The National Cholesterol Education Program

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1 122 REVIEW PAPER CME Non High-Density Lipoprotein Cholesterol: An Alternate Target for Lipid-Lowering Therapy Vera Bittner, MD, MSPH Non high-density lipoprotein (non-hdl) cholesterol level is determined by subtracting the high-density lipoprotein cholesterol level from the total cholesterol level and thus encompasses not only low-density lipoprotein cholesterol, but also the cholesterol contained in atherogenic, triglyceride-rich particles like remnants. This review summarizes data extracted from English-language publications accessible through MEDLINE on the population distribution of non-hdl cholesterol, its relationship to cardiovascular disease, and the potential benefits of treatment. Non-HDL cholesterol levels in the population vary by age, sex, and race and are closely linked to measures of obesity, especially visceral obesity. Several studies in populations with and without cardiovascular disease show that non-hdl cholesterol levels relate to atherosclerosis severity and subsequent cardiovascular morbidity and mortality. Preliminary data also suggest that pharmacologically induced changes in non-hdl cholesterol levels relate to prognosis. In the National Cholesterol Education Program Adult Treatment Panel III report, non-hdl cholesterol has been designated a secondary target of therapy among patients with hypertriglyceridemia. (Prev Cardiol. 2004;7: , 129, 130) 2004 CHF, Inc. From the Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL Address for correspondence: Vera Bittner, MD, MSPH, University of Alabama at Birmingham, LHRB 310, th Street, South Birmingham, AL vbittner@uab.edu Manuscript received December 31, 2003; revised February 3, 2004; accepted February 4, ID: 3094 The National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) report suggests non high-density lipoprotein (non- HDL) cholesterol should be a secondary target of lipid-lowering therapy among persons with triglyceride levels >200 mg/dl 1 (Table). This review summarizes the rationale for using non-hdl cholesterol level as a treatment target. The review is based on English-language published articles accessible by MEDLINE ( com/px/medlineapp/medline?cid=med) through August 2003 (keywords used were non-hdl cholesterol, apoprotein B, and triglyceride-rich lipoproteins ), a review of primary and secondary publications from pharmacologic lipid-lowering trials, and a manual search of references within articles retrieved through MEDLINE. WHAT IS NON-HDL CHOLESTEROL? Non-HDL cholesterol level is calculated by subtracting high-density lipoprotein (HDL) cholesterol level from total cholesterol level. It thus includes not only cholesterol from lipoprotein(a), low-density lipoprotein (LDL) cholesterol, and intermediate-density lipoprotein cholesterol particles that are traditionally included in the LDL cholesterol values calculated by the Friedewald formula, 2 but also cholesterol contained in potentially atherogenic triglyceride-rich lipoproteins such as very low-density lipoprotein remnants. In contrast to LDL cholesterol, non-hdl cholesterol values can be calculated from nonfasting patients without measuring triglycerides. Non-HDL cholesterol levels correlate closely with LDL cholesterol levels, more so in persons with normotriglyceridemia (e.g., correlation of 0.95 among children in the Bogalusa Heart Study 3 ) than in those with triglyceride elevations (e.g., correlation of 0.81 in a cohort of patients with coronary artery disease enrolled in an angiographic follow-up study 4 ). On average, non-hdl cholesterol levels are approximately 30 mg/dl higher than LDL cholesterol levels. 4 All the lipoprotein particles included in the

