Impact of vitamin D supplementation on all-cause mortality: Randomized trials revisited

BACKGROUND & AIMS: Vitamin D insufficiency and deficiency are common worldwide and linked to adverse health outcomes, including higher all-cause mortality. Two large randomized controlled trials (VITAL and D-Health), conducted in mostly vitamin D-sufficient populations, found no mortality benefits of vitamin D supplementation. This study aims to estimate the expected effects of vitamin D supplementation in target populations with vitamin D insufficiency or deficiency.. METHODS: We emulated the VITAL and D-Health trials using data from the UK Biobank cohort to estimate expected effects of the observed increases in serum 25-hydroxyvitamin-D (25(OH)D) concentrations by 30 nmol/L and 38 nmol/L. In alternative analyses, study populations meeting the trial inclusion criteria (n = 237,502 and 185,809) were either weighted to yield distributions of 25(OH)D as observed in the trials, or restricted to people with vitamin D insufficiency or deficiency. Expected effects on all-cause mortality over the mean trial follow up times (5.3 and 5.7 years) were estimated using Cox models. RESULTS: Emulated trials with study populations weighted to the 25(OH)D distributions of the original trials yielded null results similar to those reported (hazard ratios [HR] 0.97 [95 % CI: 0.92-1.02] and 1.02 [95%CI: 0.97-1.07]). In contrast, major mortality reduction was expected in emulated trials that were restricted to people with vitamin insufficiency (HR 0.85 [95%CI: 0.79-0.91] and 0.81 [95%CI: 0.76-0.86]) or deficiency (HR 0.79 [95%CI: 0.72-0.87] and 0.75 [95%CI: 0.69-0.81]).. CONCLUSIONS: Null effects of vitamin D supplementation were to be expected in trials conducted in vitamin D sufficient populations. Emulated trials suggest a potential for major mortality reduction in vitamin D insufficient and deficient populations..