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, Jiang Y, Chen T, Liu S, Fang Y, Chen F, Shen J, Zeng X, Li P, Qiu T, Wang J, Yu L, Zang X, Wang N, Yuan J, Pang H, Zhang W, Ni Z, Gu L, Guo Y, Lu R 2026 · Ren Fail | RCT | supports | low | 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, Sun Y, Zhang H, Li A 2026 · Medicine (Baltimore) | observational | supports | low | Single-centre prospective cohort, 799 hemorrhagic-stroke + H-type hypertension patients (tHcy >= 10 umol/L), all on one enalapril 10 mg + folic acid 0.8 mg pill, median 9.6 months; comparison is high (>=70%, n=256) vs low (<70%, n=543) ADHERENCE, not treatment vs placebo. Recurrent hemorrhagic stroke 4 vs 17 events, adjusted 'HR: 0.21; 95% CI: 0.07–0.67'; ischemic stroke 2 vs 11, adjusted HR 0.16 (0.01–2.01), not significant. Quality low: adherence was 'self-reported by patients' and computed over 'the days in the follow-up period' (exposure measured in the outcome window, so healthy-adherer and reverse-causation bias are built in); all-cause mortality HR 0.14 (0.05–0.41; 4 vs 35 deaths, only 11 vascular) is not a credible folate effect and marks that confounding; 21 hemorrhagic-stroke events total; no arm isolates folic acid from enalapril. Authors: 'residual confounding may still exist' and 'causality remains unconfirmed.' |
| Zhang N, Zhou Z, Chi X, Fan F, Li S, Song Y, Zhang Y, Qin X, Sun N, Wang X, Huo Y, Li J 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 · Journal of the American Heart Association | 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 P, Calderon Martinez E, Arvelaez Pascucci J, Livier Castillo J, Alonso-Ramírez A, Giron De Marza MM, Martinez Illan J, Sosaya Zuñiga B, Camacho Davila K, Flores Monar G, Sanchez Cruz C 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, AbuBaha M, Istetieh K, Sandouka D, Aldwaik S, AbuBaha B, Saife S, Emara A, Zahran A, Elgendy MS, Shubietah A, Baniowda MA 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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