The Effects of Vitamin D Supplementation and 25-Hydroxyvitamin D Levels on the Risk of Myocardial Infarction and Mortality

Prakash Acharya; Tarun Dalia; Sagar Ranka; Prince Sethi; Olurinde A. Oni; Maya S. Safarova; Deepak Parashara; Kamal Gupta; Rajat S. Barua


J Endo Soc. 2021;5(10) 

In This Article

Abstract and Introduction


Objective: The aim of the study was to examine the effects of the vitamin D (Vit-D) treatment and nontreatment on Vit-D–deficient patients without a prior history of myocardial infarction (MI).

Materials and Methods: This was a retrospective, observational, nested case–control study of patients (N = 20 025) with low 25-hydroxyvitamin D ([25-OH]D) levels (<20 ng/mL) who received care at the Veterans Health Administration from 1999 to 2018. Patients were divided into 3 groups: Group A (untreated, levels ≤20 ng/mL), Group B (treated, levels 21–29 ng/mL), and Group C (treated, levels ≥30 ng/mL). The risk of MI and all-cause mortality were compared utilizing propensity score–weighted Cox proportional hazard models.

Results: Among the cohort of 20 025 patients, the risk of MI was significantly lower in Group C than in Group B (hazard ratio [HR] 0.65, 95% CI 0.49–0.85, P = .002) and Group A (HR 0.73, 95% CI 0.55–0.96), P = .02). There was no difference in the risk of MI between Group B and Group A (HR 1.14, 95% CI 0.91–1.42, P = 0.24). Compared with Group A, both Group B (HR 0.59, 95% CI 0.54–0.63, P < .001) and Group C (HR 0.61, 95% CI 0.56–0.67, P < .001) had significantly lower all-cause mortality. There was no difference in all-cause mortality between Group B and Group C (HR 0.99, 95% CI 0.89–1.09, P = .78).

Conclusions: In patients with Vit-D deficiency and no prior history of MI, treatment to the (25-OH)D level of >20 ng/mL and >30 ng/mL was associated with a significantly lower risk of all-cause mortality. The lower risk of MI was observed only in individuals maintaining (25-OH)D levels ≥30 ng/mL.


There is substantial evidence implicating vitamin D (Vit-D) levels in the pathogenesis of cardiovascular risk factors such as diabetes, hypertension, hyperlipidemia, chronic kidney disease, and obesity.[1,2] Furthermore, experimental studies suggest that Vit-D may participate in pathways associated with atherosclerosis by influencing cellular growth, oxidative stress, membrane transport, cell adhesion, and gene regulation. Direct effects of Vit-D on cardiomyocytes and vascular endothelial cells were reported via Vit-D receptors.[1] The Endocrine Society defines 25-hydroxyvitamin D ([25-OH]D) levels ≤20 ng/mL as deficiency, levels 21–29 ng/mL as insufficiency, and levels ≥30 ng/mL as optimal.[3] However, data regarding the association of the (25-OH)D levels and Vit-D supplementation with myocardial infarction (MI) and mortality remains controversial.[4–14]

Several meta-analyses of epidemiological studies suggested that Vit-D deficiency is associated with an increased risk of MI and cardiovascular mortality.[8,12,14] One meta-analyses suggested that there is generally a linear, inverse association between circulating (25-OH)D levels and the risk of cardiovascular disease.[13] A Cochrane meta-analysis showed that Vit-D treatment significantly reduced mortality in subgroups of patients with a pretreatment level below 20 ng/mL.[7] However, in several randomized controlled trials, supplementation of Vit-D did not result in lower cardiovascular events and mortality.[4–6] It is important to note that majority of these randomized controlled trials had included patients who already had optimal baseline (25-OH)D levels, with most patients in these trials having pretreatment (25-OH)D levels above 25 to 30 ng/mL.[4,15] Additionally, in the majority of these clinical trials, post-treatment follow-up of (25-OH)D was not measured to account for effective supplementation and had a short-term follow-up.[4] Even in the VITAL (vit-D and omega-3 trial) and the VIDA (vit-D assessment) trials, only a small subset of the study population (6.3% and 8.6%, respectively) had a repeat measurement of post-treatment (25-OH)D level performed.[5,6] It is also worth noting that in several studies, the association between Vit-D and the risk of MI was apparent only after long-term follow-up.[8,10,11] Additionally, there are limited data available comparing the outcome of MI and mortality with respect to the levels of (25-OH)D achieved and maintained after Vit-D supplementation.

To address this gap in knowledge, we conducted a large retrospective analysis with long-term follow-up in patients with low baseline Vit-D level who had at least 2 separate measurements of (25-OH)D levels to confirm their status and to measure the effect of Vit-D supplementation on (25-OH)D levels. The goal of our study was to examine the effects of Vit-D treatment (VDT) and lack of VDT on all-cause mortality and MI in Vit-D–deficient patients without prior history of MI in relation to 3 different reference levels of (25-OH)D as defined by the Endocrine Society.