Study Sheds Light on Why Taking Vit D May Lower Diabetes Risk for Some

Vitamin D supplementation may help stave off the progression from prediabetes to type 2 diabetes, but only for individuals with certain genetic profiles, data from the D2d trial indicated.

Among 2,098 adults with prediabetes, carriers of ApaI AC and CC genotypes taking 4,000 IU of vitamin D₃ per day had a 19% reduced risk for incident diabetes compared with placebo recipients over a median of 2.5 years (HR 0.81, 95% CI 0.66-0.99).

Meanwhile, carriers of ApaI AA alleles — roughly 30% of the cohort — had no response to supplementation (HR 1.02, 95% CI 0.72-1.44), reported Bess Dawson-Hughes, MD, of the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University in Boston, and colleagues in JAMA Network Open.

This 19% risk reduction is not trivial, the authors wrote. If confirmed, high-dose vitamin D₃ — which is cheap, safe, and well tolerated — could serve as a targeted, personalized approach to reducing type 2 diabetes risk. Preventing progression “is a clinical priority,” the group emphasized, given that an estimated 464 million individuals worldwide have prediabetes.

The results offer clarity after primary results of the D2d trial, published in 2019, as well as other studies, failed to show that supplementation reduced diabetes risk.

A secondary analysis of the study, however, found that participants who maintained intratrial mean serum 25-hydroxyvitamin D (25[OH]D) levels of 40-50 ng/mL or higher had a 52% to 71% reduced diabetes risks, respectively, compared with participants those with lower levels.

When the current analysis was stratified, ApaI CC genotype carriers with levels of 40-50 ng/mL or ≥50 ng/mL had 71% and 83% lower risks for incident diabetes, respectively. AC genotype carriers had 49% and 74% reduced risks at those levels.

In an accompanying commentary, Michael F. Holick, PhD, MD, and Arash Shirvani, MD, PhD, both of the Chobanian & Avedisian Boston University School of Medicine, said it’s “no surprise that polymorphisms in the [vitamin D receptor] would be associated with alterations in vitamin D’s associated health benefits,” given that gene polymorphisms can disrupt drug responses by alterations in enzyme function, drug transport, and receptors.

This genetic nuance may explain some of the disparities in the prior research, the duo noted.

While it is “unrealistic” to determine everyone’s vitamin D receptor polymorphisms, the commentators said the findings “should be a wake-up call and the impetus for health organizations to develop strategies to improve vitamin D status for children and adults with food fortification programs, implementation of supplementation, and sensible sun exposure recommendations for those who are at risk.”

The current genetic association study analyzed three common polymorphisms — ApaI, BsmI, and FokI — among participants of D2d, which ran from October 2013 to November 2018. Models were adjusted for study site, race and ethnicity, sex, baseline age, body mass index, usual physical activity, statin use, and intratrial weight change.

Average age was 60 years, 55.7% were men, and all met criteria for prediabetes. Use of diabetes or weight-loss medication were grounds for exclusion.

Some BsmI and FokI gene polymorphisms also showed links between the achieved intratrial 25(OH)D level and diabetes risk. Carriers of BsmI CC and FokI AG had lower risks for incident diabetes at levels of ≥40 ng/mL, and BsmI TC carriers had lower risks at levels of ≥50 ng/mL.

The study was too small to analyze treatment response within individual racial and ethnic groups. Researchers also acknowledged that the study did not address possible mechanisms driving the link between certain genotypes and vitamin D response.