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Epidemiología de la Resistencia a la Insulina, Diabetes Mellitus y Enfermedad Coronaria

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Information about Epidemiología de la Resistencia a la Insulina, Diabetes Mellitus y...
Health & Medicine

Published on February 25, 2014

Author: jairgarcia

Source: slideshare.net

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Epidemiology of Insulin Resistance, Diabetes Mellitus, and Coronary Heart Disease Steven Haffner, MD Slide Source LipidsOnline www.lipidsonline.org

Criteria for the Diagnosis of Diabetes Mellitus and Hyperglycemia Plasma Glucose Concentration Fasting Glucose Diabetes Mellitus 2-Hour Post Glucose Load >7.0 (>126) >11.1 (>200) Impaired Glucose Tolerance Impaired Fasting Glucose >7.8 (>140) to <11.1 (<200) >6.1 (>110) to <7.0 (<126) Values are mmol/L (mg/dl) Adapted from World Health Organization. Definition, Diagnosis and Classification of Diabetes Mellitus Slide Source and its Complications. Geneva: World Health Organization:1999:52. LipidsOnline www.lipidsonline.org

Percent Prevalence of Diabetes in Adult Population (Aged >20 years) by Year and Region 9 8 7 6 5 4 3 2 1 0 1995 Developed Developing King H et al. Diabetes Care 1998;21:1414-1431. 2000 2025 World Slide Source LipidsOnline www.lipidsonline.org

Hospitalization Costs for Chronic Complications of Diabetes in the US Ophthalmic disease Renal disease Others Neurologic disease Peripheral vascular disease  Total costs 12 billion US $  CVD accounts for 64% of total costs Cardiovascular disease American Diabetes Association. Economic Consequences of Diabetes Mellitus in the US in 1997. Alexandria, VA: American Diabetes Association, 1998:1-14. Slide Source LipidsOnline www.lipidsonline.org

Framingham Study: DM and CHD Mortality 20-Year Follow-up Annual CHD Deaths per 1000 Persons 18 16 14 17 17 DM Non-DM 12 10 8 8 6 4 4 2 0 Men Kannel WB, McGee DL. JAMA 1979;241:2035-2038. Women Slide Source LipidsOnline www.lipidsonline.org

Mortality in People with Diabetes Causes of Death 50 % of Deaths 40 30 20 10 0 Ischemic Other Diabetes Cancer heart heart disease disease Geiss LS et al. In: Diabetes in America. 2 nd Stroke Infection Other ed. 1995; chap 11. Slide Source LipidsOnline www.lipidsonline.org

Mortality Due to Heart Disease in Men and Women with or without Diabetes (US) Mortality per 1000 person-years* 35 30 29.9 Diabetes 19.2 20 15 10 11.5 11.0 7.1 6.3 3.6 5 0 No Diabetes 23.0 25 Men Women All heart disease Men Women Ischemic heart disease *Age-adjusted Adapted from Gu K et al. Diabetes Care 1998;21:1138-1145. Slide Source LipidsOnline www.lipidsonline.org

Rate per 1000 person-years Trends in Mortality Rates for Ischemic Heart Disease in NHANES Subjects with and without Diabetes* 20 15 Diabetes Nondiabetes 17.0 Men, cohort 1* Men, cohort 2** Women, cohort 1* Women, cohort 2** 14.2 10 6.8 7.6 7.4 4.2 5 2.4 1.9 0 -16.6% (P=0.46) +10.7% (P=0.76) -43.8% (P<0.001) *Defined in 1971-1975, followed up through 1982-1984. **Defined in 1982-1984, followed up through 1992-1993. Gu K et al. JAMA 1999;281:1291-1297. -20.4% (P=0.12) Slide Source LipidsOnline www.lipidsonline.org

Survival Post-MI in Diabetic and Nondiabetic Men and Women: Minnesota Heart Survey 100 MEN WOMEN 100 80 60 n=1628 Diabetes n=228 40 0 0 20 40 60 80 Months Post-MI No diabetes Survival (%) Survival (%) No diabetes 80 n=568 60 Diabetes 40 0 0 n=156 20 40 60 80 Months Post-MI Adapted from Sprafka JM et al. Diabetes Care 1991;14:537-543. Slide Source LipidsOnline www.lipidsonline.org

% of Deaths (Crude Rate) Cardiovascular Mortality in People with Diabetes MEN 60 50 40 WOMEN 28 d – 1 y Hospitalization – 28 d 9.1 15.4 30 4.2 9.6 20 10 0 28.6 Diabetes 22.1 No Diabetes 11.1 22.7 Out of Hospital 2.8 9.0 10.9 11.9 Diabetes No Diabetes Adapted from Miettinen H et al. Diabetes Care. 1998;21:69-75. Slide Source LipidsOnline www.lipidsonline.org

Age-adjusted CVD death rate per 10,000 person-years Influence of Multiple Risk Factors* on CVD Death Rates in Diabetic and Nondiabetic Men: MRFIT Screenees 140 120 No diabetes Diabetes 100 80 60 40 20 0 None One only Two only *Serum cholesterol >200 mg/dl, smoking, SBP >120 mmHg Stamler J et al. Diabetes Care 1993;16:434-444 All three Slide Source LipidsOnline www.lipidsonline.org

Putative Mechanism for Increased Atherosclerosis in Type 2 Diabetes BLACK BOX  Dyslipidemia  Hypertension  Hyperinsulinemia/insulin resistance  Hemostatic abnormalities  Hyperglycemia  AGE proteins  Oxidative stress AGE = advanced glycation end products Adapted from Bierman EL. Arterioscler Thromb 1992;12:647-656. Slide Source LipidsOnline www.lipidsonline.org

Prevalence of Cardiovascular Risk Factors in Diabetic Subjects Relative to Nondiabetics Risk Factor Dyslipidemia Hypertriglyceridemia Low HDL Small, dense LDL Increased apo B Hypertension Hyperinsulinemia/insulin resistance Central obesity Family history of atherosclerosis Cigarette smoking Type 1 Type 2 + – – – + – – – – ++ ++ ++ ++ ++ ++ ++ + – + = moderately increased compared with nondiabetic population ++ = markedly increased compared with nondiabetic population – = not different compared with nondiabetic population Adapted from Chait A, Bierman EL. In: Joslin’s Diabetes Mellitus. Philadelphia: Lea & Febiger, Slide Source LipidsOnline 1994:648-664. www.lipidsonline.org

Differences in HDL Cholesterol and LDL Size by Diabetic Status in Women and Men Differences between participants with and without diabetes HDL Cholesterol mg/dL 0 LDL Size Å 0 -2 -2 -4 -4 -6 Women -6 Men -8 Women Men -8 Howard BV et al. Diabetes Care 1998; 21:1258-1265. Slide Source LipidsOnline www.lipidsonline.org

Strategies for Reduction of Diabetic Complications  Microvascular complications - Aggressive screening - Improved metabolic control  Macrovascular complications - Improved glycemic control (positive but minor) - Prevention of type 2 diabetes - Aggressive treatment of established CVRF in diabetic and possibly prediabetic subjects - Diabetic agents that improve cardiovascular risk Slide Source LipidsOnline www.lipidsonline.org

50 40 Years (%) Incidence per 1000 Person Incidence Rates of MI and Microvascular Endpoints by Mean Systolic Blood Pressure: UKPDS Myocardial Infarction 30 20 10 0 110 Microvascular Endpoints 120 130 140 150 160 170 Updated Mean Systolic Blood Pressure (mmHg) Adjusted for age, sex, and ethnic group Adler AI et al. BMJ 2000;321:412-419. Slide Source LipidsOnline www.lipidsonline.org

Incidence per 1000 Person Years (%) Incidence Rates of MI and Microvascular Endpoints by Mean Hemoglobin A1c: UKPDS 80 60 Myocardial Infarction 40 20 Microvascular Endpoints 0 5 6 7 8 9 10 11 Updated Mean Hemoglobin A1c Concentration (%) Adjusted for age, sex, and ethnic group Stratton IM et al. BMJ 2000;321:405-412. Slide Source LipidsOnline www.lipidsonline.org

Plasma Insulin and Triglycerides Predict Ischemic Heart Disease: Quebec Cardiovascular Study 6.7 Odds Ratio 8.0 5.4 6.0 P=0.002 p=0.005 4.0 1.5 2.0 0.0 4.6 P<0.001 p=0.001 5.3 1.0 <12 Triglycerides >150 mg/dl <150 mg/dl 12-15 F-Insulin (µU/ml) Despres JP et al. N Engl J Med 1996;334:952-957. >15 Slide Source LipidsOnline www.lipidsonline.org

Plasma Insulin and Apolipoprotein B Predict Ischemic Heart Disease: Quebec Cardiovascular Study 12.0 9.7 p<0.001 10.0 Odds Ratio 11.0 P<0.001 8.0 6.0 Apolipoprotein B 4.0 2.0 0.0 1.5 1.0 <12 3.0 3.2 p=0.04 p=0.04 12-15 >15 F-Insulin (µU/ml) Despres JP et al. N Engl J Med 1996;334:952-957. >119 mg/dl <119 mg/dl Slide Source LipidsOnline www.lipidsonline.org

LDL Particle Size and Apolipoprotein B Predict Ischemic Heart Disease: Quebec Cardiovascular Study 6 6.2 5 (p<0.001) 4 3 2.0 2 1 0 1.0 Apo B 1.0 >120 mg/dl <120 mg/dl >25.64 <25.64 LDL Peak Particle Diameter (nm) Lamarche B et al. Circulation 1997;95:69-75. Slide Source LipidsOnline www.lipidsonline.org

