Vitamin D Doesn't Reduce Type 2 Diabetes Risk...or Does It?

Miriam E. Tucker

May 26, 2022

Yet another study has found that vitamin D supplementation doesn't reduce the risk of developing type 2 diabetes in the general population with prediabetes, but it does leave the door open for benefit in those with low insulin secretion.

The new findings come from the prospective Diabetes Prevention With Active Vitamin D (DPVD) trial of more than 1200 Japanese participants with impaired glucose tolerance.

The data were published online May 25 in the British Medical Journal by Tetsuya Kawahara, MD, PhD, of Shin Komonji Hospital, Kitakyushu, Japan, and colleagues.

Treatment with 0.75 μg/day of eldecalcitol, an active vitamin D analogue, for 3 years did not prevent progression from prediabetes to type 2 diabetes, nor did it improve the rate of regression to normoglycemia compared with placebo.

However, "we showed a preventive effect of eldecalcitol after adjusting for covariables...The preventive effect of eldecalcitol on development of type 2 diabetes in a prediabetic population was seen especially among participants with insulin insufficiency," Kawahara and colleagues write.

"Remarkably Similar" Results in Several Trials

The new trial is "well conducted, with rigorously defined and tested diagnostic criteria, and of sufficient duration, but it may have been underpowered to detect a small effect," writes Tatiana Christides, MD, PhD, of Queen Mary University of London, UK, in an accompanying editorial.

Christides notes that a recent meta-analysis of intervention trials did find a significant 10% reduction in risk of type 2 diabetes with vitamin D supplementation, "a difference too small to be detected by the new trial...Although a 10% risk reduction is modest, it may be valuable at the population level and justifies further study."

The new finding, a nonsignificant 13% relative reduction in risk, is similar to the 13% relative risk reduction found in the Vitamin D and Type 2 Diabetes (D2d) trial reported in 2019.

But in that study as in this one, there was a suggested benefit in a subset of people. In D2d, it was in those who were vitamin D deficient.  

Asked to comment, D2d lead investigator Anastassios G. Pittas, MD, chief of the Division of Diabetes, Endocrinology, and Metabolism at Tufts Medical Center, Boston, Massachusetts, pointed out that the results were also "remarkably similar" to those of a third study from Norway published in 2014, which also found a 13% relative risk reduction.

"The nearly identical results from the three trials that were specifically designed and conducted to test whether vitamin D supplementation lowers diabetes clearly points to a beneficial effect of vitamin D for diabetes risk reduction. However, the overall effect in people not selected for vitamin D insufficiency seems to be less than hypothesized in each trial," Pittas told Medscape Medical News.  

He added, "there will be no more specific vitamin D and diabetes prevention trials, so we need to continue gaining insights from these three trials."

Some Patients With Prediabetes May Benefit From Vitamin D

Pittas advised that although the overall effect is modest in people with prediabetes who aren't selected for vitamin D deficiency, "given how prevalent prediabetes and type 2 diabetes are, clinicians and patients should consider vitamin D supplementation as an adjunct to weight loss for diabetes prevention. Based on analyses from the D2d study, people with prediabetes who have low levels of vitamin D and are non-obese derive the most benefit."

He noted that secondary analyses from D2d also suggest greater benefit among those achieving higher blood levels of vitamin D, but that high supplemental doses could cause adverse musculoskeletal outcomes in older adults, "so the benefit–harm ratio needs to be ascertained individually."

Christides advised, "Until further data are available from high-quality randomized trials, healthcare professionals should continue to discuss with patients the musculoskeletal health benefits of vitamin D and support them to achieve and maintain lifestyle changes that, although challenging to sustain, are known to decrease development of [type 2 diabetes]."

DPVD: Hint of Benefit in Those With Greater Insulin Resistance

The double-blind, multicenter, randomized, placebo-controlled DPVD trial took place from June 1, 2013, through to August 31, 2015, and involved 1256 participants with impaired glucose tolerance (with or without impaired fasting glucose) from 32 institutions in Japan. They were randomized 1:1 to receive eldecalcitol or placebo for 3 years.

During the 3-year period, 12.5% of the 630 patients in the eldecalcitol group and 14.2% of the 626 patients in the placebo group developed diabetes. The difference was not significant, with a hazard ratio (HR) of 0.87 (P = .39). There was also no difference in regression to normoglycemia, which had occurred in 23.0% with eldecalcitol versus 20.1% with placebo by the end of the study (P = .21).

However, eldecalcitol was effective for preventing the development of type 2 diabetes after adjustment for prespecified variables, including age, sex, hypertension, body mass index, family history of diabetes, 2-hour plasma glucose, 25-hydroxyvitamin D, and insulin resistance (hazard ratio [HR], 0.69; P = .02).

In a post-hoc analysis, eldecalcitol significantly prevented the development of type 2 diabetes among those with the lowest divisions of homeostatic model assessment (HOMA)-β (HR, 0.35; P < .001), HOMA-insulin resistance (HR, 0.37; P = .001), and fasting immunoreactive insulin (HR, 0.41; P = .001).

"These results indicate that eldecalcitol had a beneficial effect on insufficient basal insulin secretion," Kawahara and colleagues write.

Discontinuations due to adverse events occurred in 4.1% with eldecalcitol and 3.4% in the placebo group (HR, 1.23; P = .47). Rates and types of adverse events didn't differ significantly between the two groups.

The study was supported by a grant from the Kitakyushu Medical Association. The authors had no further disclosures. Christides had no disclosures. Pittas has reported receiving funding from the US National Institutes of Health.

BMJ. Published online May 25, 2022. Article, Editorial

Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape, with other work appearing in The Washington Post, NPR's Shots blog, and Diabetes Forecast magazine. She is on Twitter: @MiriamETucker.

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