1. Diabetic Dyslipidemia

2. HypertensionObesity Hyper- insulinemia Diabetes Hypertri- glyceridemia Small, dense LDL Low HDL Hypercoagu- lability Atherosclerosis Insulin Resistance Interrelation Between Atherosclerosis and Insulin Resistance

3. SHEEP: Risk Factors for Nonfatal MI in Men and Women SHEEP=Stockholm Heart Epidemiology Program. Reuterwall C et al. J Intern Med. 1999;246:161-174. Risk Factor Diabetes High TC (  6.5 mmol/L) High TG (  6.3 mmol/L) HTN (  170/95 mm Hg) Overweight (BMI  30 kg/m²) WHR (  0.85) Physical inactivity Smoking Job strain Men Women 012345678 Odds Ratio

4. National Diabetes Data Group. Diabetes in America. 2nd ed. NIH;1995. Atherosclerosis in Diabetes ~80% of all diabetic mortality –75% from coronary atherosclerosis –25% from cerebral or peripheral vascular disease >75% of all hospitalizations for diabetic complications >50% of patients with newly diagnosed type 2 diabetes have CHD

5. Haffner SM et al. N Engl J Med. 1998;339:229-234. 012345678 0 20 40 60 80 100 Nondiabetic subjects without prior MI (n=1,304) Diabetic subjects without prior MI (n=890) Nondiabetic subjects with prior MI (n=69) Diabetic subjects with prior MI (n=169) Survival (%) Year Risk Similar in Patients With Type 2 Diabetes and No Prior MI vs Nondiabetic Subjects With Prior MI

6. Kannel WB. Am Heart J. 1985;110:1100-1107. Abbott RD et al. JAMA. 1988;260:3456-3460. Women, Diabetes, and CHD Diabetic women are at high risk for CHD Diabetes eliminates relative cardioprotective effect of being premenopausal –risk of recurrent MI in diabetic women is three times that of nondiabetic women Age-adjusted mean time to recurrent MI or fatal CHD event is 5.1 yr for diabetic women vs 8.1 yr for nondiabetic women

7. Framingham Heart Study 30-Year Follow-Up: CVD Events in Patients With Diabetes (Ages 35-64) 10 9 20 11 9638 19 3* 30 0 2 4 6 8 10 Age-adjusted annual rate/1,000 MenWomen Total CVDCHDCardiac failure Intermittent claudication Stroke Risk ratio P<0.001 for all values except *P<0.05. Wilson PWF, Kannel WB. In: Hyperglycemia, Diabetes and Vascular Disease. Ruderman N et al, eds. Oxford; 1992.

8. SMC=smooth muscle cell. Adapted from Bierman EL. Arterioscler Thromb. 1992;12:647-656. Potential Mechanisms of Atherogenesis in Diabetes Abnormalities in apoprotein and lipoprotein particle distribution Glycosylation and advanced glycation of proteins in plasma and arterial wall “Glycoxidation” and oxidation Procoagulant state Insulin resistance and hyperinsulinemia Hormone-, growth-factor–, and cytokine-enhanced SMC proliferation and foam cell formation

9. 14 9 26 11 12 13 9 21* 34* 19* 0 10 20 30 40 50 Men without diabetes Men with diabetes TC  260 TG  235 VLDL-C  40 LDL-C  190 HDL-C  31 Prevalence (%) *P<0.05. LRC approximate 90th percentile age- and sex-matched values, except for HDL-C (10th percentile). Adapted from Garg A, Grundy SM. Diabetes Care. 1990;13:153-169. Abnormal Lipid Levels in Men With Type 2 Diabetes

10. 21 8 31 16 10 24 38 15 25* 17* 0 10 20 30 40 50 Women without diabetes Women with diabetes TC  275 TG  200 VLDL-C  35 LDL-C  190 HDL-C  41 Prevalence (%) *P<0.05. LRC approximate 90th percentile age- and sex-matched values, except for HDL-C (10th percentile). Adapted from Garg A, Grundy SM. Diabetes Care. 1990;13:153-169. Abnormal Lipid Levels in Women With Type 2 Diabetes

11. The Strong Heart Study: Differences in CVD Risk Factors by Diabetic Status in Men and Women* *Adjusted for age and center. Adapted from Howard BV et al.Diabetes Care. 1998;21:1258-1265. -4.4 -3.7 -7.5 -5.3 -8 -7 -6 -5 -4 -3 -2 0 Men Women HDL-C (mg/dL) LDL Size (Å) Difference between subjects with and without diabetes

