Vitamin D Supplementation and Cardiovascular Disease Risks in More Than 83 000 Individuals in 21 Randomized Clinical Trials: A Meta-analysis

Abstract

Importance: Observational studies have reported an association between low serum vitamin D levels and elevated risk of cardiovascular disease (CVD) events, but such studies cannot prove causation because of possible unmeasured confounding. Objective: We conducted a meta-analysis of randomized clinical trials that tested the association of vitamin D supplementation with reduced CVD events and all-cause mortality. Data Sources: Literature search through PubMed, the Cochrane Library, and Embase was completed by 2 reviewers from each database's inception to December 15, 2018. Study Selection: Inclusion criteria were randomized clinical trials that reported the effect of long-term (≥1 year) vitamin D supplementation on CVD events and all-cause mortality. Studies that did not include cardiovascular outcomes were excluded. Data Extraction and Synthesis: Data were abstracted independently by 2 authors. Random-effects models were used to report the risk ratios (RRs) and 95% CIs. Main Outcomes and Measures: Major adverse cardiovascular events was the primary outcome, and rates of myocardial infarction, stroke or cerebrovascular accident, CVD mortality, and all-cause mortality were the secondary end points. Results: Twenty-one randomized clinical trials were included (including 83 291 patients, of whom 41 669 received vitamin D and 41 622 received placebos). The mean (SD) age of trial participants was 65.8 (8.4) years; 61 943 (74.4%) were female. Only 4 trials had prespecified CVD as a primary end point. Vitamin D supplementation compared with placebo was not associated with reduced major adverse cardiovascular events (RR, 1.00 [95% CI, 0.95-1.06]; P = .85) nor the secondary end points of myocardial infarction (RR, 1.00 [95% CI, 0.93-1.08]; P = .92), stroke (RR, 1.06 [95% CI, 0.98-1.15]; P = .16), CVD mortality (RR, 0.98 [95% CI, 0.90-1.07]; P = .68), or all-cause mortality (RR, 0.97 [95% CI, 0.93-1.02]; P = .23). Results were generally consistent by sex, baseline 25-hydroxyvitamin D level, vitamin D dosage, formulation (daily vs bolus dosing), and presence or absence of concurrent calcium administration. Conclusions and Relevance: In this updated meta-analysis, vitamin D supplementation was not associated with reduced major adverse cardiovascular events, individual CVD end points (myocardial infarction, stroke, CVD mortality), or all-cause mortality. The findings suggest that vitamin D supplementation does not confer cardiovascular protection and is not indicated for this purpose.