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Diabetes: Classification, management and treatment goals – Controversies and News by/ Dr. Leonid Poretsky, MD, Chief, Division of Endocrinology and Metabolism; Director, Gerald J. Friedman Diabetes Institute

Capital Markets Day, NYC ─ 29 November 2012

Diabetes:Diagnosis, Classification, Management

Controversies and News

Leonid Poretsky, MDChief, Division of Endocrinology and MetabolismDirector, Gerald J. Friedman Diabetes InstituteGerald J. Friedman Chair in EndocrinologyProfessor of Medicine, Albert Einstein College of Medicine

Bianca Alfonso, MD Endocrinology Fellow, Year 1

Marina Krymskaya, ANP, CDE Diabetes Nurse Educator

Jill Gregory Medical Illustrator

Diabetes:diagnosis, classification, management

� Definition� Epidemiology� Classification� Diagnosis� Treatment� Evidence� Treatment goals

Definition

� Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both.*

� The name 'diabetes mellitus' derives from:Greek: 'diabetes' – “siphon” or “to pass through”Latin: 'mellitus' – “honeyed” or “sweet”**

* Diagnosis and Classification of Diabetes Mellitus. ADA 2009.** http://science.jrank.org/pages/2044/Diabetes-Mellitus.html

Epidemiology

� Data from the 2011 National Diabetes Fact Sheet� Total prevalence of diabetes

� Total: 25.8 million children and adults in the United States—8.3% of the population—have diabetes.

� Diagnosed: 18.8 million people

� Undiagnosed: 7.0 million people

� Prediabetes: 79 million people*

� New Cases: 1.9 million new cases of diabetes are diagnosed in people aged 20 years and older in 2010.

* In contrast to the 2007 National Diabetes Fact Sheet, which used fasting glucose data to estimate undiagnosed diabetes and prediabetes, the 2011 National Diabetes Fact Sheet uses both fasting glucose and A1C levels to derive estimates for undiagnosed diabetes and prediabetes. These tests were chosen because they are most frequently used in clinical practice.

Classification

� Type 1 diabetes� Type 2 diabetes� Other

1. Genetic defects of beta cell function2. Genetic defects in insulin action3. Diseases of the exocrine pancreas4. Endocrinopathies5. Drug/ chemical - induced 6. Infections7. Uncommon forms of immune-mediated diabetes8. Genetic syndromes sometimes associated with diabetes

� Gestational diabetes mellitus

Type 1 diabetes

� A. Immune-mediated� B. Idiopathic

� Type 1 diabetes is characterized by β-cell destruction, usually leading to absolute insulin deficiency.*

* Diagnosis and Classification of Diabetes Mellitus. ADA 2009.

Type 1 diabetes mellitus – immune mediated

� Absolute insulin deficiency

� Usually due to autoimmune destruction of the pancreatic beta cells

� Islet-cell antibodies (ICA) or other autoantibodies (antibodies to glutamic acid decarboxylase [anti-GAD] and anti-insulin)

Type 2 diabetes

� Hyperglycemia

� Insulin resistance

� Relative impairment in insulin secretion.

��-cell dysfunction and insulin resistance produce hyperglycemia in type 2 diabetes

Pancreas

Insulin Resistance

Liver

Hyperglycemia

Islet �-Cell Degranulation;Reduced Insulin Content

Muscle Adipose Tissue

Decreased Glucose Transport & Activity

(expression) of GLUT4

Increased Lipolysis

↑GlucoseProduction

↓GlucoseUptake

ReducedPlasma Insulin

Increased Glucose Output

�-Cell Dysfunction

Elevated Plasma FFA

Other specific types of diabetes –Genetic defects of beta cell function

� Maturity–onset diabetes of the young (MODY)

� 6 subtypes

Maturity:Onset diabetes of the young (MODY)

� MODY 1 - Mutation in HNF-4-alpha (transcription factor), chromosome 20

� MODY 2 - Mutation in glucokinase gene, chromosome 7

� MODY 3 - Mutation in HNF-1-alpha (transcription factor), chromosome 12 (most common form)

� MODY 4 - Mutation in insulin promoter factor-1 (IPF-1), chromosome 13

� MODY 5 - Mutation in HNF-1-beta, chromosome 17

� MODY 6 - Mutation in Neurogenic Differentiation Factor-1 (NEUROD1) , chromosome 2

Other specific types of diabetes:Genetic defects in insulin action

� Type A insulin resistance

� Leprechaunism

� Rabson- Mendenhall syndrome

� Lipoatrophic diabetes

� Others

*A clinical screening tool identifies autoimmune diabetes in adults. Fourlanos S; Perry C; Stein MS; Stankovich J; Harrison LC; Colman PG. Diabetes Care. 2006 May;29(5):970-5

Latent Autoimmune Diabetes in Adults (LADA)

� Adult-onset diabetes with circulating islet antibodies but not requiring insulin therapy initially

� Adults who should be considered for antibody testing*: � age of onset <50 years� acute symptoms� BMI <25 kg/m2

� personal or family history of autoimmune disease

Gestational DMDefinition� Any degree of impaired glucose tolerance with onset or first

recognition during pregnancy� Gestational diabetes (GDM) occurs when pancreatic function

is not sufficient to overcome the insulin resistance created by changes in diabetogenic hormones during pregnancy

