Middle-age adults who took low-dose vitamin D supplements for 5 years had a small but statistically lower risk of developing metastatic or fatal cancer, a new analysis of a randomized trial showed.
The absolute difference — 1.7% with vitamin D versus 2.1% without — represented a 17% reduction in relative risk (P=0.04). Normal-weight individuals derived the most benefit (38% risk reduction), as the risk of advanced cancer did not decrease in overweight or obese study participants.
Statistical testing confirmed a significant interaction between body mass index (BMI) and the effects of vitamin D supplementation (P=0.03), reported Paulette D. Chandler, MD, MPH, of Brigham and Women’s Hospital in Boston, and co-authors in JAMA Network Open.
“Additional randomized trials focusing on cancer patients should be considered, as well as investigations of differential benefit by BMI,” the authors concluded. “Even if the vitamin D effects were modest, vitamin D supplementation at the studied levels are much less toxic and lower cost than many current cancer therapies.”
“Although we set out hypothesizing that vitamin D sufficiency decreases cancer risk, our finest tools — RCTs [randomized controlled trials] — allow us to examine only whether vitamin D supplementation reduces the disease risk,” she stated. “The problem is that the relationship between vitamin D supplementation and vitamin D status is less closely correlated than is comfortable to acknowledge.”
“Substantial variation in the increase in 25-hydroxyvitamin D … after administration of the same vitamin D dose has been well documented. It is hard to predict how much 25-hydroxyvitamin D concentration will change in a given individual after the supplementation; however, the increase is typically less in overweight individuals.”
In addition to BMI, multiple other factors can drive heterogeneity of treatment effects, including personal, lifestyle, behavioral, environmental, dietary, and genetic factors.
“Given the expected variability of treatment effects, how can an RCT using fixed-dose vitamin D supplementation provide definitive evidence of the benefit?” Zgaga asked. “Maybe it is time to consider a study design that can accommodate heterogeneity of treatment effects without compromising the strength of evidence.”
Chandler and co-authors reported findings from a secondary analysis of the VITAL trial, which investigated the effects of supplementation with vitamin D and omega-3 fatty acids on the risk of developing invasive cancer or cardiovascular disease (CVD). As previously reported, the primary results showed that the supplements did not prevent cancer or CVD as compared with placebo. The secondary analysis focused on the outcome of advanced cancer (defined as metastatic or fatal) and the potential impact of BMI on the effects of vitamin D.
The VITAL trial included men 50 or older and women 55 or older who were free of cancer and CVD at enrollment. They were randomized to vitamin D3 (cholecalciferol 2,000 IU/d) plus omega-3 fatty acids or matching placebo. The trial included 25,871 participants, 7,843 in the range of normal weight (BMI <25), 10,122 who were overweight (BMI 25-30), and 7,289 who were obese (BMI ≥30). Data for the secondary analysis encompassed follow-up from Nov. 1, 2011 to Dec. 31, 2017.
During a median intervention period of 5.3 years, 1,617 invasive cancers were diagnosed, including 500 advanced cancers, 226 in the intervention arm and 274 in the placebo group. Though small, the 0.4% absolute difference in the endpoint achieved statistical significance in the overall analysis (HR 0.83, 95% CI 0.69-0.99).
The key subgroup analysis focused on the incidence of advanced cancer by BMI values. The benefits of vitamin D were limited to normal-weight participants (HR 0.62, 95% CI 0.45-0.86). Overweight study participants assigned to vitamin D had a nonsignificant 11% reduction in the risk of advanced cancer (HR 0.89, 95% CI 0.68-1.17), and obese participants had a numerically higher risk of developing advanced cancer (HR 1.05, 95% CI 0.74-1.49).
In their discussion of the findings, the authors suggested that a “dynamic interplay between adiposity and immunomodulatory or inflammatory mediators may contribute to the differential response to vitamin D3.”
“Although these findings could be due to chance, obesity is known to affect the vitamin D axis,” they continued. “The larger storage capacity for vitamin D in individuals with obesity by fat sequestration or volumetric dilution may result in lower plasma vitamin D.”
However, they acknowledged that the primary analysis of the VITAL trial showed no evidence of vitamin D deficiency in obese or non-obese study participants.
The VITAL study was supported by the National Institutes of Health, American Cancer Society, Pharmavite, Pronova BioPharma, BASF, and Quest Diagnostics.
Chandler reported having no relevant relationships with industry. Co-authors disclosed relationships with Pharmavite, Pronova BioPharma, and BASF.
Zgaga reported no conflicts of interest.