No Strong Evidence That Supplements Offer CV Protection

Marlene Busko

July 10, 2019

There is no strong evidence that taking any of 16 nutritional supplements or following a diet that is low in salt or "bad fat" or high in "good fat" will ward off cardiovascular (CV) disease or help people live longer, suggests a new meta-analysis that used data exclusively from randomized controlled trials (RCTs).

A few preventive nutritional measures were found to offer some protection against CV outcomes or death, but the findings were "limited by suboptimal quality of the evidence," caution the authors, led by Safi U. Khan, MD, West Virginia University, Morgantown, in their report published July 8 in the Annals of Internal Medicine.

Measures supported by suboptimal evidence, they write, included reduced dietary salt intake, which seemed to protect against all-cause or CV mortality in some populations; omega-3 long-chain polyunsaturated fatty acids (LC-PUFA), which were associated with reduced risk for myocardial infarction (MI); and folic acid, which seemed to offer protection against stroke.

Combined calcium and vitamin D supplementation, in contrast, seemed to elevate the risk for stroke.

Interestingly, the limited evidence provided some support for reduced salt intake in normotensive people, who seemed to gain some protection against all-cause mortality. Salt restriction seemed protective against CV mortality in patients with hypertension.

"Other supplements, such as multivitamins, selenium, vitamin A, vitamin B6, vitamin C, vitamin E, vitamin D alone, calcium alone, folic acid, and iron, or such dietary interventions as the Mediterranean diet, reduced saturated fat intake, modified fat intake, reduced dietary fat intake, and increased intake of omega-3 ALA [alpha-linolenic acid] or omega-6 PUFA, did not seem to have a significant effect on mortality or CVD outcomes," the report states.

The group evaluated data from 277 RCTs that encompassed almost a million participants. The data were derived from nine meta-analyses and four original trial reports.

Importantly, "we focused on randomized controlled trials and purposefully ignored epidemiologic studies and observational studies, because those studies are full of bias," Khan told | Medscape Cardiology.

Until there is better evidence, he said, clinicians can advise patients that it makes sense to take a vitamin supplement if they have a vitamin deficiency.

Otherwise, "I would suggest, 'Do not waste your money.' If you want to improve your cardiovascular health, follow a very simple behavioral regimen: take your food from nutritionally rich sources, indulge in exercise, avoid smoking, avoid alcoholism, and avoid a sedentary lifestyle."

The researchers identified nine systematic reviews of RCTs and four other recent RCTs that examined the effects of 16 nutritional supplements and eight dietary interventions on all-cause mortality or CV outcomes, which included CV death, MI, stroke, and coronary heart disease (CHD). The trials included 992,129 participants.

Although the evidence was considered weak, a low-salt diet or taking omega-3 LC-PUFA, folic acid, or calcium plus vitamin D supplements was associated with statistically significant effects on CV outcomes or all-cause mortality.

Table. Effect of Supplements and Dietary Interventions on Outcomes in Randomized Controlled Trials, Meta-Analysis

Supplement or Dietary Intervention Outcome of Interest HR (95% CI) Level of Evidence Certainty
Reduced salt intake in normotensive people All-cause mortality 0.90 (0.85 – 0.95) Moderate
Reduced salt intake in hypertensive people CV mortality 0.67 (0.46 – 0.99) Moderate
Omega-3 LC-PUFA MI 0.92 (0.85 – 0.95) Low
Omega-3 LC-PUFA CHD 0.93 (0.89 – 0.98) Low
Folic acid Stroke 0.80 (0.67 – 0.96 Low
Calcium plus vitamin D Stroke 1.17 (1.05 – 1.30) Moderate


The other studied nutritional supplements and dietary interventions. These had no apparent significant effects on mortality or CV outcomes. The evidence was of a very low to moderate level of certainty, the report says.

This was an "ambitious meta-analysis," write Amitabh C. Pandey, MD, and Eric J. Topol, MD, Scripps Research and Scripps Clinic, La Jolla, California, in an accompanying editorial.

But, its primary conclusions that "a low-salt diet may reduce the risk for all-cause mortality in persons without high blood pressure and that, with low certainty, omega-3 fatty acid and folate supplementation have a salutary effect on heart attack and stroke, respectively," they write, are "contrary to many previous reports that have found no significant benefit to the same diet modification or supplements."

There are other limitations, Pandey and Topol point out. For example, fortification of food with calcium, vitamin D, and folate differs throughout the world. In addition, the trials that contributed the data generally relied on food diaries and personal recall.

"Unfortunately, the current study leaves us with the same foggy conditions that we started with," they conclude. "Until these conditions clear, it would be reasonable to hold off on any supplement or diet modification in all guidelines and recommendations."

Three researchers were funded by the Blumenthal Scholars Fund in Preventive Cardiology at Johns Hopkins University. Khan has disclosed no relevant financial relationships. The disclosures of other authors of the study are listed with the original article. Topol is Medscape's editor-in-chief; Pandy has disclosed no relevant financial relationships.

Ann Intern Med. Published July 8, 2019. Abstract, Editorial

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