Supplements
folic acid decreases cardiovascular disease
Strong support Supplements
Part of: 🧪 Folate & L-methylfolate
RefutedContestedStrong support
consensus score 1.00
📅 Last reviewed: 2026-07-15 ⓘ
Evidence ladder
How far up the ladder this claim has climbed. A high consensus on a low rung means "consistent so far," not "proven in people."
Top evidence so far: All trials, pooled (Meta-analysis)
MechanismIn-vitroAnimalObservationalRCTMeta-analysis
How the studies fall
4 support 0 contradict 0 tested null 0 mixed · 4 sources, 4 independent groups
What the evidence shows
Folate / B-vitamin homocysteine-lowering modestly reduces stroke risk (most in low-folate / high-homocysteine settings).
The evidence (7)
| Source | Grade | Stance | Quality | Finding |
|---|---|---|---|---|
| Xie K et al 2026 · Ren Fail | RCT | supports | low | OFF-SCOPE for a stroke-specific claim: the trial's only vascular result is an undifferentiated safety tally - 'During the follow-up period, a total of 42 cardiovascular and cerebrovascular AEs occurred, including 14 and 28 in the treatment and placebo groups, respectively' (p = 0.001) - with no stroke stratum reported anywhere in the paper. Where the paper does isolate cerebrovascular disease, as cause of death, the result is null: no significant difference (p = 0.688) 'between the treatment and placebo groups in the 16 patients who died from cardiovascular and cerebrovascular diseases', and all-cause mortality was identical (12.1% vs 12.0%, p = 0.978). The intervention is also thiamin 90 mg/day PLUS folic acid 30 mg/day, and the authors concede 'The combination therapy design makes it difficult to distinguish the independent effects of thiamin and folic acid', so nothing here is attributable to folate alone. |
| Dai D et al 2026 · Medicine (Baltimore) | observational | supports | low | Prospective single-centre cohort, 799 hemorrhagic-stroke + H-type hypertension patients (tHcy >= 10 umol/L) all prescribed enalapril 10 mg + folic acid 0.8 mg daily, median 9.6 months; comparison is high (>=70%) vs low (<70%) ADHERENCE, not treatment vs placebo. 'Patients with high adherence to enalapril-folic acid therapy exhibited significantly reduced risks of CVD (hazard ratio [HR]: 0.16; 95% confidence interval [CI]: 0.06-0.45), recurrent hemorrhagic stroke (HR: 0.21; 95% CI: 0.07-0.67), and all-cause mortality (HR: 0.14; 95% CI: 0.05-0.41).' Quality low: the all-cause mortality HR 0.14 is not a credible effect of 0.8 mg folate over 9.6 months and marks the contrast as healthy-adherer confounded; only 21 recurrent-stroke events; and the fixed enalapril+folate combination has no arm isolating folic acid. Authors: 'further randomized controlled trials are required to confirm its efficacy.' |
| Zhang 2024 · Clin Nutr | meta-analysis | supports | high | MA of 21 RCTs, 115,559 participants: folic acid 'significantly reduced the risk of stroke by 10% (RR 0.90, 95%CI 0.83 to 0.98)'. Benefit is confined to unfortified/partially-fortified regions (RR 0.83, 95%CI 0.75-0.93) and absent where grain is fortified (RR 1.04, P-interaction = 0.003); within that stratum it is largest in primary prevention (RR 0.77 vs 0.94, P-interaction = 0.008). Efficacy 'remained consistent regardless of baseline folate levels ... [and] homocysteine reduction' (all P-interaction>0.05) — so the paper supports the folic-acid-to-stroke effect but not the homocysteine-lowering mechanism. |
| Kagawa Y, Sakamoto K, Shoji K, Nishijima C, Hiraoka M 2026 · Nutrients | observational | supports | low | Sakado Folate Project, Japan - self-evaluation of the corresponding author's own 20-year community programme; ECOLOGICAL, off-scope for this claim. The paper never pairs folate or homocysteine with a stroke outcome. Its measured arm is 888 volunteers (144 M mean age 66.2, 744 F mean age 63.5; MTHFR CC 299 / CT 437 / TT 152) in an uncontrolled 6-month before-after: serum folate target >=9.5 ng/mL met by 63.4% before vs 76.1% after (p<0.001) and tHcy <=7 umol/L by 33.1% vs 55.3% (p<0.001) - biochemistry only, zero clinical events. The stroke number lives in a different population entirely: the abstract's 'standardized prevalence ratios of 52% for stroke and 86% for cerebral infarction' is not what the Results show - section 3.5 reports 'Sakado City had lower