1. Lipid disorders in diabetes Dr. S.Martini MGSD, Padova, February 13, 2004

2. Lipid Metabolism

3. Lipoprotein Subclasses

4. LIPID M ETABOLISM IN DIABETES Lancet 350, SI20, 1997

5. Increased Dyslipidemia in Diabetes Decreased Triglycerides VLDL LDL and small dense LDL Apo B HDL Apo A-I

6. LIPID DISORDERS IN DIABETES

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

8. Atherogenic Lipoprotein Profile  HDL-C Small, dense LDL  TG (Austin et al. Circulation 1990) Metabolic Syndrome FCHL Type 2 Diabetes 3 to 6 Increased CAD Risk

9. LDL Atherogenicity Risk of Premature CADLow High LDL particle number Large, buoyant LDL LDL size and density Small, dense LDL Hepatic Lipase

10. LDL Subclass Phenotypes in Diabetes Mellitus Men* Men* Diabetic Nondiabetic Women** Women** Diabetic Nondiabetic ** Selby JV et al. Circulation 1993; 88:381-387. IntB * Feingold KR et al. Arterioscler Thromb 1992; 12:1496-1502. 29 87 54 543 28 47 34 85 21 29 30 9 51 24 36 6 LDL Subclass nA Percent

11. Diabetes and Atherosclerosis LDL Modifications Diabetes and Atherosclerosis LDL Modifications Normal LDL Glycated LDL Small dense LDL Oxidized LDL Monocytes -Macrophages Foam Cells

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

13. Small-dense LDL LDL Endothelium Vessel Lumen Monocyte Macrophage Adhesion Molecules Small dense LDL and Atherosclerotic Plaque Foam Cell Intima ox-LDL Cytokines Cell Proliferation Matrix Degradation Growth Factors Metalloproteinases Ross R. N Engl J Med 1999;340:115-126. MCP-1MCP-1 Unstable plaque

14. LDL LDL Miyazaki A et al. Biochim Biophys Acta 1992;1126:73-80. Endothelium Vessel Lumen Monocyte Modified LDL Macrophage HDL: Antiatherogenic Lipoprotein Intima Foam Cell HDL Promote Cholesterol Efflux HDL Inhibit Oxidation of LDL Adhesion Molecules Cytokines HDL Inhibit Adhesion Molecule Expression

15. Plasma Insulin and Triglycerides predict Ischemic Heart Disease: Quebec Cardiovascular Study Despres JP et al. N Engl J Med 1996;334:952-957. Odds Ratio <12 12-15 >15 F-Insulin (U/ml) 4.6 p=0.005 >150 mg/dl <150 mg/dl Triglycerides 1.0 1.5 5.3 p=0.001 P<0.001 6.7 5.4 P=0.002

16. Plasma Insulin and Apolipoprotein B predict Ischemic Heart Disease: Quebec Cardiovascular Study Despres JP et al. N Engl J Med 1996;334:952-957. Odds Ratio <12 12-15 >15 F-Insulin (U/ml) 3.0 p=0.04 >119 mg/dl <119 mg/dl Apolipoprotein B 1.0 1.5 3.2 p<0.001 11.0 9.7 P<0.001 p=0.04

17. LDL particle size and Apolipoprotein B predict Ischemic Heart Disease: Quebec Cardiovascular Study Lamarche B et al. Circulation 1997;95:69-75. >25.64 <25.64 LDL Peak Particle Diameter (nm) 1.0 6.2 (p<0.001) Apo B >120 mg/dl 2.0 <120 mg/dl

18. Frequency of different Forms of Dyslipidemia in men with Coronary Artery Disease Frequency (%) (Superko, Circulation, 1996) ALP ALP :  TG  HDL-C Small, dense LDL

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

20. Stepwise Selection of Risk Factors* in 2693 White Patients with Type 2 Diabetes with Dependent Variable as Time to First Event: UKPDS Variable LDL Cholesterol HDL Cholesterol Hemoglobin A 1c Systolic Blood Pressure Smoking p Value <0.0001 0.0001 0.0022 0.0065 0.056 Coronary Artery Disease (n=280) Position in Model First Second Third Fourth Fifth *Adjusted for age and sex. Turner RC et al. BMJ 1998;316:823-828.

