,
no
n-f
atal
MI
or
stro
ke, o
r am
pu
tati
on
ab
ov
e
the
ank
le f
or
crit
ical
lim
b i
sch
em
ia;
or
2)
dea
th f
rom
CH
D o
r st
rok
e. S
eco
nd
ary
end
-
po
ints
in
clu
ded
death
fro
m a
ny
cau
se;
dea
th
fro
m s
tro
ke, n
on
-fat
al
MI
or
stro
ke, o
r am
pu
-
tati
on
ab
ov
e th
e an
kle
fo
r cr
itic
al
lim
b
isch
emia
; d
evel
op
men
t o
f an
gin
a; C
AB
G;
ang
iop
last
y;
PA
D b
yp
ass
surg
ery
; P
AD
an
-
gio
pla
sty
.
Haz
ard
rati
os
(95
% c
on
fid
ence
in
terv
als
) fo
r
asp
irin
vs.
no
n-a
spir
in
Co
mp
osi
te e
nd
po
int:
0.9
8 (
0.7
6-1
.26
)
Dea
th f
rom
CH
D o
r st
rok
e: 1
.23
(0
.79-1
.93
)
Dea
th a
ny
cau
se:
0.9
3 (
0.7
1-1
.24
)
CH
D d
eath
: 0
.93
(0
.81-2
.25
)
Str
ok
e d
eath
: 0
.89
(0
.34-2
.30
)
No
n-f
atal
MI:
0.9
8 (
0.6
8-1
.43
)
No
n-f
atal
stro
ke:
0.7
1 (
0.4
4-1
.14
)
Ab
ov
e-an
kle
am
pu
tati
on
: 1
.23
(0
.51-2
.97
)
Tra
nsi
ent
isch
em
ic a
ttack
: 0
.70
(0
.36-1
.39
)
Th
e au
tho
rs f
ou
nd
no
ev
iden
ce t
o s
up
po
rt
the
use
of
asp
irin
in
th
e p
rim
ary
pre
ven
tio
n
of
card
iov
ascu
lar
even
ts o
r m
ort
alit
y i
n
peo
ple
wit
h d
iab
ete
s.
Th
e a
uth
ors
no
te t
hat
asp
irin
sh
ou
ld b
e u
sed
fo
r se
con
dar
y p
re-
ven
tio
n o
f ca
rdio
vas
cula
r ev
ents
.
Th
is s
tud
y w
as o
rig
inall
y d
esig
ned
to
re-
cru
it 1
,60
0 p
ati
ents
wit
h f
oll
ow
-up
of
fou
r
yea
rs,
wit
h o
ne e
ffec
tiv
e tr
eatm
ent
that
wo
uld
hav
e p
rov
ided
po
wer
of
90
% t
o d
e-
tect
a 2
5%
rel
ativ
e r
isk
red
ucti
on
in
a f
ou
r-
yea
r ev
ent
rate
of
28
% (
8%
per
an
nu
m a
t
the
0.0
5 l
evel)
– e
qu
atin
g t
o 3
92
ev
ents
.
Wit
h b
oth
tre
atm
ents
eq
ual
ly e
ffec
tiv
e, t
hat
wo
uld
hav
e p
rov
ided
80
% p
ow
er t
o d
etec
t
for
each
tre
atm
ent
rate
th
e s
am
e r
ela
tiv
e re
-
du
ctio
n i
n e
ven
t ra
te a
s si
gn
ific
ant, r
esu
lt-
ing
in
34
3 e
ven
ts.
Ho
wev
er,
du
e to
slo
wer
than
an
ticip
ate
d r
ecru
itm
ent
and
lo
wer
even
t ra
tes,
on
ly 1
,27
6 p
ati
ents
wer
e re
-
cru
ited
, w
ith
25
6 e
ven
ts r
esu
ltin
g p
ow
er b
e-
ing
red
uced
to
73
% t
o d
etec
t a
25
% r
ela
tiv
e
red
uct
ion
in
ev
ent
rate
an
d 8
9%
po
wer
to
det
ect
a 3
0%
red
ucti
on
in
ev
ent
rate
if
on
ly
on
e tr
eatm
ent
was
eff
ect
ive.
Wal
sh
and
Sp
url
ing
,
20
08
Nar
rati
ve
rev
iew
R
- N
arra
tiv
e r
evie
w o
f ev
iden
ce
to s
up
po
rt p
ro-
ph
yla
cti
c u
se o
f as
pir
in i
n t
yp
e 2
dia
bete
s.
Su
mm
ariz
ed f
ind
ing
s fr
om
a s
yst
emat
ic r
e-
vie
w t
hat
on
ly e
xam
ined
dia
bete
s as
a s
ub
set
of
the
stu
dy
; als
o,
they
rev
iew
ed 3
ran
dom
-
ized
co
ntr
oll
ed t
rial
s.
Th
e s
yst
em
ati
c re
vie
w
and
2 o
f th
e R
CT
s d
id n
ot
sup
po
rt t
he
use
of
asp
irin
in
peo
ple
wit
h d
iab
etes
fo
r p
rev
en-
tio
n o
f M
I o
r m
ort
ali
ty.
On
ly o
ne
(sm
all
)
RC
T s
up
po
rted
th
e u
se o
f as
pir
in.
Th
e au
tho
rs c
on
clu
de
that
mo
st a
vail
able
evid
ence
do
no
t su
pp
ort
gu
ideli
nes
fro
m t
he
Am
eric
an D
iab
ete
s A
sso
ciat
ion
an
d t
he
Au
stra
lian
Nat
ion
al H
eal
th a
nd
Med
ical
Res
earc
h C
ou
nci
l.
Conclusion Grading Worksheet E – Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Annotations #13, 14 (Aspirin Use) Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
97
Au
tho
r/Y
ear
Des
ign
T
yp
e C
lass
Q
ual
-it
y
+,–
,ø
Po
pu
lati
on
Stu
die
d/S
am
ple
Siz
e P
rim
ary
Ou
tco
me M
eas
ure
(s)/
Res
ult
s (e
.g.,
p
-val
ue,
co
nfi
den
ce
inte
rval
, re
lati
ve
risk
, o
dd
s ra
tio
, li
kel
iho
od
rati
o,
nu
mb
er n
eed
ed
to t
reat)
Au
tho
rs' C
on
clu
sio
ns/
W
ork
Gro
up
's C
om
men
ts (
ita
lici
zed
)
Gae
de,
et
al.
, 2
00
8
Th
e S
ten
o-2
S
tud
y
RC
T
A
- 1
60
pat
ien
ts w
ith
ty
pe
2 d
iab
etes
an
d p
ersi
s-te
nt
mic
roal
bu
nar
ia w
ere
ran
do
miz
ed t
o r
e-ce
ive
eith
er i
nte
nsi
ve
ther
apy
or
con
ven
tio
nal
th
erap
y.
Th
e m
ean
tre
atm
ent
per
iod
was
7.8
y
ears
.
Th
e p
rim
ary
en
d p
oin
t w
as d
eath
fro
m a
ny
ca
use
. 2
4 p
atie
nts
die
d i
n t
he
inte
nsi
ve
ther
-ap
y g
rou
p c
om
par
ed w
ith
40
in
th
e co
nv
en-
tio
n t
her
apy
gro
up
, (H
azar
d r
atio
0.5
4, [9
5%
co
nfi
den
ce i
nte
rval
0.3
2-0
.89
]).
