Vitamin D supplementation vs. placebo and incident type 2 diabetes in an ancillary study of the randomized Vitamin D and Omega-3 Trial

Deirdre K. Tobias (), Aruna D. Pradhan, Edward K. Duran, Chunying Li, Yiqing Song, Julie E. Buring, Nancy R. Cook, Samia Mora and JoAnn E. Manson
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Deirdre K. Tobias: Brigham and Women’s Hospital and Harvard Medical School
Aruna D. Pradhan: Brigham and Women’s Hospital and Harvard Medical School
Edward K. Duran: University of California
Chunying Li: Brigham and Women’s Hospital and Harvard Medical School
Yiqing Song: Brigham and Women’s Hospital and Harvard Medical School
Julie E. Buring: Brigham and Women’s Hospital and Harvard Medical School
Nancy R. Cook: Brigham and Women’s Hospital and Harvard Medical School
Samia Mora: Brigham and Women’s Hospital and Harvard Medical School
JoAnn E. Manson: Brigham and Women’s Hospital and Harvard Medical School

Nature Communications, 2025, vol. 16, issue 1, 1-8

Abstract: Abstract Observational and experimental evidence suggests that vitamin D plays a role in type 2 diabetes (T2D). However, prior randomized supplementation trials are limited to high-risk patients with prediabetes. Here we aim to evaluate whether vitamin D supplementation reduces risk of T2D in a general population of older US adults. The study design is an ancillary analysis (VITAL-T2D) of The Vitamin D and Omega-3 Trial (VITAL), a completed randomized, double-blind, placebo-controlled 2 × 2 trial of daily vitamin D3 (cholecalciferol; 2000 IU/day) and omega-3 fatty acids (1 g/day) for the primary prevention of cancer and cardiovascular disease. We also conducted a systematic review and meta-analysis of vitamin D trial (≥1000 IU/d cholecalciferol) vs. placebo and T2D risk. We analyzed 22,220 adults with mean age 67.2 years (SD = 7.1) without T2D at enrollment (2011 to 2014), randomized to vitamin D3 or placebo. Mean body mass index (BMI) was 27.5 kg/m2 (SD = 5.3), with 51% female and 17% Black race/ethnicity. A subcohort (n = 911) attended in-person visits at baseline and 2 years for glycemic trait analyses. Our meta-analysis included 3 additional trials (5205 participants; 936 T2D cases). The primary outcome for the VITAL-T2D is intention-to-treat effect of vitamin D vs. placebo for incident T2D. T2D incidence (cases/1000py) at median follow-up of 5.3 y was 3.98 for vitamin D and 4.37 for placebo (hazard ratio [HR] = 0.91; 95% confidence interval [CI] = 0.76, 1.09). Results did not differ by age, sex, BMI, or baseline 25-hydroxyvitamin D, and vitamin D had no effect on glycemic traits at 2 years. Meta-analysis of 4 trials (n = 5205; 936 T2D cases) obtained HR = 0.89 (CI = 0.80, 0.99). In conclusion, Vitamin D supplementation did not reduce T2D in older US adults, but a modest reduction was observed when meta-analyzed with prior trials. Trial Registration: ClinicalTrials.gov #NCT01633177. Systematic Review Registration: PROSPERO #CRD42019147562.

Date: 2025
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DOI: 10.1038/s41467-025-58721-6

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