Vitamin D for Diabetes Prevention: Here We Go Again

EBM Focus - Volume 18, Issue 15

Reference: Ann Intern Med. 2023 Mar;176(3):355-363

Practice Point: Vitamin D may be getting another fifteen minutes of fame for its potential role in preventing diabetes, but please don’t start “treating to target” yet.

EBM Pearl: When trials have similar enough protocols, the data points can be combined in an individual patient data meta-analysis to increase the power of a study.

Anytime a single treatment has been found ineffective for multiple conditions and then you see it being studied for yet another purpose, it’s hard not to think there is some kind of fishing expedition going on. That was our first instinct when we saw the recently published systematic review and individual patient data (IPD) meta-analysis on vitamin D for primary prevention of diabetes in patients with prediabetes.

This meta-analysis took individual data points from 3 randomized trials studying different formulations of vitamin D vs placebo in a total of 4,190 adults with prediabetes (and without vitamin D deficiency) and analyzed them together in an effort to increase study power. They were able to do that because the inclusion criteria in the 3 trials were nearly identical, and all 3 trials had the same primary outcome: progression to new-onset diabetes. None of the individual trials found a significant benefit of vitamin D.

The authors of this meta-analysis reasoned that the lack of significant findings was because the individual trials were underpowered. The individual studies were designed to detect a difference of at least 25%, (probably based on a pilot study that overestimated the magnitude of effect), and what they each found was a nonsignificant risk reduction of around 11%. When these investigators put all the data together and did a combined intention-to-treat analysis, vitamin D was associated with a 15% reduced risk of progression to diabetes (hazard ratio 0.85, 95% CI 0.75-0.96), which translates to an NNT of 30.

So, if this is a fishing expedition, what’s the catch? Although it is unusual that a higher quality trial would find significant benefit from an intervention when prior studies did not, we actually do buy the legitimacy of combining individual patient data from randomized trials in this case, given the similarity of study protocols and that the primary outcome studied was, in fact, progression to diabetes rather than some post-hoc secondary outcome. The generalizability gives us some pause, as these data only came from participants in Norway, the US, and Japan, and we don’t know if this intervention would still work in places where people get a lot more sun exposure.

What really concerns us, however, is the recommendation by the authors for a “treat to target” approach, based on the finding that higher achieved vitamin D levels were associated with lower risk of diabetes and higher likelihood of return to normal glucose. That approach would require testing for vitamin D levels, which is still a hard “no” for us based on the available evidence.

Giving patients with prediabetes 4,000 IU of vitamin D a day to prevent a future A1c ≥ 6.5 is a disease-oriented approach that is still of unproven clinical benefit*, and may not be without harm. More than that, these authors want us to treat with something that has an NNT of 30, when metformin, which has an NNT of 14 according to the Diabetes Prevention Program study, is not even recommended for patients with prediabetes! Lifestyle intervention has an NNT of 7.

When the data show us that vitamin D helps patients with prediabetes live better or longer, we’ll be the first ones casting a line. Until then, we think it’s fair to remain skeptical and focus our energy on convincing our patients to actually make some lifestyle changes which we know will do more than improve their A1c.

*It has not been established that prevention (or prethreshold treatment) of diabetes delays or prevents complications compared with treatment once diabetes is diagnosed. DynaMed considers prevention of diabetes to be a surrogate outcome unless the studies also report clinical outcomes such as cardiovascular events. While no one wants to be labeled as having diabetes, delaying the crossing of specific glycemic thresholds can be an arbitrary outcome as the impact of having a fasting blood sugar of 124 mg/dL is unlikely to be significantly different than a fasting blood sugar of 126 mg/dL.

For more information, see the topic Prediabetes in DynaMed.

DynaMed EBM Focus Editorial Team

This EBM Focus was written by Katharine DeGeorge, MD, MS, Deputy Editor at DynaMed and Associate Professor of Family Medicine at the University of Virginia. Edited by Alan Ehrlich, MD, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School; Dan Randall, MD, Deputy Editor at DynaMed; Nicole Jensen, MD, Family Physician at WholeHealth Medical; Vincent Lemaitre, PhD, Senior Medical Writer at DynaMed; Elham Razmpoosh, PhD, Postdoctoral fellow at McMaster University; and Sarah Hill, MSc, Associate Editor at DynaMed.