Baseline Anthropometric Variables and Cardiovascular Risk Factors in Subjects with Normal Glucose Tolerance at Baseline According to Conversion Status at 8-Year Followup: San Antonio Heart Study Conversion Status at Follow-up Diabetes (n=18) Normal (n=490) P 28.2 + 1.1 27.2 + 0.2 .472 Centrality* 1.38 + 0.09 1.16 + 0.2 .472 TG (mmol) 1.83 + 0.12 1.26 + 0.10 .006 HDLC (mmol) 1.14 + 0.07 1.28 + 0.02 .045 SBP (mmHg) 116.8 + 3.0 108.8 + 0.8 .004 5.28 + 0.1 5.00 + 0.02 .032 157 + 27 81 + 5 .006 BMI (kg/m2) Fasting glucose (mmol) Fasting insulin (pmol) * Ratio of subscapular to triceps skinfolds Haffner SM et al. JAMA 1990;263:2893-2898. Slide Source LipidsOnline www.lipidsonline.org

“Ticking Clock” Hypothesis For The “clock starts ticking” Microvascular complications At onset of hyperglycemia Macrovascular complications Before the diagnosis of hyperglycemia WHO. Diabetologia 1985;28:615-640; Haffner SM et al. JAMA 1990;263:2893-2898. Slide Source LipidsOnline www.lipidsonline.org

The 7-Year Age-Adjusted Incidence of CHD Mortality and All CHD Events: East-West Study 30 CHD Mortality All CHD Events 20 10 0 40 % Incidence % Incidence 40 Fasting Glucose <9.6 9.6-13.4 >13.4 P-glucose (mmol/L) Lehto S et al. Diabetes 1997;46:1354-1359. 30 Hemoglobin A1 CHD Mortality All CHD Events 20 10 0 <8.9 8.9-10.7 >10.7 HbA1 (%) Source Slide LipidsOnline www.lipidsonline.org

Stepwise Selection of Risk Factors* in 2693 White Patients with Type 2 Diabetes with Dependent Variable as Time to First Event: UKPDS Coronary Artery Disease (n=280) Position in Model Variable P Value First Low-Density Lipoprotein Cholesterol <0.0001 Second High-Density Lipoprotein Cholesterol 0.0001 Third Hemoglobin A1c 0.0022 Fourth Fifth Systolic Blood Pressure Smoking *Adjusted for age and sex. Turner RC et al. BMJ 1998;316:823-828. 0.0065 0.056 Slide Source LipidsOnline www.lipidsonline.org

Criteria for Accepting Cardiovascular Risk Factor Management as Similar in Diabetic and CHD Subjects  The risk of vascular disease is similar in diabetic subjects without pre-existing vascular disease as in nondiabetic subjects with vascular disease  Glycemia alone will not completely eliminate the excess of CHD risk in diabetic subjects  Lipid interventions to reduce CHD can be equally effective in diabetic and nondiabetic subjects Slide Source LipidsOnline www.lipidsonline.org

Incidence of Fatal or Nonfatal MI During a 7-Year Follow-up in Relation to History of MI in Nondiabetic vs Diabetic Subjects: East-West Study Incidence During Follow-up (%) 50 40 30 20 Nondiabetics with prior MI Nondiabetics with no prior MI p<0.001 Diabetics with prior MI Diabetics with no prior MI 20.2 18.8 10 0 45.0 (n=69) Events per 100 person-yr: 3.0 P<0.001 3.5 (n=1304) 0.5 Haffner SM et al. N Engl J Med 1998;339:229-234. (n=169) 7.8 (n=890) 3.2 Slide Source LipidsOnline www.lipidsonline.org

Incidence of Fatal or Nonfatal Stroke During a 7-Year Follow-up in Relation to History of MI in Nondiabetic vs Diabetic Subjects: East-West Study Incidence During Follow-up (%) 25 20 15 10 Nondiabetics with prior MI Nondiabetics with no prior MI p<0.001 Diabetics with prior MI Diabetics with no prior MI 10.3 7.2 5 0 19.5 (n=69) Events per 100 person-yr: 1.2 P=0.01 1.9 (n=1304) 0.3 Haffner SM et al. N Engl J Med 1998;339:229-234. (n=169) 3.4 (n=890) 1.6 Slide Source LipidsOnline www.lipidsonline.org

Conclusions  Epidemiological data suggest that the risk of CHD in type 2 diabetes is equivalent to that in people with prevalent CHD.  Although hyperglycemia is significantly related to CHD, the magnitude of association is unlikely to explain the entire excess risk of cardiovascular disease.  Within type 2 diabetics, increased blood pressure and LDL-C and low HDL-C also predict the risk of future myocardial infarction. Slide Source LipidsOnline www.lipidsonline.org

Clinical Trials and Guidelines for Lipid Management in the Diabetic Patient Steven Haffner, MD Slide Source LipidsOnline www.lipidsonline.org

UKPDS Design Aim  To determine whether intensified blood glucose control, with either sulphonylurea or insulin, reduces the risk of macrovascular or microvascular complications in type 2 diabetes Patients  3867 newly diagnosed type 2 diabetic patients who were asymptomatic after 3 months of diet; fasting glucose 6.1-15 mmol/L (110-270 mg/dl); treat for 10 years Adapted from UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:837-853; Slide Source LipidsOnline Turner R et al. Ann Intern Med 1996;124:136-145. www.lipidsonline.org

UKPDS 10-Year Follow-up Results: Glycemic Control, Weight, and Plasma Insulin Conventional 9 8 Intensive 7 6 0 7.5 Weight Intensive 5 2.5 0 -2.5 Conventional Baseline = 75 kg 0 1 2 3 4 5 6 7 8 9 10 11 12 Years from Randomization UKPDS Group. Lancet 1998;352:837-853. Median (%) 10 9 Fasting plasma glucose Median Change (pmol/L) Mean Change (kg) Median (mmol/L) 11 Hemoglobin A1c 8 Conventional Intensive 7 6 0 40 30 Plasma insulin 20 Intensive 10 0 -10 -20 Baseline = 89 pmol/L 0 1 2 3 4 5 6 Conventional 7 8 9 10 11 12 Years from Randomization Slide Source LipidsOnline www.lipidsonline.org

UKPDS: Proportion of Patients Taking Different Therapies in the Conventional-Therapy Group 100 Additional pharmacologic therapy % of patients 80 60 40 Diet alone 20 1 Courtesy of Dr. Amanda Adler 3 5 7 9 11 Years from randomization Slide Source LipidsOnline www.lipidsonline.org

UKPDS: Causes of Death by Glucose Treatment Group Cause MI Stroke Sudden death PVD Intensive Rate/1000 patient-years % Conventional Rate/1000 patient-years % 7.6 1.6 0.9 0.1 43 9 5 1 8.0 1.3 1.6 0.3 43 7 8 2 10.2 58 11.2 60 Renal disease 0.3 2 0.2 1 Cancer Other specified Unknown 4.4 2.4 0.5 25 13 3 4.4 2.7 0.2 24 14 1 17.8 100 18.7 100 All macrovascular Total UKPDS Group. Lancet 1998;352:837-853. Slide Source LipidsOnline www.lipidsonline.org

UKPDS: Endpoints by Glucose Treatment Group Intensive Cause Conventional Rate/1000 Rate/1000 Patient-Years Patient-Years P % Risk Reduction Any diabetes-related* 40.9 46.0 0.029 12 MI 14.7 17.4 0.052 16 Stroke 5.6 5.0 0.52 – PVD** 1.1 1.6 0.15 – Microvascular 8.6 11.4 0.0099 25 *Combined microvascular and macrovascular events **Amputation or death from PVD UKPDS Group. Lancet 1998;352:837-853. Slide Source LipidsOnline www.lipidsonline.org

UKPDS: Impact of Glucose-Lowering Agents on MI and Stroke  Sulphonylurea or exogenous insulin (n=2729) MI 16% reduction (P = 0.052) Stroke 11% increase (P = 0.52)  Metformin in overweight subjects (n = 342) MI 39% reduction (P = 0.01) Stroke 41% reduction (P = 0.13) Adapted from UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:837-853; Slide Source UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854-865. LipidsOnline www.lipidsonline.org

UKPDS Results: Intensive Blood Pressure Control Intensive Blood Pressure Control Reduction (%) P Value Any diabetes-related endpoint 24 0.0046 Deaths related to diabetes 32 0.019 Myocardial infarction 21 NS Stroke 44 0.013 Microvascular disease 37 0.092 Adapted from UK Prospective Diabetes Study Group. BMJ 1998;317:703-713. Slide Source LipidsOnline www.lipidsonline.org

Comparison of Captopril vs. Atenolol in UKPDS RR for Captopril P Value Any diabetes-related endpoint 1.10 (0.86–1.41) 0.43 Death related to diabetes 1.27 (0.82–1.97) 0.28 All-cause mortality 1.14 (0.81–1.61) 0.44 Myocardial infarction 1.20 (0.82–1.76) 0.35 Stroke 1.12 (0.59–2.12) 0.74 Peripheral vascular disease 1.48 (0.35–6.19) 0.59 Microvascular disease 1.29 (0.80–2.10) 0.30 Clinical Endpoint  Primary  Secondary Adapted from UK Prospective Diabetes Study Group. BMJ 1998;317:713-720. Slide Source LipidsOnline www.lipidsonline.org

Comparison of Glucose Lowering and Blood Pressure Lowering in UKPDS Intensive Blood Intensive Blood Glucose Control (n=2729) Pressure Control (n=758) Reduction % P Value Reduction % P Value Any diabetes-related endpoint 12 0.029 24 0.0046 Myocardial infarction 16 0.052 21 NS 11↑ NS 44 0.013 25 0.0099 37 0.092 Stroke Microvascular disease ↑ = Increase in risk Adapted from UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:837-853; Slide Source UK Prospective Diabetes Study Group. BMJ 1998;317:703-713. LipidsOnline www.lipidsonline.org

