Vitamin D lowers diabetes risk among adults with prediabetes

For adults with prediabetes, vitamin D was effective in decreasing diabetes risk, according to results of a systematic review and meta-analysis published in Annals of Internal Medicine.

“Observational studies provide strong and consistent support for an inverse association between blood 25-hydroxyvitamin D level and risk for type 2 diabetes. However, the question of whether vitamin D decreases risk for new-onset diabetes remains unanswered,” Anastassios G. Pittas, MD, MS, a professor of medicine, chief of endocrinology and director of the endocrinology fellowship program at Tufts Medical Center, and colleagues wrote.

The researchers conducted a systematic review and meta-analysis of trials that tested the impact of oral vitamin D vs. placebo on new-onset diabetes among adults with prediabetes. Ultimately, the analysis included 4,190 participants from three randomized clinical trials. Of the participants, 44% were women, 51% were white and the mean age was 61 years.

The researchers primarily sought to understand the time to event for new-onset diabetes, but also evaluated adverse events and the regression to normal glucose regulation.

Pittas and colleagues found that new-onset diabetes occurred in 524 of 2,093 participants — or 25% — in the placebo group and 475 of 2,097 — or 22.7% — in the vitamin D group over a median follow-up period of 3 years.

In adjusted analyses, vitamin D reduced diabetes risk by 15% (HR = 0.85; CI, 0.75-0.96) with a 3-year absolute risk reduction of just over 3% (95% CI, 0.6-6), they wrote.

In addition, Pittas and colleagues reported that vitamin D increased the likelihood of regression to normal glucose regulation by 30% (rate ratio = 1.3; 95% CI, 1.16-1.46).

“Beyond delaying progression to diabetes, regression to normal glucose regulation is also important because euglycemia is associated with a lower prevalence of microvascular disease, nephropathy, and retinopathy compared with prediabetes, primarily due to lower glycemic exposure over time,” they wrote.

The researchers also noted that cholecalciferol reduced the risk for diabetes by 76% (HR = 0.24; 95% CI, 0.16-0.36), with a 3-year absolute risk reduction of 18.1% (95% CI, 11.7-24.6), among participants in the vitamin D group who maintained an intratrial mean serum 25-hydroxyvitamin D level of at least 125 nmol/L compared with 50 to 74 nmol/L during follow up.

“Among participants treated with cholecalciferol, achieving and sustaining higher serum 25-hydroxyvitamin D levels conferred progressively lower risk for diabetes,” they wrote. “These findings ... are consistent with reports from aggregate meta-analyses that higher cholecalciferol doses were more effective than lower doses in reducing diabetes risk.”

Additionally, they wrote that evidence suggests obesity may repress vitamin D bioactivation by CYP2R1 — which leads to reduced production of 25-hydroxyvitamin D — and that weight loss upregulates CYP2R1 expression.

There was no effect modification by baseline BMI in the trial that used an active analogue of vitamin D that does not need hydroxylation by CYP2R1 or CYP27B1, the researchers wrote. However, in the two studies that administered cholecalciferol, requiring CYP2RI and CYP27B1 activation, there was an interaction with BMI. Participants with a baseline BMI below the median (31.3 kg/m²) had a 26% lower risk for diabetes with cholecalciferol vs. placebo. For participants with a BMI at or above the median, though, “there did not seem to be an effect.”

“Taken together, these results suggest that the effect of vitamin D on diabetes risk is mediated via its conversion to 25- hydroxyvitamin D by CYP2R1 — which is primarily expressed in the liver but also in multiple other tissues, including in pancreatic b cells — and subsequently to 1,25-dihydroxyvitamin D by CYP27B1 in the kidney and pancreatic B cells and other tissues,” they wrote. “This can explain why cholecalciferol seems to work in leaner people with prediabetes with intact CYP2R1 bioactivity but less well in those with overweight or obesity who are unable to fully convert vitamin D to 25-hydroxyvitamin D, thereby reducing the exposure of the pancreatic b cell to the beneficial effects of the fully activated vitamin D molecule.”

In terms of safety, there were no significant differences in mortality, hypercalcemia, hypercalciuria, and kidney stones between the vitamin D and placebo groups.

“Longitudinal observational studies that have reported on blood 25-hydroxyvitamin D level and diabetes risk have not reported adverse outcomes with higher levels of 25-hydroxyvitamin,” the researchers wrote. “However, the benefit and safety of vitamin D are population-specific, and the balance of benefit and safety requires constant assessment as evidence evolves.”

In a related editorial, Malachi J. McKenna, MD, an endocrinologist at St. Michael's Hospital and St. Vincent's University Hospital in Ireland, and Mary A.T. Flynn, PhD, RD, a clinical associate professor of medicine at Brown University and a research dietitian at The Miriam Hospital, wrote that “professional societies, which advise physicians about benefits and harms of vitamin D therapy, have a duty of care to understand advice from government agencies.”

“They should promote population health recommendations about vitamin D intake requirements, 25-(OH)D thresholds, and safe limits,” they wrote. “There are important differences between supplementation and therapy. Vitamin D supplementation of 10 mcg to 20 mcg (400 IU to 800 IU) daily can be applied safely at the population level to prevent skeletal, and possibly nonskeletal, disease. Very high-dose vitamin D therapy might prevent type 2 diabetes in some patients but may also cause harm.”

References:

• McKenna MJ, et al. Ann Intern Med. doi:10.7326/M23-0220.
• Pittas AG, et al. Ann Intern Med. doi:10.7326/M22-3018.