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Treatment of Dyslipidemia in Type 2 Diabetes: New Targets, New Challenges

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

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Treatment of Dyslipidemia in Type 2 Diabetes: New Targets, New Challenges

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  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) IIIDiabetes 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 HTG NTG VLDL-C VLDL-C IDL-C LDL-C IDL-C LDL-C

  6. Adult Treatment Panel III (2004 Update) 10 Y CHD RIsk LDL-CnonHDL-C (mg/dL) (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. ATP III Lipid and Lipoprotein Classification HDL Cholesterol <40 Low 60 High Serum Triglycerides • Normal <150 • Borderline high 150–199 • High 200–499 • Very high 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 10 – 20% of total energy < 10% of total energy * Up to 10% of total energy * £ 300 mg/day >25 g/day B A B C B A B Protein Fat Saturated cis-monounsaturated Polyunsaturated Carbohydrate Cholesterol Fiber *Divide 60 – 70% of daily energy between carbohydrates and cis-monounsaturated 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)

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

  15. Plasma Lipids and Lipoproteins Mono Baseline Carb Total cholesterol (mg/dL) Total triglyceride (mg/dL) VLDL-cholesterol (mg/dL) LDL-cholesterol (mg/dL) HDL-cholesterol (mg/dL) Total/HDL-cholesterol 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* 225 ± 10** 285 ± 62 58 ± 12 134 ± 13 32 ± 3 7.4 ± 0.7 *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) Mono Carb Plasma glucose (mg/dL) (03, 07, 11, 16, 20 hr q.d.) Insulin requirements (Units/d) Energy intake (Kcal/d) Weight (kg) Glycosylated hemoglobin (%) 117 ± 5 81 ± 9 2410 ± 77 86.9 ± 3.7 7.6 ± 0.8 101 ± 3* 70 ± 9* 2420 ± 70 86.8 ± 3.9 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 P Value High Fiber Diet Mean plasma glucose (mg/dL) 130  38 142  36 0.04 Urinary glucose (g/d) 2.3  4.3 1.0  1.9 0.008 Hemoglobin A1c (%) 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/dL) Plasma Cholesterol Plasma Triglycerides VLDL-Cholesterol LDL-Cholesterol HDL-Cholesterol 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 Mean  SD. Chandalia, Garg et al. NEJM 342; 1392-1398, 2000

  23. Dietary FiberFoods Rich in Soluble Fiber Fruits: Apricots Cantaloupe Cherries Grapefruit Orange Papaya Peaches Plums Prunes Raisins Beans: Chickpeas Lima beans Navy beans Split peas Vegetables: Green peas Okra Sweet potato Winter squash Zucchini Cereal: 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 Dose Range Lovastatin 20–80 mg Pravastatin 20–40 mg Simvastatin 20–80 mg Fluvastatin 20-80 mg Atorvastatin 10–80 mg Rosuvastatin 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) •Thompson PD, et al. JAMA 289;1681-90, 2003

  30. FDA Reports of Rhabdomyolysis •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

  33. Fibric Acids DrugDose • 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/dL)

  37. Bile Acid Sequestrants DrugDose Range Cholestyramine 4–16 g Colestipol 5–20 g Colesevelam 2.6–3.8 g

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

  39. Nicotinic Acid Drug FormDose Range Immediate release 1.5–3 g(crystalline) 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 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 TherapyAdvantages 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 OR 10.8 OR 1.8 Myopathy Rhabdomyolysis •Alsheikh-Ali et al. AM J Cardiol 2004; 94:935-8

  46. Reports of Rhabdomyolysis for Fibrate/ Statin Therapies •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

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