22. CVD PREDICTORS IN TYPE 2 DIABETES THE STRONG HEART STUDY Diabetes Care 26, 16, 2003

23. Abdominal obesity  TG +  HDL-C Glucose intolerance Hypertension Atherosclerosis Insulin Resistance and Hyperinsulinemia: Clinical Clues

24. The metabolic syndrome (ATPIII) Presence of 3 of the following risk factors: Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497. >102 cm >88 cm Abdominal Obesity (waist circumference) males females 110 mg/dL Fasting glucose 130/85 mm Hg Blood pressure <40 mg/dL <50 mg/dL HDL-C males females 150 mg/dL Triglycerides Cutoff LevelRisk Factor

25. 36%186202Simva 4S 25%150782Prava LIPID* Primary prevention 25%150155 LovaAFCAPS/TexCAPS Secondary prevention 127 136 127 baseline LDL-C, mg/dl Simva Prava Simvadrug HPS CARE HPSStudy 30%1978 28%586 30%3985  LDL-C  LDL-CNo. Trials of CHD prevention with Statins in Diabetics: subgroup Analysis Downs JR et al. JAMA 1998;279:1615-1622. | HPS Investigators. Lancet 2002| Goldberg RB et al. Circulation 1998;98:2513-2519. | Pyorala K et al. Diabetes Care 1997;20:614-620. | Haffner SM et al. Arch Intern Med 1999;159:2661- 2667. | LIPID Study Group. N Engl J Med 1998;339:1349-1357.

26. 42% (p=.001)32%483Simva4S Reanalysis 55% (p=.002)32%202Simva4S 19%25%782PravaLIPID Primary prevention 43% (NS)37%155LovaAFCAPS/TexCAPS Secondary prevention 24% 23% 24% Overall CHD red. Simva Prava Simvadrug HPS CARE HPSStudy 24%1978 25% (p=.05)586 26% (p<.00001)3985 CHD red. (diabetics) CHD red. (diabetics)No. Trials of CHD prevention with Statins in Diabetics: subgroup Analysis Downs JR et al. JAMA 1998;279:1615-1622. | HPS Investigators. Lancet 2002. | Goldberg RB et al. Circulation 1998;98:2513-2519. | Pyorala K et al. Diabetes Care 1997;20:614-620. | LIPID Study Group. N Engl J Med 1998;339:1349- 1357. | Haffner SM et al. Arch Intern Med 1999;159:2661-2667.

27. 1.0 0.9 0.8 0.7 0.6 0.5 0 Proportion without Major CHD Event Years Since Randomization 0123456 Pyörälä et al. Diabetes Care 1997;20:614-620. Diabetes by Hx, simvastatin Diabetes by Hx, placebo No diabetes by Hx, simvastatin No diabetes by Hx, placebo P=0.002 P=0.0001 Major Coronary Events in 4S Patients with or without Diabetes by History (n=202)

28. 1.0 0.9 0.8 0.7 0.6 0 20 40 60 <110 mg/dl Simva (n=1606) <110 mg/dl Pbo (n=1631) 110-125 mg/dl Simva (n=343) 110-125 mg/dl Pbo (n=335) DM + >126mg/dl Simva (n=251) DM + >126mg/dl Pbo (n=232) Patients Months Haffner et al, Diabetes 1998;47 (Suppl 1):A54. EXPANDED 4S DIABETES ANALYSIS Major coronary events

