The Vitamin D and Type 2 Diabetes (D2d) study was a multicenter, randomized (1:1), double-masked, placebo-controlled, parallel-group, primary prevention clinical trial with two arms (4000 IU oral daily vitamin D3 versus placebo) of participants at high risk for diabetes (with pre-diabetes) that were followed for a median of 2.5 years.

The primary objective of the D2d study was to assess whether oral daily vitamin D3 (cholecalciferol) supplementation reduced the rate of progression from pre-diabetes to diabetes as measured by time to development of diabetes.

The secondary objectives included variability of response to vitamin D supplementation by baseline characteristics and by adherence based on pills counts and by achieved 25(OH)D concentration, blood tests to diagnose and monitor diabetes development, insulin resistance and beta cell secretion, plasma 25(OH)D concentration and variability characteristics, blood pressure, and safety and tolerability of vitamin D supplementation.

The primary outcome measure of time to progression from pre-diabetes to incident (new-onset) diabetes was defined by laboratory criteria based on ADA glycemic criteria measured at study visits: fasting plasma glucose (FPG) ≥ 126 mg/dL, 2-hour plasma glucose (2hPG) ≥ 200 mg/dL, and/or hemoglobin A1c (HbA1c) ≥ 6.5%. At any single visit, two measures meeting the criteria constituted meeting the outcome. If a single measure met the criteria, a repeat measure also meeting the criteria constituted meeting the outcome. Additionally, if a participant was diagnosed with diabetes in clinical practice and could not return for a study visit prior to starting diabetes medication, there was a process for outcome event adjudication by a committee.

• Pre-diabetes defined by meeting two of the three glycemic criteria at the baseline visit: FPG = 100-125 mg/dL, 2hPG = 140-199 mg/dL, HbA1c = 5.7-6.4%
• Age ≥ 30 years (≥ 25 years for people from the following races: American Indian, Alaska Native, Native Hawaiian, or Other Pacific Islander)
• Body Mass Index ≥ 24.0 (22.5 for Asians) and ≤ 42.0 kg/m2
• Provision of signed and dated written informed consent prior to any study procedures

• Diabetes
• Use of tanning devices within 12 weeks of the baseline visit and unwilling to stop use of tanning devices for the duration of the study
• Use of supplements containing vitamin D at total doses higher than 1000 IU/day within 8-12 weeks of the baseline visit
• Use of supplements containing calcium at total doses higher than 600 mg/day within 1 week of the baseline visit
• Current use of medications or conditions that would interfere with absorption or metabolism of vitamin D, or medications for weight management
• History of intolerance to vitamin D supplements
• History of hyperparathyroidism, symptomatic or asymptomatic (i.e., radiographic) nephrolithiasis, hypercalcemia, myocardial infarction, cerebrovascular disease, cancer, kidney disease, or bariatric surgery
• Anemia or low platelet count
• Pregnant or breastfeeding
• Any other reason that would impede adherence with study procedures, hinder completion of the study, or increase risk

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. Among persons at high risk for type 2 diabetes, vitamin D3 supplementation at a dose of 4000 IU per day did not result in a significantly lower risk of diabetes than placebo.