Juri Khalid Shiha, Ibrahim Fouad A Aljohani, Mansour Hasen Alkhammash, Mostafa Ahmed M Safar, Anmar Yasser Z Rambo, Ziad Tariq M Bahwini, Faez Mutiq A Aljohani, Yousef Sami J AlNowaimi, Ahmed Ghazi A Aljuhani, Abdulqader Hani F Alkathiri, Rafif A Almatrafy, Amna Alrwili, Talal Taiseer Aljuhani, Baraa Faiez Rajab
Lipoprotein(a) (Lp(a)) is a genetically determined, low-density lipoprotein-like particle now recognized as a causal contributor to atherosclerotic cardiovascular disease (ASCVD), yet the magnitude of its association with major adverse cardiovascular events (MACE) has not been quantitatively synthesized across the expanded cohort literature published since 2016. PubMed, Embase, Web of Science, Scopus, and Google Scholar were searched (2016-2026) for cohort or registry studies reporting adjusted associations between Lp(a) and MACE (myocardial infarction, ischemic stroke, heart failure, peripheral artery disease (PAD), aortic stenosis, or cardiovascular death). Screening and extraction followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidance; risk of bias was appraised using the Newcastle-Ottawa Scale (NOS); pooled hazard ratios (HRs) were estimated by random-effects (DerSimonian-Laird) meta-analysis of the highest-versus-reference-category comparison, with subgroup and small-study-effect analyses. Of 152 reports assessed for eligibility, 22 cohort/registry studies (collectively >580,000 participants) met all criteria and were included for narrative synthesis, of which 13 contributed comparable estimates to quantitative pooling. Elevated Lp(a) was associated with significantly higher MACE risk (pooled HR, 1.61; 95% confidence interval {CI}, 1.41-1.85; I² = 87%). Estimates were directionally consistent across prospective (HR: 1.76) and retrospective (HR: 1.74) designs and numerically higher for heart-failure-specific outcomes (HR: 1.82) than for composite atherosclerotic/recurrent-event outcomes (HR: 1.47), though neither subgroup difference reached statistical significance. Egger's regression showed no significant asymmetry (intercept p = 0.18). By NOS, 10/22 studies were high, 9/22 moderate, and 3/22 low quality. Elevated Lp(a) is consistently associated with increased MACE risk across contemporary cohort studies, though substantial heterogeneity and inconsistent effect-metric reporting limit precision. These findings reinforce guideline calls for Lp(a) testing while highlighting the need for standardized categorization and outcome definitions in future cohort research.