� Most have impaired glucose tolerance that begins in pregnancy� Some have previous undiagnosed type 2 diabetes mellitus� 10% have circulating islet cell antibodies

Diagnosis

� Diabetes mellitus

� Impaired fasting glucose (IFG)

� Impaired glucose tolerance (IGT)

Diagnosis: Diabetes mellitus

1. Symptoms of diabetes (polydipsia, polyuria, unexplained weight loss) PLUS a random plasma glucose >200 mg/dL (11.1 mmol/L)

or2. Fasting plasma glucose > 126 mg/dL (7.0 mmol/L) after overnight

(at least 8 hours) fastor

3. Two-hour plasma glucose> 200mg/dL (11.1 mmol/L) during a standard 75g oral glucose tolerance test

or4. Hgb A1c > 6.5%

Diagnosis: Impaired fasting glucose (IFG)

� Fasting plasma glucose (FPG) < 100 mg/dl (5.6 mmol/l) = normal

� FPG 100-125 mg/dl (5.6-6.9 mmol/l) = impaired fasting glucose (IFG)

� Oral glucose tolerance test (OGTT) – glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water

� 2-h postload glucose < 140 mg/dl (7.8 mmol/l) = normal

� 2-h postload glucose 140 - 199 mg/dl (7.8 – 11.1 mmol/l) = impaired glucose tolerance (IGT)

Diagnosis: Impaired glucose tolerance (IGT)

Diagnosis: Gestational Diabetes Mellitus (GDM)

1. Unequivocal hyperglycemia(confirmed on a subsequent day)

2. Diagnostic OGTT

Fasting plasma glucose > 126 mg/dL (7.0 mmol/L)

Random plasma glucose >200 mg/dL (11.1 mmol/L)

OR

100-g glucose loadmg/dl mmol/l

Fasting 95 5.3

1-h 180 10.0

2-h 155 8.6

3-h 140 7.8

Treatment

� Lifestyle intervention

� Hypoglycemic drugs� oral hypoglycemic drugs� insulin and insulin analogs� others (incretins, pramlintide)

Treatment:Lifestyle Interventions

� Weight loss

� Increased exercise

Treatment:Oral Antihyperglycemic Drugs

� Biguanides� Sulfonylureas� Meglitinide analogs� Thiazolidinediones� �-Glucosidase Inhibitors� DPP-4 Inhibitors

Oral antihyperglycemic drugs: Biguanides

� Metformin (Glucophage)� Extended-release metformin (Glucophage-XR)

� decrease hepatic glucose output� lower fasting glycemia� reduce HbA1c by 1.5%� adverse effects: lactic acidosis, gastro-

intestinal disturbances

AMPK - adenosine monophosphate-activated protein kinase, ACC - acteyl-CoA carboxylase, SREPB-1 - sterol-regulatory-element-binding-protein-1.

Diagram adapted from Alice Y.Y. Cheng, I. George Fantus, 'Oral antihyperglycemic therapy for type 2 diabetes mellitus' Canadian Medical Association Journal172(2),2005 pp213-226

Oral antihyperglycemic drugs: Metformin

Oral antihyperglycemic drugs: Sulfonylureas

� 1st generation : Tolbutamide (Orinase), Tolazamide (Tolinase), Acetohexamide (Dymelor), Chlorpropamide (Diabinese)

� 2nd generation : Glyburide (DiaBeta, Glynase) Glipizide (Glucotrol), Glimepiride (Amaryl)

� enhance insulin secretion� lower HbA1c by 1.5 %� side effects: hypoglycemia, weight gain

Black C, Donnelly P, McIntyre L et al. Meglitinide analogues for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2007 Apr 18;(2):CD004654.

Oral antihyperglycemic drugs: Meglitinide analogs

� Repaglinide (Prandin)� Nateglinide (Starlix)

� enhance insulin secretion (early-phase insulin release) � lower HbA1c by 0.1- 2.1% (repaglinide) and by 0.2-

0.6% (nateglinide)� side effects: weight gain, hypoglycemia

Oral antihyperglycemic drugs: Thiazolidinediones (TZDs)

� Rosiglitazone (Avandia) � Pioglitazone (Actos)

� peroxisome proliferator-activated receptor γmodulators (PPAR γ)

� insulin sensitizers (increase the sensitivity of muscle, fat and liver to endogenous and exogenous insulin)

� lower HbA1c by 0.5 - 1.4 %� adverse effects: weight gain, fluid retention

Oral antihyperglycemic drugs:��-Glucosidase Inhibitors

� Acarbose (Precose) � Miglitol (Glyset)

� reduce the rate of digestion of polysaccharides in the proximal small intestine, primarily lowering post-prandial glucose levels

� lower HbA1c by 0.5 – 0.8 %� side effects: increased gas production and gastro-

intestinal symptoms

Oral antihyperglycemic drugs:DPP-IV inibitors

� Sitagliptin (Januvia) : DPP-IV inhibitor� Dipeptidyl peptidase IV (DPP-IV) is a ubiquitous

enzyme that deactivates a variety of bioactive peptides, including GIP and GLP-1

Oral antihyperglycemic drugs -Sitagliptin (Januvia)

� Used alone or in combination with metformin or TZDs

� Reduces HbA1c by 0.5 – 0.7 %

� Side effects: increased rate of respiratory infections, headaches

"Januvia" by Byron Rubin� Sculpture was installed at the West Point

Pennsylvania Merck location.

