Clinical Imperatives When Treating Patients with Diabetes

Diabetes, IFG, IGT: Diagnostic criteria

≥200

–

140 to 199 (ADA)

>140 to <200 (AACE)

Casual Fasting 2-hr postload*

Plasma glucose (mg/dL)

*Following equivalent of 75 g anhydrous glucose in water

ADA. Diabetes Care. 2006;29(suppl 1):S43-8.

AACE. Endocr Pract. 2003;9:240-52.

Diabetes

Impaired fasting glucose (IFG)

Impaired glucose tolerance (IGT)

≥200

–

–

≥126

100 to 125 (ADA)

>110 to <126 (AACE)

–

Target Recommendations

A1C <7%<6% if possible without inducing hypoglycemia

BP (mm Hg) <130/<80ACEI or ARB in BP-lowering regimen

Lipids (mg/dL)LDL-C

HDL-C TG

<100 (<70 optional)>40 men, >50 women <150

Statin for CV history or age >40 yr (regardless of baseline LDL) to lower LDL 30%–40%

AHA/ACC/ADA: Multiple risk reduction in diabetes

Pearson T et al. Circulation 2002.Grundy SM et al. Circulation 2004.

ADA. Diabetes Care 2006.

• ASA: Age >40 yr or with other risk factors, all with CV disease history

• ACE inhibitor: Age >55 yr with another CV risk factor

Intensive glycemic control

Intensive management of

comorbid conditions*

• A1C ≤6.5%• Glucose (mg/dL)

– Preprandial ≤110– Postprandial ≤140

• Lipid modifying• BP lowering• ASA for prevention of

vascular events

AACE: Managing diabetes

Lifestyle intervention

• Optimal nutrition• Physical activity• Smoking cessation• Weight control

AACE. Endocr Pract. 2002;8(suppl 1):40-65.

American Association of Clinical Endocrinologists

*Dyslipidemia, hypertension, early renal disease

AHA/ACC secondary prevention guidelines:Diabetes management

• Initiate lifestyle and pharmacotherapy to achieve near-normal A1C (IB)

• Begin vigorous modification of other risk factors (eg, physical activity, weight management, BP control, cholesterol management) (IB)

• Coordinate diabetic care with patient’s primary care physician or endocrinologist (IC)

Smith SC et al. Circulation. 2006;113:2363-72.

A1C goal <7%

DPP: Benefit of diet/exercise or metformin on diabetes prevention in at-risk patients

DPP Research Group. N Engl J Med. 2002;346:393-403.

Years

N = 3234 with IFG/IGT without diabetes

0

0

10

20

30

40

1.0 2.0 3.0 4.0

Placebo

Metformin

Lifestyle

Cumulativeincidence

of diabetes(%)

31%

58%

P

< 0.001

< 0.001

DPP: Benefit of diet/exercise or metformin on diabetes by race/ethnicity

DPP Research Group. N Engl J Med. 2002;346:393-403.

Reduction in new-onset diabetes

(%)

Whiten = 1768

AfricanAmerican

n = 645Hispanicn = 508

American

Indiann = 171

Asiann = 142

N = 3234 with IFG/IGT and without diabetes

Lifestyle vs placebo Metformin vs placebo Lifestyle vs metformin

0

-20

-40

-60

-80

3-Week diet + exercise yield favorable metabolic changes

*

*

†

*

*

0

50

100

150

200

250

Total-C LDL-C HDL-C TG Serumglucose

mg/dL

*P < 0.01†P < 0.05 Roberts CK. et al. J Appl Physiol. 2006;100:1657-65.

*

0

5

10

15

20

25

30

35

Insulin

μU/mL

N = 31 overweight/obese men; weight 8.4 lbs

Baseline Follow-up

3-Week diet + exercise reduce proatherogenic factors

0

0.5

1

1.5

2

2.5

CRP

0

100

200

300

400

MPO sICAM-1 sP-selectin

ng/mL

0

50

100

150

200

250

MPO = myeloperoxidase; 8-iso-PGF2α = 8-isoprostaglandin F2α sICAM-1 = soluble intracellular adhesion molecule 1*P < 0.05; †P < 0.01

Roberts CK. et al. J Appl Physiol. 2006;100:1657-65.

pg/mL mg/L

*

N = 31 overweight/obese men; weight 8.4 lbs

†

†

† *

Baseline Follow-up

8-iso-PGF2α

Beyond lifestyle: Aggressive medical therapy in diabetes

Adapted from Beckman JA et al. JAMA. 2002;287:2570-81.

