Clinical Question: Is measurement of apolipoproteins better than traditional lipid measurements for predicting cardiovascular risk? Evidence-Based Answer: Measurement of apolipoprotein B and apolipoprotein A-I is no better than traditional lipid measurements and should not be used to predict cardiovascular risk. (Strength of Recommendation: B, based on meta-analyses with conflicting results.) Apolipoprotein B and non-high-density lipoprotein cholesterol (HDL-C) predict cardiovascular risk slightly better than low-density lipoprotein cholesterol. Elevated levels of apolipoprotein A-I predict a lower risk of cardiovascular events except stroke, but not as well as elevated HDL-C levels

Chang, Jennifer G.

Paulson, Christopher P.

Smith, Rita

English

University of Missouri: MOspace

April 15, 2014 ◆ Volume 89, Number 8 www.aafp.org/afp American Family Physician 662AClinical QuestionIs measurement of apolipoproteins better than traditional lipid measurements for predicting cardiovascular risk?Evidence-Based AnswerMeasurement of apolipoprotein B and apo-lipoprotein A-I is no better than traditional lipid measurements and should not be used to predict cardiovascular risk. (Strength of Recommendation: B, based on meta-analyses with conflicting results.) Apolipoprotein B and non–high-density lipoprotein choles-terol (HDL-C) predict cardiovascular risk slightly better than low-density lipoprotein cholesterol. Elevated levels of apolipopro-tein A-I predict a lower risk of cardiovascu-lar events except stroke, but not as well as elevated HDL-C levels. Evidence SummaryApolipoproteins are structural components of lipoproteins and have a role in receptor binding and enzyme activation. Apolipopro-tein B is carried on all proatherogenic lipo-proteins in a 1:1 ratio, and apolipoprotein A-I is found on nearly all HDL particles.1High levels of apolipoprotein B predict cardiovascular risk about as well as non–HDL-C. A 2012 meta-analysis pooled data from prospective cohort studies of patients without baseline cardiovascular disease and found that non–HDL-C and apolipoprotein B levels were similarly predictive of fatal and nonfatal cardiovascular events2 (Table 1 2-4). Using a clinical model, the authors calcu-lated that substituting total cholesterol and HDL-C measurements with apolipoprotein A-I and B measurements diminished risk prediction by 1% (95% confidence interval [CI], 0.2% to 1.9%), whereas adding them did not significantly improve risk classifi-cation. A 2011 meta-analysis of prospec-tive cohort and case-control studies found that apolipoprotein B was a slightly better predictor of cardiovascular risk than non–HDL-C, and both were superior to low-density lipoprotein cholesterol.3 Among patients receiving statins, mea-surement of apolipoprotein B is comparable to that of non–HDL-C. A 2012 meta-analysis of randomized controlled trials of patients on statin therapy found that time to the first major cardiovascular event was most strongly associated with non–HDL-C levels, followed by apolipoprotein B and low-density lipo-protein cholesterol levels.4 The differences between hazard ratios were small but statis-tically significant (P = .002 for non–HDL-C vs. low-density lipoprotein cholesterol, and P = .02 for non–HDL-C vs. apolipoprotein B).The benefits of measuring apolipoprotein B include the ability to use serum from non-fasting patients, standardization, and direct measurement compared with the calculated measurement of low-density lipoprotein cholesterol, which may be inaccurate in patients with hypertriglyceridemia.5,6Elevated apolipoprotein A-I levels predict coronary events except stroke, but not as well as elevated HDL-C levels. Apolipoprotein A-I levels are inversely associated with cardio-vascular disease. In the 2012 meta-analysis discussed previously, comparable inverse associations for cardiovascular risk were seen with HDL-C and apolipoprotein A-I mea-surements.2 A 2011 prospective cohort study of healthy women found an inverse relation-ship between apolipoprotein A-I levels and the incidence of stroke and coronary events Clinical Inquiries provides answers to questions submitted by practicing family physicians to the Family Physicians Inquiries Network (FPIN). Members of the network select questions based on their relevance to family medi-cine. Answers are drawn from an approved set of evidence-based resources and undergo peer review. The strength of recom-mendations and the level of evidence for individual studies are rated using criteria developed by the Evidence-Based Medicine Working Group (http://www.cebm.net/?o=1025).The complete database of evidence-based ques-tions and answers is copyrighted by FPIN. If interested in submit-ting questions or writing answers for this series, go to http://www.fpin.org or email: questions@fpin.org.A collection of FPIN’s Clinical Inquiries pub-lished in AFP is available at http://www.aafp.org/afp/fpin.Apolipoproteins for Cardiovascular Risk AssessmentJENNIFER G. CHANG, MD, Offutt Air Force Base Family Medicine Residency, Offutt Air Force Base, NebraskaCHRISTOPHER P. PAULSON, MD, Eglin Air Force Base Family Medicine Residency, Eglin Air Force Base, FloridaRITA F. SMITH, MLS, MBA, Wilford Hall Ambulatory Surgical Center, Lackland Air Force Base, TexasFPIN’s Clinical InquiriesClinical Inquiries662B American Family Physician