Vitamin D, often hailed as the “sunshine vitamin”, is renowned for its multifaceted health benefits including promoting healthy bones, supporting immune function and facilitating calcium absorption. Yet, the spotlight has recently shifted to an altogether different aspect of its potential – cardiovascular health. Given the broad influence of vitamin D in cellular processes, including anti-inflammatory and vasculoprotective effects, speculation has been rife that Vitamin D supplementation could play a pivotal role in mitigating cardiovascular disease risks, particularly in the elderly population. However, comprehensive clinical trials and rigorous scientific scrutiny have been sorely needed to substantiate this conjecture.
In an endeavour to fill this knowledge gap, the D-Health Trial, a randomised controlled study, was launched to elucidate the potential of vitamin D supplementation to curb the incidence of major cardiovascular events among Australians aged 60 years and over. This comprehensive study involved over 21,000 participants and spanned a considerable timeframe from 2014 to 2020. Employing a robust methodology of computer generated permuted block randomisation for treatment allocation, the trial provides a rich data set to delve into this intriguing query.
This article reports on the D-Health Trial’s enlightening findings, scrutinizing whether monthly doses of 60,000 IU of Vitamin D can indeed influence the incidence of significant cardiovascular events such as myocardial infarction, stroke, and coronary revascularisation. The objective, far-reaching results revealed in this extensive study carry profound implications for future research directions, medical practice, and public health strategies. Amidst a landscape where cardiovascular disease continues to hold a firm grip as a leading cause of mortality, this investigation into the role of vitamin D supplementation could be a critical piece of the puzzle in our relentless pursuit of mitigating cardiovascular risks.
What is Vitamin D
Vitamin D is a fat-soluble nutrient that plays an integral role in many of the body’s biological functions. It exists in two major forms, D2 (ergocalciferol) and D3 (cholecalciferol). Vitamin D2 is found in some plant foods like mushrooms, while D3 is produced in the human skin upon exposure to sunlight, particularly ultraviolet B (UVB) radiation, and can also be obtained from certain animal foods like fatty fish, liver, and egg yolks. Both forms of the vitamin are biologically inert and must undergo two hydroxylation reactions – first in the liver and then in the kidneys – to be converted into the physiologically active form known as calcitriol.
The primary role of vitamin D in the body is to facilitate the absorption of calcium and phosphate from the gut, thus contributing to the formation and maintenance of strong, healthy bones and teeth. However, beyond this crucial role in skeletal health, vitamin D is involved in a variety of other physiological functions. It has a vital role in immune system regulation, contributing to both innate and adaptive immunity. Moreover, vitamin D receptors are found in numerous tissues throughout the body, suggesting the vitamin’s potential influence on various biological processes, including cell growth modulation, inflammation reduction, and regulation of neuromuscular function.
Sources of Vitamin D
Vitamin D is rather unusual compared to other vitamins because it is not typically found in abundance in most plant-based foods. This is primarily due to the fact that the most common form of vitamin D, known as vitamin D3 or cholecalciferol, is naturally produced in the skin of animals (including humans) upon exposure to sunlight. Most of the vitamin D in our diet comes from foods of animal origin or fortified foods.
However, there are a few plant sources that contain a form of vitamin D known as vitamin D2 or ergocalciferol. Certain types of mushrooms, notably maitake and UV-exposed portobello and cremini, are among the richest sources of vitamin D2 in the plant kingdom, given their unique ability to synthesize vitamin D when exposed to ultraviolet light, similar to how human skin does. Vitamin D2 is not as potent or as efficiently used by the human body as the D3 form. Consequently, individuals relying exclusively on plant-based sources for vitamin D, such as those following a vegan or vegetarian diet, might need to pay extra attention to their vitamin D status, possibly considering fortified foods or supplements if necessary.
The D-Health Trial, conducted in Australia, was a large-scale, randomised, double-blind, placebo-controlled trial designed to examine the potential impact of Vitamin D supplementation on major cardiovascular events. This investigation targeted older adults, with participants ranging from 60 to 84 years of age at enrolment. The key intervention compared was the oral intake of 60,000 IU/month of Vitamin D3 or cholecalciferol, a form of vitamin D naturally synthesized in the skin upon exposure to sunlight and also found in certain animal-based foods.
