JoAnn E. Manson, MD, DrPH
February 15, 2023
Hello. This is Dr JoAnn Manson, professor of medicine at Harvard Medical School and Brigham and Women’s Hospital. I’d like to talk with you about a recent report in Annals of Internal Medicine on vitamin D and type 2 diabetes. This report provides some new insights, but it also raises several new questions.
This was an individual participant meta-analysis of three randomized trials of people with prediabetes. One was the D2d trial, which tested 4000 IUs a day of vitamin D3. Another was the Tromsø trial from Norway, which tested bolus dosing of vitamin D3 with 20,000 IUs weekly or about 3000 IUs daily. The third was a subset trial from Japan that tested a synthetic analog of a vitamin D. These three trials in aggregate had an average of about 3 years’ duration.
The hazard ratio in the meta-analysis was 0.88 or a modest risk reduction that just met statistical significance for the intention-to-treat unadjusted analysis. After adjustment for other diabetes risk factors, it was 0.85 with a confidence interval of 0.75 to 0.96. The trials weren’t large enough or long enough to do a rigorous assessment of safety, but they didn’t see any clear safety signals looking at hypercalcemia and kidney stones. They did see a little bit of edging up toward about a doubling in risk for hypercalcemia, but it was not statistically significant.
The authors did see effect modification by body mass index (BMI), as has been seen in many other vitamin D trials. We’ve seen in our VITAL trial that BMI modified the effect of vitamin D for total invasive cancer, cancer death, autoimmune diseases, and some other outcomes. They saw that among those who had a BMI below the median of 31, there was a significant 24% reduction in risk. But those who had a BMI at the median of 31 or above had no reduction whatsoever in diabetes risk. Their hazard ratio was 1.01.
The synthetic analog trial results had a similar hazard ratio, but there was no modifying effect of BMI. The authors postulate that this is because vitamin D3, the cholecalciferol, requires conversion to 25-hydroxyvitamin D in the liver and other tissues, and that the CYP2R1 is affected by BMI. There is some evidence that weight loss can upregulate CYP2R1 expression, so a high BMI may actually interfere with the ability to convert to the biologically active form of vitamin D.
These doses of vitamin D are on the high side. In fact, they’re quite similar to the tolerable upper intake level set by the National Academy of Medicine — five to six times the recommended dietary allowance in the general population guidelines. So, clearly we need more research in terms of the safety of long-term use of vitamin D at these higher doses. But I think it’s important to compare these results with those of the Diabetes Prevention Program trial, in which people with prediabetes were also tested. Lifestyle modifications resulted in a 58% reduction in type 2 diabetes, and metformin resulted in about a 31% reduction — much larger reductions than seen with high-dose vitamin D.
We also need comparisons with moderate-dose vitamin D in people with prediabetes to see if these high doses are needed and whether more is better for this purpose. But I think it’s important to be focusing primarily on lifestyle modifications for prevention of type 2 diabetes. Additional research on vitamin D, particularly the safety of these higher doses, will be very important.
Thank you so much for your attention. This is JoAnn Manson.
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