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New research, recent controversies question vitamin D benefits in CVD
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The idea of “sunshine in a bottle” — vitamin D supplementation — has been promoted as a possible fix for everything from bone and immune system health to depression, dementia and diabetes, and the premise sells. It has also been investigated as a strategy for CVD prevention, but results to date have been negative.
According to recent CDC statistics, approximately 45% of middle-aged women and 38% of middle-aged men report taking a vitamin D supplement, and hundreds of thousands of Americans get tested for vitamin D deficiency each year.
Many clinicians, too, tout the promise and possible benefits of vitamin D, which, despite its name, is a hormone that promotes the absorption of calcium in the body. But for every positive claim attached to the over-the-counter supplement, new research suggests there is more to the story.
“It’s natural in medical thinking that if a person is deficient in something and you have a disease, maybe replacing that deficiency would either prevent it, improve it or, possibly, even cure it,” Bart L. Clarke, MD, professor of medicine in the division of endocrinology, metabolism, diabetes and nutrition at the Mayo Clinic College of Medicine in Rochester, Minnesota, and president of the American Society for Bone and Mineral Research, told Cardiology Today. “Like most things in medicine, the pendulum swings from cynicism to enthusiasm, and over time, as more data become available, things settle back down to some middle level, where it probably should have been all along.”
What constitutes the “optimal” level of vitamin D — and what that even means — remain issues of intense debate. Recently, the large-scale VITAL trial, conducted in 25,871 U.S. adults, including 5,106 black participants, suggested supplementation did not prevent major CV events or the development of invasive cancers over 5 years. The harshest critics contend the supplement is worthless.
Still, a deeper dive into the VITAL results, as well as other research conducted in adults with specific cancers, reveals a signal for benefits with vitamin D for certain subsets of patients.
For many researchers, the real benefit of vitamin D remains an open question.
“The key message here is that the results of the VITAL trial are complex,” the study’s principal investigator, JoAnn E. Manson, MD, DrPH, FAHA, chief of the division of preventive medicine at Brigham and Women’s Hospital and professor of medicine and the Michael and Lee Bell Professor of Women’s Health at Harvard Medical School, told Cardiology Today. “There is no simple summary and no one-size-fits-all recommendation based on the results of the VITAL trial.”
Manson said the study, which also looked at omega-3 supplementation, although it did not meet its primary endpoint, showed an exploratory signal for CV health benefits with fish oil, particularly relevant to those with low fish consumption at baseline, and a signal for a cancer death benefit with vitamin D supplementation.
“We need to see if these signals strengthen over time,” Manson said. “We will be following the cohort for at least 2 more years.”
CV findings
Although there has not been a proven benefit to date for the use of vitamin D for CV prevention, there are several mechanisms of action that suggest low vitamin D may be a risk factor for hypertension and CVD.
“Vitamin D deficiency has been associated with atherosclerosis in animal models related to the interaction between lymphocytes and macrophages,” Keith C. Ferdinand, MD, FACC, FAHA, FNLA, professor of medicine at Tulane University School of Medicine and Cardiology Today Editorial Board member, said in an interview. “The supplementation of vitamin D was at one time thought to have potential anti-inflammatory benefits. Furthermore, it’s been suggested that vitamin D supplementation may decrease the levels of a wide range of pro-inflammatory mediators and cytokines and decrease monocyte recruitment, potentially leading to lesion stability and less plaque rupture.”
Other possible mechanisms by which vitamin D may provide CV benefit include its impact on proliferation of smooth muscle cells in the vasculature to reduce the risk for obstructive coronary disease.
“There are a lot of theoretic mechanisms as to why it could work,” Clifford J. Rosen, MD, senior scientist and director of the Center for Clinical and Translational Research at Maine Medical Center Research Institute in Scarborough, told Cardiology Today.
Erin D. Michos, MD, MHS, FACC, FAHA, director of women’s cardiovascular health, associate director of preventive cardiology and associate professor of medicine at Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease, acknowledged that prior to VITAL, meta-analyses of trials that were performed for bone health had not shown any benefit for vitamin D with respect to CV outcomes. “But there was this remaining question: Was the dose too low, or were the studies not powered or designed to look for CV outcomes?” Michos told Cardiology Today. “This wasn’t definitive before VITAL; thus, VITAL was a critically important study to fill in some of those knowledge gaps.”
