FPIN's Clinical Inquiries

Apolipoproteins for Cardiovascular Risk Assessment

 


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Am Fam Physician. 2014 Apr 15;89(8):662A-662B.

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.

Evidence Summary

Apolipoproteins are structural components of lipoproteins and have a role in receptor binding and enzyme activation. Apolipoprotein B is carried on all proatherogenic lipoproteins in a 1:1 ratio, and apolipoprotein A-I is found on nearly all HDL particles.1

High 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 124). Using a clinical model, the authors calculated 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 classification. A 2011 meta-analysis of prospective 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

View/Print Table

Table 1.

Summary of Meta-analyses Comparing Apolipoproteins vs. Traditional Lipid Measurements for Predicting Adverse Cardiovascular Events

Number and type of studiesOutcomes measuredAdverse eventsBiomarker measuredRisk of elevated biomarker (95% CI)

26 prospective cohort trials (N = 139,581)2

Fatal and nonfatal coronary artery disease and stroke

12,234

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)3

Fatal and nonfatal ischemic cardiovascular events

22,950

Apolipoprotein B

RR = 1.43 (1.35 to 1.51)†

Non–HDL-C

RR = 1.34 (1.24 to 1.44)†

Low-density lipoprotein cholesterol

RR = 1.25 (1.18 to 1.33)†

8 randomized controlled trials (N = 38,153)4

Fatal or nonfatal myocardial infarction, fatal coronary artery disease, hospitalization for unstable angina, and fatal or nonfatal stroke at 1 year

6,286

Non–HDL-C

HR = 1.16 (1.12 to 1.19)*

Apolipoprotein B

HR = 1.14 (1.11 to 1.18)*

Low-density lipoprotein cholesterol

HR = 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.

Table 1.

Summary of Meta-analyses Comparing Apolipoproteins vs. Traditional Lipid Measurements for Predicting Adverse Cardiovascular Events

Number and type of studiesOutcomes measuredAdverse eventsBiomarker measuredRisk of elevated biomarker (95% CI)

26 prospective cohort trials (N = 139,581)2

Fatal and nonfatal coronary artery disease and stroke

12,234

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)3

Fatal and nonfatal ischemic cardiovascular events

22,950

Apolipoprotein B

RR = 1.43 (1.35 to 1.51)†

Non–HDL-C

RR = 1.34 (1.24 to 1.44)†

Low-density lipoprotein cholesterol

RR = 1.25 (1.18 to 1.33)†

8 randomized controlled trials (N = 38,153)4

Fatal or nonfatal myocardial infarction, fatal coronary artery disease, hospitalization for unstable angina, and fatal or nonfatal stroke at 1 year

6,286

Non–HDL-C

HR = 1.16 (1.12 to 1.19)*

Apolipoprotein B

HR = 1.14 (1.11 to 1.18)*

Low-density lipoprotein cholesterol

HR = 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.

Among patients receiving statins, measurement 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 lipoprotein cholesterol levels.4 The differences between hazard ratios were small but statistically 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.5,6

Elevated 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 cardiovascular disease. In the 2012 meta-analysis discussed previously, comparable inverse associations for cardiovascular risk were seen with HDL-C and apolipoprotein A-I measurements.2 A 2011 prospective cohort study of healthy women found an inverse relationship between apolipoprotein A-I levels and the incidence of stroke and coronary events (myocardial infarction, coronary revascularization, or coronary death).7 Participants included health care professionals 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 apolipoprotein 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 quintiles 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]).7

Recommendations from Others

The American College of Cardiology Foundation/American Heart Association and the National Academy of Clinical Biochemistry recommend against measurement of apolipoproteins or any additional lipid parameters beyond a standard fasting lipid panel for global cardiovascular risk assessment.8,9

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.

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.

REFERENCES

show all references

1. Rader DJ, Hobbs HH. Disorders of lipoprotein metabolism. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J, eds. Harrison'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 Collaboration. 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 cholesterol, 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 cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular 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 apolipoprotein 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 cholesterol 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 lipoprotein 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 Medicine Practice guidelines: emerging biomarkers for primary prevention of cardiovascular disease. Clin Chem. 2009;55(2):378–384.

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 medicine. Answers are drawn from an approved set of evidence-based resources and undergo peer review. The strength of recommendations 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 questions and answers is copyrighted by FPIN. If interested in submitting 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 published in AFP is available at http://www.aafp.org/afp/fpin.



 

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