JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
24, 2022
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VOL. 80, NO.
ª 2022 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
PUBLISHED BY ELSEVIER
Micronutrient Supplementation to
Reduce Cardiovascular Risk
Peng An, PHD,a,* Sitong Wan, BSC,a,* Yongting Luo, PHD,a Junjie Luo, PHD,a Xu Zhang, MSC,a Shuaishuai Zhou, MSC,a
Teng Xu, MSC,a Jingjing He, PHD,a Jeffrey I. Mechanick, MD,b Wen-Chih Wu, MD, MPH,c,d,e Fazheng Ren, PHD,a
Simin Liu, MD, SCDc,d,e
ABSTRACT
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, a-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. b-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 Cardio-
vascular Diseases; CRD42022315165) (J Am Coll Cardiol 2022;80:2269–2285) © 2022 by the American College of
Cardiology Foundation.
From the aDepartment of Nutrition and Health, Beijing Advanced Innovation Center for Food Nutrition and Human Health, Key
Laboratory of Precision Nutrition and Food Quality, China Agricultural University, Beijing, China; bKravis Center for Clinical
Cardiovascular Health at Mount Sinai Heart, Icahn School of Medicine at Mount Sinai, New York, New York, USA; cCenter
for Global Cardiometabolic Health, Department of Epidemiology, Brown University, Providence, Rhode Island, USA; dDepartment
of Medicine, Brown University, Providence, Rhode Island, USA; and the eDepartment of Surgery, Brown University, Providence,
Rhode Island, USA. *Dr An and Ms Wan contributed equally to this work.
Hector Ventura, MD, served as Guest Associate Editor for this paper. Christopher O’Connor, MD, served as Guest Editor-in-Chief
for this paper.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’
institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information,
visit the Author Center.
Manuscript received September 20, 2022; accepted September 28, 2022.
ISSN 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2022.09.048
2270 An et al
Micronutrients to Reduce Cardiovascular Risk
A
ABBREVIATIONS large portion of cardiovascular dis-
AND ACRONYMS ease (CVD) and type 2 diabetes
(T2D)-related death or disability is
A1C = hemoglobin A1C
attributed to suboptimal dietary practices.1
CVD = cardiovascular disease
Recently, a novel cardiometabolic-based
DBP = diastolic blood pressure
chronic disease model based on staged pro-
FBG = fasting blood glucose gression of multiple complex and interacting
FBI = fasting blood insulin metabolic drivers of CVD over time, as well as
HDL-C = high-density social determinants of health (including
lipoprotein cholesterol
transcultural factors), was configured into a
LDL-C = low-density 3-dimensional model to expose early and
lipoprotein cholesterol
sustainable opportunities for preventive
MI = myocardial infarction
care.2,3 Lifestyle medicine, based on chronic
RCT = randomized controlled
behavior patterns, has been shown to be a
trial
powerful preventive care modality, with
RR = relative risk
good nutrition as a critical foundation.4
SBP = systolic blood pressure
SEE PAGE 2286
T2D = type 2 diabetes
TC = total cholesterol The latest scientific statement from the
TG = triglyceride American Heart Association now recom-
mends dietary patterns, including the Mediterranean
diet and DASH (the Dietary Approach to Stop Hyper-
tension), 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 so-
dium, and rich in micronutrients such as phyto-
chemicals, unsaturated fatty acids, antioxidant
vitamins, and minerals.6 However, population in-
takes of antioxidant micronutrients from food sour-
ces 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 micro-
nutrients in the typical U.S. diet, suggesting that the
health benefits of diverse micronutrients and phyto-
chemicals intake remain obscure and misunderstood
by the general public. For example, instead of fruits
and vegetables in their natural form, tea and sup-
plements were the major dietary antioxidant sources
in supplement users; for nonusers, tea also contrib-
uted the most part of dietary antioxidants.11,12
Mechanistically, micronutrients such as vitamin C,
vitamin D, n-3 fatty acids, magnesium, and phyto-
chemicals benefit cardiometabolic health physiologi-
cally 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 b -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 micro-
nutrients on major CVDs such as stroke or myocardial
infarction (MI), which require a long intervention
JACC VOL. 80, NO. 24, 2022
DECEMBER 13, 2022:2269–2285
duration to fully capture the developmental pro-
cesses of these clinical outcomes. Recently, the
COSMOS (Cocoa Supplement and Multivitamin Out-
comes 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 impor-
tance to have a comprehensive and in-depth under-
standing of the balance of benefits and risks
associated with constituent micronutrients in diverse
dietary patterns. We therefore conducted a system-
atic review and meta-analyses of all available ran-
domized controlled trials (RCTs), investigating the
interventional effect of micronutrients with antioxi-
dant properties on CVD risk factors and events,
including the risk of T2D, in diverse populations.
METHODS
This review was performed in adherence with the
Preferred Reporting Items for Systematic Reviews
and Meta-Analyses guidelines 22 and registered at the
International Prospective Register of Systematic Re-
views (PROSPERO: CRD42022315165). RCTs included
in this meta-analysis had ethics approval from their
respective Institutional Review Boards. 单
SEARCH STRATEGY. The PubMed, Web of Science,
and Embase databases were searched to identify RCTs
published up to May 1, 2022, that used antioxidant
micronutrients to improve cardiovascular risk factors
and CVD event occurrence rates (Supplemental
Appendix 1). Articles assessing the effects of these
micronutrients on systolic blood pressure (SBP), dia-
stolic blood pressure (DBP), low-density lipoprotein
cholesterol (LDL-C), high-density lipoprotein choles-
terol (HDL-C), total cholesterol (TC), triglyceride (TG),
hemoglobin A1C (A1C), fasting blood glucose (FBG),
fasting blood insulin (FBI), all-cause mortality, CVD
mortality, MI, stroke, coronary heart disease,
arrhythmia, and T2D risk were included for further
review (Supplemental Appendices 2 and 3).
STATISTICAL ANALYSIS. Effect sizes of CVD out-
comes were obtained by using a random effects
model and are expressed here as the weighted mean
difference and 95% CI or as the relative risk (RR) and
95% CI. Mean differences with a P value <0.05 were
considered statistically significant. RevMan version
5.4 (The Cochrane Collaboration) and Stata/SE
version 17.0 (StataCorp) were used to perform all
statistical analyses (Supplemental Appendices 4 to 7).
JACC VOL. 80, NO. 24, 2022 An et al 2271
DECEMBER 13, 2022:2269–2285 Micronutrients to Reduce Cardiovascular Risk