In the VITALtrial, which assessed CVD as a prespecified endpoint, major CV event rates were similar between those assigned vitamin D or placebo (HR = 0.97; 95% CI, 0.85-1.12). Researchers observed similar findings for the expanded composite endpoint of major CV events plus coronary revascularization (HR = 0.96; 95% CI, 0.86-1.08), MI (HR = 0.96; 95% CI, 0.78-1.19), stroke (HR = 0.95; 95% CI, 0.76-1.2) and CV death (HR = 1.11; 95% CI, 0.88-1.4).
The findings, researchers wrote, were consistent with results from previous vitamin D trials, at both moderate and high doses. Most recently, in the ViDA trial, the rate of CVD was not lower among participants who received monthly administration of high-dose vitamin D compared with placebo.
“Overall, the thing I take away is that low vitamin D may not be a causal factor of heart disease,” Michos said. “It is a factor associated with risk for heart disease and other adverse outcomes. But it may just be that someone with lower levels is just not in as good health, and it might just be a marker of a poor health state, as opposed to something causal where you can treat it and improve outcomes.”
In VITAL, the baseline population had largely normal vitamin D levels, and 40% were taking statins at baseline, according to Carlos Bernal-Mizrachi, MD, the Philip E. and Carolyn E. Cryer Professor of Medicine in the division of endocrinology, metabolism and lipid research at Washington University and chief of endocrinology at St. Louis VA Medical System.
“It was not surprising that adding vitamin D supplementation did not decrease CVD,” Bernal-Mizrachi told Cardiology Today. “Perhaps future results from high-risk populations, such as people with diabetes with vitamin D deficiency, could help us to prove whether vitamin D is effective against CVD in these more specific groups and ultimately identify evidence-based cutoff points.”
More recently, Manson and colleagues published a meta-analysis of 21 randomized clinical trials in JAMA Cardiology in June, which found vitamin D did not reduce individual CV endpoints, all-cause mortality or major adverse CV events. Compared with placebo, vitamin D supplementation was not linked to reduced major adverse CV events (RR = 1; 95% CI, 0.95-1.06; I2 = 11%). This was also observed for secondary endpoints including stroke/cerebrovascular accident (RR = 1.06; 95% CI, 0.98-1.15; I2 = 0%), MI (RR = 1; 95% CI, 0.93-1.08; I2 = 0%), all-cause mortality (RR = 0.97; 95% CI, 0.93-1.02; I2 = 0%) and CV mortality (RR = 0.98; 95% CI, 0.9-1.07; I2 = 2%).
“The findings suggest that in the general ‘usual risk’ population not selected for vitamin D deficiency, vitamin D supplementation does not confer cardioprotection,” Manson told Cardiology Today. “Thus, in general community settings, routine vitamin D supplementation is unlikely to have significant CVD benefit. Patients with known vitamin D deficiency, however, should obviously be treated, given that correcting deficiency is known to be important for bone health.” Manson highlighted the need for more research on whether vitamin D reduces HF, noting that VITAL will report on this endpoint later this year.
Potential adverse effects
A vitamin D supplementation strategy may not come without potential harm.
“Many patients don’t think of [supplements] as medication,” Michos said. “There can actually be some harm with supplements. It’s hard to overdose on vitamin D, but you can if you have really massive doses.”
Furthermore, Michos and colleagues recently published an evidence review and meta-analysis of randomized clinical trials of supplements published in the Annals of Internal Medicine in July. They found that the combination of calcium and vitamin D may actually increase the risk for stroke (RR = 1.17; 95% CI, 1.05-1.3).
In a double-blind, randomized controlled trial published in Clinical Endocrinology in September 2018, researchers reported that hypercalciuria, assessed via 24-hour urinary calcium excretion, occurred in healthy, postmenopausal white women with low 25-hydroxyvitamin D levels assigned both high (10,000 IU) and low (600 IU) doses of vitamin D; however, women assigned to the high-dose vitamin D group were 3.6 times more likely to develop hypercalciuria vs. those in the lower-dose group (OR = 3.6; 95% CI, 1.39-9.3).