2 SUMMER 2004 PREVENTIVE CARDIOLOGY 123 non-hdl cholesterol calculation carry apoprotein B on their surface. Not surprisingly, non-hdl cholesterol is thus a better correlate of apoprotein B levels than LDL cholesterol in patients with both normotriglyceridemia and hypertriglyceridemia. 5 WHAT FACTORS DETERMINE NON- HDL CHOLESTEROL LEVELS IN THE US POPULATION? In US children, there are no ethnic differences, but girls tend have higher non-hdl cholesterol levels than boys. 3 In both sexes, levels correlate strongly with measures of body fatness and may be a better measure for monitoring outcomes of lifestyle changes than LDL cholesterol levels. 3 Among US adults, age-adjusted non-hdl cholesterol concentrations are lower among African Americans compared with Mexican Americans or whites. 6 Among younger persons (aged years), women have lower non- HDL cholesterol levels than men; among persons older than age 55 years, women have higher levels than men. 6 In both sexes, non-hdl cholesterol levels correlate closely with obesity and especially visceral obesity The link between non-hdl cholesterol levels and physical activity appears to be less robust, although at least one study suggested that high-intensity physical activity was associated with lower levels of non-hdl cholesterol. 11 DOES NON-HDL CHOLESTEROL CORRELATE WITH CARDIOVASCULAR RISK? Non-HDL cholesterol, in contrast to LDL cholesterol, includes the cholesterol carried in triglyceriderich lipoproteins. Why is this important? Although not well accepted in the past, recent meta-analyses suggest triglyceride levels are strongly and independently related to coronary artery disease risk. 12,13 Triglycerides are carried on triglyceride-rich lipoprotein particles that, despite their name, also carry substantial quantities of cholesterol. In vitro data, data from animal models, and data in human beings show that some of the triglyceride-rich lipoproteins (primarily the so-called remnant particles) are highly atherogenic. 14,15 The cardiovascular risk associated with plasma triglyceride concentrations is believed to be mediated through these atherogenic particles. The link between LDL cholesterol and cardiovascular risk is well established and reviewed in detail in the NCEP ATP III guidelines. 1 Similarly, there is strong evidence for the link between coronary heart disease and lipoprotein(a) and intermediate-density lipoprotein cholesterol, the two lipoprotein fractions included in the LDL cholesterol levels calculated by the Friedewald formula. 16,17 Few studies have specifically examined the link between non-hdl cholesterol levels and measures of atherosclerosis in human beings In the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study, an autopsy study of 15- to 34-year-old men and women who died of accidents, homicides, or suicides, non-hdl cholesterol levels measured postmortem were positively associated with fatty streaks, raised lesions, and stenoses 40%. 18,19 Non-HDL cholesterol levels also relate to coronary disease progression in angiographic studies 20 and to carotid intimal medial thickness as measured by high resolution B-mode ultrasound. 21 Most, but not all, epidemiologic studies that have examined the relationship between non-hdl cholesterol and cardiovascular morbidity and mortality have concluded that non-hdl cholesterol strongly predicts cardiovascular outcomes Prospective cohort studies in middle-aged men in Finland, Italy, and Great Britain showed that non-hdl cholesterol levels related to coronary heart disease morbidity and mortality Cross-sectional data from the Framingham Offspring study 25 suggested that non-hdl cholesterol was also a risk factor for coronary heart disease among middle-aged women. In a large cohort of middleaged men (n=2406) and women (n=2056) who participated in the Lipid Research Clinics program Follow-up Study, both LDL cholesterol and non-hdl cholesterol levels predicted cardiovascular death over 19 years of follow-up. 25 Non-HDL cholesterol level seemed to be a somewhat stronger predictor than LDL cholesterol level in both sexes: a 30 mg/dl difference in non-hdl cholesterol translated to a 19% difference in cardiovascular mortality risk among men and a 11% difference in risk among women; corresponding risks for LDL cholesterol were 15% among men and 8% among women, respectively. 