Physicians' Academy for Cardiovascular Education

ApoB and non-HDL-c are better markers of residual risk than LDL-c in statin-treated patients

Apolipoprotein B and Non-HDL Cholesterol Better Reflect Residual Risk Than LDL Cholesterol in Statin-Treated Patients

Literature - Johannesen CDL, Mortensen MB, Langsted A et al. - J Am Coll Cardiol. 2021 Mar 23;77(11):1439-1450. doi: 10.1016/j.jacc.2021.01.027.

Introduction and methods

LDL-c is the primary target in major guidelines on hypercholesterolemia, while apoB and non-HDL-c are secondary targets [1-3]. ApoB, non-HDL-c and LDL-c are highly correlated, but apoB and non-HDL-c include triglyceride-rich lipoproteins in addition to LDL [4-6]. Residual risk of ASCVD remains a challenge during statin therapy. Previous studies have shown that apoB and non-HDL-c are more strongly associated with ASCVD than LDL-c [7-9]. However, discordance analyses on ASCVD risk in statin-treated patients have not been performed to date. In addition, the relative importance of apoB, non-HDL-c and LDL-c on risk of all-cause mortality in patients on statin therapy remains unknown. This study evaluated whether elevated apoB and/or non-HDL-c better reflect residual risk of all-cause mortality and MI than LDL-c in statin-treated patients.

The study included 13,015 individuals from the Copenhagen General Population study. The Copenhagen General Population study was initiated in 2003 to 2015 and reflects the white Danish general population. Participants were aged 20-100 years at baseline. Individuals included in this study were treated with statins and had measurements of apoB, non-HDL-c and LDL-c at baseline. Median follow-up was 8 years. Analyses were adjusted for age, sex, smoking status, pack-years, SBP, and any diagnosis of ASCVD, cancer, or chronic obstructive pulmonary disease at baseline. Hazard ratios of all-cause mortality and MI were estimated by Cox proportional hazards regressions on categories of discordant vs. concordant categories of 1) apoB vs LDL-c; 2) non-HDL-c vs LDL-c; 3) apoB vs non-HDL-c; and 4) apoB vs non-HDL-c vs LDL-c.

Main results

Multivariable-adjusted risk of all-cause mortality

Multivariable-adjusted risk of MI


Elevated apoB and non-HDL-c were associated with increased risk of all-cause mortality and MI in statin-treated patients. No association was found between elevated LDL-c and all-cause mortality or MI. Thus, the results of this study suggest that elevated apoB and non-HDL-c better reflect residual risk in patients on statins than elevated LDL-c. Discordant analyses showed that apoB is a more accurate marker of all-cause mortality risk than LDL-c or non-HDL-c in statin-treated patients.

Editorial comment

In their editorial comment [10], Neil J. Stone, MD and Donald Lloyd-Jones, MD dive into the question which patients with low statin-treated levels still have elevated non-HDL-c or apoB. And, how can/should these patients be treated? Stone and Lloyd-Jones suggest that these patients will in general be those with metabolic disorders, such as obesity, insulin resistance and/or diabetes, with concomitant risk related to elevated triglycerides, hypercoagulability, inflammation, and elevated Lp(a). Non-HDL-c and apoB markers could be used to motivate and monitor the success of lifestyle changes, as elevations in non-HDL-c and apoB often respond well to improvements in diet, weight loss and increased physical activity. Another potential treatment option to reduce residual risk in statin-treated patients is use of high-dose icosapent ethyl in high risk patients who are well treated with statins.

Stone and Lloyd-Jones further discuss a sequential approach in the treatment of patients with hypercholesterolemia; first achieve as much risk reduction as possible through statins (and adjunctive ezetimibe or PCSK9 inhibition), and then assess the non-HDL-c and apoB level. A possible strategy to efficiently identify those with residual risk while being on optimal statin therapy could be to start with selected groups where the subsequent benefit of additional therapy is likely to be highest; those with hypertriglyceridemia, obesity, metabolic syndrome, or diabetes.

Current American and European guidelines acknowledge the usefulness of apoB and non-HDL-c in risk calculations. However, they do not strongly recommend measurement of apoB for assessing residual risk. Stone and Lloyd-Jones argue that guideline panels should consider whether apoB and non-HDL-c should be routinely or selectively measured and how these measurements could influence guideline-directed care.


Show references

Find this article online at J Am Coll Cardiol. Find the editorial comment at J Am Coll Cardiol.

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