Non-Classical Role of Vitamin D and Development of Optimal Vitamin D Cut-Offs for Cardiametabolic Health Outcomes

Over the last decade, vitamin D deficiency has emerged as a potential risk factor for the development of cardiometabolic diseases. However, the evidence from epidemiological studies and randomized controlled trials (RCT) has yielded conflicting results. Moreover, vitamin D guidelines by the Institute of Medicine and the Endocrine Society have led to substantial disagreement about what defines optimal levels of vitamin D status, owing in part to the inter-laboratory differences in the measurement of vitamin D status (as measured by total 25-hydroxyvitamin D [25(OH)D]) and the inconsistent findings from epidemiological and RCT data in relation to non-skeletal health outcomes. For non-skeletal health outcomes, disagreement still exists about whether the optimal level of 25(OH)D is higher than the currently recommended levels of 25(OH)D for bone health. Therefore, the objectives of this dissertation were; i) to assess the dose-response relationship between standardized total 25(OH)D levels and cardiometabolic health outcomes; ii) to develop optimal vitamin D cutoffs in relation to cardiometabolic health, and; iii) to assess the clinical utility of total 25(OH)D as a biomarker for adverse cardiometabolic health outcomes. Studies 1 and 2 used cross-sectional data from the National Health and Nutrition Examination Survey (NHANES, 2001-2010), and studies 3 and 4 used prospective data from NHANES III (1988-1994) mortality follow-up. Standardized total 25(OH)D data was used in all four studies.

In study 1, results showed that a higher total 25(OH)D was inversely associated with cardiometabolic disease, irrespective of race/ethnicity. In study 2, the optimal total 25(OH)D associated with normal glucose and insulin homeostasis was estimated at 60 nmol/L overall, but differed by race/ethnicity (non-Hispanic whites: 68 nmol/L, non-Hispanic blacks: 41 nmol/L, and Mexican-Americans: 54 nmol/L). In study 3, low total 25(OH)D (<50 nmol/L) exacerbated the risk of cardiometabolic mortality associated with metabolic dysfunction in normal-weight and obesity groups. Finally, in study 4, a single measurement of total 25(OH)D <30 nmol/L in middle- to older-aged adults was associated with high lifetime risk of cardiometabolic mortality, particularly among those with 2 major traditional CVD risk factors. Taken together, these findings suggest that low total 25(OH)D is a strong risk marker of adverse cardiometabolic health outcomes.