Small dense low-density lipoprotein cholesterol and risk of cardiovascular events in general adults: a systematic review and meta-analysis of prospective studies.

OBJECTIVES

Small dense low-density lipoprotein cholesterol (sdLDL-C) is considered one of the most atherogenic lipid fractions, but its association with cardiovascular events and whether this differs by assessment method remain uncertain. We conducted a systematic review and meta-analysis of prospective cohort studies to quantify this association.

DESIGN

Systematic review and meta-analysis of prospective cohorts; PROSPERO registered (CRD420261411427).

DATA SOURCES: PubMed, ProQuest Health & Medical Collection, MEDLINE (Ovid) and Web of Science Core Collection were searched from inception to June 2026.

ELIGIBILITY CRITERIA: Prospective cohort studies of community-based or population-based adults reporting HRs for incident cardiovascular events across baseline sdLDL-C categories were eligible.

DATA EXTRACTION AND SYNTHESIS: Data were extracted independently by two reviewers. Random-effects restricted maximum likelihood models pooled HRs for the highest versus lowest sdLDL-C categories and for quartile (Q)2, Q3 and Q4 versus Q1 comparisons, stratified by sdLDL-C assessment method. Sensitivity analyses, risk-of-bias assessment, Bayesian hierarchical relative-to-an-identified-distribution (RIDIT)-based modelling and Grading of Recommendations, Assessment, Development and Evaluations (GRADE) assessment were performed.

RESULTS

Fourteen studies were included, comprising 738 114 participants and 77 839 incident cardiovascular events. In the highest-versus-lowest comparison, the pooled HR was 1.47 (95% CI 1.32 to 1.63). The association was stronger for directly measured than calculated sdLDL-C (HR 1.64, 95% CI 1.38 to 1.94 vs HR 1.37, 95% CI 1.21 to 1.54). Between-study heterogeneity was substantial in several analyses. Pairwise quantile and Bayesian RIDIT-based analyses supported a graded positive exposure–risk pattern. Leave-one-out analyses did not materially change the estimates, and Egger’s tests showed no small-study effects. Risk of bias was low to moderate. GRADE certainty was moderate for calculated sdLDL-C and low for the overall and directly measured analyses.

CONCLUSION

Higher baseline sdLDL-C is associated with increased incident cardiovascular event risk in general adult populations and may serve as an accessible marker of atherogenic cardiovascular risk.