26 High non-hdl cholesterol levels in this study also predicted all-cause mortality in both sexes, whereas LDL cholesterol levels did not. 26 Data from the Stanford Five-City Project suggest the predictive value of non-hdl cholesterol level is independent of LDL particle size. 27 Data among older persons are less clear. In the Systolic Hypertension in the Elderly Program (SHEP), which enrolled older men and women with hypertension, non-hdl cholesterol level predicted the combined end point of nonfatal myocardial infarction or coronary heart disease death over 4.5 years of follow-up after controlling for age, race, gender, history of coronary disease, diastolic blood pressure, smoking, diabetes, alcohol use, uric acid level, Rose questionnaire angina, presence of carotid bruit, and HDL cholesterol and triglyceride levels. 28 The relative risk was the same as for LDL cholesterol in comparable models. 28 In contrast, investigators from the Rancho Bernardo Study found no relationship between non-hdl cholesterol level and coronary disease and cardiovascular disease mortality at 3, 5, and 10 years of follow-up among older women and only a weak association between non-hdl cholesterol level and these outcomes among older men (these became nonsignificant after adjusting for other cardiovascular risk factors). 28 Interestingly, LDL cholesterol level was also not predictive in this cohort of older patients without a history of cardiovascular disease. 29

3 124 Lehto et al. 30 showed that non-hdl cholesterol level, but not LDL cholesterol level, was a predictor of 7-year coronary heart disease mortality among patients with diabetes; when nonfatal events were included in the analysis, LDL cholesterol level was significant, but the hazard ratio (HR) was higher for non-hdl cholesterol level. In the Strong Heart Study, non-hdl cholesterol level among American- Indian subjects with diabetes predicted cardiovascular events at 9 years of follow-up even after adjusting for age, body mass index, smoking status, study center, systolic blood pressure, glycosylated hemoglobin level, fibrinogen, insulin, and ratio of albumin to creatinine. 31 HRs for non-hdl cholesterol in this study were somewhat higher than those for LDL cholesterol in both sexes (HR 2.23 and 1.80 for the highest tertile of non-hdl cholesterol level among men and women, respectively, vs and 1.61 for the highest tertile of LDL cholesterol level among men and women, respectively). Non-HDL cholesterol levels strongly predicted coronary heart disease, especially myocardial infarction, but not stroke. Data on the relationship between non-hdl cholesterol and cardiovascular outcomes among patients with established coronary heart disease are more limited. 32,33 In the Scandinavian Simvastatin Survival Study (4S), non-hdl cholesterol levels in the placebo group seemed to be a slightly better predictor of major coronary events at 5.4 years than corresponding LDL cholesterol levels ( 16.4% risk reduction vs. 12.8% risk reduction, respectively, for every 1 mmol/l [38.7 mg/dl] lower level). 32 In the Bypass Angioplasty Revascularization Investigation (BARI), a randomized trial of angioplasty vs. coronary artery bypass surgery among patients with multivessel coronary artery disease, baseline non-hdl cholesterol level (but not LDL cholesterol level) was an independent predictor of nonfatal myocardial infarction and angina pectoris at 5 years, even after adjustment for age, sex, race, history of hypertension, history of diabetes, angiographically determined severity of coronary artery disease, and treatment assignment to angioplasty or coronary bypass surgery. 33 In time-dependent analyses, every 10 mg/dl increment in average non-hdl cholesterol level increased the risk of nonfatal myocardial infarction by 5% and the odds of angina pectoris by 10%. 