In
ten
siv
e th
erap
y w
as a
sso
ciat
ed w
ith
a
low
er r
isk
of
dea
th f
rom
car
dio
vas
cula
r ca
use
s, (
Haz
ard
rat
io 0
.43
(9
5%
CI
0.1
9-
0.9
4)
and
lo
wer
ris
k o
f ca
rdio
vas
cula
r ev
ents
(H
azar
d r
atio
0.4
1 [
95
% C
I 0
.25
-0.6
7])
. A
spir
in u
se f
or
the
inte
nsi
ve
vs.
con
ven
tio
nal
g
rou
p, re
spec
tiv
ely
, w
ere
14
% a
nd
13
% a
t b
asel
ine,
87
% a
nd
56
% a
t en
d o
f in
terv
en-
tio
n,
and
85
% a
nd
76
% a
t en
d o
f fo
llo
w-u
p.
At
the
end
of
foll
ow
-up
, th
ere
was
no
t a
sta-
tist
ical
dif
fere
nce
in
asp
irin
use
bet
wee
n
gro
up
s.
Th
e au
tho
rs c
on
clu
de
that
in
at-
risk
pat
ien
ts
wit
h t
yp
e 2
dia
bet
es,
inte
nsi
ve
inte
rven
tio
n
wit
h m
ult
iple
dru
g c
om
bin
atio
ns
and
be-
hav
ior
mo
dif
icat
ion
had
su
stai
ned
ben
efi-
cial
eff
ects
wit
h r
esp
ect
to v
ascu
lar
com
pli
-ca
tio
ns
and
on
rat
es o
f d
eath
fro
m a
ny
ca
use
an
d f
rom
car
dio
vas
cula
r ca
use
s.
Th
is s
tud
y w
as n
ot
des
ign
ed t
o i
den
tify
w
hic
h e
lem
ents
of
inte
nsi
ve
dia
bet
es t
her
-ap
y c
on
trib
ute
d m
ost
to
red
uct
ion
in
car
-d
iov
ascu
lar
risk
.
[Wit
h r
ega
rd t
o a
spir
in,
ther
e i
s n
o e
vi-
den
ce i
n t
his
pa
per
th
at
dir
ectl
y su
pp
ort
s
the
use
of
asp
irin
fo
r p
rim
ary
pre
ven
tio
n i
n
pa
tien
ts w
ith
dia
bete
s.
Ba
sed
on
th
e fi
nd
-
ing
s p
rese
nte
d,
it i
s im
po
ssib
le t
o d
ete
rmin
e
wh
at,
if
an
y, o
f th
e b
enefi
t is
att
rib
uta
ble
to
asp
irin
. I
t is
fu
rth
er c
om
pli
cate
d b
y fa
ct
tha
t a
t th
e en
d o
f th
e fo
llo
w-u
p p
eri
od
,
ther
e w
as
no
dif
fere
nce
in a
spir
in u
se b
e-
twee
n g
rou
ps.
]
Sir
ois
, et
al.,
20
08
Sy
stem
-
atic
re-
vie
w
M
Ø
Med
lin
e an
d E
mb
ase
dat
abas
es w
ere
sear
ched
for
stu
die
s ev
alu
atin
g t
he
effe
ct o
f as
pir
in o
n
card
iov
ascu
lar
ou
tco
mes
in
pat
ien
ts w
ith
ty
pe
2 d
iab
etes
.
Fo
ur
stu
die
s m
et t
he
incl
usi
on
cri
teri
a –
th
ree
RC
Ts
and
on
e o
bse
rvat
ion
al s
tud
y.
Th
e th
ree
RC
Ts
did
no
t p
rov
ide
evid
ence
to
sup
-p
ort
asp
irin
th
erap
y i
n t
yp
e 2
dia
bet
es.
Re-
du
ctio
n i
n c
ard
iac
mo
rtal
ity
was
fo
un
d i
n t
he
ob
serv
atio
nal
stu
dy
.
Th
ese
fin
din
gs
sug
ges
t th
at t
he
clin
ical
gu
idel
ines
may
be
bas
ed o
n e
xp
ecte
d b
ene-
fit
corr
elat
ed t
o w
hat
has
bee
n o
bse
rved
in
o
ther
hig
h-r
isk
po
pu
lati
on
s.
G
iven
th
e la
ck o
f h
ard
ev
iden
ce a
nd
th
e d
if-
fere
nce
in
pla
tele
t p
hy
sio
log
y i
n d
iab
etes
p
atie
nts
, as
pir
in u
se a
s a
stan
dar
d t
reat
men
t sh
ou
ld b
e re
vis
ited
.
Conclusion Grading Worksheet E – Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Annotations #13, 14 (Aspirin Use) Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
98
Au
tho
r/
Yea
r D
esig
n
Ty
pe
Cla
ss
Qu
al-
ity
+
,–,ø
Po
pu
lati
on
Stu
die
d/S
am
ple
Siz
e P
rim
ary
Ou
tco
me M
eas
ure
(s)/
Res
ult
s (e
.g.,
p
-val
ue,
co
nfi
den
ce
inte
rval
, re
lati
ve
risk
, o
dd
s ra
tio
, li
kel
iho
od
rati
o,
nu
mb
er n
eed
ed
to t
reat)
Au
tho
rs' C
on
clu
sio
ns/
W
ork
Gro
up
's C
om
men
ts (
ita
lici
zed
)
Ev
ang
elis
ta,
et a
l.,
20
07
C
ase
con
tro
l st
ud
y
C
Ø
Cas
es w
ere
82
pat
ien
ts w
ho
wer
e ta
kin
g a
s-p
irin
10
0 m
g/d
ay f
or
at l
east
on
e m
on
th w
ith
an
d w
ith
ou
t p
rio
r C
VD
ev
ents
. C
on
tro
ls p
a-ti
ents
wer
e id
enti
fied
am
on
g t
ho
se a
tten
din
g
card
iolo
gy
ou
tpat
ien
t u
nit
fo
r a
rou
tin
e v
isit
. C
on
tro
l p
atie
nts
did
no
t h
ave
dia
bet
es.
Con
-se
cuti
ve
pat
ien
ts w
ere
enro
lled
wit
h a
mat
ch
of
2:1
(ca
ses:
con
tro
ls).
Th
e o
bje
ctiv
e o
f th
is s
tud
y w
as t
o e
xp
lore
th
e h
yp
oth
esis
th
at a
spir
in i
s le
ss l
ikel
y t
o
adeq
uat
ely
su
pp
ress
bio
chem
ical
mar
ker
s o
f in
flam
mat
ion
an
d p
late
let
acti
vat
ion
in
pa-
tien
ts w
ith
dia
bet
es c
om
par
ed t
o t
ho
se w
ith
-o
ut
dia
bet
es.
Th
e re
sult
s sh
ow
ed t
hat
Tx
A2
(p
har
mac
ol-
og
ical
tar
get
of
asp
irin
) sy
nth
esis
an
d c
ircu
-la
tio
n l
evel
s o
f m
ark
ers
of
pla
tele
t ac
tivat
ion
sC
D4
0L
an
d s
P-s
elec
tio
n)
in p
atie
nts
wit
h
and
wit
ho
ut
dia
bet
es w
ho
wer
e tr
eate
d w
ith
lo
w-d
ose
asp
irin
. T
he
od
ds
of
hav
ing
11-
deh
yd
ro-T
xB
2 w
ith
in t
he
up
per
qu
arti
le w
as
3.9
(9
5%
CI
1.1
-14
.3)
in p
atie
nts
wit
h d
iabe-
tes
com
par
ed t
o c
on
tro
ls.
Th
e o
dd
s o
f h
av-
ing
sC
D4
0L
an
d s
P-s
elec
tio
n w
ith
in t
he
up
-p
er q
uar
tile
was
12
.6 (
95
% C
I 2
.4-6
5.5
) h
igh
er i
n c
ases
th
an c
on
tro
ls.
