Type 2 Diabetes Glucose Management Goals 1. AACE Comprehensive Diabetes Care: Glucose Goals...

Type 2 Diabetes Glucose Management Goals

1

2

AACE Comprehensive Diabetes Care: Glucose Goals Parameter Treatment Goal for Nonpregnant Adults

A1C (%) Individualize based on age, comorbidities, and duration of disease*

• ≤6.5 for most• Closer to normal for healthy• Less stringent for “less healthy”

FPG (mg/dL) <110

2- hour PPG (mg/dL) <140

Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.

*Considerations include

• Residual life expectancy• Duration of T2DM• Presence or absence of

microvascular and macrovascular complications

• CVD risk factors• Comorbid conditions• Risk for severe hypoglycemia• Patient’s psychological, social,

and economic status

3

Well-Recognized Risks for Hypoglycemia in T2DM

• Use of insulin secretagogues and insulin therapy in any of the following settings:– Missed or irregular meals– Advanced age– Longer duration of diabetes– Impaired awareness of hypoglycemia– Exercise– Taking greater than the prescribed medication dose – Excessive alcohol intake– Preexisting impairment, or sudden worsening, of renal or hepatic

function• Less well-recognized risks: female sex, African-American

race, less education (ACCORD)

Amiel SA, et al. Diabet Med. 2008;25:245-254.ADA. Diabetes Care. 2005;28:1245-1249.

4

Limitations of Management Goals: Potential Consequences of Hypoglycemia

• Neurogenic symptoms– Tremor, palpitations, anxiety, sweating, hunger (weight gain),

paresthesias

• Neuroglycopenia morbidity– Cognitive impairment, psychomotor abnormalities, abnormal behavior,

seizure, coma, mortality (brain death)

• Rebound hyperglycemia, brittle diabetes• Barrier to glycemic control and adherence to treatment

secondary to fear of hypoglycemia• Greater risk of dementia• Prolonged QT interval with increased risk of dysrhythmias,

sudden death• Harm to property or to others (eg, if driving)

Cryer PE. J Clin Invest. 2007;117:868-870.Cryer PE. Diabetes Care. 2003;26:1902-1912.

5

Mortality Risk

Mortality Benefit

Glucose Control and Mortality:ACCORD Posthoc Analysis

66%

<0.0001

Risk increase with each 1% increase in A1C

P Value

14%

0.17

1

0

-1

6 7 8 9

Adjusted Log (Hazard Ratio) by Treatment Strategy

Relative to Standard at A1C of 6%

Lo

g (

Haz

ard

Rat

io)

Average A1C (%)

Standard

Intensive

Riddle MC, et al. Diabetes Care. 2010;33:983-990.

6

Algorithm for Individualizing Glycemic Targets

Ismail-Beigi F, Moghissi E, et al. Ann Intern Med. 2011;154:554-559.

Highly motivated, adherent, knowledgeable, excellent self-care capacities, and comprehensive support systems

Less motivated, nonadherent, limited insight, poor self-care capacities, and

weak support systems

Psychosocioeconomic considerations

Hypoglycemia riskLow Moderate High

Patient age, years40 45 50 55 60 65 70 75

Disease duration, years5 10 15 20

Other comorbid conditionsNone Few or mild Multiple or severe

Established vascular complicationsNone Cardiovascular disease

Early microvascular Advanced microvascular

Most intensive Less intensive Least intensive6.0% 7.0% 8.0%

ADA-Recommended Approach to Management of Hyperglycemia

Inzucchi SE, et al. Diabetes Care. 2012;35:1364-1379.

More Stringent Less Stringent

Patient attitude and expected treatment efforts Highly motivated, adherent,

excellent self-care capacitiesLess motivated, nonadherent,

poor self-care capacities

Risks potentially associated with hypoglycemia, other adverse events Low High

Disease durationNewly diagnosed Long-standing

Life expectancyLong Short

Resources, support systemReadily available Limited

Important comorbiditiesAbsent SevereFew/mild

Established vascular complicationsAbsent SevereFew/mild

7

8

Hyperglycemia and Microvascular Complications

9

Hyperglycemia-Induced Tissue Damage: General Features

Diabetic tissue damage

Genetic determinants of individual susceptibility

Repeated acute changes in cellular

metabolism

Cumulative long-term changes in stable macromolecules

Independent accelerating factors

(eg, hypertension, dyslipidemia)

Hyperglycemia

Brownlee M. Diabetes. 2005;54:1615-1625.

