Vitamin D Supplements and Prevention of Cardiovascular Disease

Abstract

Purpose of review:

The role of vitamin D supplementation for prevention of cardiovascular disease (CVD) outcomes has been rigorously studied only recently. This review briefly summarizes results from recent randomized controlled trials in the context of prior laboratory and epidemiologic data.

Recent Findings:

Randomized trials of vitamin D that included CVD outcomes, as well as two recently published large population-based trials that prespecified CVD as a primary endpoint (ViDA and VITAL), indicate that vitamin D supplementation does not decrease CVD incidence, when compared to placebo.

Summary:

Evidence to date suggests that vitamin D supplementation in the general community does not reduce the risk of major cardiovascular events. Other trials are ongoing and future studies will explore additional CVD outcomes such as heart failure and assess high-risk populations such as those with chronic kidney disease.

Introduction

In the early 19^th century scientists postulated that cod-liver oil could treat the bone weakening disease rickets.¹ In 1925, the role of UV light in the synthesis of vitamin D was hypothesized. A collaboration that began in 1916, spanning Germany, England and New York, led to the ultimate discovery of pro-vitamin D, cholecalciferol (D₃), ergocalciferol (D₂), and calcitriol. In the post-World War I era, vitamins and micronutrients were quickly incorporated into the diet. Ecological and observational data in the ensuing decades have suggested an association between low levels of vitamin D and multiple health outcomes, including cardiovascular disease (CVD), impaired glucose metabolism, inflammatory conditions, cancer, and even death.²

The leading cause of death worldwide remains CVD, attributed in part to longer survival of the population through effective prevention of communicable diseases and maternal-fetal mortality.³ Identifying targets for prevention that may impact large segments of the population, such as vitamin D deficiency, has been an important public health goal. A meta-analysis of observational data that included information from 849,412 individuals suggested a significant association between low serum 25-hydroxyvitamin D (25OHD) levels, a marker for vitamin D status, and risk of CVD.⁴ However, the role of vitamin D supplementation specifically for prevention of CVD outcomes has been rigorously studied only recently.⁵ The publication of two major vitamin D trials in 2017 and 2018 finally provide needed data to understand the effect of vitamin D supplementation on CVD outcomes.

In this review we will a) describe the mechanisms through which vitamin D is postulated to prevent CVD, b) summarize existing evidence from observational studies and limitations to these findings, and c) synthesize evidence from randomized controlled trials (RCTs). Specifically, we will contextualize available data in light of recently published trial data from ViDA and VITAL, two large-scale RCTs that examined the effect of vitamin D supplementation on CVD outcomes.

Potential mechanisms of Vitamin D to lower CVD risk

Exposure to ultraviolet B light converts 7-dehydrocholesterol, a fat-soluble compound in the skin, to cholecalciferol (vitamin D₃) via photoisomerization. After ingestion of foods containing vitamin D, D₃ is converted in the liver, through hydroxylation, to 25-hydroxyvitamin D. This compound includes both 25OHD₂ and 25OHD₃. In the kidney, 25OHD is hydroxylated further to 1,25-dihydroxyvitamin D, 1,25(OH)₂D, or calcitriol. Vitamin D is often measured according to serum 25OHD levels, which have a longer half-life than calcitriol and reflect both endogenous and exogenous sources.⁶

Vitamin D has been postulated to lower the risk of CVD through multiple pathways, including immunomodulation, inhibition of vascular smooth muscle proliferation, regulation of glucose metabolism and blood pressure (Figure).^5–7 Although bone health benefits have been established for vitamin D, receptors for vitamin D have been isolated throughout the cardiovascular system including cardiomyocytes, coronary artery endothelium, and vascular smooth muscle cells.⁶ In vitamin D receptor knockout mice, there is evidence of perturbations in the renin-angiotensin-aldosterone (RAAS) system leading to elevations in blood pressure, left ventricular hypertrophy, heart failure, increased platelet aggregation, and the development of CVD events.^8–11 In humans, vitamin D deficiency has been associated with the atherogenic process through endothelial dysfunction, subclinical atherosclerosis and atheroma formation, coronary artery calcification, as well as impaired glucose metabolism and hypertension.^11,12

Figure 1.

