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Approach to the Management of Hypertriglyceridemia

Approach to the Management of Hypertriglyceridemia. Timothy A. Denton, M.D. Attending Cardiologist High Desert Heart Institute Victorville, CA. Outline. Lipids / Triglyceride metabolism Etiology of hypertriglyceridemia Therapy of hypertriglyceridemia Special considerations.

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Approach to the Management of Hypertriglyceridemia

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  1. Approach to theManagement ofHypertriglyceridemia Timothy A. Denton, M.D. Attending Cardiologist High Desert Heart Institute Victorville, CA

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

  3. Can you identify these?

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

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

  6. Egg McMuffin Calories 290 Calories from fat 110 Total fat 12 g Saturated fat 4.5 g Cholesterol 235 mg Sodium 790 mg Carbohydrates 27g Protein 17g http://www.mcdonalds.com/countries/usa/

  7. Chylomycron Production Intestinal Brush Border

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

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

  10. Fatty Acid Cholesterol O C OH HO Cholesterol Ester O C O + H O H

  11. 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

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

  13. PUFA (polyunsaturated fatty acid) Nomenclature 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 O     HO    18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 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

  14. O HO REALLY, REALLY Essential Fatty Acids 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 Linoleic acid (18:2, n-6) O HO -Linolenic acid (18:3, n-3)

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

  16. Lipemia

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

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

  19. LDL and IDL

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

  21. 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

  22. Fredrickson Classification

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

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

  25. Therapy of Hypertriglyceridemia • Underlying cause • Diet • Drugs • Plasmapheresis • Special considerations

  26. Underlying Cause • EtOH • DM • Obesity • HIV drugs

  27. Underlying Cause

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

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

  30. 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)

  31. Diet

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

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

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

  35. Partial Ileal Bypass

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

  37. Drugs • Statins • Niacin • Fibrates • Fish oil

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

  39. Niacin Nicotinic acid Niacin (Vit B3) Nicotinamide (no antilipemic activity) O O HO NH2 N N

  40. Niacin Forms

  41. Niacin Onset of Action

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

  43. Fibrates

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

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

  46. Effect of FenoFibrate on Lipid Levels

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

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

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