10

Microvascular Complications of Diabetes

Nephropathy Retinopathy Neuropathy

11

Microvascular Complications Increase With Increasing A1C

0

2

4

6

8

10

12

14

16

18

20

6 7 8 9 10 11 12

Rel

ativ

e R

isk

Retinopathy

Nephropathy

Neuropathy

Microalbuminuria

A1C (%)

Diabetes Control and Complications Trial

Skyler JS. Endocrinol Metab Clin North Am. 1996;25:243-254.

12

Reducing A1C Reduces Microvascular Risk

United Kingdom Prospective Diabetes Study

Stratton IM, et al. BMJ. 2000;321:405-412.

37% Decrease per 1% reduction in A1C

Updated Mean A1C

Mic

rova

scu

lar

Co

mp

licat

ion

sH

azar

d R

atio

0.5

1

10

0 5 6 7 8 9 10

P<0.0001

Reducing A1C Reduces Nephropathy Risk in T2DM

13

UKPDS ADVANCE ACCORD

A1C reduction (%)* 0.9 0.8 1.3

Nephropathy risk reduction (%)* 30 21 21

Newonsetmicro-

albuminuria(P=0.033)

New orworsening

nephropathy(P=0.006)

Newmicroalbuminuria

(P=0.0005)

*Intensive vs standard glucose control.1. UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-853.

2. ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-2572.3. Ismail-Beigi F, et al. Lancet. 2010;376:419-430.

14

Prevalence of CKD in Diagnosed Diabetes

*Pathologic abnormalities or markers of damage, including abnormalities in blood or urine tests or imaging studies.ESRD, end-stage renal disease; GFR, glomerular filtration rate (mL/min/1.73 m2); NKF, National Kidney Foundation.

CDC. National diabetes fact sheet, 2011. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf. Plantinga LC, et al. Clin J Am Soc Nephrol. 2010;5:673-682.

Stage 1; 10.4%

Stage 2; 13.4%

Stage 3; 14.1%

Stage 4; 1.1%

No kidney disease;

60.4%

NKF Stage

Description GFR

1Kidney damage* with normal or GFR

≥90

2Kidney damage* with mild GFR

60-89

3 Moderate GFR 30-59

4 Severe GFR 15-29

5Kidney failure or ESRD

<15 or dialysis

Diabetic Kidney Disease Is the Leading Cause of Kidney Failure in the United States

15

Genetically susceptible individuals

Hyperglycemia

Hypertension

Angiotensin II

Hyperfiltration

Enlarged kidneys

Breakdown of glomerular

filtration barrier

Micro-albuminuria

Macro-albuminuria

Decreasing GFR

Capillary occlusion

Protein reabsorption and accumulation in

renal epithelial cells

Release of vasoactive and inflammatory

cytokines

Tubule and podocyte damage

Tubular atrophy and fibrosis,

podocyte destruction

Development ofDiabetic Nephropathy

Radbill B, et al. Mayo Clin Proc. 2008;83:1373-1381.Remuzzi G, Bertani T. N Engl J Med. 1998;339:1448-1456.

Renal failure

16

CV Risk Increases With Comorbid Diabetes and CKD

AMI, acute myocardial infarction; ASVD, atherosclerotic vascular disease; CHF, congestive heart failure; CVA/TIA, cerebrovascular accident/transient ischemic attack; PVD, peripheral vascular disease.

*ASVD was defined as the first occurrence of AMI, CVA/TIA, or PVD.Foley RN, et al. J Am Soc Nephrol. 2005;16:489-495.

CHF AMI CVA/TIA PVD ASVD* Death0

10

20

30

40

50

60

No diabetes/no CKD Diabetes/no CKD Diabetes/CKD

Inc

ide

nc

e p

er

10

0 P

ati

en

t-Y

ea

rs

x 2.8

x 2.3

x 1.7x 2.1

x 2.0

x 2.5

17

Appropriate Staging and Management of DKD

DKD, diabetic kidney disease.*Includes actions from preceding stages.

†Pathologic abnormalities or markers of damage, including abnormalities in blood or urine tests or imaging studies.National Kidney Foundation. Am J Kidney Dis. 2002;39(suppl 1):S1-S266.

