Monthly high-dose vitamin D supplementation does not prevent cardiovascular disease (CVD), according to a randomized double-blinded placebo-controlled trial published in JAMA Cardiology.1
Several previous meta-analyses have found an association between low vitamin D levels and increased risk of CVD.2,3 Given the numerous limitations of prior trials, including low vitamin D dosing and poor adherence,4,5 investigators of the current study conducted a large trial to determine whether monthly high-dose oral supplementation decreases the incidence of CVD compared with placebo.1
Robert Scragg, MBBS, PhD, of the School of Population Health at the University of Auckland in New Zealand, and colleagues randomly assigned 5110 participants (mean age 65.9±8.3 years; 58.1% men) to receive either 2.5 mg or 100,000 IU oral vitamin D3 supplementation (n=2558) or placebo (n=2552) over a median of 3.3 years.
Given the robust national health registry of the country in which this study was set, the researchers were able to track all deaths, hospital discharges, and dispensed medications. This data was used to define CVD outcomes in combination with data about prior CVD collected during the baseline interview. Corrected serum calcium, serum total cholesterol, and serum high-density lipoprotein levels were measured at baseline; 25(OH)D concertation was 25.3±9.5 ng/mL at baseline, with 24.9% of patients considered vitamin D-deficient.1
Intention to treat analyses showed that mean observed serum 25(OH)D concentration was 20ng/mL higher in the treatment group vs the placebo group. The primary study outcome of CVD occurred in 11.8% of participants in the treatment arm vs 11.5% of participants in the control arm (hazard ratio [HR] 1.02; 95% CI, 0.87-1.20).
No significant difference was found between the treatment and placebo groups in time to first CVD event, or in the frequency of hypertension (HR 0.84; 95% CI, 0.53-1.33), myocardial infarction (HR 0.90; 95% CI, 0.54-1.50), angina (HR 1.43; 95% CI, 0.90-2.26), or venous thrombosis (HR 0.74; 95% CI, 0.34-1.61), among other disease-specific secondary outcomes.1
No significant difference was noted in any CVD events in either the vitamin D or placebo groups (11.8% and 11.5%, respectively; HR 1.02; 95% CI, 0.87-1.20). Results were comparable in participants with vitamin D deficiency (HR 1.00; 95% CI, 0.74-1.35).
“Our results do not support the findings from observational studies that report an inverse association between 25(OH)D and CVD,” the researchers concluded.
Given the short half-life of vitamin D, the researchers noted that dosing frequency of high-dose vitamin D supplementation may be another area for future study.
Likewise, the researchers note that there is a possibility that “25(OH)D concentrations are a surrogate marker of sun exposure,” which may have its own effects on cardiovascular health outcomes independent of vitamin D.1
- Event rate was lower than expected, which had an effect on the study’s statistical power. The power to detect a 20% reduction was 75% or the equivalent of 80% power to detect a 21% reduction.
- Funding prevented median follow-up for continuing longer than a median of 3.3 years; therefore, the researchers cannot rule out “possible longer-term beneficial events.”
1. Scragg R, Stewart AW, Waayer D, et al. Effect of monthly high-dose vitamin D supplementation on cardiovascular disease in the vitamin D assessment study: a randomized clinical trial [published online April 5, 2017]. JAMA Cardiology. doi:10.1001/jamacardio.2017.0175
2. Wang L, Song Y, Manson JE, et al. Circulating 25-hydroxy-vitamin D and risk of cardiovascular disease: a meta-analysis of prospective studies. Circ Cardiovasc Qual Outcomes. 2012;5(6):819-829. doi:10.1161/CIRCOUTCOMES.112.967604
3. Schöttker B, Jorde R, Peasey A, et al, for the Consortium on Health and Ageing: Network of Cohorts in Europe and the United States. Vitamin D and mortality: meta-analysis of individual participant data from a large consortium of cohort studies from Europe and the United States. BMJ. 2014;348:g3656. doi:10.1136/bmj.g3656
4. Wactawski-Wende J, Kotchen JM, Anderson GL, et al, for the Women’s Health Initiative Investigators. Calcium plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med. 2006;354(7):684-696. doi:10.1056/NEJMoa055222
5. Newmark HL, Heaney RP. Calcium, vitamin D, and risk reduction of colorectal cancer. Nutr Cancer. 2006:56(1):1-2. doi:10.1207/s15327914nc5601_1