Contents I. CV disease and insulin resistance: Challenges and opportunities II. Insulin sensitizers: Surrogate and clinical outcomes studies IV. Identifying and treating patients with insulin resistance
Ford and colleagues estimated from NHANES III that the metabolic syndrome was present in approximately 22% of all U.S. adults age 20 years and older. Of interest, unlike our data, which showed a relatively constant prevalence by age group, the age-specific prevalence of the metabolic syndrome in the general population increased dramatically, from just over 12% among individuals in their thirties to 20% among those in their forties, 35% among those in their fifties, and 45% thereafter
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) NCEP ATP III. JAMA. 2001;285:2486-97.
Family history of type 2 diabetes or CAD Overactive sympathetic nervous system Uric acid Cohn GS et al. Am J Hypertens. 2005;18:1099-103.
Survival Rates All Causes Survival Rates CV Disease The Funagata Diabetes Study Cumulative Cardiovascular Survival 1.00 1.00 0.99 0.98 0.98 0.97 0.96 0.96 0.95 0.94 0 Normal IGT (2 hr PG 140 200) DM (2 hr PG >200) 0 1 2 3 4 5 6 7 0.94 0.92 0 Normal IFG (FPG 110 126) DM (FPG >126) 0 1 2 3 4 5 6 7 Year Year Tominaga M et al. Diabetes Care. 1999;22:920-924.
Ridker et al. N Engl J Med. 1997. 336;973-979.
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 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.
2000 Behavioral Risk Factor Surveillance System; N = 153,805 100 80 76.7 77.8 % Respondents 60 40 59.9 24 20 0 Smokers BMI 25 kg/m 2 Consumes fruits/vegetables <5x/day Infrequent exercise (<5x/week) Reeves MJ, Rafferty AP. Arch Intern Med. 2005;165:854-7.
Patients with insulin resistance syndrome (%) 60 40 20 Cardiac rehabilitation Acute MI 58 59 50 0 N = 1912 Savage, 2005 N = 235 Milani, 2003 N = 85 Curran, 2004 Savage PD et al. Am Heart J. 2005;149:627-31. Milani RV, Lavie CJ. Am J Cardiol. 2003;92:50-4. Curran PJ et al. J Am Coll Cardiol. 2004;43(suppl A):249A.
N = 181 consecutive patients admitted to CCU 70 66 Patients (%) 50 30 31 Undiagnosed diabetes 10 0 35 Glucose tolerance test results Impaired glucose tolerance (IGT) Norhammar A et al. Lancet. 2002;359:2140-4.
Cooperative Cardiovascular Project 1994 1996; N =141,680 100 80 Mortality rate (%) 60 40 20 0 110 >110 140 >140 170 >170 240 >240 Glucose groups (mg/dl) Without diabetes With diabetes Kosiborod M et al. Circulation. 2005;111:3078-86.
Visceral Obesity Caloric intake Sedentary lifestyle Genetic factors Free fatty acids Glucose Lipids Oxidative stress Inflammation Insulin resistance Adapted from Wellen KE, Hotamisligil GS. J Clin Invest. 2005;115:1111-9.
Atherogenic CRP IL-6 PAI-1 Angiotensinogen Leptin Resistin MCP-1 Antiatherogenic Adiponectin Lau DCW et al. Am J Physiol Heart Circ Physiol. 2005;288:H2031-41. Wellen KE, Hotamisligil GS. J Clin Invest. 2005;115:1111-9.
Liver IL-6 Adipose tissue CRP PPAR Glucose Insulin resistance Lau DCW et al. Am J Physiol Heart Circ Physiol. 2005;288:H2031-41.
N = 354 with untreated hypertension 60 P = 0.003 59 45 40 Patients (%) 30 15 10 P = 0.04 19 0 Microalbuminuria* LV hypertrophy Without insulin resistance syndrome* With insulin resistance syndrome* *Modified ATP III definition Leoncini G et al. J Intern Med. 2005;257:454-60.
Hyperglycemia (glucose toxicity) Insulin resistance -cell Lipotoxicity (elevated FFA, TG) Adapted from Kahn SE. J Clin Endocrinol Metab. 2001;86:4047-58. Adapted from Ludwig DS. JAMA. 2002;287:2414-23.
