Does Sufficient Evidence Exist to Support a Causal Association between Vitamin D Status and Cardiovascular Disease Risk? An Assessment Using Hill’s Criteria for Causality

Serum 25-hydroxyvitamin D (25(OH)D) levels have been found to be inversely associated with both prevalent and incident cardiovascular disease (CVD) risk factors; dyslipidemia, hypertension and diabetes mellitus. This review looks for evidence of a causal association between low 25(OH)D levels and increased CVD risk. We evaluated journal articles in light of Hill’s criteria for causality in a biological system. The results of our assessment are as follows. Strength of association: many randomized controlled trials (RCTs), prospective and cross-sectional studies found statistically significant inverse associations between 25(OH)D levels and CVD risk factors. Consistency of observed association: most studies found statistically significant inverse associations between 25(OH)D levels and CVD risk factors in various populations, locations and circumstances. Temporality of association: many RCTs and prospective studies found statistically significant inverse associations between 25(OH)D levels and CVD risk factors. Biological gradient (dose-response curve): most studies assessing 25(OH)D levels and CVD risk found an inverse association exhibiting a linear biological gradient. Plausibility of biology: several plausible cellular-level causative mechanisms and biological pathways may lead from a low 25(OH)D level to increased risk for CVD with mediators, such as dyslipidemia, hypertension and diabetes mellitus. Experimental evidence: some well-designed RCTs found increased CVD risk factors with decreasing 25(OH)D levels. Analogy: the association between serum 25(OH)D levels and CVD risk is analogous to that between 25(OH)D levels and the risk of overall cancer, periodontal disease, multiple sclerosis and breast cancer. Conclusion: all relevant Hill criteria for a causal association in a biological system are satisfied to indicate a low 25(OH)D level as a CVD risk factor.     

Evolution of Serum 25OHD in Response to Vitamin D3–Fortified Yogurts Consumed by Healthy Menopausal Women: A 6-Month Randomized Controlled Trial Assessing the Interactions between Doses,Baseline Vitamin D Status,and Seasonality

Background: Adequate vitamin D status contributes to bone fragility risk reduction and possibly other pathological conditions that occur with aging. In response to pharmaceutical vitamin D₃ supplements, several studies have documented the influence of doses, baseline status, and seasonality on serum 25-hydroyvitamin D (s25OHD).

Objective: Using fortified yogurt, we investigated in one randomized controlled trial how both baseline status, as assessed by measuring s25OHD prior the onset of the trial, and the season of enrollment quantitatively influenced the response to the supplemented (Suppl.) of vitamin D₃ (VitD₃) in healthy community-dwelling women.

Methods: A 24-week controlled trial was conducted in menopausal women (mean age: 61.5). Participants were randomized into 3 groups (Gr): Gr.Suppl.0, time controls maintaining dietary habits; Gr.Suppl.5 and Gr.Suppl.10 consuming one and two 125-g servings of VitD₃-fortified yogurts with 5- and 10-µg daily doses, respectively. The 16 intervention weeks lasted from early January to mid-August, the 8 follow-up weeks, without product, from late August to mid-October. Before enrollment, subjects were randomized into 2 s25OHD strata: low stratum (LoStr): 25–50 nmol/L; high stratum (HiStr): >50–75 nmol/L.

Results: All enrolled participants adhered to the protocol throughout the 24-week study: Gr.Suppl.0 (n = 45), Gr.Suppl.5 (n = 44), and Gr.Suppl.10 (n = 44). Over the 16 intervention and 8 follow-up weeks, s25OHD increased in both supplemented groups, more in Gr.Suppl.10 than in Gr.Suppl.5. At the end of the intervention, the subject proportion with s25OHD ≥ 50 nmol/L was 37.8, 54.5, and 63.6% in Gr.Suppl.0, Gr.Suppl.5, and Gr.Suppl.10, respectively. The constant rate of s25OHD per supplemental VitD₃ microgram was greater in LoStr than HiStr. The s25OHD increase was greater with late (mid-March) than early (mid-January) inclusion.

Conclusion: This randomized trial demonstrates (1) a dose-dependent s25OHD improvement related to fortified yogurt consumption; (2) an inversely baseline-dependent increase in s25OHD; and (3) a seasonal effect that highlights the importance of VitD₃-fortified foods during winter, even at 5 µg/d, in healthy menopausal women.