Drug Treatment of Hyperlipidemia Drug Treatment of Hyperlipidemia Philip Marcus, MD MPH

Atherosclerotic Cardiovascular Disease and Hypercholesterolemia 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

Ischemic Heart Disease: 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

Development of Atheromatous Plaque Development of Atheromatous Plaque

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

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

Lipoproteins and ASCVD: 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

Lipoprotein Classification: Lipoprotein Classification: HDL LDL VLDL Chylomicrons

Chylomicrons: Largest, lightest of particles 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

Very Low Density Lipoprotein (VLDL) 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

Low Density Lipoprotein (LDL): 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

Low Density Lipoprotein (LDL): 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

High Density Lipoprotein (HDL): 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

Major Enzymes in Lipoprotein Metabolism 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

Hyperlipidemias: Primary 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.

Hyperlipidemias: Primary 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

Hyperlipidemias: Primary 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

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

Drugs for Lipids Lipid-regulating drugs must be taken indefinitely 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

Drugs Used in Treatment: Past and Present 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)

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

Bile Acid Binding Resins: 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

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

Cholestyramine: Bile acid effects

Bile Acid Binding Resins: 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

Bile Acid Binding Resins: 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

Bile Acid Binding Resins: 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

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

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

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

Ezetimibe (Zetia®) Well-absorbed orally 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

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

Fibric Acid Derivatives 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

Fibric Acid Derivatives Fibric Acid Derivatives

Fibric Acid Derivatives 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

Fibric Acid Derivatives 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

Fibric Acid Derivatives 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 ®)

Fibric Acid Derivatives 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

Niacin (Nicotinic Acid): 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

Niacin (Nicotinic Acid): 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

Niacin (Nicotinic Acid): 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)

Niacin (Nicotinic Acid): Toxicity 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

Niacin Immediate release, quickly-absorbed 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

Probucol (Lorelco ®) Lowers LDL, up to 15% Also lowers HDL, up to 30% Mechanism of action: Inhibits oxidation of cholesterol Prevents ingestion of cholesterol by macrophages May slow development of atherosclerosis Effects on cholesterol in 1 to 3 months Lipophilic compound Persists in adipose tissues for months Prolongs cardiac action potential Avoid in long QT interval Avoid Amiodarone, Sotalol, Quinidine, etc Not shown to prevent or retard atherosclerosis Removed from Market

In-vivo Cholesterol Synthesis

HMG-CoA-Reductase Inhibitors: 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

HMG-CoA-Reductase Inhibitors: 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

HMG-CoA-Reductase Inhibitors: 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%)

HMG-CoA-Reductase Inhibitors: Adverse Effects 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

HMG-CoA-Reductase Inhibitors: Adverse Effects Muscle Myalgia and muscle weakness With or without increases in CK Myopathy and rhabdomyolysis (rare) May lead to renal failure; dose related Renal insufficiency predisposing factor Myopathy often caused by drug interactions Concurrent use of CYP3A4 inhibitors increase levels Itraconazole, ketoconazole, erythromycin, clarithromycin, teilithromycin, HIV antivirals Grapefruit juice Cyclosporine Drug interactions Gemfibrozil inhibits metabolism of all statins Inhibits statin glucuronidation Increases risk of rhabdomyolysis Increased anticoagulant effect when used with warfarin

HMG-CoA-Reductase Inhibitors: HMG-CoA-Reductase Inhibitors: See dose related decrease in LDL-cholesterol Occurs within 3 days Peaks at one month 25 to 45% reduction in cholesterol Reduces Apo B Also causes reduction in TG (up to 25%) Raises HDL up to 10% Effective in all Hyperlipoproteinemias Less effective in familial homozygous Type IIA Lack LDL receptors Often combined with other agents to increase effect Administer once daily in the evening

HMG-CoA-Reductase Inhibitors: HMG-CoA-Reductase Inhibitors: Pravastatin and atorvastatin indicated for children Lovastatin indicated for primary prevention of coronary artery disease

Beneficial Effects of Statins: Beneficial Effects of Statins: Angiogenic role Promote formation of new blood vessels Reduction in mortality independent of effect on cholesterol concentration Activates protein kinase Akt Leads to NO production Promotes endothelial cell survival Enhances revascularization of ischemic tissue ? Inhibits cell apoptosis rather than stimulation of vessel growth Nature Med 2000;6:1004-10

Beneficial Effects of Statins: Beneficial Effects of Statins: Individuals of 50 years and older who were prescribed statins had a substantially lowered risk of developing dementia, independent of the presence or absence of untreated hyperlipidemia, or exposure to non statin LLAs. The available data do not distinguish between Alzheimer’s disease and other forms of dementia. Adjusted relative risk for those prescribed statins was 0.29 (0.13-0.63; p=0.002) Nested case-control study (UK) Jick, et al, Lancet 2000; 356: 1627-31

Beneficial Effects of Statins: Beneficial Effects of Statins: Reduction in plasma viscosity Decrease in platelet aggregation and thrombin formation Reduction in inflammation Decrease in CRP Reduction in fractures