F I G U R E 1 Flowchart of Study Selection

Search of published Search of RCTs

systematic reviews 7,026 articles identified
n = 276 in PubMed PubMed, n = 2,589
Web of Science, n = 2,331
Embase, n = 2,106

Eligible systematic reviews

n = 84
Duplication removal
consisting of 441 articles
n = 3,613

Title and abstract screening

n = 3,854

Excluded based on title and abstract

n = 2,341

Full-text review, n = 1,513

Articles excluded
No randomization, n = 361
No relevant outcome, n = 275
Studies with short intervention duration, n = 58
Studies on CVD risk factors were performed
in patients with severe cardiometabolic
disorders, n = 68

Articles included
n = 751, consisting of 884 RCTs

The PubMed, Web of Science, and the Embase databases were searched to identify randomized controlled trials (RCTs) that used antioxidant
micronutrients to improve cardiovascular disease (CVD) risk factors, CVD, and type 2 diabetes event occurrence rates. Based on the
predefined eligibility criteria, a total of 884 RCTs were included.

RESULTS of micronutrients were included in the current study

(Supplemental Appendix 2).
STUDY SELECTION AND CHARACTERISTICS OF
INCLUDED TRIALS. The selection process of this EFFECTS OF MICRONUTRIENT SUPPLEMENTATION
study is summarized as a flowchart in Figure 1. A total ON BLOOD PRESSURE. Twenty-five of the micro-
of 884 RCTs involving 883,627 participants nutrients studied were assessed for effects of sup-
(4,895,544 person-years) studying 27 different types plementation on SBP and DBP (Figure 2). Seven of
2272 An et al
Micronutrients to Reduce Cardiovascular Risk
these lowered both SBP and DBP levels, including
L -arginine (median dose 6 g/d; range 1.3-30 g/d),
L -citrulline (median dose 6 g/d; range 2-6 g/d), folic
acid (median dose 5 mg/d; range 0.25-15 mg/d),
magnesium (median dose 400 mg/d;
200-729 mg/d), a -lipoic acid (median dose 600 mg/d;
range 100-2,400 mg/d), genistein (median dose
54 mg/d; range 50-90 mg/d), and resveratrol (median
dose 390 mg/d; range 75-3,000 mg/d). The blood
pressure–lowering effects were comparable in per-
sons receiving L -arginine (SBP
4.51 mm Hg [95% CI:

6.64 to
2.37 mm Hg], DBP
2.31 mm Hg [95% CI:

3.64 to
0.98 mm Hg]), L -citrulline

3.10 mm Hg [95% CI:
5.25 to
0.95 mm Hg], DBP

3.37 mm Hg [95% CI:
5.14 to
1.59 mm Hg]),
folic acid (SBP
2.74 mm Hg [95% CI:
4.50
to
0.98 mm Hg], DBP
1.56 mm Hg [95% CI:
2.38 to

0.74 mm Hg]), magnesium (SBP
4.91 mm Hg [95%
CI:
8.04 to
1.78 mm Hg], DBP
2.75 mm Hg [95%
CI:
4.51 to
0.99 mm Hg]), a -lipoic acid (SBP

6.02 mm Hg [95% CI:
9.73 to
2.31 mm Hg], DBP

3.73 mm Hg [95% CI:
6.02 to
1.44 mm Hg]),
genistein (SBP
10.02 mm Hg [95% CI:
11.55
to
8.49 mm Hg], DBP
9.13 mm Hg [95% CI:
12.80
to
5.46 mm Hg]), and resveratrol (SBP
3.26 mm Hg
[95% CI:
6.36 to
0.16 mm Hg], DBP
2.04 mm Hg
[95% CI:
3.93 to
0.15 mm Hg]).
EFFECTS OF MICRONUTRIENT SUPPLEMENTATION
ON BLOOD LIPIDS. Twenty-six of the micronutrients
studied were assessed for effects of supplementation
on blood lipid levels (Figures 3 and 4). Seven micro-
nutrients improved multiple blood lipid parameters:
anthocyanin, folic acid, n-6 fatty acid, n-3 fatty-acid,
genistein, magnesium, and zinc. Supplementation of
a median dose of 160 mg/d anthocyanin (range
1.65-1,024 mg/d) improved LDL-C (
0.18 mmol/L [95%
CI:
0.31 to
0.06 mmol/L]), TC (
0.18 mmol/L [95%
CI:
0.33 to
0.02 mmol/L]), HDL-C (0.18 mmol/L
[95% CI: 0.12 to 0.25 mmol/L]), and TG (
0.47 mmol/L
[95% CI:
0.70 to
0.24 mmol/L]). Supplementation of
a median dose of 5 mg/d folic acid (range 0.25-15 mg/d)
improved LDL-C (
0.33 mmol/L [95% CI:
0.43 to

0.23 mmol/L]), TC (
0.17 mmol/L [95% CI:
0.30 to

0.04 mmol/L]), and TG (
0.79 mmol/L [95% CI:
1.42
to
0.15 mmol/L]). Supplementation of a median
dose of 4.25 g/d n-6 fatty acid (range 1-20 g/d)
improved LDL-C (
0.19 mmol/L [95% CI:
0.35 to

0.03 mmol/L]), TC (
0.24 mmol/L [95% CI:
0.37 to

0.11 mmol/L]), and HDL-C (0.04 mmol/L [95% CI:
0.01 to 0.07 mmol/L]). Supplementation of a median
dose of 54 mg/d genistein (range 50-90 mg/d)
improved LDL-C (
0.43 mmol/L [95% CI:
0.81 to

0.04 mmol/L]) and TC (
0.22 mmol/L [95% CI:
0.35
JACC VOL. 80, NO. 24, 2022
DECEMBER 13, 2022:2269–2285
to
0.08 mmol/L]). Supplementation of a median dose
of 400 mg/d magnesium (range 200-729 mg/d)
improved TG (
0.14 mmol/L [95% CI:
0.26 to

