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Does Vitamin D Provide Cardiovascular Benefit?

  • Authors: News Author: Marilynn Larkin; CME Author: Charles P. Vega
  • CME / ABIM MOC / CE Released: 8/25/2023
  • Valid for credit through: 8/25/2024, 11:59 PM EST
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This activity is intended for primary care clinicians, cardiologists, endocrinologists, nurses/nurse practitioners, pharmacists, and other members of the healthcare team who treat and manage older adults at risk for cardiovascular disease.

The goal of this activity is for members of the health care team to be better able to evaluate the effects of vitamin D supplementation on the risk for cardiovascular events.

Upon completion of this activity, participants will:

  • Analyze the effects of vitamin D supplementation on the risk for mortality
  • Evaluate the effects of vitamin D supplementation on the risk for cardiovascular events
  • Outline implications for the healthcare team


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News Author

  • Marilynn Larkin

    Freelance writer, Medscape


    Marilynn Larkin has no relevant financial relationships.

CME Author

  • Charles P. Vega, MD

    Health Sciences Clinical Professor of Family Medicine
    University of California, Irvine School of Medicine


    Charles P. Vega, MD, has the following relevant financial relationships:
    Consultant or advisor for: Boehringer Ingelheim Pharmaceuticals, Inc.; GlaxoSmithKline; Johnson & Johnson

Editor/Compliance Reviewer

  • Amanda Jett, PharmD, BCACP

    Associate Director, Accreditation and Compliance, Medscape, LLC


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  • Leigh Schmidt, MSN, RN, CNE, CHCP

    Associate Director, Accreditation and Compliance, Medscape, LLC


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Does Vitamin D Provide Cardiovascular Benefit?

Authors: News Author: Marilynn Larkin; CME Author: Charles P. VegaFaculty and Disclosures

CME / ABIM MOC / CE Released: 8/25/2023

Valid for credit through: 8/25/2024, 11:59 PM EST


Clinical Context

The clinical benefits of vitamin D supplementation in a general adult population has been a highly controversial issue in health care, and multiple trials of vitamin D have failed to demonstrate a benefit for health outcomes. A meta-analysis by Zhang and colleagues, published in 2019 in the British Medical Journal, assessed the effects of vitamin D on mortality outcomes in 50 randomized trials.[1]

The studies enrolled a total of 74,655 patients. The overall risk ratio for mortality in comparing vitamin D with control treatment was 0.98 (95% CI, 0.95-1.02). The respective risk ratios for cardiovascular mortality and cancer mortality were 0.98 (95% CI, 0.88-1.08) and 0.85 (95% CI, 0.74-0.97). Mortality rates were lower in trials that involved vitamin D3 vs vitamin D2, although neither form of the vitamin was more effective than control therapy in reducing the risk for overall mortality.

In another major study, the Vitamin D and Omega-3 Trial (VITAL) failed to demonstrate a benefit for vitamin D3 at a dose of 2000 IU daily vs placebo in the outcomes of incident cardiovascular disease and cancer after a mean follow-up of 5.3 years.[2] VITAL also failed to demonstrate any mortality benefit associated with vitamin D.

Nonetheless, VITAL excluded adults with a history of cardiovascular disease. The current study examines the potential cardiovascular effects of vitamin D in a broader cohort of older adults.

Study Synopsis and Perspective

Adults aged 60 years or older who received high monthly doses of vitamin D for 5 years failed to show a significant drop in risk for cardiovascular (CV) events in general, but may have benefited for other CV outcomes in an analysis from a large prospective randomized trial.

Risk reductions on vitamin D in the mixed primary and secondary prevention population were slight in absolute terms, but reached a significant 19% in the case of myocardial infarction (MI).

Over the course of 5 years, 6.6% of those in placebo group experienced major CV events, which was the primary endpoint, compared with 6.0% in the vitamin D group. The difference, which corresponded to 5.8 fewer events per 1000 participants, was short of significance in adjusted analysis.

Still, vitamin D supplementation was associated with the potential MI benefit and an 11% drop in risk for coronary revascularization.

In addition, a subgroup analysis hinted at a potentially reduced CV event risk from vitamin D supplementation among individuals who entered the trial on statins or other CV medications generally.

“Most other studies have not found benefit for vitamin D for major CV events,” senior investigator Rachel E. Neale, PhD, told Cardiology. Although there was a significant effect for MI, the difference in the composite primary endpoint fell short of significance, “in keeping with the other studies.”

“However, the effects for [MI] in people taking statins or cardiovascular disease drugs at baseline are suggestive of benefit,” said Dr Neale, of QIMR Berghofer Medical Research Institute, Queensland, Australia. Still, “It is important to keep in mind that these may be chance findings.”

The analysis based on the D-Health study was published online June 28 in the BMJ.[3]

Benefits Minimal

The 21,302 patients in the trial, called D-Health and conducted in Australia from 2014 to 2020, were randomly assigned double-blind to receive either placebo or vitamin D3 supplements for a planned 5 years. They were instructed to take 1 placebo or vitamin D capsule per month, with each active capsule containing 60,000 IU of the vitamin.

People with self-reported hypercalcemia, hyperparathyroidism, kidney stones, osteomalacia, or sarcoidosis and those receiving more than 500 IU/day vitamin D supplements were excluded from enrollment. Participants ranged in age from 60 to 84 years at randomization, and 46% were women.

With 80% of the 10,658 participants assigned to vitamin D and 78% of the 10,644 control subjects completing the 5-year intervention, 6.0% and 6.6%, respectively, met the primary endpoint of a major CV event, defined as MI, stroke, or coronary revascularization.