Atherosclerosis

Platelet activationand aggregation

Dyslipidemia

HyperglycemiaInsulin resistance

Hypertension

MetforminTZDs

SulfonylureasNonsulfonylureas

SecretagoguesInsulin

StatinsFibric acid derivatives

ACE inhibitorsARBs

β-blockersCCBs

Diuretics

ASAClopidogrelTiclopidine

Steno-2 supports aggressive multifactorial intervention in type 2 diabetes

• Objective: Target-driven, long-term, intensified intervention aimed at multiple risk factors compared with conventional therapy

• N = 160 patients with type 2 diabetes and microalbuminuria

• Intensive treatment targets– BP <130/80 mm Hg – A1C <6.5%– Total-C <175 mg/dL– Triglycerides <150 mg/dL

Gæde P et al. N Engl J Med. 2003;348:383-93.

Steno-2: Multifactorial intervention on CV outcomesN = 160 with type 2 diabetes and microalbuminuria

Gæde P et al.N Engl J Med. 2003;348:383-93.

*CV death, MI, stroke, CABG/PCI, amputation, PAD surgery†Adjusted for duration of diabetes, age, sex, smoking, CV disease

Primary composite outcome*

(%)

60

50

40

30

20

10

0

53% RRR†

P = 0.01

Follow-up (months)

Conventional

Intensive

0 12 24 36 48 60 72 84 96

8

Steno-2: Better risk factor control with intensive therapy

Gæde P et al. N Engl J Med. 2003;348:383-93.

Conventional therapy (n = 80) Intensive therapy (n = 80)

0056789

1110

AlC(%)

Follow-up (years)

0

110120130

140

150160170

0

SBP(mm Hg)

Follow-up (years)

0

50100150200250300350

0

TG (mg/dL)

00

50100150200250300350

Total-C(mg/dL)

1 2 3 4 5 6 7 8

P < 0.001

1 2 3 4 5 6 7 8

P < 0.001

1 2 3 4 5 6 7

P = 0.015

1 2 3 4 5 6 7 8

P < 0.001

Steno-2: Effects of multifactorial intervention on microvascular and neuropathic outcomes

Gæde P et al. N Engl J Med. 2003;348:383-93.

Nephropathy

Retinopathy

Autonomicneuropathy

Peripheralneuropathy

Variable RR P

0.39

0.42

0.37

1.09

0.003

0.02

0.002

0.66

Reductions in the risk of microvascular complications were maintained at 8 years

0.0 0.5 1.0 1.5 2.0 2.5

Intensive better

Conventionalbetter

Relative risk

Benefits of aggressive LDL-C lowering in diabetes

Shepherd J et al. Diabetes Care 2006. Sever PS et al. Diabetes Care 2005. HPS Collaborative Group. Lancet 2003. Colhoun HM et al. Lancet

2004.

Difference in LDL-C

(mg/dL)

Aggressive lipid-lowering

better

Aggressive lipid-loweringworse

0.026

0.036

0.001

<0.0001

0.0003

Primary event rate (%)

17.9

11.9

9.0

12.6

13.5

Control

13.8

9.2

5.8

9.4

9.3

Treatment

0.63

0.67

0.73

P

TNT Diabetes, CHD

ASCOT-LLA Diabetes, HTN

CARDS Diabetes, no CVD

HPS All diabetes

Diabetes, no CVD

*Atorvastatin 10 vs 80 mg/day†Statin vs placebo

Relative risk

0.7 0.9 10.5 1.7

0.77

22*

35†

46†

39†

39†

0.75

Event rate (%)

HPS: Statin beneficial irrespective of baseline lipid level and diabetes status

Placebon = 10,267

0.4 1.0 1.40.6 0.8 1.2

Simvastatinn = 10,269

Event rate ratio

Statin better Placebo betterLDL-C <116 mg/dL

With diabetes

No diabetes

15.7

18.8

20.9

22.9

LDL-C ≥116 mg/dL

With diabetes

No diabetes

23.3

20.0

27.9

26.2

24% reductionP < 0.000125.219.8All patients

HPS Collaborative Group. Lancet. 2003;361:2005-16.

Heart Protection Study

ASCOT-LLA: Atorvastatin reduces CV events in patients with diabetes and hypertension N = 2532, baseline LDL-C 128 mg/dL

Nonfatal MI, CV mortality, UA, stable angina, arrhythmias, stroke, TIA, PAD, retinal vascular thrombosis, revascularization

Sever PS et al. Diabetes Care. 2005;28:1151-7.

%

Number at riskPlacebo 1258

Atorvastatin 1274

14.0

12.0

10.0

8.0

6.0

4.0

2.0

00

1231 1209 1191 1171 1065 699 3701237 1219 1200 1175 1058 714 375

0.5 1.0 1.5 2.0 2.5 3.0 3.5 Years

Atorvastatin 10 mg

Placebo

HR = 0.77 (0.61–0.98)

23% Risk reductionP = 0.036

HOPE Study Investigators. Lancet. 2000;355:253-9.Daly CA et al. Eur Heart J. 2005;26:1369-78.