Treatment Strategies for Diabetic Dyslipidemia  Primary Strategy - Lower LDL cholesterol  Secondary Strategy - Raise HDL cholesterol - Lower triglycerides  Other Approaches - Non-HDL cholesterol - ApoB - Remnants Adapted from American Diabetes Association. Diabetes Care. 2000;23(suppl 1):S57-S60; Chait A, Brunzell JD. Diabetes Mellitus. A Fundamental and Clinical Text. Philadelphia: Lippincott Raven, 1996;772-779; Source Slide LipidsOnline European Diabetes Policy Group 1999. Diabet Med. 1999;16:716-730. www.lipidsonline.org

CHD Prevention Trials with Statins in Diabetic Subjects: Subgroup Analyses Study Drug No. Baseline LDL-C, mg/dl (mmol/L) LDL-C Lowering Primary Prevention AFCAPS/TexCAPS Lovastatin 239 150 (3.9) 25% CARE Pravastatin 586 136 (3.6) 28% 4S Simvastatin 202 186 (4.8) 36% LIPID Pravastatin 782 150* (3.9) 25%* Secondary Prevention *Values for overall group Adapted from Downs JR et al. JAMA 1998;279:1615-1622; Goldberg RB et al. Circulation 1998;98:2513-2519; Pyörälä K et al. Diabetes Care 1997;20:614-620; Haffner SM et al. Arch Intern Med 1999;159:2661-2667; The Long-Term Slide Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med 1998;339:1349-1357. Source LipidsOnline www.lipidsonline.org

CHD Prevention Trials with Statins in Diabetic Subjects: Subgroup Analyses (cont’d) Study Drug CHD Risk Reduction No. (overall) CHD Risk Reduction (diabetes) Primary Prevention AFCAPS/TexCAPS Lovastatin 239 37% 43% CARE Pravastatin 586 23% 25% (p=0.05) 4S Simvastatin 202 32% 55% (p=0.002) LIPID Pravastatin 782 25% 19% 4S-Extended Simvastatin 483 32% 42% (p=0.001) Secondary Prevention Adapted from Downs JR et al. JAMA 1998;279:1615-1622; Goldberg RB et al. Circulation 1998;98:2513-2519; Pyörälä K et al. Diabetes Care 1997;20:614-620; The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med 1998;339:1349-1357; Haffner SM et al. Arch Intern Med 1999;159:2661-2667. Slide Source LipidsOnline www.lipidsonline.org

Diabetic vs. Nondiabetic Patients in 4S Placebo Better Simvastatin Better P=0.001 P=0.087 Total mortality CHD mortality P<0.0001 P=0.242 Major CHD event P<0.0001 P=0.002 Cerebrovascular event P=0.097 P=0.071 Any atherosclerotic event P<0.0001 P=0.018 0 No diabetes Diabetes 0.2 0.4 0.6 0.8 1.0 1.2 1.4 Relative Risk with 95% Confidence Intervals Reduced Adapted from Pyörälä et al. Diabetes Care 1997;20:614-620. Increased Slide Source LipidsOnline www.lipidsonline.org

Major Coronary Events in 4S Patients with or without Diabetes by History (n=202) Proportion without Major CHD Event 1.0 0.9 0.8 0.7 0.6 Diabetes by Hx, simvastatin Diabetes by Hx, placebo 0.5 No diabetes by Hx, simvastatin No diabetes by Hx, placebo 0 0 1 P=0.002 P=0.0001 2 3 4 5 Years Since Randomization Adapted from Pyörälä et al. Diabetes Care 1997;20:614-620. 6 Slide Source LipidsOnline www.lipidsonline.org

4S: Extended Diabetic Subgroup Analysis: Diabetes (n=483; 251 on Simvastatin) — Fasting Glucose >7 mmol/L (126 mg/dl) 0.72 CHD mortality (P=0.26) 0.79 Total mortality (P=0.34) 0.52 Revascularizations (P=0.005) 0.58 Major coronary events (P=0.001) 0.0 0.2 0.4 0.6 0.8 1.0 Relative Risk Adapted from Haffner SM et al. Arch Intern Med 1999;159:2661-2667 1.2 1.4 Slide Source LipidsOnline www.lipidsonline.org

4S: Extended Diabetic Subgroup Analysis: Impaired Fasting Glucose (n=678; 343 on Simvastatin) — Fasting Glucose 6.0-6.9 mmol/L (110-125 mg/dl) 0.45 CHD mortality (P=0.007) 0.57 Total mortality (P=0.02) 0.57 Revascularizations (P=0.01) 0.62 Major coronary events (P=0.003) 0.0 0.2 0.4 0.6 0.8 1.0 Relative Risk Adapted from Haffner SM et al. Arch Intern Med 1999;159:2661-2667 1.2 1.4 Slide Source LipidsOnline www.lipidsonline.org

4S: Effect of Statin Therapy on Hospital Stay Bed Days (per 100 Pts) 1200 ↓ 55% 1000 800 600 (p<0.001) ↓ 28% (p<0.001) ↓ 38% (p=0.005) 400 200 0 Simvastatin Placebo Normal fasting glucose Simvastatin Placebo Simvastatin Impaired fasting glucose Adapted from Herman WH et al. Diabetes Care 1999;22:1771-1778. Placebo Diabetes mellitus Slide Source LipidsOnline www.lipidsonline.org

CARE: Major Coronary Events in Diabetic Subgroups Relative risk = 0.77 P<0.001 35 30 25 Placebo 20 15 10 Pravastatin 5 0 0 1 2 3 4 5 6 Follow-up Time (years) 45 Percent with Event Percent with Event 45 No Diabetes by History 35 30 25 Diabetes by History Relative risk = 0.75 P=0.05 Placebo 20 Pravastatin 15 10 5 0 0 1 2 3 4 5 6 Follow-up Time (years) Adapted from Goldberg RB et al. Circulation 1998;98:2513-2519. Slide Source LipidsOnline www.lipidsonline.org

AFCAPS/TexCAPS: Subgroup Analysis 0 Men Women Older Smokers HTN Diabetes % Risk Reduction -10 -20 -30 -40 -50 -31 -37 -38 -46 -60 -70 -42 -58 Lovastatin Reduced the Risk of Acute MCE Downs JR et al. JAMA 1998;279:1615-1622. Slide Source LipidsOnline www.lipidsonline.org

45 40 35 30 25 20 15 10 5 0 No Diabetes by History Relative risk = 0.77 P<0.001 Placebo Pravastatin 0 1 2 3 4 5 6 Follow-up Time (years) Percent with Event Percent with Event CARE: Major Coronary Events in Diabetic Subgroups 45 40 35 30 25 20 15 10 5 0 Diabetes by History Relative risk = 0.75 P=0.05 Placebo Pravastatin 0 1 2 3 4 5 6 Follow-up Time (years) Adapted from Goldberg RB et al. Circulation 1998;98:2513-2519. Slide Source LipidsOnline www.lipidsonline.org

Per-Patient % of Grafts POST-CABG: Effect of Aggressive Lipid Lowering on Progression in a Diabetic Subgroup 50 Diabetes (n=116) No Diabetes (n=1235) 40 30 51%  40%  20 10 0 99% CI (0.20-1.19) Aggressive Moderate Rx Rx Hoogwerf BJ et al. Diabetes. 1999;48:1289-1294. 99% CI (0.46-0.79) Aggressive Moderate Rx Rx Slide Source LipidsOnline www.lipidsonline.org

CHD Prevention Trials with Fibrates in Diabetic Subjects: Subgroup Analyses Drug Dose Study Baseline LDL-C, mg/dl No. (mmol/L) LDL-C CHD Lowering Reduction Primary Prevention Helsinki Heart Study Gemfibrozil 135 (1200 mg/d) 203 (5.2) 6% 68% NS 112 (2.9) – 24% p=0.05 Secondary Prevention VA-HIT Gemfibrozil 627 (1200 mg/d) Adapted from Koskinen P et al. Diabetes Care 1992;15:820-825; Rubins HB et al. N Engl J Med 1999;341:410-418. Slide Source LipidsOnline www.lipidsonline.org

5-Year Incidence of CHD (%) Primary CHD* Prevention in Type 2 Diabetic Patients: The Helsinki Heart Study 15 P=0.19 10.5 P<0.02 10 7.4 5 0 3.4 3.3 Type 2 (n=135) Others (n=3946) Type 2 on Placebo (n=76) *Myocardial infarction or cardiac death Adapted from Koskinen P et al. Diabetes Care 1992;15:820-825. Type 2 on Gemfibrozil (n=59) Slide Source LipidsOnline www.lipidsonline.org

Cumulative Incidence (%) VA-HIT: Incidence of Death from CHD and Nonfatal MI 25 20 Placebo 15 Gemfibrozil 10 5 0 1 2 3 Year 4 Adapted from Rubins HB et al. N Engl J Med 1999;341:410-418. 5 6 Slide Source LipidsOnline www.lipidsonline.org

VA-HIT: Death Due to CHD, Nonfatal MI, and Confirmed Stroke in Diabetic Patients Placebo* 88/309 24% 0.05 (28) 214/949 170/955 24% 0.009 (23) No diabetes 116/318 (36) Diabetes Gemfibrozil* Risk Reduction (18) *Values are numbers with events/total numbers (%) Adapted from Rubins HB et al. N Engl J Med 1999;341:410-418. P Value Slide Source LipidsOnline www.lipidsonline.org

