Drug Treatment of Hyperlipidemia

1. 0 Drug Treatment of Hyperlipidemia Philip Marcus, MD MPH

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3. 0 Atherosclerotic Cardiovascular Disease and Hypercholesterolemia • 7 Million Americans with symptomatic ASCVD • 1:2 deaths in US attributed to ASCVD • $120 billion spent to treat ASCVD • 1/500 has genetic predisposition leading to premature ASCVD • Heterozygous familial hypercholesterolemia • Lifestyle is contributing factor in remainder • 31% of Americans have borderline to high total cholesterol • 20% of Americans have high total cholesterol

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5. 0 Ischemic Heart Disease: • Plaques of atheroma in coronary arteries • Partially occlude • May rupture exposing subendothelium • Focus for thromboses • Can result in Myocardial Infarction • Prevention of Myocardial Infarction • Reduce progression of atheroma • Produce regression of existing plaques

6. 0 Development of Atheromatous Plaque

7. 0 Ischemic Heart Disease: Atheroma • Coronary Arteries • Myocardial Infarction • Cerebral Arteries • Stroke • Peripheral Arteries • Peripheral Vascular Disease (PVD) • Renal Arteries • Hypertension • Renal failure

8. 0 Atheromatous Disease: Risk Factors • Family History • Hypertension • Cigarette Smoking • Hyperglycemia • Obesity • Physical Inactivity • High serum cholesterol (LDL) • Hyperhomocysteinemia

9. 0 Lipoproteins and ASCVD: • Lipoproteins • Play essential role in transporting lipids between tissues • Lipids insoluble in plasma and therefore require lipoproteins for transport • Composition of Lipoproteins • Central Core • Contains lipid (Triglyceride or cholesterol esters) • Hydrophobic • Hydrophilic Coat • Polar • Contains Phospholipids, Free Cholesterol, Apolipoproteins

10. 0 Lipoprotein Classification: • HDL • LDL • VLDL • Chylomicrons

11. 0 Chylomicrons: • Largest, lightest of particles • Synthesized in intestinal mucosa • Carry Triglyceride of dietary origin • Appear after a fatty meal • Milky plasma • Cleared in 8 to 12 hours • Via lipoprotein lipase • Converts TG to FFA and Glycerol • Heparin and Apo C-II cofactors • Type I Hyperlipoproteinemia • Familial • Lipoprotein Lipase Deficiency • Delayed chylomicron clearance, elevated serum TG • No increase in coronary artery disease

12. 0 Very Low Density Lipoprotein (VLDL) • Smaller and denser particles • Secreted by liver • Synthesized from carbohydrate, fatty acids and others • Principal carrier of endogenous Triglyceride • Major lipid is TG, also contains Cholesterol • Excess VLDL = Elevated TG • Contains Apo B100 • Metabolized by lipoprotein lipase • TG converted to FFA (cell permeable) • Elevated LDL results from increased VLDL secretion or from decrease in LDL catabolism

13. 0 Low Density Lipoprotein (LDL): • Smaller, denser and more soluble • Principal lipid is cholesterol (up to 75%) • ½ to 1/3 of total cholesterol carried by LDL • Low in TG, no turbidity • Derived mainly from VLDL catabolism via IDL • Contains Apo B100 • Allows binding to LDL receptor • LDL particles, on binding to LDL receptors on hepatocytes and peripheral cells, deliver cholesterol for synthesis of cell membranes and steroid hormones

14. 0 Low Density Lipoprotein (LDL): • Some cholesterol, upon presentation to LDL receptors, undergo esterification by fatty acids and are reincorporated into HDL • Half-Life = 2.5 days • Type IIA Hyperlipoproteinemia • Familial hypercholesterolemia • Elevated LDL with normal VLDL levels • Due to block in LDL degradation • Caused by decreased number of LDL receptors • Associated with accelerated coronary artery disease