Stage Description GFR(mL/min/1.73 m2)

Action*

1Kidney damage† with normal or GFR ≥90

Diagnose and treat CKD, slow progression of CKD, treat comorbid conditions, reduce CVD risk factors

2Kidney damage† with mild GFR 60-89 Estimate progression

3 Moderate GFR 30-59 Evaluate and treat complications

4 Severe GFR 15-29 Prepare for kidney replacement therapy

5

Kidney failure <15 or dialysis

Kidney replacement, if uremia present

ESRD Renal replacement therapy

18

KDIGO CKD Classification by Relative Risk

Albuminuria stages (mg/g)

A1 A2 A3

Optimal and high

normalHigh

Very high and nephrotic

<10 10-29 30-299 300-1999 ≥2000

GFR stages(mL/min per 1.73 m2 body surface area)

G1High and optimal

>105Very low Very low Low Moderate Very high

90-104

G2 Mild75-89

Very low Very low Low Moderate Very high60-74

G3aMild to moderate

45-59 Low Low Moderate High Very high

G3bModerate to severe

30-44 Moderate Moderate High High Very high

G4 Severe 15-29 High High High High Very high

G5Kidney failure

<15 Very high Very high Very high Very high Very high

Levey AS, et al. Kidney Int. 2011;80:17-28.

DKD Risk Factor Management

Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.National Kidney Foundation. Am J Kidney Dis. 2007;49(suppl 2):S1-S179.

Risk Factor Goal Management Recommendation

Hyperglycemia

Individualized A1C goals

≤6.5% for most (AACE)

<7.0% (NKF)

Avoid biguanide in moderate to severe CKD

Consider need for dose reductions and/or risk of hypoglycemia and other renal-related AEs with other antidiabetic agents

Hypertension BP <130/80 mmHgUse ACE inhibitor or ARB in combination with other antihypertensive agents as needed

Proteinuria Use ACE inhibitor or ARB as directed

DyslipidemiaLDL-C <100 mg/dL,<70 mg/dL an option for high risk

Statin therapy recommended

Fibrate dose reduction may be required

19

Use of Noninsulin Antidiabetic Therapies in Patients With Kidney

Disease

Inzucchi SE, et al. Diabetes Care. 2012;35:1364-1379.Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.

National Kidney Foundation. Am J Kidney Dis. 2007;49(suppl 2):S1-S179.

Class Agent(s) Kidney Disease Recommendation

Amylin analog Pramlintide No dosage adjustment

Thiazolidinediones Pioglitazone, rosiglitazone No dosage adjustment

Bile acid sequestrant Colesevelam No dosage adjustment

DPP-4 inhibitors Linagliptin, saxagliptin, sitagliptinReduce dosage for saxagliptin and

sitagliptin if CrCl <50 mg/dL

Dopamine-2 agonist Bromocriptine Use with caution

Glinides Nateglinide, repaglinideUse lowest effective dose of nateglinide

for stage ≥3 CKD

InsulinAspart, detemir, glargine, glulisine, lispro, NPH, regular

Dosage reduction needed instage 4-5 CKD

Sulfonylureas Glimepiride, glipizide, glyburideGlimepiride preferred, use lowest effective dose; avoid other SUs

GLP-1 receptor agonists Exenatide, exenatide XR, liraglutideUse with caution in stage 3 CKD;

avoid in stage 4-5 CKD

-Glucosidase inhibitors Acarbose, miglitolNot recommended if SCr >2 mg/dL;

avoid in dialysis

Biguanide MetforminContraindicated if SCr >1.5 in men or

1.4 in women

20

Dietary Guidelines for DKD

CKD Stage

Macronutrient 1-2 1-4 3-4

Sodium <2.3

Total fat, % calories* <30

Saturated fat, % calories <10

Cholesterol, mg/day <200

Carbohydrate, % calories 50-60

Protein, g/kg/day (% calories) 0.8 (~10) 0.6-0.8 (~8-10)

Phosphorus 1.7 0.8-1.0

Potassium >4 2.4

*Adjust so total calories from protein, fat, and carbohydrate are 100%.

Emphasize such whole-food sources as fresh vegetables, whole grains, nuts, legumes, low-fat or nonfat dairy products, canola oil, olive oil, cold-water fish, and poultry.

Tailor dietary counseling to cultural food preferences.

Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.National Kidney Foundation. Am J Kidney Dis. 2007;49(suppl 2):S1-S179.

21

22

Reducing A1C Reduces Retinopathy Progression in T2DM

*Intensive vs standard glucose control.UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-853.

Ismail-Beigi F, et al. Lancet. 2010;376:419-430.Chew EY, et al. N Engl J Med. 2010;363:233-244.

