1. 1 Treatment of Dyslipidemia in Type 2 Diabetes: New Targets, New Challenges Keystone, Colorado August 2005 Abhimanyu Garg, M.D. Professor of Internal Medicine Chief, Division of Nutrition and Metabolic Diseases Endowed Chair in Human Nutrition Research The University of Texas Southwestern Medical Center at Dallas

2. 2 Adult Treatment Panel (ATP) III Diabetes as a CHD Risk Equivalent 10-year risk for CHD  20% High mortality with established CHD –High mortality with acute MI –High mortality post acute MI

3. 3 ATP III (Metabolic Syndrome) Abdominal obesity: Waist Men >40 in, F >35 in Impaired FPG ≥100 <126 mg/dL BP ≥ 130/80 mm Hg TG ≥ 150 mg/dL HDL-C: Men <40, F <50 mg/dL Presence of ≥ 3 criteria

4. 4 New Features of ATP III For patients with triglycerides  200 mg/dL –LDL cholesterol: primary target of therapy –Non-HDL cholesterol: secondary target of therapy Non HDL-C = total cholesterol – HDL cholesterol

5. 5 NonHDL Cholesterol VLDL-C IDL-C LDL-C NTG HTG

6. 6 Adult Treatment Panel III (2004 Update) 10 Y CHD RIsk LDL-CnonHDL-C(mg/dL) Very High Risk*>20%<70<100(optional) High Risk*>20%<100<130 Moderately High Risk 10-20%<130<160 Moderate Risk <10%<130<160 Lower risk <10%<160<190 * CHD or CHD risk equivalents Grundy et al. Circulation 2004; 110; 227-39

7. 7 ATP III Lipid and Lipoprotein Classification HDL Cholesterol <40 Low  60 High Serum Triglycerides Normal <150 Borderline high150–199 High200–499 Very high  500

8. 8 Management of Dyslipidemia in T2DM Diet, Exercise, Weight loss Hypoglycemic Drugs Lipid Lowering Drugs

9. 9 Management of Dyslipidemia Dietary Principle Evidence Based Approach

10. 10 ADA Recommendations 2002 Protein Fat Saturated cis-monounsaturated Polyunsaturated Carbohydrate Cholesterol Fiber 10 – 20% of total energy < 10% of total energy * Up to 10% of total energy *  300 mg/day >25 g/day *Divide 60 – 70% of daily energy between carbohydrates and cis- monounsaturated fats BABCBABBABCBAB Level of Evidence

11. 11 Dietary Fats Saturated –Short, Medium, Long chain Monounsaturated –cis, trans Polyunsaturated –  -3,  -6

12. 12 Saturated Fats Long chain saturates except stearic acid [18:0] raise LDL cholesterol Main sources: Ghee, Butter, Palm Oil Medium chain saturates also raise LDL cholesterol Main sources: Coconut oil

13. 13 Trans-Monounsaturated Fats Trans fatty acids like elaidic acid (18:1 trans) raise LDL cholesterol and lower HDL cholesterol Main sources: Hydrogenated fats –Margarines, Shortenings, Frying oils Butter, milk fat (traces)

14. 14 cis-Monounsaturated vs. Polyunsaturated fats Both reduce LDL cholesterol equally High intakes of n-6 polyunsaturated fats may reduce HDL cholesterol

15. 15 Plasma Lipids and Lipoproteins Total cholesterol (mg/dL) Total triglyceride (mg/dL) VLDL-cholesterol (mg/dL) LDL-cholesterol (mg/dL) HDL-cholesterol (mg/dL) Total/HDL-cholesterol BaselineCarb 225 ± 10 ** 285 ± 62 58 ± 12 134 ± 13 32 ± 3 7.4 ± 0.7 205 ± 7 218 ± 32 43 ± 7 131 ± 8 30 ± 2 7.2 ± 6 196 ± 9 163 ± 26 ** 28 ± 5 *** 134 ± 8 34 ± 2 *** 6.0 ± 0.5 * Mono *p < 0.05 **p < 0.01 ***p < 0.005 Garg et al. N Engl J Med 1988;319; 829-34