0.02 mmol/L]) and HDL-C (0.04 mmol/L [95% CI:
range 0.01 to 0.07 mmol/L]). Supplementation of a median
dose of 30 mg/d zinc (range 5-200 mg/d) improved TC
(
0.34 mmol/L [95% CI:
0.52 to
0.16 mmol/L]) and
TG (
0.28 mmol/L [95% CI:
0.45 to
0.11 mmol/L]).
EFFECTS OF MICRONUTRIENT SUPPLEMENTATION
ON BLOOD GLUCOSE. Twenty-two of the micro-
nutrients studied were assessed for effects of sup-
plementation on blood glucose (Figures 5 and 6). Eight
(SBP micronutrients lowered multiple glycemic parame-
ters: curcumin, zinc, L-arginine, folic acid, vitamin D,
catechin, flavanol, and genistein. Curcumin decreased
A1C (
0.55% [95% CI:
0.99% to
0.12%]), FBG
(
0.44 mmol/L [95% CI:
0.70 to
0.18 mmol/L]), and
FBI (
8.45 pmol/L [95% CI:
10.45 to
6.44 pmol/L]).
Zinc decreased A1C (
0.56% [95% CI:
0.97% to

0.16%]), FBG (
0.71 mmol/L [95% CI:
1.35 to

0.07 mmol/L]), and FBI (
22.79 pmol/L [95% CI:

38.43 to
7.15 pmol/L]). L –arginine decreased FBG
(
0.22 mmol/L [95% CI:
0.42 to
0.02 mmol/L]) and
FBI (
11.33 pmol/L [95% CI:
21.65 to
1.02 pmol/L]).
Folic acid decreased FBG (
0.07 mmol/L [95% CI:

0.15 to 0.00 mmol/L]) and FBI (
25.73 pmol/L [95%
CI:
36.41 to
15.04 pmol/L]). Vitamin D decreased
A1C (
0.10% [95% CI:
0.15% to
0.04%]) and FBG
(
0.12 pmol/L [95% CI:
0.23 to
0.02 pmol/L]).
Catechin decreased A1C (
0.12% [95% CI:
0.23% to

0.02%]) and FBG (
0.10 pmol/L [95% CI:
0.17 to

0.03 pmol/L]). Flavanol decreased FBG
(
0.19 mmol/L [95% CI:
0.33 to
0.05 mmol/L]) and
FBI (
14.86 pmol/L [95% CI:
21.02 to
8.71 pmol/L]).
Genistein decreased FBG (
0.44 mmol/L [95% CI:

0.52 to
0.37 mmol/L]) and FBI (
11.61 pmol/L [95%
CI:
15.40 to
7.82 pmol/L]).
EFFECTS OF POLYPHENOL SUPPLEMENTATION AMONG
INDIVIDUALS WITH DIFFERENT CARDIOMETABOLIC
HEALTH PROFILES. Subgroup analysis of polyphenol
supplementation was performed in participants with
different cardiometabolic health profiles (Figure 7).
For apparently healthy individuals, a median dose of
146.5 mg/d (range 6.5-20,000 mg/d) polyphenol
supplementation improved blood lipids (TC

0.06 mmol/L [95% CI:
0.12 to
0.01 mmol/L]),
HDL–C (0.09 mmol/L [95% CI: 0.03 to 0.14 mmol/L]),
TG (
0.17 mmol/L [95% CI:
0.32 to
0.02 mmol/L]),
and blood glucose (FBG
0.16 mmol/L [95% CI:
0.28
to
0.05 mmol/L]), and 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 (A1C
0.19%
JACC VOL. 80, NO. 24, 2022 An et al 2273
DECEMBER 13, 2022:2269–2285 Micronutrients to Reduce Cardiovascular Risk

F I G U R E 2 Effects of Antioxidant Micronutrients on Blood Pressure

Micronutrient Outcome Study N (Int/Con) WMD [95% CI] Blood Pressure I2 Egger’s Test GRADE Score

n-3 fatty acid Systolic BP 55 2,950/2,933 —1.21 [—3.08 to 0.65] 0.98 0.085 Moderatea
Diastolic BP 51 2,705/2,694 —0.28 [—1.14 to 0.59] 0.89 0.161 Moderatea
n-6 fatty acid Systolic BP 15 593/596 0.47 [—1.85 to 2.78] 0.82 0.579 Moderatea
Diastolic BP 14 573/576 —0.31 [—2.32 to 1.70] 0.90 0.677 Moderatea
L-arginine Systolic BP 25 644/641 —4.51 [–6.64 to —2.37] 0.76 0.179 Moderateb
Diastolic BP 23 510/507 —2.31 [–3.64 to —0.98] 0.75 0.311 Moderateb
L-citrulline Systolic BP 13 158/161 —3.10 [–5.25 to —0.95] 0.41 0.795 Moderatea
Diastolic BP 13 158/161 —3.37 [–5.14 to —1.59] 0.64 0.121 Lowa,b