33 DO CURRENTLY AVAILABLE LIPID- LOWERING TREATMENTS AFFECT NON-HDL CHOLESTEROL LEVELS? Statins, fibrates, nicotinic acid, and ezetimibe lower LDL cholesterol levels, lower triglycerides, and increase HDL cholesterol levels to varying degrees depending on the underlying lipid abnormality and would thus be expected to lower non-hdl cholesterol levels in most persons with dyslipidemia. Few studies have specifically reported changes in non- HDL cholesterol levels with therapy. Ballantyne et al. 34 compared lipid-lowering effects of atorvastatin, Table. Therapeutic Targets for Low-Density Lipoprotein (LDL) Cholesterol and Non High- Density Lipoprotein (non-hdl) Cholesterol as Recommended by the National Cholesterol Education Program Adult Treatment Panel III LDL NON-HDL RISK LEVEL CHOLESTEROL GOAL CHOLESTEROL GOAL CHD and <100 mg/dl <130 mg/dl CHD risk equivalents* Multiple (2+) <130 mg/dl <160 mg/dl risk factors (10-year CHD risk 20%) 0 1 Risk factor <160 mg/dl <190 mg/dl CHD=coronary heart disease; *CHD risk equivalents include persons with CHD, those with peripheral vascular disease or symptomatic carotid artery disease, patients with diabetes, and patients with multiple risk factors for CHD who have a 10-year risk of hard CHD end points of >20%. Reprinted from Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults Final Report. 1 fluvastatin, lovastatin, pravastatin, and simvastatin in more than 3500 patients who had LDL cholesterol levels between 130 mg/dl and 300 mg/dl and triglycerides <400 mg/dl. All statins lowered non- HDL cholesterol levels in a dose-dependent fashion (range 23.6% to 39.2%) independent of baseline triglyceride levels. 34 In a group of healthy adults with baseline LDL cholesterol levels between 160 and 250 mg/dl and triglycerides <400 mg/dl, reductions in non-hdl cholesterol level up to 50% and 57% have been reported with high-dose atorvastatin and highdose rosuvastatin therapy, respectively. 35 Isaacsohn et al. 36 evaluated the effects of simvastatin on non-hdl cholesterol in patients with hypertriglyceridemia and found up to 40% reduction at the highest statin dose. In the Helsinki Heart Study, gemfibrozil therapy reduced non-hdl cholesterol level by 14% among middle-aged men with baseline non-hdl cholesterol levels >5.2 mmol/l (201 mg/dl). 37 Ezetimibe lowered non-hdl cholesterol level by 17% in a small group of patients with LDL cholesterol levels between 145 and 250 mg/dl and triglycerides 350 mg/dl and provided an additional 11% 13% decrement in non-hdl cholesterol level when combined with atorvastatin or simvastatin. 38,39 DO CHANGES IN NON-HDL CHOLESTEROL RESULT IN CHANGES IN CARDIOVASCULAR OUTCOMES? Only a few clinical trials have reported non-hdl cholesterol levels and changes in non-hdl cholesterol level in relation to physiologic outcomes or clinical events and mortality. Reductions in

4 SUMMER 2004 PREVENTIVE CARDIOLOGY 125 non-hdl cholesterol level with statin therapy (mean 44%) were associated with improvements in brachial artery endothelial function in patients with nephrotic syndrome. 40 In the Helsinki Heart Study, 4081 men free of documented coronary heart disease who had elevated non-hdl cholesterol levels were randomized to gemfibrozil therapy or placebo and incident coronary heart disease was evaluated over a mean follow-up of 60.4 months. 41 Cox proportional hazard models were used to estimate the percentage reduction of coronary heart disease risk attributable to treatment-induced changes in various lipid fractions. The estimated risk reduction for the change in HDL cholesterol level was 23%, for LDL cholesterol level the change was 15%, for non-hdl cholesterol level the change was 22%, and for HDL cholesterol and LDL cholesterol levels combined the change was 28%. 41 The 4S study randomized 4444 patients with coronary heart disease, serum cholesterol level of mg/dl, and triglyceride levels <220 mg/dl to simvastatin or placebo for 5.4 years. 32 In this cohort of patients, each 1% decrease in levels of non-hdl cholesterol and LDL cholesterol with simvastatin therapy resulted in a 1.7% reduction in events. 32 In the Greek Atorvastatin and Coronary Heart Disease Evaluation Study (GREACE), LDL cholesterol level was lowered by 46%, non-hdl cholesterol level was lowered by 44%, and HDL cholesterol level increased 7%. 