Apolipoprotein B and cardiovascular risk

Despite advances in understanding the pathogenesis and prevention of atherosclerotic cardiovascular disease (ASCVD), coronary heart disease (CHD) remains the leading cause of death in the United States.^1,2 Approximately 1 of every 4 deaths in the United States is related to CHD.^1,2

Key contributors to risk reduction for cardiovascular disease (CVD) include management of traditional risk factors (eg, smoking, high blood pressure) and lowering low-density lipoprotein cholesterol (LDL-C).² Earlier interventions provide greater benefits.² Managing inflammation also plays an important role in reducing the buildup of cholesterol and decreasing CVD risk.³ However, managing traditional risk factors and lowering LDL-C to conventional target concentrations may not adequately reduce risk for some patients.² Once identified, patients with risk-enhancing factors (see Sidebar) may benefit from more intensive treatment to improve outcomes.²

High serum levels of apolipoprotein B-100 (ApoB), the primary apolipoprotein attached to atherogenic particles (LDL-C and others), are associated with increased risk of CHD.⁴ Recent studies have indicated that ApoB may have predictive value beyond that of LDL-C and triglyceride (TG) levels, especially in certain at-risk patients.⁵ This article will discuss ApoB in the context of ASCVD and the inclusion of ApoB in guidelines for risk stratification.

ASCVD, lipoproteins, and ApoB

ASCVD is driven by infiltration of the arterial wall by atherogenic particles that are <70 nm in diameter, including LDL-C, intermediate-density lipoprotein cholesterol (IDL-C), very low-density lipoprotein cholesterol (VLDL-C), and lipoprotein (Lp) (a).^2,5,6 Trapped lipoprotein particles cause atherosclerosis through inflammation, the development of a “fatty streak” that leads to smooth muscle proliferation, and eventual development of a plaque.^2,5 Plaques can become large enough that they occlude blood flow, or they can become unstable and rupture, leading to distal artery occlusion.^2,5

The concentration of ApoB represents the concentration of atherogenic lipoprotein particles  because each lipoprotein particle contains 1 molecule of ApoB.⁷ As such, ApoB is a better indicator of atherogenic lipid status than is LDL-C because it also reflects atherogenic TG-rich lipoproteins, such as IDL-C, VLDL-C, and Lp (a).⁸

LDL-C cutpoints and targets may underestimate the risk of developing ASCVD, particularly in conditions associated with very high TG levels, such as insulin resistance, diabetes, metabolic syndrome, and obesity (see Sidebar).^9,10 In persons with these conditions, high TG levels lead to high levels of TG-rich lipoproteins and ApoB levels that are disproportionally high relative to LDL-C. Consequently, LDL-C may be normal, but the overall lipid profile is atherogenic.⁶ Thus, ApoB levels may be a better indicator of atherogenic lipid status than is LDL-C, which may underrepresent ASCVD risk in these patients.¹⁰ High-risk patients on lipid-lowering therapies who have achieved desirable LDL-C levels (eg, <70 mg/dL) may also benefit from measurement of ApoB if their TG levels and, hence, total atherogenic particle concentration remain high.⁶

Measuring ApoB

ApoB concentration is measured directly by automated immunoassays that do not require fasting or complex lipoprotein subfractionation techniques.¹¹ A limitation is that standardized ApoB testing is not yet widely adopted, which can make interlaboratory comparisons challenging and limit its use in determining target levels to begin, or intensify, lipid-lowering therapy (see below).¹²

Evidence supporting ApoB in prediction of CVD risk

Recent evidence supports the hypothesis that ApoB concentration is strongly and independently associated with CVD risk.

• Predictors of myocardial infarction (MI) were examined in a population-based study that included approximately 400,000 persons who were not taking lipid-lowering therapy (primary prevention group) and approximately 40,000 patients with established atherosclerosis who were receiving statin treatment (secondary prevention group).¹³ In both groups, ApoB concentration was the only independent lipid-associated factor that correlated with risk of MI. Other measures, such as total cholesterol and TG level, did not confer additional risk beyond that of ApoB particle concentration. 
• In another study of approximately 13,000 patients receiving statin treatment (median follow-up of 8 years), ApoB was a more accurate marker of all-cause mortality than was LDL-C or non–high-density lipoprotein cholesterol (non–HDL-C) and was a more accurate predictor of MI than was LDL-C.¹³

Guideline recommendations for ApoB testing

American Heart Association/American College of Cardiology (AHA/ACC)

The most recent AHA/ACC guidelines for the Primary Prevention of CVD (2019)² and those for the Management of Blood Cholesterol (2018)¹⁵ include measurement of ApoB to further define risk in intermediate-risk patients. AHA/ACC considers persistent elevation of ApoB (≥130 mg/dL, corresponding to an LDL-C level ≥160 mg/dL) to be a “risk-enhancing factor” that may be useful when TG concentration is ≥200 mg/dL (see Sidebar).^2,15