Future Directions Ongoing Trials with Lipid-Lowering Focus Drug HPS Simvastatin ASPEN Atorvastatin CARDS Atorvastatin LDS Cerivastatin + fenofibrate micronized DAIS Fenofibrate micronized FIELD Fenofibrate micronized HPS = Heart Protection Study; ASPEN = Atorvastatin Study in Preventing Endpoints in NIDDM; CARDS = Collaborative Atorvastatin Diabetes Study; LDS = Lipids in Diabetes Study; DAIS = Diabetes Atherosclerosis Intervention Study; FIELD = Fenofibrate Intervention Slide Source and Event Lowering in Diabetes LipidsOnline www.lipidsonline.org

Heart Protection Study  Primary prevention with risk factors (hypertension, diabetes, and CVA)  2x2 factorial design simvastatin 40 mg/day, antioxidant cocktail (600 mg vitamin E, 250 mg vitamin C, 20 mg beta carotene)  N = 20,000; subgroups include: Women (n ~ 5,000) Elderly (>65, n ~ 10,000) Diabetics (n ~ 6,000) Stroke (n ~ 3,000) Hypertension (n ~ 8,000) Noncoronary vascular disease (n ~ 7,000) Low to average blood cholesterol (n ~ 8,000)  FPI – 1996, fully enrolled, results 2001 Medical Research Council. August 1994 Slide Source LipidsOnline www.lipidsonline.org

Endpoint Studies: Treating to New Targets (TNT): Study Design Atorvastatin 80 mg 10,000 CAD Patients LDL 75 mg/dL 5 Years Atorvastatin LDL 10 mg 100 mg/dL Site Selection November 1997 Investigator Meeting March 1998 Recruitment Complete June 1999 Study End Dec 2004 Slide Source LipidsOnline www.lipidsonline.org

Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine with Simvastatin and Folic Acid/Vitamin B12 (SEARCH): Study Design  Primary objective: To determine whether the greater cholesterol reductions achieved with simvastatin 80 mg produce greater CHD reductions in post-MI patients than achieved with simvastatin 20 mg  Secondary prevention  2x2 factorial design: simvastatin 20 or 80 mg; 2 mg folic acid/1 mg Vitamin B12  N = 12,000  FPI – 12/97, results 2003 Slide Source LipidsOnline www.lipidsonline.org

Lipids in Diabetes Study (LDS): Two-by-Two Factorial Randomization Fenofibrate Arm Cerivastatin Arm Cerivastatin Fenofibrate (n=1,250) Placebo Fenofibrate (n=1,250) 2,500 active fenofibrate Cerivastatin Placebo (n=1,250) Placebo Placebo (n=1,250) 2,500 placebo fenofibrate n=2,500 active cerivastatin n=2,500 placebo cerivastatin 5,000 pts in total Slide Source LipidsOnline www.lipidsonline.org

Conclusions  CHD risk is extremely high in diabetic subjects  Benefits of risk-factor modification in intervention trials also apply to subgroups with diabetes  Results of strict glycemic control on macrovascular disease are inconclusive Slide Source LipidsOnline www.lipidsonline.org

Clinical Evaluation and Nonlipid Treatment of Coronary Artery Disease in the Diabetic Patient Richard Nesto, MD Slide Source LipidsOnline www.lipidsonline.org

Prevalence of Asymptomatic CAD in Diabetes Mellitus Positive Positive ETT Koistinen MJ. BMJ 1990;301:92-95. Type 2 Type 1 Controls Angiography n = 64 n = 72 n = 80 36% 24% 9% 9% 11% 9% n = 142 n = 149 31% 30% 12.1% 5.3% n = 925 12.1% Naka M et al. Am Heart J 1992;123:46-53. Type 2 Controls MiSAD Group. Am J Cardiol 1997;79:134-139. Type 2 6.4% (thal201) Rutter MK et al. Am J Cardiol 1999;83:27-31. Type 2 w microalb Type 2 w/o microalb n = 43 n = 43 65% 40% — — Le A et al. Am J Kidney Dis 1994;24:65-71. Type 1 Renal Transplant 58% 35% 55% 43% Holley JL et al. Am J Med 1991;90:563-570. Type 1 & 2 Renal Transplant Slide Source LipidsOnline www.lipidsonline.org

Indications for Cardiac Testing in Diabetic Patients  Typical or atypical cardiac symptoms  Resting ECG suggestive of ischemia or infarction  Peripheral or carotid occlusive arterial disease  Sedentary lifestyle or plan to begin a vigorous exercise program  Two or more of the risk factors listed below - Total cholesterol >240 mg/dL, LDL cholesterol >160 mg/dL, or HDL cholesterol <35 mg/dL - Blood pressure >140/90 mmHg - Smoking - Family history of premature CAD - Positive micro/macroalbuminuria Slide Source LipidsOnline www.lipidsonline.org

Factors Limiting Accuracy of Noninvasive "Stress" Tests for CAD  Hypertensive Cardiomyopathy  Diabetic Cardiomyopathy  Autonomic Cardiomyopathy  Renal Insufficiency  Microvascular Dysfunction Slide Source LipidsOnline www.lipidsonline.org

Benefits of Early Detection of CAD  Implement more aggressive CHD prevention regimen  Initiate anti-ischemic medications  Identify patients who would benefit from revascularization  Educate patients to recognize coronary symptoms Slide Source LipidsOnline www.lipidsonline.org

MEN 180 No Glucose Intolerance 160 140 174 Glucose Intolerance 120 119 100 90 80 77 60 40 20 0 59 50 38 24 105 135 165 Age-adjusted CV Event Rate/1,000 Age-adjusted CV Event Rate/1,000 Blood Pressure and CVD: Framingham Heart Study WOMEN 180 No Glucose Intolerance 160 140 Glucose Intolerance 120 113 100 80 74 60 40 20 195 Systolic BP (mmHg) Kannel WB et al. Am Heart J 1991;121:1268-1273. 0 56 48 31 15 105 36 23 135 165 195 Systolic BP (mmHg) Slide Source LipidsOnline www.lipidsonline.org

Effect of Glycemic Control in the UK Prospective Diabetes Study (UKPDS) Endpoints Intensive (rate/1000 pt yrs) Conventional (rate/1000 pt yrs) P % Decrease Any diabetes related* 40.9 46 0.029 11 MI 17.4 0.052 16 14.7 Stroke 5.6 5 0.52 – PVD 1.1 1.6 0.15 – Microvascular 8.6 11.4 0.0099 25 * Combined microvascular and macrovascular events UKPDS Group. Lancet 1998;352:837-853. Slide Source LipidsOnline www.lipidsonline.org

Reasons for Death in UKPDS Intensive Treatment Arm: 10-Year Follow-up N= 2729 (%) Fatal MI or SD 231 (8.4%) Cancer 120 (4.4%) Other 74 (2.9%) Fatal Stroke 43 (1.6%) Renal Disease 16 (0.6%) Accidents 5 (0.2%) PVD 2 (0.07%) Hypo- or Hyperglycemia 1 (0.04%) Accidents, PVD, Hypo& Hyperglycemia Renal 3.3% 2.5% 15% Other 24% Cancer 47% MI or SD 8.7% Stroke UKPDS Group. Lancet 1998;352:837-853. Slide Source LipidsOnline www.lipidsonline.org

Effect of Blood Pressure Control in the UKPDS Tight vs. Less Tight Control  1,148 Type 2 patients  Average BP lowered to 144/82 mmHg (controls: 154/87); 9-year follow-up Tight Control Risk Reduction (%) P value Any diabetes-related endpoint 24 0.0046 Diabetes-related deaths 32 0.019 Heart failure 56 0.0043 Stroke 44 0.013 Myocardial infarction 21 NS Microvascular disease 37 0.0092 UKPDS Group. BMJ 1998;317:703-713. Slide Source LipidsOnline www.lipidsonline.org

UKPDS: ACE Inhibitor vs. Beta-blocker for HTN Aggregate Clinical Endpoints Relative Risk & 95% CI RR p Any diabetes-related endpoint 1.10 1.27 1.14 0.44 Myocardial infarction 1.20 0.35 Stroke 1.12 0.74 Microvascular 1.29 2 0.28 All-cause mortality 1 0.43 Diabetes-related deaths 0.5 0.30 Favors ACE inhibitor UKPDS Group. BMJ 1998;317:713-720. Favors Beta blocker Slide Source LipidsOnline www.lipidsonline.org

Systolic Hypertension in Europe (Syst-Eur) Trial: Events / 1000 Pt-Years Effect of Systolic BP Control on All Cardiovascular Events at 2 Years 70 60 50 40 30 20 10 0 57.6 25% 62% Risk Reduction 22.0 Placebo Active Rx Diabetic Patients N=492; P=0.002 Tuomilehto J et al. NEJM 1999;340: 677-684. 31.4 Risk Reduction 23.5 Placebo Active Rx Nondiabetic Patients N=4,203; P=0.02 Slide Source LipidsOnline www.lipidsonline.org

Major Outcomes of the Hypertension Optimal Treatment (HOT) Trial: Diabetes Subgroup Events / 1000 Pt-Years 30 25 Diastolic Target p<0.005 <90 mmHg (N=501) <85 mmHg (N=501) 20 <80 mmHg (N=499) 15 p<0.045 10 p<0.016 5 0 Major CV Events Hansson L et al. Lancet 1998;351: 1755-1762. MI CV Mortality Slide Source LipidsOnline www.lipidsonline.org

Events / 1000 Pt-Years HOT Trial:Cardiovascular Events in Diabetics and Nondiabetics—Effect of Diastolic Target at 4 Years 30 25 20 15 10 24.4 48% Risk 18.6 Reduction 11.9 5 0 <90 <85 <80 Diabetic Patients n=1,501; p=0.016 Hansson L et al. Lancet 1998;351: 1755-1762. 9.9 10.0 9.3 <90 <85 <80 Nondiabetic Patients n=18,790; p=NS Slide Source LipidsOnline www.lipidsonline.org