Potential mechanisms through which vitamin D may prevent CVD

COX-2, cyxlooxygenase-2; CRP, C-reactive protein IL-6, interleukin-6; IL-10, interleukin-10l RAAS, renin-angiotensin-aldosterone system TNFα, tumor-necrosis factor-α

Observational research on vitamin D and CVD risk

Observational research in has suggested that low serum 25OHD levels is associated with both incident CVD events and CVD mortality. A meta-analysis of 34 prospective, observational studies that included data from 180,667 participants reported a significant inverse association between serum 25OHD levels and CVD outcomes; the pooled RRs per 10-ng/mL increase in level of serum 25OHD for CVD events was 0.90 [95% CI 0.86-0.94] and for CVD mortality was 0.88 [0.80-0.96].¹³ The nadir for CVD risk appeared to be at a 25OHD level of about 20-25 ng/ml. There was heterogeneity amongst the studies, I² = 90.6%, p<0.001. On the other hand, a combined meta-analysis of 73 cohort studies with data from 849,412 participants demonstrated an elevated risk of CVD mortality, with a pooled risk ratio for of 1.43 (95% CI 1.25-1.64), although there was also a high level of heterogeneity, I² =83.9%.⁴

Generally, in non-randomized studies, there are several potential sources of confounding that must be considered, particularly when considering the use of a preventive, “health conscious” supplement such as vitamin D. In addition to a healthy user bias, variables such as obesity, sun exposure, exercise and physical activity, skin pigmentation, nutritional status, and use of other medications, all of which may be imperfectly measured, may result in residual confounding of these associations. Importantly, observational studies can only suggest an association but cannot prove causation between an exposure and outcome.

For this reason, after reviewing the available evidence, the 2014 US Preventive Services Task Force (USPSTF) concluded that there was insufficient evidence to recommend vitamin D supplementation for the prevention of cardiovascular disease.¹⁴ This recommendation followed the 2011 Institute of Medicine report which had similarly concluded that that the existing evidence for vitamin D and prevention of CVD was inadequate.¹⁵

Large-Scale RandomizedTrials of Vitamin D that Include CVD Endpoints

Many trials have randomized participants to vitamin D vs placebo for prevention of fractures and other bone health outcomes, and secondary analyses have been performed to examine CVD outcomes. However, these trials were not designed to primarily examine CVD outcomes, and thus the results (often negative) have largely been considered hypothesis generating. Several notable trials with >2000 participants are reviewed here and summarized in the Table.

Table 1.

Summary of Completed Vitamin D trials with at least 2000 participants that examined CVD outcomes

Trial	Year published	Participants	Primary study question	Age at enrollment	% Female	Vitamin D intervention	Follow-up duration	CVD finding
British Vitamin D3 Trial1	2003	2,686	Primary fracture prevention	65-85	24	100 000 IU every 4 months vs placebo	5 years	No significant increase or decrease in CVD events
RECORD2,3	2005, 2014	5,292	Secondary fracture prevention	≥70	85	800 IU daily + 1000mg calcium vs 800 IU daily vs 1000mg Ca vs placebo	5 years +3 year follow up for CV events	No increase or decrease in MI or stroke; possible decrease in CHF
WHI4	2007	36,282 Post-menopausal women	Fracture prevention	50-79	100	400 IU daily + 1000mg Ca vs placebo	7 years	No increase or decrease in risk of MI or stroke
ViDA5	2017	5,110	CVD and mortality prevention	50-84	42	Loading dose 200,000 then 100,000 IU monthly vs placebo	Median 3.3 years	No increase or decrease in incident CV events or mortality
VITAL6	2018	25,871	CVD and Cancer prevention	Men ≥50 Women ≥55	51	2000 IU daily vs placebo	Median 5.3 years	No increase or decrease in risk of major CV events

RECORD, Randomised Evaluation of Calcium Or vitamin D trial; WHI, Women’s Health Initiative; ViDA, Vitamin D Assessment Study; VITAL, VITamin D and OmegA-3 TriaL

^1.Trivedi DP, Doll R, Khaw KT. Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial. BMJ (Clinical research ed) 2003; 326(7387): 469.

^2.Grant AM, Avenell A, Campbell MK, et al. Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial. Lancet 2005; 365(9471): 1621-8.

^3.Ford JA, MacLennan GS, Avenell A, Bolland M, Grey A, Witham M. Cardiovascular disease and vitamin D supplementation: trial analysis, systematic review, and meta-analysis. The American journal of clinical nutrition 2014; 100(3): 746-55.

^4.Hsia J, Heiss G, Ren H, et al. Calcium/vitamin D supplementation and cardiovascular events. Circulation 2007; 115(7): 846-54.

^5.Scragg R, Waayer D, Stewart AW, et al. The Vitamin D Assessment (ViDA) Study: design of a randomized controlled trial of vitamin D supplementation for the prevention of cardiovascular disease, acute respiratory infection, falls and non-vertebral fractures. The Journal of steroid biochemistry and molecular biology 2016; 164: 318-25.