Other antihyperglycemic drugs: Incretins

� Exenatide (Byetta)� glucagon-like peptide 1 (GLP-1) agonist

Antihyperglycemic drugs: Exenatide (Byetta)

Glucagon-like Peptide - 1� The majority of GLP-1 producing cells are in the terminal

ileum and proximal colon.

� GLP-1 levels in the blood increase rapidly after a meal.

� Half-life being very short, approximately one minute.

� GLP-1 binding to its G-protein coupled receptor on ß-cells increases glucose stimulated insulin secretion

� GLP-1 infused into healthy subjects decreases gastric emptying, causes a sensation of satiety, and decreases appetite.

� Effects:

� enhances insulin secretion

� limits postprandial hyperglycemia.

Figure 1. Insulin levels following oral vs IV glucose administration in healthy individuals. Despite identical glucose concentrations, plasma insulin levels peaked much earlier and were greater in response to an oral vs IV dose of glucose.

Figure 2. Insulin levels following oral vs IV glucose administration in patients with type 2 diabetes. The markedly reduced early peak of insulin after oral glucose, along with the smaller differences in insulin levels in response to oral and IV glucose doses, illustrate the diminished incretin effect.

Data extrapolated from Perley, et al. @ http://www.byettahcp.com/hcp/hcp_incretin_effect.jsp

Incretin Effect

Antihyperglycemic drugs:Exenatide (Byetta)

� active ingredient in Exenatide (Byetta) is a synthetic version of a protein present in the saliva of the Gila monster


� Added to metformin or sulfonylureas will reduce HbA1c by 0.4-0.6 %

� Side effects:� nausea (dose-depended, declines with time) � acute pancreatitis (some necrotizing or hemorrhagic

pancreatitis cases reported as well)

Antihyperglycemic drugs: Others

� Pramlintide (Symlin) � synthetic analog of amylin

Amylin� Stored in insulin secretory granules in the ß-

cells� Co-secreted with insulin� Decreases glucagon� Satiety signal?� Decreases GI motility

Antihyperglycemic drugs:Pramlintide (Symlin)

� Delays gastric emptying, suppresses glucagon secretion, decreases appetite

� Associated with weight loss (1 - 1.5 kg over 6 months)

� Used only in conjunction with insulin treatment� Reduces HbA1c by 0.5 - 0.7 %� Side effects: nausea, gastro-intestinal symptoms

Antihyperglycemic drugs:Pramlintide (Symlin)

Product (Manufacturer) Form

Rapid Acting (Onset 15-30 min, duration hrs 3-4)

Insulin AnalogAspart - Novolog (Novo Nordisk)Lispro - Humalog (Lilly)Glulisine – Apidra (Aventis)

Analog**Analog**

Short Acting (Onset 0.5-1 hr, duration hrs 5-7)*

Human InsulinNovolin R (Rugular) (Novo Nordisk)Humulin R (Regular) (Lilly)

Human**Human**

Purified InsulinRegular Iletin II (Lilly) Pork

Intermediate Acting (Onset 1-4 hrs, duration hrs 18-24)*

Human InsulinNovolin N (NPH) (Lilly)Humulin N (NPH) (Lilly)Humulin L (Lente) (Lilly)

Human**Human**Human**

Purified InsulinNPH Iletin III (Lilly) Pork

Long Acting (Onset 4-6 hrs, duration hrs 24-34)*

Human InsulinHumulin Ultralente (Lilly) Human**

Basal Peakless InsulinGlargine-Lantus (Aventis)Detemir – Levemir (Novo Nordisk)

Analog**Analog**

Mixed Insulins

70/30 InsulinNovolin 70/30 (Novo Nordisk)Humulin 70/30 (Lilly)Humulin 50/50 (Lilly)Humalog 50/50

Human**Human**Human**Analog**

Product (Manufacturer) Form

Analog MixHumalog 75/25 MixNovolog Mix 70/30 (combination of fast and

intermediate acting insulin with action similar to that of Humalog 75/25 mix)

Analog**Analog**

Insulin for Special Use

Buffered Insulin (for pumps)Humulin BR

Refills for Novolin PenNovolin R PenFillNovolin N PenFillNovolin 70/30 PenFillNovolog Mix 70/30 PenFill

Prefilled PensNovolin RNovolin NNovolin 70/30NovologNovolog Mix 70/30HumalogHumalog Mix 75/25Humalog Mix 50/50Humulin NApidra

Human**Human**Human**Analog**

Human**Human**Human**Analog**Analog**Analog**Analog**Analog**Human**Analog**

* Onset and duration are rough estimates. They can vary greatly within the range listed and from person to person

** Human insulin is made by recombinant DNA technology

AVAILABLE INSULIN PREPARATIONS

Initiation and adjustment of insulin regimens. Insulin regimens should be designed taking lifestyle and meal schedule into account. The algorithm can only provide basic guidelines for initiation and adjustment of insulin. See reference 90 for more detailed instructions. aPremixed insulins not recommended during adjustment of doses; however, they can be used conveniently, usually before breakfast and/or dinner, if proportion of rapid-and intermediate-acting insulins is similar to the fixed proportions available. bg, blood glucose.