In insulin resistance, LDL-C levels are similar or only slightly elevated vs general population However, atherogenicity of LDL particles varies according to density More dense = more atherogenic Proportion of small, dense LDL particles greater in patients with insulin resistance or diabetes vs general population Miranda PJ et al. Am Heart J. 2005;149:33-45.
N = 2072 men without IHD at baseline;13-year follow-up 1.00 Survival probabilities 0.90 P < 0.001 0.80 0 2 4 6 8 10 12 Follow-up (years) Tertiles of LDL-C255Å <1.07 mmol/l 1.07 1.86 mmol/l 1.86 mmol/l IHD = ischemic heart disease St-Pierre AC et al. Arterioscler Thromb Vasc Biol. 2005;25:553-9.
Susceptible to oxidation Binds to arterial wall Penetrates arterial wall Toxic to endothelial cells Promotes PAI-1 production by endothelial cells Promotes thromboxane production by endothelial cells Accumulates Ca 2+ in vascular smooth muscle cells Binds to LDL scavenger receptor Adapted from Sniderman AD et al. Ann Intern Med. 2001;135:447-59.
Cumulative Incidence of Diabetes (%) 40 Placebo 30 Metformin 20 Lifestyle 10 0 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 Years Knowler WC, et al. NEJM. 2002;346:393-403.
N = 302; rosiglitazone 8 mg LDL particle size LDL density 8 P < 0.0001 0.04 Diameter vs baseline (Angstroms) 4 4.8 Relative flotation vs baseline 0.02 P < 0.0001 0.019 0 0 Brunzell JD et al. Circulation. 2004;110(suppl):III-143.
Human umbilical-vein endothelial cells 800 600 PAI-1 (ng) 400 200 * * Trog = troglitazone *P < 0.001 P < 0.005 0 TNF- 1 ng/ml TNF- 1 ng/ml + Trog 10 µm TNF- 10 ng/ml TNF- 10 ng/ml + Trog 10 µm TNF- 100 ng/ml TNF- 100 ng/ml + Trog 10 µm Hamaguchi E et al. J Pharmacol Exp Ther. 2003;307:987-94.
N = 27, 12 weeks 35 30 PAI-1 activity (U/mL) A1C = 1.3% FPG = 55 mg/dl * P = 0.001 vs placebo 25 20 15 10 5 0 Basal Placebo Metformin 2.5 g Results at 12 weeks Nagi DK, Yudkin JS. Diabetes Care. 1993;16:621-9. *
Weeks 8 24 30 20 MMP-9 * 22.2 Baseline (%) 10 0 10 20 30 40 9.8 * CRP 26.9 P = 0.026 PAl-1 0.56 32.76 P < 0.001 14.35 P = 0.046 Metformin 2 g (n = 70) Metformin 1 g + rosiglitazone 8 mg (n = 57) *NS vs baseline Weissman PN et al. Diabetes. 2004;53(suppl 2):A28.
Overview of Trials in Prediabetes Pharmacologic Intervention Pharmacologic intervention provides benefit but with increased adverse effects with some drugs Study N Intervention Treatment Risk Reduction Diabetes Prevention Program IGT 3324 Metformin (DPP) 1,2 3 years 10 years 31% 18% DREAM 3 IGT 5269 Rosiglitazone 3 years 60% STOP- NIDDM 4,5 IGT 1429 Acarbose 3 years 21% ACT NOW 6 IFG ~600 Pioglitazone 3 years 81% 1. Diabetes Care. 2003;6:977 980. 2. Lancet. 2009;374:1677-1686. 3. Diabetes Care. 2011;34:1265-1269. 4. Lancet. 2002;359:2072-2077. 5. JAMA. 2003;290:486-494. 6. N Engl J Med. 2011;364:1104-1115.
N = 40 women with gestational diabetes treated with troglitazone for 3 months 500 400 % Change in insulin sensitivity ( Si) 300 200 100 50 25 25 50 75 100 100 % Change in HMW/total adiponectin ( SA) Pajvani UB et al. J Biol Chem. 2004;279:12152-62.
