Lipids: The Good, The Bad, and The Ugly

Educational Objectives

The goal of this program is to reduce cardiovascular risk by improving management of dyslipidemia. After hearing and assimilating this program, the clinician will be better able to:

1.   Assess cardiovascular risk and establish appropriate targets for lipid-lowering therapy.

2.   Compare safety and efficacy profiles of the available lipid-lowering agents.

3.   Evaluate the efficacy of statin monotherapy and combination therapy.

4.   Describe the relationships between triglycerides, low-density lipoprotein cholesterol, and high-density lipopro­tein cholesterol (HDL-C), and the risks associated with abnormal levels.

5.   Discuss the clinical relevance of non–HDL-C.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any per­sonal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Basile has relationships with Abbott Laboratories, AstraZeneca, Daiichi-Sankyo, GlaxoSmithKline, Merck, Novartis, and Pfizer. Dr. McBride and the planning committee reported nothing to disclose.

Acknowledgments

Dr. Basile was recorded at Medical Dilemmas in Primary Care, presented by the Southern Medical Association and held December 19-21, 2008, in New York, NY. Dr. McBride was recorded at 2008 Primary Care Conference, pre­sented by the University of Wisconsin School of Medicine, Public Health Departments of Family Medicine and Med­icine, and University of Wisconsin-Madison Continuing Education in Nursing, and held November 13-14, 2008, in Madison, WI. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the produc­tion of this program.

Managing Dyslipidemia

Jan N. Basile, MD, Professor of Medicine, Division of General Internal Medicine/Geriatrics, Medical Univer­sity of South Carolina, and Chief, Primary Care Service Line, Ralph H. Johnson Veterans Affairs Medical Cen­ter, Charleston, SC

Trends: coronary heart disease (CHD) remains leading cause of death in United States; prevalence expected to in­crease; some improvements in trends (eg, total cholesterol levels), but 48% of adults have total cholesterol levels ³200 mg/dL, 33% have elevated levels of low-density lipoprotein cholesterol (LDL-C), and 17% have low levels of high-density lipoprotein cholesterol (HDL-C)

Risk assessment: Framingham risk calculator  —  calculates risk based on levels of LDL-C and HDL-C, systolic blood pressure, smoking, age, and gender; estimates 10-yr risk for non-fatal myocardial infarction (MI) or fatal CHD; coronary equivalents  —  diabetes; abdominal aortic aneurysm ³3.5 cm; peripheral vascular disease; carotid disease or history of transient ischemic attack (TIA); Framingham risk ³20%; lower LDL targets recommended for patients with coronary equivalents; identifying at-risk patients  —  important to identify patients with multiple risk factors who have not yet had cardiac event; risk calculators available online; document calculated risk and discuss implications with patients

LDL goals: target <100 mg/dL for high-risk patients; target <70 mg/dL recommended if patient has cardiovascular (CV) disease and multiple risk factors (eg, diabetes, metabolic syndrome, acute coronary syndrome [ACS]); best evidence for patients with CV disease and ACS; for patients with ACS or unstable angina, initiate lipid-lowering therapy within 24 hr or before discharge, unless contraindicated; management  —lifestyle interventions; statins as first-line medical therapy; adjunctive therapies include bile acid resins, ezetimibe, and niacin

Statins: effects  —  LDL-C level lowered; endothelial function restored; decreased level of high-sensitivity C-reactive protein (hsCRP); fewer ischemic episodes on exercise stress tests; plaques stabilized; decreased risk for cardiac events; decreased mortality rate; options  —  6 agents available; potencies, pharmacokinetics, drug interactions, and metabolic pathways differ; generic simvastatin available; atorvastatin, lovastatin, and simvastatin metabo­lized via cytochrome P450 3A4 system (interact with azole antifungal agents, HIV medications, or macrolide an­tibiotics; decrease dose, withhold statin, or switch to other statin with no interaction)

