Treatment of Dyslipidemia in Type 2 Diabetes New Targets New Challenges

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/dL • BP ≥ 130/80 mm Hg • TG ≥ 150 mg/dL • HDL-C: Men <40, F <50 mg/dL Presence of ≥ 3 criteria 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 NonHDL Cholesterol NTG VLDL-C HTG VLDL-C IDL-C IDL-C LDL-C LDL-C 6 Adult Treatment Panel III (2004 Update) 10 Y CHD RIsk LDL-C (mg/dL) Very High Risk* High Risk* Moderately High Risk >20% >20% 10-20% <70 <100 <130 nonHDL-C (mg/dL) <100 (optional) <130 <160 Moderate Risk Lower risk * CHD or CHD risk equivalents <10% <10% <130 <160 <160 <190 Grundy et al. Circulation 2004; 110; 227-39 7 ATP III Lipid and Lipoprotein Classification HDL Cholesterol <40 60 Low High Serum Triglycerides • Normal • Borderline high • High • Very high <150 150–199 200–499 500 8 Management of Dyslipidemia in T2DM • 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 Protein Fat 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 cismonounsaturated fats B A B C B A B Saturated cis-monounsaturated Polyunsaturated Carbohydrate Cholesterol Fiber 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) 14 cis-Monounsaturated vs. Polyunsaturated fats • Both reduce LDL cholesterol equally • High intakes of n-6 polyunsaturated fats may reduce HDL cholesterol 15 Plasma Lipids and Lipoproteins Baseline Total cholesterol (mg/dL) Total triglyceride (mg/dL) Carb 205 ± 7 218 ± 32 Mono 196 ± 9 163 ± 26** 225 ± 10** 285 ± 62 58 ± 12 134 ± 13 32 ± 3 VLDL-cholesterol (mg/dL) LDL-cholesterol (mg/dL) HDL-cholesterol (mg/dL) Total/HDL-cholesterol *p < 0.05 **p < 0.01 ***p < 0.005 43 ± 7 131 ± 8 30 ± 2 7.2 ± 6 28 ± 5*** 134 ± 8 34 ± 2*** 6.0 ± 0.5* 7.4 ± 0.7 Garg et al. N Engl J Med 1988;319; 829-34 16 Metabolic Variables (Day 21 to 28) Carb Plasma glucose (mg/dL) (03, 07, 11, 16, 20 hr q.d.) Insulin requirements (Units/d) Energy intake (Kcal/d) Weight (kg) Mono 101 ± 3* 70 ± 9* 2420 ± 70 86.8 ± 3.9 117 ± 5 81 ± 9 2410 ± 77 86.9 ± 3.7 Glycosylated hemoglobin (%) 7.6 ± 0.8 8.1 ± 0.5 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 (C20:1) Canola Oil contains oleic acid (C18:1) 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) ADA Diet High Fiber Fiber (g) Soluble (g) Insoluble (g) 24 8 16 50 25 25 Chandalia, Garg et al. NEJM 342; 1392-1398, 2000 21 Metabolic Variables ADA Diet Mean plasma glucose (mg/dL) Urinary glucose (g/d) Hemoglobin A1c (%) Mean  SD values. Chandalia, Garg et al. NEJM 342; 1392-1398, 2000 P High Fiber Value Diet 130  38 1.0  1.9 6.9  1.2 0.04 0.008 142  36 2.3  4.3 7.2  1.3 0.09 22 Plasma Lipids and Lipoproteins ADA Diet High Fiber Diet (mg/dL) P Value Plasma Cholesterol Plasma Triglycerides VLDL-Cholesterol LDL-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 0.02 0.01 0.11 0.80 Chandalia, Garg et al. NEJM 342; 1392-1398, 2000 23 Dietary Fiber Foods Rich in Soluble Fiber Fruits: Vegetables: Green peas Okra Sweet potato Winter squash Zucchini Cereal: Beans: Chickpeas Lima beans Navy beans Split peas Apricots Cantaloupe Cherries Grapefruit Orange Papaya Peaches Plums Prunes Raisins Granola Oat Bran Oatmeal 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 CoA Reductase Inhibitors (Statins) Statin Lovastatin Pravastatin Simvastatin Fluvastatin Atorvastatin Rosuvastatin Dose Range 20–80 mg 20–40 mg 20–80 mg 20-80 mg 10–80 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 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 Statin Associated Myopathy (Controlled Studies) Myalgia Lovastatin Placebo 1.7 Statin 3.0 Pravastatin Simvastatin 1.0 1.3 2.7 1.2 Fluvastatin Atorvastatin Cerivastatin 4.5 1.1 2.3 5.0 3.2 2.5 •Thompson PD, et al. JAMA 289;1681-90, 2003 30 FDA Reports of Rhabdomyolysis Drugs Cerivastatin Simvastatin Atorvastatin Pravastatin No. of Reports 1899 612 383 243 Reports of Rhabdomyolysis Due to Drug 56.9% 18.3% 11.5% 7.3% Lovastatin Fluvastatin Total 147 55 3339 4.4% 1.6% 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 32 Cholesterol Biosynthetic Pathway HMG-CoA HMG-CoA Reductase Statins Mevalonate Isopentenyl Pyrophosphate Farnesyl Pyrophosphate Squalene Prenylation Geranylgeranyl Pyrophosphate Prenylation Cholesterol Isoprenylated Proteins Ubiquinone 33 Fibric Acids Drug • Gemfibrozil • Fenofibrate Dose 600 mg BID 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/dL) 37 Bile Acid Sequestrants Drug Cholestyramine Colestipol Colesevelam Dose Range 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 Immediate release (crystalline) Extended release Dose Range 1.5–3 g 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 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 Combination Therapy For LDL reduction: • Statins + Bile Acid Sequestrants • Statins + Ezetimibe For TG and LDL reduction: Fibrates + Statins Statins + Niacin 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 Myopathy with Fibrates 70 OR 10.8 Adverse Events per One Million Prescriptions 60 50 40 30 20 10 0 OR 1.8 Gemfibrozil Fenofibrate Myopathy Rhabdomyolysis •Alsheikh-Ali et al. AM J Cardiol 2004; 94:935-8 Reports of Rhabdomyolysis for Fibrate/ Statin Therapies Medication Fenofibrate With cerivastatin With other statins Fenofibrate total Gemfibrozil 14 2 16 100,000 3,419,000 3,519,000 140 0.58 4.5 46 No. Cases Reported No. Prescriptions Dispensed No. Cases Reported per Million Prescriptions With cerivastatin With other statins Gemfibrozil total 533 57 590 116,000 6,641,000 6,757,000 4,600 8.6 87 •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