Folic acid Systolic BP 18 4,775/4,843 –2.74 [—4.50 to —0.98] 0.91 0.039 Lowa,b
Diastolic BP 16 4,750/4,818 –1.56 [—2.38 to —0.74] 0.78 0.101 Lowa,b
Vitamin C Systolic BP 12 479/480 —0.62 [—1.84 to 0.60] 0.00 0.442 Moderatea
Diastolic BP 11 284/285 —0.66 [—2.87 to 1.55] 0.61 0.945 Moderatea
Vitamin C + E Systolic BP 2 97/99 —5.45 [—11.03 to 0.13] 0.00 - Moderatea
Diastolic BP 2 97/99 —3.38 [—7.54 to 0.78] 0.00 - Moderatea

Vitamin D Systolic BP 32 2,664/2,698 —0.69 [—1.55 to 0.18] 0.64 0.047 Moderatea

Diastolic BP 32 2,668/2,698 —0.48 [—1.07 to 0.11] 0.50 0.094 Moderatea
Vitamin E Systolic BP 18 418/411 —3.48 [—8.82 to 1.86] 0.96 0.053 Moderatea
Diastolic BP 14 302/295 —0.15 [—1.29 to 0.98] 0.56 0.107 Moderatea

α-lipoic acid Systolic BP 10 431/433 —6.02 [–9.73 to —2.31] 0.48 0.147 High
Diastolic BP 10 431/442 —3.73 [–6.02 to —1.44] 0.67 0.301 Lowa,b
Coenzyme Q10 Systolic BP 19 504/508 —3.55 [—6.70 to —0.41] 0.66 0.556 Lowa,b
Diastolic BP 18 539/490 —0.92 [—3.08 to 1.25] 0.70 0.914 Moderateb
Lycopene Systolic BP 15 499/462 —1.95 [–3.54 to —0.36] 0.63 0.859 Very lowa,b,c
Diastolic BP 1 333/296 —1.12 [—2.84 to 0.61] 0.22 0.281 Lowa,c
Melatonin Systolic BP 9 223/201 —1.97 [—5.72 to 1.78] 0.55 0.329 Moderatea
Diastolic BP 7 179/157 —0.53 [—2.76 to 1.70] 0.31 0.629 Moderatea
Selenium Systolic BP 2 61/62 0.57 [—2.11 to 3.26] 0.00 - Moderatea
Diastolic BP 2 61/62 —0.54 [—2.30 to 1.22] 0.00 - Moderatea
Magnesium Systolic BP 15 414/424 —4.91 [—8.04 to —1.78] 0.61 0.490 Lowa,b
Diastolic BP 15 414/424 —2.75 [—4.51 to —0.99] 0.55 0.564 Lowa,b
Zinc Systolic BP 7 252/267 —1.82 [—3.97 to 0.34] 0.00 0.942 Moderatea
Diastolic BP 7 252/267 —0.85 [—2.19 to 0.49] 0.00 0.916 Moderatea
Anthocyanin Systolic BP 29 717/708 —0.43 [—1.82 to 0.96] 0.80 0.733 Moderatea
Diastolic BP 28 633/681 —0.57 [—1.87 to 0.74] 0.86 0.279 Moderatea
Catechin Systolic BP 28 894/865 —0.61 [—1.55 to 0.32] 0.13 0.618 Moderatea
Diastolic BP 26 804/779 —0.79 [—1.61 to 0.02] 0.39 0.345 Moderatea
Curcumin Systolic BP 13 426/426 —1.16 [—2.19 to —0.14] 0.17 0.128 Moderatea
Diastolic BP 12 421/413 —0.02 [—1.27 to 1.23] 0.67 0.187 Moderatea