Th
ere
wer
e n
ot
sub
stan
tial
dif
fere
nce
s in
lo
w-g
rad
e in
flam
mat
ory
rea
ctio
n b
etw
een
ca
ses
and
co
ntr
ols
.
Th
e au
tho
rs s
ug
ges
t re
con
sid
erat
ion
of
the
clin
ical
ph
arm
aco
log
y o
f as
pir
in i
n d
iab
e-te
s.
Th
ey f
urt
her
ex
pla
in t
hat
th
e si
mil
arit
y o
f in
flam
mat
ory
mar
ker
s in
cas
es a
nd
con
tro
ls
ind
icat
es a
sim
ilar
ath
ero
scle
roti
c an
d in
-
flam
mat
ory
bac
kg
rou
nd
an
d s
ug
ges
ts t
hat
u
p-r
egu
lati
on
of
the
pla
tele
t re
spon
se i
s n
ot
mai
nly
rel
ated
to
dif
fere
nce
s in
vas
cula
r-in
flam
mat
ory
en
vir
on
men
t.
Rat
her
, an
up-
reg
ula
tio
n o
f p
late
let
resp
on
se a
pp
ears
to
be
du
e to
in
trin
sic
pla
tele
t al
tera
tio
n a
sso
ciat
ed
wit
h i
nsu
ffic
ien
t m
etab
oli
c co
ntr
ol.
Conclusion Grading Worksheet E – Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Annotations #13, 14 (Aspirin Use) Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
99
Au
tho
r/
Yea
r D
esig
n
Ty
pe
Cla
ss
Qu
al-
ity
+
,–,ø
Po
pu
lati
on
Stu
die
d/S
am
ple
Siz
e P
rim
ary
Ou
tco
me M
eas
ure
(s)/
Res
ult
s (e
.g.,
p
-val
ue,
co
nfi
den
ce
inte
rval
, re
lati
ve
risk
, o
dd
s ra
tio
, li
kel
iho
od
rati
o,
nu
mb
er n
eed
ed
to t
reat)
Au
tho
rs' C
on
clu
sio
ns/
W
ork
Gro
up
's C
om
men
ts (
ita
lici
zed
)
Ser
ebru
-an
y, et
al.
, 2
00
8
PL
UT
O-
Dia
bet
es
Tri
al
RC
T
A
Ø
70
pat
ien
ts w
ith
do
cum
ente
d d
iab
etes
alr
ead
y
trea
ted
wit
h a
nte
ced
ent
asp
irin
wer
e ra
nd
om
ly
assi
gn
ed t
o r
ecei
ve
clo
pid
og
rel
and
81
mg
as-
pir
in o
r 8
1 m
g a
spir
in a
lon
e.
Th
e p
rim
ary
ob
ject
ive
of
this
stu
dy
was
to
co
mp
are
chan
ges
in
mu
ltip
le p
late
let
acti
va-
tio
n b
iom
ark
ers
wit
h 2
an
tip
late
let
stra
teg
ies
ov
er a
tre
atm
ent
per
iod
of
3 d
ays.
T
her
e w
ere
no
sig
nif
ican
t ch
ang
es f
rom
b
asel
ine
to 3
0 d
ays
in t
he
asp
irin
-alo
ne
gro
up
. I
n t
he
clo
pid
og
rel-
plu
s-as
pir
in g
rou
p,
ther
e w
as s
ign
ific
ant
inh
ibit
ion
of
pla
tele
t ac
tiv
ity
ass
esse
d b
y a
den
osi
ne
dip
ho
sph
ate
agg
reg
atio
n (
p=
0.0
00
1),
clo
sure
tim
e p
ro-
lon
gat
ion
(p
=0
.00
03
) an
d r
edu
ctio
n o
f p
late
-le
t ac
tiv
atio
n u
nit
s (p
=0
.00
01
) an
d e
xp
res-
sio
n o
f p
late
let/
end
oth
elia
l ce
ll a
dh
esio
n
mo
lecu
le (
p=
0.0
2),
gly
cop
rote
in a
nti
gen
(p
=0
.00
02
).
Th
e au
tho
rs c
on
clu
de
that
tre
atm
ent
wit
h
clo
pid
og
rel
and
asp
irin
fo
r 1
mo
nth
pro
-v
ides
sig
nif
ican
tly
gre
ater
in
hib
itio
n o
f p
late
let
acti
vit
y t
han
asp
irin
alo
ne
in p
a-ti
ents
wit
h t
yp
e 2
dia
bet
es.
Th
is i
s in
con
-tr
ast
to i
den
tica
lly
des
ign
ed s
tud
ies
in c
oro
-n
ary
art
ery
dis
ease
, p
ost
-str
ok
e o
r h
eart
fail
ure
pat
ien
ts w
ho
ex
hib
it l
ow
er r
esid
ual
p
late
let
acti
vat
ion
co
mp
ared
to
dia
bet
es p
a-ti
ents
.
Th
e im
pli
cati
on
s o
f th
is s
tud
y f
or
clin
ical
p
ract
ice
are
no
t ev
iden
t. It
can
no
t b
e de-
term
ined
fro
m t
his
sh
ort
stu
dy
wh
eth
er
mo
re p
ote
nt
anti
-pla
tele
t p
ote
ncy
wit
h
com
bin
atio
n t
her
apy
wil
l re
sult
in
bet
ter
ou
tco
mes
.
[Th
is s
tud
y i
s d
esi
gn
ed a
s a
pil
ot, s
o i
t is
no
t p
ow
ered
ad
equ
ate
ly t
o d
etec
t sm
all
dif
-
fere
nces
.]
Conclusion Grading Worksheet E – Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Annotations #13, 14 (Aspirin Use) Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
100
Conclusion Grading Worksheet F – Annotations #28, 36 (Treatment with ACE Inhibitors or ARBs)
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Thirteenth Edition/May 2009
Work
Grou
p's
Con
clu
sion
: F
or
pat
ien
ts w
ith
ty
pe
2 d
iab
etes
mel
litu
s, A
CE
in
hib
ito
rs o
r A
RB
s ca
n r
edu
ce p
rog
ress
ion
of
mic
ro-
and
mac
rov
ascu
lar
com
pli
cati
on
s.
