Small benefit of vitamin D for advanced cancer risk

Middle-aged 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 study 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 obtained the most benefit (38% risk reduction), as the risk of advanced cancer did not decrease in overweight or obese study participants.

Statistical tests 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 studies focusing on cancer patients should be considered, as well as investigations into the differential benefit of BMI,” the authors concluded. “Even if the effects of vitamin D were modest, supplementing vitamin D at the levels studied is much less toxic and cheaper than many current cancer therapies.”

Vitamin D Research Sometimes Resembles a Chinese Whispering Game, Lina Zgaga, PhD, of Trinity College Dublin in Ireland, noted in an accompanying editorial.

“Even though we hypothesized that getting enough vitamin D decreases cancer risk, our best tools – RCT [randomized controlled trials] – to allow us to examine only whether vitamin D supplementation reduces the risk of disease, “he said.” The problem is that the relationship between vitamin D supplementation and vitamin D status is less closely related than it is convenient to recognize. “

“The substantial change in the increase in 25-hydroxyvitamin D … after administration of the same dose of vitamin D has been well documented. It is difficult to predict how much the concentration of 25-hydroxyvitamin D will change in a given individual after supplementation; however, the increase is generally smaller in overweight individuals. “

In addition to BMI, many other factors can drive the 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 proof of benefit?” Zgaga asked. “Perhaps it’s time to consider a study design that accommodates the heterogeneity of treatment effects without compromising the strength of the evidence.”

Chandler and co-authors reported the results of a secondary analysis of the VITAL study, which investigated the effects of supplementing 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 supplements did not prevent cancer or cardiovascular disease compared to placebo. 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 study included men aged 50 and over and women aged 55 and over who had no cancer and cardiovascular disease at the time of enrollment. They were randomized to vitamin D.₃ (cholecalciferol 2,000 IU / day) plus omega-3 fatty acids or corresponding placebo. The study included 25,871 participants, 7,843 in the normal weight range (BMI <25), 10,122 who were overweight (BMI 25-30) and 7,289 who were obese (BMI ≥30). Data for secondary analysis included follow-up from November 1, 2011 to December 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. Although small, the absolute difference of 0.4% in the endpoint reached statistical significance in the overall analysis (HR 0.83, 95% CI 0.69-0.99).

Key subgroup analysis focused on advanced cancer incidence based on BMI values. 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 advanced cancer risk (HR 0.89, 95% CI 0.68-1.17) and obese participants had a numerically higher risk elevated to develop advanced cancer (HR 1.05, 95% CI 0.74-1.49).

In their discussion of the results, the authors suggested that “a dynamic interaction between adiposity and immunomodulatory or inflammatory mediators may contribute to the differential response to vitamin D₃. “

“Although these findings may be due to chance, obesity is known to affect the vitamin D axis,” they continued. “The increased storage capacity of vitamin D in individuals with obesity through fat sequestration or volumetric dilution may result in lower plasma vitamin D.”

However, they acknowledged that the primary analysis of the VITAL study showed no evidence of vitamin D deficiency in obese or non-obese study participants.