Simeon Margolis, MD, PhD

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1 Simeon Margolis, MD, PhD Decisions on when to lower LDL cholesterol are based on a combination of risk status and the LDL cholesterol Cigarette smoking Hypertension HDL cholesterol <40 mg/ml Age (men > 45, women >55) Family history of premature coronary artery disease Male 1 st degree relative <55 Female 1 st degree relative <65 HDL cholesterol >60 is a negative risk factor Coronary heart disease Peripheral arterial disease Abdominal aortic aneurysm Symptomatic carotid artery disease Diabetes mellitus Multiple risk factors that confer > 20% risk of a coronary event in the next 10 years Risk category LDL-ch goal Zero to one risk factor <160 Two or more risk factors <130 High risk <100 (CHD or CHD equivalents) Very high risk (CHD+) <70 1

2 Lipoprotein Major component CHD risk VLDL Triglycerides Increased LDL Cholesterol Increased Lower total and LDL cholesterol Lower triglycerides Raise HDL cholesterol HDL Protein Decreased Proper diet Weight loss Exercise <10% of energy intake from saturated fat <7% of energy intake if LDL needs to be lowered Dietary cholesterol intake <300 mg/day <200 mg/d if LDL needs to be lowered Increase soluble fiber and plant stanol/sterol esters Unsaturated fat: unsaturated ~10% of energy intake monounsaturated preferred eat fish at least 2 times a week if coronary disease known, take fish oil supplements Minimize intake of trans fatty acids WEIGHT LOSS Supplements of omega-3 fatty acids Patients with triglycerides > 500 mg/dl need fat restriction and medications. 2

3 Weight loss Exercise Moderate alcohol intake Patients fail to comply with diet. Diet doesn t lower lipids enough. Drug Statins Bile acid sequestrants Ezetimibe Niacin Fibrates Mechanism Inhibit cholesterol synthesis Inhibit bile acid reabsorption Inhibits cholesterol absorption Inhibits VLDL synthesis Speed conversion of VLDL to LDL Statins - first choice Add-on drugs to achieve LDL-Ch, TG, or HDL-Ch goals Major use: Lower LDL cholesterol Lipid/lipoprotein effects: Lower LDL-Ch up to 60% Raise HDL-Ch 8 to 10% Lower triglycerides 10 to 30% Contraindications: Active liver disease Rosuvastatin Pitavastatin Atorvastatin Simvastatin* Pravastatin* = lovastatin* Fluvastatin * Indicates off-patent 3

4 Muscle pain Ask about muscle pain and weakness Myositis : symptoms + elevated CK Rhabdomyolysis and renal failure Permanent liver damage never reported Stop statin and measure CK If CK < 1000, restart same stain when muscle pain is no longer present If muscle pain recurs, Try different statins Low dose or less frequent dose Baseline LFT s only Follow-up LFTs not needed CP if muscle pain or weakness Fibrates especially gemfibrozil Macrolide antibiotics Erythromycin Clarithromycin Rifampin Azole antifungals Calcium channel blockers Amiodarone Cyclosporin Failure to start drug at hospital discharge Poor patient compliance Failure of physicians to monitor compliance Inadequate dose of medication Blocks absorption of dietary and biliary cholesterol Lowers LDL cholesterol by about 15% Useful in combination with statin (Vytorin) Few side effects 4

5 Major use: Lower LDL-ch Lipid/lipoprotein effects: Lower LDL-ch 10 to 25% Raise HDL-ch 1 to 3% Triglycerides: increase or no change Contraindications: Elevated triglycerides Major adverse effects: Gastrointestinal symptoms, decreased absorption of some drugs, elevated liver transaminases Cholestyramine (Questran) Colestipol (Colestid) Colesevelam (WelChol) Increase triglycerides Absolute contraindication TGs > 400 mg/dl Relative contraindication TG mg/dl Decreased absorption of anionic drugs and vitamins Not a problem with colesevelam Bloating, constipation, even bowel obstruction Taurine 500 mg may decrease constipation Classification Normal Borderline high High Very high Serum Level <150 mg/dl mg/dl mg/dl >500 mg/dl Goal: Prevent pancreatitis Very low fat diet (<15% of calories) TG-lowering drug usually required Reduce TG before lowering LDL-Ch 5

6 Primary target: lower LDL cholesterol Secondary target: Non-HDL cholesterol Achieve LDL goal with statins before treating non-hdl cholesterol Non-HDL-Ch = Total Ch HDL-Ch Non-HDL-Ch includes atherogenic VLDL and chylomicron remnants Non HDL-Ch goal = LDL-Ch goal + 30 mg/dl May predict CHD risk better than LDL-Ch By 20 to 50% Fibrates: gemfibrozil, fenofibrate Niacin Omega-3 fish oil Over-the counter Prescription By 7 to 25% Statins Lower triglycerides 20 to 50% Lower non-hdl-ch 12 to 18% Raise HDL-Ch 8 to 10% Lower total Ch 8 to 12 % But May raise LDL-Ch Use with caution: Gemfibrozil with statin, renal insufficiency Major adverse effects: GI symptoms, elevated liver transaminases, myositis with statins Dyspepsia Gallstones Elevated LFTs Venous thrombosis and pulmonary emboli Prothrombin time raised with warfarin Rx Reduce warfarin dose Lower dose in patients with impaired renal function Avoid gemfibrozil with statins Epidemiologic studies have shown that elevated triglycerides and low HDL-Ch are independent risk factors for coronary heart disease. BUT little proof that lowering triglycerides or raising HDL-Ch reduces CHD events 6

7 Two studies have shown a significant reduction in coronary events with gemfibrozil treatment. Helsinki Heart Study VA/HIT Study Niacin is most effective Fibrates and statins raise HDL cholesterol by about 8% to 10% Estrogens after the menopause Lower LDL-Ch 10 to 25% Raise HDL-Ch 15 to 35% Lower triglycerides 20 to 50% Flushing, itching, redness Liver toxicity Dyspepsia, nausea, vomiting Increased uric acid levels and gout Slight rise in fasting glucose and HbA1c Liver disease History of peptic ulcer or GI bleed Gout Start with low niacin dose Less flushing with extended-release niacin Flushing worsened with hot beverages, spicy foods, alcohol, hot showers Aspirin or other NSAIDs 30 to 60 min before niacin dose Flushing diminishes over time with consistent dosing 7

8 Immediate release - crystalline niacin Sustained (Slow) release Extended release (Niaspan) Immediate release no cases with < 3 g Extended release 2 g 0/223 subjects Sustained releases 1.5 to 3g 12/223 Reports of severe liver toxicity DON T use sustained release Drug Cholesterol Triglycerides HDL-CH Bile acid sequestrants -or - Niacin Statins Fibrates Ezetimibe - - 8

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