Multivitamins, selenium, vitamin A, vitamin B6, vitamin C, vitamin E, vitamin D alone, calcium alone, folic acid, and iron, did not seem to have a significant effect on mortality or cardiovascular outcomes, according to the paper, published yesterday in Annals of Internal Medicine.
Neither do dietary interventions such as the Mediterranean diet, reduced saturated fat intake, modified fat intake, and reduced dietary fat intake.
Meanwhile, supplementation of calcium plus vitamin D might be harmful, the authors argued, as it may increase risk for stroke.
Omega-3 and folate supplements were the only ones which “could reduce risk for some cardiovascular outcomes in adults,” according to the authors. For the dietary interventions, the authors said reduced salt intake may have some positive benefit.
These were the findings from a systematic review of 277 published clinical trials in nearly a million people around the world led by Safi U. Khan, MD, of West Virginia University.
The paper’s other authors were affiliated with Johns Hopkins' Bloomberg School of Public Health and School of Medicine, East Carolina University, Mayo Clinic, Cleveland Clinic, and the Guthrie Robert Packer Hospital.
Holding off on any supplement, diet modification in guidelines?
The study was circulated under embargo to the press last week alongside a link to the abstract, an editorial video with an interview with lead author Dr Khan, and a press release titled ‘Evidence suggests that most nutritional supplements and dietary interventions offer no protection against cardiovascular disease or death.’
The press materials were prepared for and distributed by the American College of Physicians, a national association of internists.
Together with the paper, the journal also published an editorial titled Dispense with Supplements for Improving Heart Outcomes by doctors Amitabh C. Pandey, MD, and Eric J. Topol, MD, of the Scripps Research Translational Institute in California responding to Dr Khan’s team’s paper.
Raising questions about the veracity of the data
Criticisms of the study led by Dr Safi U. Khan focused on the variability of data that the paper referenced.
"Testing any diet or supplement in a broad population without acknowledging interindividual variability seems like a recipe for failure," according to doctors Amitabh C. Pandey, MD, and Eric J. Topol, MD, of the Scripps Research Translational Institute in California in an editorial responding to Dr Khan’s team’s paper.
“Unfortunately, the current study leaves us with the same foggy conditions that we started with,” Drs Pandey and Topol wrote in their editorial.
They were commenting on how Dr Khan’s paper amalgamated data from people and cultures with markedly different diet and supplement baselines.
“Until these conditions clear, it would be reasonable to hold off on any supplement or diet modification in all guidelines and recommendations,” they wrote.
CRN: Study ‘dismisses decades of nutrition research’
“This study is a coordinated, all-out assault on nutrition, and the critical role it plays in maintaining health and reducing the risk of chronic disease,” said Steve Mister, president and CEO of the Council for Responsible Nutrition, a dietary supplement industry trade group, in a statement to press.
His statement addressed the study as well as the editorial materials circulated with it. “Along with a companion editorial and video, this attack recklessly disregards decades of comprehensive carefully developed and well-conducted nutrition research on the benefits of both supplemental nutrients and healthy dietary patterns,” he said.
“The study maligns not only dietary supplements, but also well-established dietary patterns, such as the Mediterranean Diet.”
Excluding observational studies, and ‘ignoring the proper role of supplements’
Moreover, Mister pointed two things he called ‘major limitations’ of the study. The exclusion of epidemiological studies in the researchers’ synthesis was the first. “Epidemiological data are critical and serve as the basis of many recommendations made in the Dietary Guidelines for Americans,” he said.
Secondly, he said that the study ignored the proper role of dietary supplements, which he argued was to fill nutrient gaps.
“Consumers turn to many of these dietary supplements not to reduce their risk of death or prevent heart disease, but rather to fill nutrient gaps in their diets and to maintain health in other ways (e.g., folic acid to prevent birth defects, calcium and vitamin D to prevent falls and fractures, iron to address anemia),” he said.
Omega-3 results ‘not to be generalized to dietary supplement formulations’
The paper by Dr Khan’s team associated intake of omega-3s to reduction of cardiovascular risks in adults, though with low certainty, citing the publication of recent, high-profile studies on the fatty acids.
They characterized the body of clinical science around omega-3 long chain polyunsaturated fatty acids (LC-PUFA) to be ‘conflicting.’ While results from a study nicknamed ASCEND, published in October 2018, did “not find convincing evidence of protective effects of omega03 LC-PUFA for overall cardiovascular benefits,” a similarly large study, VITAL, showed a 19% reduction in cardiovascular outcomes among supplement participants with low dietary fish intake, they wrote.
They also cited the Amarin-sponsored study nicknamed REDUCE-IT, which found a 25% reduction in cardiovascular end points with the use of icosapent ethyl, a modified and highly purified form of EPA.
“It is unclear whether the effects observed in REDUCE-IT are specific for icosapent ethyl or reflect use of the higher dose of omega-3 LC-PUFA,” according to the recent paper.
The authors added that “the results should thus not be generalized to dietary supplement formulations.” They also perpetuated a common misunderstanding by calling supplemental omega-3s ‘unregulated’ compared to drugs (the Food and Drug Administration does regulate omega-3 supplements, but differently than drugs).
The editorial by Drs Pandey and Topol of Scripps noted that Dr Khan’s team’s study concluded “with low certainty, omega-3 fatty acid…[had] a salutary effect on heart attack.”
They added that “recent randomized trials in the general population and in patients with diabetes have failed to confirm any benefit in cardiovascular outcomes. The results of these trials would tend to downgrade the low certainty rating of omega-3 fatty acid supplements to uncertain at best.”
GOED: Omega-3 benefits were downplayed
Dr Khan’s paper provided clear evidence of omega-3s benefits for heart attack and coronary heart disease, according to Harry Rice, PhD, VP of regulatory and scientific affairs at the Global Organization for EPA & DHA Omega-3s.
“Even for cardiovascular mortality, the authors reported a 7% risk reduction, which is similar to what others, as well as GOED's commissioned meta-analysis from a couple of years ago, have reported,” he told us.
“Unfortunately, the results in the present publication were downplayed, because they JUST missed statistical significance.”
Contrary to Drs Topol and Pandey's editorial comments, omega-3s' heart health benefits are well-substantiated, he added.
“[The editorial’s] characterization of omega-3s' benefits as ‘uncertain at best’ is unfortunate. One of the studies cited by them as supporting his opinion is VITAL, and while that study did not achieve the trial’s primary outcome of significantly reducing major CVD events, omega-3s were associated with a 28% risk reduction for heart attack and a 17% risk reduction for coronary heart disease.”