1. Approach to the Management of Hypertriglyceridemia Timothy A. Denton, M.D. Attending Cardiologist High Desert Heart Institute Victorville, CA

4. Outline Lipids / Triglyceride metabolism Etiology of hypertriglyceridemia Therapy of hypertriglyceridemia Special considerations

5. Can you identify these?

6. VLDL B100 CI CII CIII E IDL B100 E LDL B100 Chylomicrons B100 CI CII CIII E AI AII AIV B48 Remnants B48 E HDL2 AI AII AI AII HDL3 HDL1 AI AII

7. VLDL Chylomicrons Remnants HDL2 IDL LDL HDL1 HDL3 50-90 A 90-120 A 120-180 A 180-280 A 250-350 A 300-800 A 800-5000 A >300 A

8. Egg McMuffin Calories290 Calories from fat110 Total fat12 g Saturated fat4.5 g Cholesterol235 mg Sodium790 mg Carbohydrates27g Protein17g http://www.mcdonalds.com/countries/usa/

9. Chylomycron Production Intestinal Brush Border

10. Triglyceride Concentration over Time Ng et al. Arterio Thromb Vasc Biol 1995;15:2157-2164

11. C = 8 - 24 Fatty Acids Lipids HO O Triglycerides O O O O O O Phospholipids O O O O O P G O O

12. HO Cholesterol O Cholesterol Ester Fatty Acid OHC O + H O H C O

13. Fatty Acids Number of carbons are multiples of 2 (from Acetyl-CoA) Length of FA Short chain = 2-6 carbons Medium chain = 8-14 carbons Long chain = 16 + Saturated FA contain no double bonds Monounsaturated FA contain 1 double bond Polyunsaturated FA (PUFA) contain 2 or more double bonds Many, many other types of FA

14. Fatty Acids C H H C H H C H C H C H H C H H cis trans C H H C H H C H CC H H C H H H C H H C H H C H H C H H C H H C Cis is GOOD C H H C H H C H C C H H C H H H Trans is BAD

15. PUFA (polyunsaturated fatty acid) Nomenclature 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Common name -  -Linoleic acid Systematic name - all cis-9,12-octadecadienoic acid Systematic name - cis-9, cis-12-octadecadienoic acid Chemist’s name - 18:2 (9Z, 12Z) (Z=cis, E=trans) Chemist’s name - 18:2  9,12 (assume cis, indicate trans) Nutritionist’s name #1 - 18:2 (n-6) Nutritionist’s name #2 - 18:2  -6 HO O 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1       

16. REALLY, REALLY Essential Fatty Acids HO O Linoleic acid (18:2, n-6) HO O  -Linolenic acid (18:3, n-3) Corn oil Cotton seed oil Linseed oil (flax) Rapeseed (canola) oil Soya oil Walnut oil, walnuts Peanuts Beef Spinach Fish oils eicosa docosa Sardines, Salmon, Mackerel, Cod, Halibut, Herring, Trout, Tuna, Haddock

17. Lipid Metabolism Gut LIPOPROTEIN LIPASE Fatty acids Chylomicron remnant Liver Chylomicron VLDL IDL LDL What you make What you eat 1,000 mg/day 300 mg/day Bile

18. Lipemia

19. Apo B-48 Chylomicron Metabolism Apo A-1 Apo C-II Apo A-IV Gut Apo E Apo C-III LIPOPROTEIN LIPASE Fatty acids Apo A-1, A-IV Apo C-II, C-III Chylomicron remnant = cholesterol = triglyceride = phospholipid Liver = cholesterol ester

20. Fatty Acid Transport Triglyceride-rich lipoprotein Lipoprotein lipase Apo C-II Fatty acids Triglyceride synthesis lipase Triglyceride storage Energy FATTY ACID-ALBUMIN COMPLEXES Liver Adipose tissue Muscle Fatty acids

21. LDL and IDL

22. Metabolism of VLDL Apo B-100 Apo E Nascent VLDL Mature VLDL VLDL Remnant LDL Liver LIPOPROTEIN LIPASE HDL Cholesterol esters Apo E Apo C-II,C-III Phospholipids Fatty acids HDL Apo C-II, C-III Apo C-III Apo C-II Fibrates

23. Etiology Genetic Familial dysbetalipoproteinemia Familial combined hyperlipoproteinemia Familial hypertriglyceridemia (unknown) LPL deficiency / inhibition Apo C-II deficiency (LPL activator) Apo E defects / Apo E-2 Acquired Diet Alcohol Uremia Pregnancy Drug use Hypothyroidism

