Vitamin D supplementation and major cardiovascular events: D-Health randomised controlled trial

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Vitamin D supplementation and major cardiovascular events: D-Health randomised controlled trial

BMJ 2023; 381 doi: https://doi.org/10.1136/bmj-2023-075230 (Published 28 June 2023)Cite this as: BMJ 2023;381:e075230

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1. Bridie Thompson, research officer1,  
2. Mary Waterhouse, statistician epidemiologist1,  
3. Dallas R English, professor2,  
4. Donald S McLeod, senior research officer1,  
5. Bruce K Armstrong, professor3,  
6. Catherine Baxter, project manager1,  
7. Briony Duarte Romero, research assistant1,  
8. Peter R Ebeling, professor4,  
9. Gunter Hartel, head of statistics5,  
10. , professor6,  
11. Sabbir T Rahman, research officer1,  
12. Jolieke C van der Pols, associate professor7,  
13. Alison J Venn, professor8,  
14. Penelope M Webb, professor1,  
15. David C Whiteman, professor1,  
16. Rachel E Neale, professor1

Author affiliations

1. Correspondence to: R Neale rachel.neale@qimrberghofer.edu.au

• Accepted 18 May 2023

Abstract

Objective  

To investigate whether supplementing older adults with monthly doses of vitamin D alters the incidence of major cardiovascular events.

 Design  

 

Randomised, double blind, placebo controlled trial of monthly vitamin D (the D-Health Trial). Computer generated permuted block randomisation was used to allocate treatments.

 Setting Australia from 2014 to 2020.

 Participants  

 

21,315 participants aged 60-84 years at enrolment. Exclusion criteria were self-reported hypercalcaemia, hyperparathyroidism, kidney stones, osteomalacia, sarcoidosis, taking >500 IU/day supplemental vitamin D, or unable to give consent because of language or cognitive impairment.

 Intervention 60 000 IU/month vitamin D3 (n=10 662) or placebo (n=10 653) taken orally for up to five years. 16 882 participants completed the intervention period: placebo 8270 (77.6%); vitamin D 8552 (80.2%).

Main outcome measures  

 The main outcome for this analysis was the occurrence of a major cardiovascular event, including myocardial infarction, stroke, and coronary revascularisation, determined through linkage with administrative datasets. Each event was analysed separately as secondary outcomes. Flexible parametric survival models were used to estimate hazard ratios and 95% confidence intervals.

Results  

 

21,302 people were included in the analysis. The median intervention period was five years. 1336 participants experienced a major cardiovascular event (placebo 699 (6.6%); vitamin D 637 (6.0%)). The rate of major cardiovascular events was lower in the vitamin D group than in the placebo group (hazard ratio 0.91, 95% confidence interval 0.81 to 1.01), especially among those who were taking cardiovascular drugs at baseline (0.84, 0.74 to 0.97; P for interaction=0.12), although the P value for interaction was not significant (<0.05). Overall, the difference in standardised cause specific cumulative incidence at five years was −5.8 events per 1000 participants (95% confidence interval −12.2 to 0.5 per 1000 participants), resulting in a number needed to treat to avoid one major cardiovascular event of 172. The rate of myocardial infarction (hazard ratio 0.81, 95% confidence interval 0.67 to 0.98) and coronary revascularisation (0.89, 0.78 to 1.01) was lower in the vitamin D group, but there was no difference in the rate of stroke (0.99, 0.80 to 1.23).

 Conclusions  

Vitamin D supplementation might reduce the incidence of major cardiovascular events, although the absolute risk difference was small and the confidence interval was consistent with a null finding. These findings could prompt further evaluation of the role of vitamin D supplementation, particularly in people taking drugs for prevention or treatment of cardiovascular disease.

 Trial registration ACTRN12613000743763

 Coronary heart disease and stroke are the leading causes of death globally.1 The risk of these events increases with age, and they are more prevalent in men than women.2 The number of cardiovascular disease events will probably continue to increase in developed countries as populations age, and in low to middle income countries as non-communicable diseases become dominant.3 Vitamin D has biological effects which suggest it could influence cardiovascular disease. The vitamin D receptor is expressed in cells throughout the vascular system; many of these also express 1α-hydroxylase, and are therefore able to convert 25-hydroxyvitamin D (25(OH)D) to calcitriol, the active form of vitamin D. Calcitriol reduces inflammation, regulates the renin-angiotensin-aldosterone system, and inhibits proliferation of vascular smooth muscle.4

Meta-analyses of observational studies have found inverse associations between serum 25(OH)D concentration and risk of cardiovascular disease.56789 However, these findings might be due to reverse causality or uncontrolled confounding. Of three Mendelian randomisation studies, which largely overcome these biases, one reported an inverse association between genetically predicted 25(OH)D concentration up to 50 nmol/L and cardiovascular disease.10 The other studies found no association, but did not allow for nonlinear effects.1112 A meta-analysis of randomised controlled trials concluded that vitamin D supplementation does not prevent cardiovascular events.13 However, 45% of the 83 291 participants included in the meta-analysis were from the Women’s Health Initiative Trial, which was restricted to women, used a low dose of vitamin D, and had relatively low compliance.14 Cardiovascular disease was the primary outcome of the Vitamin D Assessment (ViDA) study15 and the Vitamin D and Omega 3 trial (VITAL).16 Despite different outcome definitions, both randomised controlled trials found that vitamin D supplementation had no effect on cardiovascular disease,1516 but VITAL excluded people with a history of cardiovascular disease and the ViDA study had relatively few events.

We launched the D-Health Trial to determine if monthly vitamin D supplementation can improve health outcomes in the older general population. It was a large intermittent dosing trial of vitamin D supplementation (n=21 315). Previous analysis of the D-Health cohort found that vitamin D supplementation did not reduce all cause mortality (the primary outcome of the overall trial) or mortality due to cardiovascular disease,17 but the effect on the incidence of major cardiovascular events has not been analysed.

For the current study we analysed data from the D-Health Trial to examine whether supplementing Australians aged ≥60 years with monthly doses of 60 000 IU of vitamin D altered the incidence of major cardiovascular events.