Efficacy and safety of folic acid on homocysteine and cardiovascular surrogate biomarkers in hyperhomocysteinemia: a systematic review and meta-analysis of RCTs.

objectiveTo quantify the effect of folic acid supplementation on homocysteine (Hcy) levels and associated cardiovascular risk-related surrogate biomarkers in adults with hyperhomocysteinemia (Hhcy), and to summarise the available safety data.

methodsWe conducted a systematic review and meta-analysis (PROSPERO CRD42024617901) adhering to PRISMA 2020. randomized controlled trials (RCTs) that enrolled adults with Hhcy and compared folic acid monotherapy with placebo or usual care were identified in Web of Science, PubMed, Embase and Cochrane Library (inception-October 2024). Primary outcomes were change in plasma total Hcy and folate concentrations. Secondary outcomes included cardiovascular risk-related surrogate biomarkers: systolic/diastolic blood pressure (SBP/DBP) and lipid profiles.

resultsThirty-six RCTs were included. Folic acid supplementation was associated with dose-dependent reductions in tHcy levels (standardised mean difference [SMD] = - 0.99; 95% CI - 1.15 to - 0.83; I²= 90%). However, these results are statistically significant but highly heterogeneous and at substantial risk of bias, with likely overestimation of effect sizes due to small-study effects and publication bias. The largest SMDs were observed in the higher dose categories (5-15 mg/day) and after ≥ 6 months of treatment. Folate concentrations increased (SMD = 1.61; 95% CI 1.30-1.93). Statistically significant changes were observed in cardiovascular surrogate biomarkers: SBP (SMD = - 0.54), DBP (SMD = - 0.32), high-density lipoprotein cholesterol (HDL-C) (weighted mean difference [WMD] = + 1.37) and low-density lipoprotein cholesterol (LDL-C) (WMD = - 3.64). No cardiovascular adverse events were observed at doses ≤ 10 mg/day, whereas increased cardiovascular events occurred in trials using 15 mg/day (three studies; 35 events). Notably, no study provided adjudicated cardiovascular events (e.g., myocardial infarction, stroke, cardiovascular mortality), and all observed changes are limited to surrogate biomarkers rather than hard clinical endpoints. Therefore, no conclusions can be drawn regarding the reduction of clinical cardiovascular events based on the current evidence.

conclusionsThis meta-analysis indicates that folic acid is associated with low-certainty evidence of reduced total homocysteine (tHcy) and elevated folate levels-the efficacy of folic acid in this analysis is limited to these biomarker changes-along with modest changes in blood pressure and lipid cardiovascular surrogate biomarkers in adults with hyperhomocysteinemia (Hhcy), with a dose-dependent safety profile: no cardiovascular adverse events were observed at doses ≤ 10 mg/day, while increased events occurred exclusively at the 15 mg/day dose. Critically, no included studies reported adjudicated cardiovascular hard endpoints (myocardial infarction, stroke, cardiovascular mortality); target tHcy reduction remains an unvalidated surrogate for clinical cardiovascular disease (CVD) risk reduction, no optimal folic acid dose can be definitively defined from this analysis, and all dose-related considerations are strictly hypothesis-generating. No direct evidence supports that folic acid supplementation reduces clinical cardiovascular event risk. Interpretations of the clinical relevance of these findings must be extremely cautious, and large-scale, high-quality randomized controlled trials with adjudicated cardiovascular hard endpoints are urgently needed to validate the associations of folic acid supplementation with changes in clinical outcomes.