UKPDS ACCORD

A1C reduction (%) 0.9 1.3

Retinopathy risk reduction (%)* 29 17 33

Retinopathy onset

(P=0.003)

Retinopathy progression(P=0.017)

Retinopathy progression(P=0.003)

Vision-threaten-ing*; 4.4%

NPDR; 24.1%

None; 71.5%

Prevalence of Diabetic Retinopathy

*Severe NPDR, PDR, or clinically significant macular edema.NPDR, nonproliferative diabetic retinopathy; PDR, proliferative diabetic retinopathy; T2DM, type 2 diabetes mellitus.

CDC. National diabetes fact sheet, 2011. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf. Zhang X, et al. JAMA. 2010;304:649-656.

NHANES 2005-2008Adults Age ≥40 Years (N=1006)

Diabetic Retinopathy Is the Leading Cause of Adult Blindness in the United States

23

24

Diabetic Retinopathy Management

Lesion Type Management Recommendation

Background or nonproliferative retinopathy

• Optimal glucose and blood pressure control

Macular edema • Optimal glucose and blood pressure control• Ranibizumab injection therapy• Focused laser photocoagulation guided by fluorescein

angiography

Preproliferative retinopathy • Optimal glucose and blood pressure control• Panretinal scatter laser photocoagulation

Proliferative retinopathy • Optimal glucose and blood pressure control• Panretinal scatter laser photocoagulation• Vitrectomy for patients with persistent vitreous

hemorrhage or significant vitreous scarring and debris

• Goal: detect clinically significant retinopathy before vision is threatened• Annual dilated eye examination by experienced ophthalmologist,

starting at diagnosis for all T2DM patients


25

Reducing A1C Reduces Neuropathy Risk in T2DM

*Intensive vs standard glucose control.Ismail-Beigi F, et al. Lancet. 2010;376:419-430.

ACCORD

A1C reduction (%) 1.3

Neuropathy risk reduction (%)* 12

Loss of sensation to light touch(P=0.045)

26

• Neuropathy is a heterogenous disorder

• 70% to 100% of T2DM patients may have at least mild damage to– Proximal nerves

– Distal nerves

– Somatic nerves

– Autonomic nerves

• Neuropathy may be– Acute and self-limiting

– Chronic and indolent

Prevalence of Diabetic Neuropathy

CDC. National diabetes fact sheet, 2011. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf.

Gregg EW, et al. Diabetes Res Clin Pract. 2007;77:485-488.Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.

None; 81.5%

DPN; 18.5%

NHANES 1999-2004Adults With Diabetes, Age ≥40 Years3

(N=559)

Diabetic Peripheral Neuropathy Is the LeadingCause of Nontraumatic Amputations in the United States

27

Diabetic Neuropathies: Key Characteristics and Management Recommendations

Type Condition(s) Clinical Features Treatment

Focal Mononeuritis Single nerve involvement

Entrapment

Carpal tunnel syndrome Proximal lumbosacral Thoracic Cervical radiculoplexus

neuropathies involving the proximal limb girdle

Inflammatory demyelinating conditions

Immunotherapy

• Optimize glucose, lipid, and blood pressure control for all T2DM patients


28



Distal neuropathy

Large-fiber sensorimotor polyneuropathy

Symmetric, glove and stocking distribution with Loss of sensation Poor coordination Ataxia

Low-impact activities that improve muscular strength and coordination and challenge the vestibular system Pilates Yoga Tai Chi

Small-fiber neuropathy

Symmetric, glove and stocking distribution with Loss of sensation Pain Autonomic features

Protect insensate feet from ulceration Padded socks Daily inspection by patient Moisturizing lotionsTreat neuropathic pain Amitriptyline Gabapentin Pregabalin Duloxetine Topical lidocaine



29



Autonomic Cardiac Symptoms Tachycardia Exercise intolerance Orthostatic hypotension, weakness,

fatigue, syncopeAssociated with significant mortality and possibly also Silent myocardial ischemia Coronary artery disease Stroke Diabetic nephropathy progression Perioperative morbidity

Intensive control of CV risk factors For tachycardia, exercise intolerance Supervised exercise ACE inhibitors -adrenergic blockersFor hypotension, weakness, etc Mechanical measures Clonidine Midodrine Octreotide Erythropoietin



30



Autonomic Gastrointestinal Gastroparesis, erratic glucose control Frequent small mealsProkinetic agents Metoclopramide Domperidone Erythromycin