ADA Treatment Algorithm

Evidence

ACCORD� 10,251 patients with DM2� Mean age – 62.2 yrs� Baseline A1C – 8.1%� Intensive glucose

control vs. standard control

� Median f/up 3.5 yrs� primary outcome:

� nonfatal myocardial infarction

� nonfatal stroke� death from CV causes

Intensive Standard RR reduction

A1C 6.4% 7.5%

Primary outcome 6.9% 7.2% 10%

Death from any cause

5.0% 4.0% ↑22%*

Non-fatal MI 3.6% 4.6% 24%*Severe hypoglycemia

2.7% 1.5%

The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358:2545-2559

* P-value < 0.05

ACCORD� Action to Control Cardiovascular Risk in Diabetes

(ACCORD) trial� Designed primarily to examine the effects of

glycemic control, lower than had previously been achieved, on CVD in subjects with long-standing diabetes

� 10,250 adults (mean age 62 years) with a median diabetes duration of ten years and at high risk for cardiovascular disease (diagnosed with CVD or two risk factors in addition to diabetes)

� Intensive treatment group with the aim of achieving A1C of < 6 % or a standard treatment group with a A1C goal of 7.0 to 7.9 %.

� After 3.5 years, the intensive arm was halted due to a higher number of total deaths: 257 deaths in subjects assigned to intensive therapy versus 203 deaths in patients assigned to standard treatment group.*

� The primary outcome (a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes) occurred in 352 and 371 patients in the intensive and standard therapy groups, respectively (HR 0.90, 95% CI 0.78-1.04).

* hazard ratio, 1.22; 95% CI, 1.01 to 1.46; P=0.04

ACCORD

� Preliminary information : extensive analyses have not identified a specific cause for the excess mortality in the intensive treatment group.

� Subjects in the intensive group rapidly achievedtarget A1C values and experienced a greater number of severe hypoglycemic events (annualized rate of 3.1 versus 1.0 percent) and more weight gain (mean 3.5 versus 0.4 kg at three years) than the standard group (median A1C 7.5 percent).

ACCORD

ADVANCE

� 11,140 patients with DM2

� Mean age – 66 yrs� Baseline A1C - 7.5%� Intensive glucose

control vs. standard control

� Median f/up 5 yrs� 1º end-points: major

macro- and micro vascular events


A1C 6.5% 7.3%

Major microvascular 9.4% 10.9% 14% *

New/worsening nephropathy

4.1% 5.2% 21%*

New onset microalbuminuria

23.7% 25.7% 9% *

Major macrovascular

10.0% 10.6% 6%

The ADVANCE Collaborative Group. N Engl J Med 2008;358:2560-2572

* P-value < 0.05

ADVANCE

� Mean glycated hemoglobin level was lower in the intensive-control group (6.5%) than in the standard-control group (7.3%)

� Intensive control � reduced the incidence of combined major macrovascular and

microvascular events (18.1% vs 20.0% with standard control; hazard ratio 0.90, 95% confidence interval (CI), 0.82 to 0.98; p=0.01)

� reduced the incidence of major microvascular events (9.4% vs 10.9%; hazard ratio, 0.86; 95% CI, 0.77 to 0.97; p=0.01)

� This occurred primarily because of a reduction in the incidence of the nephropathy (4.1% vs 5.2%; hazard ratio, 0.79; 95% CI, 0.66 to 0.93; p=0.006) with NO effect on retinopathy (p=0.50)

� NO significant effects of the type of glucose control for:� major macrovascular events (hazard ratio with

intensive control 0.94; 95% CI, 0.84 to 1.06; p=0.32)� death from CV causes (hazard ratio with intensive

control 0.88; 95% CI, 0.74 to 1.04; p=0.12)� death from any cause (hazard ratio with intensive

control 0.93; 95% CI, 0.83 to 1.06; p=0.28)

ADVANCE

ADVANCE

� Intensive control that resulted in HbA1c of 6.5% yielded a 10% relative reduction in the combined outcome of major macrovascular and microvascular events, primarily as a consequence of a 21% relative reduction in nephropathy

The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329:977-986

* P-value < 0.05

DCCT

� 1441 patients with DM1� Age: 13-39� No history of

cardiovascular disease� IIT vs. conventional IT

for 6.5 yrs� 1º prevention group:

� Retinopathy� Neuropathy� Nephropathy


A1C 7.4% 9.1%New retinopathy 1.2 per 100

pt-yr4.7 per 100 pt-yr

76%*

Microalbuminuria 2.2 per 100 pt-yr

3.4 per 100 pt-yr

34%*

Clinical neuropathy 3.1 per 100 pt-yr

9.8 per 100 pt-yr

68%*

Macrovascular disease

0.5 per 100 pt-yr

0.8 per 100 pt-yr

41%

� 93% of DCCT patients f/up for additional 11 yrs

� At the end of the DCCT:� the conventional-treatment

group intensive treatment (all participants returned totheir own health careproviders for diabetes care)

� No hx of cardiovascular disease� IIT vs. conventional IT for 6.5

yrs� 1º prevention group:

� Retinopathy� Neuropathy� Nephropathy

Year 11th of EDIC Intensive Standard RR reduction

A1C 7.9% 7.8%

Microalbuminuria 9% 17% 38%*

Cr>2.0 0% 2.0% 46%*

Progressive retinopathy

6% 21% 75%*

Major CV events 0.38 per 100 pt-yr

0.8% per 100 pt-yr

42%*

Non-fatal MI CVA, death from CVD

11 25 57%*

Epidemiology of diabetes interventions and Complications (EDIC, 1994- 2006) follow-up study

EDIC

(DCCT/EDIC Research Group. Epidemiology of Diabetes Interventions and Complications (EDIC). Design, implementation, and preliminary results of a long-term follow-up of the Diabetes Control and Complications Trial cohort. Diabetes Care 1999; 22: 99- 111.