12. AB Intermediate pattern 0 2 4 6 8 10 12 Glucose (mmol/L) Adapted from Reaven GM et al. J Clin Invest. 1993;92:141-146. Steady-state plasma glucose n=19 n=17 n=19 Association of Small, Dense LDL With Insulin Resistance

13. 0 1 2 3 CHD mortality (per 1,000) Fontbonne AM et al. Diabetes Care. 1991;14:461-469.  2930-5051-7273-114  115 Quintiles (pmol) of fasting plasma insulin P<0.01 CHD Mortality and Hyperinsulinemia: Paris Prospective Study (n=943)

14. 0 10 20 30 40 50 60 12345 % Macrovascular disease P<0.001 0 10 20 30 40 50 60 70 80 12345 % Macrovascular disease P<0.05 0 10 20 30 40 50 60 12345 % CHD P<0.002 0 10 20 30 40 50 60 70 80 12345 % CHD Nondiabetic controls (n=178) Noninsulin-treated type 2 diabetics (n=154) Fasting C-peptide quintiles (1-5) Janka HU. Horm Metab Res. 1985;15(suppl):15-19. Prevalence of Macrovascular Disease and CHD According to Quintiles of Fasting C-Peptide

15. Glucose (mmol/L) Time (min) Reaven GM et al. J Clin Invest. 1993;92:141-146. Insulin (pmol/L) 0 2 4 6 8 10 3060120180 Plasma glucose LDL diameter average Pattern A: 268±4 (n=52) Intermediate: 261±3 (n=29) Pattern B: 250±4(n=19) 0 200 400 600 800 1000 3060120180 Insulin Responses to a 75-g Oral Glucose Challenge in Relation to LDL Particle Diameter

16. 7.4 3.3 10.5 3.4 0 5 10 15 Type 2 (n=135) Others (n=3,946) Type 2 on placebo (n=76) Type 2 on gemfibrozil (n=59) 5-Yr incidence of CHD (%) *Myocardial infarction or cardiac death. NS=not significant. Koskinen P et al. Diabetes Care. 1992;15:820-825. P<0.02 P=NS Primary CHD* Prevention in Patients With Type 2 Diabetes: The Helsinki Heart Study

17. UKPDS: Intensive Blood-Glucose vs Conventional Treatment in Patients With Type 2 Diabetes RR=relative risk. PVD=peripheral vascular disease. UKPDS Group.Lancet. 1998;352:837-853. Any diabetes-related end point0.88 (0.79–0.99)0.029 Diabetes-related deaths0.90 (0.73–1.11)0.34 All-cause mortality0.94 (0.80–1.10)0.44 MI0.84 (0.71–1.00)0.052 Stroke1.11 (0.81–1.51)0.52 Amputation or death from PVD0.65 (0.36–1.18)0.15 Microvascular disease0.75 (0.60–0.93)0.0099 Favors Log-rank RR (95% CI)intensiveconventional P value Clinical End Point 0.1110

18. Any diabetes-related end point0.76 (0.62–0.92)0.0046 Diabetes-related deaths0.68 (0.49–0.94)0.019 All-cause mortality0.82 (0.63–1.08)0.17 MI0.79 (0.59–1.07)0.13 Stroke0.56 (0.35–0.89)0.013 Peripheral vascular disease0.51 (0.19–1.37)0.17 Microvascular disease0.63 (0.44–0.89)0.0092 UKPDS: Tight Blood Pressure Control vs Less Tight Control in Patients With Type 2 Diabetes RR=relative risk. UKPDS Group.BMJ. 1998;317:703-713. RR forFavors tight controltightless tight P (95% CI)control value Clinical End Point 10.110

19. Secondary Prevention: CHD Risk Reduction in the 4S Subgroup of Patients With Diabetes Pyörälä K et al. Diabetes Care. 1997;20:614-620. Total mortality232167 2415 CHD mortality17299 1712 Major CHD event578407 4424 Any CHD event871667 5641 CABG or PTCA363238 2015 Cerebrovascular event9070 125 Any atherosclerotic event961750 6146 Nondiabetic Diabetic PSPS 00.20.40.60.81.01.21.4 RR with 95% CIs No. patientsSimvastatinPlacebo with eventsbetterbetter

