Randomized clinical trial of folate supplementation in patients with peripheral arterial disease

Randomized controlled trial in adults with peripheral arterial disease and intermittent claudication, aged 45-85 years, recruited from vascular clinics in England. Participants were white Europeans and were generally receiving antiplatelet/anticoagulant and lipid-lowering therapy; active intervention arms included 45 participants in the folic acid group and 48 in the 5-MTHF group.

Two oral folate regimens were tested for 16 weeks: folic acid 400 µg/day and 5-MTHF 400 µg/day, each given as a daily capsule. Both active arms were compared with placebo; no clear advantage of one folate form over the other was shown.

Folate supplementation lowered plasma total homocysteine and produced a modest improvement in arterial function versus placebo, with no significant effect on inflammatory markers. Compared with placebo, total homocysteine fell by -2.12 (-3.70, -0.75) with folic acid (P = 0.002) and -2.07 (-3.48, -0.54) with 5-MTHF (P = 0.007); ABPI improved by 0.07 (0.04, 0.11) and 0.05 (0.01, 0.10), respectively. Pulse wave velocity also improved, especially with 5-MTHF: bk-PWV -0.90 (-2.10, 0.00) m/s (P = 0.051) for folic acid and -1.10 (-2.20, -0.20) m/s (P = 0.011) for 5-MTHF; ba-PWV -0.60 (-0.86, 0.00) m/s (P = 0.081) and -0.80 (-1.30, -0.17) m/s (P = 0.013). Folic acid and 5-MTHF were similarly effective, with no clear between-group difference.

The trial was relatively small and short (16 weeks), which limits detection of longer-term clinical effects. The sample was restricted to white Europeans with peripheral arterial disease in one region of England, reducing generalizability. Dietary intake and physical activity were not assessed, and participants were already receiving background cardiovascular medications, which may limit attribution and external validity.