Efficacy: strategies for increasing efficacy  —  double dose (results in additional 6% reduction in level of LDL-C); switch to more potent statin; add adjunctive therapy (eg, ezetimibe, bile acid resin); relative efficacies  —  trial showed 20 mg rosuvastatin produced reduction in LDL-C similar to that seen with 40 to 80 mg atorvastatin, pravastatin, or simvastatin; measuring markers of risk  —  clinical trial showed combination agent (simvastatin plus ezetimibe [Vytorin]) associated with additional reductions in levels of LDL-C and hsCRP (compared to sim­vastatin alone) but no additional improvement in carotid intima-medial thickness; finding led to concern about extrapolating effects on markers of risk (eg, hsCRP) to CV outcomes (new study will analyze effect on CV end points)

Safety and tolerability: although generally safe and well-tolerated, over-the-counter formulations not recommended by speaker; monitoring important; also important to know when (and why) patients discontinue taking statins; trials comparing different statins and different dosing regimens conclude that lowering LDL-C levels to <40 mg/dL improves outcomes without compromising safety; higher doses associated with higher rate of discontinu­ation (related mostly to elevated liver enzymes, not to increased myalgias); hepatotoxicity  —  generally low; risk increases with alcohol use and drug interactions; myalgia  —  relatively low incidence, but one study showed pathologic changes on muscle biopsy in some patients; consider discontinuing or switching to different statin, even if creatine kinase level not elevated; most trial data do not support supplementation with coenzyme Q₁₀, but some patients report improvement with 100 to 200 mg/day

High-sensitivity CRP: independent marker of CV risk; optional component of coronary risk assessment in adults without known CV disease; most useful for patients at intermediate risk; elevated CRP (1-3 mg/L) may be reason to decrease LDL goal to <100 mg/dL; Framingham Heart Study identified hsCRP as predictor of CV disease

Primary prevention: Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvas­tatin (JUPITER)  —  double blind, randomized trial comparing 20 mg rosuvastatin to placebo for primary prevention of CV events among adults with LDL-C <130 mg/dL and hsCRP >2 mg/L, but no history of CV disease or diabe­tes; data monitoring board stopped study early because of benefit seen with active treatment; treatment associated with improved LDL, hsCRP, and all CV outcomes, except for hospitalization for unstable angina; clinical implications  —  in JUPITER, hsCRP measured as marker of risk, not as means of guiding therapy; data support ex­panding use of statins for primary prevention; considerations include potential benefits, long-term safety, and cost-effectiveness

Risk-based management: Heart Protection Study (HPS)  —>20,000 participants, 40 to 80 yr of age, with high CV risk, randomized to 40 mg simvastatin or placebo; simvastatin associated with 34% reduction in mortality and CV events, regardless of baseline LDL-C (including patients with baseline LDL-C <80 mg/dL); results suggest that overall CV risk (instead of LDL-C level alone) should guide therapy; American Diabetes Association recommendations  —  statins indicated for diabetic patients ³40 yr of age (unless contraindication present), regard­less of LDL-C level

Non–HDL-C: clinical trials of statin therapy show that residual CV risk exists after LDL-C target met; residual risk associated with other atherogenic lipoproteins; calculating non–HDL-C  —subtract HDL-C from total cholesterol; goal  —  30 mg/dL higher than goal for LDL-C; clinical relevance  —  correlates closely with obesity, visceral adipos­ity, and metabolic syndrome; predicts CV risk more strongly than does LDL-C; includes LDL-C, intermediate-den­sity lipoproteins, chylomicrons and chylomicron remnants; in Framingham Heart Study, little association found between level of LDL-C and risk for CHD, after controlling for level of HDL-C, but HDL-C strongly associated with risk, even after controlling for level of LDL-C; Strong Heart Study  —  non–HDL-C predicted CV risk as well as LDL-C among American Indian men and women; ratio of total cholesterol to HDL-C also good predictor (target ratio <3.5); guidelines  —  non–HDL-C recommended as secondary target of therapy for patients with triglyceride levels ³200 mg/dL

Raising HDL-C: agents  —  nicotinic acid (niacin; considered most effective agent); fibrates; fish oils; benefits  —  low level of HDL-C associated with increased risk for CV events, but no good evidence that raising level (independent of other changes in lipid profile) improves outcomes