EDIC� Goal : examine the longer term effects of the original

DCCT interventions (applied to cardiovascular, retinal and renal complications)

� Discovered the long term “imprinting” effects (metabolic memory) of the previous intensive and standard treatments

� Established (first time) the role of intensive therapy and chronic glycemia with regard to atherosclerosis

Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications inpatients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998 Sep 12;352(9131):837-53.

United Kingdom Prospective Diabetes Study (UKPDS)

� 3867 patients with newly diagnosed DM2� Randomized to conventional-therapy group (diet

alone) or intensive-therapy group: sulfonylurea (chlorpropamide, glibenclamide, glipizide) or insulin

� Metformin added to sulfonylurea if optimal control not achieved

� Insulin initiated if combination of oral agents was ineffective

United Kingdom Prospective Diabetes Study (UKPDS)

� Drugs added to conventional group if symptoms of hyperglycemia or FPG>270 mg/dl

� Goal of therapy: FPG<108 mg/dl

� Microvascular and Macrovascular complications examined

� 11 percent reduction in A1C ( 7.0% vs. 7.9%)

� 25 percent risk reduction in microvascular disease(P = 0.001) � defined as renal failure,

death from renal failure, retinal photocoagulation, or vitreous hemorrhage

UKPDS: results

UKPDS: results

� No reduction in macrovascular disease

� More hypoglycemic episodes and weight gain in the intensive therapy group

10 year follow-up of intensive glucose control in type 2 diabetes. R Holman et al. NEJM 2008;359:1577-89

10 year follow-up of intensive glucose control in type 2 diabetes

year followww- p of intensive glucose control in type 2 diabetes. R Holman et alupu l. EJMNE M 008;359:1572 777- 998

� United Kingdom Prospective Diabetes Study (UKPDS)- 4209 patients in conventional or intensive therapy

� Post-trial monitor – 3277 patients followed up:� first 5 years: annual UKPDS clinic visits (no

attempts to maintain previously assigned therapy)� years 6 – 10: annual questionnaires

10 year follow-up of intensive glucose control in type 2 diabetes. R Holman et al. NEJM 2008;359:1577-89

10 year follow-up of intensive glucose control in type 2 diabetes

Results� HbA1c: differences between groups in were lost after the first year� Sulfonylurea-insulin group:

� any diabetes-related end point- relative risk reduction persisted at 10 years (9%, p=0.04)

� microvascular disease - relative risk reduction persisted at 10 years (24%, p=0.001)

� myocardial infarction - risk reduction emerged over time (15%, p=0.01) � death from any cause - risk reduction emerged over time (13%, p=0.007)

� Metformin group: � any diabetes-related end point - significant risk reductions persisted (21%,

p=0.010)� myocardial infarction - significant risk reductions persisted (33%, p=0.005) � death from any cause - significant risk reductions persisted (27%, p=0.002)

Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes. Duckworth W et al. NEJM 2009;360:129-139

Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes

ucose Control and Vascular Complications in Veterans with Type 2 Diabetes. Duckworth W et al. NEJM 2009;360:129-139

� 1791 military veterans with suboptimal response to therapy for type 2 DM

� mean age: 60.4 years� Mean number of years since diagnosis with diabetes: 11.5� 40% had already had one CV event� 2 groups

� intensive glucose control� standard glucose control

� Goal: absolute reduction of 1.5 percentage points in HbA1c in intensive treatment group compared to the standard treatment

� Primary outcome: time from randomization to first major CV event


� Follow-up: 5.6 years� Primary outcome occurred in 264 patients in the standard

treatment group vs 235 patients in the intensive therapy group (HR: 0.88; 95%CI, 0.74 to 1.05; p=0.14)

� Median glycated hemoglobin levels were 8.4% in the standard therapy group vs 6.9% in the intensive-treatment group.

� Rate of adverse events were 17.6% in the standard therapy group and 24.1% in the intensive therapy group (p=0.05).

� Hypoglycemia (most common side effect) occurred significantly more in the intensive treatment group than in the standard treatment group (p<0.001)


� Results� NO significant difference between the 2 groups in any

component of the primary outcome (the time from randomization to a major CV event) or in the rate of death from any cause.

� NO difference between the 2 groups was observed for microvascular complications

� Note! Correction: progression of microalbuminuria favors intensive therapy group (9.1% vs. 13.8 % in a standard group, P=0.04).*

* NEJM 361;10, September 3, 2009

Effect of a Multifactorial Intervention on Mortality in Type 2 Diabetes

Effect of a Multifactorial Intervention on Mortality in Type 2 Diabetes. Gæde P, M.D., D.M.Sc., Lund-Andersen H, M.D., D.M.Sc.,

Parving H, M.D., D.M.Sc., and Pedersen O, M.D., D.M.Sc. N Engl J Med. 2008 Feb 7;358(6):580-91.

