A meta-anaylsis of three trials has found that in adults with prediabetes, vitamin D helped decrease the risk of developing diabetes by a statistically significant 15% in adjusted analyses. The three-year absolute risk reduction was 3.3%.
Results of the analysis, led by Dr Anastassios Pittas, with the division of endocrinology, diabetes, and metabolism at Tufts Medical Centree, Boston, were published online in Annals of Internal Medicine.
Medscape reports that all three eligible trials included in the analysis were randomised, double blinded and placebo controlled. The 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 said they found no difference in the rate ratios for adverse events (kidney stones, 1.17, 95% confidence interval, 0.69-1.99; hypercalcaemia, 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, with mixed results.
The authors note that two previous meta-analyses included trials with “relatively short durations for assessment of diabetes risk (for example, ≤ 1 year), 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, Pittas and colleagues said.
“The present study does not reach an opposite conclusion from the D2d study," said Pittas, who co-authored 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 vitamin D reduced the risk of progression from prediabetes to diabetes by 15%, which 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.”
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 in 2002.
But “extrapolating to the more than 374m adults worldwide who have prediabetes suggests that inexpensive vitamin D supplementation could delay the development of diabetes in more than 10m people”, they said.
As for how high vitamin D levels need to be, the authors said their research indicates that the optimal level of vitamin D in the blood needed to reduce diabetes risk might 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,” they said.
Editorialists urge caution
In an accompanying editorial also published in the Annals of Internal Medicine, Dr Malachi McKenna, with the department of clinical chemistry, at St Vincent’s University Hospital, and Mary 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 non-skeletal disease. Very-high-dose vitamin D therapy might prevent type 2 diabetes in some patients but may also cause harm,” they note.
Pittas said 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 generalisable 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. 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.”
He cautions 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.
Study details
Vitamin D and Risk for Type 2 Diabetes in People With Prediabetes:
A Systematic Review and Meta-analysis of Individual Participant Data From 3 Randomized Clinical Trials
Anastassios Pittas, Tetsuya Kawahara, Rolf Jorde, et al
Published in the Annals of Internal Medicine on 7 February 2023
Abstract
Background
The role of vitamin D in people who are at risk for type 2 diabetes remains unclear.
Purpose
To evaluate whether administration of vitamin D decreases risk for diabetes among people with prediabetes.
Study Selection
Eligible trials that were specifically designed and conducted to test the effects of oral vitamin D versus placebo on new-onset diabetes in adults with prediabetes.
Data Synthesis
Three randomised trials were included, which tested cholecalciferol, 20 000 IU (500 mcg) weekly; cholecalciferol, 4000 IU (100 mcg) daily; or eldecalcitol, 0.75 mcg daily, versus matching placebos. Trials were at low risk of bias. Vitamin D reduced risk for diabetes by 15% (hazard ratio, 0.85 [95% CI, 0.75 to 0.96]) in adjusted analyses, with a 3-year absolute risk reduction of 3.3% (CI, 0.6% to 6.0%). The effect of vitamin D did not differ in prespecified subgroups. Among participants assigned to the vitamin D group who maintained an intratrial mean serum 25-hydroxyvitamin D level of at least 125 nmol/L (≥50 ng/mL) compared with 50 to 74 nmol/L (20 to 29 ng/mL) during follow-up, cholecalciferol reduced risk for diabetes by 76% (hazard ratio, 0.24 [CI, 0.16 to 0.36]), with a 3-year absolute risk reduction of 18.1% (CI, 11.7% to 24.6%). Vitamin D increased the likelihood of regression to normal glucose regulation by 30% (rate ratio, 1.30 [CI, 1.16 to 1.46]). There was no evidence of difference in the rate ratios for adverse events (kidney stones: 1.17 [CI, 0.69 to 1.99]; hypercalcaemia: 2.34 [CI, 0.83 to 6.66]; hypercalciuria: 1.65 [CI, 0.83 to 3.28]; death: 0.85 [CI, 0.31 to 2.36]).
Limitations
Studies of people with prediabetes do not apply to the general population. Trials may not have been powered for safety outcomes.
Conclusion
In adults with prediabetes, vitamin D was effective in decreasing risk for diabetes.
Accompany editorial – Preventing Type 2 Diabetes With Vitamin D: Therapy Versus Supplementation
NEJM D2D study – Vitamin D Supplementation and Prevention of Type 2 Diabetes (Open access)
Medscape article – In Adults With Prediabetes, Vitamin D Cuts Diabetes Risk (Open access)
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