European Society of Cardiology/European Atherosclerosis Society (ESC/EAS)

ESC/EAS guidelines recommend ApoB testing for risk assessment, particularly in persons with high TG, diabetes, obesity, or metabolic syndrome, and those with very low LDL-C.⁷ The guidelines indicate that ApoB, if available, can be used as an alternative to LDL-C as the primary measurement for screening, diagnosis, and management and may be preferred over non–HDL-C in people with high TG, diabetes, obesity, or very low LDL-C. ApoB goals are <65 mg/dL for persons with very high cardiovascular risk, 80 mg/dL for high risk, and 100 mg/dL for moderate risk.⁷

National Lipid Association (NLA)

The NLA recently provided guidance regarding the measurement of lipids in the management of cardiovascular diseases.⁶ They advised that ApoB may be useful as part of the initial evaluation ordered by clinicians to assess for ASCVD risk enhancers. They also found ApoB measurement to be reasonable for patients on lipid-lowering therapy. In addition, the NLA recommends measuring ApoB to diagnose lipid disorders strongly associated with premature ASCVD, such as familial combined hyperlipidemia and familial dysbetalipoproteinemia (type III hyperproteinemia). The diagnosis is facilitated by assessing ApoB, total cholesterol/ApoB, and TG/ApoB. Notably, the NLA reiterated its 2015 guidance for targets of <80 mg for high-risk patients and <90 mg/dL for primary prevention, but it did not specify a level of ApoB to begin or intensify therapy.^6,16

ApoB as a treatment target

Ongoing studies are examining whether targeting ApoB (eg, modulators of ApoB biogenesis) can serve as an alternate target for cholesterol-lowering drugs; however, no conclusive results have been reported to date.^8,17

Risk-enhancing factors for CVD²

• Family history of premature ASCVD (males, <55 years; females, <65 years)
• Primary hypercholesterolemia (LDL-C, 160-189 mg/dL; non-HDL-C,190-219 mg/dL)
• Metabolic syndrome (assessed by elevations in TGs, blood pressure, or glucose; increased waist circumference; or low HDL: the presence of 3 of these factors makes the diagnosis)
• Chronic kidney disease (estimated glomerular filtration rate [eGFR] 15-59 mL/min/1.73 m² with or without albuminuria; not treated with dialysis or kidney transplantation)
• Chronic inflammatory conditions (eg, psoriasis, rheumatoid arthritis, lupus, HIV/AIDS)
• History of premature menopause (<40 years) and pregnancy-associated conditions that increase later ASCVD risk (eg, preeclampsia)
• High risk based on race or ethnicity
• Lipids biomarkers
  • Persistently elevated hypertriglyceridemia (TG ≥175 mg/dL, non-fasting)
  • Elevated high-sensitivity C-reactive protein (≥2.0 mg/L)
  • Elevated Lp (a): ≥50 mg/dL constitutes risk-enhancing factor; relative indication for measurement is family history of premature ASCVD
  • Elevated ApoB (≥130 mg/dL) constitutes risk-enhancing factor; relative indication for measurement is TG ≥200 mg/dL (≥130 mg/dL corresponds to LDL-C >160 mg/dL)

Prevalence of insulin resistance, metabolic syndrome, diabetes, and obesity in the United States

In recent decades, the prevalence of insulin resistance, metabolic syndrome, diabetes, and obesity has reached epidemic proportions. In persons with these conditions, ApoB concentration may better reflect ASCVD risk than LDL-C concentration:

• National Health and Nutrition Examination Survey (NHANES) data showed that the prevalence of insulin resistance among persons 18 to 44 years of age with no history of diabetes was 45% in the 2007-2010 cycle and 40% in the 2015-2018 cycle.¹⁸
• Analysis of NHANES data from 2011 to 2016 found that the prevalence of metabolic syndrome in the United States was 35%.¹⁹
• The Centers for Disease Control and Prevention (CDC) estimated that in 2018, 34 million adults in the United States 18 years or older (13% of all adults) had diabetes, and approximately 7 million did not know they had the condition.²⁰
• The CDC reported that the prevalence of obesity in the United States was 42% in 2017-2018.²¹

How the laboratory can help

Quest Diagnostics offers testing to evaluate CVD risk and help manage patients with increased or normal risk. Tests include Apolipoprotein B (test code 5224) and Cardio IQ^® Apolipoprotein B (test code 91726), the latter providing an in-depth assessment of cardiovascular risks to guide individualized treatment options for patients. Testing is also available for the prevention, diagnosis, and management of heart failure and other cardiovascular conditions. Additional information is available at QuestDiagnostics.com/Healthcare-Professionals/About-Our-Tests/Cardiovascular.