15. 0 High Density Lipoprotein (HDL): • Smallest, most dense and most soluble • Produced by liver and small intestine in nascent form (HDL3) • Discoidal HDL3 acquires protein from catabolism of TG rich lipoproteins to become mature, spheroidal HDL2 particles • Apo AI major protein component of HDL • Activates lecithin cholesterol acetyltransferase • HDL acts in transport of cholesterol between cells and plasma • Provides mechanism for removing cholesterol from tissue • Inverse relationship between HDL and coronary artery disease • Protective effect via HDL2

16. 0 Major Enzymes in Lipoprotein Metabolism • Lipoprotein Lipase • Located in muscle and adipose tissue • Hydrolyzes chylomicron and VLDL Triglyceride • Lecithin-Cholesterol Acetyltransferase • Found in plasma • Esterifies free cholesterol on HDL surface • Triglyceride Lipase • Located in liver • Hydrolyzes TG within IDL and HDL particles

17. 0 Hyperlipidemias: Primary • Type I • Familial Hyperchylomicronemia • Elevated TG, Mildly elevated CHOL • Treated by LOW FAT diet • Type IIA • Familial Hypercholesterolemia • Elevated CHOL, Normal TG • Elevated LDL • Treatment with low cholesterol and low saturated fat diet. Drug therapy effective.

18. 0 Hyperlipidemias: Primary • Type IIB • Familial combined hyperlipidemia • Similar to IIA, but elevated VLDL also • Elevated CHOL and TG • Caused by overproduction of VLDL by liver • Treatment with low cholesterol and low saturated fat diet. Avoidance of alcohol. Low CHO. • Type III • Familial dysbetalipoproteinemia • Increased levels of IDL • Increased TG and CHOL • Overproduction/underutilization of IDL, abnormal ApoE • Accelerated coronary artery disease • Treatment similar to IIB

19. 0 Hyperlipidemias: Primary • Type IV • Familial hypertriglyceridemia • Marked increase in VLDL, normal LDL • Relatively common • Often associated with hyperuricemia, obesity, diabetes • Accelerated coronary disease noted • Treatment with low CHO diet, weight reduction, avoidance of alcohol • Type V • Familial mixed hypertriglyceridemia • Type I + Type IV • Elevated VLDL + chylomicrons • Low fat and low CHO diet

20. 0 Hyperlipidemia: Secondary • Disease states • Diabetes mellitus • Alcoholism • Nephrotic syndrome • Chronic renal failure • Hypothyroidism • Liver disease • Drugs • Thiazides • Estrogens • b-blockers • Isotretinoin

21. 0 Drugs for Lipids • Lipid-regulating drugs must be taken indefinitely • Plasma lipid levels return to pretreatment levels within 2-3 weeks when stopped • Should NOT be a substitute for lifestyle changes • Diet + Exercise + Lipid-lowering drugs optimal for treatment/prevention

22. 0 Drugs Used in Treatment: Past and Present • Thyroid hormones • Dextrothyroxine • Estrogens • Neomycin • Bile Acid Binding Resins • Ezetimibe • Fibric Acid Derivatives • Niacin • Probucol • HMG-CoA-Reductase inhibitors (statins)

23. 0 Natural “Alternatives”Dietary Supplements • Garlic • Plant Sterols • Benecol® • Also as margarine product • Red Rice Yeast • Contains Lovastatin • FDA attempting to regulate as drug • Niacin

24. 0 Bile Acid Binding Resins: • Cholestyramine, Colestipol, Colesevelam • Anion exchange resins • Large polymeric cations • Insoluble chloride salt • Ion exchange sites are trimethyl-benzyl-ammonium groups • Bind negatively charged bile acids and bile salts in small intestine • Prevents absorption of bile acids and cholesterol • Chloride exchanged for bile acids • Resin itself not absorbed

25. 0 Cholestyramine (Questran®, LoCHOLEST®) Colestipol (Colestid®) Colesevelam (Welchol®)- hydrophilic polymer Resins

