BACKGROUNDObservational 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. METHODSWe 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 D 3 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. RESULTSA 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. CONCLUSIONSAmong persons at high risk for type 2 diabetes not selected for vitamin D insufficiency, vitamin D 3 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.)A BS TR AC T

IntroductionType 2 diabetes mellitus (T2DM) is caused by insulin resistance and pancreatic islet insufficiency. Vitamin D deficiency and T2DM share common demographic characteristics for their risk groups (elderly, darkskinned individuals, obese), and patients with T2DM are reported to have higher rates of vitamin D deficiency.1 Epidemiological studies also suggest a higher prevalence of metabolic syndrome and its components (central obesity, hypertension, dyslipidemia, and glucose intolerance) among individuals with low circulating vitamin D concentrations. AbstractBackground: Epidemiological studies suggest a higher prevalence of metabolic syndrome and its components among individuals with vitamin D deficiency. The aim of the present study was to determine whether vitamin D treatment improves glucose control and insulin sensitivity in Type 2 diabetes mellitus (T2DM). Methods: Subjects with T2DM and serum 25-hydroxyvitamin D (25(OH)D) concentrations <25 ng ⁄ mL were randomized to receive 400 IU (Group 1) or 1200 IU (Group 2) cholecalciferol for 4 months. Fasting plasma glucose, glycosylated hemoglobin (HbA1c), Quantitative Insulin Sensitivity Check Index (QUICKI), serum lipid levels and serum adiponectin were measured at baseline and at 4 months. Results: Mean 25(OH)D levels increased in both groups (from 17.6 ± 1.5 to 25.5 ± 1.8 ng ⁄ mL in Group 1 and from 15.6 ± 1.4 to 27.4 ± 2.4 ng ⁄ mL in Group 2; P £ 0.001 vs baseline for each group). No significant differences were noted in fasting plasma glucose, HbA1c, QUICKI, serum adiponectin, and lipid levels compared with baseline within groups or between the two groups. Conclusions: In the present pilot study, conventional vitamin D treatment at a level improving, but not optimizing, serum 25(OH)D did not improve glycemia, insulin sensitivity, or lipid profile. However, diabetes and lipids were relatively well controlled at baseline. Future studies should be designed to achieve optimal concentrations of serum 25(OH)D (at least >32 ng ⁄ mL) and should include subjects showing more abnormal parameters of glycemia, lipid, and insulin sensitivity at baseline.

Background/Objectives Routine use of vitamin D supplements has increased substantially in the United States. However, the safety and tolerability of long-term use of high-dose vitamin D are not known. We assessed the safety and tolerability of high-dose, daily vitamin D3 in the vitamin D and type 2 diabetes (D2d) study. Subjects/Methods In total, 2423 overweight/obese persons with prediabetes were randomized in a double-blind manner to either 4000 IU of vitamin D3 (the tolerable upper intake level for adults by the National Academy of Medicine) taken daily or matching placebo. All participants were included in this analysis. Incident adverse events (AE) were ascertained 4 times a year at in-person visits (twice a year) and interim remote encounters (twice a year) and were defined as untoward or unfavorable medical occurrences. Serious adverse events (SAE) included death, life-threatening events, and hospitalizations. Results A total of 8304 AEs occurred during 3 years of follow-up and were less frequent in the vitamin D group compared to placebo (Incidence Rate Ratio [IRR] = 0.94; 95% Confidence Interval (CI) 0.90, 0.98). The overall frequency of protocol-specified AEs of interest, which included nephrolithiasis, hypercalcemia, hypercalciuria, or low estimated glomerular filtration rate, was low and did not differ by group. There were no significant between-group differences in total SAEs (IRR = 0.96 (0.81, 1.14)). Conclusion Vitamin D3 supplementation at 4000 IU per day was safe and well tolerated among overweight/obese participants at high risk for diabetes who were appropriately monitored for safety. In this population, this dose of vitamin D3 did not increase risk of AEs or SAEs, including those previously associated with vitamin D such as hypercalcemia, hypercalciuria, or nephrolithiasis. Clinical Trial Registration ClinicalTrials.gov NCT01942694, prospectively registered September 16, 2013

Objective Fasting plasma glucose (FPG), 2-hour plasma glucose (2hPG) from a 75-g oral glucose tolerance test (OGTT) and glycated hemoglobin (HbA1c) can lead to different results when diagnosing prediabetes and diabetes. The Hemoglobin Glycation Index (HGI) quantifies the interindividual variation in glycation resulting in discrepancies between FPG and HbA1c. We used data from the Vitamin D and Type 2 Diabetes (D2d) study to calculate HGI, to identify HGI-associated variables, and to determine how HGI affects prediabetes and diabetes diagnosis. Measurements A linear regression equation [HbA1c (%) = 0.0164 × FPG (mg/dL) + 4.2] was derived using the screening cohort (n = 6829) and applied to calculate predicted HbA1c. This was subtracted from the observed HbA1c to determine HGI in the baseline cohort with 2hPG data (n = 3945). Baseline variables plus prediabetes and diabetes diagnosis by FPG, HbA1c, and 2hPG were compared among low, moderate, and high HGI subgroups. Results The proportion of women and Black/African American individuals increased from low to high HGI subgroups. Mean FPG decreased and mean HbA1c increased from low to high HGI subgroups, consistent with the HGI calculation; however, mean 2hPG was not significantly different among HGI subgroups. Conclusions High HGI was associated with Black race and female sex as reported previously. The observation that 2hPG was not different across HGI subgroups suggests that variation in postprandial glucose is not a significant source of population variation in HGI. Exclusive use of HbA1c for diagnosis will classify more Black individuals and women as having prediabetes compared with using FPG or 2hPG.