24. Fredrickson Classification

25. LDL Cholesterol Goals and Cutpoints for Therapeutic Lifestyle Changes (TLC) and Drug Therapy in Different Risk Categories  190 (160–189: LDL- lowering drug optional)  160 <160 0–1 Risk Factor 10-year risk 10–20%:  130 10-year risk <10%:  160  130 <130 2+ Risk Factors (10-year risk  20%)  130 (100–129: drug optional)  100 <100 CHD or CHD Risk Equivalents (10-year risk >20%) LDL Level at Which to Consider Drug Therapy (mg/dL) LDL Level at Which to Initiate Therapeutic Lifestyle Changes (TLC) (mg/dL) LDL Goal (mg/dL) Risk Category

26. Approach to the treatment of Hypertriglyceridemia Elevated TG’s >200 mg/dl “Abdominal” TG’s >500-1000 mg/dl

27. Therapy of Hypertriglyceridemia Underlying cause Diet Drugs Plasmapheresis Special considerations

28. Underlying Cause EtOH DM Obesity HIV drugs

29. Underlying Cause

30. Central Obesity Contributes to Insulin Resistance Abdominal fat: high rate of FA turnover high rate of lipolysis

31. Classic Diabetic Lipid Pattern Low HDL High LDL High TG’s

32. HIV Drugs HIV itself Protease inhibitors Unclear etiology High TG’s (800-3000 mg/dl) Low HDL (as low as 1 mg/dl) High LDL (300-800 mg/dl)

33. Diet

34. Ornish D, et al. Lancet 1990;336:129 Lifestyle Heart Trial

35. Ornish D, et al. Lancet 1990;336:129 Lifestyle Heart Trial

36. Dietary Goals NOT total fat reduction Total fat 10-20%

37. Partial Ileal Bypass

38. POSCH -- Program On Surgical Control of Hyperlipidemias Arch Int Med 1998;158:1253

39. Drugs Statins Niacin Fibrates Fish oil

40. Statins Jones et al. Am J Cardiol2003;92:152 Prava Simva Atorv Rosuva

41. Niacin Nicotinic acid Niacin (Vit B 3 ) N O HO N O NH 2 Nicotinamide (no antilipemic activity)

42. Niacin Forms

43. Niacin Onset of Action

44. Apo B Pathway Apo B-100 Apo E Nascent VLDL Mature VLDL VLDL Remnant LDL Liver LIPOPROTEIN LIPASE HDL Cholesterol esters Apo E Apo C-II,C-III Phospholipids Fatty acids HDL Apo C-II, C-III Apo C-III Apo C-II Niacin

45. Fibrates

46. Effect of Fibrates on Lipid Levels VA-HIT NEJM 1999;341:410 Increased Lipoprotein lipase activity Increased liver uptake of FA, decreased TG production Increased LDL affinity for receptor Lower exchange between LDL and VLDL Increased HDL production PPARs

47. Effect of Fibrates on Lipid Levels VA-HIT NEJM 1999;341:410

48. Effect of FenoFibrate on Lipid Levels

49. LDL Profile of Fenofibrate Caslake; Arterioscler Thromb 1993:13;702-11 % Change TCLDL-C LDL Receptor Uptake Large Buoyant LDL Small Dense LDL

50. BIP Bezafibrate Infarction Prevention Study Circulation 2000;102:21-27

51. Diabetes Atherosclerosis Intervention Study DAIS 1. DM II, with and without coronary intervention 2. Randomized, prospective fenofibrate vs placebo 3. 418 randomized 4. Follow-up - 39.6 months 5. End-points minimum lumen diameter mean segment diameter mean % stenosis

52. Diabetes Atherosclerosis Intervention Study DAIS P=0.02 P=0.03 P=0.17

53. Fenofibrate Adverse Events  Generally well tolerated  Most frequent discontinuation - rash (6% vs 2%)  Other events: pruritis, constipation, diarrhea  G.I. Upset 2% ( less than placebo)  LFTs elevations 6.3% vs 2.1% for placebo  Increased warfarin levels (monitor INR)

54. PPARs are the CENTER of the UNIVERSE Peroxisome Proliferator Activated Receptor PPARα -- Fibrates PPARγ -- Thiazolidinediones

55. PPARα Stimulation: 1.Reduces production of Apo CIII (inhibitor of lipolysis) 2.Activates Lipoprotein Lipase 3.Fall in TG levels 4.Switch from small dense to large “fluffy” LDL 5.Increases synthesis of Apo AI and AII

56. Fish Oil n-3 PUFA’s Epidemiologic data on survival GISSI-Prevenzione Effects on Triglycerides

57. Fish Oil 9 patients 6 weeks 1 g/d N-3 PUFA 1 U tocopherol/d 6 weeks 5 g/d fish oil Slower VLDL and LDL oxidation Hau et al. Arterio Thromb Vasc Biol 1996;16:1197

