Vitamin D Supplementation and Prevention of Type 2 Diabetes

Abstract

Background: Observational studies support an association between a low blood 25-hydroxyvitamin D level and the risk of type 2 diabetes. However, whether vitamin D supplementation lowers the risk of diabetes is unknown.

Methods: We randomly assigned adults who met at least two of three glycemic criteria for prediabetes (fasting plasma glucose level, 100 to 125 mg per deciliter; plasma glucose level 2 hours after a 75-g oral glucose load, 140 to 199 mg per deciliter; and glycated hemoglobin level, 5.7 to 6.4%) and no diagnostic criteria for diabetes to receive 4000 IU per day of vitamin D₃ or placebo, regardless of the baseline serum 25-hydroxyvitamin D level. The primary outcome in this time-to-event analysis was new-onset diabetes, and the trial design was event-driven, with a target number of diabetes events of 508.

Results: A total of 2423 participants underwent randomization (1211 to the vitamin D group and 1212 to the placebo group). By month 24, the mean serum 25-hydroxyvitamin D level in the vitamin D group was 54.3 ng per milliliter (from 27.7 ng per milliliter at baseline), as compared with 28.8 ng per milliliter in the placebo group (from 28.2 ng per milliliter at baseline). After a median follow-up of 2.5 years, the primary outcome of diabetes occurred in 293 participants in the vitamin D group and 323 in the placebo group (9.39 and 10.66 events per 100 person-years, respectively). The hazard ratio for vitamin D as compared with placebo was 0.88 (95% confidence interval, 0.75 to 1.04; P = 0.12). The incidence of adverse events did not differ significantly between the two groups.

Conclusions: Among persons at high risk for type 2 diabetes not selected for vitamin D insufficiency, vitamin D₃ supplementation at a dose of 4000 IU per day did not result in a significantly lower risk of diabetes than placebo. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; D2d ClinicalTrials.gov number, NCT01942694.).

Figure 1.. Screening, Randomization, and Follow-up.

One participant in the vitamin D group was withdrawn administratively after a clinical site closed down early in the trial. Protocol-specified adverse events that led to discontinuation of the trial pills were hypercalcemia, a fasting urine calcium:creatinine ratio of more than 0.375, a low estimated glomerular filtration rate, and nephrolithiasis. Of the 2423 participants who underwent randomization, 14 (9 in the vitamin D group and 5 in the placebo group) were subsequently found not to meet all eligibility criteria.

Figure 2.. Kaplan–Meier Curves for Survival Free from Diabetes among Adults at Risk for Type 2 Diabetes.

The hazard ratio for new-onset diabetes between the vitamin D group and the placebo group is derived from Cox regression, with stratification according to trial site, body-mass index, and race.

Figure 3.. Prespecified Subgroup Analyses.

Participants met at least two of three glycemic criteria for prediabetes: fasting plasma glucose level, 100 to 125 mg per deciliter (5.6 to 6.9 mmol per liter); plasma glucose level 2 hours after a 75-g oral glucose load, 140 to 199 mg per deciliter (7.8 to 11.0 mmol per liter) (impaired glucose tolerance); and glycated hemoglobin level, 5.7 to 6.4% (39 to 47 mmol per mole). To convert the values for 25-hydroxyvitamin D to nanomoles per liter, multiply by 2.496.