To D or not to D? The Relationship between Cardiovascular Disease and Vitamin D

For years, clinical research has been unclear regarding the relationship between vitamin D and cardiovascular disease (CVD). While low levels of vitamin D are correlated with increased risk of CV outcomes including myocardial infarction, stroke, heart failure, and atrial fibrillation, this does not necessarily indicate causation of poor CVD outcomes. Specifically, Mendelian randomization (MR) studies (a study design which measures variation in genes to determine a causal relationship between exposure and outcome) and other randomized controlled trials and meta-analysis have refuted the notion that Vitamin D replacement causing a reduction in CVD mortality or major adverse cardiac events.1-9

What could explain this discrepancy between expected vs observed benefit of Vitamin D supplementation? This topic was explored during CardioNerds Episode 91: Aspirin, Vitamin D, Calcium & Omega 3 Fatty Acids Supplementation with Dr. Erin Michos. Based on the Women’s Health Initiative study, Calcium and Vitamin D supplementation (400 IU D3) had no effect on incident coronary or cerebrovascular events.1 However, what if the supplementation regimen was too low? The ViDA study tested monthly high dose vitamin D supplementation (100,000 IU of D3) which still did not show CVD prevention, but this was considered an atypical supplementation regimen.2  What if these patients had a longer follow up period? Would vitamin D supplementation show benefit then? The Vital Trial has shown no benefit with Vitamin D supplementation among healthy middle-aged men and women over a 5-year follow up period.3  The caveat to the studies mentioned above are that they assume there is a linear relationship between Vitamin D supplementation and CVD benefit. Dose response studies evaluating the relationship between Vitamin D supplementation and CVD indicate there is a nonlinear relationship.10-11 However, studies establishing causation between vitamin D and CVD benefit have been limited (as mentioned previously).

While MR studies in the past were designed to evaluate linear relationships, recently in December 2021, a study was published in the European Heart Journal evaluating both linear and nonlinear MR analysis of vitamin D deficiency and CVD risk.12 In this study, MR analysis revealed a nonlinear association between vitamin D concentration and CVD risk with an L-shaped curve depicting high CVD risk at vitamin D levels below 50nmol/L (P=0.007). In other words, individuals with vitamin D levels at 25nmol/L had an 11% (95% CI: 1.05 to 1.18) higher odds of CVD compared with those with 50nmol/L.  These results highlight not only the nonlinear relationship between vitamin D concentrations and CVD risk, but also provides a threshold by which high CVD risk is conferred.

So, to D or not to D? Will vitamin D supplementation be considered an important tool for CVD prevention? Future studies evaluating the nonlinear relationship between the two in different populations may be the next step to inform clinicians of the utility of vitamin D supplementation for cardio-prevention.

Najah Khan, MD, is an internal medicine resident at Houston Methodist Hospital in Houston, TX and a correspondent with the CardioNerds.


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