www.aafp.org/afp Volume 89, Number 8 ◆ April 15, 2014(myocardial infarction, coronary revascularization, or coronary death).7 Participants included health care pro-fessionals 45 years and older who were not receiving lipid-lowering therapy and had a low risk of cardiovascular disease. They were grouped into quintiles based on apo-lipoprotein A-I or HDL-C levels. The average follow-up was 11.1 years. There were 319 strokes and 602 coronary events among the 26,881 women. Lower apolipoprotein A-I and HDL-C levels were associated with a higher risk of coronary events except stroke. However, in all quin-tiles the coronary event association with apolipoprotein A-I was weaker than that of HDL-C (hazard ratio for apolipoprotein A-I [lowest vs. highest quintiles] = 1.58 [95% CI, 1.14 to 2.20]; hazard ratio for HDL-C [lowest vs. highest quintiles] = 2.19 [95% CI, 1.51 to 3.19]).7Recommendations from OthersThe American College of Cardiology Foundation/ American Heart Association and the National Academy of Clinical Biochemistry recommend against measure-ment of apolipoproteins or any additional lipid param-eters beyond a standard fasting lipid panel for global cardiovascular risk assessment.8,9 The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the U.S. Air Force Medical Service or the U.S. Air Force at large.Copyright Family Physicians Inquiries Network. Used with permission.Address correspondence to Jennifer G. Chang, MD, at jennifer.chang@us.af.mil. Reprints are not available from the authors.Author disclosure: No relevant financial affiliations. REFERENCES 1. Rader DJ, Hobbs HH. Disorders of lipoprotein metabolism. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J, eds. Harri-son’s Principles of Internal Medicine. 18th ed. New York, NY: McGraw-Hill; 2012:3145-3161. 2. Di Angelantonio E, Gao P, Pennells L, et al.; Emerging Risk Factors Col-laboration. Lipid-related markers and cardiovascular disease prediction. JAMA. 2012;307(23):2499-2506. 3. Sniderman AD, Williams K, Contois JH, et al. A meta-analysis of low-density lipoprotein cholesterol, non-high-density lipoprotein cho-lesterol, and apolipoprotein B as markers of cardiovascular risk. Circ Cardiovasc Qual Outcomes. 2011;4(3):337-345. 4. Boekholdt SM, Arsenault BJ, Mora S, et al. Association of LDL choles-terol, non-HDL cholesterol, and apolipoprotein B levels with risk of car-diovascular events among patients treated with statins: a meta-analysis [published corrections appear in JAMA. 2012;307(16):1694 and JAMA. 2012;307(18):1915]. JAMA. 2012;307(12):1302-1309. 5. Denke MA. Weighing in before the fight: low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol versus apoli-poprotein B as the best predictor for coronary heart disease and the best measure of therapy. Circulation. 2005;112(22):3368-3370. 6. Ramjee V, Sperling LS, Jacobson TA. Non-high-density lipoprotein cho-lesterol versus apolipoprotein B in cardiovascular risk stratification: do the math. J Am Coll Cardiol. 2011;58(5):457-463. 7. Mora S, Buring JE, Ridker PM, Cui Y. Association of high-density lipo-protein cholesterol with incident cardiovascular events in women, by low-density lipoprotein cholesterol and apolipoprotein B100 levels: a cohort study. Ann Intern Med. 2011;155(11):742-750. 8. Greenland P, Alpert JS, Beller GA, et al. 2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2010; 56(25):e50-e103. 9. Myers GL, Christenson RH, Cushman M, et al.; NACB LMPG Committee Members. National Academy of Clinical Biochemistry Laboratory Medi-cine Practice guidelines: emerging biomarkers for primary prevention of cardiovascular disease. Clin Chem. 2009;55(2):378-384. ■Table 1. Summary of Meta-analyses Comparing Apolipoproteins vs. Traditional Lipid Measurements for Predicting Adverse Cardiovascular EventsNumber and type  of studies Outcomes measuredAdverse  events Biomarker measuredRisk of elevated biomarker  (95% CI)26 prospective cohort trials  (N = 139,581)2Fatal and nonfatal coronary artery disease and stroke12,234 Non–HDL-C HR = 1.27 (1.22 to 1.33)*Apolipoprotein B HR = 1.24 (1.19 to 1.29)*Apolipoprotein A-I HR = 0.87 (0.84 to 0.90)*HDL-C HR = 0.83 (0.78 to 0.87)*12 (8 prospective cohort and case-control studies;  N = 233,455)3Fatal and nonfatal ischemic cardiovascular events22,950 Apolipoprotein B RR = 1.43 (1.35 to 1.51)†Non–HDL-C RR = 1.34 (1.24 to 1.44)†Low-density lipoprotein cholesterolRR = 1.25 (1.18 to 1.33)†8 randomized controlled trials  (N = 38,153)4Fatal or nonfatal myocardial infarction, fatal coronary artery disease, hospitalization for unstable angina, and fatal or nonfatal stroke at 1 year6,286 Non–HDL-C HR = 1.16 (1.12 to 1.19)*Apolipoprotein B HR = 1.14 (1.11 to 1.18)*Low-density lipoprotein cholesterolHR = 1.13 (1.10 to 1.17)*CI = confidence interval; HDL-C = high-density lipoprotein cholesterol; HR = hazard ratio; RR = relative risk.*—HR is calculated as the increased or decreased risk of an adverse event per standard deviation increase in the biomarker.†—RR is calculated as the increased risk of an adverse event per standard deviation increase in the biomarker.Information from references 2 through 4.

Apolipoproteins for Cardiovascular Risk Assessment

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Apolipoproteins for Cardiovascular Risk Assessment

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