Flavanol Systolic BP 19 534/508 —1.47 [—2.89 to —0.06] 0.81 0.018 Lowa,b

Diastolic BP 17 456/439 —0.86 [—1.99 to 0.28] 0.71 0.065 Moderatea
Flavonoid Systolic BP 11 345/339 —1.73 [—4.15 to 0.69] 0.66 0.280 Lowa,b
Diastolic BP 11 345/340 —1.68 [—3.34 to —0.03] 0.70 0.225 Very lowa,b,c
Genistein Systolic BP 2 71/71 —10.02 [—11.55 to —8.49] 0.00 – High
Diastolic BP 2 71/71 —9.13 [—12.80 to —5.46] 0.34 – High

Hesperidin Systolic BP 5 137/128 1.01 [—0.70 to 2.72] 0.00 0.733 Moderatea

Diastolic BP 4 125/116 —1.39 [—3.92 to 1.14] 0.79 0.345 Moderatea

Isoflavone Systolic BP 24 898/901 —0.87 [—2.32 to 0.59] 0.34 0.855 Moderatea

Diastolic BP 24 944/944 —0.54 [—1.47 to 0.40] 0.47 0.571 Moderatea

Quercetin Systolic BP 13 300/298 —1.38 [—2.63 to —0.13] 0.00 0.435 Moderatea

Diastolic BP 13 300/298 —1.11 [—2.25 to 0.02] 0.00 0.574 Moderatea

Resveratrol Systolic BP 18 412/414 —3.26 [—6.36 to —0.16] 0.85 0.489 Lowa,b

Diastolic BP 18 412/414 —2.04 [—3.93 to —0.15] 0.80 0.060 Lowa,b

–10 –5 0 5 10 mm Hg
Micronutrient vs Control

Twenty-five micronutrients were assessed for the supplemental effects on systolic blood pressure (BP) and diastolic BP. aRated down for
imprecision. bRated down for inconsistency. cRated down for risk of bias. GRADE ¼ Grading of Recommendations, Assessment, Development
and Evaluation; Int/Con ¼ intervention/control; WMD ¼ weighted mean difference.
2274 An et al JACC VOL. 80, NO. 24, 2022

Micronutrients to Reduce Cardiovascular Risk DECEMBER 13, 2022:2269–2285

F I G U R E 3 Effects of Antioxidant Micronutrients on Blood Lipids

Micronutrient Outcome Study N (Int/Con) WMD [95% CI] Blood Lipid I2 Egger's Test GRADE Score

n-3 fatty acid TC 54 1,836/1,779 —0.05 [—0.19 to 0.08] 0.88 0.250 Moderatea
LDL-C 54 2,097/2,004 0.03 [—0.08 to 0.15] 0.95 0.332 Moderatea
TG 57 2,105/2,077 —0.33 [—0.42 to —0.24] 0.86 0.719 Moderateb
HDL-C 58 2,172/2,133 0.21 [0.14 to 0.29] 0.98 0.232 Moderateb

n-6 fatty acid TC 18 547/403 —0.24 [—0.37 to —0.11] 0.03 0.871 High
LDL-C 17 520/526 —0.19 [—0.35 to —0.03] 0.65 0.318 Lowa,b
TG 17 354/343 —0.17 [—0.55 to 0.22] 0.91 0.422 Moderatea
HDL-C 19 587/593 0.04 [0.01 to 0.07] 0.00 0.744 Moderatea

n-9 fatty acid TC 10 200/200 —0.05 [—0.22 to 0.13] 0.90 0.825 Moderatea
LDL-C 11 247/218 —0.06 [—0.16 to 0.04] 0.41 0.021 Moderatea
TG 11 218/218 0.05 [0.00 to 0.10] 0.00 0.485 Moderatea
HDL-C 11 218/218 —0.01 [—0.03 to 0.02] 0.00 0.183 Moderatea

L-arginine TC 15 311/313 —0.05 [—0.22 to 0.11] 0.00 0.840 Moderatea

LDL-C 14 267/269 —0.09 [—0.25 to 0.07] 0.00 0.665 Moderatea
TG 19 503/505 —0.16 [—0.36 to 0.04] 0.00 0.658 Moderatea
HDL-C 16 401/403 0.05 [—0.18 to 0.28] 0.52 0.273 Moderatea