29. Adapted from Haffner SM et al. Arch Intern Med 1999;159:2661-2667 4S: Extended Diabetic Subgroup Analysis: Diabetes (n=483; 251 on Simvastatin) — Fasting Glucose >126 mg/dl 0.0 0.20.4 0.8 1.4 Relative Risk CHD mortality (P=0.26) Total mortality (P=0.34) Revascularizations (P=0.005) Major coronary events (P=0.001) 0.61.01.2 0.72 0.79 0.52 0.58

30. Adapted from Haffner SM et al. Arch Intern Med 1999;159:2661-2667 4S: Extended Diabetic Subgroup Analysis: Impaired Fasting Glucose (n=678; 343 on Simvastatin) — Fasting Glucose 110-125 mg/dl 0.0 0.2 0.4 0.8 1.4 Relative Risk CHD mortality (P=0.007) Total mortality (P=0.02) Revascularizations (P=0.01) Major coronary events (P=0.003) 0.61.01.2 0.45 0.57 0.62

31. Heart Protection Study: Vascular Events by Baseline Disease 215182CVD 427332PVD 12551007Previous MI 2606 (25.4%) 2042 (19.9%) All patients 369279Diabetes No prior CHD 1234914Other CHD Placebo n=10,267 Simva n=10,269Baseline feature Collins R. Lancet 2002 Risk ratio and 95% CI Statin better Statin worse  24 ± 2.6% (2P <0.00001) 0.40.60.81.01.21.4

32. Lancet 361, 2005, 2003 HEART PROTECTION STUDY

33. CARE: Major Coronary Events in Diabetic Subgroups Goldberg RB et al. Circulation 1998;98:2513-2519. 45 40 35 30 25 20 15 10 5 0 Percent with Event No Diabetes by History Diabetes by History Follow-up Time (years) Percent with Event Follow-up Time (years) 01234650123465 Placebo Pravastatin Placebo Relative risk = 0.75 P=0.05 Relative risk = 0.77 P<0.001 45 40 35 30 25 20 15 10 5 0

34. Coronary heart disease in patients with low LDL- cholesterol: benefit of pravastatin in diabetics and enhanced role for HDL-cholesterol and triglycerides as risk factors Coronary heart disease in patients with low LDL- cholesterol: benefit of pravastatin in diabetics and enhanced role for HDL-cholesterol and triglycerides as risk factors Circulation 2002 Mar 26;105(12):1424-8 Combined analysis CARE and LIPID studies(PPP study) Combined analysis CARE and LIPID studies(PPP study) 13173 patients 13173 patients 2607 with LDL-C < 125 mg/dl 2607 with LDL-C < 125 mg/dl 270 diabetics with LDL-C < 125 mg/dl 270 diabetics with LDL-C < 125 mg/dl

35. 418 627 135No. 23% NS 6%130Fenofibrate (200 mg/d) DAIS Primary prevention 68% NS 6%203Gemfibrozil (1200 mg/d) Helsinki Heart Study Secondary prev. –  LDL- C Gemfibrozil (1200 mg/d)drug(dose) VA-HIT Study 24% P=.05 112*CHDreduction LDL-C baseline mg/dl CHD Prevention Trials with Fibrates in Diabetic Subjects: Subgroup Analyses Koskinen P et al. Diabetes Care 1992;15:820-825. | Rubins HB et al. N Engl J Med 1999;341:410-418. | DAIS Investigators. Lancet 2001;357:905-910.

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

37. Year Cumulative Incidence (%) VA-HIT: Incidence of Death from CHD and Nonfatal MI Placebo Rubins HB et al. N Engl J Med 1999;341:410-418. Gemfibrozil

38. VA-HIT SUB-GROUP ANALYSIS Arch Intern Med 162, 2597, 2002

39. CHD Risk Equivalent Patients with established CHD have a risk for recurrent MI and CHD death that exceeds 20% per 10 years. Clinically evident noncoronary atherosclerosis, as well as type 2 diabetes mellitus, impose an approximately equal risk for developing CHD in patients without clinical CHD. CHD risk equivalents: – Multiple risk factors (>20% 10-year CHD risk) – Type 2 diabetes mellitus – Peripheral arterial disease – Abdominal aortic aneurysm – Carotid artery disease Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.

