Higher-dose vitamin D ‘promising approach’ to prevent type 2 diabetes
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Daily vitamin D supplementation to achieve blood levels of vitamin D higher than typically recommended for bone health may reduce risk for type 2 diabetes among adults with prediabetes, according to a new analysis of the D2d study.
“Among people with prediabetes, in addition to optimizing lifestyle to lose and maintain normal weight, supplementation with daily vitamin D may help reduce risk of developing diabetes,” Anastassios G. Pittas, MD, MS, professor of medicine at Tufts University School of Medicine and Tufts Medical Center in Boston, told Healio. “Intermittent, high doses of vitamin D supplementation may not achieve the same protection.”
As Healio previously reported, the D2d study showed that adults with prediabetes assigned to daily vitamin D supplementation for 2.5 years were just as likely to develop type 2 diabetes during follow-up as similar patients assigned to placebo, regardless of baseline vitamin D status. The findings were presented at the 2019 American Diabetes Association Scientific Sessions and published in The New England Journal of Medicine.
For the original study, researchers analyzed data from 2,423 participants aged at least 30 years with a BMI between 24 kg/m² and 42 kg/m² who met at least two of three glycemic criteria for prediabetes, including a fasting plasma glucose level between 100 mg/dL and 125 mg/dL, a plasma glucose level between 140 mg/dL and 199 mg/dL after a 2-hour oral glucose tolerance test or an HbA1c between 5.7% and 6.4% (44.8% women; mean age, 60 years; mean BMI, 32 kg/m²; 33.3% nonwhite). Between October 2013 and February 2017, researchers randomly assigned participants to 4,000 IU daily vitamin D (n = 1,211; mean baseline vitamin D level, 27.7 ng/mL) or placebo (n = 1,212; mean baseline vitamin D level, 28.2 ng/mL), regardless of serum 25-hydroxyvitamin D level.
In a new analysis of D2d published in Diabetes Care, Pittas and colleagues analyzed intratrial vitamin D exposure among D2d participants, calculated as the cumulative rolling mean of annual serum 25-(OH)D measurements. Researchers compared HRs for diabetes among participants who had intratrial 25-(OH)D levels of less than 50 nmol/L, 75 nmol/L to 99 nmol/L, 100 nmol/L to 124 nmol/L and at least 125 nmol/L with those with levels of 50 nmol/L to 74 nmol/L, which is the range considered adequate by the National Academy of Medicine in the entire cohort and by trial assignment (vitamin D vs. placebo).
Researchers observed an interaction of trial assignment with intratrial 25-(OH)D level in predicting diabetes risk (P = .018). The HR for diabetes for an increase of 25 nmol/L in intratrial 25-(OH)D level was 0.75 (95% CI, 0.68-0.82) among those assigned to vitamin D and 0.9 (95% CI, 0.8-1.02) among those assigned to placebo.
HRs for developing type 2 diabetes among participants who received vitamin D and maintained intratrial 25-(OH)D levels of 100 nmol/L to 124 nmol/L and at least 125 nmol/L were 0.48 (95% CI, 0.29-0.8) and 0.29 (95% CI, 0.17-0.5), respectively, compared with those who maintained a level of 50 nmol/L to 74 nmol/L.
The researchers noted that daily vitamin D supplementation to maintain a serum 25-(OH)D level of at least 100 nmol/L is a “promising approach” to reducing the risk for type 2 diabetes among adults with prediabetes.
“It is unlikely that another large diabetes prevention trial with vitamin D supplementation will be completed, so we have to learn from what is already available,” Pittas said. “Because this was an observational analysis, a final recommendation on vitamin D and diabetes must await full publication of the second largest trial, the DPVD study in Japan, and results from individual participant data meta-analyses that combine results from the three large trials that were specifically designed and conducted to test the hypothesis that vitamin D supplementation reduces diabetes risk.”
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Anastassios G. Pittas, MD, MS, can be reached at email: apittas@tuftsmedicalcenter.org; Twitter: @PittasMD.
