Patients at high risk for developing type 2 diabetes who received high-dose vitamin D supplementation showed no reduction in the risk of developing diabetes in a recent trial.
Anastassios G. Pittas, MD, with the Division of Endocrinology, Diabetes, and Metabolism, Tufts Medical Center, Boston, and colleagues reported their findings in the August 8, 2019 issue of The New England Journal of Medicine.
The Center for Disease Control and Prevention (CDC) reports that approximately 84 million adults in the United States have prediabetes. The first step in preventing progression to diabetes is lifestyle adjustment, mainly diet and exercise, to achieve weight loss and serum glucose level reduction. Given the difficulty many patients have adhering to lifestyle changes, researchers are studying several supplements and pharmaceutical agents to assist patients while lifestyle adjustments are ongoing. For example, metformin, a biguanide antihyperglyemic agent has been shown to independently reduce the risk of Type 2 diabetes in prediabetic patients. Other agents such as thiazolidinediones and alpha-glucosidase inhibitors are similarly being studied.
Vitamin D has also been linked to diabetes. Vitamin D levels are associated with several aspects of cellular function and health outcomes. Observational studies have shown a correlation between low vitamin D levels and decreased pancreatic beta-cell function and insulin resistance. Other short-term studies have shown an improvement in beta-cell function after vitamin D supplementation. It is unclear, however, if adding vitamin D prevents progression to diabetes.
This study was a randomized, double-blind, placebo-controlled trial, called the Vitamin D and Type 2 Diabetes trial (D2d). The trial enrolled participants 30 years of age or older who had a body-mass index (BMI) of 24 to 42, and had at least two of three criteria for prediabetes: increased fasting plasma glucose level (100-125 mg per deciliter), increased glucose level two hours after a 75-g oral glucose dose (140-199 mg per deciliter), and increased glycated hemoglobin level (5.7 to 6.4%). Patients were not selected for vitamin D deficiency and could be taking up to 1000 IU of vitamin D daily at the time of entry into the trial.
A total of 7133 persons were screened and 2423 were included in the intention-to-treat population. 1211 participants were randomly assigned to receive 4000 IU of vitamin D₃ daily, and 1212 participants to receive placebo. The development of new-onset diabetes was assessed and compared between groups.
After a mean follow-up period of 2.5 years, new-onset diabetes developed in 293 participants in the vitamin D group and 323 participants in the placebo group (9.4 events and 10.7 events per 100 person-years, respectively. The hazard ratio in the vitamin D group was .88; (95% confidence interval [CI], 0.75 to 1.04; P=0.12). The mean baseline serum 25-hydroxyvitamin D level was 28.0 ng per milliliter, with no significant between-group difference. Measured at months 12 and 24, the mean 25-hydroxyvitamin D levels in the vitamin D group were 52.3 and 54.3 ng per milliliter, respectively, and in the placebo group, the levels were 28.1 and 28.8 ng per milliliter, respectively.
There was no significant difference in the rate of adverse events reported between the groups. This included specific vitamin D-related concerns for the development of hypercalcemia, nephrolithiasis, and decreased glomerular filtration rate (GFR). 47 participants (3.9%) in the vitamin D group stopped the study drug because of an adverse event, as compared with 37 (3.1%) in the placebo group (between-group difference, 0.8%; 95% CI, -0.7 to 2.3).
The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others. A full list of disclosures is provided in the journal article.
Pittas, AG, et al. Vitamin D Supplementation and Prevention of Type 2 Diabetes. N Engl J Med. 2019; 381:520-30.
Comments
- in an editorial accompanying this study, Deborah J. Wexler, MD notes that the hazard ratio of 0.88 for development of new-onset diabetes does not rule out a modest benefit of vitamin D; a larger or longer trial would be needed to show this benefit
- post hoc analysis done from 103 participants who had vitamin D deficiency (<12 ng per milliliter) showed a hazard ratio for the risk of developing diabetes with vitamin D supplementation of 0.38 (95% CI, 0.18 to 0.80)
- further studies of those with vitamin D deficiency may help determine whether vitamin D supplementation prevents prediabetes from progressing to diabetes in that subgroup