Completed Clinical Trials with Antihypertensive Agents in Diabetes Trial Diabetic/Total SHEP 583/4736 Beneficial GISSI-3 2790/18,131 Beneficial Syst-Eur 492/4695 Beneficial 1501/18,790 Beneficial UKPDS 1148 Beneficial CAPPP 572/10,985 Beneficial HOT Results on CVD SHEP = Systolic Hypertension in the Elderly Program; GISSI = Grupo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico; Syst-Eur = Systolic Hypertension in Europe; HOT = Hypertension Optimal Treatment; CAPPP = Captopril Prevention Project Curb JD et al. JAMA 1996;276:1886-1892; Zuanetti G et al. Circulation 1997;96:4239-4245; Staessen JA et al. Am J Cardiol 1998;82:20R-22R; Hansson L et al. Lancet 1998;351:1755-1762;UK Prospective Diabetes Study Slide Source Group. BMJ 1998;317:703-713; Hansson L et al. Lancet 1999;353:611-616. LipidsOnline www.lipidsonline.org

Heart Outcomes Prevention Evaluation (HOPE) Study Effect of Ramipril on Cardiovascular Events (Myocardial Infarction, Stroke, or CVD Death) ~ 4.5 Yrs % of Patients 25 20 15 24% 19.8 Risk Reduction 15.0 10 21% 16.4 Risk Reduction 13.0 5 0 Placebo Ramipril Diabetic Patients N=3,578, P=<0.001 Hope Study Investigators. NEJM 2000;342:145-153. Placebo Ramipril Nondiabetic Patients N=5,719, P=<0.001 Slide Source LipidsOnline www.lipidsonline.org

Diabetes Increases Risk of Coronary Plaque Disruption and Thrombosis Cause of Myocardial Infarction Platelet Aggregation F VII Fibrinogen F VIII vWF Coronary Artery Thrombus Plaque Formation Plaque Disruption Sympathetic Tone PAI-1 TPA PGI2 Slide Source LipidsOnline www.lipidsonline.org

Impact of Serum Fibrinogen and Total Cholesterol Levels on Risk of Coronary Events in ECAT 21/305 16/304 7 6 Risk of Coronary Events (%) 3/247 5 4 3 2 5/311 10/281 9/261 4/306 11/266 10/282 1 Total Cholesterol Higher Middle 0 Lower Middle Fibrinogen Thompson SG. N Engl J Med 1995;332:635-641. Lower Higher Slide Source LipidsOnline www.lipidsonline.org

Effect of Aspirin on Mortality in Type 2 Patients with CHD: Bezafibrate Infarction Prevention Study 100 Survival (%) OR=0.7 (0.6-0.8) No diabetes 90 OR=0.8 (0.7-0.9) 80 Type 2 diabetes No aspirin Aspirin 70 0 1 2 3 4 Time (Years) Harpaz D et al. Am J Med 1998;105:494-499. 5 6 Slide Source LipidsOnline www.lipidsonline.org

Antiplatelet Agents Reduce CVD Events in Patients with Diabetes: Antiplatelet Trialists’ Collaboration CVD Events (%) 25 P<0.002 Antiplatelet Therapy Control 20 P<0.00001 15 10 5 0 Diabetes Antiplatelet Trialists’ Collaboration. BMJ 1994;308:81-106. No Diabetes Slide Source LipidsOnline www.lipidsonline.org

Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial Infarction (DIGAMI): Benefit of Tight Glycemic Control in No Insulin – Low Risk Cohort Total Cohort p = .0111 Mortality 0.6 0.7 0.5 Control 0.4 n=306 0.3 0.2 0 0 1 2 3 4 Years in Study 0.5 n=133 0.4 Control 0.3 0.2 Insulin-glucose Infusion 0.1 p = .004 0.6 n=314 Mortality 0.7 No Insulin – Low Risk n=139 0.1 5 Malmberg K et al. BMJ 1997;314:1512-1515. 0 0 Insulin-glucose Infusion 1 2 3 4 Years in Study Slide Source LipidsOnline www.lipidsonline.org 5

Effect of Trandolapril on Post-MI CHF Progression: Trandolapril Cardiac Evaluation (TRACE) Diabetics (n=237) 0.5 0.5 Placebo 0.4 Event Rate Event Rate 0.4 0.3 Trandolapril 0.2 0.1 0.0 Nondiabetics (n=1512) 1 2 Years 3 Placebo 0.2 Trandolapril 0.1 Relative risk, 0.38 P<0.001 0 0.3 4 0.0 Gustafsson I et al. J Am Coll Cardiol 1999;34:83-89. Relative risk, 0.81 P = 0.1 0 1 2 Years 3 Slide Source LipidsOnline www.lipidsonline.org 4

Effect of Trandolapril on Secondary Endpoints in TRACE Diabetics End Point RR (95% CI) Interaction Nondiabetics P RR (95% CI) P P Cardiovascular death 0.56 (0.37-0.85) 0.01 0.79 (0.66-0.96) 0.02 0.17 Sudden death 0.46 (0.25-0.85) 0.01 0.84 (0.63-1.12) 0.23 0.09 Reinfarction 0.55 (0.29-1.07) 0.08 0.93 (0.69-1.26) 0.65 0.15 Progression in CHF 0.38 (0.21-0.67) <0.001 0.81 (0.63-1.04) 0.10 0.03 CI = confidence interval; RR = relative risk. Gustafsson I et al. J Am Coll Cardiol 1999;34:83-89. Slide Source LipidsOnline www.lipidsonline.org

Effect of Diabetes on 30-Day Mortality: Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-I) 2.7 Diabetes vs no diabetes (unadjusted) 2.1 Adjusted for clinical variables 2.4 Adjusted for angiographic variables 2.0 Adjusted for clinical & angiographic variables 0 1 2 3 4 Odds Ratio for 30-Day Mortality Woodfield SL et al. J Am Coll Cardiol 1996;28:1661-1669. Slide Source LipidsOnline www.lipidsonline.org 5

Overall 5-Year Mortality in the Bypass Angioplasty Revascularization Investigation (BARI-1) 1.0 DM-PTCA Mortality 0.8 DM-CABG Non DM-CABG 0.6 Non DM-PTCA 0.4 0.25 0.18 0.08 0.07 0.2 0.0 0 1 2 3 Follow-up (years) Detre KM et al. N Engl J Med 2000;342:989-997. 4 5 Slide Source LipidsOnline www.lipidsonline.org

Impact of PTCA vs. CABG on Mortality in BARI-1 Mortality in Patients without Q-MI 1.0 DM-CABG 0.8 Non DM-CABG Non DM-PTCA 0.6 Mortality Mortality 1.0 DM-PTCA 0.8 0.4 0.2 0.0 0 1 2 3 4 Follow-up (years) Mortality in Patients After Q-MI 0.79 0.6 0.4 0.22 0.2 0.16 0.07 0.06 0.0 5 Detre KM et al. N Engl J Med 2000;342:989-997. 0.29 0.27 0.17 0 1 2 3 4 Years after Q-MI 5 Slide Source LipidsOnline www.lipidsonline.org

Impact of Diabetes on 7-year Survival in BARI All Patients 84.4 80.9 80 60 40 CABG (n=914) PTCA (n=915) 20 0 1 2 3 Patients with Treated Diabetes 100 % Survival 0 76.4 60 55.7 CABG (n=180) PTCA (n=173) 20 0 0 1 2 3 4 p = 0.0011 4 5 6 5 6 7 80 86.8 86.4 60 40 CABG (n=734) PTCA (n=742) 20 0 Years 7 Patients without Treated Diabetes 100 80 40 p = 0.0425 % Survival % Survival 100 0 BARI Investigators. J Am Coll Cardiol 2000;35:1122-1129. 1 2 3 p = 0.7155 4 5 Source 7 Slide 6 LipidsOnline www.lipidsonline.org

Eight-Year Mortality in Emory Angioplasty vs Surgery Trial (EAST) All EAST Patients % Survival 100 80 60 40 CABG (n=194) PTCA (n=198) 20 0 0 1 2 4 5 60 40 CABG (n=30) PTCA (n=29) 20 p = 0.23 6 100 % Survival 80 0 3 p = 0.40 Treated Diabetic Patients 100 % Survival 82.7 79.3 7 8 Patients without Diabetes 80 60 40 20 CABG (n=164) PTCA (n=169) 0 7 8 0 1 2 Years after Randomization King SB III et al. J Am Coll Cardiol 2000;35:1116-1121. 0 1 2 3 4 5 6 3 4 p = 0.71 5 6 7 Slide Source LipidsOnline www.lipidsonline.org 8

6-Month Angiographic Outcome after PTCA in Diabetes (377 Patients with 476 Lesions) Lesions (%) 75 62% 50 49% 25 0 Restenosis (n = 237) Total Occlusion (n = 60) 13% 100 Total Occlusion 75 Patients (%) 100 Overall Restenosis Rate 50 37% 25% 25 11% 0 Angiographic FU = 6 months Van Belle E et al. J Am Coll Cardiol 1999;34:476-485. 1 Site 2 Sites 3 Sites PTCA Site(s) Slide Source LipidsOnline www.lipidsonline.org

Impact of Restenosis and Total Occlusion on LV Function in Diabetes 15 Restenosis (–) Restenosis (+) Total Occlusion (+) Total Occlusion (–) Total Occlusion (–) (n = 297) (n = 237) (n = 60) ∆ in EF (%) 10 5 0 -5 -1.5+9.5 +0.5+9.9 -6.2+9.9 -10 -15 -20 p = ns p = ns Van Belle E et al. J Am Coll Cardiol 1999;34:476-485. p = 0.0001 Slide Source LipidsOnline www.lipidsonline.org

