Micronutrient Supplementation to Reduce Cardiovascular Risk

Peng An, PHD; Sitong Wan, BSC; Yongting Luo, PHD; Junjie Luo, PHD; Xu Zhang, MSC; Shuaishuai Zhou, MSC; Teng Xu, MSC; Jingjing He, PHD; Jeffrey I. Mechanick, MD; Wen-Chih Wu, MD, MPH; Fazheng Ren, PHD; Simin Liu, MD, SCD


J Am Coll Cardiol. 2022;80(24):2269-2285. 

In This Article

Abstract and Introduction


Background: Healthy dietary patterns are rich in micronutrients, but their influence on cardiovascular disease (CVD) risks has not been systematically quantified.

Objectives: The goal of this study was to provide a comprehensive and most up-to-date evidence-based map that systematically quantifies the impact of micronutrients on CVD outcomes.

Methods: This study comprised a systematic review and meta-analysis of randomized controlled intervention trials of micronutrients on CVD risk factors and clinical events.

Results: A total of 884 randomized controlled intervention trials evaluating 27 types of micronutrients among 883,627 participants (4,895,544 person-years) were identified. Supplementation with n-3 fatty acid, n-6 fatty acid, l-arginine, l-citrulline, folic acid, vitamin D, magnesium, zinc, α-lipoic acid, coenzyme Q10, melatonin, catechin, curcumin, flavanol, genistein, and quercetin showed moderate- to high-quality evidence for reducing CVD risk factors. Specifically, n-3 fatty acid supplementation decreased CVD mortality (relative risk [RR]: 0.93; 95% 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 coenzyme Q10 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. β-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).

Conclusions: Supplementation of some but not all micronutrients may benefit cardiometabolic health. This study highlights the importance of micronutrient diversity and the balance of benefits and risks to promote and maintain cardiovascular health in diverse populations. (Antioxidant Supplementation in the Prevention and Treatment of Cardiovascular Diseases; CRD42022315165)


A large portion of cardiovascular disease (CVD) and type 2 diabetes (T2D)-related death or disability is attributed to suboptimal dietary practices.[1] Recently, a novel cardiometabolic-based chronic disease model based on staged progression of multiple complex and interacting metabolic drivers of CVD over time, as well as social determinants of health (including transcultural factors), was configured into a 3-dimensional model to expose early and sustainable opportunities for preventive care.[2,3] Lifestyle medicine, based on chronic behavior patterns, has been shown to be a powerful preventive care modality, with good nutrition as a critical foundation.[4]

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.[5] 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.[6] However, population intakes of antioxidant micronutrients from food sources has remained unchanged in the United States in recent decades.[7–10] Survey data also indicated a lack of diversity in the source of antioxidant micronutrients in the typical U.S. diet, suggesting that the health benefits of diverse micronutrients and phytochemicals intake remain obscure and misunderstood by the general public. For example, instead of fruits and vegetables in their natural form, tea and supplements were the major dietary antioxidant sources in supplement users; for nonusers, tea also contributed the most part of dietary antioxidants.[11,12]

Mechanistically, micronutrients such as vitamin C, vitamin D, n-3 fatty acids, magnesium, and phytochemicals benefit cardiometabolic health physiologically by eliminating free radicals and reducing inflammatory and platelet activity, while maintaining the homeostasis of endothelial cells and cardiac function.[13–17] Free radicals also impair β-cell function and insulin sensitivity, contributing to hyperglycemia and insulin resistance, which could further promote the development of CVD.[18,19] Few studies could directly examine the efficacy of antioxidant micronutrients on major CVDs such as stroke or myocardial infarction (MI), which require a long intervention duration to fully capture the developmental processes of these clinical outcomes. Recently, the COSMOS (Cocoa Supplement and Multivitamin Outcomes Study) trial investigators[20,21] reported some favorable effects of polyphenols on CVD risk, although much of the dietary evidence in humans comes from intervention trials of micronutrients on CVD risk factors such as blood pressure, blood lipids, and T2D risk.

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. 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.