Con
clu
sio
n G
rad
e: I
Au
tho
r/
Yea
r
De-
sig
n
Ty
pe
Cla
ss
Qu
al-
ity
+
,–,ø
Po
pu
lati
on
Stu
die
d/S
am
ple
Siz
e P
rim
ary
Ou
tco
me M
eas
ure
(s)/
Res
ult
s (e
.g.,
p-v
alu
e,
con
fid
ence
inte
rval
, re
lati
ve r
isk
, o
dd
s ra
tio
, li
kel
iho
od
ra
tio
, n
um
ber
need
ed t
o t
reat)
Au
tho
rs' C
on
clu
sio
ns/
Wo
rk G
rou
p's
Co
mm
ents
(it
ali
cize
d)
Lew
is,
et
al.,
NE
JM,
20
01
RC
T
A
+
-1,7
15
pat
ien
ts (
30
-70
yea
rs)
fro
m 2
10
cl
inic
al
cen
ters
wit
h h
yp
erte
nsi
on
, n
eph
-ro
pat
hy
(u
rin
ary
pro
tein
ex
cret
ion
>8
99
m
g/2
4 h
ou
r), cr
eati
nin
e 1
.0-3
.0 m
g/d
L
(men
) o
r 1
.2-3
.0 m
g/d
L (
wo
men
), a
nd
ty
pe
2 d
iab
etes
-P
atie
nts
ran
do
mly
ass
ign
ed 3
00
mg
/day
o
f ir
bes
arta
n, 1
0 m
g/d
ay o
f am
lod
ipin
e,
or
pla
ceb
o
-Pat
ien
t, p
rov
ider
an
d d
ata
analy
sts
wer
e b
lin
ded
-Mean
fo
llo
w-u
p 2
.6 y
ears
-Pri
mar
y c
om
po
site
en
d p
oin
t (P
CE
): d
ou
bli
ng
bas
e-li
ne c
reati
nin
e, o
nse
t o
f E
SR
D (
dia
lysi
s, t
ran
spla
nta
-ti
on
or
creat
inin
e >
5.9
mg
/dL
), o
r d
eat
h f
rom
an
y
cau
se
-Car
dio
vas
cula
r co
mp
osi
te e
nd
po
int
(CC
E):
car
dio
-v
ascu
lar
dea
th, n
on-f
ata
l M
I, C
HF
req
uir
ing
hosp
ital
i-za
tio
n,
per
man
ent
neu
rolo
gic
al
def
icit
fro
m C
VA
, o
r lo
wer
lim
b a
mp
uta
tio
n a
bo
ve a
nk
le
-PC
E s
ho
wed
a 2
0%
rela
tiv
e ri
sk (
RR
) re
du
ctio
n f
or
irb
esar
tan
vs.
pla
ceb
o (
p=
0.0
06
) an
d a
23
% R
R r
educ-
tio
n f
or
irb
esar
tan
vs.
am
lod
ipin
e (
p=
0.0
06
)
-Th
ere
wer
e n
o s
ign
ific
ant
dif
fere
nce
s in
CC
Es
or
rate
s o
f d
eath
fro
m a
ny
cau
se b
etw
een
gro
up
s
-Th
e an
gio
ten
sin
-II-
recep
tor
blo
cker
ir
bes
arta
n i
s ef
fecti
ve
in p
rote
ctin
g
agai
nst
th
e p
rog
ress
ion
of
nep
hro
pa-
thy
du
e to
ty
pe
2 d
iab
etes
. T
his
pro
-
tect
ion
is
ind
epen
den
t o
f th
e re
du
cti
on
in
blo
od
pre
ssu
re i
t cau
ses.
Hea
rt O
ut-
com
es P
re-
ven
tio
n
Ev
alu
atio
n
(HO
PE
) S
tud
y I
n-
ves
tig
ato
rs,
Lan
cet
, 2
00
0
RC
T
A
+
-3,5
77
pat
ien
ts w
ith
dia
bet
es i
nclu
ded
in
th
e H
OP
E s
tud
y (
pati
ents
had
pre
vio
us
card
iov
asc
ula
r ev
ent
or
at l
east
on
e
oth
er c
ard
iov
asc
ula
r ri
sk f
acto
r, n
o
clin
ical
pro
tein
uri
a, h
eart
fai
lure
, o
r lo
w
ejec
tio
n f
racti
on
, an
d n
ot
tak
ing
AC
E
inh
ibit
ors
) -P
atie
nts
ran
do
mly
ass
ign
ed r
amip
ril
(10
mg
/day
) o
r p
lace
bo
, an
d v
itam
in E
o
r p
lace
bo
in
2 b
y 2
fac
tori
al d
esig
n
-All
pat
ien
ts a
ges
55
year
s o
f ag
e o
r
old
er
-4.5
-yea
r fo
llo
w-u
p
-Co
mb
ined
pri
mar
y o
utc
om
e: M
I, s
tro
ke a
nd
car
dio
-v
ascu
lar
dea
th
-Ram
ipri
l re
du
ced
th
e ri
sk o
f co
mb
ined
pri
mar
y o
ut-
com
e b
y 2
5%
(9
5C
I 1
2%
-36
%,
p=
0.0
00
4),
MI
by
22
%
(95
CI
6%
-36
%, p
=0
.01
), s
tro
ke
by
33
% (
95
CI
10
%-
50
%, p
=0
.00
74
), c
ard
iov
ascu
lar
deat
h b
y 3
7%
(9
5C
I 2
1%
-51
%, p
=0
.00
01
), t
ota
l m
ort
alit
y b
y 2
4%
(9
5C
I 8
%-3
7%
, p
=0
.00
4),
rev
ascu
lari
zati
on
by
17
% (
95
CI
2%
-30
%,
p=
0.0
31
), o
ver
t n
eph
rop
ath
y b
y 2
4%
(9
5C
I 3
%-4
0%
, p
=0
.00
04
), c
om
bin
ed p
rim
ary
outc
om
e b
y
25
% (
95
CI
12
-36
, p
=0
.02
7)
-Aft
er a
dju
stm
ent
for
chan
ges
in s
yst
oli
c a
nd
dia
sto
lic
blo
od
pre
ssu
res,
ram
ipri
l st
ill
low
ered
th
e r
isk
of
the
com
bin
ed p
rim
ary
ou
tco
me b
y 2
5%
(9
5C
I 1
2%
-36
%,
p=
0.0
00
4)
-Th
e st
ud
y w
as
sto
pp
ed 6
mo
nth
s ea
rly
beca
use
of
a co
nsi
sten
t b
enef
it o
f ra
mip
ril
com
par
ed t
o p
lace
bo
-Ram
ipri
l w
as b
enef
icia
l fo
r ca
rdio
-v
ascu
lar
even
ts a
nd
ov
ert
nep
hro
pat
hy
in
peo
ple
wit
h d
iab
ete
s.
Th
e c
ard
io-
vas
cula
r b
enef
it w
as g
reate
r th
an t
hat
attr
ibu
tab
le t
o t
he
dec
reas
e in
BP
.
Th
is t
reat
men
t re
pre
sen
ts a
vas
culo
-p
rote
cti
ve
and
ren
op
rote
ctiv
e e
ffect
fo
r p
eop
le w
ith
dia
bete
s.
Institute for Clinical Systems Improvement
www.icsi.org
101
Conclusion Grading Worksheet G – Annotations # 28, 36 (Thiazide Diuretics)
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Thirteenth Edition/May 2009
Wo
rk
Gro
up
's C
on
clu
sio
n:
Fo
r p
ati
ents
wit
h t
yp
e 2
dia
bet
es
mel
litu
s, t
hia
zide
diu
reti
cs i
n t
he
trea
tmen
t o
f h
yp
erte
nsi
on
can
red
uce
car
dio
-
vas
cula
r ev
ents
, p
arti
cula
rly
hea
rt f
ailu
re.
Co
nclu
sio
n G
ra
de:
I
Au
tho
r/
Yea
r D
e-si
gn
T
yp
e
Cla
ss
Qu
al-
ity
+
,–,ø
Po
pu
lati
on
Stu
die
d/S
am
ple
Siz
e P
rim
ary
Ou
tco
me M
eas
ure
(s)/
Res
ult
s (e
.g.,
p-v
alu
e, c
on
fi-
den
ce i
nte
rval,
rela
tiv
e ri
sk, o
dd
s ra
tio
, li
keli
ho
od
rati
o, n
um
-b
er n
eed
ed t
o t
reat)
Au
tho
rs' C
on
clu
sio
ns/
W
ork
Gro
up
's C
om
men
ts (
ita
lici
zed
)
An
tih
yp
er-
ten
siv
e an
d
Lip
id-
Lo
wer
ing
Tre
atm
ent
to P
rev
ent
Hea
rt A
t-
tack
Tri
al
(AL
LH
AT
)
Off
icer
s an
d
Res
earc
h
Gro
up
,
20
02
AL
LH
AT
tria
l
RC
T
A
+
-12
,06
3 p
atie
nts
wit
h t
yp
e 2
dia
-
bet
es
wit
h h
yp
erte
nsi
on
as
par
t o
f
a la
rge, m
ult
icen
ter
(62
3 N
ort
h
Am
eric
an c
ente
rs)
incl
ud
ing
a to
-
tal
of
33
,35
7 p
ati
ents
-Mean
ag
e 6
7 y
ears
-53
% m
ale;
47
% W
hit
e, 3
2%
Bla
ck, an
d 1
5%
His
pan
ic
-Mean
fo
llo
w-u
p 4
.9 y
ears
Am
lod
ipin
e 2
.5-1
0 m
gm
vs.