40. Diabetes as a CHD Risk Equivalent Implies that enhanced benefit will be achieved from aggressive LDL-lowering therapy Post-hoc analysis of all statin trials showed a trend for benefit of LDL lowering in persons with diabetes

41. LDL Cholesterol Goals and Cutpoints (mg/dl) for Therapy in Different Risk Categories  190 (160–189: LDL- lowering drug optional)  160 <160 0–1 Risk Factor 10-year risk 10– 20%:  130 10-year risk <10%:  160  130 <130 2+ Risk Factors (10-year risk  20%)  130 (100–129: drug optional)  100 <100 CHD or CHD Risk Equivalents (10-year risk >20%) LDL Level at Which to Consider Drug Therapy LDL Level at Which to Initiate Therapeutic Lifestyle Changes LDL Goal Risk Category

42. Non-HDL-C Goals in Patients with TG  200 mg/dL <1900–1 risk factor <160 2+ risk factors (10-yr risk  20%) <130 CHD or CHD risk equivalents (10-yr risk >20%) Non-HDL-C goal (mg/dL) Risk category Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.

43. ATP III: Management of Diabetic Dyslipidemia Primary target of therapy: LDL-C Diabetes: CHD risk equivalent Therefore, goal for persons with diabetes: <100 mg/dL Therapeutic options: – LDL-C 100–129 mg/dL: increase intensity of TLC; add drug to modify atherogenic dyslipidemia (fibrate or nicotinic acid); intensify statin therapy – LDL-C  130 mg/dL: simultaneously initiate TLC and LDL- C–lowering drugs After LDL-C goal is met, if TG  200 mg/dL: non–HDL-C (<130 mg/dl) becomes secondary target ATP III. JAMA 2001;285:2486-2497.

44. Clinical Management of Metabolic Syndrome Management of underlying causes – Weight control enhances LDL lowering and reduces all risk factors – Physical activity reduces VLDL and LDL and increases HDL Treat lipid and nonlipid risk factors – Hypertension – Aspirin in CHD patients – Elevated triglycerides – Low HDL Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.

45. Treatment Strategies for Diabetic Dyslipidemia Primary Strategy - Lower LDL cholesterol Secondary Strategy - Raise HDL cholesterol - Lower triglycerides Other Approaches - Non-HDL cholesterol - ApoB - Remnants 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; European Diabetes Policy Group 1999. Diabet Med. 1999;16:716-730.

46. LDL cholesterol lowering* LDL cholesterol lowering* - First choice: HMG CoA reductase inhibitor (statin) - Second choice: Bile acid binding resin or fenofibrate HDL cholesterol raising HDL cholesterol raising - Behavioral 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 Triglyceride lowering - Glycemic control first priority - Fibric acid derivatives (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. Order of Priorities for Treatment of Diabetic Dyslipidemia in Adults* American Diabetes Association. Diabetes Care 2000;23(suppl 1):S57-S60.

47. Diabetes Care 26, suppl 1, 2003

49. European Task Force 2003 : definition of high risk Subjects with established cardiovascular disease (CHD, PAD, CVD) Asymptomatic subjects who have: a) multiple risk factors resulting in a 10 year risk of fatal cardiovascular events  5% (now or extrapolated to age 60) b) markedly raised levels of single risk factors: CT  320, LDL-C  240, blood pressure  180/110 c) diabetes type II and diabetes type I with microalbuminuria

50. European Task Force 2003 : goals of treatment in type 2 diabetes HbA 1c < 6.1% Fasting/pre-prandial venous plasma glucose < 110 mg/dl Self-monitored blood glucose : Fasting/pre-prandial 70-90 mg/dl; post-prandial 70-135 mg/dl blood pressure < 130/80 total cholesterol < 175 mg/dl LDL cholesterol < 100 mg/dl