58. Fish Oil vs Gemfibrozil Gemfibrozil 1,200 mg/d Fish oil 4g/day Stalenhoef et al Atherosclerosis 2000;153:129

59. n-3 PUFA’s and SCD Albert et al NEJM 2002;346:1113

60. GISSI-Prevenzione GISSI group, Lancet 1999;354:447

61. Mediterranian Diet J. THOMSON "Chart of the Mediterranean Sea" Edin.18I7

62. Lyon Heart Trial De Lorgeril et al Circulation 1999;99:779 First MI Randomized Mediterranian vs Prudent 5 year trial stopped early <35% energy as fat <10% energy saturated fat <4% energy as linoleic acid >0.6% of energy as alpha-linolenic (18:3 or n-3) Eat more bread Eat more fish, less meat Eat more vegetables Must have fruit every day All butter and margarine replaced with olive oil and canola oil

63. Lyon Heart Trial De Lorgeril et al Circulation 1999;99:779 Survival with: No MI Survival with: No MI Angina CHF CVA PE Periph embol Survival with: No MI Angina CHF CVA PE Periph embol Stable angina PTCA, CABG Restenosis

64. Lyon Heart Trial De Lorgeril et al Circulation 1999;99:779 Differences in LDL-C

65. Plasmapheresis Apheresis = Pheresis = Hemapheresis Apheresis -- (Latin, Greek -- aphairesis) to take out, take away, snatch, detach, separation,or abstract.

66. Combination Therapy Statin + niacin Statin + fibrate Statin + ezetimibe Statin + resin When in doubt, drop the statin to 20% of maximum dose, Add second drug Titrate up while watching symptoms and LFT’s

67. Combination Therapy 2. The dose of simvastatin should not exceed 10 mg daily in patients receiving concomitant medication with gemfibrozil. The combined use of simvastatin with gemfibrozil should be avoided, unless the benefits are likely to outweigh the increased risks of this drug combination. Caution should be used when prescribing other lipid-lowering drugs (other fibrates or lipid-lowering doses (1 g/day) of niacin) with simvastatin, as these agents can cause myopathy when given alone. The benefit of further alterations in lipid levels by the combined use of simvastatin with fibrates or niacin should be carefully weighed against the potential risks of these combinations. Addition of fibrates or niacin to simvastatin typically provides little additional reduction in LDL-C, but further reductions of TG and further increases in HDL-C may be obtained. Zocor Package Insert

68. Combination Therapy Crestor Package Insert Fenofibrate: Coadministration of fenofibrate (67 mg three times daily) with rosuvastatin (10 mg) resulted in no significant changes in plasma concentrations of rosuvastatin or fenofibrate (see PRECAUTIONS, Drug Interactions, and WARNINGS, Myopathy/Rhabdomyolysis). Gemfibrozil: Coadministration of gemfibrozil (600 mg twice daily for 7 days) with rosuvastatin (80 mg) resulted in a 90% and 120% increase for AUC and Cmax of rosuvastatin, respectively. This increase is considered to be clinically significant (see PRECAUTIONS, Drug Interactions, WARNINGS, Myopathy/Rhabdomyolysis, DOSAGE AND ADMINISTRATION).

69. Special Considerations

70. Central Obesity Contributes to Insulin Resistance Abdominal fat: high rate of FA turnover high rate of lipolysis

71. Diabetes and Lipids Elevated LDL Elevated TG’s Low HDL

72. LDL Sizing Ultracentrifugation NMR Gel elecrophoresis

73. A B

74. Diabetes Atherosclerosis Intervention Study DAIS 1. DM II, with and without coronary intervention 2. Randomized, prospective fenofibrate vs placebo 3. 418 randomized 4. Follow-up - 39.6 months 5. End-points minimum lumen diameter mean segment diameter mean % stenosis

75. Diabetes Atherosclerosis Intervention Study DAIS * = P < 0.001 ** = P < 0.05 Change in Percentage Diameter Stenosis

76. Effect of Exercise on Lipids Kokkinos Arch Int Med 1995:155:415  2906 men  age 30-64 years  exercise treadmill test to exhaustion  classified into 6 groups based on average miles run per week

77. Effect of Exercise on Lipids Kokkinos Arch Int Med 1995:155:415

78. Trans-Fatty Acids Lichtenstein NEJM 1999;340:1933

79. Trans-Fatty Acids Lichtenstein NEJM 1999;340:1933

80. Summary Elevated TG’s are a risk factor atherosclerosis pancreatitis Treat underlying cause Use fibrates early Use in combination carefully

81. End

82. Hypertriglyceridemia Familial chylomicronemia deficiency or inhibitor of LPL or activator Apo C-II eruptive xanthomas, abdominal pain diet Rx -- short-chain fatty acids Dysbetaliproproteinemia homozygous for Apo E-2 high IDL -- chylo and VLDL remnants accumulate diet therapy Familial endogenous hypertriglyceridemia Familial combined hyperlipidemia

83. Diet

84. Digestion