Ch
lort
ha
lid
on
e 1
2.5
-25
mg
m/d
-All
-cau
se m
ort
ali
ty:
rela
tiv
e ri
sk (
RR
) 0
.96
(9
5%
CI
0.8
2-
1.0
7)
-Str
ok
e: R
R 0
.9 (
95
%C
I 0
.75-1
.08
)
-Co
mb
ined
CV
dis
eas
e: R
R 1
.06
(9
5%
CI
0.9
8-1
.15
)
-An
y h
eart
fail
ure
: R
R 1
.42
(9
5%
CI
1.2
3-1
.64
)
Lis
ino
pri
l 1
0-4
0 m
gm
vs
Ch
lort
ha
lid
on
e 1
2.5
-25
mg
m/d
-All
-cau
se m
ort
ali
ty:
RR
1.0
2 (
95
%C
I 0
.91-1
.13
)
-Str
ok
e: R
R 1
.07
(9
5%
CI
0.9
-1.2
8)
-Co
mb
ined
CV
dis
eas
e: R
R 1
.08
(9
5%
CI
1.0
-1.1
7)
-An
y h
eart
fail
ure
: R
R 1
.22
(9
5%
CI
1.0
6-1
.42
)
-Fo
r ty
pe
2 d
iab
etic
pati
ents
, li
sino
pri
l
app
eare
d t
o h
ave n
o s
peci
al a
dv
anta
ge
(an
d a
mlo
dip
ine
no
sp
ecia
l d
etri
men
-
tal
effe
ct)
fo
r m
ost
CV
D o
utc
om
es
wh
en c
om
par
ed w
ith
ch
lort
hali
do
ne.
-Bec
au
se t
he
ma
in i
nte
nt
wa
s to
com
-
pa
re t
hia
zid
e, c
alc
ium
ch
an
nel
blo
cker
, a
nd
AC
E i
nh
ibit
or
trea
tmen
t,
the
ava
ila
ble
ste
p-u
p f
or
furt
her
ma
n-
ag
emen
t o
f h
yper
ten
sio
n f
or
pa
tien
ts
on
AC
E i
nh
ibit
ors
led
to
les
s th
an
typ
ica
l re
gim
en (
use
of
sym
pa
tho
lyti
cs
rath
er t
ha
n d
iure
tics
an
d c
alc
ium
cha
nn
el b
locke
rs).
S
ince
a l
arg
e p
ro-
po
rtio
n o
f d
iab
ete
s p
ati
ents
req
uir
e
mo
re t
ha
n o
ne
dru
g t
o c
on
tro
l th
eir
BP
, th
is s
tud
y s
ug
ges
ts t
ha
t a
diu
reti
c
sho
uld
be
inclu
ded
in
all
mu
ltid
rug
reg
imen
s.
Win
g e
t al.
,
20
03
AN
BP
2
Tri
al
RC
T
A
ø
-6,0
83
pat
ien
ts (
fro
m 1
,59
4 f
am-
ily
med
ical
pra
cti
ces
thro
ugh
ou
t
Au
stra
lia)
-On
ly 7
% w
ith
dia
bete
s
-95
% C
aucas
ian
-Mean
ag
e 7
2 y
ears
-Pat
ien
t g
rou
ps
wer
e eq
ual
at
ran
-
do
miz
atio
n, fo
llo
wed
fo
r 4
.1
yea
rs w
ith
in
ten
tio
n-t
o-t
reat
anal
ysi
s (0
.2%
lo
st t
o f
/u)
-En
ala
pri
l (A
CE
in
hib
ito
r) v
s. H
yd
roch
loro
thia
zid
e (d
iu-
reti
c)
-All
CV
ev
ents
or
deat
h f
rom
an
y c
ause
: H
azar
d r
ati
o (
HR
)
0.8
9 (
95
%C
I 0
.79
-1.0
0)
-Fir
st C
V e
ven
t o
r d
eat
h f
rom
an
y c
ause
: H
R 0
.89
(9
5%
CI
0.7
9-1
.01
)
-Dea
th f
rom
an
y c
ause
: H
R 0
.9 (
95
%C
I 0
.75-1
.09
)
-58
%-6
2%
rec
eiv
ing
tre
atm
ent
assi
gn
ed a
t th
e en
d o
f st
ud
y
and
eq
ual
BP
res
po
nse
(sy
sto
lic/
dia
sto
lic)
in
bo
th g
rou
ps
-in
po
st h
oc
analy
sis,
lar
gest
eff
ect
seen
in
male
pat
ien
ts
-In
itia
tio
n o
f an
tih
yp
erte
nsi
ve
trea
t-
men
t in
vo
lvin
g A
CE
in
hib
ito
rs i
n
old
er s
ub
jects
, p
arti
cula
rly
men
, ap
-
pea
rs t
o l
ead
to
bett
er o
utc
om
es
than
trea
tmen
t w
ith
diu
reti
c a
gen
ts, d
esp
ite
sim
ilar
red
uct
ion
s o
f b
loo
d p
ress
ure
.
-Th
ere w
as
a l
ow
er p
reva
len
ce o
f
dia
bet
es t
ha
n m
igh
t h
ave
been
ex-
pec
ted
(7
%)
mo
stly
beca
use
th
e s
tud
y
po
pu
lati
on
wa
s o
verr
epre
sen
ted
by
eld
erl
y C
au
casi
an
pa
tien
ts.
-Va
scu
lar
ou
tco
mes
an
d d
eath
wer
e
wo
rse
usi
ng
hyp
erte
nsi
ve r
egim
en
emp
ha
sizi
ng
hyd
roch
loro
thia
zid
e
com
pa
red
to
AC
E i
nh
ibit
ion
.
-Als
o,
insu
ffic
ien
t in
form
ati
on
is
pro
-
vid
ed t
o d
isce
rn w
het
her
gro
up
s w
ere
trea
ted
eq
ua
lly.
102
I ICSI NSTITUTE FOR C LINICAL S YSTEMS I MPROVEMENT
Support for Implementation:
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults
Copyright © 2009 by Institute for Clinical Systems Improvement
This section provides resources, strategies and measurement specifications for use in closing the gap between current clinical practice and the recommendations set forth in the guideline.
The subdivisions of this section are:
• Priority Aims and Suggested Measures
• Key Implementation Recommendations
• Knowledge Resources
• Resources Available
Institute for Clinical Systems Improvement
www.icsi.org
103
Priority Aims and Suggested Measures
A multifactorial intervention targeting hyperglycemia and cardiovascular risk factors in individuals with diabetes is most effective. Both individual measures of diabetes care, as well as comprehensive measures of performance on broader sets of measures, are recommended. A randomized controlled trial has shown a 50% reduction in major cardiovascular events through a multifactorial intervention targeting hypergly-cemia, hypertension, dyslipidemia, microalbuminuria, aspirin and ACE inhibitor use in individuals with microalbuminuria (Gaede, 2003 [A]).
