The association between remnant cholesterol and cardiovascular events: A systematic review and meta-regression

BACKGROUND Despite extensive efforts to lower low-density lipoprotein cholesterol (LDL-C), cardiovascular disease remains highly prevalent. Remnant cholesterol (RC) has been proposed as a potentially more relevant therapeutic target. OBJECTIVE To evaluate the association between RC reduction and cardiovascular outcomes in randomized controlled trials (RCTs) of cholesterol- and triglyceride-lowering therapies, assessing whether RC independently influences cardiovascular risk. METHODS Cochrane Central and Embase were searched for RCTs with ≥1000 participants and ≥2 years' planned duration that assessed cholesterol- or triglyceride-lowering therapies vs placebo, usual care, or other lipid-lowering drugs in adults. Two reviewers independently extracted data and evaluated methodological quality. Meta-analysis and meta-regression were performed. RESULTS Forty-three RCTs met the inclusion criteria; most had some risk of bias, and evidence certainty was moderate. Meta-analysis showed absolute risk reductions of 0.4% (95% CI 0.1%-0.6%) for all-cause mortality, 1.3% (95% CI 1.1%-1.6%) for myocardial infarction, and 0.4% (95% CI 0.2%-0.6%) for stroke in treatment vs control groups. Meta-regression demonstrated no association between RC reduction and any clinical outcome, whereas LDL-C and non–high-density lipoprotein cholesterol reductions were associated with risk reduction. CONCLUSION RC reduction was not associated with cardiovascular benefit. This contrasts with observational and Mendelian randomization studies, likely reflecting methodological differences; MR estimates lifelong genetically mediated exposure and may not reliably predict the effects of short-term pharmacological lipid lowering. Lay summary In a review of 43 large clinical trials, lowering "remnant cholesterol" did not reduce heart attacks, strokes, or deaths — unlike lowering LDL ("bad") cholesterol, which did — suggesting that remnant cholesterol may not be a useful treatment target despite earlier studies hinting otherwise. Summary sentence A review of 43 clinical trials found that lowering remnant cholesterol did not translate into fewer deaths, heart attacks, or strokes. •Cholesterol-lowering treatments modestly reduced deaths, heart attacks, and strokes overall. •These benefits were not linked to changes in remnant cholesterol levels. Main findings