Copyright © 2005, Duke Internal Medicine Residency Curriculum and DHTS Technology Education Services Duke Internal Medicine Residency Curriculum The Management of Hyperlipidemia Author: Laura Leigh Fitzpatrick MD, MPH Editor: Amy Shaheen, MD, Assistant Professor of Clinical Medicine Duke University Medical Center

Copyright © 2005, Duke Internal Medicine Residency Curriculum and DHTS Technology Education Services Duke Internal Medicine Residency Curriculum The NCEP/ ATP III guidelines Assigns levels of risk based on the Framingham score. Sets goals for LDL-c lowering based on level of risk.

Copyright © 2005, Duke Internal Medicine Residency Curriculum and DHTS Technology Education Services Duke Internal Medicine Residency Curriculum Classification of hyperlipidemia

Copyright © 2005, Duke Internal Medicine Residency Curriculum and DHTS Technology Education Services Duke Internal Medicine Residency Curriculum Identify the patient’s risk Identify history of CHD, or “CHD equivalent” –Diabetes mellitus –Peripheral arterial disease –Abdominal aortic aneurysm –Symptomatic carotid artery disease –Multiple RF’s conferring > 20% Framingham risk over 10 years.

Copyright © 2005, Duke Internal Medicine Residency Curriculum and DHTS Technology Education Services Duke Internal Medicine Residency Curriculum Identify other risk factors than CHD Cigarette smoking FH premature CAD Age >45 in men, >55 in women Hypertension Low HDL (<40) HDL > 60 counts as a “negative” RF

Copyright © 2005, Duke Internal Medicine Residency Curriculum and DHTS Technology Education Services Duke Internal Medicine Residency Curriculum Determine LDL-c goal and therapy Click here for a link to a.pdf file of this table

Copyright © 2005, Duke Internal Medicine Residency Curriculum and DHTS Technology Education Services Duke Internal Medicine Residency Curriculum More simply… If CHD or equivalent, LDL-c goal 130. If 2 or more RF’s, LDL-c goal is 130, lifestyle changes for , unless 10-yr. risk is >10%, then start drugs. If 0-1 RF’s, LDL-c goal is 160, lifestyle changes , drugs for >190.

Copyright © 2005, Duke Internal Medicine Residency Curriculum and DHTS Technology Education Services Duke Internal Medicine Residency Curriculum Other measures of cholesterol One study compared 4 different measures and their correlation with risk of coronary disease and coronary death: –Total cholesterol –LDL –Total/ HDL ratio –LDL/HDL ratio –The study found that total/ HDL ratio identified larger at-risk groups than did LDL alone. –Although the total/ HDL ratio may be better at predicting coronary risk, no lipid-lowering studies are based upon that ratio. Therefore, we target LDL. (Ann Intern Med 1994 Nov 1;121(9):641-7 )

Copyright © 2005, Duke Internal Medicine Residency Curriculum and DHTS Technology Education Services Duke Internal Medicine Residency Curriculum Drug therapy for hyperlipidemia: statins

Copyright © 2005, Duke Internal Medicine Residency Curriculum and DHTS Technology Education Services Duke Internal Medicine Residency Curriculum Drug therapy for hyperlipidemia Statins – (HMG CoA reductase inhibitors) –These reduce intracellular cholesterol; and cause upregulation of the LDL-receptor, increasing LDL-c removal from blood. –Potency with respect to LDL lowering: Pravastatin (pravachol), fluvastatin (lescol) – least potent Simvastatin (zocor), lovastatin (mevacor) – intermediate Rosuvastatin (crestor), atorvastatin (lipitor) – most potent –On average, statins lower TG’s by 20% and raise HDL by 5%. They lower LDL by 30-60%.