16. 16 Metabolic Variables (Day 21 to 28) Plasma glucose (mg/dL) (03, 07, 11, 16, 20 hr q.d.) Insulin requirements (Units/d) Energy intake (Kcal/d) Weight (kg) Glycosylated hemoglobin (%) Carb 117 ± 5 81 ± 9 2410 ± 77 86.9 ± 3.7 7.6 ± 0.8 Mono Mean ± SEM, *p < 0.05 101 ± 3* 70 ± 9* 2420 ± 70 86.8 ± 3.9 8.1 ± 0.5 Garg et al. N Engl J Med 1988;319; 829-34

17. 17 Sources of cis-monounsaturated Fats Mustard oil contains erucic acid (C20:1) Canola Oil contains oleic acid (C18:1)

18. 18 N-3 polyunsaturated Fats N-3 Fatty acids (EPA (20:5)/DHA (22:6) from fish oils) lower triglycerides May raise LDL cholesterol Can adversely affect glycemia Main sources: Fish Sources of  -linolenic acid (18:3): Vegetables, Flaxseed oil (No TG reduction)

19. 19 Alcohol Daily intake: <1 drink/d for women and <2 drinks/d for men To avoid hypoglycemia consume with food Raises TG and blood pressure Contributes to obesity

20. 20 Dietary Fiber Study (Diet Composition) ADA Diet High Fiber Fiber (g) Soluble (g) Insoluble (g) 24 8 16 50 25 Chandalia, Garg et al. NEJM 342; 1392-1398, 2000

21. 21 Metabolic Variables ADA Diet High Fiber Diet P Value Mean  SD values. Mean plasma glucose (mg/dL) 142  36 2.3  4.3 7.2  1.3 130  38 1.0  1.9 6.9  1.2 0.04 0.008 0.09 Urinary glucose (g/d) Hemoglobin A 1c (%) Chandalia, Garg et al. NEJM 342; 1392-1398, 2000

22. 22 Plasma Lipids and Lipoproteins ADA Diet High Fiber Diet Plasma Cholesterol Plasma Triglycerides VLDL-Cholesterol LDL-Cholesterol HDL-Cholesterol 210  33 205  95 40  19 142  29 29  7 0.02 0.01 0.11 0.80 P Value 196  31 184  76 35  16 133  29 28  4 (mg/dL) Mean  SD. Chandalia, Garg et al. NEJM 342; 1392-1398, 2000

23. 23 Dietary Fiber Foods Rich in Soluble Fiber Fruits: Apricots Cantaloupe Cherries Grapefruit Orange Papaya Peaches Plums Prunes Raisins Vegetables: Green peas Okra Sweet potato Winter squash Zucchini Cereal: Granola Oat Bran Oatmeal Beans: Chickpeas Lima beans Navy beans Split peas

24. 24 Sources of Dietary Sterols Cholesterol –Meats, sea food, eggs Phytosterols –Oils from plants –Sitostanol reduces LDL-C by 15%

25. 25 Lipid Lowering Drugs Statins Fibrates Bile acid sequestrants Niacin Ezetimibe Combination Therapy

26. 26 HMG CoA Reductase Inhibitors (Statins) StatinDose Range Lovastatin20–80 mg Pravastatin20–40 mg Simvastatin20–80 mg Fluvastatin20-80 mg Atorvastatin10–80 mg Rosuvastatin10–40 mg

27. 27 Statins Reduce LDL-C 18–55% & TG 7–30% Raise HDL-C 5–15% Major side effects –Myopathy –Increased liver enzymes Contraindications –Absolute: liver disease –Relative: use with certain drugs

28. 28 HMG CoA Reductase Inhibitors (Statins) Demonstrated Therapeutic Benefits Reduce major coronary events Reduce CHD mortality Reduce coronary procedures (PTCA/CABG) Reduce stroke Reduce total mortality

29. 29 Statin Associated Myopathy (Controlled Studies) MyalgiaPlaceboStatin Lovastatin1.73.0 Pravastatin1.02.7 Simvastatin1.31.2 Fluvastatin4.55.0 Atorvastatin1.13.2 Cerivastatin2.32.5 Thompson PD, et al. JAMA 289;1681-90, 2003

30. 30 FDA Reports of Rhabdomyolysis DrugsNo. of Reports Reports of Rhabdomyolysis Due to Drug Cerivastatin189956.9% Simvastatin61218.3% Atorvastatin38311.5% Pravastatin2437.3% Lovastatin1474.4% Fluvastatin551.6% Total3339100% Thompson PD, et al. JAMA 289;1681-90, 2003

