Financial Disclosures

Transcription

1 1 Lipids in Type 2 Diabetes July 20, 2013 Abhimanyu Garg, M.D. Professor of Internal Medicine Chief, Division of Nutrition and Metabolic Diseases Distinguished Chair in Human Nutrition Research UT Southwestern Medical Center, Dallas, TX Financial Disclosures Consultant: Aegerion, Pfizer, Bristol-Myers-Squibb Speakers Bureau: Merck Research Grant: Bristol-Myers Squibb, Pfizer

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

3 3 Adult Treatment Panel III Lipid Goals for T2DM 10 Y CHD RIsk LDL-C nonhdl-c (mg/dl) (mg/dl) Very High Risk* >20% <70 <100 (optional) High Risk* >20% <100 <130 * CHD or CHD risk equivalents Grundy et al. Circulation 2004; 110;

4 4 NonHDL Cholesterol NTG VLDL-C IDL-C HTG VLDL-C IDL-C LDL-C LDL-C

5 Peculiar Issues in Treatment of Diabetic Dyslipidemia 5 Hyperglycemia Pattern of dyslipidemia Type 5 with chylomicronemia Wikipedia Type 3 with remnant lipoproteins Diabetic nephropathy: proteinuria, renal insufficiency, dialysis Autonomic neuropathy: constipation

6 6 Goals of Therapy for Diabetic Dyslipidemia Prevent atherosclerotic vascular disease CHD/PVD/CVA/Amputations Prevent acute pancreatitis Resolve xanthomas (cosmetic and discomfort)

7 Stepwise Approach to Dyslipidemia in Diabetes and Metabolic Syndrome 7 Diet, Exercise and weight loss Achieve good glycemic control Lipid lowering drugs

8 8 ADA Dietary Recommendations 2008 Level of Evidence Protein Fat Saturated cis-monounsaturated Polyunsaturated Carbohydrate Cholesterol Fiber 15 20% of total energy < 7% of total energy * * >130 g/day 200 mg/day >14 g/1,000 kcal E A B E

9 9 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

10 10 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)

11 cis-monounsaturated vs. 11 Polyunsaturated fats Both reduce LDL cholesterol equally High intakes of n-6 polyunsaturated fats may reduce HDL cholesterol

12 12 Sources of cis-monounsaturated Fats Mustard oil contains erucic acid (C20:1) Canola Oil contains oleic acid (C18:1)

13 Which macronutrient is more beneficial? Complex Carbohydrates or Cis-monounsaturated fats

14 Diet Composition (%Kcal/d) Protein Carbohydrate Simple Complex Fat Saturated cis-monounsaturated Polyunsaturated Cholesterol (mg) Fiber (g) Mono Carb Garg et al. N Engl J Med 319: , 1988

15 Plasma Lipids and Lipoproteins Baseline Carb Mono Total cholesterol (mg/dl) 225 ± 10 ** 205 ± ± 9 Total triglyceride (mg/dl) 285 ± ± ± 26 ** VLDL-cholesterol (mg/dl) 58 ± ± 7 28 ± 5 *** LDL-cholesterol (mg/dl) 134 ± ± ± 8 HDL-cholesterol (mg/dl) 32 ± 3 30 ± 2 34 ± 2 *** Total/HDL-cholesterol 7.4 ± ± ± 0.5 * *p < 0.05 **p < 0.01 ***p < Garg et al. N Engl J Med 319: , 1988

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 ± ± ± ± 0.8 Mono 101 ± 3* 70 ± 9* 2420 ± ± ± 0.5 Mean ± SEM, *p < 0.05 Garg et al. N Engl J Med 319: , 1988

17 Plasma Glucose Profile Mono Carb 160 mg/dl Clock Time (hours) Garg et al. N Engl J Med 319: , 1988

18 Plasma Triglyceride Profile Mono Carb mg/dl Clock Time (hours) Garg et al. N Engl J Med 319: , 1988

19 High Fiber Diet Study Diet Composition ADA Diet High Fiber Fiber (g) Soluble (g) Insoluble (g) Chandalia, Garg et al. NEJM 342; , 2002

20 Plasma Lipids and Lipoproteins ADA Diet High Fiber Diet P Value Plasma Cholesterol Plasma Triglycerides VLDL-Cholesterol LDL-Cholesterol HDL-Cholesterol mean SD. (mg/dl) Chandalia, Garg et al. NEJM 342; , 2002

21 Effect of High Fiber Diet on Plasma Glucose Plasma Glucose (mg/dl) ADA Diet High Fiber Diet Clock Time (hours) Chandalia, Garg et al. NEJM 342; , 2002

22 Effect of High Fiber Diet on Plasma Insulin Plasma Insulin ( U ml) ADA Diet High Fiber Diet Clock Time (hours) Chandalia, Garg et al. NEJM 342; , 2002

23 Dietary Fiber Foods Rich in Soluble Fiber 23 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 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)

25 25 Sources of Dietary Sterols Cholesterol Meats, sea food, eggs Phytosterols Oils from plants Sitostanol reduces LDL-C by 15%

26 26 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

27 27 Lipid Lowering Drugs Statins Fibrates Bile acid sequestrants Niacin Ezetimibe Combination Therapy

28 28 Statins Drug Lovastatin Pravastatin Simvastatin Atorvastatin Fluvastatin Rosuvastatin Pitavastatin

29 Lovastatin for Dyslipidemia in T2DM 29 LDL Cholesterol Triglycerides VLDL Cholesterol mg/dl 140 mg/dl 300 mg/dl Placebo Lovastatin 0 Placebo Lovastatin 0 Placebo Lovastatin Normotriglyceridemic Borderline Hypertriglyceridemic Garg & Grundy. NEJM 318: 81-86, 1988