Copyright © 2005, Duke Internal Medicine Residency Curriculum and DHTS Technology Education Services Duke Internal Medicine Residency Curriculum Primary prevention WOSCOPS (1995) – among middle-aged men with LDL-c >155, pravastatin reduced coronary events and coronary mortality. AFCAPS/TexCAPS (1998) – among low-risk men and women with average cholesterol, lovastatin reduced USA, fatal/ nonfatal MI and sudden cardiac death. ASCOT (2003) – men and women with normal cholesterol, but with HTN and >=3 RF’s, atorvastatin 10 mg reduced MI, CV events/ procedures and CVA.

Copyright © 2005, Duke Internal Medicine Residency Curriculum and DHTS Technology Education Services Duke Internal Medicine Residency Curriculum Secondary prevention 4S trial (1994) – pts with elevated total cholesterol given simvastatin for 5 yrs, had significant reductions in mortality, major coronary events, cerebrovascular events, CHD deaths, coronary procedures. (Lancet 1994 Nov 19;344(8934):1383-9) CARE (1996) – pts with average cholesterol treated with pravastatin, at 5 yrs, had reduced coronary death, nonfatal MI, frequency CVA/ TIA’s, and decrease in CABG/PTCA. (Sacks et al. N Engl J Med 1996 Oct 3;335(14):1001-9)

Copyright © 2005, Duke Internal Medicine Residency Curriculum and DHTS Technology Education Services Duke Internal Medicine Residency Curriculum Secondary prevention Heart Protection Study (2002) –20,000 pts with coronary disease, occlusive arterial disease or diabetes randomized to simvastatin 40 mg vs placebo. –Followed for 5 years –Outcomes: reduced all-cause mortality (p=.0003) reduced MI, CVA, revascularization by about 25% (Lancet 2002 Jul 6;360(9326):7-22)

Copyright © 2005, Duke Internal Medicine Residency Curriculum and DHTS Technology Education Services Duke Internal Medicine Residency Curriculum Heart Protection Study

Copyright © 2005, Duke Internal Medicine Residency Curriculum and DHTS Technology Education Services Duke Internal Medicine Residency Curriculum Heart Protection Study

Copyright © 2005, Duke Internal Medicine Residency Curriculum and DHTS Technology Education Services Duke Internal Medicine Residency Curriculum CARE Sacks et al. N Engl J Med 1996;335:1001-9

Copyright © 2005, Duke Internal Medicine Residency Curriculum and DHTS Technology Education Services Duke Internal Medicine Residency Curriculum Secondary prevention PROVE IT trial (2004) –Randomized 4000 pts with ACS in the prior 10 days to pravastatin 40mg or atorvastatin 80mg. –LDL: 95- (pravastatin); 62- (atorvastatin) – Primary endpoints of death, MI, revascularization, USA were significantly reduced with atorvastatin at 2 years. (Cannon et al. N Engl J Med 2004 Apr 8;350(15): )

Copyright © 2005, Duke Internal Medicine Residency Curriculum and DHTS Technology Education Services Duke Internal Medicine Residency Curriculum PROVE IT (2004)

Copyright © 2005, Duke Internal Medicine Residency Curriculum and DHTS Technology Education Services Duke Internal Medicine Residency Curriculum Secondary Prevention REVERSAL trial (2004) –RCT of 654 patients with coronary disease randomized to atorvastatin 80 mg vs. pravastatin 40 mg. –Mean LDL -150, was reduced to 110 in pravastatin group, 79 in atorvastatin group. –Progression of atherosclerosis by IVUS far less in the atorvastatin group. (p=.02) (JAMA 2004 Mar 3;291(9): )

Copyright © 2005, Duke Internal Medicine Residency Curriculum and DHTS Technology Education Services Duke Internal Medicine Residency Curriculum Benefits of Statins Lipid lowering –Decreased plaque cholesterol content  increased plaque stability  decreased CV events Anti-inflammatory effects Anti-thrombotic effects Endothelial effects ? Can they lower risk of diabetes and lower BP ?