26. 0 Bile Acid Binding Resins: • Bile acids normally 95% reabsorbed in jejunum • 10 fold excretion of bile acids noted • Bile acids are metabolites of cholesterol • Lowering bile acids causes hepatocytes to increase conversion of cholesterol to bile acids • Intracellular cholesterol concentration decreases • Activates hepatic uptake of LDL and fall in serum LDL • Increased uptake mediated by up-regulation of cell surface LDL receptors

27. 0 Bile Acid Binding Resins: • Drugs of choice in treating IIA and IIB • For homozygous IIA, no effect since LDL receptors lacking • 20-25% reduction in LDL-C after 2 to 4 weeks • Increase in HDL-C • Toxicity • Unpleasant texture • Nausea, constipation, bloating, flatulence • Need large amount of fluids, high bulk diet • Impaired absorption of fat-soluble vitamins • Useful also in itching associated with partial biliary obstruction

28. 0 Bile Acid Binding Resins: • Drug Interactions • Interfere with intestinal absorption of anionic drugs • Thiazides • Digoxin • Warfarin • Thyroxin • Tetracycline • Drugs to be taken 2 hours before or 4 hours after cholestyramine or colestipol • Large Doses needed • Cholestyramine 8 grams three times daily • Colesevelam 3 tablets (1875 mg) twice a day

29. 0 Ezetimibe (Zetia®) • Localizes and acts at brush border of small intestine • Inhibits absorption of cholesterol • Leads to decrease in delivery of intestinal cholesterol to the liver • Causes reduction of hepatic cholesterol stores and increase in clearance of cholesterol from the blood

30. 0 Ezetimibe (Zetia®) • Mechanism of action is complementary to that of HMG-CoA reductase inhibitors • Results in reductions in: • Total cholesterol • LDL-C (18%) • Apolipoprotein B • Triglycerides • Results in increase in HDL-cholesterol

31. 0 Ezetimibe (Zetia®) • Inhibits intestinal absorption of cholesterol by 54% • No effect on plasma concentrations of Vitamins A, D or E • No impairment of steroid hormone synthesis

32. 0 Ezetimibe (Zetia®) • Well-absorbed orally • Extensively conjugated to pharmacologically active glucuronide • Highly bound to plasma proteins • Metabolized in liver and small bowel via glucuronide conjugation • Biliary and renal excretion

33. 0 Ezetimibe (Zetia®) • Well tolerated • Adverse reactions no different than placebo • Antacids and cholestyramine decrease effect of ezetimibe • 10 mg once daily

34. 0 Fibric Acid Derivatives • Activate the nuclear transcription factor peroxisome proliferator activated receptor alpha (PPAR-alpha) which relates genes that control lipid metabolism • Stimulates lipoprotein lipase • Results in hydrolysis of TG in chylomicrons and VLDL • Accelerates removal of VLDL and chylomicrons • Does not alter secretion of VLDL from liver • Also lower fibrinogen levels

35. 0 Fibric Acid Derivatives

36. 0 Fibric Acid Derivatives • Clofibrate (Atromid-S ®) • First agent used in clinical practice • Caused 22% lowering of TG, 6% lowering of cholesterol • Long-term use associated with complications • Thromboembolic disease • Cholelithiasis and pancreatitis • Increased malignancies • No beneficial effects on progression of heart disease

37. 0 Fibric Acid Derivatives • Gemfibrozil (Lopid ®) • Same mechanism of action • More commonly used • Used in hypertriglyceridemia • Useful in Type III • Adjunct to diet in Type IV • Completely absorbed • Extensively bound to albumin

38. 0 Fibric Acid Derivatives • Gemfibrozil • Adverse effects • GI effects • Myositis syndrome • Elevated CK, AST • Patients with renal disease at greatest risk • Myopathy reported in conjunction with statins • Hepatotoxicity • Elevated transaminase levels • Reversible upon discontinuation • Cholelithiasis • Drug interactions • Competes with highly bound drugs to albumin • Major problem with warfarin (Coumadin ®)