In contrast, there are some studies where patients did not experience adverse effects with vitamin D supplementation. Manson noted that the VITAL study demonstrated safety in a large population assigned to a 2,000 IU daily dose over 5 years of follow-up.
“However, we do think patients should be cautioned against ‘mega-dosing’ on these supplements,” Manson said. “Very high doses are associated with risks like hypercalcemia and hypercalciuria, and also CV outcomes may be adversely affected.”
Vitamin D deficiency could predispose patients to statin-related myalgia, Ferdinand said. On the other hand, vitamin D may increase calcium levels in patients taking thiazide diuretics and blunt the effects of calcium-channel blockers for cardioprotection and BP lowering.
“There’s no specific role for vitamin D supplementation for [CVD] prevention at this point. Nevertheless, if a person is in a deficient level with levels below 20 ng/mL, it would be reasonable to suggest vitamin D for overall health,” Ferdinand said.
In contrast, some experts believe that there is no real risk associated with giving patients vitamin D.
Possible cancer benefit
Vitamin D supplementation may also have an additional benefit of reducing the risk for cancer. In the vitamin D portion of VITAL, invasive cancer was diagnosed in 1,617 participants, including 793 in the vitamin D group and 824 in the placebo group, for an HR of 0.96 (95% CI, 0.88-1.06). In the analyses of secondary endpoints in VITAL, HRs were 0.83 for overall cancer death (95% CI, 0.67-1.02), 1.02 for breast cancer (95% CI, 0.79-1.31), 0.88 for prostate cancer (95% CI, 0.72-1.07) and 1.09 for colorectal cancer (95% CI, 0.73-1.62). With longer treatment, cancer death was significantly reduced by 25%.
“The findings are along the lines of what I expected to see,” Kimmie Ng, MD, MPH, director of clinical research at Dana-Farber Cancer Institute’s Gastrointestinal Cancer Center and assistant professor of medicine at Harvard Medical School, told Cardiology Today. “There hasn’t been a randomized controlled trial of chemoprevention using vitamin D that has shown a significant benefit in terms of reducing the risk for developing colorectal cancer. Many of the previous randomized controlled trials looked at cancer or cancer death as a secondary endpoint. This one actually was powered to detect an effect on whether it can protect against cancer. This was a very well-designed, adequately powered study.”
The observed outcomes in VITAL, Ng said, may have to do with the 5-year duration of the trial, as other studies have shown it may take more than 10 years to show a protective effect against cancer.
Bone health
In a meta-analysis published in October in The Lancet Diabetes & Endocrinology, Mark J. Bolland, MBChB, PhD, associate professor in the department of medicine at the University of Auckland, New Zealand, and colleagues analyzed 81 randomized controlled trials that compared vitamin D with no treatment, placebo or lower-dose vitamin D supplements, reporting on fracture, falls or bone mineral density. In pooled analyses, vitamin D had no effect on total fracture, hip fracture, falls or bone mineral density at any site, with results persisting in subgroup analyses using doses greater than 800 IU per day.
However, research suggests that vitamin D works synergistically with calcium, Clarke noted, and studies that try to separate the two will often not show any benefit.
Whom to screen
A clinical practice guideline issued by the Endocrine Society in 2011 states that there is currently not sufficient evidence to recommend screening individuals who are not at risk for vitamin D deficiency or to prescribe vitamin D to attain a noncalcemic benefit for CV protection. At the time, the task force also advised measuring serum 25-hydroxyvitamin D level by a reliable assay as the initial diagnostic test in patients at risk for deficiency, with treatment with either vitamin D2 or vitamin D3 recommended for deficient patients.
Similarly, the U.S. Preventive Services Task Force concluded in 2015 that “current evidence is insufficient to assess the balance of benefits and harms of screening for vitamin D deficiency in asymptomatic adults.” In addition, the American Society for Clinical Pathology recommends against screening for vitamin D deficiency in the general population.