Copyright © 2005, Duke Internal Medicine Residency Curriculum and DHTS Technology Education Services Duke Internal Medicine Residency Curriculum Anti-inflammatory effects

Copyright © 2005, Duke Internal Medicine Residency Curriculum and DHTS Technology Education Services Duke Internal Medicine Residency Curriculum Anti-thrombotic effects

Copyright © 2005, Duke Internal Medicine Residency Curriculum and DHTS Technology Education Services Duke Internal Medicine Residency Curriculum Endothelial effects After plaque rupture, loss of endothelial cell monolayer predisposes to constriction. Coronary reendothelialization important for myocardial perfusion and endothelial fxn. Statins observed to accelerate this process in rats, following balloon-mediated vascular injury.

Copyright © 2005, Duke Internal Medicine Residency Curriculum and DHTS Technology Education Services Duke Internal Medicine Residency Curriculum Adverse effects of statins Muscle – uncommon with statin therapy alone: 2-11% myalgias, 0.5% myositis, <0.1% rhabdomyolysis. –? Less risk with pravastatin, fluvastatin Hepatic – statins are associated with a 0.5-3% incidence in transaminase elevations. –Occur early, usually in the 1 st 3 months –Dose-dependent

Copyright © 2005, Duke Internal Medicine Residency Curriculum and DHTS Technology Education Services Duke Internal Medicine Residency Curriculum Adverse effects of statins High potential for drug interactions, particularly with other drugs metabolized via the CYP3A4 system. –Antifungals (azoles) –HIV protease inhibitors –SSRI’s/ benzos –CV meds: CCB’s, amiodarone, dig Can avoid this with pravastatin, rosuvastatin, fluvastatin as they are not metabolized by CYP3A4.

Copyright © 2005, Duke Internal Medicine Residency Curriculum and DHTS Technology Education Services Duke Internal Medicine Residency Curriculum Other therapies: Ezetimibe Fibrates Bile acid sequestrants Niacin Fish oil

Copyright © 2005, Duke Internal Medicine Residency Curriculum and DHTS Technology Education Services Duke Internal Medicine Residency Curriculum Comparison of lipid lowering effects

Copyright © 2005, Duke Internal Medicine Residency Curriculum and DHTS Technology Education Services Duke Internal Medicine Residency Curriculum Lipid-lowering therapies Ezetimibe (Zetia®) –cholesterol absorption inhibitor –works at the brush border of the small intestine –no clinical outcomes data –provides a small amount of LDL lowering alone, but best used in conjunction with a statin. Avoids high doses of statins.

Copyright © 2005, Duke Internal Medicine Residency Curriculum and DHTS Technology Education Services Duke Internal Medicine Residency Curriculum Fibrates gemfibrozil, fenofibrate lower triglycerides (- 35 to 50%) raise HDL (+15 to 25%) ? Decreased cardiac risk Side effects: –Muscle toxicity (particularly w/ statin) –Interferes with warfarin ( ↑ levels )

Copyright © 2005, Duke Internal Medicine Residency Curriculum and DHTS Technology Education Services Duke Internal Medicine Residency Curriculum Bile acid sequestrants Cholestyramine, cholestipol, colesevelem Bind bile acids in the intestine Side effects: GI effects, nausea, flatulence, elevation in TG No clinical outcomes data

Copyright © 2005, Duke Internal Medicine Residency Curriculum and DHTS Technology Education Services Duke Internal Medicine Residency Curriculum Nicotinic acid Raises HDL, lowers LDL and TG Inhibits hepatic production of VLDL Adverse effects: flushing, nausea, pruritis, liver toxicity, insulin resistance, hyperuricemia, hypotension. No good outcomes

Copyright © 2005, Duke Internal Medicine Residency Curriculum and DHTS Technology Education Services Duke Internal Medicine Residency Curriculum Fish oil Reduce triglycerides Need high doses, many tabs/ day The GISSI prevention study looked at fish oil vs. vitamin E, or both in patients just having an MI. –Found reduced incidence of sudden death, cardiac and coronary deaths. (Lancet 1999 Aug 7;354(9177):447-55)

Copyright © 2005, Duke Internal Medicine Residency Curriculum and DHTS Technology Education Services Duke Internal Medicine Residency Curriculum Hypertriglyceridemia Less data to support treatment ATP III recommends: –Treat LDL first –For TG : weight loss and exercise –For : can consider fibrate or niacin –For >500: start TG-lowering meds to prevent pancreatitis.