Participants in the study were divided into two groups, with 10,662 individuals taking the Vitamin D3 supplement and 10,653 receiving a placebo. They took their respective treatments for up to five years. By comparing the incidence of cardiovascular events between these two groups, the research aimed to determine if there was a statistically significant difference that could suggest a protective effect of Vitamin D3 supplementation. Outcomes of interest included major cardiovascular events such as myocardial infarction, stroke, and coronary revascularisation. The trial thus focused on the role of Vitamin D3 and did not compare different types of Vitamin D or include a comparison with Vitamin D2.
- The Vitamin D Assessment (ViDA) Study: The ViDA study, conducted in New Zealand, was a randomized, double-blind, placebo-controlled trial that investigated the effects of vitamin D supplementation on various health outcomes, including cardiovascular disease. Around 5,100 participants aged 50-84 years received either a monthly dose of 100,000 IU vitamin D3 or a placebo. The primary outcome was the number of participants with at least one incident of non-vertebral fracture or fall injury. Cardiovascular disease was one of the secondary outcomes studied. Similar to the D-Health Trial, the ViDA study found no significant effect of vitamin D supplementation on the incidence of cardiovascular disease.
- The Vitamin D and Omega-3 Trial (VITAL): The VITAL trial, a large US-based study, was a randomized, double-blind, placebo-controlled trial designed to test the effects of vitamin D3 (cholecalciferol) and omega-3 fatty acids on the primary prevention of cancer and cardiovascular disease among men aged 50 years or older and women aged 55 years or older. Participants received 2,000 IU/day of vitamin D3 and 1g/day of marine omega-3 fatty acids or a placebo. The trial found no significant reduction in major cardiovascular events with vitamin D supplementation.
- Women’s Health Initiative (WHI) Calcium/Vitamin D Trial: The WHI study, conducted in the United States, examined the effects of daily supplementation with 1,000mg of calcium carbonate and 400 IU of vitamin D3 on fracture incidence in postmenopausal women. The trial included over 36,000 women aged 50-79 years, who were randomized to receive the supplements or a placebo. Secondary outcomes included coronary heart disease and stroke. The WHI trial found no significant effect of combined calcium and vitamin D3 supplementation on the incidence of coronary heart disease or stroke. However, it’s important to note that this trial used a lower dose of vitamin D than the D-Health, ViDA, and VITAL trials.
The D-Health Trial began in 2014 and was completed in 2015, with more than 21,000 people agreeing to participate. Half of them were given vitamin D supplements while the other half were given a placebo. Participants were roughly equally split between the two groups, and over five years, almost 80% of them were still taking their assigned tablets. The trial noted that during the study, those who were taking vitamin D had higher average levels of the vitamin in their blood compared to those on the placebo.
Demographically, the study participants were well-distributed in terms of age, sex, and body mass index, with an average age of 69 years and a slightly higher proportion of men (54%). The health profiles of the two groups were also similar in terms of baseline characteristics, including the use of statins and cardiovascular drugs.
During the study period, 1,336 major cardiovascular events were recorded, slightly more in the placebo group compared to the vitamin D group. The rate of these major cardiovascular events was found to be marginally lower in the vitamin D group, though not significantly so. Therefore, it could be suggested that vitamin D has a potentially beneficial but not definitively proven impact on the incidence of major cardiovascular events.
Interestingly, the results suggest that those with higher initial vitamin D levels and those using statins or cardiovascular drugs at the beginning of the trial benefited more from the vitamin D supplementation. Also, people who had not reported a history of a major cardiovascular event saw a slightly stronger beneficial effect from the vitamin D supplementation than those who had such a history.
Looking at specific cardiovascular events, it was observed that the incidence of heart attacks was lower in the vitamin D group, as was the occurrence of coronary revascularisation – a procedure to improve blood flow to the heart. However, the study did not find any noticeable effect of vitamin D supplementation on the incidence of stroke.
So, in summary, the results suggest that vitamin D supplementation might provide some protective benefits against certain cardiovascular events, particularly for individuals with higher baseline vitamin D levels and those already on cardiovascular medication. However, more definitive conclusions would require further research.
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
- Bridie Thompson, research officer1,
- Mary Waterhouse, statistician epidemiologist1,
- Dallas R English, professor2,
- Donald S McLeod, senior research officer1,
- Bruce K Armstrong, professor3,
- Catherine Baxter, project manager1,
- Briony Duarte Romero, research assistant1,
- Peter R Ebeling, professor4,
- Gunter Hartel, head of statistics5,
- Michael G Kimlin, professor6,
- Sabbir T Rahman, research officer1,
- Jolieke C van der Pols, associate professor7,
- Alison J Venn, professor8,
- Penelope M Webb, professor1,
- David C Whiteman, professor1,
- Rachel E Neale, professor1