Beyond statins: niacin  —  Coronary Drug Project showed monotherapy associated with significantly decreased risks for coronary death and nonfatal MI (compared to placebo); gemfibrozil  —  monotherapy shown beneficial for sec­ondary prevention in population with underlying CHD; take-home point  —  patients unable to take statins have op­tions including bile acid resins, ezetimibe, niacin, and fibrates

Combination therapies: insufficient evidence that specific combinations result in improved risk reduction; niacin, fi­brates, and omega-3 fatty acids suggested as possible combination therapies; statin plus niacin  —  HDL-Atheroscle­rosis Treatment Study (HATS); 160 patients with known coronary disease, low level of HDL-C, and LDL-C <145 mg/dL at baseline randomized to simvastatin plus niacin, antioxidants alone, combination of simvastatin, niacin, and antioxidants, or placebo; simvastatin plus niacin associated with improvements in lipid profiles and significant reductions in risks for coronary death, MI, stroke, and revascularization and in regression of coronary stenosis; no benefit seen with antioxidants; adding antioxidants appeared to reduce efficacy of combination therapy; larger study (in progress) comparing simvastatin monotherapy with simvastatin plus niacin; statin plus fibrate  —  no clini­cal trial has compared combination to statin monotherapy; gemfibrozil should not be combined with higher doses of statins, because of increased risk for rhabdomyolysis; fenofibrate safe to combine with statins; arm of Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial (in progress) will compare simvastatin alone to simvas­tatin plus fenofibrate in patients with type 2 diabetes

Questions and answers: statins for primary prevention in premenopausal women  —  decision to treat based on CV risk; generally, premenopausal women have low risk; statins recommended for women with underlying CV disease, diabetes, or other high risk; statins as effective in women as in men (matched for risk); statins and risk for diabetes  —  trial showed treatment with rosuvastatin increased risk for new-onset diabetes but decreased mortality; significance unclear; myalgias  — discontinue statin; measure creatine kinase (if normal, consider other causes); myalgia should resolve in 1 to 2 wk after discontinuation (if not, consider other causes); augmentative medications (eg, ezetimibe) also may cause myalgias; elevated liver enzymes  —  reduce dose or discontinue statin if aspartate aminotransferase or alanine aminotransferase >3 times upper limit of normal (ULN); moderate elevations (eg, up to 4 times ULN) of creatine kinase acceptable as long as patient remains asymptomatic; fish oil  —  good adjunctive therapy; evidence for use in patients with underlying CV disease; for primary prevention, benefit unclear

Beyond LDL Cholesterol

Patrick E. McBride, MD, MPH, Professor of Medicine and Family Medicine, and Associate Dean for Students, University of Wisconsin School of Medicine and Public Health, Madison

Dyslipidemia and CV risk: statin therapy effectively reduces level of LDL-C, but patients with high triglycerides and low levels of HDL-C have residual risk for atherosclerosis; important to address all aspects of dyslipidemia; triglycerides  — independent predictor of CV disease; Framingham study found triglyceride level and HDL-C level more predictive in women than men; another study showed that, among individuals with premature heart disease and family history of CV disease, triglyceride level associated with increased risk (11-fold higher when >500 mg/dL vs <100 mg/dL; 17-fold higher when triglyceride level >300 mg/dL and HDL-C level <30 mg/dL)

Lipoprotein interactions: when triglycerides elevated, cells produce abnormal forms of cholesterol (especially in patients with abdominal obesity); triglycerides transiently inserted into LDL particle, then removed by cholesterol-ester transfer protein, creating small, dense LDLs; these small LDLs oxidize easily and penetrate arteries more rap­idly than larger LDL particles; standard lipid profile does not detect small LDLs; situation common among patients with abdominal obesity, high triglycerides, and low level of HDL; individuals with low levels of triglycerides do not produce small LDLs; production of small LDLs substantially increases when triglyceride level reaches 80 to 100 mg/dL; by 150 mg/dL, almost all LDL particles are small LDLs; guidelines list triglyceride level of ³150 mg/dL as risk factor (cutoff may change to 100 mg/dL in next version of guidelines)

