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Daily higher-dose vitamin D supplementation may help stave off diabetes in an at-risk population, researchers reported.

In a meta-analysis of three randomized clinical trials, vitamin D reduced the risk for type 2 diabetes by 15% in people with prediabetes (adjusted HR 0.85, 95% CI 0.75-0.96) in a model adjusted for age, gender, body mass index (BMI), race, and HbA1c, according to Anastassios Pittas, MD, MS, of Tufts Medical Center in Boston, and colleagues.

This translated to a 3.3% (95% CI 0.6-6.0%) absolute risk reduction over the course of 3 years, the researchers wrote in .

The reduced risk of full-blown diabetes among vitamin D users persisted in a secondary analysis that excluded those who stopped taking the trial pills, started using a diabetes or weight loss medication, or took supplemental vitamin D at a dose above 1,000 IU/d outside the trial (HR 0.83, 95% CI 0.73-0.94).

Pittas' group also found that those who took vitamin D supplementation had a 30% increased likelihood of returning to normal glucose levels (rate ratio 1.30, 95% CI 1.16-1.46).

In the three trials included, participants took 20,000 IU (500 mcg) per week of cholecalciferol, 4,000 IU (100 mcg) daily of cholecalciferol in the D2d study, or 0.75 mcg daily of eldecalcitol in the DPVD study, all compared with matching placebo. Lead investigators from all three trials were involved in the meta-analysis.

However, authors Malachi McKenna, MD, of University College Dublin, and Mary Flynn, PhD, RD, of Food Safety Authority of Ireland, Dublin, pointed out that on their own, all three of these trials found similarly nonsignificant diabetes risk reductions associated with vitamin D supplementation:

• : HR 0.90 (95% CI 0.69-1.18)
• D2d study: HR 0.88 (95% CI 0.75-1.04)
• : HR 0.87 (95% CI 0.67-1.17)

Pittas and colleagues argued the stand-alone original trials were simply "underpowered" to detect this benefit on diabetes progression.

"Although the degree of relative reduction in risk for diabetes with vitamin D is small (15%) compared with other diabetes prevention strategies ... the 3-year absolute risk reduction was 3.3%, translating to a number of persons with prediabetes needed to treat of 30 (compared with 7 with intensive lifestyle modification and 14 with metformin in the Diabetes Prevention Program study)," the group said.

"Extrapolating to the more than 374 million adults worldwide who have prediabetes suggests that inexpensive vitamin D supplementation could delay the development of diabetes in more than 10 million people," they estimated.

While no safety signals emerged in any of the meta-analysis (no increased risk for kidney stones, hypercalcemia, or hypercalciuria), McKenna and Flynn warned that very high doses of vitamin D supplements may cause harm beyond the 10 to 20 mcg (400 to 800 IU) daily that is considered safe.

"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 continued. "They should promote population health recommendations about vitamin D intake requirements, 25-(OH)D thresholds, and safe limits."

When the three trials were combined, there was a total of 4,190 individuals: 2,097 who received vitamin D and 2,093 who received placebo. The average age was 61 years and 44% were women. About half were white, 15% Black, and 33% Asian. The average BMI was 29.5 and HbA1c was 5.9 at baseline.

Over the median 3-year follow-up, there were 475 new diabetes cases diagnosed among those taking vitamin D versus 524 across the placebo groups.

In a subgroup analysis, Pittas' group found the risk reduction was far more pronounced for those who maintained higher serum 25-hydroxyvitamin D levels.

When compared with those who maintained lower serum levels during follow-up -- falling within the 50 to 74 nmol/L (20 to 29 ng/mL) range -- those who maintained levels of at least 125 nmol/L (≥50 ng/mL) had a 76% reduced risk for progression to diabetes (HR 0.24, 95% CI 0.16-0.36). This translated to a 3-year absolute risk reduction of 18.1% (95% CI 11.7-24.6%).

But the editorialists raised concern, pointing out that this "optimal effect" for vitamin D supplementation was seen above the – corresponding to a daily intake of 100 mcg (4,000 IU) -- that most government agencies, like the NIH, set as the highest level of daily vitamin D intake to avoid unnecessary adverse effects.

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