1. Identifying and Treating Patients with Insulin Resistance

2. Diagnosis of diabetes, IFG, and IGT
Plasma glucose (mg/dL)
Casual
Fasting
2-hr postload*
Diabetes
Impaired fasting glucose (IFG)
Impaired glucose tolerance (IGT)
≥200 –
≥126
100 to 125 (ADA)
>110 to ≤126 (AACE) –
≥200 –
140 to 199 (ADA)
>140 to <200 (AACE)
• Impaired fasting glucose (IFG) and IGT (measured following consumption of the equivalent of 75 g anhydrous glucose) are recognized markers of a prediabetic state.
• As shown, the American Diabetes Association (ADA) and a task force created by the American Association of Endocrinologists (AACE) and the American College of Endocrinology (ACE) differ slightly in their definitions.1,2
• However, there is consensus regarding glucose levels that are diagnostic for diabetes.1,2
• IFG is most commonly used in the diagnosis of the insulin resistance syndrome (in conjunction with other clinical parameters as discussed in the following slides).
*Following equivalent of 75 g anhydrous glucose in water
ADA. Diabetes Care. 2005;28(suppl 1):S4-36. AACE. Endocr Pract. 2003;9:
1. American Diabetes Association. Standards of medical care in diabetes. Diabetes Care. 2005;28(suppl 1):S4-S36.
2. American College of Endocrinology. ACE position statement on the insulin resistance syndrome. Endocr Pract. 2003;9:

3. Metabolic syndrome diagnosis: ATP III emphasizes clinical practice
Risk factor Defining level
Abdominal obesity (in) Waist: Men >40 Women >35
Triglycerides (mg/dL) ≥150
HDL-C (mg/dL) Men <40 Women <50
BP (mm Hg) ≥130/≥85
Fasting glucose (mg/dL) ≥110 (ADA ≥100)
• ATP III bases the diagnosis of the metabolic syndrome on the presence of ≥3 of the following easily measured parameters1,2:
o Abdominal obesity (assessed by waist circumference, measured midway between the bottom of the rib cage and the iliac crest)
o Elevated triglycerides
o Low HDL-C
o Elevated blood pressure
o High fasting glucose
• The ICD-9 code for the metabolic syndrome (as defined by these criteria) is 277.7, although Medicare allows physicians to use other codes as appropriate.
NCEP ATP III. JAMA. 2001;285:
1. 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:
2. Després J-P, Lemieux I, Prud’homme D. Treatment of obesity: Need to focus on high risk abdominally obese patients. BMJ. 2001;322:

4. Metabolic syndrome diagnosis: IDF emphasizes central obesity
International Diabetes Federation
Central obesity
Plus any 2 of the following:
• The International Diabetes Federation (IDF) definition of metabolic syndrome is similar to that of the ATP III report, but with a greater focus on central obesity.1
• Waist circumference is measured midway between the bottom of the rib cage and the iliac crest.2
Defined according to waist circumference (ethnic- and gender-specific)
Plasma triglycerides >150 mg/dL*
HDL-C <40 mg/dL*
BP 140/90 mm Hg*
Fasting glucose 100 mg/dL or previously diagnosed type 2 diabetes
*Or receiving specific treatment for this abnormality
Accessed August 2005.
1. International Diabetes Federation. The IDF consensus worldwide definition of the metabolic syndrome. Available at: Accessed August 2005.
2. Després J-P, Lemieux I, Prud’homme D. Treatment of obesity: Need to focus on high risk abdominally obese patients. BMJ. 2001;322:

5. IDF ethnic- and gender-specific criteria for central obesity
Waist circumference (inches)
Men
Women
European 37 32
Sub-Saharan African
Middle Eastern
South Asian 35 32
South/Central American
Chinese 35 32
Japanese 34 35
• The IDF also avoids a “one size fits all” approach to defining central obesity.1
• As shown, different cutpoints are used depending on an individual’s gender or ethnicity.
Accessed August 2005.
International Diabetes Federation. The IDF consensus worldwide definition of the metabolic syndrome. Available at: Accessed August 2005.