Copyright © 2005, Duke Internal Medicine Residency Curriculum and DHTS Technology Education Services Duke Internal Medicine Residency Curriculum Case 1 A 54 y.o. WM with PMH of CAD s/p MI 3 years ago presents to your office to establish a new PCP. His bp is 156/92, fasting lipid panel: LDL- 167, HDL- 34, TG (1)What is his goal LDL-c, given the above data? (2)What are his other CV risk factors? (3)What is your first step in management of his hyperlipidemia? (4)Would you treat his triglycerides? (5) By how much would you expect his lipids to change, if you decide to start a statin?

Copyright © 2005, Duke Internal Medicine Residency Curriculum and DHTS Technology Education Services Duke Internal Medicine Residency Curriculum Answers (1)What is his goal LDL-c, given the above data? Goal LDL-c is 100, given his past history of CAD. (2)What are his other CV risk factors? age>45, hypertension, low HDL (<40). (3)What is your first step in management of his hyperlipidemia? Start a statin. (4)Would you treat his triglycerides? Treat his LDL first, recommend diet and exercise changes. This alone may correct his high TG;s. If they remain high, could consider niacin or a fibrate. (5)By how much would you expect his lipids to change, if you decide to start a statin? On average, statins lower TG’s by 20% and raise HDL by 5%. They lower LDL by 30-60%

Copyright © 2005, Duke Internal Medicine Residency Curriculum and DHTS Technology Education Services Duke Internal Medicine Residency Curriculum Cases A 62 y.o. AAF presents with hyperlipidemia but no other past medical history. She has never smoked, reports no FH of premature CAD, BP= 124/78. Her fasting lipid panel: LDL-c: 178, HDL: 55, TG (1)What is her goal LDL-c? (2)What is the first step in managing her lipids?

Copyright © 2005, Duke Internal Medicine Residency Curriculum and DHTS Technology Education Services Duke Internal Medicine Residency Curriculum Answers (1)What is her goal LDL-c? She has 1 known additional risk factor, her age. Her goal is therefore 160. (2)What is the first step in managing her lipids? You can suggest lifestyle modifications, but if these fail, starting a statin is appropriate.

Copyright © 2005, Duke Internal Medicine Residency Curriculum and DHTS Technology Education Services Duke Internal Medicine Residency Curriculum Cases You have a 52 y.o. WM with type 2 DM, previous MI, HTN and a fasting lipid panel: LDL-c: 99, HDL: 39, TG He is a smoker. He asks you if his cholesterol is “good”. What do you tell him? (1)“Your cholesterol is fine.” (2)“Your cholesterol is almost at goal, you need to try diet and exercise.” (3)“Let’s talk about starting a new medication.”

Copyright © 2005, Duke Internal Medicine Residency Curriculum and DHTS Technology Education Services Duke Internal Medicine Residency Curriculum Answers The patient’s official LDL-c goal is <100, given his history of CAD or even given his diabetes alone. However, this patient is at extremely high risk for another CV event. The Heart Protection Study and PROVE IT suggested benefit to lowering LDL-c to levels even when already around or less than 100. Other studies are underway to determine if lowering LDL to very low levels has additional benefit. In this particular patient, starting a statin is reasonable. Some recent publications are suggesting an LDL goal of <70 in such high-risk patients. (Grundy et al. Circulation. 2004; 110: )

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