Effect of Stents on Target Vessel Revascularization (TVR) after PTCA in Diabetes Proportion Free of TVR 1.00 p = 0.021 df = 3, Log-rank Test 0.95 0.90 0.85 1997 0.80 Year 0 17.4 425 24.9 1996 480 41.0 1997 0 305 1995 0.70 % Stent 1994 0.75 N 288 55.5 2 1996 1995 1994 4 6 8 10 12 Months Post PTCA Rankin JM et al. Circulation 1998;98:I-79. Slide Source LipidsOnline www.lipidsonline.org

Patients with Diabetes (n = 491) 20 Stent + Placebo Stent + Abciximab Angioplasty + Abciximab 15 16.6% 10 8.1% 5 0 18.4% 0 30 60 90 120 150 180 Incidence of repeated TVR at 6 mos. (%) Incidence of repeated TVR at 6 mos. (%) Evaluation of Platelet IIb/IIIa Inhibitor for Stenting Trial (EPISTENT): Benefit of Abciximab and Stenting in Diabetes on Reducing TVR Days after Randomization Lincoff AM et al. N Engl J Med 1999;341:319-327. Patients without Diabetes (n = 1908) 20 Stent + Placebo Stent + Abciximab Angioplasty + Abciximab 15 9.0% 10 8.8% 5 0 14.6% 0 30 60 90 120 150 180 Days after Randomization Slide Source LipidsOnline www.lipidsonline.org

EPISTENT: Optimization of PTCA/Stent Outcomes with Platelet IIb/IIIa Inhibition 6-Month Death, MI for Diabetics 15 % of Patients 12.7% p = 0.029 10 7.8% 6.2% 5 0 Stent + Placebo Stent + Abciximab PTCA + Abciximab 0 30 60 90 Days Marso SP et al. Circulation 1999;100:2477-2484. 120 150 180 Slide Source LipidsOnline www.lipidsonline.org

Conclusions In patients with diabetes mellitus, there are numerous opportunities to reduce morbidity and mortality from CAD:  identify diabetic patients with particularly high risk for CAD and perform appropriate screening  aggressively identify and modify coronary risk factors  explore and implement treatment to protect the left ventricle from ischemic injury  maintain tight but judicious glycemic control in acute coronary syndromes  use medications proven to dramatically improve outcomes in acute MI (beta blockers, ACE inhibitors, aspirin, IIb/IIIa platelet inhibitors, statins) Slide Source LipidsOnline www.lipidsonline.org

Future Directions  Additional clinical trials are needed to evaluate cardiovascular therapeutic interventions in diabetic patients, because certain therapies may produce different results in the presence of diabetes Slide Source LipidsOnline www.lipidsonline.org

Diabetic Dyslipidemia and Atherosclerosis Henry Ginsberg, MD Slide Source LipidsOnline www.lipidsonline.org

Interrelation Between Atherosclerosis and Insulin Resistance Hypertension Obesity Hyperinsulinemia Insulin Insulin Resistance Resistance Diabetes Hypertriglyceridemia Atherosclerosis Atherosclerosis Small, dense LDL Low HDL Hypercoagulability Slide Source LipidsOnline www.lipidsonline.org

Insulin Resistance and Hyperinsulinemia: Clinical Clues  Abdominal obesity   TG +  HDL-C  Glucose intolerance  Hypertension  Atherosclerosis  Ethnicity Slide Source LipidsOnline www.lipidsonline.org

Dyslipidemia in the Insulin Resistance Syndrome  Elevated total TG  Reduced HDL-C  Small, dense LDL-C Slide Source LipidsOnline www.lipidsonline.org

Dyslipidemias in Adults with Diabetes Framingham Heart Study MEN WOMEN Normal DM Normal DM Increased cholesterol 14% 13% 21% 24% Increased LDL 11% 9% 16% 15% Decreased HDL 12% 21% 10% 25% 9% 19% 8% 17% Increased triglycerides Garg A et al. Diabetes Care 1990;13:153-169. Slide Source LipidsOnline www.lipidsonline.org

Mean Plasma Lipids at Diagnosis of Type 2 Diabetes - UKPDS MEN Type 2 WOMEN Control Type 2 Control 2139 52 1574 143 TC (mg/dl) 213 205 224 217 LDL-C (mg/dl) 139 132 151* 135 43 43* 55 103 159* 95 Number of Pts HDL-C (mg/dl) TG (mg/dl) 39** 159* * P<0.001, ** P<0.02 comparing type 2 vs. controll UKPDS Group. Diabetes Care 1997;20:1683-1687. Slide Source LipidsOnline www.lipidsonline.org

Relation Between Insulin Resistance and Hypertriglyceridemia Plasma TG (mg/dL) 625 500 r = 0.73 P < 0.0001 400 300 200 100 100 200 300 400 500 600 Insulin Response to Oral Glucose* * Total area under 3-hour response curve (mean of 2 tests). Olefsky JM et al. Am J Med. 1974;57:551-560. Slide Source LipidsOnline www.lipidsonline.org

Association Between Hyperinsulinemia and Low HDL-C HDL-C (mg/dL) 60 50 Hyperinsulinemic P<0.005 Normoinsulinemic P<0.005 40 30 20 Nonobese Reaven GM. In: LeRoith D et al., eds. Diabetes Mellitus. Philadelphia: Lippincott-Raven,1996:509-519. Obese Slide Source LipidsOnline www.lipidsonline.org

Mechanisms Relating Insulin Resistance and Dyslipidemia Fat Cells Liver  FFA IR X Insulin Slide Source LipidsOnline www.lipidsonline.org

Mechanisms Relating Insulin Resistance and Dyslipidemia Fat Cells Liver  FFA IR X    TG Apo B VLDL VLDL Insulin Slide Source LipidsOnline www.lipidsonline.org

Mechanisms Relating Insulin Resistance and Dyslipidemia Fat Cells Liver  FFA IR X Insulin    CE TG Apo B VLDL  VLDL (CETP) HDL TG (hepatic lipase) Apo A-1 Kidney Slide Source LipidsOnline www.lipidsonline.org

Mechanisms Relating Insulin Resistance and Dyslipidemia Fat Cells Liver  FFA IR X    CE TG Apo B VLDL  VLDL (hepatic (CETP) HDL lipase) TG Apo A-1 CE (CETP) TG Insulin LDL Kidney SD LDL (lipoprotein or hepatic lipase) Slide Source LipidsOnline www.lipidsonline.org

Dyslipidemia in Diabetes Increased Decreased  Triglycerides  HDL  VLDL  Apo A-I  LDL and small dense LDL  Apo B Slide Source LipidsOnline www.lipidsonline.org

LDL Subclass Phenotypes in Diabetes Mellitus LDL Subclass n A Int B 51 24 36 6 Men* Diabetic Nondiabetic 29 87 28 47 Percent 21 29 Women** Diabetic Nondiabetic 54 543 34 85 30 9 * Feingold KR et al. Arterioscler Thromb 1992; 12:1496-1502. ** Selby JV et al. Circulation 1993; 88:381-387. Slide Source LipidsOnline www.lipidsonline.org

Small Dense LDL and CHD: Potential Atherogenic Mechanisms  Increased susceptibility to oxidation  Increased vascular permeability  Conformational change in apo B  Decreased affinity for LDL receptor  Association with insulin resistance syndrome  Association with high TG and low HDL Austin MA et al. Curr Opin Lipidol 1996;7:167-171. Slide Source LipidsOnline www.lipidsonline.org

Hypertriglyceridemia and CHD Risk: Associated Abnormalities  Accumulation of chylomicron remnants  Accumulation of VLDL remnants  Generation of small, dense LDL-C  Association with low HDL-C  Increased coagulability -  plasminogen activator inhibitor (PAI-1) -  factor VIIc - Activation of prothrombin to thrombin Slide Source LipidsOnline www.lipidsonline.org

TG Metabolism in CHD: Studies in the Postprandial State Corrected for Fasting TG (mg/dL) 400 300 Uncorrected CHD Cases 300 TG Level* 200 CHD Cases 200 Controls 100 0 0 100 Controls 2 4 0 0 6 8 2 Hours after Test Meal 4 6 8 Error bars = SEM Patsch JR et al. Arterioscler Thromb 1992;12:1336-1345. Slide Source LipidsOnline www.lipidsonline.org

Factors Promoting Thromboembolic Disease in Diabetes  Increased plasma fibrinogen  Increased plasminogen activator inhibitor 1  Increased platelet aggregability Thompson SG et al. N Engl J Med 1995;332:635-641. Slide Source LipidsOnline www.lipidsonline.org

Adverse Effects on Balance Between Thrombosis and Fibrinolysis in Subjects with Diabetes  Predisposition to thrombosis - Platelet hyperaggregability - Elevated concentrations of procoagulants - Decreased concentration and activity of antithrombotic factors  Predisposition to attenuation of fibrinolysis - Decreased t-PA activity - Increased PAI-1 - Decreased concentrations of α2-antiplasmin Sobel BE. Circulation 1996;93:1613-1615. Slide Source LipidsOnline www.lipidsonline.org

PAI-1 Activity in Blood in Patients with Type 2 Diabetes PAI-1 Activity (AU/mL) 20 15 No Diabetes Diabetes 10 5 0 Lean PAI-1 = plasminogen activator inhibitor type 1 McGill JB et al. Diabetes. 1994;43:104-109. Obese Slide Source LipidsOnline www.lipidsonline.org

