Circulating vitamin D metabolites are distinctly associated with all-cause and cardiovascular mortality: a prospective study.

The epidemiological findings on specific vitamin D metabolites and health outcomes remain inconsistent and limited. We hypothesized that vitamin D metabolites may have distinct associations with all-cause and cardiovascular disease (CVD) mortality. This study included 24,592 participants from the National Health and Nutrition Examination Survey 2007 to 2018. Baseline serum vitamin D metabolites, including 25(OH)D3, its epimer 3‑epi-25(OH)D3, and 25(OH)D2, were quantified using standardized liquid chromatography-tandem mass spectrometry. Data on death and causes were obtained through the National Death Index records. Cox proportional-hazard models were used to estimate the hazard ratios and 95% confidence intervals (CIs). During a median follow-up of 6.4 years, 1397 all-cause deaths and 371 CVD deaths were documented. Serum 25(OH)D3 and total 25(OH)D exhibited L-shaped inverse associations with all-cause and CVD mortality, whereas 25(OH)D2 showed no association. When comparing extreme quartiles, the multivariable-adjusted hazard ratios for 25(OH)D3 were 0.68 (95% CI: 0.56-0.83) for all-cause mortality and 0.71 (95% CI: 0.50-0.99) for CVD mortality. For 3‑epi-25(OH)D3, we observed a nonlinear inverse association with all-cause mortality that attenuated to null at around 10.7 nmol/L. Moreover, mediation analysis suggested that alkaline phosphatase and albumin collectively explained 20.0% and 20.4% of the associations of 25(OH)D3 and total 25(OH)D with CVD mortality, respectively. In a nationally representative population, serum 25(OH)D3 was inversely associated with all-cause and CVD mortality, while 3‑epi-25(OH)D3 and 25(OH)D2 showed distinct patterns of association with mortality. Our findings highlight the importance of distinguishing among vitamin D metabolites in mortality risk assessment.