42 These lipid changes were associated with large reductions in total mortality ( 43%), coronary mortality ( 47%), coronary morbidity ( 54%), and stroke ( 47%), but the authors did not report risk reductions attributable to specific lipoprotein changes. 42 SUMMARY Non-HDL cholesterol level is a more comprehensive measure of atherogenic particles than LDL cholesterol level. It is easy to calculate and can be measured in the nonfasting state. Non-HDL cholesterol level is strongly related to cardiovascular risk among persons of various ages, among both sexes, among diabetic and nondiabetic patients, and among persons with and without documented cardiovascular disease. Non-HDL cholesterol level predicts atherosclerosis progression after as little as 2 years of follow-up, and cardiovascular events and mortality over follow-up periods as short as 5 years and as long as 24 years. Because LDL cholesterol and non-hdl cholesterol levels are strongly correlated, direct comparison of the prognostic value of LDL cholesterol level and non-hdl cholesterol level is difficult, but available data suggest that non- HDL cholesterol level is as good as or better than LDL cholesterol level in predicting cardiovascular risk. Currently available lipid-lowering agents can substantially reduce non-hdl cholesterol levels and these reductions correlate with reductions in subsequent cardiovascular morbidity and mortality. Non-HDL cholesterol values are available in all large datasets derived from contemporary clinical trials of lipid-lowering therapy. Additional analyses of these datasets to clarify the relationship between non-hdl cholesterol levels and angiographic disease progression and cardiovascular event rates would be a valuable addition to the existing literature. Such analyses would likely underestimate the potential usefulness of targeting non-hdl cholesterol because patients with hypertriglyceridemia (in whom the discrepancy between LDL cholesterol level and non-hdl cholesterol level would be the greatest and who would be expected to benefit the most from a non-hdl cholesterol-targeted strategy) have been excluded from most lipid-lowering trials. Clinical trials that include a broad spectrum of patients with dyslipidemia are needed to directly compare an LDL cholesterol-lowering strategy with a non-hdl cholesterol-lowering strategy to determine whether the latter could lead to greater reductions in cardiovascular disease events. REFERENCES 1 Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Final Report. Bethesda, MD: National Heart, Lung, and Blood Institute; NIH Publication No Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma without use of the preparative ultracentrifuge. Clin Chem. 1972;18: Srinivasan S, Myers L, Berenson GS. Distribution and correlates of non-high-density lipoprotein cholesterol in children. The Bogalusa Heart Study. Pediatrics. 2002;110(3):e29. 4 Frost PH, Havel RJ. Rationale for use of non-high-density lipoprotein cholesterol rather than low-density lipoprotein cholesterol as a tool for lipoprotein cholesterol screening and assessment of risk and therapy. Am J Cardiol. 1998;81(4A):26B 31B. 5 Sniderman AD, St-Pierre AC, Cantin B, et al. Concordance /discordance between plasma apolipoprotein B levels and the cholesterol indexes of atherosclerotic risk. Am J Cardiol. 2003;91: Gardner CD, Winkelby M, Fortman SP. Population frequency distribution of non-high- density lipoprotein cholesterol (Third National Health and Nutrition Examination Survey (NHANES III), ). Am J Cardiol. 2000;86: Denke MA, Sempos CT, Grundy SM. Excess body weight. An under-recognized contributor to dyslipidemia in white American women. Arch Intern Med. 1994;154: Denke MA, Sempos CT, Grundy SM. Excess body weight. An under-recognized contributor to high blood cholesterol levels in white American men. Arch Intern Med. 1994;153: Galanis D, Sobal J, McGarvey ST, et al. Ten-year changes in the obesity, abdominal adiposity, and serum lipoprotein cholesterol measures of Western Samoan men. J Clin Epidemiol. 1995;48: Chan DC, Watts GF, Barrett PH, et al. Markers of triglyceride-rich lipoprotein remnant metabolism in visceral obesity. Clin Chem. 2002;48: Marrugat J, Elosua R, Covas MI, et al. Amount and intensity of physical activity, physical fitness, and serum lipids in men. Am J Epidemiol. 1996;143: Austin MA, Hokanson JE, Edwards KL. Hypertriglyceridemia as a cardiovascular risk factor. Am J Cardiol. 1998;81:7B 12B. 13 Assmann G, Schulte H, Funke H, et al. The emergence of triglycerides as a significant independent risk factor in coronary