160 patients with type 2 diabetes mellitus and persistent microalbuminuria

Intensive, target-driven treatment Conventional multifactorial treatment

Followed for a mean of 5.5 years

Targets:- HbA1c < 6.5% - fasting serum total cholesterol < 175 mg/dl (4.5 mmol/l)- fasting serum triglyceride < 150 mg/dl (1.7 mmol per liter)- blood pressure: systolic <130 mm Hg, diastolic < 80 mm Hg.

Effect of a Multifactorial Intervention on Mortality in Type 2 Diabetes: End points

1. Primary end point: � time to death from any cause

2. Secondary end points: � death from cardiovascular causes � a composite of cardiovascular disease events (death from

cardiovascular causes, nonfatal stroke, nonfatal myocardial infarction, coronary-artery bypass grafting, percutaneous coronary intervention or revascularization for peripheral atherosclerotic arterial disease, and amputation because of ischemia)

3. Tertiary end points:� incident diabetic nephropathy� development or progression of diabetic retinopathy or neuropathy

Effect of a Multifactorial Intervention on Mortality in Type 2 Diabetes: Results

Intensive group

� 24 patients died (30%) vs 40 patients (50%) in the conventional treatment group (hazard ratio for death in the intensive group vs conventional group: 0.54; 95% confidence interval, 0.32 to 0.89; p=0.02)

Effect of a Multifactorial Intervention on Mortality in Type 2 Diabetes: Results

� Lower risk of death from cardiovascular causes (HR 0.43; 95% CI, 0.19 to 0.94; p=0.04) compared to conventional treatment group

� Lower risk of cardiovascular events (HR 0.41; 95% CI, 0.25 to 0.0.67; p<0.001) vs conventional treatment group

� 1 patient had progression to end-stage renal disease vs 6 patients in the conventional treatment group (p=0.04)

� Fewer patients required retinal photocoagulation (relative risk, 0.45; 95% CI, 0.23 to 0.86; p=0.02) compared to the other group

S.E. Nissen, M.D., and K. Wolski, M.P.H. Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes. NEJM 2007; 356:2457-2471

Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes

� Meta-analysis � Searches

� published literature, � FDA website, � GlaxoSmithKline clinical trial registry

� Inclusion criteria� study duration > 24 weeks, � use of a control group not receiving rosiglitazone, � availability of outcome data for myocardial infarction and death from

cardiovascular causes� Included: 42 trials (out of 116 potentially relevant trials)� Tabulated all occurrences of myocardial infarction and death

from any cardiovascular causes� Mean age of subjects: 56 years� Mean baseline HbA1c: 8.2%

S.E. Nissen, M.D., and K. Wolski, M.P.H. Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes. NEJM 2007; 356:2457-2471

Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes

Results� Myocardial infarction: OR=1.43 in the

rosiglitazone group compared with the control group (95% CI, 1.03 to 1.98; p=0.03)

� Death from cardiovascular causes: OR=1.64 in the rosiglitazone group compared with the control group (95% CI, 0.98 to 2.74; p=0.06)

Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. S E Kahn et al. NEJM 2006;355:2427-43

Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy

ADOPT - A Diabetes Outcome Progression Trial

� Evaluate rosiglitazone, metformin and glyburide as initial treatment for recently diagnosed type 2 diabetes

� Double-blind, randomized, controlled clinical trial� 4360 patients enrolled� Median treatment time: 4.0 years


Outcomes� Primary outcome: time to monotherapy failure (FPG> 180

mg/dl) for rosiglitazone, as compared to metformin or glyburide

� Secondary outcomes: FPG levels, glycated hemoglobin, insulin sensitivity, and beta-cell function


Results� 5 years cumulative incidence of monotherapy failure: 15%

with rosiglitazone, 21% with metformin, 34% with glyburide. This represents a risk reduction of 32% for rosiglitazone as compared with metformin and 64% as compared with glyburide (p<0.01 for both)

� Risk of cardiovascular (CV) events: glyburide was associated with lower CV risk than rosiglitazone (p<0.05) and risk was similar between the rosiglitazone group and metformin group

� Rosiglitazone was associated with more weight gain and edema than either glyburide or metformin; less hypoglycemia than glyburide and less GI effects than metformin (p<0.001 for all)

� Rosiglitazone was associated with a higher rate of fractures in women

Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD)

Design� To evaluate long-term impact of rosiglitazone on

cardiovascular outcomes and blood glucose control, compared to the conventional medications metformin and sulfonylureas

� 338 centers in 23 countries,� 5.5 years duration� randomized 4447 people with type 2 diabetes who

were already taking metformin or sulfonylurea alone


� 4447 people with type 2 diabetes with mean HbA1c: 7.9%, who were already taking metformin or sulfonylurea alone

1. Add-on rosiglitazone 2. Combination of metformin and sulfonylurea

Goal: HbA1c: 7.0 or less

If HbA1c >8.5

Add a third oral glucose-lowering agent Add insulin


� On the composite outcomes of cardiovascular death, stroke and heart attack the result was slightly but not statistically significant in favor of rosiglitazone

� Rosiglitazone was shown to be superior in controlling blood glucose than older metformin and sulfonylurea therapies