Goals for A1c, low-density lipoprotein and other diabetes measures should be personalized, and lower goals for A1c and low-density lipoprotein than those included here in the priority aims and measures may be clinically justified in some adults with type 2 diabetes. However, efforts to achieve lower A1c below 7% may increase risk of mortality, weight gain, hypoglycemia and other adverse effects in many patients with type 2 diabetes. Therefore, the aims and measures listed here are selected carefully in the interests of patient safety.
1. Diabetes Optimal Care Measures: Maximize the percentage of adult patients, ages 18-75 with type 2 diabetes mellitus, who in a defined period of time achieve any of the following measures of established control:
Possible measures for accomplishing this aim:
a. Percentage A1c less than 8%
b. Percentage on a statin
c. Percentage with LDL less than 100 mg/dL
d. Percentage of type 2 diabetes patients with blood pressure measured in last year and most recent BP less than 130/80 mmHg
e. Percentage of type 2 diabetes patients who are current documented non-smokers
f. Percentage of type 2 diabetes patients ages 41-75 with type 2 diabetes mellitus and with coronary artery disease (CHD, defined as one or more ICD-9 codes for CHD listed at ncqa.org) who take daily aspirin or another antiplatelet medication
Notes to diabetes optimal care measures:
1a. A1c measure: The A1c goal for type 2 diabetes patients should be personalized. The optimal clinical A1c goal for many diabetes patients is lower than 8% (see Annotation # 11).
1c. Low-density lipoprotein measure: The optimal clinical low-density protein goal for some patients with diabetes, such as those with coronary artery disease, may be lower than 100 mg/dL. Patients who are or may become pregnant should not use most lipid-lowering agents including statins. The benefit of low-density protein reduction is less in younger than in middle-aged or older patients with type 2 diabetes.
1f. Aspirin measure: This recommendation is subject to modification on the basis of clinical trials that are expected to report their findings in the next year.
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
104
2. Diabetes Optimal Care Comprehensive Measure Set: Maximize the percentage of adult patients ages 18-75 with type 2 diabetes mellitus, who in a one-year period of time achieve each of the following measures of care.
Possible measures for accomplishing this aim:
a. Percentage with A1c less than 8%
b. Percentage with LDL less than 100 mg/dL
c. Percentage with blood pressure measured in last year and most recent blood pressure less than or equal to 130/80 mmHg
d. Percentage who are current documented non-smokers.
Notes to diabetes optimal care comprehensive measures:
All-or-none approach of process quality yields a picture quite different from either the item-by-item approach or the composite approach (Nolan, 2006 []). All or none more closely reflects the interests and likely desires of the patient.
2a. A1c measure: The A1c goal for type 2 diabetes patients should be personalized. The optimal clinical A1c goal for many diabetes patients is lower than 8% (see Annotation #11).
2b. Low-density protein measure: The optimal clinical low-density protein goal for some patients with diabetes, such as those with coronary artery disease, may be lower than 100 mg/dL. Patients who are or may become pregnant should not use most lipid-lowering agents including statins. The benefit of low-density protein reduction is less in younger than in middle-aged or older patients with type 2 diabetes.
3. Diabetes Process of Care Measure Set: Maximize the percentage of adult patients ages 18-75 with type 2 diabetes mellitus for whom recommended screening procedures are done.
Possible measures for accomplishing this aim:
a. Percentage of patients with type 2 diabetes mellitus with A1c test in the last 12 months.
b. Percentage of patients with type 2 diabetes mellitus receiving a lipid profile in the last 12 months.
c. Percentage of patients with type 2 diabetes mellitus receiving one or more blood pressure measure-ments in the last 12 months.
d. Nephropathy screening rate: DENOMINATOR: Include those patients with type 2 diabetes mellitus who are either (a) not on an ACE or ARB medication OR (b) not diagnosed with chronic kidney disease. NUMERATOR: Those who are included in the denominator who have one or more microalbuminuria tests within the last 12 months. (Suitable tests include CPT Codes such as 820.43 ["urine, microalbumin, quantitative"], or 841.55 ["protein; total, except refractometry"]).
e. Retinopathy screening rate: percentage of patients with type 2 diabetes mellitus with dilated eye exam within the last 24 months. The nature of the exam is not specified and may be completed by an ophthalmologist or optometrist.
f. Foot care screening rate: percentage of patients with type 2 diabetes mellitus with a comprehensive foot exam documented in the last year (HEDIS, 2009).
g. Diabetes process of care comprehensive measure: percentage of patients with type 2 diabetes, age 18-75 with type 2 diabetes mellitus, for whom all the recommended screening procedures (3a to 3f above) were done in the indicated time frames.
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Priority Aims and Suggested Measures Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
105
Notes to diabetes process of care measure set:
3e. Retinopathy screening intervals should be personalized to the patient. Some patients, especially those with elevated A1c or blood pressure, or with a previously abnormal retinal exam, may benefit from shorter screening intervals.
3g. Unlike the Diabetes Optimal Measures, there is no upper limit recommended on appropriate levels of performance on the Diabetes Process of Care Measure Set.
4. High-Risk Population Measures: The purpose of this aim is to identify and focus on a higher risk population by decreasing the percentage of adult patients, ages 18-75 with type 2 diabetes mellitus, with poorly controlled glucose and cardiovascular risk factors (clinical strategies that target high-risk populations may be more viable with limited resources).
Possible measures for accomplishing this aim:
a. Percentage of patients with type 2 diabetes mellitus with Alc test in the last year greater than 9%. (HEDIS, 2009)
b. Percentage of patients with type 2 diabetes mellitus with low-density lipoprotein test in the last year greater than 130 mm/dL.
c. Percentage of patients with type 2 diabetes mellitus with blood pressure greater than 140/90 mmHg.
d. Percentage of patients with type 2 diabetes mellitus with A1c greater than 9% or low-density lipopro-tein greater than 130 Mg/dL or blood pressure greater than 140/90 mmHg (high-risk comprehensive measures).
e. Percentage of patients with type 2 diabetes mellitus who are active smokers.
At this point in development for this guideline, there are no specifications written for possible measures listed above. ICSI will seek input from the medical groups on what measures are of most use as they implement the guideline. In a future revision of the guideline, measurement specifications may be included.
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Priority Aims and Suggested Measures Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
106
Key Implementation Recommendations
The implementation of type 2 diabetes mellitus clinical guidelines at medical groups and clinics is a complex and challenging task. However, a number of key processes have been shown to accelerate effective clinical guideline implementation and care improvement (Sperl-Hillen, 2005 [D]). These overlapping care elements can be categorized at the medical group and provider levels:
• Essential Elements at the Medical Group Level:
- Leadership. Medical group leaders must communicate the need for change in clinical practice patterns and consistently identify improvement priorities.
- Resources. Resources adequate to the task at hand will be needed to assure the success of a change effort. Resources may include staff time, money and provision of tools (such as elec-tronic medical records) to support care improvement.
- Select Specific Improvement Goals and Measures. For most chronic diseases, including diabetes, the most efficient improvement strategy is to focus on a limited number of specific improvement goals. These may be based on observed gaps in care, potential clinical impact, cost considerations or other criteria (O'Connor, 2005a [D]). In type 2 diabetes, focusing on glycemic control, lipid control and blood pressure control is a strategy that has been shown to be effective in preventing up to 53% of heart attacks and strokes, the leading drivers of excess mortality and costs in adults with diabetes (Gaede, 2003 [A]).