VBWG N = 24 nondiabetic hypertensives; rosiglitazone 8 mg, 16 weeks 20 in 24-h systolic BP (mm Hg) 10 0 10 20 2 1 0 1 2 3 Change in insulin sensitivity (mg/kg/min) P < 0.005 r = 0.59 Nonmodulators Low-renin hypertension Raji A et al. Diabetes Care. 2003;26:172-8.
N = 668 with type 2 diabetes Baseline metformin 6 months 12 months Baseline sulfonylurea 6 months 12 months Rosiglitazone added to baseline therapy 6 5 4 3 2 1 0 1 24-h systolic BP * Reduction from baseline (mm Hg, 95% CI) 5 4 3 2 1 0 1 24-h diastolic BP * Treatment differences (mm Hg, 95% CI) * Ambulatory BP Home PD et al. Diabetes. 2005;54(suppl 1):A134.
400 350 300 Metformin 1000 mg (3 months) * Placebo Increase in forearm blood flow (%) 250 200 150 * 100 50 * 0 3 10 30 3 10 30 Acetylcholine ( g/min) Before treatment After treatment * P = 0.0027 vs placebo Mather KJ et al. J Am Coll Cardiol. 2001;37:1344-50.
8872 acute MI patients, mean age 76.4 years, discharged on glucose-lowering medication 1.00 0.95 No insulin sensitizer (n = 6641) Thiazolidinediones (n = 1273) Metformin (n = 819) TZD + MET (n = 139) Proportion of patients surviving 0.90 0.85 48% Relative risk reduction 0.80 0 50 100 150 200 250 300 350 Days from discharge Inzucchi SE et al. Diabetes Care. 2005;28:1680-9.
8872 acute MI patients, mean age 76.4 years, discharged on glucose-lowering medication Metformin TZD Both Mortality 0.92 (0.81 1.06) 0.92 (0.80 1.05) 0.52 (0.34 0.82) Myocardial infarction readmission 1.02 (0.86 1.20) 0.92 (0.77 1.10) 0.88 (0.56 1.37) Heart failure readmission 1.06 (0.95 1.18) 1.17 (1.05 1.30) 1.24 (0.94 1.63) All-cause readmission 1.04 (0.96 1.13) 1.09 (1.00 1.20) 1.06 (0.87 1.30) Inzucchi SE et al. Diabetes Care. 2005;28:1680-9.
N = 4075 with type 2 diabetes Aggregate endpoints P* All-cause mortality Metformin Intensive Favors metformin or intensive Favors conventional 0.021 Myocardial infarction Metformin Intensive Stroke Metformin Intensive 0.021 0.021 *metformin vs intensive therapy 0.1 1 10 Relative risk reduction (95% CI) UKPDS Group. Lancet. 1998;352:854-65.
Tight blood pressure control (144/82 mmhg) lead to: 32% reduction in diabetes deaths 44% reduction in stroke 37% reduction in microvascular complications BMJ. 1998 Sep 12;317(7160):703-13.
After median 8.8 years post-trial follow-up Aggregate Endpoint 1997 2007 Any diabetes related endpoint RRR: 12% 9% P: 0.029 0.040 Microvascular disease RRR: 25% 24% P: 0.009 0.001 Myocardial infarction RRR: 16% 15% P: 0.052 0.014 All-cause mortality RRR: 6% 13% P: 0.44 0.007 RRR = Relative Risk Reduction P = Log Rank Holman RR, et al. New England Journal of Medicine 2008; 359:1577-1589.
AHA/ADA consensus statement summary NYHA class I/II HF: Thiazolidinediones may be used cautiously, with initiation of treatment at the lowest dose and gradual dose escalation Allow more time than usual to achieve target A1C NYHA class III/IV HF: Thiazolidinediones should not be used at this time Nesto RW et al. Circulation. 2003;108:2941-8.
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 multifactorial treatment in patients with diabetes or prediabetes PPAR modulation is a potentially important strategy for improving insulin sensitivity and blunting atherosclerosis progression