5 126 artery disease. Eur Heart J. 1998;19(suppl M):M8 M Gianturco SH, Bradley WA. Pathophysiology of triglyceride-rich lipoproteins in atherothrombosis: cellular aspects. Clin Cardiol. 1999;22:II7 II Hodis HN, Mack WJ, Krauss RM, et al. Pathophysiology of triglyceride-rich lipoproteins in atherothrombosis: clinical aspects. Clin Cardiol. 1999;22:II15 II Danesh J, Collins R, Peto R. Lipoprotein(a) and coronary heart disease. Meta-analysis of prospective studies. Circulation. 2000;102: Zambon A, Hokanson JE. Lipoprotein classes and coronary disease regression. Curr Opin Lipidol. 1998;9: Rainwater DL, McMahan A, Malcom GT, et al. Lipid and apolipoprotein predictors of atherosclerosis in youth. Apolipoprotein concentrations do not materially improve prediction of arterial lesions in PDAY subjects. Arterioscler Thromb Vasc Biol. 1999;19: McGill HC, McMahan A, Zieske AW, et al. Association of coronary heart disease risk factors with microscopic qualities of coronary atherosclerosis in youth. Circulation. 2000;102: Blankenhorn DH, Alaupovic P, Wickham E, et al. Prediction of angiographic change in native human coronary arteries and aortocoronary bypass grafts. Lipid and nonlipid factors. Circulation. 1990;81: Shoji T, Emoto M, Tabata T, et al. Advanced atherosclerosis in predialysis patients with chronic renal failure. Kidney Int. 2002;61: Keys A, Karvonen MJ, Punsar S, et al. HDL serum cholesterol and 24-year mortality of men in Finland. Int J Epidemiol. 1984;13: Pocock SJ, Shaper AG, Phillips AN, et al. High density lipoprotein cholesterol is not a major risk factor for ischaemic heart disease in British men. BMJ. 1986;292: Menotti A, Spagnolo A, Scanga M, et al. Multivariate prediction of coronary deaths in a 10 year follow-up of an Italian occupational male cohort. Acta Cardiol. 1992;47: Schaefer EJ, Lamon-Fava S, Cohn SD, et al. Effects of age, gender, and menopausal status on plasma low density lipoprotein cholesterol and apolipoprotein B levels in the Framingham Offspring Study. J Lipid Res. 1994;35: Cui Y, Blumenthal RS, Flaws JA, et al. Non-high-density lipoprotein cholesterol level as a predictor of cardiovascular disease mortality. Arch Intern Med. 2001;161: Gardner CD, Fortmann SP, Krauss RM. Association of small low-density lipoprotein particles with the incidence of coronary artery disease in men and women. JAMA. 1996;276: Frost PH, Davis BR, Burlando AJ, et al. Serum lipids and incidence of coronary heart disease. Circulation. 1996;94: Von Muehlen D, Langer RD, Barrett-Connor E. Sex and time differences in the associations of non-high-density lipoprotein cholesterol versus other lipid and lipoprotein factors in the prediction of cardiovascular death. The Rancho Bernardo Study. Am J Cardiol. 2003;91: Lehto S, Roennemaa T, Haffner SM, et al. Dyslipidemia and hyperglycemia predict coronary heart disease events in middleaged patients with NIDDM. Diabetes. 1997;46: Lu W, Resnick HE, Jablonski KA, et al. Non-HDL cholesterol as a predictor of cardiovascular disease in Type 2 diabetes. Diabetes Care. 2003;26: Pedersen TR, Olsson AG, Faergeman O, et al. Lipoprotein changes and reduction in the incidence of major coronary heart disase events in the Scandinavian Simvastatin Survival Study (4S). Circulation. 1998;97: Bittner V, Hardison R, Kelsey SF, et al. Non-high-density lipoprotein cholesterol levels predict five-year outcome in the Bypass Angioplasty Revascularization Investigation (BARI). Circulation. 2002;106: Ballantyne CM, Andrews TC, Hsia JA, et al. Correlation of non-high-density lipoprotein cholesterol with apolipoprotein B: effect of 5 hydroxymethylglutaryl coenzyme A reductase inhibitors on non-high density lipoprotein cholesterol levels. Am J Cardiol. 