^6.Manson JE, Cook NR, Lee IM, et al. Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease. The New England journal of medicine 2019; 380(1): 33-44.

Women’s Health Initiative

The Women’s Health Initiative was a trial of 36,282 postmenopausal women aged 50-79 years randomized to 1000mg elemental calcium plus 400 IU of vitamin D₃ daily vs placebo, with the primary outcome being hip fractures and other major fractures. In prespecified secondary analysis, after 7 years of follow-up, there was no difference in the CVD endpoints between the two groups, HR (95% CI) for MI and stroke outcomes were: 1.04 [0.92-1.18] and HR 0.95 [0.82-1.10].¹⁶ The vitamin D dose was relatively low at 400 IU daily, which may have been too low to have influenced CVD outcomes.

British Vitamin D₃ Trial

In a trial of 2,686 community-dwelling individuals aged 65-85 years conducted in Britain, participants were randomized to 100,000 IU vitamin D₃ every 4 months (equivalent to approximately 833 IU daily) vs placebo and followed for 5 years. The primary outcome was incident fractures.¹⁷ Secondary outcomes included incident CVD events. Amongst those randomized to vitamin D, there were 477 CVD events vs 503 in the placebo group, adjusted relative risk 0.90 [0.77 to 1.06]. Although this was not a statistically significant result, there was a suggestion of a lower risk of CVD events. A major limitation of this trial was that endpoints were taken from self-reported questionnaires and were not rigorously adjudicated.

RECORD trial

The Randomised Evaluation of Calcium Or vitamin D (RECORD) trial enrolled 5,292 participants with a primary outcome of recurrent fracture, in a 2×2 factorial design to vitamin D₃ (800 IU/d) plus calcium (1000 mg calcium carbonate/d), vitamin D₃ only, calcium only, or placebo.¹⁸ After a median follow up of 6.2 years, there was no difference in the CVD endpoints MI, stroke, or composite events, HR: 0.97 [0.75-1.26], 1.06 [0.85-1.32], and 0.92 [0.80-1.08] respectively.¹⁹ There was a reduction in heart failure in those randomized to vitamin D vs placebo, HR 0.75 [0.58-0.97]. When combined in a meta-analysis including information from 13,033 participants in 21 prior randomized trials, including unpublished data from 12 trials, no meaningful effect of vitamin D was seen for any CVD outcomes: HR 0.96 [0.83-1.10] for MI, 1.07 [0.91-1.29] for stroke, and 0.82 [0.58-1.15] for heart failure.¹⁹ A sensitivity analysis of the meta-analysis included post-intervention phase events from the RECORD trial (events that occurred in the 3-yr follow up period following conclusion of the trial) and suggested a reduction in heart failure events, with an overall HR of 0.79 [0.59-0.99], with no evidence that vitamin D had any effect on MI or stroke, HRs 0.99 [0.87-1.11 and 1.07 [0.91-1.24] respectively.

Given the lack of data from large-scale studies designed to primarily examine CVD outcomes, several trials were proposed and undertaken from 2010 onward to assess CVD, cancer, or other non-skeletal outcomes:²⁰

ViDA trial

The Vitamin D Assessment Study (ViDA) was conducted in New Zealand, and recruited 5,110 participants aged 50 to 84, randomized to a loading dose of 200,000 IU of vitamin D₃, followed by 100,000 IU monthly (equivalent to approximately 3333 IU daily) vs placebo.²¹ Median follow up was 3.3 years. For the primary endpoint of incident CVD, there was no difference between vitamin D and placebo: HR 1.02 [0.87-1.20]. For the prespecified endpoint of MI, and stroke, results did not show any meaningful effect : HR 0.90 [0.54-1.50] and 0.95 [0.55-1.62] respectively.²² Results did not change when stratifying by low vs. high baseline 25OHD levels.

VITAL Trial

The VITamin D and OmegA-3 TriaL (VITAL) was the first large-scale trial conducted to assess the efficacy of vitamin D₃ supplementation on the main outcomes of cancer or CVD.^23,24 A total of 25,871 participants were randomized to 2000 IU per day of vitamin D₃ vs placebo. The average age of participants was 67 years, 51% female, with a median follow up of 5.3 years. For the primary endpoint of major CV events (a composite of MI, stroke, or CV death), there was no effect of vitamin D, with 396 events in the group randomized to vitamin D and 409 in those taking placebo, HR 0.97 [0.85-0.69]. When the composite end-point was expanded to include coronary revascularization, results did not change. HR for MI, stroke, and CV-death were 0.96 [0.78-1.19], 0.95 [0.76-1.20], and 1.11 [0.88-1.40] respectively. Results were unchanged after stratifying by baseline levels of serum vitamin D (low vs. high) or after excluding data from the first 2 years of follow-up.