6. Metabolic syndrome diagnosis: WHO emphasizes central role of insulin resistance
Type 2 diabetes, or
Impaired fasting glucose, or
If fasting glucose <110 mg/dL, glucose uptake below lowest quartile
• ATP III requires explicit demonstration of insulin resistance for the diagnosis of the metabolic syndrome. In contrast, the criteria suggested by a consultation group of the World Health Organization (WHO) make insulin resistance a required component for diagnosis, in recognition of the central role it plays in the pathophysiology of the metabolic syndrome.1,2
• Insulin resistance is defined as one of the following:
o Type 2 diabetes
o Impaired fasting glucose
o Impaired glucose tolerance
o Glucose uptake below the lowest quartile for background population under
hyperinsulinemic, euglycemic conditions (fasting glucose <110 mg/dL).
• Two additional risk factors are required for a diagnosis of the metabolic syndrome.
Plus any 2 of the following:
Antihypertensive medication and/or BP ≥140/90 mm Hg
Plasma triglycerides ≥150 mg/dL
HDL-C <35 mg/dL (men) or <39 mg/dL (women)
BMI >30 kg/m2 and/or waist-hip ratio >0.9 (men); >0.85 (women)
Urinary albumin excretion rate ≥20 µg/min or albumin-creatinine ratio ≥30 mg/g
Grundy SM et al. Circulation. 2004;109: Adapted from Alberti KG, Zimmet PZ. Diabet Med.1998;15:
1. Grundy SM, Brewer HB Jr, Cleeman JI, Smith SC Jr, Lenfant C; for the conference participants. Definition of metabolic syndrome: Report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation. 2004;109:
2. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: Diagnosis and classification of diabetes mellitus: Provisional report of a WHO consultation. Diabet Med. 1998;15:

7. Other markers of insulin resistance
Family history of type 2 diabetes or CAD
Overactive sympathetic nervous system
Uric acid
Simple criteria help identify insulin-resistant patients.
The ATP III criteria for diagnosing metabolic syndrome may not identify all patients with insulin resistance.
Cohn et al1 reviewed relevant studies to identify additional, easily measured criteria that might aid in diagnosis.
Cohn GS et al. Am J Hypertens. 2005;18:
1. Cohn GS, Kittleson MM, Blumenthal RS. Toward an improved diagnosis of the metabolic syndrome: Other clues to the presence of insulin resistance. Am J Hypertens. 2005;18:

8. ABCs of coronary prevention
Aspirin ACE inhibition A1C control B
Beta-blockade Blood pressure control
Compelling evidence from randomized clinical trials supports the use of four classes of therapies for CV risk reduction that can be remembered by a simple mnemonic, ABC1:
A: ACE inhibitors
Antiplatelet agents (aspirin)
B: Beta-blockers
BP control
C: Cholesterol management
Important lifestyle recommendations can be incorporated into the mnemonic:
D: Diet
Don’t smoke
E: Exercise C
Cholesterol management D
Diet
Don’t smoke E
Exercise
Adapted from Cohen JD. Lancet. 2001;357:972-3.
1. Cohen JD. ABCs of secondary prevention of CHD: Easier said than done. Lancet. 2001;357:

9. Multidisciplinary consensus on managing metabolic syndrome
AHA / NHLBI / ADA
Modify lifestyle (weight loss, physical activity)
Assess risk
Framingham Risk Score
CRP (optional)
Reduce risk factors (ATP III, JNC 7, ADA)
Lipids, BP, thrombosis, glucose
• This slide summarizes the findings of a conference cosponsored by the American Heart Association (AHA) in partnership with the National Heart, Lung, and Blood Institute (NHLBI), and by the ADA, devoted to clinical management of the metabolic syndrome.
• Conference findings1:
○ Risk assessment using the Framingham Risk Score was recognized to be critical for setting goals of therapy.
○ Given the increasing evidence that suggests a role for inflammatory processes in the metabolic syndrome, conference participants also recognized that C-reactive protein
(CRP) testing may also be carried out at the physician’s discretion.
○ Drug therapy may be necessary in many patients to achieve recommended goals Specifically, medical therapy would be used to help in control of lipids, blood pressure, glucose, and to reduce risk of thrombosis.
• The emerging role of improving insulin sensitivity was also noted. Pharmacotherapies that improve insulin sensitivity have the potential to improve insulin resistance.
“There is growing interest in the possibility that drugs that reduce insulin resistance will delay onset of type 2 diabetes and will reduce CVD risk when the metabolic syndrome is present.”
Grundy SM et al. Circulation. 2004;109:551-6.
1. Grundy SM, Hansen B, Smith SC Jr, Cleeman JI, Kahn RA; for conference participants. Clinical management of metabolic syndrome: Report of the American Heart Association/National Heart, Lung, and Blood Institute/American Diabetes Association conference on scientific issues related to management. Circulation. 2004;109:

10. DPP: Impact of lifestyle intervention or metformin on diabetes40
Placebo
N = 3234, no diabetes
Age 50
207 lbs
Glucose 107 P 30
Metformin
• Incidence of type 2 diabetes (average follow-up, 2.8 years): 11 cases/100 person-years in the placebo group vs 7.8 in the metformin and 4.8 in the lifestyle-intervention groups (data not shown).1
o This represents a reduction of 58% in diabetes incidence with lifestyle interventions and 31% with metformin.
• The effects were similar in both men and women and in all racial and ethnic groups. Intensive lifestyle intervention was at least as effective in older as in younger participants.
• Results support the hypothesis that type 2 diabetes can be prevented or delayed in persons who are at high risk for the disease by treatment with metformin and lifestyle modification.
o Lifestyle intervention was particularly effective—1 case of diabetes was prevented per 7 persons treated for 3 years.
31%
< 0.001
Cumulative
incidence of
diabetes
(%) 20
Lifestyle
58%
< 0.001 10
Lose 5–10 lbs
Exercise 2.5 hrs/wk
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
Year
DPP = Diabetes Prevention Program
DPP Research Group. N Engl J Med. 2002;346:
1. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM; for the Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:

11. Tight glucose (A1C 7% vs 7.9%)
UKPDS: Comparison of tight control of BP vs glycemia on risk of diabetes complications
Any diabetes- related
outcome
Diabetes- related
death
Coronary heart
failure
Micro- vascular
Retinopathy
Stroke
• The slide compares the effect of tight control of both BP and glycemia on a number of outcomes in patients with type 2 diabetes in the UK Prospective Diabetes Study (UKPDS).1
• Over 10 years, hemoglobin A1c (A1C) was 7.0% in the intensive group vs 7.9% in the conventional group, an 11% reduction, and associated with a reduced risk in some outcomes.
• Tight blood-glucose control reduced the risk for any diabetes-related endpoint by 12% (P = 0.029). There was a significant 25% risk reduction (P = ) in microvascular endpoints, including the need for retinal photocoagulation and a nonsignificant risk reduction of 10% for any diabetes-related death (P = 0.34) and 6% for all-cause mortality (P = 0.44).
• Thus, intensive blood-glucose control substantially decreases the risk of microvascular complications in patients with type 2 diabetes, but it does not reduce risk of macrovascular disease.
• By comparison, patients in the tight BP-control group achieved a mean BP of 144/82 mm Hg vs 154/87 mm Hg with less-tight control.1 Tight BP-control was associated with significant reductions for any diabetes-related outcome (24%, P = ), deaths related to diabetes (32%, P = 0.019), microvascular disease (37%, P = ), stroke (44%, P = 0.013), and heart failure (56%, P = ).
• As seen here, more substantial risk reductions in diabetes complications were achieved with tight BP control.
–10
–20
% Patients
–30
–40
–50
–60
Tight BP (144/82 vs 154/87 mm Hg)
Tight glucose (A1C 7% vs 7.9%)
UKPDS = UK Prospective Diabetes Study
UKPDS Group. BMJ. 1998;317:
1. UK Prospective Diabetes Study (UKPDS) Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes. BMJ. 1998;317:

12. HPS and CARDS: Benefits of lowering LDL-C in diabetes
Event rate (%)
Statin
better
Placebo
better
Δ LDL-C (mg/dL)*
Statin
Placebo P
• Two recent large trials provide compelling evidence for the importance of LDL-C lowering in persons with diabetes.
• HPS1: The Heart Protection Study included 5963 persons with diabetes (33% prior CHD) randomized to simvastatin 40 mg daily or placebo regardless of baseline lipid levels. Primary outcome: MI or coronary death; mean follow-up, 4.8 years. Results:
o LDL-C: Statin treatment reduced LDL-C from 124 mg/dL to 85 mg/dL.
o Primary outcome: 27% relative risk reduction (RRR) in MI or coronary death and % RRR in stroke (P < , both comparisons).
o Patients with diabetes but without CHD or other vascular disease at baseline: % RRR—similar to reduction achieved in the group without diabetes (27% primary outcome).
• CARDS2: The Collaborative AtoRvastatin Diabetes Study was the first prospective evaluation of a statin in a population comprised solely of persons with type 2 diabetes. CARDS randomized 2838 patients with type 2 diabetes plus ≥1 other CV risk factors (but no history of CHD, MI, or stroke) to atorvastatin 10 mg or placebo. Primary outcome: composite of major coronary events, revascularization, unstable angina, resuscitated cardiac arrest, and stroke. Study was terminated 2 years early, after median follow-up of 3.9 years. Results:
o LDL-C: Statin treatment reduced LDL-C from 118 mg/dL to 82 mg/dL.
o Primary outcome: 37% RRR (HR, 0.63; 95% CI 0.48–0.83; P = 0.001); 48% RRR (HR, 0.52; 95% CI, 0.31–0.89; P value not reported).
HPS
9.4
9.3
5.8
12.6
13.5
9.0
0.73
All diabetes
<0.0001
0.0003
0.001
34.8
0.67
Diabetes, no CVD
34.8
0.63
46.4
CARDS
0.5
0.7
0.9 1
1.7
Relative risk
*Statin vs placebo
HPS = Heart Protection Study
CARDS = Collaborative Atorvastatin Diabetes Study
HPS Collaborative Group. Lancet. 2003;361: Colhoun HM et al. Lancet. 2004;364:
1. Collins R, Armitage J, Parish S, Sleigh P, Peto R; on behalf of the Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: A randomised placebo-controlled trial. Lancet. 2003;361:
2. Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HAW, Livingston SJ, et al; on behalf of the CARDS Investigators. 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:

13. ASCOT-LLA: Atorvastatin reduces CV events in patients with diabetes and hypertension
N = 2532, baseline LDL-C 128 mg/dL
14.0
12.0
23% Risk reduction
P = 0.036
Placebo
10.0
In the BP-lowering arm of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), atorvastatin 10 mg showed significant improvement in cardiovascular parameters in patients with diabetes and hypertension.1
8.0 %
6.0
Atorvastatin 10 mg
4.0
2.0
HR = 0.77 (0.61–0.98)
0.0
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
Years
Number at risk
Placebo
1258
1231
1209
1191
1171
1065
699
370
Atorvastatin
1274
1237
1219
1200
1175
1058
714
375
Nonfatal MI, CV mortality, UA, stable angina, arrhythmias, stroke, TIA, PAD, retinal vascular thrombosis, revascularization ASCOT-LLA = Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm
Sever PS et al. Diabetes Care ;28:
1. Sever PS, Poulter NR, Dahlöf B, Wedel H, Collins R, Beevers G, 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:

