For an adult patient without a history of coronary artery disease, should I order apolipoprotein B and apolipoprotein A‑I levels and calculate the ApoB/ApoA‑I ratio to evaluate cardiovascular risk?

Apolipoprotein Testing for Cardiovascular Risk Assessment

Do not routinely order apolipoprotein B, apolipoprotein A-I, or calculate the ApoB/ApoA-I ratio for cardiovascular risk assessment in asymptomatic adults without established coronary artery disease. The ACC/AHA provides a Class III (No Benefit) recommendation against measuring lipid parameters including apolipoproteins beyond a standard fasting lipid profile for risk assessment in asymptomatic adults 1.

Guideline-Based Recommendations Against Routine Testing

The 2010 ACC/AHA guideline explicitly states that measurement of apolipoproteins beyond standard lipid profiles is not recommended for cardiovascular risk assessment in asymptomatic adults 1. This represents the strongest level of recommendation against routine use 2.

Key evidence supporting this recommendation:

• The Framingham Heart Study demonstrated little additional risk information from ApoB or ApoB/ApoA-I ratio compared with the total/HDL-cholesterol ratio 1
• Systematic reviews found no study has reported incremental predictive value of apolipoprotein measurements beyond traditional cardiovascular risk factors 1
• No evidence exists that assessment of additional lipid parameters leads to improved net health outcomes 1

Limited Exceptions Where ApoB May Be Considered

ApoB measurement (not ApoA-I or the ratio) may be reasonable in highly selected patients:

The 2018 ACC/AHA cholesterol guideline identifies specific circumstances where ApoB measurement could refine risk assessment 1, 3:

• Adults aged 40-75 years with borderline (5-7.4%) or intermediate (7.5-19.9%) 10-year ASCVD risk 3, 2
• Patients with persistent triglycerides ≥200 mg/dL, where discordance between LDL-C and actual atherogenic particle number is common 1, 3
• Patients with metabolic syndrome, diabetes, or chronic kidney disease 3, 2

In these selected cases, ApoB ≥130 mg/dL constitutes a risk-enhancing factor that favors statin initiation or intensification 1, 3, 2.

Why ApoA-I and the ApoB/ApoA-I Ratio Are Not Recommended

The evidence base for therapeutic interventions is fundamentally asymmetric:

• Lowering ApoB (the numerator) has very strong evidence from statin trials 1, 4
• Raising ApoA-I (the denominator) lacks evidence for clinical benefit 1, 4
• No controlled trials have evaluated ApoA-I as a primary treatment target 4

Critical pitfall: The ApoB/ApoA-I ratio could theoretically be lowered by raising HDL/ApoA-I while leaving LDL/ApoB unchanged, but there is no evidence that drug therapy to increase HDL improves outcomes 1. This makes the ratio problematic as a treatment target despite some observational studies showing associations with coronary disease 5, 6, 7.

Practical Clinical Algorithm

For routine cardiovascular risk assessment in asymptomatic adults:

1. Obtain standard fasting lipid profile (total cholesterol, LDL-C, HDL-C, triglycerides) 1, 2
2. Calculate 10-year ASCVD risk using validated risk calculators 2
3. Do not order ApoA-I or ApoB/ApoA-I ratio 1, 2

For selected intermediate-risk patients with persistent hypertriglyceridemia:

1. If triglycerides persistently ≥200 mg/dL and 10-year ASCVD risk is 5-19.9%, consider measuring ApoB only (not ApoA-I) 1, 3
2. If ApoB ≥130 mg/dL, this constitutes a risk-enhancing factor favoring statin therapy 1, 3
3. Target ApoB <100 mg/dL for high-risk patients or <80 mg/dL for very high-risk patients if treatment is initiated 3, 4

Important Caveats

Standardization and cost concerns: ApoB measurement carries extra expense, and measurement reliability varies across laboratories 1. Traditional lipid measurements remain robust and supported by a major evidence base 4.

Research versus clinical practice disconnect: While some observational studies suggest ApoB and the ApoB/ApoA-I ratio predict coronary events better than standard lipids 5, 6, 7, 8, these associations have not translated into improved clinical outcomes or risk reclassification in prospective validation studies 1. The 2004 and 2009 studies showing superior prediction with apolipoproteins 5, 8 predate the definitive 2010 ACC/AHA guideline analysis that found no incremental benefit 1.

The relationship between ApoA and HDL is less direct than between ApoB and LDL, making ApoA-I a less reliable marker 1, 2. Each LDL particle contains exactly one ApoB molecule, but the ApoA-I to HDL relationship is more complex 1, 4.