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Vitamin D supplements fail to prevent CVD
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Monthly high-dose vitamin D supplementation did not prevent the incidence of CVD or death in adults aged 50 to 84 years, according to published findings.
“The possibility that UV radiation, through a mechanism that involves vitamin D, may protect against CVD was initially proposed in 1981,” Robert Scragg, MBBS, PhD, professor of epidemiology and biostatistics in the School of Population Health at The University of Auckland, New Zealand, and colleagues wrote in the study background. “Given the limited (and mixed) [randomized clinical trial] evidence on vitamin D supplementation and CVD, we performed a large [randomized clinical trial] with recruitment from the general population.”
Scragg and colleagues recruited participants from mostly family practices in New Zealand.
Participants (n = 5,108; 58% men; mean age, 66 years) were randomly assigned to receive placebo or oral vitamin D3 with an initial dose of 200,000 IU followed by a monthly dose of 100,000 IU delivered via the mail for a median follow-up of 3.3 years.
Mean baseline deseasonalized 25-hydroxyvitamin D concentration was 26.5 ng/mL; 24.9% of participants were vitamin D deficient (concentrations < 20 ng/mL). Adherence was 84.9% in the study group and 82.9% in the placebo group, according to self-reported questionnaires.
In a random sample (n = 438), participants receiving supplements had greater than 20 ng/mL higher vitamin D concentrations at the end of follow-up vs. the placebo group.
Incident CVD occurred in 11.8% of the supplement group and in 11.5% of the placebo group (HR = 1.02; 95% CI, 0.87-1.2).
Similar outcomes were seen for MI, angina, HF, hypertension, arrhythmias, arteriosclerosis, stroke and venous thrombosis. No difference was seen in the vitamin D-deficient patients.
“The results of this large population-based [randomized clinical trial] indicate that vitamin D supplementation given in the dose and frequency we used does not prevent CVD, and the findings are consistent with previous [randomized clinical trial] of vitamin D supplementation and mendelian randomization studies,” the researchers wrote. “However, it remains possible that monthly doses of vitamin D are less effective in preventing disease than daily or weekly doses.” – by Cassie Homer
Disclosure: The researchers report no relevant financial disclosures.
Perspective
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Erin D. Michos, MD, MHS, FACC, FAHA
The Vitamin D Assessment (ViDA) study was a well done randomized clinical trial that found that high-dose monthly vitamin D supplementation did not reduce CVD events in a general ambulatory population in New Zealand over 3.3 years of follow-up.
Alas, this trial adds to mounting evidence that is putting the nail in the coffin for vitamin D enthusiasm, and fits with other evidence that taking vitamin and mineral supplements does not reduce chronic diseases in most individuals. Low serum 25-hydroxyvitamin D levels [25(OH)D] levels likely are just a very good surrogate marker of someone who is in a poorer health state and has other risk factors. Mendelian randomization studies have also not supported a causal role of 25(OH)D and CVD (Manousaki D, et al. Circ Cardiovasc Genet. 2016;doi:10.1161/CIRCGENETICS.116.001396).
However, there is likely heterogeneity of the effect of vitamin D based on one’s baseline vitamin D status and genetics related to key genes in vitamin D metabolism.
The Institute of Medicine reported that 25(OH)D levels ≥ 20 ng/ml are adequate for bone health in the vast majority of individuals (Ross AC, et al. J Clin Endocrinol Metab. 2011;doi:10.1210/jc.2010-2704). Perhaps there is little justification for pushing individuals beyond this point with pharmacological interventions, and there may be a U-shaped curve for risk at both high and low levels.
Only 25% of ViDA participants were 25(OH)D deficient at baseline. Similar to prior observational studies, ViDA also found that low 25(OH)D levels were associated with incident CVD risk, but supplementation did not improve outcomes in this group. However, I wonder if this group was adequately powered and about those with more severe deficiency such as < 15 ng/ml. Only a small random sample (n = 438 out of 5108) had on-treatment serum 25(OH)D measured. There was a ~28 ng/ml difference in on-treatment 25(OH)D levels between groups (54.1 vs 26.4 ng/ml), but likely one gains little additional benefit above 20 ng/ml.
ViDA was underpowered to look at association of 25(OH)D among specific subgroups like patients with prior HF, where there is much interest for its purported benefits. The VINDICATE trial suggested that among HF patients with low 25(OH)D, supplementation modestly improved left ventricular ejection fraction and LV dimensions, but not 6-minute walk distance (Witte KK, et al. J Am Coll Cardiol. 2016;doi:10.1016/j.jacc.2016.03.508). Whether vitamin D treatment can reduce HF outcomes in this population remains uncertain.
I am somewhat concerned about large bolus dose given (200,000 IU initially and then 100,000/month). Although no safety concern was raised here, previous studies have suggested harm with giving a large dose all at once, such as 500,000 IU annually (Sanders KM, et al. JAMA. 2010;doi:10.1001/jama.2010.594), which is not physiologic and may transiently raise serum calcium levels. Smaller doses daily or weekly may be closer to physiologic and safer. This needs to be further explored.
The ongoing VITAL randomized trial will provide further insight into whether vitamin D supplementation can reduce cancer and CVD outcomes. I am anticipating that overall VITAL trial will be null as well, but I am interested in subgroup analyses (Manson JE, et al. Contemp Clin Trials. 2012;doi:10.1016/j.cct.2011.09.009.) Before we give up on vitamin D, we are going to need to investigate this in larger, more diverse populations and explore key subgroups by race, 25(OH)D levels and vitamin D genetics. I don’t want to throw the baby out with the bathwater — while the general population might not need supplementation, there might be a key demographic group that does.
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