Effect of vitamin D supplementation on cardiovascular outcomes: randomized trials revisited

This study aims to estimate the effects of vitamin D supplementation on cardiovascular diseases in populations with different baseline vitamin D distributions, by emulating the VITAL and D-Health trials within the UK Biobank. We emulated randomized trials using subcohorts of the UK Biobank selected to match the inclusion criteria of the VITAL and D-Health trials (n = 237,502 and 185,809, respectively). Exposures were defined as increases in serum 25-hydroxyvitamin-D concentrations of 30 nmol/L and 38 nmol/L, corresponding to the intervention effects in the trials. Outcomes included cardiovascular mortality, myocardial infarction, ischemic stroke, and major adverse cardiovascular events. Expected hazard ratios over trial median follow-up durations of 5.3 and 5.7 years were estimated using Cox proportional hazards models. Vitamin D insufficiency was more common in the UK Biobank than in the original trials. When participants were weighted to match the trial baseline 25-hydroxyvitamin-D distributions, the expected effects became more similar to the largely null findings reported in the original trials. By contrast, among individuals with vitamin D insufficiency or deficiency, increases in 25-hydroxyvitamin-D concentration as achieved in the trials were associated with significantly lower risks of cardiovascular outcomes, except ischemic stroke. For cardiovascular mortality, hazard ratios ranged from 0.74 (95% CI 0.62-0.88) to 0.79 (95% CI 0.69-0.91) across both trial emulations. The largely null findings observed in the trials may partly reflect that the trial populations were predominantly vitamin D-replete. Our emulated trials suggest that substantial cardiovascular benefits from vitamin D supplementation may be expected among populations with low vitamin D status.