31. 31 Concomitant Medications increasing Risk of Statin-associated Myopathy Fibric acid derivatives, especially gemfibrozil Niacin Cyclosporine Azole antifungals Macrolide antibiotics HIV protease inhibitors Nefazodone Verapamil and diltiazem Amiodarone Grapefruit juice, >1 qt/d

32. 32 Cholesterol Biosynthetic Pathway

33. 33 Fibric Acids DrugDose Gemfibrozil600 mg BID Fenofibrate200 mg QD Clofibrate1000 mg BID

34. 34 Fibric Acids Major actions –Lower LDL-C 5–20% (with normal TG) –May raise LDL-C (with high TG) –Lower TG 20–50% –Raise HDL-C 10–20% Side effects: dyspepsia, gallstones, myopathy Contraindications: Severe renal or hepatic disease

35. 35 Fibric acids Demonstrated Therapeutic Benefits Reduce progression of coronary lesions Reduce major coronary events

36. 36 Bile Acid Sequestrants Major actions –Reduce LDL-C 15 – 30% –Raise HDL-C 3 – 5% –May increase TG Side effects –GI distress/constipation –Decreased absorption of other drugs Contraindications –Dysbetalipoproteinemia –Raised TG (especially >400 mg/dL)

37. 37 Bile Acid Sequestrants DrugDose Range Cholestyramine4–16 g Colestipol5–20 g Colesevelam2.6–3.8 g

38. 38 Bile Acid Sequestrants Demonstrated Therapeutic Benefits Reduce major coronary events Reduce CHD mortality

39. 39 Nicotinic Acid Drug FormDose Range Immediate release1.5–3 g (crystalline) Extended release1–2 g Sustained release1–2 g

40. 40 Nicotinic Acid Major actions –Lowers LDL-C 5 – 25% –Lowers TG 20 – 50% –Raises HDL-C 15 – 35% Side effects: flushing, hyperglycemia, hyperuricemia, upper GI distress, hepatotoxicity Contraindications: Diabetes, liver disease, severe gout, peptic ulcer

41. 41 Nicotinic Acid Demonstrated Therapeutic Benefits Reduces major coronary events Possible reduction in total mortality

42. 42 Ezetimibe Reduces cholesterol absorption by inhibiting NPC1L1 receptors in small intestine 10 mg per day can reduce LDL cholesterol by 15-20% More LDL reduction in combination with statins Negligible side effects

43. 43 Combination Therapy For LDL reduction: Statins + Bile Acid Sequestrants Statins + Ezetimibe For TG and LDL reduction: Fibrates + Statins Statins + Niacin

44. 44 Statin/Fibrate Combination Therapy Advantages Disadvantages  LDL-C,  TG,  HDL-C  nonHDL-C  LDL particle size  CHD protection (?)  AEs (myopathy/ rhabdomyolysis)  Cost Lack of proven outcome benefit Modified from Jones PH.

45. 45 Myopathy with Fibrates Alsheikh-Ali et al. AM J Cardiol 2004; 94:935-8 Myopathy Rhabdomyolysis OR 1.8 OR 10.8

46. 46 Reports of Rhabdomyolysis for Fibrate/ Statin Therapies MedicationNo. Cases ReportedNo. Prescriptions Dispensed No. Cases Reported per Million Prescriptions Fenofibrate With cerivastatin14100,000140 With other statins23,419,0000.58 Fenofibrate total163,519,0004.5 Gemfibrozil With cerivastatin533116,0004,600 With other statins576,641,0008.6 Gemfibrozil total5906,757,00087 Jones & Davidson AM J Cardiol 2005; 95:120-2 FDA Adverse Event Report Jan ’98 to Mar ’02 IMS Health & Varispan LLC Report

47. 47 Management of Dyslipidemia in Diabetics (Conclusions) Attempt intensive glycemic control with diet, physical activity and anti-diabetic drugs For patients with NTG or borderline HTG- Statins For patients with HTG- Fibrates Consider statin + fibrate combination for HTG patients unable to achieve goals Consider risk/benefit ratio for individual patient

48. 48 Acknowledgments Scott M. Grundy, M.D. Ph.D. Manisha Chandalia, M.D. Andrea Bonanome, M.D. Beverley Adams-Huet, M.S. Linda Brinkley, M.S. Meredith Millay, B.S. Patient volunteers