The hazard ratio (HR) for a vitamin D effect on the primary endpoint was 0.91 (95% CI, 0.81-1.01). The number needed to treat to avoid 1 major CV event was 172.

The HR for MI was 0.81 (95% CI, 0.67-0.98), for coronary intervention it was 0.89 (95% CI, 0.78-1.01), and for stroke it was 0.99 (95% CI, 0.80-1.23).

Adverse event rates were similar, at about 16%, in both groups and included hypercalcemia, kidney stones, gastrointestinal issues, and skin rash.

Vitamin D at moderate dosages has low toxicity, Dr Neale said, “so I think it would be reasonable for clinicians to consider supplementing elderly people who do not have contraindications, particularly those who have underlying risk factors for CV disease.” However, patients should be told that the evidence for such a recommendation is not strong, so they can make an informed decision, she added.

Also, in general, “we would be cautious about extrapolating to formulations other than those used in the study,” Dr Neale said. “However, in this case, I think it would be reasonable to extrapolate to the use of 2000 IU per day taken orally, provided that the same adherence can be maintained for a lengthy period.”

Chance Findings?

On the basis of the current study and in light of prior research, “it is premature to recommend vitamin D supplementation for cardiovascular disease prevention specifically,” Nour Makarem, PhD, from the Mailman School of Public Health, Columbia University, New York City, told Cardiology.

“Prior clinical trials did not show an association between vitamin D supplementation and cardiovascular events,” observed Dr Makarem, who was not affiliated with the current study. Also, she agreed, it looked at “multiple outcomes, which increases the likelihood that findings may be due to chance.”

In addition, she said, the study’s authors observed a possible vitamin D protective effect “among people who were vitamin D sufficient at baseline, but not among those who were insufficient. It is important to interpret this finding with caution because they used predicted, not measured, vitamin D status for these analyses.”

There’s a need for studies in other populations, including younger persons and “particularly populations with higher rates of vitamin D deficiency,” Dr Makarem observed. Also, further research should aim to “understand the interactions between vitamin D supplementation and cardiovascular medications, including statins.” 

The D-Health Trial is funded by National Health and Medical Research Council project grants. Dr Neale was supported by fellowships from the National Health and Medical Research Council. Neither she nor Dr Makarem reported any relevant financial relationships.

BMJ. Published online June 28.

Study Highlights

  • The D-Health Trial is a randomized, placebo-controlled study among adults between 60 and 79 years of age in Australia.
  • Adults with a history of hypercalcemia, hyperparathyroidism, kidney stones, osteomalacia, sarcoidosis, or daily consumption of a vitamin D supplement of 500 IU or more were excluded from the study protocol.
  • Participants were randomly assigned to receive 60,000 IU of vitamin D3 in a monthly dose, or matching placebo. The intervention period was 5 years.
  • The D-Health Trial is assessing 45 different tertiary outcomes, and the current report focuses on incident cardiovascular events, including MI, stroke, and coronary revascularization.
  • The use of vitamin D supplements outside the study protocol was discouraged but were allowed at doses up to 2000 IU.
  • Participants completed a health questionnaire and examination at baseline. A national drug database was applied to assess the use of statins and antihypertensive drugs in the study cohort.
  • The study analysis adjusted for age, sex, body mass index, vitamin D concentrations at baseline, and the use of statins and antihypertensive drugs.
  • 21,315 participants were recruited into the study, and 21,302 provided data for study analysis. The mean age of participants was 69 years, and 54% were men.
  • Adherence to study treatment was excellent, with nearly 80% of participants in the vitamin D and placebo groups still receiving their monthly treatment at 5 years.
  • The mean 25-hydroxyvitamin-D (25-OH-D) levels during the intervention were 77 nmol/L and 115 nmol/L in the placebo and vitamin D groups, respectively.
  • There were 1336 cardiovascular events during 5 years of follow-up. The HR for the composite of cardiovascular events in comparing the vitamin D and placebo groups was 0.91 (95% CI, 0.81-1.01).
  • There was no significant difference in the main study outcome based on age, sex, or body mass index.
  • The HR for vitamin D vs placebo was lower among persons with a predicted 25(OH)D concentration of at least 50 nmol/L (0.87; 95% CI, 0.76-0.98). It was also lower among adults using statins at baseline (0.83; 95% CI, 0.71-0.97) and other cardiovascular drugs, principally antihypertensive agents (0.84; 95% CI, 0.74-0.97).
  • Another subgroup analysis that focused on participants who reported a prior history of cardiovascular disease yielded an HR of 0.89 (95% CI, 0.78-1.01) for cardiovascular events in comparing the vitamin D and placebo cohorts.
  • Among individual cardiovascular events, vitamin D appeared most effective at reducing the risk for MI (HR, 0.81; 95% CI, 0.67-0.98). It was not significantly effective in the prevention of stroke or coronary revascularization.
  • The incidence of adverse events was similar in the vitamin D and placebo groups.

Implications for the healthcare team

  • A prior study used data from 50 randomized trials to demonstrate that vitamin D supplementation did not improve cardiovascular or overall mortality, but it had a significant effect on the risk for cancer mortality.
  • The current study did find a significant benefit of monthly vitamin D supplementation in the risk for cardiovascular events, including in an analysis limited to participants who reported a history of cardiovascular disease. However, patients who were receiving statins and antihypertensive drugs experienced a small benefit in the risk for cardiovascular events with vitamin D vs placebo.
  • The healthcare team should recognize the generally lackluster performance of routine vitamin D supplementation in clinical trials. The current study suggests that vitamin D supplements may improve the risk for cardiovascular events among patients receiving statins and antihypertensive drugs


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