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  • Not All Antioxidants Are Equal: Meta-Analysis Suggests Certain Dietary Supplements Benefit Cardiovascular Health

    Supplementation of some, but not all, micronutrients may benefit cardiometabolic health, with omega-3, folic acid and coenzyme Q10 (CoQ10) among the micronutrients that reduce cardiovascular risks, according to a new meta-analysis of more than 800 studies.

    The study, published online Monday and in the Dec. 13 issue of Journal of the American College of Cardiology, analyzed data from more than 880,000 patients taking part in 884 studies to produce a “comprehensive evidence map,” which those behind the study say highlights the importance of micronutrient diversity and the balance of benefits and risks in the design of whole food–based dietary patterns to promote cardiometabolic health.

    The research team, led by Peng An, PhD, and Sitong Wan, BSc, from the China Agricultural University, Beijing, analyzed data from 884 randomized, controlled intervention trials evaluating 27 different types of antioxidant supplements – finding strong evidence that several offered cardiovascular benefit.

    Beneficial supplements included omega-3 fatty acid, which decreased mortality from cardiovascular disease (CVD); folic acid, which lowered stroke risk; and CoQ10, which decreased all-cause mortality, they noted. Meanwhile, omega-6 fatty acid, L-arginine, L-citrulline, vitamin D, magnesium, zinc, alpha-lipoic acid, melatonin, catechin, curcumin, flavanol, genistein and quercetin also showed evidence of reducing cardiovascular risk.

    However, not all supplements were beneficial, the research team noted, revealing that vitamin C, vitamin D, vitamin E and selenium showed no effect on long-term cardiovascular disease outcomes or type-2 diabetes risk, while beta-carotene supplements were linked to increased all-cause mortality.

    “For the first time, we developed a comprehensive, evidence-based integrative map to characterize and quantify micronutrient supplements’ potential effects on cardiometabolic outcomes,” commented study principal investigator Simin Liu, MD, MS, MPH, ScD, from Brown University, in a press release.

    He noted that the findings of the meta-analysis could be used as the basis of future clinical trials to study specific combinations of micronutrients and their impact on cardiovascular health.

    Diet interactions

    The team noted that a large portion of CVD and type 2 diabetes (T2D)-related death or disability is attributed to suboptimal dietary practices and that lifestyle medicine, based on chronic behavior patterns, has been shown to be a powerful preventive care modality – with good nutrition as a critical foundation.

    “The latest scientific statement from the American Heart Association now recommends dietary patterns, including the Mediterranean diet and DASH (the Dietary Approach to Stop Hypertension), as preventive or treatment approaches for CVDs and T2D,” they said.

    “A common feature of these dietary patterns is that they are low in nutrients associated with higher CVD risk such as saturated fat and sodium, and rich in micronutrients such as phytochemicals, unsaturated fatty acids, antioxidant vitamins, and minerals.”

    They added that mechanistically, micronutrients such as vitamin C, vitamin D, omega-3 fatty acids, magnesium, and phytochemicals are suggested to benefit cardiometabolic health physiologically by eliminating free radicals and reducing inflammatory and platelet activity while maintaining the homeostasis of endothelial cells and cardiac function.

    “To personalize cardiometabolic preventive and therapeutic dietary practices, it is of critical importance to have a comprehensive and in-depth understanding of the balance of benefits and risks associated with constituent micronutrients in diverse dietary patterns,” the authors noted.

    “We therefore conducted a systematic review and meta-analyses of all available randomized controlled trials (RCTs), investigating the interventional effect of micronutrients with antioxidant properties on CVD risk factors and events, including the risk of T2D, in diverse populations.”

    Study setup

    The research team set out to compile the most comprehensive and up-to-date evidence-based map to systematically quantify the impact of different micronutrients on CVD outcomes, noting that previous research on supplementation has generally focused on the health effects of a single nutrient or a few vitamins and minerals.

    They pooled data from a total of 884 randomized controlled intervention trials evaluating 27 types of micronutrients, in which 883,627 participants (4,895,544 person-years) were identified.

    “We decided to take a comprehensive and systematic approach to evaluate all the publicly available and accessible studies reporting all micronutrients, including phytochemicals and antioxidant supplements and their effects on cardiovascular risk factors as well as multiple cardiovascular diseases,” said Liu.

    The team reviewed a total of 256 meta-analyses reporting on the effects of a wide variety of micronutrients on blood pressure, blood lipids, blood glucose, all-cause mortality, CVD risks, and T2D risk: “According to the magnitudes and directions, we provided a summary of effects as either ‘benefit,’ ‘harm,’ or ‘neutral,’ and the evidence quality as high/moderate/low/very low.”

    The evidence was graded as high for 3.13% (n = 8), moderate for 74.61% (n = 191), low for 21.09% (n = 54), and very low for 1.17% (n = 3) of all meta-analyses, they said.