� Found a double risk for heart failure� Found an increased risk of arm and lower leg

fractures in women

A Randomized Trial of Therapies for Type 2 Diabetes and Coronary Artery Disease.The BARI 2D Study Group. NEJM, 360:2503-2515

Angioplasty Revascularization Investigation in Type 2 Diabetes (BARI 2D) study

� Evaluated the cardiovascular treatment approach compared to a diabetes control approach in persons with type 2 diabetes and stable coronary artery disease to reduce deaths or deaths and cardiovascular events (MI, stroke) combined

� 2368 people with stable heart disease and type 2 diabetes

� 5 years average follow up


� Prompt bypass surgery or angioplasty does NOT lower mortality risk compared to drug therapy in people with type 2 diabetes and stable heart disease.

� No difference in mortality risk between drugs that reduce insulin resistance and drugs that provide insulin


� No increase in heart attacks was observed in the rosiglitazone group

� Prompt CABG had significantly better outcomes when compared to medical treatment alone when CV events were considered in addition to death (non-fatal MI)

� Among the subgroup of patients pre-identified as candidates for CABG, the subgroup that received prompt surgery had fewer heart attacks or strokes compared to those receiving intensive medical therapy alone

* Postprandial measurements should be made 1-2 h after the beginning of the meal, generally peak levels in patients with diabetes.

Standards of Medical Care in Diabetes–2009. ADA Position Statement. Diabetes Care;32:S13-S61.

Glycemic goals: non-pregnant adults with diabetes

* Postprandial measurements should be made 1-2 h after the beginning of the meal, generally peak levels in patients with diabetes.

� HbA1c < 7.0%� Preprandial capillary plasma glucose 70-130 mg/dl (3.9-7.2 mmol/l) � Peak postprandial capillary plasma glucose < 180 mg/dl (< 10.0 mmol/l)*� Key concepts in setting glycemic goals� HbA1c is the primary target for glycemic control� Goals should be individualized based on:

� duration of diabetes� age/life expectancy� comorbid conditions� known CVD or advanced microvascular complications� hypoglycemia unawareness� individual patient considerations

� More or less stringent glycemic goals may be appropriate for individual patients

� Postprandial glucose may be targeted if HbA1c goals are not met despite reaching preprandial glucose goals

Road Maps to Achieve Glycemic ControlIn Type 2 Diabetes Mellitus

ACE/AACE Diabetes Road Map Task Force

ChairpersonsPaul S. Jellinger, MD, MACE, Co-Chair

Jaime A. Davidson, MD, FACE, Co-Chair

Task Force MembersLawrence Blonde, MD, FACP, FACEDaniel Einhorn, MD, FACP, FACE

George Grunberger, MD, FACP, FACEYehuda Handelsman, MD, FACP, FACE

Richard Hellman, MD, FACP, FACEHarold Lebovitz, MD, FACE

Philip Levy, MD, FACEVictor L. Roberts, MD, MBA, FACP, FACE

© 2008 AACE. All rights reserved. No portion of the Roadmap may be altered, reproducedor distributed in any form without the express permission of AACE.

Revision April 2008

www.medscape.com/viewarticle/559463

Algorithm for the metabolic management of type 2 diabetes; Reinforce lifestyle interventions at every visit and check A1C every 3 months until A1C is <7% and then at least every 6 months. The interventions should be changed if A1C is ≥7%. a)Sulfonylureas other thanglybenclamide (glyburide) or chlorpropamide. b)Insufficient clinical use to be confident regarding safety.

ADA Treatment Algorithm

Medications used for weight loss*

* http://www.uptodate.com/contents/drug-therapy-of-obesity?source=search_result&search=obesity+drug+therapy&selectedTitle=1%7E150

Liraglutide (Victoza)* � Victoza®, GLP-1 receptor agonist, is indicated as an adjunct to diet and exercise to

improve glycemic control in adults with type 2 diabetes mellitus � Administered as a subcutaneous injection once daily, any time of day, independent of

meals � Impacts beta-cell function to help regulate insulin secretion� Reduces FPG and PPG� May reduce weight (Victoza® is not indicated for the management of obesity, and weight

change was a secondary end point) � On average, patients in the monotherapy trial lost 5.5 lb with Victoza® 1.8 mg and 4.6 lb

with Victoza® 1.2 mg,

* http://www.victozapro.com

Exenatide (Byetta, Bydureon)*� Long-acting synthetic peptide that is a GLP-1 receptor agonist, is available for adjunctive

therapy for patients with type 2 diabetes who are inadequately controlled on oral agents.� Exenatide in its Byetta form is administered as a subcutaneous injection any time within the

60 minutes before the first and last meal of the day. � A once-weekly injection has been approved as of January 27, 2012 under the trademark

Bydureon.� Dose-dependent weight loss has been reported in trials of exenatide in patients with type 2

diabetes not well controlled on oral agents.� Whether this weight loss was related to nausea, a common side effect of exenatide, is not

known. However, in one of the trials, a post-hoc analysis showed no correlation between change in body weight and duration of nausea. Weight loss after 18 months was 4.5 kg without any dietary or exercise program.

*http://www.nytimes.com/2012/01/28/health/bydureon-a-diabetes-drug-from-amylin-wins-fda-approval.html.