Abdominal pain, early satiety, nausea, vomiting, bloating, belching

AntibioticsAntiemeticsBulking agents

Tricyclic antidepressantsPyloric BotoxGastric pacing

Constipation High-fiber dietBulking agentsOsmotic laxativesLubricating agents

Diarrhea (often nocturnal, alternating with constipation)

Soluble dietary fiberGluten and lactose restrictionAnticholinergic agents

CholestyramineAntibioticsSomatostatinPancreatic enzyme supplements



31



Autonomic Sexual dysfunction Erectile dysfunction Sex therapyPsychological counseling5′-phosphodiesterase inhibitorsProstaglandin E1 injectionsDevicesProstheses

Vaginal dryness Vaginal lubricants

Bladder dysfunction Frequency, urgency, nocturia, urinary retention, incontinence

BethanecholIntermittent catheterization

Sudomotor dysfunction

AnhidrosisHeat intoleranceDry skinHyperhidrosis

Emollients and skin lubricantsScopolamineGlycopyrrolateBotulinum toxinVasodilators



32

Hyperglycemia and Macrovascular Complications

33

Series10

10

20

30

40

50

3.5

18.8 20.2

45

Diabetes Is a Cardiovascular Disease Risk Equivalent

7-Y

ear

Inci

den

ce o

f M

I (%

)

Diabetic(n=1059)

Prior MINo prior MIPrior MINo prior MI

Nondiabetic(n=1373)

MI, myocardial infarction.Grundy SM, et al. Circulation. 2004;110:227-239.

Haffner SM, et al. N Engl J Med. 1998;339:229-234.

P<0.001

P<0.001

Lower A1C Is Associated With Lower Risk of Myocardial Infarction

Stratton IM et al. BMJ. 2000;321:405-412.

United Kingdom Prospective Diabetes Study

14% Decrease per 1% reduction in A1C

Updated Mean A1C

0.5

1

10

0 5 6 7 8 9 10

P<0.0001

Myo

card

ial I

nfa

rcti

on

Haz

ard

Rat

io

34

35

0.12

0.10

0.08

0.06

0.02

Randomizedtreatment

Intensive Glycemic Control Reduces Long-term Macrovascular Risk in Younger Patients With Shorter Duration of Disease

Randomizedtreatment

0.04

0.00

0 5 10 15 20

No. at RiskConventional 714 688 618 92Intensive 705 683 629 113

Years

DCCTT1DM, 5-6 years duration (N=1441)

42% risk reductionP=0.02

Conventional

Intensive

CV

Ou

tco

me

C

um

ula

tive

in

cid

en

ce

UKPDST2DM, newly diagnosed (N=4209)

15% risk reductionP=0.01

1138 1013 857 578 221 202729 2488 2097 1459 577 66

1.0

0.8

0.6

0.4

0.2

0.0

0 5 10 20 25Years

Conventional

Intensive

Pro

po

rtio

n

Wit

h M

I15

CV, cardiovascular; DCCT, Diabetes Control and Complications Trial; MI, myocardial infarction;UKPDS, United Kingdom Prospective Diabetes Study. Nathan DM, et al. N Engl J Med. 2005;353:2643-2653.Holman RR, et al. N Engl J Med. 2008;359:1577-1589.

36

ACCORD ADVANCE VADT

T2DM duration (years) 10 8 12

A1C reduction (%)* 0.9 0.8 1.3

Macrovascular risk (%)* 10 6 12

P=0.16Mortality

increased in intensively

treated patients (P=0.04)

P=0.32 P=0.14

Intensive Glycemic Control Does Not Reduce Macrovascular Risk in Older

Patients With Longer Duration of Disease

*Intensive vs standard glucose control.ACCORD Study Group. N Engl J Med. 2008;358:2545-2559.

ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-2572.Duckworth W, et al. N Engl J Med. 2009;360:129-139.

37

Macrovascular Risk Reduction in T2DM

• Individualized glucose control• Hypertension control• Dyslipidemia control• Smoking cessation• Aspirin therapy• Diagnosis and management of:

– Autonomic cardiac neuropathy– Kidney disease


Type 2 Diabetes Glucose Management Goals 1. AACE Comprehensive Diabetes Care: Glucose Goals...

Documents

Transcript of Type 2 Diabetes Glucose Management Goals 1. AACE Comprehensive Diabetes Care: Glucose Goals...