- Accountability. Accountability within the medical group is a management responsibility, but external accountability may also play an important enhancing role to motivate sustained efforts to implement guidelines and improve care. Examples of external accountability include participation in shared learning activities (such as Institute for Healthcare Improvement or ICSI and its action groups), or public reporting of results (such as in pay-for-performance or the Minnesota Community Measures Project).
- Prepared Practiced Teams. The medical group may need to foster the development of prepared practice teams that are designed to meet the many challenges of delivering high-quality chronic disease care.
• Essential Elements at the Clinic Level:
- Develop "Smart" Patient Registries. These are registries that are designed to identify, automatically monitor, and prioritize patients with diabetes based on their risk, current level of control, and possibly patient readiness-to-change.
- Assure "Value-Added" Visits. These are office visits or other patient encounters (by phone, e-mail, etc.) that include intensification of treatment if the patient has not yet reached his/her evidence-based clinical goals. Failure of providers and patients to intensify treatment when indicated (referred to as "clinical inertia") is a key obstacle to better diabetes care (O'Connor, 2003 [R]; O'Connor, 2005a [R]; O'Connor, 2005b [R]). HSR editorial. Previsit planning and best practice prompts may help to increase the efficiency of patient visits and remind providers of needed tests and care.
- Develop "Active Outreach." These are strategies to reach patients with chronic disease who have not returned for follow-up or for other selected elements of care. Outreach strategies that enhance the likeliness of a future provider encounter that addresses one of the barriers to patient activation (discussed below) may be more effective. Simple reporting of lab test results or care suggestions through the mail may be ineffective at addressing these barriers.
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
107
- Emphasize "Patient Activation" Strategies. These may include diabetes education and other actions designed to sustain engagement of patients with their diabetes care. Many patients with diabetes either (a) do not really believe they have diabetes, or (b) do not really believe that diabetes is a serious disease, or (c) lack motivation for behavioral change, or (d) do not believe that recommended treatments will make a difference to their own outcomes. For care to be effective, these issues must be addressed for many patients (O'Connor, 1997 [D]).
Knowledge Resources
Criteria for Selecting ResourcesThe following resources were selected by the Diagnosis and Management of Type 2 Diabetes Mellitus in Adults guideline work group as additional resources for providers and/or patients. The following criteria were considered in selecting these resources.
• The site contains information specific to the topic of the guideline.
• The content is supported by evidence-based research.
• The content includes the source/author and contact information.
• The content clearly states revision dates or the date the information was published.
• The content is clear about potential biases, noting conflict of interest and/or disclaimers as appropriate.
Resources Available to ICSI Members OnlyICSI has a wide variety of knowledge resources that are only available to ICSI members (these are indicated with an asterisk in far left-hand column of the Resources Available table). In addition to the resources listed in the table, ICSI members have access to a broad range of materials including tool kits on CQI processes and Rapid Cycling that can be helpful. To obtain copies of these or other Knowledge Resources, go to http://www.icsi.org/improvement_resources. To access these materials on the Web site, you must be logged in as an ICSI member.
The resources in the table on the next page that are not reserved for ICSI members are available to the public free-of-charge.
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Key Implementation Recommendations Thirteenth Edition/May 2009
Institute for Clinical Systems Improvement
www.icsi.org
108
Resources Available
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Thirteenth Edition/May 2009
* Available to ICSI members only.
* Author/Organization Title/Description Audience Web Sites/Order InformationAmerican DiabetesAssociation
American Diabetes Association:The mission of the association is to prevent and cure diabetes and to improve the lives of all people affected by diabetes.
All About Diabetes
Patients and Families
http://www.diabetes.org/about-diabetes.jsp1-800-232-6733
American DiabetesAssociation
American Diabetes Association: The mission of the association is to prevent and cure diabetes and to improve the lives of all people affected by diabetes.
Basic Carbohydrate Counting (booklet)
Patients and Families
http://www.diabetes.org/shop-for-books-and-gifts.jspAmerican Drug Administration #S623-011-800-232-6733
American DiabetesAssociation
American Diabetes Association: The mission of the association is to prevent and cure diabetes and to improve the lives of all people affected by diabetes.
Complete Guide to Diabetes (book)
Patients and Families
http://www.diabetes.org/shop-for-books-and-gifts.jspAmerican Drug Administration #4809-04;1-800-232-6733
American DiabetesAssociation
American Diabetes Association: The mission of the association is to prevent and cure diabetes and to improve the lives of all people affected by diabetes.
Complete Guide to Carbohydrate Counting (booklet)
Patients and Families
http://www.diabetes.org/shop-for-books-and-gifts.jspAmerican Drug Administration #4715-021-800-232-6733
American DiabetesAssociation
American Diabetes Association: The mission of the association is to prevent and cure diabetes and to improve the lives of all people affected by diabetes.
Complete Guide to Diabetes (book)
Patients and Families
http://www.diabetes.org/shop-for-books-and-gifts.jspAmerican Drug Administration #4809-04;1-800-232-6733
American DiabetesAssociation
American Diabetes Association and American Dietetic Association: The mission of the associations are to prevent and cure diabetes and to improve the lives of all people affected by diabetes.
Exchange Lists for Meal Planning (pamphlet)
Patients and Families
http://www.diabetes.org/nutrition-and-recipes/nutrition/exchangelist.jsp1-800-232-6733
Institute for Clinical Systems Improvement
www.icsi.org
109
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Resources Available Thirteenth Edition/May 2009
* Available to ICSI members only.
* Author/Organization Title/Description Audience Web Sites/Order InformationAmerican DiabetesAssociation
American Diabetes Association: The mission of the association is to prevent and cure diabetes and to improve the lives of all people affected by diabetes.
Healthy Food Choices (pamphlet)
Patients and Families
http://www.diabetes.org/nutrition-and-recipes/nutrition/healthyfoodchoices.jsp1-800-232-6733#5903-03 (English)#5903-13 (Spanish)
American DiabetesAssociation
American Diabetes Association: The mission of the association is to prevent and cure diabetes and to improve the lives of all people affected by diabetes.
Wide variety of information on diabetes as well as recent publications; series of journals for both consumers and health professionals; community resources.
Patients and Families; Health Care Professionals
http://www.diabetes.org
Centers for DiseaseControl and Prevention
Centers for Disease Control and Prevention: Educational materials in Spanish as well as English, and low literacy public health and community campaigns for educating about diabetes and diabetes prevention.
Patients and Families
http://www.cdc.gov/diabetes
HealthFinder HealthFinder: A-Z health information organizations and health care topics.
Patients and Families
http://www.healthfinder.gov
* ICSI Chronic Care Action Group Summary 2002: ICSI Action Group/Redesign Collaborative Summary Reports are designed to describe key activities conducted in a collaborative while highlighting results achieved by participating member organizations.
Health Care Professionals
http://www.icsi.org
* ICSI Chronic Care Action Group Summary 2003: ICSI Action Group/Redesign Collaborative Summary Reports are designed to describe key activities conducted in a collaborative while highlighting results achieved by participating member organizations.
Health Care Professionals
http://www.icsi.org
* ICSI Continual Improvement Collabora-tive within the Disease Management Strategy Program at Mayo Clinic, Rochester: Describes Mayo Clinic's approach to utilizing teams to imple-ment health care guidelines & improve care to patients. (12/99)
Health Care Professionals
http://www.icsi.org
Institute for Clinical Systems Improvement
www.icsi.org
110
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Resources Available Thirteenth Edition/May 2009
* Author/Organization Title/Description Audience Web Sites/Order Information* ICSI Diabetes Action Group 1997-2005
Summary: ICSI Action Group/Rede-sign Collaborative Summary Reports are designed to describe key activities conducted in a collaborative while highlighting results achieved by partici-pating member organizations.
