Trial Information

Diabetes Prevention in the Vitamin D and Omega-3 Trial

Emerging evidence suggests favorable effects of both vitamin D and marine omega-3 fatty
acids on glucose homeostasis. Optimal vitamin D intake is essential for insulin secretion
and action, and omega-3 fatty acids may reduce diabetes risk as a result of favorable
effects on insulin sensitivity, endothelial function, chronic inflammation, or other
metabolic abnormalities. Although the metabolic effects of vitamin D and omega-3 fatty acids
show considerable promise for the primary prevention of type 2 diabetes (T2D), there are no
completed, ongoing, or planned randomized clinical trials of vitamin D or omega-3
supplements that include T2D as a primary outcome in a general population.

We thus propose to utilize an NIH-funded randomized trial (1 U01 CA138962) to test the
hypothesis that vitamin D and omega-3 supplementation will reduce the risk of T2D. We will
further assess whether and to what extent vitamin D or omega-3 supplementation will improve
insulin sensitivity and pancreatic beta-cell function in a subsample of the trial cohort.
The VITamin D and OmegA-3 TriaL (VITAL) is a randomized, double-blind, placebo-controlled
trial specifically designed to evaluate the benefits and risks of vitamin D3 (2,000 IU/day)
and marine omega-3 fatty acid (eicosapentaenoic acid [EPA] + docosahexaenoic acid [DHA],
1g/day) supplements in the primary prevention of cancer and cardiovascular disease (CVD).
The VITAL trial will aim to enroll 20,000 men and women (aged ≥50 and ≥55 years,
respectively). The planned treatment duration is 5 years after a 1.5-year recruitment
period. This diabetes ancillary study aims to implement an inexpensive and efficient
strategy to validate self-reported incident T2D cases in the entire trial population and to
collect pre- and post-intervention measures of glucose, insulin, and hemoglobin A1c (HbA1c)
in a subset of participants. Two methods of diabetes case validation are proposed. First, we
plan to collect detailed information about diagnostic glucose testing and anti-diabetic
medication use from medical records and/or supplementary questionnaires completed by the
participant's physician. Second, to complement our diabetes ascertainment process, we will
also plan to retrieve additional data on diabetes diagnoses and hypoglycemic medications by
linking the participants with the Centers for Medicare and Medicaid Services (CMS) database.
In addition to evaluating whether the study interventions impact the onset of clinical
diabetes, we propose to collect pre- and post-intervention measures of glucose, insulin, and
HbA1c in a subset of the participants to reliably assess whether vitamin D or omega-3
supplementation alters insulin and glucose homeostasis. We plan to recruit 1,000
participants without prior clinical diabetes at the Clinical and Translational Science
Center (CTSC) site at Brigham and Women's Hospital. A standard 2-hour oral glucose tolerance
test (OGTT) and HbA1c measurements will be performed during the CTSC visits at baseline and
at 2-year post-randomization.

Primary Aims:

1. To test whether vitamin D3 and/or EPA+DHA supplementation reduces the risk of T2D among
all initially non-diabetic participants in the VITAL trial.

2. To test whether vitamin D3 and/or EPA+DHA supplementation improves insulin sensitivity
and beta-cell function in a subset of 1,000 non-diabetic participants receiving OGTT at
baseline and 2-year post-randomization.

Secondary Aims:

1. To test whether vitamin D3 and/or EPA+DHA supplementation lowers HbA1c, fasting glucose
and insulin, as well as other surrogate indices of insulin sensitivity and beta-cell
function as determined by the homeostasis model assessment (HOMA-IR and HOMA-%B,
respectively) in our substudy.

2. To test whether vitamin D3 and EPA+DHA supplementation exerts synergistic or additive
effects on the risk of T2D among all initially non-diabetic participants in the VITAL
trial.

3. To test whether vitamin D3 and EPA+DHA supplementation exerts synergistic or additive
effects on insulin sensitivity and beta-cell function as assessed by OGTT in our
substudy.

For the above main effect estimates, we will further explore whether the effect of vitamin
D3 or EPA+DHA supplementation varies by (1) age, (2) sex, (3) baseline intakes of these
nutrients, (4) baseline levels of 25(OH)D (for vitamin D3), (5) race/skin pigmentation (for
vitamin D3), (6) geographic region (for vitamin D3), and (7) BMI (for vitamin D3).