expenditure rates for many diseases, including stroke (52%) and diabetes mellitus (76%)', Figure 8 is captioned as relative medical EXPENSES vs Saitama Prefecture (2015, sourced to ref [26], not computed here), no standardization method appears anywhere, and the 86% cerebral-infarction figure is absent from the body. In that population the exposure is imputed, not measured: 'Since plasma fatty acids, FADS1 genotypes, folate and homocysteine levels are not analyzed in the National and local Health Checkup, these analyses were conducted in a subset of participants'. Exposure is also not folate - the programme counselled on MTHFR (folate), AGT (salt <6 g/d), ADRB3 + UCP1 (200 kcal/d restriction), later FADS1 (fish/DHA), atop citywide lectures and a school Shokuiku programme; 888 of 99,565 residents (0.9%) received it and only ~39% attend any checkup. Volunteers were 'more health-conscious than the general population' by the authors' own admission, and they concede 'causal relationships cannot be established because of the observational nature of the population-level analysis.' Retained as an off-scope record, not a vote. |
| folate-stroke-2016 2016 | meta-analysis | supports | moderate | MA of 30 RCTs (82,334 participants); stroke arm 20 RCTs, 77,816 participants: RR 0.90 (0.84-0.96) fixed-effect, 0.88 (0.80-0.98) random-effects (the pre-specified primary model). No CHD effect: RR 1.04 (0.99-1.09). Benefit concentrated where baseline folate was low: RR 0.79 (0.69-0.89) at folate <16 nmol/L vs 0.97 (0.86-1.08) at >=16 nmol/L, P=0.02 for interaction; and in primary prevention, RR 0.86 (0.79-0.94) without preexisting CVD vs 0.98 (0.94-1.03) with. Every included trial enrolled people with preexisting disease. Authors' own caveat: 'The lack of a dose-response relationship between degree of homocysteine reduction and risk of stroke may not support a causal link between folic acid supplementation and stroke.' Funding: 'This research is partly supported by Metagenics'; 'Dr Hu has received research support from Metagenics and served as a consultant for Metagenics.' |
| Ghattas Hasbun 2025 · BMC Nutr 2025;11:203 | meta-analysis | supports | moderate | MA of 45 RCTs / 96,962 participants (PROSPERO CRD42024525945). Stroke arm 23 studies, 83,247 participants: 'patients receiving folic acid supplementation had a stroke risk of RR 0.85 (95% CI: 0.76; 0.96, p < 0.01, I2 = 47%). The prediction interval ranged from 0.59 to 1.23' — so the pooled effect is significant but the prediction interval crosses null; excluding one outlier (Ebbing 2008) attenuates it to RR 0.89 (0.82-0.97), I2=24%. Composite CVD RR 0.95 (0.90-0.99, p=0.04); null for mortality RR 0.98 (0.93-1.02), CHD RR 0.98 (0.91-1.06), PAD RR 0.94 (0.75-1.17), HDL and LDL. Effect modification runs through FOLATE status, not homocysteine: stroke RR 0.72 (0.54-0.96) at baseline folate <16 nmol/L vs 0.93 (0.81-1.07) above, while degree of homocysteine lowering did not predict stroke benefit (fall >4 µmol/L RR 0.92, 0.81-1.04; baseline Hcy >15 µmol/L RR 0.98, 0.74-1.29; Suppl. Table 9). Low-risk-of-bias studies alone: RR 0.85 (0.73-1.00). Funnel plot asymmetric (Egger's p=0.47). No external funding, no declared competing interests. NOT independent of folate-stroke-2016: 'Additionally, 30 records were identified from a previous meta-analysis, but only 27 were retrieved.' |
| Awashra A et al 2026 · Nutr Metab (Lond) | observational | supports | moderate | Narrative review (non-systematic PubMed/Scopus/Google Scholar search, no protocol or risk-of-bias appraisal), zero-weighted as review. Its stroke conclusion matches the claim including the conditioning: 'folic acid supplementation significantly reduces stroke incidence in populations who lack mandatory folate fortification, whereas trials conducted in folate-sufficient cohorts generally demonstrated no added cardiovascular benefit.' Anchored on CSPPT - 'adding folic acid to antihypertensive therapy reduced the risk of first stroke by 21% among hypertensive adults without folate fortification, an effect that was strongest in those with low baseline folate' - plus Hsu 2018 meta-analysis on fortification and stroke mortality. Contributes no independent data: same CSPPT result as the primary sources. |
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