14. MICRO-HOPE, PERSUADE: Reduction in primary outcome with ACEI
CV death/MI/stroke
PERSUADE
(N = 1502)
CV death/MI/cardiac arrest
In MICRO-HOPE, Kaplan Meier curves show an early and consistent benefit of ramipril 10 mg in patients with diabetes. There was a 25% relative risk reduction in the primary outcome of MI, stroke, or CV death (P = ).1
In PERSUADE, treatment with perindopril 8 mg once daily for 5 years reduced the primary outcome of CV death, MI, and cardiac arrest by 19% (P = 0.131).2
The results of PERSUADE support and extend the observations in MICRO-HOPE to a somewhat lower-risk population of diabetic patients.
Placebo
Ramipril
10 mg 25 20 15 10 5 %
Follow-up (years) 1 2 3 4
25% Risk reduction
RR 0.75 (0.64–0.88)
P = 25 20
Placebo
19% Risk reduction
P = 0.131 15 10
Perindopril
8 mg 5 1 2 3 4 5
Follow-up (years)
HOPE Study Investigators. Lancet. 2000;355:253-9.
Daly CA et al. Eur Heart J. 2005;26:
1. HOPE Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: Results of the HOPE study and MICRO- HOPE substudy. Lancet. 2000;355: Daly CA, Fox KM, Remme WJ, Bertrand ME, Ferrari R, Simoons ML, on behalf of the EUROPA investigators. The effects of perindopril on cardiovascular morbidity and mortality in patients with diabetes in the EUROPA study: Results from the PERSUADE substudy. Eur Heart J. 2005;26:

15. 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
Design: 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
In Steno-2, patients in the conventional-therapy group received usual care according to the 1998 and 2000 recommendations of the Danish Medical Association.
The intensified-intervention group received the following1:
ACEI or ARB ± diuretic/CCB/-blocker
Metformin or gliclazide
Atorvastatin
Fibrate
Aspirin and vitamin supplementation
Gæde P et al. N Engl J Med. 2003;348:
1. Gæde P, Vedel P, Larsen N, Jensen GVH, Parving H-H, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003;348:

16. Steno-2: Effects of multifactorial intervention on CV outcomes
N = 160 with type 2 diabetes and microalbuminuria 60 50
Conventional
Multifactorial intervention reduced CV outcomes.
Significantly more patients in the intensive-treatment group reached goals.
There was a 53% reduction in the primary outcome, a composite of death from CV causes, nonfatal MI, nonfatal stroke, revascularization, and amputation.1
The continued divergence in rates of primary outcome suggests that therapy for even longer periods might achieve an even better prognosis.
Primary composite outcome* (%) 40
53% risk reduction P = 0.01 30 20
Intensive 10 12 24 36 48 60 72 84 96
Follow-up (months)
*CV death, MI, stroke, revascularization, amputation
Gæde P et al. N Engl J Med. 2003;348:
1. Gæde P, Vedel P, Larsen N, Jensen GVH, Parving H-H, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003;348:

17. Summary
The majority of patients seen in cardiology practices have insulin resistance
Synergistic interaction of risk factors associated with insulin resistance places patients at high risk for CV disease
Current guidelines recommend aggressive multi- factorial treatment in patients with diabetes or prediabetes
PPAR modulation is a potentially important strategy for improving insulin sensitivity and blunting atherosclerosis progression
• Insulin resistance, as clinically manifest in the metabolic syndrome, is highly prevalent in the patient population commonly seen by cardiologists.
• Although individual risk factors of the metabolic syndrome may not be substantially greater than the general population, the synergistic interaction of these risk factors (driven in large part by insulin resistance) places these patients at high global risk for CV events.
• Activation of PPAR receptors with thiazolidinediones has broad ranging effects on insulin sensitivity, inflammation, and atherosclerosis progression.
• A number of outcomes studies are in progress to more fully characterize the therapeutic potential of this approach.