Calcium plus vitamin D3 supplementation (1,000 mg plus 400 IU daily, respectively) did not reduce the risk of developing drug-treated diabetes over 7 years of follow-up in the WHI CaD randomized placebo-controlled trial. This null result was robust in subgroup analyses, efficacy (adherence-based) analyses, and analyses examining change in laboratory measurements of glucose, insulin, and insulin resistance as assessed by HOMA-IR scores. The hazard ratio for incident diabetes of 1.01 and tight surrounding 95% CI (0.94–1.10) suggest that a clinically significant benefit for this specific intervention with regard to diabetes prevention is unlikely among generally healthy postmenopausal women.
In prior observational studies, greater baseline intakes of calcium, vitamin D, and/or dairy products were associated with reduced risk for subsequent diabetes (13
). In the current study, when we examined our data as an observational cohort study, greater baseline total calcium and vitamin D intakes were associated with modestly lower unadjusted incidence rates of diabetes. These observational results are consistent with prior observational studies, but carry similar potential limitations. In contrast, null results examining the randomly assigned calcium/vitamin D intervention conflict with observational studies.
What explains this discrepancy? First, it is possible that calcium and/or vitamin D do prevent diabetes, but that the doses used in the WHI CaD trial were insufficient to affect this outcome. This explanation appears unlikely for calcium, since the dose of calcium used is large compared with typical dietary intakes (24
). For vitamin D, however, a relatively small dose was prescribed. Vitamin D3 400 IU daily would be expected to raise 25-hydroxyvitamin D concentrations from 43.7 nmol/l (the median baseline value in this study) to ~65.7 nmol/l (33
), still less than the 80 nmol/l threshold currently recommend by many experts (34
). Alternatively, it is possible that calcium and vitamin D have no causal effect on glucose metabolism and that observational studies, as well as the observational results presented here, were limited by confounding. Differences in dietary calcium, dietary vitamin D, and serum vitamin D concentrations may reflect differences in lifestyle (for example, dietary preferences or physical activity not easily ascertained) or unmeasured attributes of health status (such as body composition). It is also possible that nutrients commonly consumed with calcium and vitamin D may improve glucose metabolism, while calcium and vitamin D in themselves do not, or that foods rich in calcium and/or vitamin D may displace other foods that cause diabetes.
Prior intervention studies assessing the effects of vitamin D supplementation on glucose metabolism have yielded mixed results (1
). These studies were generally limited by small size, short duration, and/or lack of appropriate controls. Recently, a larger (n
= 314) 3-year study of calcium plus vitamin D3 supplementation (500 mg plus 700 IU, respectively) reported improvement in fasting glucose concentrations and HOMA-IR scores, compared with placebo, among women with baseline impaired fasting glucose, but not among women with normal fasting glucose (21
). Similar effect modification by baseline glucose concentration was not observed in the current study. Differences in dose and formulation of study medications, adherence and nonstudy supplement use, and/or sample size may contribute to differing results.
We observed a trend toward a protective effect of calcium/vitamin D supplementation among participants with greater baseline dietary intakes of calcium or dairy products. It is possible that greater nonstudy calcium intake allowed for a synergistic effect with study vitamin D; however, this seems unlikely, since all participants receiving active study medication also received relatively large doses of calcium. Alternatively, this may represent a chance finding from multiple testing of interactions, with two potentially significant interactions observed because of correlation between dietary calcium and dairy intake.
There are a number of potential limitations to this study. First, longitudinal fasting glucose measurements were available for only a subset of trial participants, limiting the primary study outcome to self-reported drug-treated diabetes. Although not strictly consistent with the American Diabetes Association definition of diabetes (31
), it is important to note that drug-treated diabetes is a clinically relevant outcome. Moreover, two observations suggest that the outcome definition used in this study is valid: 1
) results were similar whether the outcome was defined as treated diabetes only or treated plus untreated diabetes (American Diabetes Association definition) among the subset of participants with laboratory measurements, and 2
) expected associations of covariates with incident diabetes were observed. Second, nonadherence and nonstudy use of supplements may have biased results toward the null. However, reasonable separation of 25-hydroxyvitamin D concentrations by treatment assignment was observed within the subgroup of participants for whom measurements were made, and sensitivity analyses accounting for nonadherence and nonstudy use of supplements suggested that the study result was robust. Finally, only one intervention dose was prescribed, which may have included insufficient vitamin D to influence diabetes risk.
This study also has important strengths. The large number of incident diabetes cases lends great power to this study and facilitates accurate subgroup analyses. For analyses of laboratory outcomes, the subset of participants with available measurements in itself was larger than prior intervention studies. More importantly, the randomly assigned intervention and long duration of follow-up allow a valid and unique assessment of the long-term risk of incident diabetes associated with calcium and vitamin D supplementation.
In conclusion, calcium plus vitamin D3 supplementation did not reduce the risk of developing diabetes over 7 years of follow-up in this randomized placebo-controlled trial of generally healthy postmenopausal women. Future research should seek explanations for differing results comparing observational studies to randomized trials and/or examine higher doses of vitamin D.