PERSUADE(n = 1502)

CV death/MI/cardiac arrest

MICRO-HOPE(n = 3577)

CV death/MI/stroke

MICRO-HOPE, PERSUADE: ACEI reduces CV events in diabetes

Placebo

25

Ramipril10 mg

20

15

10

5

0

Primary outcome

(%)

Follow-up (years)0 1 2 3 4 5

25% RRRP = 0.0004

20

15

10

5

0

0 1 2 3 4 5Follow-up (years)

Placebo

Perindopril8 mg

19% RRRP = 0.13

25

-50

-40

-30

-20

-10

0

CRP MMP- 9 sCD40L

0

50

100

150

200

250

300

350

TZD + statin: Favorable effects on inflammatory markers and adiponectin

*P < 0.05 vs baseline; †P < 0.05 vs ROSI monotherapy Chu C-S et al. Am J Cardiol. 2006;97:646-50.

N = 30 with DM2 and hyperlipidemia treated with rosiglitazone; add-on atorvastatin after 3 months; follow-up 6 months

Adiponectin†

Change from

baseline (%)

†

†

*

*

*

* **

ROSI 4 mg ROSI 4 mg + ATORVA 10 mg

Principal mechanisms of action for oral diabetic agents

Adapted from Krentz AJ, Bailey CJ. Drugs. 2005;65:385-411.

α-Glucosidase inhibitors

Intestine: ↓glucose absorption

Biguanides

Liver: ↓hepatic glucose output

↑glucose uptake

Blood glucose

Sulfonylureas and repaglinide

Pancreas: ↑insulin

secretion

Muscle and adipose tissue: ↓insulin resistance

↑glucose uptake

Thiazolidinediones

Oral antihyperglycemic agents

Drug class Agents Mechanism of action

Alpha-glucosidase inhibitors

Acarbose, miglitol Delay intestinal carbohydrate absorption

Biguanides Metformin ↓ Hepatic glucose production ↑ Liver and muscle insulin sensitivity

Insulin secretagogues—Sulfonylureas

Glimepiride, glipizide, glyburide

↑ Insulin secretion from pancreatic β-cells

Insulin secretagogues—Meglitinides

Nateglinide, repaglinide ↑ Insulin secretion from pancreatic β-cells

Thiazolidinediones Pioglitazone, rosiglitazone ↑ Adipose and muscle insulin sensitivity

Trujillo J. Formulary. 2006;41:130-41.Luna B, Feinglos MN. Am Fam Physician. 2001;63:1747-56.

Beyond glucose lowering: Effects of antidiabetic agents

TZD MetforminInsulin

secretagogues* AGI

Insulin resistance

Hypertension or or

Altered hemostasisPAI-1tPA

or or

NANA

DyslipidemiaTGHDL-CLDL particle size

or or

or or

NA

or or

NA

C-reactive protein NA

*Sulfonylureas and meglitinides AGI = alpha glucosidase inhibitor = no change

Adapted from Granberry MC, Fonseca VA.Am J Cardiovasc Drugs. 2005;5:201-9.

NA = data not available

TZD vs sulfonylurea: Glycemic control over time

ROSI GLYB

St. John Sutton M et al. Diabetes Care. 2002;25:2058-64.

N = 203 patients with type 2 diabetes

A1C Fasting plasma glucose

mg/dL

0

8.5

10.0

Treatment week

%

9.5

9.0

8.0

7.5

-8 -4 0 4 8 12 16 28 40 52

GLYBROSI 8 mg/d

GLYB = glyburide

Baseline Week 8 Week 52

0

200

250

TZD + sulfonylurea efficacy in type 2 diabetes

Pfützner A et al. Metabol Clin Exp. 2006;55:20-5.

N = 102; changes after 16 weeks

-80

-60

-40

-20

0

20

40Adiponectin‡

%Change

*P < 0.05 vs baseline†P < 0.005 vs baseline‡Adjusted for BMI changesGLIM = glimepiride 3 mg; ROSI = rosiglitazone

GLIM GLIM + ROSI 4 mg GLIM + ROSI 8 mg

HOMA-IR Intact proinsulin

CRP

*

†

*†

*

†

-20

0

80

160

*

PROactive: Reduced requirement for insulin use

Dormandy JA et al. Lancet. 2005;366:1279-89.

5

10

15

25

06

20

0 12 18 24 30 36

Pioglitazonen = 183 (11%)

Placebon = 362 (21%)

Follow-up (months)

Patients(%)

53% RRRHR 0.47 (0.39–0.56)*

P < 0.0001

*Unadjusted

Sulfonylurea + TZD or metformin: Comparison of lipid and renal effects

Hanefeld M et al. Diabetes Care. 2004;27:141-7.