Many high-risk populations should be screened for deficiency, Bernal-Mizrachi said, including nursing home residents, patients with osteoporosis or fractures, patients with limited sun exposure, black women of childbearing age, malnourished populations with low intake or people with severe liver disease or chronic renal failure.
‘No magic bullet’
There will be 23 ancillary studies coming from VITAL, Manson said, including analyses assessing the association between vitamin D and diabetes, HF, cognitive function, depression, autoimmune disease and other health outcomes that could inform clinical decision-making.
Most experts agree that, for people already taking vitamin D supplements, there is no clear need to stop taking them. Any supplements, however, should be part of an overall healthy diet and lifestyle.
“There is no magic bullet for heart health,” Michos said. “I encourage people to eat a balanced diet, include some fatty fish in their diet if they eat that because that contains vitamin D, maintain a healthy weight, because obesity is associated with low vitamin D levels, and get a little sun. Most people don’t need to be taking a vitamin D supplement.”
Supplementation could confer a benefit for people with severe vitamin D deficiency — a level defined by the Institute of Medicine as less than 12 ng/mL, Michos said.
“I still treat those people in my clinical practice for bone health,” she said.
Clarke said the large-scale VITAL findings hardly close the door on the vitamin D debate. Still, he remains skeptical of any benefit.
“There have been a number of investigators who have hyped vitamin D findings,” Clarke said. “I think vitamin D is important, and the fact so many people around the world are deficient probably does lead to a variety of different things, maybe in the onset of disease; but once the disease gets started, it’s an open question as to whether replacing vitamin D would have therapeutic benefit. The hope is that this would be cheap and easy if it worked, and it would be great if it solved many different conditions, but that enthusiasm is always tempered by experience.” – by Regina Schaffer, with additional reporting by Darlene Dobkowski
- References:
- Aloia JF, et al. Clin Endocrinol. 2018;doi:10.1111/cen.13848.
- American Society for Clinical Pathology. www.choosingwisely.org/societies/american-society-for-clinical-pathology. Accessed Aug. 12, 2019.
- Barbarawi M, et al. JAMA Cardiol. 2019;doi:10.1001/jamacardio.2019.1870.
- Bolland MJ, et al. Lancet Diabetes Endocrinol. 2018;doi:10.1016/S2213-8587(18)30265-1.
- Hurley DL, et al. Endocr Pract. 2018;doi:10.4158/PS-2018-0050.
- Keaney JF Jr, et al. N Engl J Med. 2018;doi:10.1056/NEJMe1814933.
- Khan SU, et al. Ann Intern Med. 2019;doi:10.7326/M19-0341.
- Khaw K, et al. Lancet Diabetes Endocrinol. 2017;doi:10.1016/s2213-8587(17)30103-1.
- LeFevre ML, et al. Ann Intern Med. 2015;doi:10.7326/M14-2450.
- Manson JE, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1809944.
- Ross AC, et al. Dietary Reference Intakes for Calcium and Vitamin D. Washington, D.C.: National Academies Press; 2011.
- For more information:
- Carlos Bernal-Mizrachi, MD, can be reached at cbernal@wustl.edu.
- Bart L. Clarke, MD, can be reached at clarke.bart@mayo.edu.
- Keith C. Ferdinand, MD, FACC, FAHA, FNLA, can be reached at kferdina@tulane.edu.
- JoAnn E. Manson, MD, DrPH, FAHA, can be reached at jmanson@rics.bwh.harvard.edu.
- Erin D. Michos, MD, MHS, FACC, FAHA, can be reached at edonnell@jhmi.edu; Twitter: @erinmichos.
- Kimmie Ng, MD, MPH, can be reached at kimmie_ng@dfci.harvard.edu.
- Clifford J. Rosen, MD, can be reached at rosenc@mmc.org.
Disclosures: VITAL was supported by the NIH. Manson reports she received grants from the NIH, nonfinancial support from BASF, Pharmavite, Pronova BioPharma and Quest Diagnostics during the conduct of the VITAL study. Ng reports she received research funding from Pharmavite. Bernal-Mizrachi, Clarke, Ferdinand, Michos and Rosen report no relevant financial disclosures.