There are several important trials underway around the world that will continue to add to the literature. These are highlighted below:

FIND Trial

The Finnish Vitamin D (FIND) trial is an ongoing trial in Finland that has enrolled approximately 2500 women >65 years and men >60 to assess the effect of 1600 vs 3200 IU of vitamin D₃ daily on cancer, diabetes and CVD endpoints.²⁵ The trial has had difficulty recruiting and is significantly smaller than the initially proposed 18,000 participants. Results are expected in 2020.

DO-HEALTH

The vitamin D₃ - Omega3 - Home Exercise - Healthy Ageing and Longevity (DO-HEALTH) Trial is ongoing in 8 European cities, testing 2000 IU vitamin D₃ vs placebo in 2,500 participants >70 years.²⁶ There are multiple primary outcomes, including effects on blood pressure, though CV outcomes are not primarily being studied.

VIDAL

The Vitamin D and Longevity (VIDAL) Trial is a randomized feasibility study enrolling 1,600 individuals aged 65-84 years in the UK to assess the effect of 60,000 IU of vitamin D monthly on longevity.²⁷ If successful, the study will expand to recruit 20,000 participants.

D-Health

Recruiting participants in Australia, the D-Health Trial has enrolled 21,315 participants aged 65-84 years, randomized to a monthly dose of 60,0000 IU (equivalent to approximately 2000 IU daily) of vitamin D₃.²⁸ Participants will be followed for 5 years to assess the effect of vitamin D on all-cause mortality, with a secondary outcome of incident total cancers and colorectal cancer.

Synthesis – what this means for practice

Prior to VITAL and ViDA, there was limited research testing moderate-high doses of vitamin D supplementation for prevention of CVD as a prespecified primary endpoint. Taken together, evidence to date consistently indicates that vitamin D supplementation in the general community does not have a role in the prevention of major cardiovascular events.

What has not been answered and should be done in the future?

Additional research on the outcome of heart failure is needed. In VITAL, heart failure is being examined as an ancillary study outcome, and the results should be reported soon. Among individuals with chronic kidney disease (CKD), who have known low levels of vitamin D in part related to reduced conversion of vitamin D due to impaired kidney function, rates of CVD are substantially higher than in the general population.¹¹ Data on whether vitamin D supplementation can lower the risk of CVD events or death among those with CKD is limited to observational studies.^11,29 A limitation to including those with CKD in randomized trials is that vitamin D supplementation is already part of the treatment protocols for CKD due to the known benefits for bone health. Trials focused on those with chronic kidney disease are needed, however, and potential effect modification by kidney function in existing data should be assessed.

Additionally, among populations with low serum levels of vitamin D, there remains a paucity of data for CVD outcomes following vitamin D supplementation. Both ViDA and VITAL had an average baseline vitamin D level within a normal range (25.3±9.5 ng/mL and 30.8±10.0 ng/ml, respectively). Whether vitamin D supplementation in those with lower 25OHD levels can reduce the risk for CVD outcomes is unclear. However, there are ethical considerations that limit the conduct of such trials due to the known deleterious effects on bone health when vitamin D is withheld from those with vitamin D deficiency.

To date there remains an ongoing debate as to what constitutes “optimal” levels of vitamin D. It is possible that longer follow up may be needed from the existing trials to understand the long-term effects of vitamin D supplementation on CVD events, particularly on heart failure, for which a potential protective signal was seen in the RECORD trial. Individualized targets of vitamin D levels may be needed to realize the benefit of vitamin D for CVD and other chronic disease outcomes, as well as to pursue the goal of precision prevention.

Conclusion

Based on the evidence to date, including newly published large-scale randomized controlled trial data, vitamin D supplementation does not appear to prevent cardiovascular events in general community settings. Future studies will explore whether there is a role of vitamin D supplementation for prevention of specific cardiovascular outcomes such as heart failure, or for particular populations, such as those with CKD.

Key Points:

• The role of vitamin D supplementation specifically for prevention of cardiovascular disease (CVD) outcomes has been limited by conflicting results from observational research and secondary analyses of trials.

• Two recently published large-scale randomized controlled trials with primary aims to test the effect of vitamin D supplementation on cardiovascular events, together with results of other trials assessing CVD in secondary analyses, do not support the role of vitamin D for prevention of CVD in the general population.

• Additional research is needed to understand the role of vitamin D in the prevention of heart failure and in specific high-risk populations such as those with chronic kidney disease.