Elevation of PAI-1 Induced by Hyperinsulinemia, Hyperglycemia, and Increased FFA in Blood of Normal Subjects PAI-I (mg/mL) 21 18 Infusion of glucose and intralipid 15 12 * 9 6 3 0 0 Values are mean + SD 2 4 6 Time (h) *P<0.05 vs saline infusions in same subjects Calles-Escandon J et al. Diabetes. 1998;47:290-293. 8 10 12 Slide Source LipidsOnline www.lipidsonline.org

Pharmacologic Agents for Treatment of Dyslipidemia Effect on lipoprotein LDL HDL Triglyceride First-line agents  HMG CoA reductase inhibitor  Fibric acid derivative Second-line agents  Bile acid binding resins  Nicotinic acid In diabetic patients, nicotinic acid should be restricted to <2g/day. Short-acting nicotinic acid is preferred. American Diabetes Association. Diabetes Care 2000;23(suppl 1):S57-S60. Slide Source LipidsOnline www.lipidsonline.org

Order of Priorities for Treatment of Diabetic Dyslipidemia in Adults*  LDL cholesterol lowering* - First choice: HMG CoA reductase inhibitor (statin) - Second choice: Bile acid binding resin or fenofibrate  HDL cholesterol raising - Behavior interventions such as weight loss, increased physical activity and smoking cessation - Glycemic control - Difficult except with nicotinic acid, which is relatively contraindicated, or fibrates  Triglyceride lowering - Glycemic control first priority - Fibric acid derivative (gemfibrozil, fenofibrate) - Statins are moderately effective at high dose in hypertriglyceridemic subjects who also have high LDL cholesterol * Decision for treatment of high LDL before elevated triglyceride is based on clinical trial data indicating safety as well as efficacy of the available agents. Slide Source Adapted from American Diabetes Association. Diabetes Care 2000;23(suppl 1):S57-S60. LipidsOnline www.lipidsonline.org

Update on the Metabolic Syndrome Steven Haffner, MD Slide Source LipidsOnline www.lipidsonline.org

Metabolic Syndrome Increases Risk for CHD and Type 2 Diabetes High LDL-C Metabolic Syndrome Type 2 Diabetes Coronary Heart Disease Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497. Slide Source LipidsOnline www.lipidsonline.org

High Risk of Impaired Glucose Tolerance and Type 2 Diabetes by OGTT in Post-MI Patients without Known Diabetes % of Patients 100 IGT n = 181 80 60 40 New DM 35% 40% 31% 25% 20 0 At discharge 3 mo later Norhammar A et al. Lancet 2002;359:2140-2144. At discharge 3 mo later Slide Source LipidsOnline www.lipidsonline.org

Increased Metabolic Syndrome in Prediabetic Subjects: Baseline Risk Factors in Subjects with Normal Glucose Tolerance at Baseline according to Conversion Status at 8-Year Follow-up: San Antonio Heart Study Conversion Status at Follow-up Diabetes (n=18) Normal (n=490) P 28.2 ± 1.1 27.2 ± 0.2 .472 Centrality* 1.38 ± 0.09 1.16 ± 0.2 .472 TG (mmol) 1.83 ± 0.12 1.26 ± 0.10 .006 HDL-C (mmol) 1.14 ± 0.07 1.28 ± 0.02 .045 SBP (mm Hg) 116.8 ± 3.0 108.8 ± 0.8 .004 5.28 ± 0.1 5.00 ± 0.02 .032 157 ± 27 81 ± 5 .006 BMI (kg/m2) Fasting glucose (mmol) Fasting insulin (pmol) * Ratio of subscapular to triceps skinfolds Haffner SM et al. JAMA 1990;263:2893-2898. Slide Source LipidsOnline www.lipidsonline.org

Elevated Risk of CVD Prior to Clinical Diagnosis of Type 2 Diabetes: Nurses’ Health Study Relative Risk 6 5.02 5 3.71 4 2.82 3 2 1 1 0 Nondiabetic throughout the study Prior to diagnosis of diabetes Copyright © 2002 American Diabetes Association From Diabetes Care, Vol. 25, 2002; 1129-1134 Reprinted with permission from The American Diabetes Association. After diagnosis of diabetes Diabetic at baseline Slide Source LipidsOnline www.lipidsonline.org

Risk of Major CHD Event Associated with Insulin Quintiles in Nondiabetic Subjects: Helsinki Policemen Study Proportion without Major CHD Event 1.00 0.95 0.90 Q1 0.85 Q2 Log rank: Overall P = .001 Q5 vs. Q1 P < .001 0.80 0.75 Q3 Q4 Q5 0 0.70 0 5 10 Years Pyörälä M et al. Circulation 1998;98:398-404. 15 20 25 Slide Source LipidsOnline www.lipidsonline.org

CVD Risk Factors across HOMA-IR Quintiles: San Antonio Heart Study (Phase II) HOMA-IR Q1 Q2 Q3 Q4 Q5 HDL-C (mg/dl) 51.7 49.3 47.8 45.0 41.2 LDL-C (mg/dl) 115.7 119.3 125.0 128.1 124.8 Cholesterol (mg/dl) 188.0 191.6 197.9 200.8 199.0 Triglyceride (mg/dl) 105.7 116.6 129.7 145.4 187.2 Systolic BP (mm Hg) 114.9 116.5 118.3 119.3 123.0 69.0 70.4 71.9 73.1 75.4 Diastolic BP (mm Hg) Adjusted for age, sex, ethnicity All p(trend) < 0.0001; quintile cutpoints: 1.0, 1.6, 2.5, 4.8 Copyright © 2002 American Diabetes Association From Diabetes Care, Vol. 25, 2002; 1177-1184 Reprinted with permission from The American Diabetes Association. Slide Source LipidsOnline www.lipidsonline.org

Definitions of the Metabolic Syndrome  According to clinical outcomes  According to underlying causes  According to metabolic components  According to clinical criteria Slide Source LipidsOnline www.lipidsonline.org

Definition of Metabolic Syndrome: According to Underlying Causes  Insulin resistance (1999 WHO)  Insulin resistance syndrome  Lifestyle: especially obesity (NCEP ATP III)  Metabolic syndrome  Subclinical inflammation WHO. Definition, Diagnosis and Classification of Diabetes Mellitus and Its Complications: Report of a WHO Consultation. Geneva: WHO, 1999. | Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497. Slide Source LipidsOnline www.lipidsonline.org

Therapeutic Implications: According to Underlying Causes  Insulin resistance  Treat insulin resistance  Lifestyle: especially obesity  Prevent and treat obesity  Subclinical inflammation  Treat obesity  Statins, TZDs, etc. Slide Source LipidsOnline www.lipidsonline.org

ATP III: The Metabolic Syndrome Diagnosis is established when ≥ 3 of these risk factors are present Risk Factor Defining Level Abdominal obesity (Waist circumference) Men Women >102 cm (>40 in) >88 cm (>35 in) ≥150 mg/dl TG HDL-C Men Women <40 mg/dl <50 mg/dl Blood pressure ≥130/≥85 mm Hg Fasting glucose ≥110 mg/dl Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497. Slide Source LipidsOnline www.lipidsonline.org

Prevalence of the NCEP Metabolic Syndrome: NHANES III by Age Prevalence, % 50% 44% 44% Men 40% Women 30% 24% 23% 20% 10% 0% 8% 6% 20–70+ 20–29 20 30–39 30 40–49 50–59 Age, years Ford ES et al. JAMA 2002;287:356-359. 60–69 60 ≥70 Slide Source LipidsOnline www.lipidsonline.org

Prevalence of the NCEP Metabolic Syndrome: NHANES III by Sex and Race/Ethnicity White African American Mexican American Other Prevalence, % 40% 30% 28% 25% 26% 21% 20% 36% 23% 20% 16% 10% 0% Men Ford ES et al. JAMA 2002;287:356-359. Women Slide Source LipidsOnline www.lipidsonline.org

Prevalence of CHD by the Metabolic Syndrome and Diabetes in the NHANES Population Age 50+ 25% CHD Prevalence 19.2% 20% 13.9% 15% 10% 8.7% 7.5% 5% 0% No MS/No DM % of Population = 54.2% MS/No DM 28.7% Alexander CM et al. Diabetes 2003;52:1210-1214.. DM/No MS 2.3% DM/MS 14.8% Slide Source LipidsOnline www.lipidsonline.org

ATP III Metabolic Syndrome: Therapeutic Implications  Focus on obesity (especially abdominal obesity) as the underlying cause of the metabolic syndrome  Therefore, prevent development of obesity in the general population  Also, treat obesity in the clinical setting (NHLBI/NIDDK Obesity Education Initiative) Slide Source LipidsOnline www.lipidsonline.org

Different Components of the NCEP Metabolic Syndrome Predict CHD: NHANES Prediction of CHD Prevalence using Multivariate Logistic Regression Odds Ratio Lower 95% Limit Upper 95% Limit Waist circumference 1.13 0.85 1.51 Triglycerides 1.12 0.71 1.77 HDL cholesterol* 1.74 1.18 2.58 Blood pressure* 1.87 1.37 2.56 Impaired fasting glucose 0.96 0.60 1.54 Diabetes* 1.55 1.07 2.25 Metabolic syndrome 0.94 0.54 1.68 Variable *Significant predictors of prevalent CHD Copyright © 2003 American Diabetes Association From Diabetes, Vol. 52, 2003; 1210-1214 Reprinted with permission from The American Diabetes Association. Slide Source LipidsOnline www.lipidsonline.org