L-citrulline TC 2 44/44 —0.15 [—0.36 to 0.07] 0.00 - Moderatea

LDL-C 2 44/44 —0.09 [—0.26 to 0.08] 0.00 - Moderatea
TG 2 44/44 —0.07 [—0.20 to 0.06] 0.00 - Moderatea
HDL-C 2 44/44 —0.10 [—0.25 to 0.04] 0.00 - Moderatea

Folic acid TC 16 4,590/4,654 —0.17 [—0.30 to —0.04] 0.75 0.040 Lowa,b

LDL-C 12 297/296 —0.33 [—0.43 to —0.23] 0.08 0.136 High
TG 16 515/510 —0.79 [—1.42 to —0.15] 0.97 0.031 Moderateb
HDL-C 15 491/490 —0.01 [—0.04 to 0.01] 0.32 0.908 Moderatea

Vitamin C TC 15 436/444 —0.19 [—0.48 to 0.10] 0.86 0.276 Moderatea

LDL-C 12 170/179 0.03 [—0.26 to 0.32] 0.86 0.444 Moderatea
TG 15 246/257 —0.06 [—0.34 to 0.23] 0.60 0.356 Moderatea
HDL-C 16 437/446 0.03 [0.00 to 0.06] 0.00 0.387 Moderatea

Vitamin C + E TC 2 73/73 0.00 [—0.40 to 0.41] 0.00 - Moderatea

LDL-C 2 73/73 —0.01 [—0.28 to 0.27] 0.00 - Moderatea
TG 2 73/73 0.00 [—0.25 to 0.26] 0.00 - Moderatea
HDL-C 2 73/73 0.10 [—0.17 to 0.37] 0.84 - Moderatea

Vitamin D TC 38 2,077/1,973 —0.07 [—0.17 to 0.03] 0.71 0.529 Moderatea

LDL-C 39 2,221/2,143 —0.03 [—0.15 to 0.08] 0.90 0.953 Moderatea
TG 40 2,204/2,204 —0.01 [—0.10 to 0.08] 0.87 0.093 Moderatea
HDL-C 39 2,221/2,143 0.02 [—0.01 to 0.05] 0.65 0.023 Moderatea

Vitamin E TC 22 505/508 —0.20 [—0.56 to 0.16] 0.99 0.024 Moderatea

LDL-C 21 463/455 —0.02 [—0.26 to 0.22] 0.88 0.505 Moderatea
TG 16 404/416 —0.16 [—0.36 to 0.05] 0.90 0.142 Moderatea
HDL-C 16 433/425 0.02 [—0.04 to 0.08] 0.57 0.616 Moderatea

α-lipoic acid TC 9 431/452 —0.16 [—0.82 to 0.50] 0.90 0.688 Moderatea

LDL-C 3 74/80 —0.45 [—1.30 to 0.40] 0.88 0.282 Moderatea
TG 6 256/268 —0.28 [—0.65 to 0.09] 0.91 0.590 Moderatea
HDL-C 7 306/313 0.01 [0.00 to 0.03] 0.09 0.487 Moderatea

Coenzyme Q1O TC 12 276/267 —0.81 [—1.64 to 0.03] 0.98 0.003 Lowa,b

LDL-C 15 352/356 —0.57 [—1.31 to 0.16] 0.99 0.229 Moderatea
TG 16 354/347 —0.25 [—0.34 to —0.17] 0.00 0.819 High
HDL-C 16 354/346 0.02 [—0.02 to 0.06] O.14 0.625 Moderatea

Lycopene TC 2 149/149 0.00 [—0.22 to 0.22] 0.00 - Lowa,c

LDL-C 4 197/176 —0.01 [—0.17 to 0.16] 0.00 0.146 Lowa,c
TG 2 149/152 —0.02 [—0.15 to 0.10] 0.00 - Lowa,c
HDL-C 4 197/176 —0.03 [—0.12 to 0.06] 0.00 0.573 Lowa,c

Melatonin TC 6 136/134 —0.46 [—0.76 to —0.17] 0.00 0.088 High

LDL-C 7 184/165 —0.20 [—0.54 to 0.15] 0.72 0.545 Moderatea
TG 7 184/166 —0.35 [—0.96 to 0.26] 0.76 0.461 Moderatea
HDL-C 5 152/133 0.05 [—0.04 to 0.14] 0.00 0.612 Moderatea

