American Diabetes Association 79th Scientific Sessions:

Uncertainty of Vitamin D Benefit Persists in Diabetes Progression

with Anastassios G. Pittas, MD

Vitamin D insufficiency has emerged as a key potential contributor in the development of type 2 diabetes (T2D). The suggestion that vitamin D status may influence the risk of diabetes was biologically plausible because both impaired pancreatic beta cell function and insulin resistance have been reported when low blood 25-hydroxyvitamin D levels also were indicated.

Findings from observational studies, most notably the PROspective metabolism and Islet Cell Evaluation (PROMISE) Cohort Study supported an association between a low 25-hydroxyvitamin D level and risk of developing type 2 diabetes.1

In short-term mechanistic studies, vitamin D supplementation improved the disposition index—a measure of pancreatic beta-cell function—by 40%.2

However, long-term clinical trial data have been lacking.

Large Trial Seeks Definitive Answer on Role of Vitamin D in Diabetes

Results of the multicenter, randomized, controlled Vitamin D and Type 2 Diabetes (D2d) Study were presented at the American Diabetes Association 79th Scientific Sessions in San Francisco, California,3 and simultaneously published in the New England Journal of Medicine.4 This was the largest study to examine whether there was any benefit to vitamin D supplementation in slowing progression of diabetes in patients known to have a diagnosis of prediabetes.1

“Though many studies have observed that individuals with low vitamin D levels were at increased risk of type 2 diabetes, it was not known whether taking steps to increase vitamin D would reduce their risk of diabetes,” said the lead author, Anastassios G. Pittas, MD, MS, an endocrinologist at the Diabetes and Lipid Center and professor of medicine at Tufts Medical Center in Boston, Massachusetts.

“Our results did not find a statistically significant benefit of vitamin D supplementation in decreasing progression to type 2 diabetes,” Dr. Pittas told EndocrineWeb. “These findings underscore the need for clinical trials to confirm hypotheses raised in observational studies as a necessary step in developing additional public and clinical recommendations.” 

Protocol for Vitamin D Influence on Type 2 Diabetes Outcomes

The D2d trial was conducted in 22 cities across the United States to determine whether vitamin D supplementation was safe and effective in delaying the onset of type 2 diabetes in patients with prediabetes and to gain a better understanding of how vitamin D affects glucose metabolism.4

The study, designed as an event-driven trial with a target 508 total diabetes events, was conducted with 2,423 adults who were diagnosed with prediabetes as defined utilizing the American Diabetes Association 2010 guidelines for high risk patients as meeting at least two of three glycemic criteria for prediabetes: 5

  • Fasting glucose 100 – 125 mg/dL (5.6 – 6.9 mmoL/L)
  • 2-h post load glucose after 75-g glucose load 140 – 199 mg/dL (7.8 – 11.0 mmoL/L)
  • Hemoglobin A1c (HbA1c) 5.7% – 6.4% (39 – 47 mmoL/mol)

Participants were 30 years and older with body mass indexes of ≥ 25 (except ≥ 23 for Asian Americans) to 42 kg/m2, and approximately 40% of those enrolled were non-Caucasian. Participants were randomized to taking a pill containing 4000 IU of vitamin D3 (cholecalciferol) daily or placebo and followed for new-onset diabetes with blood tests drawn every six months for a median of 2.5 years.4

"The dose of 4.000 IU per day was chosen to balance efficacy and safety since this dose is the upper limit set by the NAM,5 and higher doses may potentially be associated with toxicity. The way the body responds to taking a supplemental dose such as with vitamin D likely depends on how much of the vitamin is already in the body,” said Dr. Pittas. 

"To maximize the study’s impact, we designed D2d specifically to include patients with prediabetes regardless of their vitamin D level,” he said, and "participants were asked to refrain from using diabetes-specific and weight loss medications during the study and to limit their use of outside-of-study vitamin D to 1000 IU daily from all supplements including multivitamins."4

At the end of the study, fewer participants in the vitamin D group (293 of 1211 participants in the vitamin D group, 24.2%) developed diabetes compared vs the placebo group (323 of 1212 participants in the placebo group, 26.7%). This amounted to a 12% reduction,3said Dr. Pittas said. 

Critical Look at Vitamin D Supplementation—Is 4,000 IU Sufficient?

“Our results did not find a statistically significant benefit of vitamin D supplementation in decreasing progression to type 2 diabetes in patients overall,” Dr. Pittas told EndocrineWeb. The study was unable to show that vitamin D decreased the risk of diabetes by the target of  ≥ 25%.4

“At the start of the study, approximately 80% of participants harbored vitamin D levels considered sufficient by US nutritional standards (≥ 20 ng/mL). This high percentage may have reduced our ability to detect an overall benefit of vitamin D supplementation in the total study population,” he said.

When the researchers looked only at the subset of participants with prediabetes who presented with very low vitamin D levels at baseline, the supplemental vitamin D appeared to reduced their risk of diabetes by 62%.

“However, since only approximately 4% of participants harbored low levels of vitamin D initially, no firm conclusions can be drawn and further research will be needed to confirm this preliminary observation,” said Dr. Pittas.

Drawing on Earlier Studies for Insights into Vitamin D, Prediabetes

Findings from both the 2016 Tromsø Vitamin D and T2DM Trial6 and 2016 Diabetes Prevention7 with Active Vitamin D study showed similar vitamin D hazard ratios as the D2d trial.  

The Tromsø study randomized 511 white adults with prediabetes to 20,000 IU of vitamin D weekly (ie, approximately 2900 IU daily) or placebo, reporting a numerically lower risk of diabetes in the vitamin D supplement group, but the difference was not significant.6

Similarly, the 2016 Diabetes Prevention with Active Vitamin D study randomized adults with prediabetes (n = 1,256) to an active form of vitamin D analog (eldecalcitol) or placebo.7 The risk of diabetes was lower in individuals receiving supplemental vitamin D but not with statistical significance.7

Across all three major vitamin D trials, vitamin D supplementation suggested a decrease in diabetes risk among patients with prediabetes (10% to 15%), but none of the trials were powered to test the smaller effect size.4,6,7

“We plan to combine our D2d data with those of the Tromsø Vitamin D and T2DM Trial and Diabetes Prevention with Active Vitamin D Study,” Dr. Pittas said in order to continue investigating the potential for vitamin D to arrest diabetes progression in patients with prediabetes and vitamin D deficiency to better define the effect size of D2d.

Deeper Analysis Needed to Assess Role of Vitamin D in Diabetes Progression

In addition, the research team intends to analyze data from D2d to determine whether any effect from vitamin D supplementation may be found regarding production of or response to insulin as well as to examine the impact of vitamin D on other conditions including heart disease, cancer, and kidney function in patients with prediabetes,4 according to Dr. Pittas. They will also conduct further analyses to examine the overall safety of taking 4000 units daily of vitamin D over extended periods of time.

“The findings do not alter the need for the entire population to meet the National Academy of Medicine requirement for daily vitamin D supplementation of 4,000 IU,” he said. “Nor do our results change the recommendation that people at high risk for type 2 diabetes should commit to lifestyle changes–including improved diet, weight loss and increased physical activity–to lower their chances of developing diabetes.”

“However, these findings underscore the need for clinical trials to confirm hypotheses raised in observational studies as a necessary step in developing additional public and clinical recommendations,” he said.

Dr. Pittas reported no financial conflicts of interest.

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