39. 0 Fibric Acid Derivatives • Fenofibrate (Tricor®) • Adjunctive therapy • Adult patients • Elevated serum triglycerides • At risk of pancreatitis • No response to dietary manipulation • Inhibits TG synthesis • Decreases VLDL • Stimulates catabolism of VLDL • Once daily administration

40. 0 Niacin (Nicotinic Acid): • Found to lower cholesterol levels in large doses as early as 1955 • Gram doses rather than mg doses used as vitamin • Niacin, not niacinamide (nicotinamide) • Vitamin B3 • Acts to decrease VLDL and LDL • Lowers cholesterol(10%) and TG (30%) • Maximal effects in 3 to 5 weeks • Raises HDL

41. 0 Niacin (Nicotinic Acid): • Mechanism of Action: • Inhibits lipolysis in adipose tissue • Adipose tissue primary producer of FFA • FFA major precursor for TG synthesis • Decreases esterification of TG in liver • Increases lipoprotein lipase activity • Inhibits VLDL secretion and synthesis in liver • Decreases LDL production • Increases secretion of tPA and lowers fibrinogen • Reverses endothelial cell dysfunction contributing to thrombosis and atherosclerosis • Decreases HDL catabolism • Changes LDL particles from small, dense ones to ones that are large and buoyant

42. 0 Niacin (Nicotinic Acid): • Pharmacokinetics • Orally administered • Rapidly absorbed • Peak levels in under one hour • Converted to nicotinamide • Incorporated into cofactor NAD • Excreted in urine • 88% excreted unchanged • Therapeutic Use • Type IIB and Type IV • Raises HDL (most effective agent) • Used with bile acid resins in Type IIB (heterozygotes)

43. 0 Niacin (Nicotinic Acid): Toxicity • Many untoward effects limit usefulness • Flushing • Cutaneous vasodilatation in almost all • Accompanied by warmth and itching • Tolerance within one to two weeks • Blunted by use of aspirin ½ hour earlier • GI distress • Liver dysfunction • Hyperuricemia • Inhibits tubular secretion of uric acid • Impaired glucose tolerance • Acanthosis appearance associated with insulin resistance

44. 0 Niacin • Immediate release, quickly-absorbed • Extended release, absorbed over 8 hrs • Sustained release, absorbed over 12-24 hours • Combination of extended release niacin and immediate release lovastatin

45. 0 In-vivo Cholesterol Synthesis

46. 0 HMG-CoA-Reductase Inhibitors: • Inhibit first step rate-limiting in sterol (cholesterol) synthesis • Structural analogs of natural substrate • 3-hydroxy-3-methyl-glutaric acid • Block hydroxy-methyl-glutaryl-Coenzyme A reductase • Reduces conversion of HMG-CoA to mevalonic acid • Most compounds are related to compounds occurring naturally in fungi • Lovastatin first agent in class • Inhibit de novo cholesterol synthesis • Deplete intracellular supply of cholesterol • Increase LDL receptors

47. 0 HMG-CoA-Reductase Inhibitors: • Lovastatin (Mevacor®) 1987 • Simvastatin (Zocor®) 1991 • Pravastatin (Pravachol®) 1991 • Fluvastatin (Lescol®) 1993 • Atorvastatin (Lipitor®) 1996 • Cerivastatin (Baycol®) • Withdrawn because of toxicity • Rosuvastatin (Crestor®) 2003

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49. 0 HMG-CoA-Reductase Inhibitors: • Lovastatin and simvastatin are lactones which are hydrolyzed to active drug • Pravastatin, fluvastatin, atorvastatin are active • Agents differ primarily in bioavailability, half-life and metabolism • Highly protein bound (>95%) • Biotransformed in liver • Metabolites mostly active • Excretion mostly through bile and feces (83%)

50. 0 HMG-CoA-Reductase Inhibitors:Adverse Effects • Generally well tolerated; few adverse effects • Patients who don’t tolerate one statin may tolerate another • Hepatic dysfunction • Elevation in transaminase levels • >3x ULN increase occurs in 1-2% • Symptomatic hepatitis rare • Contraindicated in pregnancy