Health Care Professionals
http://www.icsi.org
* ICSI Diabetes Education Program – Patient Survey at HealthEast: HealthEast implemented a Diabetes Education Program to increase patient self-management of diabetes. Feedback was solicited from patients to identify the types of education & follow-up they needed to manage their diabetes. (12/99)
Health Care Professionals
http://www.icsi.org
* ICSI Diabetes Patient Registries: Three Medical Groups' Experience:HealthEast Clinics, HealthPartners Medical Group and Mayo Clinic have developed a patient registry to improve management of diabetes care. This report explores how these three groups are using the registry to best use and design criteria for the registry. (3/01)
Health Care Professionals
http://www.icsi.org
ICSI Translation for Patients of the ICSI Type 2 Diabetes Mellitus guideline (guideline)
Patients and Families
(952) 814-7060 orhttp://www.icsi.org
International Diabetes Center
International Diabetes Center:International Diabetes Center at Park Nicollet has provided world-class dia-betes care, education, publications and research programs that have met the needs of people with diabetes and their families since 1967.
Blood Glucose Patterns (booklet)
Patients and Families
http://www.idcpublishing.comIDC #2058-816A
International Diabetes Center
International Diabetes Center: International Diabetes Center at Park Nicollet has provided world-class diabetes care, education, publications and research programs that have met the needs of people with diabetes and their families since 1967.
Carbohydrate Counting Booklet
Patients and Families
http://www.idcpublishing.comIDC #2058-802
* Available to ICSI members only.
Institute for Clinical Systems Improvement
www.icsi.org
111
* Author/Organization Title/Description Audience Web Sites/Order InformationInternational Diabetes Center
International Diabetes Center:International Diabetes Center at Park Nicollet has provided world-class dia-betes care, education, publications and research programs that have met the needs of people with diabetes and their families since 1967.
Exchanges for All Occasions - Pocket Edition (book)
Patients and Families
http://www.idcpublishing.comIDC #2058-EAOP
International Diabetes Center
International Diabetes Center: International Diabetes Center at Park Nicollet has provided world-class diabetes care, education, publications and research programs that have met the needs of people with diabetes and their families since 1967.
Fast Food Facts - Pocket Edition (book)
Patients and Families
http://www.idcpublishing.comIDC #2058-853
International Diabetes Center
International Diabetes Center:International Diabetes Center at Park Nicollet has provided world-class dia-betes care, education, publications and research programs that have met the needs of people with diabetes and their families since 1967.
Healthy Eating (booklet)
Patients and Families
IDC#2058-814 (English)#2058-821 (Spanish)
International Diabetes Center
International Diabetes Center:International Diabetes Center at Park Nicollet has provided world-class dia-betes care, education, publications and research programs that have met the needs of people with diabetes and their families since 1967.
Managing Type 2 Diabetes (book)
Patients and Families
http://www.idcpublishing.comIDC #2058-850
International Diabetes Center
International Diabetes Center: International Diabetes Center at Park Nicollet has provided world-class diabetes care, education, publications and research programs that have met the needs of people with diabetes and their families since 1967.
My Food Plan (pamphlet)
Patients and Families
http://www.idcpublishing.comIDC#2058-25 (English)#2058-823 (Spanish)
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Resources Available Thirteenth Edition/May 2009
* Available to ICSI members only.
Institute for Clinical Systems Improvement
www.icsi.org
112
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Resources Available Thirteenth Edition/May 2009
* Author/Organization Title/Description Audience Web Sites/Order InformationInternational Diabetes Center
International Diabetes Center: International Diabetes Center at Park Nicollet has provided world-class diabetes care, education, publications and research programs that have met the needs of people with diabetes and their families since 1967.
My Insulin Plan (pamphlet)
Patients and Families
http://www.idcpublishing.comIDC #2058-827
International Diabetes Center
International Diabetes Center: International Diabetes Center at Park Nicollet has provided world-class diabetes care, education, publications and research programs that have met the needs of people with diabetes and their families since 1967.
Record booklet
Patients and Families
http://www.idcpublishing.comIDC #2058-231
International Diabetes Center
International Diabetes Center: International Diabetes Center at Park Nicollet has provided world-class diabetes care, education, publications and research programs that have met the needs of people with diabetes and their families since 1967.
Safe and Healthy Exercise (booklet)
Patients and Families
http://www.idcpublishing.comIDC-2058-805
International Diabetes Center
International Diabetes Center: International Diabetes Center at Park Nicollet has provided world-class dia-betes care, education, publications and research programs that have met the needs of people with diabetes and their families since 1967.
Staying Healthy with Type 2Diabetes (booklet)
Patients and Families
http://www.idcpublishing.comIDC#2058-824 (English)#2058-825 (Spanish)
International Diabetes Center
International Diabetes Center:International Diabetes Center at Park Nicollet has provided world-class dia-betes care, education, publications and research programs that have met the needs of people with diabetes and their families since 1967.
Type 2 Diabetes Basics (client book)
Patients and Families
http://www.idcpublishing.comIDC-2058-BCBK
* Available to ICSI members only.
Institute for Clinical Systems Improvement
www.icsi.org
113
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Resources Available Thirteenth Edition/May 2009
* Author/Organization Title/Description Audience Web Sites/Order InformationLabat & Maggi Weight Management for Type II
Diabetes (book)Patients and Families
pub. by Wiley & SonsISBN #0471347507
Mayo Clinic Mayo Clinic: Disease and Condition Centers Information and tools to help you manage a chronic disease or condi-tion.
Patients and Families
http://www.mayoclinic.com
Minnesota Community Measurement
The D5.org
The D5 is a set of five treatment goals that, when achieved together, repre-sent the gold standard for managing diabetes. Reaching all five goals greatly reduces a patient's risk for the cardio-vascular problems associated with diabetes.
Patients and Families
http://www.theD5.org
National Institutes of Diabetes, Digestive and Kidney Diseases
National Institute of Diabetes, Digestive and Kidney Diseases: Data, statistics, information for health professionals, educational materials in Spanish as well as English, and low literacy.
This Web site is a division of the National Institutes of Health.
Patients and Families; Health Care Professionals
http://www.niddk.nih.gov
Also, links to NDEP, NKDEP, NIDDK
National Institutes of Health
National Institutes of Health: This user-friendly site helps you start a search for health information by directing you to some credible data-bases.
Health Care Professionals
http://www.nih.gov
* Park Nicollet Health Services
Diabetes, What You Need To Know: Provided by Park Nicollet Health Services (brochure)
Patients and Families
http://www.icsi.org
Protocol DrivenHealthcare
Protocol Driven Healthcare: Self-management interactive site, informa-tion on diabetes and managing it, chat rooms, capacity to e-mail for questions.
Patients and Families
http://www.mydiabetes.com
Staywell/Krames Diabetes and Exercise (brochure) Patients and Families
1-800-333-3032
* Available to ICSI members only.
Institute for Clinical Systems Improvement
www.icsi.org
114
Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Resources Available Thirteenth Edition/May 2009
* Author/Organization Title/Description Audience Web Sites/Order InformationThe Food and Nutrition Information Center
The Food and Nutrition Informa-tion Center: Sponsored by the United States Department of Agriculture (USDA), this site is user friendly and filled with current information on almost any nutrition topic.
Patients and Families; Health Care Professionals
http://www.nal.usda.gov/fnic/
WebMD Corporation Web MD: Wide variety of informa-tion on diabetes as well as recent publications; series of journals for both consumers and health professionals; clinical resource for providers, and education materials that providers can download for their patients.
Patients and Families; Health Care Professionals
http://www.webMD.com
* Available to ICSI members only.