2001;88: Schneck DW, Knopp RH, Ballantyne CM, et al. Comparative effects of rosuvastatin and atorvastatin across their dose ranges in patients with hypercholesterolemia and without active arterial disease. Am J Cardiol. 2003;91: Isaacsohn J, Hunninghake D, Schrott H, et al. Effects of simvastatin, an HMG-CoA reductase inhibitor in patients with hypertriglyceridemia. Clin Cardiol. 2003;26: Frick H, Elo O, Haapa K, et al. Helsinki Heart Study: Primary prevention trial with gemfibrozil in middle-aged men with dyslipidemia. N Engl J Med. 1987;317: Ballantyne CM, Houri J, Notarbartolo A, et al. Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia. Circulation. 2003;107: Davidson MH, McGarry T, Bettis R, et al. Effect of ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia. J Am Coll Cardiol. 2002;40: Dogra GK, Watts GF, Herrmann S, et al. Statin therapy improves brachial artery endothelial function in nephrotic syndrome. Kidney Int. 2002;62: Manninen V, Elo MO, Frick H, et al. Lipid alterations and decline in the incidence of coronary heart disease in the Helsinki Heart Study. JAMA. 1988;260: Athyros VG, Papageorgiou AA, Mercouris BR, et al. Treatment with atorvastatin to the National Cholesterol Educational Program goal versus usual care in secondary prevention of coronary heart disease. The GReEk Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study. Curr Med Res Opin. 2002;4:

6 SUMMER 2004 PREVENTIVE CARDIOLOGY 129 CME QUESTIONS AND ANSWERS Insert your answers on the response page 1. In addition to low-density lipoprotein cholesterol, the following is/are components of non high-density lipoprotein cholesterol: A. Lp(a) B. Triglycerides C. Intermediate-density lipoprotein cholesterol D. All of the above 2. Which of the following statements is/are true? A. Non high-density lipoprotein cholesterol levels are approximately 30 mg/dl higher than low-density lipoprotein cholesterol B. All lipoprotein particles included in non highdensity lipoprotein cholesterol carry apoprotein A on their surfaces C. A and B D. Neither A nor B 3. Which of the following statements is/are true? A. Non high-density lipoprotein cholesterol can be measured in the non-fasting state B. Non high-density lipoprotein cholesterol does not correlate with cardiovascular risk in the elderly C. Statins, fibrates, and ezetimibe lower non highdensity lipoprotein cholesterol D. A and C ACCREDITATION: The University of California, Davis, Health System is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to sponsor continuing medical education for physicians. This activity has been planned and implemented in accordance with the Essential Areas and Policies of the ACCME through the joint sponsorship of Oakstone Medical Publishing and Continuing Medical Education, UC Davis Health System. This CME activity was planned in accordance with the ACCME essentials for enduring materials. Length of time has been determined to be 1 hour. Please read the date of release and date of approval. PHYSICIAN CREDIT: Continuing Medical Education at the University of California, Davis, Health System designates this continuing medical education for 1 hour in Category 1 of the Physician s Recognition Award of the American Medical Association and the Certification Program of the California Medical Association. No partial credit is allowed for this CME activity. FACULTY DISCLOSURE: In accordance with standards of the ACCME and the guidelines of the Association of American Medical Colleges, the authors of this material have been asked to disclose any real or apparent conflicts of interest which may have a direct bearing on the subject matter presented. Authors are expected to disclose: 1) any significant financial interests or other relationships with manufacturers of commercial products and/or providers of commercial services discussed in their presentations; and 2) any off-label uses for pharmaceutical or medical device products discussed in their materials. The intent of this disclosure is not