30 Results From Statin Trials for 30 Patients With Diabetes

31 Relative Risk Reduction for Primary Prevention of CHD in DM (Major Statin Trials) 31 Study (n) Statin dose ALLHAT-LLT 3,638 Pravastatin 40 mg HPS 5,963 Simvastatin 40 mg ASCOT-LLA 2,532 Atorvastatin 10 mg CARDS 2,838 Atorvastatin 10 mg Favors Statins Favors Placebo Risk Difference Garg A. Lancet 364: 641-2, 2004

32 Statins for all Diabetics? Not so soon. Understudied subjects 32 Type 1 Diabetics Younger Patients < 40 years Premenopausal women T2DM from populations with low risk of CHD Pima Indians, Chinese, Japanese etc. Garg A. Lancet 2004; 364:641-2.

33 Statins for all Diabetics? Not so soon. Subjects with High Risk of Statin Therapy 33 > 75 years of age Chronic renal insufficiency ESRD on dialysis Organ transplantation Extremely hypertriglyceridemic patients on fibrates Garg A. Lancet 2004; 364:641-

34 34 Safety concerns with Statins Myositis Hepatotoxicity Increase risk of DM Cognitive impairment Sleep disturbances

35 35 Fibric Acids Drug Gemfibrozil Fenofibrate Dose 600 mg BID 150 mg QD

36 Gemfibrozil for Severe Hypertriglyceridemia in T2DM Triglycerides 180 VLDL Cholesterol 30 HDL Cholesterol 140 LDL Cholesterol mg/dl 600 mg/dl mg/dl mg/dl Placebo Gemfibrozil Placebo Gemfibrozil Placebo Gemfibrozil Placebo Gemfibrozil Garg & Grundy. Diabetes 38: , 1989

37 VA-HIT Study: Effect of Gemfibrozil on Vascular Events* (5.1 Years) P=.05 P=.009 % % Risk Reduction % Risk Reduction Placebo Gemfibrozil Placebo Gemfibrozil Diabetic (n=627) Nondiabetic (n=1904) *CHD death, nonfatal MI, or stroke. Rubins et al. N Engl J Med. 1999; 341:410.

38 FIELD: Primary Outcome 38

39 ACCORD Lipid Trial 39 5,518 participants ACCORD Study Group, N Engl J Med. 2010;362: randomized to fenofibrate 2753 randomized to placebo

40 40 Comparison of ACCORD subgroup results with those from prior fibrate studies Trial (Drug) Primary Endpoint: Entire Cohort (P-value) Lipid Subgroup Criterion Primary Endpoint: Subgroup HHS (Gemfibrozil) -34% (0.02) TG > 200 mg/dl LDL-C/HDL-C > % (0.005) BIP (Bezafibrate) -7.3% (0.24) TG > 200 mg/dl -39.5% (0.02) FIELD (Fenofibrate) -11% (0.16) TG > 204 mg/dl HDL-C < 42 mg/dl -27% (0.005) ACCORD (Fenofibrate) -8% (0.32) TG > 204 mg/dl HDL-C < 34 mg/dl -31%

41 41 Myopathy with Fibrates 70 OR 10.8 Adverse Events per One Million Prescriptions OR 1.8 Gemfibrozil Fenofibrate 0 Myopathy Rhabdomyolysis Alsheikh-Ali et al. AM J Cardiol 2004; 94:935-8

42 42 New safety concerns with fenofibrate Myositis Cholelithiasis Thromboembolic disease Pancreatitis Increase in serum creatinine Increase in serum homocysteine

43 43 Bile Acid Sequestrants Drug Cholestyramine Colestipol Colesevelam Dose Range 4 16 g 5 20 g g

44 44 Bile Acid Sequestrants for Diabetics Major actions Reduce LDL-C 15 30% Increase TG Improve glycemic control modestly Side effects GI distress/constipation (especially careful if autonomic neuropathy) Decreased absorption of other drugs Contraindications Dysbetalipoproteinemia Raised TG (especially >400 mg/dl)

45 45 Bile Acid Sequestrants Demonstrated Therapeutic Benefits Reduce major coronary events Reduce CHD mortality

46 46 Nicotinic Acid Drug Form Immediate release (crystalline) Extended release Sustained release Dose Range g 1 2 g 1 2 g

47 47 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

48 48 Nicotinic Acid Therapeutic Benefits Reduces major coronary events? Possible reduction in total mortality? AIM-HIGH and HPS2-THRIVE studies negative

49 49 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 Side effects: Myopathy

50 50 Combination Therapy For LDL reduction: Statins + Bile Acid Sequestrants Statins + Ezetimibe For TG and LDL reduction: Fibrates + Statins Statins + Fish oil

51 Statin/Fibrate Combination Therapy Advantages Disadvantages 51 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.

52 52 Lipid Lowering in Diabetic Nephropathy Low saturated fat, low cholesterol diet n-3 polyunsaturated fatty acids Exercise during hemodialysis Bile acid binding resins HMG CoA reductase inhibitors Low dose fibrates If HTG, stop phosphate binding gel

53 Choice of Lipid Lowering Drugs for Dyslipidemia in T2DM 53 Diet & Good Glycemic Control nonhdl-c mg/dl Or LDL-C mg/dl Check Fasting Plasma Triglyceride Levels Normal < 150 mg/dl Borderline-High mg/dl High > 400 mg/dl Statins Bile acid sequestrants Ezetimibe Combination Therapy Statins Fibrates in some Avoid sequestrants if TG 300 mg/dl Fibrates Fish Oil Combination with Statins Avoid nicotinic acid