Perspective
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Carlos Bernal-Mizrachi, MD
Data from multiple observational studies indicate consistent associations between lower 25-(OH)D level concentration and increased diabetes risk. However, the evidence to support general supplementation for the prevention of type 2 diabetes is controversial, mainly because there are significant limitations to the data used to make such recommendations.
The results of the original D2d trial showed no significant differences between the vitamin D and placebo groups in the development of diabetes. Still, there was a trend toward mild risk reduction with vitamin D intervention compared with placebo, suggesting the potential benefit of vitamin D supplementation in this population.
In this new analysis, the authors recognized the post-randomization biases from the D2d trial, including participants who initiated diabetes or weight-loss medication, stopped the trial pills, or took out-of-trial vitamin D from supplements above the trial limit of 1000 IU per day. Therefore, they focused this secondary analysis on determining whether high serum 25-(OH)D level levels measured during the D2d trial prevented the onset of type 2 diabetes.
This study used the cumulative average measure of serum 25-(OH)D level during the trial — intratrial vitamin D — before the primary endpoint's occurrence as the predictor variable. Participants were stratified based on their 25-(OH)D levels. The HRs for diabetes were estimated by comparing the participants in each intratrial mean 25-(OH)D category to the lowest category of vitamin D sufficiency, equivalent to 20 ng/mL to 30 ng/mL. The results indicate that participants in the vitamin D supplementation treatment group who achieved serum 25-(OH)D levels of 40 ng/mL to 49 ng/mL or at least 50 ng/mL had a diabetes risk that was 48% and 29% of that of their counterparts who only achieved serum vitamin D levels within the normal range. Interestingly, this effect was not significant among individuals in the placebo group who achieved mean intratrial 25-(OH)D levels of at least 40 ng/mL despite a tendency toward diabetes risk reduction. Less than 12% of participants in the placebo group achieved high intratrial levels of at least 40 ng/mL, and there was wide mean intratrial 25-(OH)D coefficient of variation in this group, likely due to lack of continuous daily vitamin D supplementation, that may account for the lack of significance within this group.
This study highlights the importance of future intervention studies with a treat-to-target design to sustain higher 25(OH)D levels and assess whether preventive effects on diabetes progression are sustainable. Further confirmation of these results has the potential to alter the approach to prediabetics and prompt vitamin D supplementation to achieve 25(OH)D levels of at least 40 ng/mL to 50 ng/mL to prevent diabetes progression.
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JoAnn E. Manson, MD, DrPH, MACP, FAHA
This new analysis of the D2d trial is interesting but has the limitations of an observational study. The achieved blood level of 25-hydroxyvitamin D, or 25-(OH)D, is going to be correlated with the baseline 25-(OH)D level, BMI, demographic factors, and lifestyle factors such as physical activity and diet, which are known to be associated with risk for developing type 2 diabetes. Even after adjusting for the variables in the model, the potential for residual confounding persists. Data in the paper reflect these correlations.
The D2d trial had already shown a signal that BMI modified the efficacy of vitamin D supplementation. Those with a BMI below 30 kg/m² at baseline had a 29% lower incidence of type 2 diabetes with vitamin D treatment compared with those assigned placebo; however, those who had a high baseline BMI had no benefit.
There is mounting evidence that higher adiposity interferes with the bioactivity of vitamin D. This is really important to understand more fully. The insights may inform efforts to make vitamin D more effective for people of all body weights. I was surprised that the modifying effect of BMI wasn’t given greater attention, especially because two recent meta-analyses of randomized trials of vitamin D and type 2 diabetes support this interaction (Zhang Y, et al. Diabetes Care. 2020; doi:10.2337/dc19-1708.; Barbarawi M, et al. J Clin Endocrinol Metab. 2020; doi:10.1210/clinem/dgaa335).
We already have hundreds of observational studies looking at associations between 25-OHD levels and type 2 diabetes risk. This is why the randomized controlled trials are so important — to avoiding the confounding by all of the other correlated factors. When you depart from the randomized design, then the analysis will be susceptible to confounding and selection biases. Correlation does not prove causation, and this is the very reason we need randomized clinical trials.
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