Different Components of the NCEP Metabolic Syndrome Predict Diabetes: San Antonio Heart Study Risk of Type 2 Diabetes per Unit Change in Risk Trait Levels 8% FPG per mg/dl 2% SBP per mm Hg HDL-C per mg/dl decrease 4% 7% BMI per kg/m2 0% 2% 4% Stern MP et al. Ann Intern Med 2002;136:575-581. 6% 8% 10% Slide Source LipidsOnline www.lipidsonline.org

WHO Metabolic Syndrome Definition 1999: Based on Clinical Criteria  Insulin resistance (type 2 diabetes, IFG, IGT)*  Plus any 2 of the following:  Elevated BP (≥140/90 or drug Rx)  Plasma TG ≥150 mg/dl  HDL <35 mg/dl (men); <40 mg/dl (women)  BMI >30 and/or W/H >0.9 (men), >0.85 (women)  Urinary albumin >20 mg/min; Alb/Cr >30 mg/g * Note that 1999 WHO uses hyperinsulinemic euglycemic clamp whereas 1998 WHO and EGIR use HOMA-IR. WHO. Definition, Diagnosis and Classification of Diabetes Mellitus and Its Complications: Report of a WHO Consultation. Geneva: WHO, 1999. Slide Source LipidsOnline www.lipidsonline.org

Must Insulin Resistance be Present for a Patient to Have the Metabolic Syndrome?  WHO 1999 clinical definition  Yes  ATP III 2001 clinical definition  No, but it is usually present  Multiple metabolic risk factors are sufficient  Obesity can produce the metabolic syndrome without insulin resistance WHO. Definition, Diagnosis and Classification of Diabetes Mellitus and Its Complications: Report of a WHO Consultation. Geneva: WHO, 1999. | Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497. Slide Source LipidsOnline www.lipidsonline.org

WHO Metabolic Syndrome Definition 1999: Therapeutic Implications  Focus on insulin resistance as the underlying cause of the metabolic syndrome  More emphasis on the genetic basis of the metabolic syndrome rather than obesity  Leads to increased thinking about the use of drugs to treat insulin resistance in patients with the metabolic syndrome Slide Source LipidsOnline www.lipidsonline.org

Therapeutic Implications of Definition of Metabolic Syndrome  If focus is on obesity as underlying cause  Prevent and treat obesity  If focus is on insulin resistance as underlying cause  Treat insulin resistance  If focus is on metabolic risk factors  Treat individual risk factors Slide Source LipidsOnline www.lipidsonline.org

Criteria for Comparing Different Definitions of Metabolic Syndrome  Risk of:  CHD  DM  Relation to:  Insulin resistance  Obesity  Prevalence in community could differ by race  How simple is the definition? Slide Source LipidsOnline www.lipidsonline.org

Intensity of Therapy Should be Proportionate to Level of Risk  What is the impact of the metabolic syndrome on health outcomes?  Cardiovascular disease  Type 2 diabetes Slide Source LipidsOnline www.lipidsonline.org

Cumulative Hazard, % Cardiovascular Disease Mortality Increased in the Metabolic Syndrome: Kuopio Ischaemic Heart Disease Risk Factor Study 15 10 Cardiovascular Disease Mortality Metabolic Syndrome: RR (95% CI), 3.55 (1.98–6.43) YES 5 0 0 NO 2 4 6 8 Follow-up, y Lakka HM et al. JAMA 2002;288:2709-2716. 10 12 Slide Source LipidsOnline www.lipidsonline.org

Cox Proportional Hazard Ratios (and 95% Confidence Intervals) Predicting All-Cause and Cardiovascular Mortality: San Antonio Heart Study 14-Year Followup NCEP MetS WHO MetS All Cause 1.43 (1.10–1.87) 1.25 (0.96–1.63) CVD 2.55 (1.75–3.72) 1.64 (1.13–2.37) All Cause 1.11 (0.74–1.67) 0.87 (0.57–1.33) CVD 2.04 (1.14–3.63) 0.77 (0.38–1.55) Total Population Disease Free* * Those without diabetes, cardiovascular disease, or cancer. Adjusted for age, gender, and ethnic group. Hunt KJ et al. Diabetes 2003;52:A221-A222. Slide Source LipidsOnline www.lipidsonline.org

% in Lowest Quartile of Si Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Resistant Subjects: IRAS 90 80 70 60 50 40 30 20 10 0 Overall Hispanics Non-Hispanic whites African Americans Neither NCEP Only Hanley AJ et al. Diabetes 2003;52:2740-2747. WHO Only Both Slide Source LipidsOnline www.lipidsonline.org

CRP Adds Prognostic Information at All Levels of Risk as Defined by the Framingham Risk Score 25 20 15 ks R ev t a e R i i l 10 >3.0 5 0 1.0–3.0 <1.0 hs-CRP 10+ 5–9 2–4 0–1 (mg/L) Framingham 10-Year Risk (%) Ridker PM et al. N Engl J Med 2002;347:1557-1565. Copyright © 2002 Massachusetts Medical Society. All rights reserved. Adapted with permission. Slide Source LipidsOnline www.lipidsonline.org

Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Adjusted for Age, Sex, Clinic, Ethnicity, and Smoking Status: IRAS CRP WBC BMI 0.40‡ 0.17‡ 0.22‡ Waist 0.43‡ 0.18‡ 0.27‡ Systolic BP 0.20‡ 0.08* 0.11† Fasting glucose 0.18‡ 0.13‡ 0.07* Fasting insulin 0.33‡ 0.24‡ 0.18‡ –0.37‡ –0.24‡ –0.18‡ Si Fibrinogen *P<0.05, †P<0.005, ‡P<0.0001 CRP=C-reactive protein; IRS=insulin-resistance syndrome; WBC=white blood cell count. Festa A et al. Circulation 2000;102:42–47. Slide Source LipidsOnline www.lipidsonline.org

e u a V nae M l Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia, Upper Body Adiposity, Insulin Resistance, Hypertension): IRAS 1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0 0 1 2 3 Number of Metabolic Disorders Festa A et al. Circulation 2000;102:42–47. 4 Slide Source LipidsOnline www.lipidsonline.org

Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Proteins: IRAS Quartiles: Incidence, % 25 1st P=0.06 2nd P=0.001 3rd 4th P=0.001 20 15 10 5 0 Fibrinogen Festa A et al. Diabetes 2002;51:1131-1137. CRP PAI-1 Slide Source LipidsOnline www.lipidsonline.org

The Effect of Rosiglitazone on CRP Difference = –21.8 (95% CI: –34.7, –5.6) Change from Baseline to Week 26, % Difference = –26.8 (95% CI: –39.7, –21.8) 0 n=95 n=124 n=134 Rosiglitazone 4 mg/d Rosiglitazone 8 mg/d -10 -20 -30 -40 -50 Placebo Haffner SM et al. Circulation 2002;106:679-684. Slide Source LipidsOnline www.lipidsonline.org

The Effect of Rosiglitazone on IL-6 Difference = 0.0 (95% CI: –9.0, 10.0) Change from Baseline to Week 26, % Difference = –1.9 (95% CI: –11.3, 9.3) 0 n=91 n=120 n=132 Placebo Rosiglitazone 4 mg/d Rosiglitazone 8 mg/d -10 -20 -30 -40 -50 Haffner SM et al. Circulation 2002;106:679-684. Slide Source LipidsOnline www.lipidsonline.org

Reduction of CRP Levels with Statin Therapy (n=22) 6 ** p<0.025 vs. Baseline p<0.025 vs. Baseline 5 * 4 * 3 * ) L/ g m P RC s h ( - 2 1 0 Baseline Pravastatin (40 mg/d) Jialal I et al. Circulation 2001;103:1933-1935. Simvastatin (20 mg/d) Atorvastatin (10 mg/d) Slide Source LipidsOnline www.lipidsonline.org

Summary  Insulin resistance is related to increased PAI-1, fibrinogen, and CRP levels cross-sectionally  Increased levels of PAI-1, CRP, and fibrinogen (weak) predict the development of type 2 diabetes. In some analyses, these associations are independent of obesity and insulin resistance  Rosiglitazone, a TZD, decreases levels of PAI-1, CRP, and MMP-9 Slide Source LipidsOnline www.lipidsonline.org

Does Lipid and Blood Pressure Therapy Work in Subjects with the Metabolic Syndrome?  Diabetic subjects  Blood pressure: YES  Statin therapy: YES  Nondiabetic subjects  Little data available Slide Source LipidsOnline www.lipidsonline.org

CHD Prevention Trials with Statins in Diabetic Subjects: Subgroup Analyses Study Drug No. CHD Risk Reduction Overall CHD Risk Reduction in Diabetics Primary Prevention AFCAPS/TexCAPS Lovastatin 155 37% 43% (NS) Simvastatin 2912 24% 33% (p=.0003) CARE Pravastatin 586 23% 25% (p=.05) 4S Simvastatin 202 32% 55% (p=.002) LIPID Pravastatin 782 25% 19% 4S Reanalysis Simvastatin 483 32% 42% (p=.001) HPS Simvastatin 1981 24% 15% HPS Secondary Prevention Downs JR et al. JAMA 1998;279:1615-1622. | HPS Collaborative Group. Lancet 2003;361:2005-2016. | Goldberg RB et al. Circulation 1998;98:2513-2519. | Pyörälä K et al. Diabetes Care 1997;20:614-620. | LIPID Study Group. N Engl J Med 1998;339:1349Slide Source LipidsOnline 1357. | Haffner SM et al. Arch Intern Med 1999;159:2661-2667. www.lipidsonline.org

Completed Clinical Trials with Antihypertensive Agents in Diabetes Trial Diabetic/Total Results SHEP 583/4736 Beneficial GISSI-3 2790/18,131 Beneficial Syst-Eur 492/4695 Beneficial 1501/18,790 Beneficial UKPDS 1148 Beneficial

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