Pramlinide (Symlin)� Antihyperglycemic drug for use in patients with diabetes treated with

insulin, is a synthetic analog of human amylin, anaturally occurring neuroendocrine hormone synthesized by pancreatic beta cells that contributes to glucose control during the postprandial period.

� Administered as a subcutaneous injection within 15 min before breakfast, lunch and dinner.

� Associated with modest weight loss. In a meta-analysis of eight randomized trials, pramlintide reduced weight compared with placebo (mean difference -2.57 and -2.27 kg, in patients with and without diabetes, respectively).

Orlistat (Xenical)� Lipase inhibitor, used for management of

obesity, including weight loss and weight management, when used in conjunction with a reduced-calorie and low-fat diet;

� Reduces the risk of weight regain after prior weight loss;

� Indicated for obese patients with an initial body mass index (BMI) ≥30 kg/m2 or ≥27 kg/m2 in the presence of other risk factors (eg, diabetes, dyslipidemia, hypertension)

� Pooled data from five clinical trials indicated that the overall mean weight loss from randomization to the end of 1 year of treatment in the intent-to-treat population was 13.4 lbs in the patients treated with XENICAL and 5.8 lbs in the placebo-treated patients.*

*http://www.gene.com/gene/products/information/xenical/pdf/pi.pdf

Qsymia*� Anorexiant, anticonvulsant, is indicated as an adjunct to a reduced-calorie diet and increased physical activity for

chronic weight management in adult patients with an initial body mass index (BMI) of30 kg/m2 or greater (obese), or 27 kg/m2 or greater (overweight) in the presence of at least one weight related comorbidity such as ypertension, type 2 diabetes mellitus, or dyslipidemia

� Phentermine 3.75 mg/topiramate 23 mg once daily for 14 days. Increase dose to phentermine 7.5 mg/topiramate 46 mg once daily for 12 weeks then evaluate weight loss. If 3% of baseline body weight has not been lost, discontinue use or increase dose to phentermine 11.25 mg/topiramate 69 mg once daily for 14 days, and then to phentermine 15 mg/topiramate 92 mg once daily. Evaluate weight loss after 12 weeks on phentermine 15 mg/topiramate 92 mg; if 5% of baseline body weight has not been lost at dose of phentermine 15 mg/topiramate 92 mg gradually discontinue therapy (eg, 1 dose every other day for at least 1 week).

� The effect of Qsymia on weight loss in conjunction with reduced caloric intake and increased physical activity was studied in 2 randomized, double-blind, placebo controlled studies in obese patients (Study 1) and in obese and overweight patients with two or more significant co-morbidities (Study 2). Both studies had a 4-week titration period, followed by 52 weeks of treatment.

� After 1 year of treatment with Qsymia, all dose levels resulted in statistically significant weight loss compared to placebo. A statistically significant greater proportion of the patients randomized to Qsymia than placebo achieved 5% and 10% weight loss.*

*http://www.vivus.com/docs/QsymiaPI.pdf

Lorcaserin (Belviq®)� Serotonin 5-HT2C Receptor Agonist

� Product Availability Belviq®: FDA approved June 2012; anticipated availability is first quarter of 2013. Consult prescribing information for additional information.

� Use Chronic weight management, as an adjunct to a reduced-calorie diet and increased physical activity, in patients with either an initial body mass index (BMI) of ≥30 kg/m2 or an initial BMI of ≥27 kg/m2 and at least one weight-related comorbid condition (eg, hypertension, dyslipidemia, type 2 diabetes).

� In the BELVIQ placebo-controlled clinical database of trials of at least one year in duration, of 6888 patients (3451 BELVIQ vs. 3437 placebo; age range 18-66 years, 79.3% women, 66.6% Caucasians, 19.2% Blacks, 11.8% Hispanics, 2.4% other, 7.4% type 2 diabetics), a total of 1969 patients were exposed to BELVIQ 10 mg twice daily for 1 year and 426 patients were exposed for 2 years.

� Approval was based on data from three double-blind, randomized, placebo-controlled trials lasting 52 to 104 weeks. The studies included patients with (n = 499) and without (n = 6,136) type 2 diabetes. Lorcaserin, along with diet and exercise, was more effective than diet and exercise alone in helping patients lose 5% or more of their body weight after 1 year and managing the weight loss for up to 2 years*.

* http://www.pharmacist.com/node/29402

Name Pharmacologic Category Dose

Route of

administration

Image

Liraglutide (Victoza)

GLP-1 Receptor agonist

0.6mg1.2 mg1.8 mg SC

Exenatide (Byetta, Bydureon)

GLP-1 receptor agonist

5 mcg10 mcg2mg

SC

Pramlinide (Symlin)

synthetic analog of human amylin

15 mcg 60 mcg30 mcg 120 mcg45 mcg

SC

Orlistat (Xenical) Lipase inhibitor 120 mg PO

Phentermine and topiramate(Qsymia)

anorexiant, anticonvulsant

3.75 mg/23mg7. 5 mg/46mg15mg/92mg PO

Lorcaserin (Belviq®)

serotonin 5-HT2C Receptor Agonist

10 mg PO

Thank you

11/29/2012

Diabetes: controversies and newsedg1.vcall.com/docs/170278/New/2.pdf · Diabetes: Diagnosis,...

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