Trial of vitamin D supplementation raises questions about CV effects on older adults
Click Here to Manage Email Alerts
Key takeaways:
- In older adults, vitamin D supplementation trended toward reducing risk for major cardiovascular events.
- The findings are inconsistent with previous trials of the CV effects of vitamin D supplementation.
In a trial of more than 20,000 older adults, vitamin D supplementation trended toward reducing risk for major CV events in older adults compared with placebo, a finding differing from previous studies.
Bridie Thompson, PhD, MPH, BSc, postdoctoral researcher in the Population Health Program, QIMR Berghofer Medical Research Institute in Herston, Queensland, Australia, and colleagues published an analysis the D-Health Trial to determine whether vitamin D supplementation reduced risk for major CV events in 21,315 participants aged 60 to 84 years compared with placebo.
Data were derived from Thompson B, et al. BMJ. 2023;doi:10.1136/bmj-2023-075230.
In the main results from the D-Health Trial published in The Lancet in January 2022, there was no difference between the groups in all-cause mortality, CVD mortality, cancer mortality or other causes of mortality.
Participants were assigned 60,000 IU per month of vitamin D or placebo taken orally for up to 5 years. At 5 years, follow-up was completed by 80.2% of the vitamin D group and 77.6% of the placebo group, and 84% of the vitamin D group and 82% of the placebo group reported taking at least 80% of the study tablets.
At 5 years, a major CV event, defined as MI, stroke or coronary revascularization, occurred in 6.6% of the placebo group and 6% of the vitamin D group (HR = 0.91; 95% CI, 0.81-1.01), Thompson and colleagues found.
The treatment effect was more pronounced but was not significantly greater in participants who were also taking CV drugs at baseline (HR = 0.84; 95% CI, 0.74-0.97; P for interaction = .12), according to the researchers.
“There was high concurrent use of statins and other cardiovascular drugs, and the interaction could reflect an effect in people who are already at high risk of experiencing a cardiovascular event, rather than a synergistic effect between vitamin D and a particular drug,” Thompson and colleagues wrote. “However, the exploratory analysis by self-reported history of major cardiovascular events was inconsistent with this hypothesis, and it is plausible that there is an interaction between vitamin D and the drugs examined.”
The difference in standardized cause-specific cumulative incidence of major CV events at 5 years was –5.8 events per 1,000 participants (95% CI, –12.2 to 0.5), which translated to a number needed to treat of 172 to avoid one major CV event, Thompson and colleagues wrote.
Compared with the placebo group, the vitamin D group had lower rates of MI (HR = 0.81; 95% CI, 0.67-0.98) and coronary revascularization (HR = 0.89; 95% CI, 0.78-1.01) but not stroke (HR = 0.99; 95% CI, 0.8-1.23), according to the researchers.
The findings differ from the VITAL, ViDA and several other large trials of vitamin D, which found no CV benefit associated with vitamin D supplementation.
“If the effect on myocardial infarction observed in the D-Health Trial is a true effect, and not due to chance, the reasons for the lack of consistency across studies are unclear,” Thompson and colleagues wrote. “The discrepancy with VITAL might partly be caused by differences in study design and adherence.”
The researchers concluded that “these findings indicate that vitamin D supplementation might reduce the incidence of major cardiovascular events, particularly myocardial infarction and coronary revascularization. This protective effect could be more marked in those taking statins or other cardiovascular drugs at baseline. Subgroup analyses in other large trials might help to clarify this issue. In the meantime, these findings suggest that conclusions that vitamin D supplementation does not alter risk of cardiovascular disease are premature.”
References:
- Manson JE, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1809944.
- Neale RE, et al. Lancet. 2022;doi:10.1016/S1040-6736(21)00345-4.
- Scragg R, et al. JAMA Cardiol. 2017;doi:10.1001/jamacardio.2017.0175.
Perspective
Back to Top
JoAnn E. Manson, MD, DrPH, MACP, FAHA
These are likely chance findings when considered in the context of the totality of the evidence. The findings are neither convincing nor persuasive. We need to consider that the analyses in this report are secondary or subgroup findings, most of which are not statistically significant or would not hold up after multiple-comparison testing. The main D-Health Trial was designed to assess vitamin D for reducing mortality, and the primary results for all-cause and cause-specific mortality were null. Moreover, some concern was raised by a signal of increased risk for cancer mortality from vitamin D supplementation in this trial. The trial tested bolus dosing (60,000 IU monthly), which is not considered to be as physiological as daily dosing.
The evidence has been quite compelling from multiple clinical trials that vitamin D supplementation does not reduce risk for CV events, especially in populations not preselected for vitamin D deficiency. Our group performed a meta-analysis (Barbarawi M, et al. JAMA Cardiol. 2019;doi:10.1001/jamacardio.2019.1870) of 21 randomized clinical trials with more than 83,000 participants, and not a single one showed a benefit of vitamin D supplementation for preventing CVD. The overall meta-analysis RR was 1.0, completely null. Even in subgroups looked at by age, sex, CVD risk factors and blood levels of 25-hydroxyvitamin D, no clear benefits were seen.
This doesn’t mean that vitamin D has no role in maintaining CV health. There’s no question that we need at least a small to moderate amount of vitamin D to achieve optimal CV health, as well as for bone health, cognition and prevention of many chronic diseases. However, ‘more is not necessarily better’ when it comes to vitamin D or other nutrients or supplements. In a generally replete population not preselected for profound vitamin D deficiency, supplementation with vitamin D does not appear to confer additional CV benefits in most randomized trials. And high-dose bolus vitamin D has even been linked to an increased risk for falls and fractures in several other trials. It’s important to avoid thinking that any supplement will be a magic bullet for good health. That can be a distraction from more important strategies for prevention of CVD, such as lifestyle modifications, including physical activity and eating a heart-healthy diet, cholesterol-lowering therapies and controlling blood pressure. Although additional large-scale trials of vitamin D and CVD are unlikely to be helpful, more could be done with individual participant-level meta-analyses of existing randomized trials to look at those with specific CV diagnoses or use of certain medications; this could shed further light on the effects of vitamin D supplementation among those at high CV risk.
Collapse
Read more about
Click Here to Manage Email Alerts