N = 639 with poorly controlled DM2; change after 52 weeks

-20

-15

-10

-5

0

5

10

15

TG HDL-C TC:HDL-C LDL-C Alb:Cr

*

†

‡

†

†

*P = 0.008, †P < 0.001, ‡P = NS

Pioglitazone 15–45 mg + sulfonylurea Metformin 850–2550 mg + sulfonylurea

Change(%)

TZDs and metformin reduce risk of MICase-control study of first MI in patients with type 2 diabetes

*Adjusted for age, sex, BMI, ACE inhibitor use, history of hypertension or hypercholesterolemia Sauer WH et al. Am J Cardiol. 2006; 97:651-4.

Monotherapy

Metformin

TZD

TZD + sulfonylurea

Metformin + sulfonylurea

Insulin-sensitizing drugs

Sulfonylureamonotherapy

P

0.01

0.03

0.04

0.19

Odds ratio for MI (95% CI)*

Combination therapy

Patients Controls

38 87

7 19

7 18

40 62

0 0.2 0.4 0.6 0.8 1.0 1.2

n

Improving blood glucose control: Potential role of combination therapy

48.4

58.1

0

10

20

30

40

50

60

AACEGoal6.5

%

ADAGoal <7%

Baseline A1C (%) =n =

7.9277

8.0296

Adapted from Weissman P et al. Curr Med Res Opin. 2005;21:2029-2035.

Metformin 1 g/dayUptitrated to 2 g/day

Rosiglitazone 8 mg/day +Metformin 1 g/day

Patients reaching A1C goal

(%)

DPP-IV inhibitors

• Potentially important in early DM2 to prevent deterioration of glucose metabolism

• Decrease rate of GLP-1 degradation

• Partially restore impaired insulin secretion

• Protect -cells

• Oral DPP-IV inhibitors in phase 3 development– Sitagliptin– Vildagliptin

Smyth S, Heron A. Nat Med. 2005;12:75-80.

DPP-IV = dipeptidyl peptidase-IVGLP-1 = glucagon-like peptide-1

DPP-IV inhibitors, GLP-1 analogs: New classes of antidiabetic agents

GLP-1 is released after mealsGlucose-dependent insulin secretion from -cells Levels in type 2 diabetes (“incretin defect”)Rapidly inactivated by DPP-IV

GLP-1: An incretin hormone

GLP-1 degradationGlucose-dependent insulin secretion

DPP-IV inhibitors

Mest H-J, Mentlein R. Diabetologia. 2005;48:616-20. Smyth S, Heron A. Nat Med. 2005;12:75-80.

GLP-1 analogs

Glucose-dependent insulin secretionResistant to DPP-IV degradation

New antidiabetic agents: Dual actions

AMIGO trials: GLP-1 analog in type 2 diabetes

Active treatmentChange from baseline

Exenatide 5 µg bid

Exenatide 10 µg bid

Placebo

Sulfonylurea1 A1C (%) –0.46 –0.86 +0.12

(N = 377) Weight (lb) –2.0 –3.6 –1.3

Metformin2 A1C (%) –0.40 –0.78 +0.08

(N = 336) Weight (lb) –3.6 –6.2 –0.7

Metformin + sulfonylurea3 A1C (%) –0.55 –0.77 +0.23

(N = 733) Weight (lb) –3.6 –3.6 –2.0

AC 2993: Diabetes Management for Improving Glucose Outcomes; 30-week, placebo-controlled trials of exenatide sc added to oral hypoglycemic therapy

1Buse JB et al. Diabetes Care. 2004;27:2628-35.2DeFronzo RA et al. Diabetes Care. 2005;28:1092-100.

3Kendall DM et al. Diabetes Care. 2005;28:1083-91.

Adapted from Cohen JD. Lancet. 2001;357:972-3.

B -blockadeBlood pressure control

A AspirinACE inhibitionA1C control

C Cholesterol management

Managing diabetes as a CHD equivalent: ABCs of coronary prevention

DietDon’t smokeDecrease diabetes risk

D

ExerciseE

Insulin resistance

Proatherogenic effects of insulin resistance

Hypertension Obesity Inflammation Hyperinsulinemia Diabetes Dyslipidemia Thrombosis

Atherosclerosis

Summary: Expanding risk factor control to enhance CV outcomes

• Insulin resistance is an independent risk factor for atherosclerosis

• Aggressive lifestyle modification and pharmacotherapy can decrease CV risk and prevent new-onset diabetes

• TZDs target insulin resistance and appear to improve CV risk factors