    Key findings

    Supplementation with omega-3 fatty acid, omega-6 fatty acid, L-arginine, L-citrulline, folic acid, vitamin D, magnesium, zinc, a-lipoic acid, CoQ10, melatonin, catechin, curcumin, flavanol, genistein, and quercetin showed moderate- to high-quality evidence for reducing CVD risk factors.

    Specifically, omega-3 fatty acid supplementation decreased CVD mortality (relative risk [RR]: 0.93; 95% confidence interval [CI]: 0.88-0.97), myocardial infarction (RR: 0.85; 95% CI: 0.78-0.92), and coronary heart disease events (RR: 0.86; 95% CI: 0.80-0.93).

    Folic acid supplementation decreased stroke risk (RR: 0.84; 95% CI: 0.72-0.97), and CoQ10 supplementation decreased all-cause mortality events (RR: 0.68; 95% CI: 0.49-0.94).

    Vitamin C, vitamin D, vitamin E, and selenium showed no effect on CVD or type 2 diabetes risk. Meanwhile, beta-carotene supplementation increased all-cause mortality (RR: 1.10; 95% CI: 1.05- 1.15), CVD mortality events (RR: 1.12; 95% CI: 1.06-1.18), and stroke risk (RR: 1.09; 95% CI: 1.01-1.17).

    “Our systematic assessment and quantification of multiple differential effects of a wide variety of micronutrients and phytochemicals on cardiometabolic health indicate that an optimal nutritional strategy to promote cardiometabolic health will likely involve personalized combinations of these nutrients,” said the team.

    Polyphenol effects

    The pooled effects of polyphenol intake on individuals with various cardiometabolic health profiles were also assessed, with special emphasis on the quality of evidence that could guide their clinical application for the prevention and control of CVD risk, noted the team.

    For apparently healthy individuals, a median dose of 146.5 mg/d (range 6.5-20,000 mg/d) polyphenol supplementation improved blood lipids including total cholesterol (TC: -0.06 mmol/L [95% CI: -0.12 to -0.01 mmol/L]); high-density lipoprotein cholesterol (0.09 mmol/L [95% CI: 0.03 to 0.14 mmol/L]); and triglycerides (TG: -0.17 mmol/L [95% CI: -0.32 to -0.02 mmol/L]). Furthermore, it was associated with improved fasting blood glucose (FBG: -0.16 mmol/L [95% CI: -0.28 to -0.05 mmol/L]), and fasting blood insulin (FBI: -5.32 pmol/L [95% CI: -9.02 to -1.62 pmol/L]).

    For people with pre-T2D or T2D, a median dose of 261.8 mg/d polyphenols (range 25–1,344 mg/d) improved blood glucose including hemoglobin A1C (A1C: -0.19% [95% CI: -0.35% to -0.02%]) and FBG (-0.46 mmol/L [95% CI: -0.67 to -0.25 mmol/L]). Benefits were also seen for blood lipids (TC -0.20 mmol/L [95% CI: -0.33 to -0.07 mmol/L]); TG (-0.27 mmol/L [95% CI: -0.46 to -0.07 mmol/L]); and HDL–C (0.12 mmol/L [95% CI: 0.05 to 0.19 mmol/L]), and blood pressure (systolic blood pressure: -4.54 mm Hg [95% CI: -7.14 to -1.93 mm Hg]).

    Pleiotropic effects

    Writing in an accompanying editorial comment, Juan G. Gormaz, PhD, from the University of Chile, Santiago, and Rodrigo Carrasco, MD, PhD, of the Chilean Society of Cardiology and Cardiovascular Surgery, said the meta-analysis found that moderate to high evidence of event reduction correlated with those substances that, in addition to antioxidant capacity, have important pleiotropic effects.

    “By contrast, supplementation with some ‘antioxidants par excellence’ such as vitamins C and E did not show effects, and beta-carotene increased all-cause mortality,” they noted.

    The editorialists noted that to date, analysis of other well-designed trials and pre-clinical research studies has led to a suggestion that supplementation with pure free radical scavengers may not be sufficient to bring about beneficial effects in prevention models, with only compounds able to have an impact on oxidative stress through more than one pathway and/or that have pleiotropic properties suggested to have a significant clinical effect.

    “This view is also supported by several basic research studies that have shown that high loads of some free radical scavengers may propagate oxidative stress rather than attenuate it,” they said.

    The expert commentators noted that the current meta-analysis provides evidence to support this hypothesis: “Their results indicate that supplementation benefits for cardiovascular prevention would be proportional to the level of pleiotropic effects of the administered substances.”

    However, they warned that while from a research point of view the current study opens interesting perspectives for future consolidation of some antioxidants in preventive cardiology, “there is still a long way to go in terms of generating evidence.”


    An P, Wan S, Luo Y, et al. Micronutrient Supplementation to Reduce Cardiovascular Risk. J Am Coll Cardiol 2022;80:2269-2285.

    Gormaz JG, Carrasco R. Antioxidant Supplementation in Cardiovascular Prevention: New Challenges in the Face of New Evidence. J Am Coll Cardiol 2022;80:2286-2288.

    Image Credit: ronstik –

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