A new study shows apolipoprotein B (apoB) and non-high-density-lipoprotein (non-HDL) cholesterol — but not low-density-lipoprotein (LDL) cholesterol — are associated with increased risk for all-cause mortality and myocardial infarction (MI) in patients taking statins.

Moreover, apoB was a more accurate marker of all-cause mortality risk than non-HDL or LDL cholesterol and was more accurate at identifying MI risk than LDL cholesterol.

“Any patient that comes to a doctor for evaluation, if statin treatment is sufficient, the doctor should look not only at LDL cholesterol but HDL cholesterol and apoB, if its available — that is the take-home message,” senior author Børge Grønne Nordestgaard, MD, DMSC, University of Copenhagen, told theheart.org | Medscape Cardiology.

The findings are very relevant to clinical practice because international guidelines focus on LDL cholesterol and “many doctors are brainwashed that that is the only thing they should look at, just to keep LDL cholesterol down,” he said. “I’ve worked for years with triglyceride lipoproteins, what I call remnant cholesterol, and I think that the risk is very high also when you have high remnant cholesterol.”

Previous work has shown that apoB and non-HDL cholesterol better reflect atherosclerotic cardiovascular disease (ASCVD) risk than LDL cholesterol. This is the first study, however, to show that elevated apoB and non-HDL cholesterol are associated with a higher risk for all-cause death in statin-treated patients with low LDL cholesterol, Nordestgaard noted.

The investigators compared outcomes among 13,015 statin-treated participants in the Copenhagen General Population Study using median baseline values of 92 mg/dL for apoB, 3.1 mmol/L (120 mg/dL) for non-HDL cholesterol, and 2.3 mmol/L (89 mg/dL) for LDL cholesterol. Over a median follow-up of 8 years, there were 2,499 deaths and 537 myocardial infarctions.

As reported in the Journal of the American College of Cardiology, discordant apoB above the median with LDL cholesterol below was associated with a 21% increased risk for all-cause mortality (hazard ratio [HR], 1.21; 95% CI, 1.07 – 1.36) and 49% increased risk for MI (HR, 1.49; 95% CI, 1.15 – 1.92), compared with concordant apoB and LDL cholesterol below the medians.

Similar results were found for discordant non-HDL cholesterol above the median with low LDL cholesterol for all-cause mortality (HR, 1.18; 95% CI, 1.02 – 1.36) and MI (1.78; 95% CI, 1.35 – 2.34).

No such associations with mortality or MI were observed when LDL cholesterol was above the median and apoB or non-HDL below.

Additional analyses showed that high apoB with low non-HDL cholesterol was associated with a higher risk for all-cause mortality (HR, 1.21; 95% CI, 1.03- 1.41), whereas high non-HDL with low apoB was associated with a lower risk (HR, 0.75; 95% CI, 0.62 – 0.92).

Current guidelines define apoB greater than 130 mg/dL as a risk modifier in patients not using statins but, the authors write, “based on our results, the threshold for apoB as a risk modifier in statin-treated patients should be closer to 92 mg/dL than to 130 mg/dL.”

In an accompanying editorial, Neil J. Stone, MD, and Donald Lloyd-Jones, MD, both from Northwestern University, Chicago, say that American and European guidelines acknowledge the usefulness of apoB and non-HDL cholesterol in their risk algorithms and as possible targets to indicate efficacy, but don’t give a strong recommendation for apoB to assess residual risk.

“This paper suggests that in the next iteration, we’ve got to give a stronger thought to measuring apoB for residual risk in those with secondary prevention,” Stone, vice-chair of the 2018 American Heart Association/ACC cholesterol guidelines, told theheart.org | Medscape Cardiology.

“The whole part of the guidelines was not to focus on any one number but to focus on the clinical risk as a whole,” he said. “You can enlarge your understanding of the patient by looking at their non-HDL, which you have anyway, and in certain circumstances, for example, people with metabolic syndrome, diabetes, obesity, or high triglycerides, those people might very well benefit from an apoB to further understand their risk. This paper simply highlights that and, therefore, was very valuable.”

Stone and Lloyd-Jones, however, point out that statin use was self-reported and information was lacking on adherence, dose intensity, and the amount of LDL lowering from baseline. LDL levels were also above current recommendations for optimizing risk reduction. “If statin dosing and LDL-C were not optimized already, then there may have been ‘room’ for non-HDL-C and apoB to add value in understanding residual risk,” they write.

The editorialists suggest sequential use, rather than regular use, of apoB and non-HDL cholesterol may be best and that incorporating this information may be particularly beneficial for patients with metabolic disorders and elevated triglycerides after statin therapy.

“Maybe this paper is a wake-up call that there are other markers out there that can tell you that you still have higher risk and need to tighten up lifestyle and maybe be more adherent,” Stone said. “I think this is a wonderful chance to say that preventive cardiology isn’t just ‘set it and forget it’.”

C. Noel Bairey Merz, MD, who coauthored the 2018 cholesterol guidelines, agreed there’s “an over exuberant focus on LDL for residual risk” and highlighted a recent systematic review of statin, ezetimibe, and PCSK9 cardiovascular outcomes trials that showed very little gain from aggressively driving down LDL below 100 mg/dL, unless the patient is at extremely high risk.

“If I, as a treating cardiologist who spends a lot of time on lipids, had a patient on a high-intensity statin and they didn’t drop [their LDL] 50% and I already had them going to cardiac rehab and they were already losing weight, would I measure apoB? Yeah, I might, to motivate them to do more or to take Vascepa,” she said.

“This study is a useful addition to a relatively important problem, which is residual risk, and really supports personalized or precision medicine,” added Bairey Merz, MD, Cedars-Sinai Medical Center, Los Angeles. “But now we have to do the work and do an intervention trial in these people and see whether these markers make a difference.”

The study was supported by Herlev and Gentofte Hospital ‘s Research Fund and the Department of Clinical Biochemistry, Herlev and Gentofte Hospital , Copenhagen University Hospital . Nordestgaard has had consultancies or talks sponsored by AstraZeneca, Sanofi, Regeneron, Akcea, Amarin, Amgen, Esperion, Kowa, Novartis, Novo Nordisk, and Silence Therapeutics. All other authors, Stone, and Lloyd-Jones reported no conflicts. Merz reports no relevant disclosures.

J Am Coll Cardiol. 2021;77:1439-1450, 1451-1453. Abstract, Editorial

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