Most Supplements and Diets Don’t Lower CVD or Mortality Risks

The vast majority of dietary interventions and nutritional supplements, including multivitamins, selenium, and antioxidants, do not lower the risk of death, nor do they provide any protection against cardiovascular disease, according to a large umbrella analysis of several systematic reviews and randomized controlled trials.

There was, however, a modest benefit of reduced salt intake, omega-3 polyunsaturated fatty acids, and folate supplementation. On the other hand, the combination of calcium and vitamin D appeared to increase the risk of stroke.

“The supplement industry continues to be a billion-dollar industry and Americans spend $21 billion every year buying vitamins and supplements,” senior investigator Erin Michos, MD (Johns Hopkins School of Medicine, Baltimore, MD), told TCTMD. “It’s estimated that by 2024, there will be $300 billion spent globally on supplements. Of course, with precious healthcare resources, this is a question about whether it’s a good investment for people’s money and whether it would be better spent on other preventative measures.”

In 2014, the United States Preventive Services Task Force (USPSTF) published their recommendations stating that there was insufficient evidence to assess the benefits and harms of multivitamins or single- or paired-nutrient supplements for the prevention of cardiovascular disease or cancer. The USPSTF also advised against the use of beta-carotene and vitamin E for the prevention of cardiovascular disease and cancer and said there was insufficient evidence to support the use of vitamin D and calcium for reducing fractures.

“Despite these recommendations, one out of every two Americans—based on [National Health and Nutrition Examination Survey] data—report taking any supplements, and it’s not really clear why or how much they’ll gain,” said Michos. “When you start talking about older people, those 60 years and older, roughly 70%, or the majority, takes at least one supplement, and more than a quarter take at least four supplements.”

‘Probably Wasting Their Money’

Given this scope of use, the researchers wanted to assess high-quality evidence testing what effect various nutritional supplements and dietary interventions might have on clinical cardiovascular endpoints.

Published July 8, 2019, in the Annals on Internal Medicine, the new umbrella analysis includes nine systematic reviews and four randomized controlled trials on these topics that assessed all-cause mortality, cardiovascular mortality, MI, stroke, and coronary heart disease. In total, lead investigator Safi Khan, MD (West Virginia University, Morgantown), along with Michos and colleagues looked at 277 studies, 24 interventions, and 992,129 participants, including data from the VITAL and ASCEND studies looking at vitamin D and omega-3 polyunsaturated fatty acids. 

Overall, there was “moderate-certainty” evidence that reduced salt intake had a modest effect on all-cause mortality in people with normal blood pressure (RR 0.90; 95% CI 0.85-0.95) and cardiovascular mortality in hypertensive individuals (RR 0.67; 95% CI 0.46-0.99). Additionally, there was “low-certainty” evidence that omega-3 polyunsaturated fatty acids modestly reduce the risk of MI and coronary heart disease. There was also low-certainty data suggesting that folic acid reduces the risk of stroke, a benefit that was largely driven by a single study in China where food sources are not supplemented with folate. Finally, there was moderate-certainty evidence that calcium and vitamin D increase the risk of stroke (RR 1.17; 95% CI 1.05-1.30).

What I find in my conversations is that they think they’re getting more benefit than the evidence really shows. I also think a lot of people are completely unaware of the risks. Erin Michos

No other supplement, including vitamins A, B complex, B₆, C, D, or E, antioxidants, or iron, and no other dietary intervention, including reduced fat intake, had any impact on mortality or cardiovascular events. “For the vast majority of interventions and supplements, we found no signal of benefit or harm,” said Michos. “I can’t emphasize enough that people are probably wasting their money, particularly on all these vitamins and supplements. They would be better [off getting] their nutrients from food sources.”

Khan told TCTMD he was surprised their analysis showed no effect from the Mediterranean diet on mortality or cardiovascular outcomes given results of the PREDIMED study and meta-analyses suggesting benefits with a diet rich in plants, whole grains, nuts, and olive oil. He speculated that the PREDIMED findings might have been outweighed by other null studies, adding that the current analysis employed different statistical adjustments than conventional meta-analyses, which tightened  the confidence intervals around the relative benefits and risks of the interventions. When these were applied, their analysis showed a null effect.

“All we can say at this point in time is that the evidence isn’t really convincing,” Khan said of the Mediterranean diet. “Perhaps we need more randomized trials and to show a consistent benefit over and over again in subsequent studies.”

Signal of Benefit With Omega-3 Fatty Acids

With respect to omega-3 polyunsaturated fatty acids, Michos noted that while the VITAL study was negative for its primary and secondary endpoint, investigators did observe a significant reduction in the risk of MI. The REDUCE-IT study, which wasn’t included in the umbrella analysis because the intervention was a high-dose purified ester of eicosapentaenoic acid available only as a prescription, also showed a reduction in the risk of major cardiovascular events.

“Although we didn’t include REDUCE-IT, the fact that we saw a signal for fish oil for MI, the same signal seen in VITAL, which we did include, is important,” said Michos. There is some thought the omega-3 fatty acids protect against cardiovascular events through various anti-inflammatory or antithrombotic effects, she added.

At the end of the day, it’s the patient’s right if they want to continue the medication or not, but being a physician it’s my job to tell them. Safi Khan

Regarding the increased risk of stroke with the combination of calcium plus vitamin D supplementation, Michos said she’s been concerned about the adverse effects of calcium for some time. In 2016, she published data from the MESA trial showing that calcium supplements, not dietary calcium, were associated with an increase in coronary artery calcification. Given that calcium is part of the clotting cascade, Michos suggested that a high-dose supplement could transiently increase blood calcium and potentially trigger the clotting process.

In clinical practice, Michos said she will ask patients if they are taking nutritional supplements and why. When doing so, she’ll cite the evidence and then have a discussion, but allow patients to ultimately make their own decisions. “What I find in my conversations is that they think they’re getting more benefit than the evidence really shows,” she said. “I also think a lot of people are completely unaware of the risks. They think just because it’s available over-the-counter there is no harm, but when I talk about some potential interactions, it sometimes helps them rethink their decisions.”

Khan said he will also ask patients why they are taking the supplements and will allow patients with deficiencies in certain vitamins, such as D or B₁₂, to continue taking them. “But if they believe it will improve their survival and cardiovascular health, regardless of whether they have a deficiency or not, I try to convince them that there isn’t strong evidence and you’re spending your money [for no reason],” he said. “At the end of the day, it’s the patient’s right if they want to continue the medication or not, but being a physician it’s my job to tell them.”  

The researchers also developed an “evidence map” of the available data and its strength regarding nutritional supplements/dietary interventions on cardiovascular morbidity and mortality, Khan noted. “This is something any physician can show to their patient while they’re in the clinic,” he said.

In an accompanying editorial, Amitabh Pandey, MD, and Eric Topol, MD (both from Scripps Research Translational Institute, La Jolla, CA), say the study leaves many physicians with the “same foggy conditions” as before. Until things clear, “it would be reasonable to hold off on any supplement or dietary modification in all guidelines and recommendations,” they conclude.