Total number of LDL particles: best predictor of CV risk; tests  —  Vertical Auto Profile (VAP) test and Berkeley HeartLab test measure size, but not number of particles; LipoProfile nuclear magnetic resonance (NMR) spectros­copy measures number and size of lipoprotein particles; individuals who produce small LDL particles also tend to produce small HDL particles, which have impaired function (less protective than normal-sized HDL particles); target  —  10 times target level of LDL (eg, if LDL goal <100 mg/dL, total particle number should be <1000)

Non–HDL-cholesterol: high consumption of carbohydrates results in production of inflammatory, proatherogenic triglyceride-rich particles (eg, very low-density lipoproteins [VLDL], intermediate-density lipoproteins [IDL]); measuring non–HLD-C  —  subtract HDL-C from total cholesterol; inexpensive test; advantages  —  best lipid pa­rameter for predicting atherosclerosis in adults, adolescents, and children; fasting not required (convenient; reflects “real life” postprandial status); high correlation with visceral adiposity

HDL-cholesterol: low levels associated with increased risk for CHD, especially among women; effects  —  participates in reverse cholesterol transport; reduces oxidation; decreases risk for thrombosis; improves arterial function; inhibits inflammatory molecules

Fibrates: gemfibrozil  —  lowers triglycerides and raises level of HDL-C, but has little effect on LDL-C; treatment as­sociated with 70% reduction in relative risk for coronary events among patients with high levels of triglycerides (>200 mg/dL) and low levels of HDL-C; little benefit seen among those with lower levels of triglycerides; study in patients with CV disease, LDL-C <130 mg/dL, triglycerides >150 mg/dL, and HDL-C <40 mg/dL showed mono­therapy resulted in 8% reduction in absolute risk (for vascular events over 5 yr) among patients with diabetes and 5% absolute risk reduction among patients without diabetes (similar to or better than that associated with statin therapy in patients with CHD); fenofibrate  —study found no significant differences in primary end points between active-treatment and control groups, but patient population poorly selected (ie, included patients not expected to benefit)

Niacin: vitamin B₃; long-term clinical trials (eg, Coronary Drug Project) showed treatment associated with decreased rates of CV events, coronary mortality, and total mortality; aggressive combination therapy may result in regression of atherosclerosis; recommendations for improving tolerance  —  take aspirin before taking niacin; take with food and water

Combination therapy: appropriate for high-risk patients with >1 component of dyslipidemia; combination therapy with bile acid resin (colestipol) plus niacin or statin results in significantly greater risk reduction (total mortality and CV events) compared to statin monotherapy; aggressive therapy reduces 10-yr mortality rate by 18%; if com­bining statin with fibrate, use fenofibrate

Suggested Reading

Brown BG et al: Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 345:1583, 2001; Grundy SM et al: Effectiveness and tolerability of simvastatin plus fenofibrate for combined hyperlipid­emia (the SAFARI trial). Am J Cardiol 95:462, 2005; Heart Protection Study Collaborative Group: MRC/BHF Heart Protec­tion Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 360:7, 2002; Hopkins PN et al: Plasma triglycerides and type III hyperlipidemia are independently associated with premature fa­milial coronary artery disease. J Am Coll Cardiol 45:1003, 2005; Jones PH, Davidson MH: Reporting rate of rhabdomyolysis with fenofibrate + statin versus gemfibrozil + any statin. Am J Cardiol 95:120, 2005; Jones PH et al: Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR Trial). Am J Cardiol 92:152, 2003; Kastelein JJ et al: Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med 358:1431, 2008; Koren MJ et al: Impact of high-dose atorvastatin in coronary heart disease patients age 65 to 78 years. Clin Cardiol 32:256, 2009; Marcoff L, Thompson PD: The role of coenzyme Q10 in statin-associated myopathy: a systematic review. J Am Coll Car­diol 49:2231, 2007; National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treat­ment of High Blood Cholesterol in Adults: Third report of the NCEP Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults final report. Circulation 106:3143, 2002; Ridker PM et al: Baseline characteristics of partici­pants in the JUPITER trial. Am J Cardiol 100:1659, 2007; Rubins HB et al: Gemfibrozil for the secondary prevention of coro­nary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med 341:410, 1999.