Intervention at Circulating Homocysteine Levels >10 µmol/L for Primary Prevention of Cardiovascular Diseases: A Systematic Review and Dose-Response Meta-Analysis.

Objective: Several studies suggested that the risk of cardiovascular disease (CVD) had increased before individuals developed hyperhomocysteinemia. This study aimed to investigate the dose-response relationship between circulating homocysteine (Hcy) levels and the risk of CVD.

Methods: Observational studies examining the relationship between circulating Hcy levels and CVD risks were included. Searches were conducted on English databases (PubMed, Embase, and Web of Science) and Chinese databases (CNKI, WanFang, VIP, and SinoMed) in May 2025. Combined relative risks (RRs) or odds ratios (ORs) were calculated using random-effects models. The dose-response relationship between circulating Hcy levels and CVD risks was assessed using restricted cubic spline analysis. The risk of bias was assessed using the Newcastle-Ottawa Scale for cohort and case-control studies, and the Agency for Healthcare Research and Quality criteria for cross-sectional studies. Publication bias was assessed using funnel plots and the trim-and-fill method.

Results: A total of 117 original studies (35 cohort studies, 60 case-control studies, and 22 cross-sectional studies) were included, involving 504,469 participants with 43,089 CVD cases. Elevated circulating Hcy levels were significantly associated with increased CVD risks in all study types (RRs/ORs: 1.61-2.14). A non-linear dose-response relationship was observed between circulating Hcy levels and CVD risks (all p < 0.001), with thresholds at 10.4 µmol/L for cohort studies, and 10.0 µmol/L for both case-control studies and cross-sectional studies.

Conclusions: In this meta-analysis, increased Hcy levels were linked to higher CVD risks. Circulating Hcy level >10 µmol/L may implement nutritional intervention in primary prevention of CVD.