1 Treatment of Dyslipidemia in Type 2 Diabetes

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

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

5 Non. HDL Cholesterol NTG VLDL-C IDL-C HTG VLDL-C IDL-C LDL-C

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

7 ATP III Lipid and Lipoprotein Classification HDL Cholesterol Serum Triglycerides <40 Low • Normal <150 60 High • Borderline high 150– 199 • High 200– 499 • Very high 500

8 Management of Dyslipidemia in T 2 DM • Diet, Exercise, Weight loss • Hypoglycemic Drugs • Lipid Lowering Drugs

9 Management of Dyslipidemia Dietary Principle Evidence Based Approach

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

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

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 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)

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

15 Plasma Lipids and Lipoproteins Baseline Carb Mono Total cholesterol (mg/d. L) 225 ± 10** 205 ± 7 196 ± 9 Total triglyceride (mg/d. L) 285 ± 62 218 ± 32 163 ± 26** VLDL-cholesterol (mg/d. L) 58 ± 12 43 ± 7 28 ± 5*** LDL-cholesterol (mg/d. L) 134 ± 13 131 ± 8 HDL-cholesterol (mg/d. L) 32 ± 3 30 ± 2 34 ± 2*** Total/HDL-cholesterol 7. 4 ± 0. 7 7. 2 ± 6 6. 0 ± 0. 5* 134 ± 8 *p < 0. 05 **p < 0. 01 ***p < 0. 005 Garg et al. N Engl J Med 1988; 319; 829 -34

16 Metabolic Variables (Day 21 to 28) Plasma glucose (mg/d. L) (03, 07, 11, 16, 20 hr q. d. ) Insulin requirements (Units/d) Carb Mono 117 ± 5 101 ± 3* 81 ± 9 70 ± 9* Energy intake (Kcal/d) 2410 ± 77 2420 ± 70 Weight (kg) 86. 9 ± 3. 7 86. 8 ± 3. 9 7. 6 ± 0. 8 8. 1 ± 0. 5 Glycosylated hemoglobin (%) Mean ± SEM, *p < 0. 05 Garg et al. N Engl J Med 1988; 319; 829 -34

17 Sources of cis-monounsaturated Fats Mustard oil contains erucic acid (C 20: 1) Canola Oil contains oleic acid (C 18: 1)

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

21 Metabolic Variables ADA Diet P High Fiber Value Diet Mean plasma glucose 142 36 (mg/d. L) 130 38 0. 04 Urinary glucose (g/d) 2. 3 4. 3 1. 0 1. 9 0. 008 Hemoglobin A 1 c (%) 7. 2 1. 3 6. 9 1. 2 0. 09 Mean SD values. Chandalia, Garg et al. NEJM 342; 1392 -1398, 2000

22 Plasma Lipids and Lipoproteins ADA Diet High Fiber Diet P Value (mg/d. L) Plasma Cholesterol Plasma Triglycerides VLDL-Cholesterol HDL-Cholesterol Mean SD. 210 33 205 95 40 19 142 29 29 7 196 31 184 76 35 16 133 29 28 4 0. 02 0. 01 0. 11 0. 80 Chandalia, Garg et al. NEJM 342; 1392 -1398, 2000

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

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

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

26 HMG Co. A Reductase Inhibitors (Statins) Statin Dose Range Lovastatin Pravastatin Simvastatin Fluvastatin Atorvastatin Rosuvastatin 20– 80 mg 20– 40 mg 20– 80 mg 20 -80 mg 10– 40 mg

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

29 Statin Associated Myopathy (Controlled Studies) Myalgia Placebo Statin Lovastatin 1. 7 3. 0 Pravastatin 1. 0 2. 7 Simvastatin 1. 3 1. 2 Fluvastatin 4. 5 5. 0 Atorvastatin 1. 1 3. 2 Cerivastatin 2. 3 2. 5 • Thompson PD, et al. JAMA 289; 1681 -90, 2003

30 FDA Reports of Rhabdomyolysis Drugs No. of Reports Cerivastatin 1899 Reports of Rhabdomyolysis Due to Drug 56. 9% Simvastatin 612 18. 3% Atorvastatin 383 11. 5% Pravastatin 243 7. 3% Lovastatin 147 4. 4% Fluvastatin 55 1. 6% Total 3339 100% • Thompson PD, et al. JAMA 289; 1681 -90, 2003

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

Cholesterol Biosynthetic Pathway 32

33 Fibric Acids Drug Dose • Gemfibrozil 600 mg BID • Fenofibrate 200 mg QD • Clofibrate 1000 mg BID

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

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/d. L)

37 Bile Acid Sequestrants Drug Dose Range Cholestyramine Colestipol Colesevelam 4– 16 g 5– 20 g 2. 6– 3. 8 g

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

39 Nicotinic Acid Drug Form. Dose Range Immediate release (crystalline) 1. 5– 3 g Extended release 1– 2 g Sustained release 1– 2 g

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

42 Ezetimibe • Reduces cholesterol absorption by inhibiting NPC 1 L 1 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 Combination Therapy For LDL reduction: • Statins + Bile Acid Sequestrants • Statins + Ezetimibe For TG and LDL reduction: Fibrates + Statins + Niacin

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

45 Myopathy with Fibrates OR 10. 8 OR 1. 8 Myopathy Rhabdomyolysis • Alsheikh-Ali et al. AM J Cardiol 2004; 94: 935 -8

Reports of Rhabdomyolysis for Fibrate/ Statin Therapies 46 No. Cases Reported No. Prescriptions Dispensed No. Cases Reported per Million Prescriptions With cerivastatin 14 100, 000 140 With other statins 2 3, 419, 000 0. 58 Fenofibrate total 16 3, 519, 000 4. 5 With cerivastatin 533 116, 000 4, 600 With other statins 57 6, 641, 000 8. 6 Gemfibrozil total 590 6, 757, 000 87 Medication Fenofibrate Gemfibrozil • Jones & Davidson AM J Cardiol 2005; 95: 120 -2 • FDA Adverse Event Report Jan ’ 98 to Mar ’ 02 • IMS Health & Varispan LLC Report

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 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