Homocysteine Lowering with B Vitamins for Stroke Prevention—A History

Abstract

Early trials of B vitamin therapy to lower plasma total homocysteine (tHcy) reported no reduction of stroke with high doses of folate/B6 and cyanocobalamin 400–1,000 μg daily. In patients with diabetic nephropathy, folate/B6 and cyanocobalamin 1,000 μg daily accelerated the decline of renal function and doubled cardiovascular events. Patients with renal failure have high cyanide levels. The French SUpplementation with FOlate, vitamin B6 and B12 and/or OMega-3 fatty acids (Su.Fol.OM3) trial—with the best renal function of the early trials and the lowest dose of cyanocobalamin (20 μg daily)—reported a 43% reduction of stroke. Then the China Stroke Primary Prevention Trial (CSPPT) reported that folic acid alone reduced stroke and was beneficial even in patients with impaired renal function. Patient-level data from the Vitamin Intervention to Prevent Stroke (VISP) and VITAmins TO Prevent Stroke (VITATOPS) trials and meta-analyses stratified by renal function and dose of cyanocobalamin confirmed that harm from cyanocobalamin among participants with renal impairment obscured the benefit of B vitamins in the early trials. It does seem that B vitamins reduce the risk of stroke. In the era of folate fortification, B12 is the main nutritional determinant of tHcy, and metabolic B12 deficiency is very common and usually missed. Therefore, folate alone is not the optimal way to lower tHcy: the use of folate (and possibly B6) with methylcobalamin or oxocobalamin should be considered.