20. 0.60 0.70 0.80 0.90 1.00 4S: Total Mortality Reduction in a Subgroup of Patients With Diabetes Pyörälä K et al. Diabetes Care. 1997;20:614-620. Proportion alive Yr since randomization - P=0.08 - P=0.001 Diabetic, simvastatin Diabetic, placebo Nondiabetic, simvastatin Nondiabetic, placebo 29% 43%

21. 4S:Major CHD Event Reduction in a Subgroup of Patients With Diabetes Pyörälä K et al. Diabetes Care. 1997;20:614-620. Proportion without major CHD event Yr since randomization - P=0.002 - P=0.0001 Diabetic, simvastatin Diabetic, placebo Nondiabetic, simvastatin Nondiabetic, placebo 32% 55%

22. 4S: Treatment Benefit in Subgroup With Impaired Fasting Glucose (FG 110-125 mg/dL) Haffner SM et al. Diabetes. 1998;(suppl 1):A54. Abstract. Total mortality Coronary mortality Major coronary events Revas- culari- zations  in events (%) P=0.005 P=0.001 P=0.010

23. CARE: Reduction of Coronary Events in Patients With Diabetes N=4,159 males and females; 976 diabetics. Goldberg R et al. Circulation. 1996;94:I-540. Abstract. 0 5 10 15 20 25 30 35 40 012345 % with event Yr 27% 22% - P=0.001 Diabetic, pravastatin Diabetic, placebo Nondiabetic, pravastatin Nondiabetic, placebo - P=0.012 6

24. Post-CABG: Effect of Aggressive Lipid Lowering on a Subgroup of Patients With Diabetes Substantial progression Per patient % of grafts27.043.30.4927.839.00.60 (0.20-1.19) (0.46-0.79) Number of grafts1221041,2381,214 Occlusion Per patient % of grafts11.519.20.5410.416.00.61 (0.15-2.02) (0.41-0.92) Number of grafts1221041,2381,214 Therapy DiabetesNo Diabetes Hoogwerf BJ et al. Diabetes. 1999;48:1289-1294. RR RR AggressiveModerate (99% CI)AggressiveModerate(99% CI)

25. DAIS: Impact of Aggressive Therapy on Atherosclerosis in Patients With Type 2 Diabetes Study population N=418 (305 men, 113 women) Type 2 diabetes  1 minimal lesion on angiography Mild elevations of LDL-C or TG + TC:HDL-C  4 Treatment 8 weeks on Step I diet Randomized, blinded to micronized fenofibrate (200 mg/d) and placebo Primary end point Progression or regression of CAD on quantitative angiography DAIS=Diabetes Atherosclerosis Intervention Study. Steiner G et al. Am J Cardiol. 1999;84:1004-1010.

26. mg/dL * Significant difference between genders. Steiner G et al. Am J Cardiol. 1999;84:1004-1010. DAIS: Mean Baseline Lipoprotein Levels P=0.0005* P=0.0001* P=NS

27. Mean %  *P=0.0001. Steiner G. Diabetes. 1999;48(suppl 1):A2. Abstract 0005. DAIS: Interim Lipid Results in Patients With Type 2 Diabetes

28. *Researchers report that results suggest benefit to patients. Steiner G. XIIth International Symposium on Atherosclerosis; June 27, 2000; Stockholm, Sweden. DAIS: Final Results in Patients With Type 2 Diabetes CAD Treatment with fenofibrate resulted in 40% reduction in rate of progression of localized CAD versus placebo 23% reduction in combined coronary events following fenofibrate treatment (P=NS*) Lipids Average reductions with fenofibrate: TC, 10%; LDL-C, 6%; TG, 29%; average increase in HDL-C, 6% Safety Very few serious adverse events; no significant differences in tolerability between fenofibrate and placebo treatments; 95% compliance

29. ADA-Suggested Standards for Biochemical Indices of Metabolic Control Biochemical indexAcceptableBorderline*High Fasting plasma glucose (mg/dL) 200 Postprandial (2 hr) plasma glucose (mg/dL) 235 Hemoglobin A 1c (%) † (Goal: 7>10 Fasting plasma TC (mg/dL)<200200-239  240 Fasting plasma TG (mg/dL)<200200-399  400 Fasting plasma LDL-C (mg/dL)<100100-129  130 (  100 if CAD) Fasting plasma HDL-C (mg/dL) >4535-45<35 * Current ADA recommendations call for therapeutic action for values above “borderline.” † Adjust for normal lab values. Adapted from Garber AJ et al. Diabetes Care. 1992;15:1068-1074; ADA. Diabetes Care. 1993;16:828-834; and ADA. Diabetes Care. 1998;21(suppl 1):S36-S39.