to prevent authors with significant financial or other relationships from making presentations, but rather to provide participants with information with which they can make their own judgments. AUTHOR DISCLOSURE: Dr. Bittner has participated in clinical trials for Pfizer, AtheroGenics, and Merck; and is a member of the speakers bureau for Merck and Merck/Schering-Plough. HOW TO OBTAIN CME CREDIT: To obtain CME credit, the University of California, Davis, Health System, Continuing Medical Education requires that you complete and return the answer sheet and program evaluation form with a check for $25, or you may fax the materials with Visa/MasterCard information for payment. Checks should be made payable to Regents of the University of California and mailed to: Continuing Medical Education, UC Davis Health System, 3560 Business Drive, Suite 130, Sacramento, CA To pay by Visa/Mastercard, please complete the entire application to include credit card number, expiration date and name of cardholder. You may fax this information to (916) Upon completion of the above, your certificate of credit will be mailed to you within 4 weeks. All required information for enduring materials are located at the Office of Continuing Medical Education, UC Davis Health System, 3560 Business Drive, Suite 130, Sacramento, CA Any questions about this process may be directed to Pamela Stotlar-McAuliffe at (916) ; pamela.stotlar-mcauliffe@ucdmc. ucdavis.edu. FACULTY ADVISOR: Ezra A. Amsterdam, MD, Professor of Medicine, Division of Cardiovascular Medicine, University of California, Davis, School of Medicine, and Director, Cardiac Care Unit, University of California, Davis, Medical Center, Sacramento, CA OBJECTIVE AND TARGET AUDIENCE: All primary care physicians and cardiologists are eligible to receive credit. At the conclusion of this activity, participants should be able to: 1) summarize the important points discussed in the paper reviewed; 2) identify patients to whom the paper is relevant; 3) modify management practices as new information is learned; and 4) identify deficiencies in their knowledge base. CME Answers are available on the Preventive Cardiology page at

7 130 INSTRUCTIONS: In order to complete this educational activity successfully, you must: o Complete the post-test. o Complete the program evaluation form. o Enclose a check for $25 payable to: Regents of the University of California or o Submit Visa/MasterCard information. PROGRAM EVALUATION 1. Did the material presented in this educational activity meet the stated learning objectives? o Yes o No 2. Please rate the contents of this activity using the following scale: 1=Poor; 2=Fair; 3=Good; 4=Very Good; 5=Excellent (circle the response for each question) Poor Excellent Timely and up-to-date? Practical? Relevant to your practice? Are there any other topics you would like to have seen addressed in this activity? o Yes (please specify): o No o Mail or fax your completed answer sheet and check to: Continuing Medical Education, UC Davis Health System, 3560 Business Drive, Suite 130, Sacramento, CA 95820; fax: In order to receive CME credit, the answer sheet must be received by July 2006 Thank you 4. Please describe any changes you plan to make in your clinical practice based on the information presented in this program. 5. Did you detect any commercial bias in this activity? o Yes o No If yes, please describe: 6. Any other comments/suggestions for future educational activities relating to preventive cardiology? POST-TEST RESPONSES (Please check the single BEST answer) 1. A B C D 2. A B C D 3. A B C D Please type or print clearly: Re: Bittner V. Non high-density lipoprotein cholesterol: an alternate target for lipid-lowering therapy. Prev Cardiol. 2004;7: , 129, 130. Name: First Last Specialty Degree Street address City State ZIP code Office phone with area code Social Security # (for transcript purposes only) Signature Date Please check your payment method: o Check payable to: Regents of the University of California o Visa o MasterCard Account Number expiration date Authorized signature