Clinical Context

Vitamin D supplementation is a controversial area in health care, but a previous study by Manson and colleagues cast doubt on its benefits in the adult general population. The Vitamin D and Omega 3 Trial (VITAL) randomly assigned more than 25,000 adults to vitamin D, omega-3 fatty acid, or placebo, with the primary endpoints of cardiovascular disease (CVD) and cancer. The results for these outcomes were published in the January 3, 2019 issue of The New England Journal of Medicine.^[1]

Overall, vitamin D was not associated with significant improvement vs placebo for incident CVD or cancer. In fact, it failed to improve the risk for any particular cancer as well as specific cardiovascular (CV) outcomes. Vitamin D also did not improve mortality outcomes. Subgroup analyses generally failed to demonstrate any benefit for vitamin D, including among more than 5000 Black adults, but researchers did find a lower risk for cancer in the vitamin D vs placebo group among adults with a body mass index (BMI) < 25 kg/m².

Previous research has suggested that vitamin D supplements are less impactful among overweight and obese adults. The current study by Tobias and colleagues revisits VITAL to assess this hypothesis.

Study Synopsis and Perspective

People who are overweight or have obesity appear to show a blunted response to vitamin D supplementation compared with normal-weight individuals in a new analysis of a randomized trial.

"There seems to be something different happening with vitamin D metabolism at higher body weights, and this study may help explain diminished outcomes of supplementation for individuals with an elevated body mass index (BMI)," said first author Deirdre K. Tobias, ScD, an associate epidemiologist in Brigham's Division of Preventive Medicine. She made the comments in a press statement issued with the study, published online this week in JAMA Network Open.^[2]

The findings are from a post-hoc analysis of the large-scale Vitamin D and Omega-3 Trial (VITAL), which overall showed no benefits among persons randomly assigned to 5 years of vitamin D supplementation (2000 IU/d) vs placebo in terms of the primary endpoints of cancer or major CVD outcomes.

Nonetheless, prespecified secondary analyses according to body weight showed that persons of normal weight (BMI < 25 kg/m²) did have significant benefits from supplementation vs placebo in terms of cancer incidence (24% lower), cancer mortality (42% lower), and autoimmune disease (22% lower), although no corresponding benefits were observed among persons who were overweight or had obesity.

The new analysis adds important context to the trial's overall findings, notes Katherine N. Bachmann, MD, in an accompanying editorial.^[3]

"Thanks to its very large sample size and detailed biomarker analyses, the current study is able to provide novel evidence that responses to vitamin D supplementation may be attenuated in individuals with overweight and obesity, and that this may contribute to the differential outcomes by BMI noted in the original VITAL," she wrote.

"Further studies are warranted to determine the optimal dose or circulating vitamin D level for individuals with obesity for nonskeletal health-related outcomes," added Bachmann, Division of Diabetes, Endocrinology, and Metabolism at Vanderbilt University Medical Center in Nashville, Tennessee.

New Analysis Examined Vitamin D and Biomarkers at Baseline and 2 Years

To take a closer look at the specific changes in vitamin D serum and biomarker levels between the different body weight groups, Tobias and colleagues evaluated data from 16,515 participants in the trial (of the 25,000 originally included in VITAL) and looked at changes in key vitamin D serum levels and biomarkers at baseline and follow-up.

Consistent with common observations of lower vitamin D levels with obesity, participants in the higher BMI categories had incrementally lower mean levels of serum total 25-hydroxyvitamin D (25-OHD) before randomization, with levels ranging from 32.3 ng/mL for normal-weight individuals to 28 ng/mL for persons with obesity class II (P < .001 for a linear trend).

Baseline levels of other vitamin D biomarkers were also lower with higher BMI, including total 25-OHD 3, free vitamin D (FVD), and bioavailable vitamin D (BioD). Among 2742 participants with repeated blood collections at year 2, researchers observed significant mean increases overall at the end of the study period in serum 25-OHD levels (11.9 ng/mL) among persons randomly assigned to vitamin D supplementation compared with little change in the placebo group (−0.7 ng/mL).

There were also significant increases, overall, in mean total 25-OHD, 25-OHD3, FVD, and BioD levels at 2 years among persons receiving supplementation, with little or no change in the placebo group.

When stratified by BMI level, however, the magnitude of increase was lower among persons with higher baseline BMI (all treatment effect interactions, P < .001). For instance, the mean increases in total 25-OHD level at 2 years for supplementation vs placebo were 13.5 ng/mL for persons with a BMI < 25 kg/m² vs only 10 ng/mL for persons with a BMI ≥ 35 kg/m².

Importantly, even after controlling for baseline vitamin D status of sufficiency or insufficiency, BMI was still significantly associated with changes seen with supplementation.

"It was surprising that even in the context of low vitamin D levels, persons with higher BMI still had a blunted response to supplementation, suggesting the interaction between supplementation and BMI with health outcomes is not simply due to higher prevalence of deficiency," Tobias told Medscape Medical News. "It really does seem that even with insufficient or low levels at baseline, those with higher BMI are not able to catch up to sufficient levels as well as those with normal BMI."

Mechanisms?

Among leading theories as to why higher BMI would be associated with lower serum vitamin D levels and a lower response to supplementation is that because vitamin D is a fat-soluble vitamin, the increased adiposity and fat storage capacity with higher BMI results in greater removal of the vitamin from circulation.

"Our results are largely consistent with this hypothesis," the authors noted.

They added that weight loss studies, including those involving bariatric surgery, have further shown greater increases in serum 25-OHD or circulating vitamin D levels after weight loss compared with baseline.

Other theories suggest that obesity-induced hepatic dysfunction can contribute to impaired vitamin D metabolism.

Without a clear understanding of the exact mechanisms, the potential for addressing the lower vitamin D levels with, for instance, higher doses of supplementation among those with obesity, also remains unclear, Tobias noted.

"I think once there's more clarity on what the mechanism is, then it would make sense to consider what doses could be necessary to achieve the internal levels desired," she said.

The VITAL study received funding from a grant from the National Center for Complementary and Integrative Health and other sources. The authors' complete disclosures are detailed in the published study.

Clinical Implications

• VITAL found that vitamin D supplements were not associated with significant improvement vs placebo for incident CVD or cancer. In fact, vitamin D failed to improve the risk for any particular cancer or specific CV outcomes. Vitamin D also did not improve mortality outcomes. Subgroup analyses generally failed to demonstrate any benefit for vitamin D, including among more than 5000 Black adults.
• The current study by Tobias and colleagues found an inverse relationship between BMI and the increase in 25-OH-D associated with vitamin D supplements. Vitamin D supplementation failed to affect levels of free vitamin D, PTH, or calcium. BMI was also not significantly associated with these outcomes.
• Implications for the healthcare team: The healthcare team should consider the potential modifying effects of BMI when recommending vitamin D supplementation.

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