Is an apolipoprotein test warranted for a patient with a low-density lipoprotein (LDL) level of 81 mg/dL who is already on a high-intensity statin?

Apolipoprotein B Testing in Patients with LDL 81 mg/dL on High-Intensity Statins

Yes, apolipoprotein B (apoB) testing is warranted in this patient, as it provides critical information about residual cardiovascular risk that LDL-C alone cannot capture, particularly in statin-treated patients.

Why ApoB Testing Matters Despite Controlled LDL-C

ApoB is a superior marker of residual cardiovascular risk in statin-treated patients compared to LDL-C alone. In patients receiving statin therapy, LDL-C, non-HDL-C, and apoB are all markers of residual risk, but apoB provides unique information 1. Research demonstrates that among statin-treated patients, non-HDL cholesterol and apoB are more closely associated with cardiovascular outcomes than LDL-C levels 2.

The Problem of Discordance

Even when LDL-C appears well-controlled at 81 mg/dL, there can be substantial variability in apoB levels:

• At an LDL-C of approximately 130 mg/dL (±10 mg/dL), the apoB range necessary to capture 95% of observations spans 85.8-108.8 mg/dL—a clinically meaningful difference 3
• Patients with high apoB despite controlled LDL-C have significantly higher 10-year cardiovascular event rates (7.3% vs 4.0%) compared to those with low apoB at similar LDL-C levels 3
• Among patients already at LDL-C goal for non-HDL-C, 50% of those with coronary heart disease and 33% of other high-risk adults were not at apoB goals 4

Evidence for Residual Risk Assessment

The correlation between apoB and LDL-C, while strong overall (r=0.96), becomes less reliable during statin treatment 5. Importantly:

• In adjusted models accounting for traditional risk factors, residual apoB remained statistically significant for predicting cardiovascular events even after accounting for LDL-C and HDL-C (hazard ratio 1.06,95% CI 1.0-1.07) 3
• When apoB was included in prediction models, residuals of LDL-C no longer remained significant, demonstrating that apoB captures information that LDL-C misses 3
• Among statin users in the National Health and Nutrition Examination Survey, only 52% were at apoB goal despite 64% being at LDL-C goal 4

When ApoB Testing is Most Valuable

ApoB testing should be prioritized in patients with clearly established cardiovascular risk to guide residual risk discussions 1. This is particularly important for:

• Secondary prevention patients (those with established atherosclerotic cardiovascular disease) where the benefits of further lipid lowering are clearest 1
• Patients with elevated triglycerides and/or low HDL-C, as these conditions increase discordance between LDL-C and apoB 1
• Younger patients on statin therapy, where the association of on-statin apoB with cardiovascular risk is more pronounced 6

Clinical Application

The guideline framework suggests that lipid goals should be used to guide residual risk discussions on follow-up among those with clearly established ASCVD risk, with maximizing statin dose as the first priority 1. However, this does not mean abandoning additional risk assessment:

• An apoB goal of 80 mg/dL corresponds to an LDL-C of approximately 74 mg/dL during statin therapy (lower than the traditional 70 mg/dL target) 5
• For patients with high triglycerides, the corresponding on-treatment LDL-C target to match apoB of 80 mg/dL is even lower at 68 mg/dL 5
• If apoB is elevated despite LDL-C of 81 mg/dL, this should prompt a discussion about residual risk and options for further intensification, including lifestyle improvements and consideration of add-on therapy such as ezetimibe 1

Common Pitfalls to Avoid

• Do not assume that an LDL-C of 81 mg/dL means optimal risk reduction has been achieved—the wide variability in apoB at this LDL-C level means some patients remain at substantially elevated risk 3
• Do not reflexively add medications based solely on apoB results—the measurement should prompt a risk discussion and consideration of whether the patient is truly at "very high risk" where additional therapy is most clearly beneficial 1
• Do not ignore that non-HDL cholesterol (calculated as total cholesterol minus HDL-C) is an adequate surrogate for apoB during statin therapy if apoB testing is unavailable, with a target of approximately 92 mg/dL to match an apoB goal of 80 mg/dL 5

The 2019 ACC/AHA Guideline Framework

For patients with clinical atherosclerotic cardiovascular disease who are at "very high risk" (history of multiple major ASCVD events or one major event plus multiple high-risk conditions), if on maximal statin therapy with LDL-C ≥70 mg/dL, adding ezetimibe is reasonable 1. ApoB testing helps identify which patients at LDL-C 81 mg/dL actually have residual atherogenic particle burden warranting this discussion, as some may have apoB levels well above 80 mg/dL despite seemingly controlled LDL-C 4, 3.