Vitamin D and Diabetes: What We Learned From the D2d Trial

This transcript has been edited for clarity.

Jay H. Shubrook, DO: I'm Jay Shubrook. We're here at the 79th Scientific Sessions of the American Diabetes Association in San Francisco, California. Today we're going to talk about the D2d study.^[1] I'm happy to have with me Anastassios Pittas, the lead investigator, from Tufts Medical Center. I'm happy to have you on the show today.

Anastassios G. Pittas, MD, MS: Pleasure to be here.

Shubrook: Tell me about the D2d study, please.

Pittas: Observational studies have shown that people with low vitamin D levels have a high risk of developing diabetes. However, whether vitamin D supplementation lowers the risk for diabetes is not known. We did the D2d study to test the hypothesis that vitamin D supplementation lowers risk for diabetes in people who are at risk for diabetes.

Shubrook: Certainly we see that as a very common finding. What were the main results?

Pittas: First of all, we found that the 4000 units per day that we gave to participants did not have any safety signals, and in the overall cohort, we found a 12% risk reduction in diabetes. However, the effect was not statistically significant.

Shubrook: Okay. For that population, [vitamin D supplementation] did not reduce the risk for diabetes. Was that true across the entire population, or were there some differences within the population?

Pittas: We looked at a small subgroup of the cohort with vitamin D deficiency, defined by the Institute of Medicine as < 12 ng/mL. Among those participants, there was a 62% reduction in diabetes risk. Subgroup analyses should be interpreted conservatively, but this is a large effect size and consistent with physiology, so it's probably true.

Shubrook: So for people who had insufficient vitamin D, they saw a benefit.

Pittas: That's right.

Shubrook: And the rest of the population had plenty of vitamin D?

Pittas: Yes. About 80% of participants at baseline had a level > 20 ng/mL, which would be considered sufficient by most US guidelines. We know from physiology that the response to a nutrient depends on where you start. If levels are sufficient to begin with, it may be less likely to see an effect, and vice versa.

Shubrook: So a high dose of vitamin D is probably not protective if you're already sufficient.

Pittas: It would be much more difficult to show an effect because you've already neared optimal levels.

Effect of Adherence

Shubrook: Okay. So in many of the trials, having patients or participants follow the instructions is important. And we use intention-to-treat analysis. Was there an effect of adherence in this study that made a difference?

Pittas: Overall, adherence in the study was extremely good. We're very happy. However, among nonadherent participants, there were some differences. More people in the placebo group took diabetes medications, weight loss medications, or high doses of vitamin D outside of the study.

On the other hand, more people in the vitamin D group stopped the study for any reason. We think that these differences may have shifted the result toward the null in the intent-to-treat analysis, so we did a per-protocol analysis. When we did this, the risk reduction improved to about 16% overall.

Shubrook: So the overall results of the study are that vitamin D supplementation did not prevent type 2 diabetes in the overall population, but in those who were insufficient and those who were adherent, there were some benefits.

Pittas: That's correct.

Shubrook: What would be the next logical step in studying vitamin D in type 2 diabetes?

Pittas: We have done quite a few studies in this area, and other large studies will also be published soon. We can learn from those studies.

I wanted to point out two other relatively large studies,^[2,3] one from Norway and one from Japan, that tested vitamin D supplementation for risk reduction in diabetes among those at high risk for diabetes. Their results were also not statistically significant, but they were nearly identical to ours. Our team plans to combine data from these three trials to see if we can learn more from what has already been done.

Translation to Clinical Practice

Shubrook: So in clinical practice, what do I do with vitamin D in people who are at risk for diabetes?

Pittas: I think we need to follow the general recommendations. Having a level > 20 ng/mL is probably sufficient. Vitamin D deficiency, defined as < 12 ng/mL, should be avoided for a number of reasons, including probably diabetes.

Shubrook: Thank you. That's important. I think I also heard you say that in your study, the safety data were there as well. So I can feel comfortable in clinical practice giving 4000 IU of vitamin D supplementation, even if the patient's levels are mildly lower, not insufficient. Is that true?

Pittas: That's correct. The safety-benefit ratio is probably very high.

Shubrook: To summarize, the D2d study found that, overall, vitamin D supplementation in the general population did not reduce new onset of type 2 diabetes. But there were subgroups that seemed to benefit, particularly those who stayed on the treatment, as well as those who were insufficient. And we now know that vitamin D supplementation is clearly safe at a 4000 IU per day dose.

Pittas: That's correct. We also plan to look at the effect of vitamin D on insulin secretion and insulin sensitivity. We will be looking at mechanisms as well to support the data that we already have.

Shubrook: Thank you so much for joining us today and sharing the results of the D2d trial.

Pittas: Thank you for the opportunity.

Shubrook: And I want to thank all of you for watching.

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