30. Glycemic Control for People With Diabetes DiabeticAction Biochemical indexNondiabeticgoalsuggested Preprandial glucose (mg/dL) 126 Bedtime glucose (mg/dL) 160 Hemoglobin A 1c (%) 8 These values are for nonpregnant individuals. “Action suggested” depends on individual patient circumstances. Hemoglobin A 1c is referenced to a nondiabetic range of 4.0-6.0% (mean 5.0%, standard deviation 0.5%). ADA. Diabetes Care. 1996;19(suppl 1):S8-S15.

31. 1999 ADA Risk Stratification Based on Lipoprotein Levels in Adults With Diabetes* ADA. Diabetes Care. 1999;22:S56-S59. RiskLDL-CHDL-CTG High  130<35  400 Borderline100-12935-45200-399 Low 45<200 *Values represent mg/dL. For women, HDL-C should be increased by 10 mg/dL.

32. 1999 ADA Recommendations Based on LDL-C Levels in Adults With Diabetes* ADA. Diabetes Care. 1999;22:S56-S59. InitiationLDL-CInitiationLDL-C Statuslevelgoallevelgoal With CHD, PVD or CVD>100  100>100  100 Without CHD, PVD, and CVD>100  100  130 †  100 *Values represent mg/dL. † Some authorities recommend drug initiation between 100 and 130 mg/dL. Medical nutrition txDrug tx

33. Order of Priorities for Treatment of Diabetic Dyslipidemia in Adults LDL-C lowering –first choice: HMG-CoA reductase inhibitors (statins) –second choice: bile acid binding resin or fenofibrate HDL-C raising –behavioral interventions (weight loss,  physical activity, smoking cessation) –glycemic control –difficult (except with niacin, which is relatively contraindicated, or fibrates) TG lowering –glycemic control first priority –fibric acid derivative (gemfibrozil, fenofibrate) –statins (moderately effective at high dose in patients with  TG and  LDL-C) ADA. Diabetes Care. 1999;22:S56-S59.

34. Order of Priorities for Treatment of Diabetic Dyslipidemia in Adults Combined hyperlipidemia –first choice: improved glycemic control plus high-dose statin –second choice: improved glycemic control plus statin plus fibric acid derivative (gemfibrozil or fenofibrate) –third choice: improved glycemic control plus resin plus fibric acid derivative or improved glycemic control plus statin plus niacin (glycemic control must be monitored carefully) ADA. Diabetes Care. 1999;22:S56-S59.

35. *Without vascular disease. † With vascular disease. Approach to Patients With Diabetes and Hyperlipidemia Acceptable LDL-C <100 TG <200 Monitor annually Improvement Hypercholesterolemia Goal LDL-C <130* LDL-C <100 † HMG-CoA Resin Hypertriglyceridemia Goal TG <400* TG <200 † Fibrate HMG-CoA if LDL  Mixed Dyslipidemia Goal TG <400 LDL-C <130* TG <200LDL-C <100 † HDL-C >35 HMG-CoA Fibrate + resin Hyperchylomicronemia TG  1000 Fibrate and fat restriction (<10% of calories) Measure (fasting): TC, TG, HDL-C, LDL-C (calculated), glucose, HbA 1c Higher risk: LDL-C  130, TG  400, HDL-C <35 Lower risk: LDL-C 45 Regulate diabetes: weight loss, exercise, restrict dietary saturated fat and cholesterol No improvement

36. Continuum of Patients at Risk for a CHD Event Post MI/Angina Other Atherosclerotic Manifestations Subclinical Atherosclerosis Multiple Risk Factors Low Risk Secondary Prevention Primary Prevention Courtesy of CD Furberg.

37. CV Health Discontinued Tx Intolerance to Tx Inappropriate TxNo Tx Under-recognition Aggressive Tx Drug Tx NCEP ATP-II Diet/Exercise Awareness Dead End Progress Road Complacency Way The Solution? It’s Our Choice CHD #1 Killer