In adults with prediabetes, vitamin D helped decrease the risk that these individuals would develop diabetes, suggests a meta-analysis of three trials.
Results of the analysis, led by Anastassios G. Pittas, MD, MS, with the division of endocrinology, diabetes, and metabolism at Tufts Medical Center, in Boston, were published online in Annals of Internal Medicine (2023 Feb 7. doi: 10.7326/M22-3018).
All three eligible trials included in the analysis were randomized, double blinded, and placebo controlled. The three eligible trials tested three oral formulations of Vitamin D: cholecalciferol, 20,000 IU (500 mcg) weekly; cholecalciferol, 4,000 IU (100 mcg) daily; or eldecalcitol, 0.75 mcg daily, against placebos.
The authors of the new paper found that vitamin D reduced the risk for diabetes in people with prediabetes by a statistically significant 15% in adjusted analyses. The 3-year absolute risk reduction was 3.3%.
They found no difference in the rate ratios for adverse events (kidney stones, 1.17, 95% confidence interval, 0.69-1.99; hypercalcemia, 2.34; 95% CI, 0.83-6.66]; hypercalciuria, 1.65; 95% CI, 0.83-3.28]; death, 0.85; 95% CI, 0.31-2.36]) when study participants got vitamin D instead of placebo.
Differences from previous analyses
The relationship between vitamin D levels and risk for type 2 diabetes has been studied in previous trials and results have been mixed.
The authors note that two previous meta-analyses included trials “that had relatively short durations for assessment of diabetes risk (for example, ≤ 1 year), had high risk of bias (for example, open-label trials), or were not specifically designed and conducted for primary prevention of type 2 diabetes, potentially undermining the validity of the results.”
Each of the trials in this meta-analysis had a low risk of bias as determined by the Cochrane risk-of-bias tool, Dr. Pittas and colleagues said.
“The present study does not reach an opposite conclusion from the D2d study,” said Dr. Pittas, who coauthored that paper as well. “Rather, it confirms the results of the D2d study. In D2d and two other similar vitamin D and diabetes prevention trials (one in Norway and one in Japan), vitamin D reduced the rate of progression to diabetes in adults with prediabetes, but the observed differences were not statistically significant because the reported relative risk reductions (10%-13%) were smaller than each trial was powered to detect (25%-36%).”
“Individual participant data meta-analyses increase the statistical power to detect an effect. After combining data, we found that vitamin D reduced the risk of progression from prediabetes to diabetes by 15% and this result was statistically significant. So, the conclusion of the meta-analysis is essentially the same conclusion as in D2d and the other two trials. The difference is that the result is now statistically significant,” Dr. Pittas added.
Small reduction but large population
The authors acknowledged that the absolute risk reduction number is small, especially when compared with the risk reduction seen with intensive lifestyle changes (58%) and metformin (31%), as reported in an article published in the New England of Journal of Medicine (2002 Feb 7;346:393-403). But “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 said.
As for how high vitamin D levels need to be, the authors write that their research indicates that the optimal level of vitamin D in the blood needed to reduce diabetes risk may be higher than an Institute of Medicine committee recommendation in 2011.
“The blood 25-hydroxy vitamin D level needed to optimally reduce diabetes risk may be near and possibly above the range of 125-150 nmol/L (50-60 ng/mL) that the 2011 Institute of Medicine Committee to Review Dietary Reference Intakes for Calcium and Vitamin D provided as the range corresponding to the tolerable upper intake level (UL) of 4,000 IU/d for vitamin D,” the authors of the new paper said.
Editorialists urge caution
In an accompanying editorial also published in the Annals of Internal Medicine, Malachi J. McKenna, MD, with the department of clinical chemistry, at St. Vincent’s University Hospital, and Mary A.T. Flynn, PhD, RD, with the Food Safety Authority of Ireland in Dublin, urge caution regarding vitamin D dosing.
They write that there are important distinctions between vitamin D supplements and vitamin D therapy, and the potential harms of high-dose vitamin D are still unclear.
“Vitamin D supplementation of 10 to 20 mcg (400 to 800 IU) daily can be applied safely at the population level to prevent skeletal and possibly nonskeletal disease. Very-high-dose vitamin D therapy might prevent type 2 diabetes in some patients but may also cause harm,” they note.
Dr. Pittas said in an interview that there have been some studies with high-dose vitamin D (up to 500,000 IU a year in one study) that reported an increased fall risk in older adults who had high fall risk. “However, these findings are not generalizable to other populations that are younger and at low or average fall risk, such as the prediabetes population to which the results of this meta-analysis apply,” he noted.
“The benefit-to-risk ratio for vitamin D depends on the target population and medical condition,” Dr. Pittas said. “The editorial refers to the NAM (National Academy of Medicine) vitamin D guidelines for the general, healthy population to promote bone health. The guidelines should not be extrapolated to specific populations, for example [patients with] prediabetes,” where the vitamin D benefit-to-risk ratio would be different from that in the general population.
Dr. Pittas and colleagues caution that the people studied in this meta-analysis were at high risk for type 2 diabetes, so these results do not apply to the general healthy population. The results also should not be extrapolated to people at average risk for any type of diabetes, they add.
Dr. Pittas reports the National Institutes of Health and the American Diabetes Association made payments to his institution to conduct Vitamin D-related research. He is an unpaid cochair of the Endocrine Society’s Evaluation, Treatment and Prevention of Vitamin D Deficiency Clinical Practice Guideline team. Coauthor Dr. Jorde reports grants from Novo Nordisk Foundation, North Norwegian Regional Health Authorities, and the Research Council of Norway. Dr. Dawson-Hughes reports she is on the DSMB for AgNovos Healthcare. AgNovos is developing a bone implant to reduce hip fracture risk and she gets a stipend from the company. She reports Helsinn Therapeutics provided anamorelin and matching placebo for an NIH-funded clinical trial. Dr. Trikalinos was supported by the D2d study. He is a technical methodological consultant to Latham and Watkins, who is retained by Pacira Pharmaceuticals. Dr. Angellotti has been employed by Takeda and owns stock in the company. The editorialists report no relevant financial relationships.
This article originally appeared on MDedge.com , part of the Medscape Professional Network.