Selenium TC 12 510/505 —0.08 [—0.19 to 0.03] 0.00 0.199 Moderatea

LDL-C 11 500/495 —0.03 [—0.19 to 0.14] 0.36 0.186 Moderatea
TG 11 500/495 0.03 [—0.28 to 0.34] 0.49 0 663 Moderatea
HDL-C 15 815/810 —0.03 [—0.08 to 0.02] 0.54 0.551 Moderatea

Magnesium TC 12 349/353 0.01 [—0.11 to 0.12] 0.00 0.654 Moderatea

LDL-C 10 319/322 —0.06 [—0.21 to 0.09] 0.11 0.996 Moderatea
TG 15 448/454 —0.14 [—0.26 to —0.02] 0.10 0.121 Moderatea
HDL-C 15 448/454 0.04 [0.01 to 0.07] 0.04 0.732 Moderatea

Zinc TC 22 809/832 —0.34 [—0.52 to —0.16] 0.78 0.045 Moderateb

LDL-C 20 798/822 —0.01 [—0.08 to 0.07] 0.09 0.246 Moderatea
TG 21 818/842 —0.28 [—0.45 to —0.11] 0.76 0.071 Moderateb
HDL-C 23 836/860 0.01 [—0.08 to 0.09] 0.91 0.634 Moderatea

–0.5 –0.25 0 0.25 0.5 mmol/L

Micronutrient vs Control

Seventeen micronutrients were assessed for the supplemental effects on total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C),
triglyceride (TG), and high-density lipoprotein cholesterol (HDL-C). aRated down for imprecision. bRated down for inconsistency. cRated
down for risk of bias. See Figure 2 for other abbreviations.
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F I G U R E 4 Effects of Antioxidant Micronutrients (Polyphenols) on Blood Lipids

Micronutrient Outcome Study N (Int/Con) WMD [95% CI] Blood Lipid I 2 Egger's Test GRADE Score

Anthocyanin TC 36 1,045/1,009 —0.18 [–0.33 to —0.02] 0.88 0.065 Lowa,b

LDL-C 34 976/940 —0.18 [–0.31 to —0.06] 0.87 0.976 Lowa,b
TG 34 994/958 —0.47 [–0.70 to —0.24] 0.96 0.009 Moderateb
HDL-C 35 1,010/980 0.18 [0.12 to 0.25] 0.94 0.026 Moderateb

Catechin TC 26 855/830 —0.11 [—0.18 to —0.04] 0.00 0.290 Moderatea

LDL-C 26 865/845 —0.06 [—0.15 to 0.02] 0.30 0.588 Moderatea
TG 28 900/875 —0.03 [—0.11 to 0.05] 0.15 0.144 Moderatea
HDL-C 27 882/861 —0.00 [—0.02 to 0.02] 0.00 0.883 Moderatea

Curcumin TC 12 365/407 —0.01 [—0.18 to 0.17] 0.06 0.683 Moderatea

LDL-C 15 500/499 —0.12 [—0.31 to 0.07] 0.85 0.101 Moderatea
TG 14 480/484 —0.20 [—0.45 to 0.06] 0.97 0.154 Moderatea
HDL-C 17 517/520 0.42 [0.24 to 0.59] 0.96 0.004 Moderateb

Flavanol TC 17 492/480 —0.03 [—0.10 to 0.04] 0.51 0.640 Moderatea

LDL-C 17 492/480 —0.23 [—0.67 to 0.21] 1.00 0.021 Moderatea
TG 17 499/486 —0.02 [—0.10 to 0.07] 0.80 0.217 Moderatea
HDL-C 17 499/486 0.08 [0.04 to 0.13] 0.73 0.020 Lowa,b

Flavonoid TC 4 120/93 —0.21 [—0.63 to 0.21] 0.47 0.457 Lowa,c

LDL-C 3 80/78 —0.16 [—0.31 to —0.01] 0.00 0.942 Lowa,c
TG 4 120/117 —0.26 [—0.84 to 0.33] 0.52 0.363 Lowa,c
HDL-C 4 120/117 0.04 [—0.03 to 0.10] 0.00 0.586 Lowa,c

Genistein TC 9 589/589 —0.22 [—0.35 to —0.08] 0.27 0.563 Moderatea

LDL-C 9 580/589 —0.43 [—0.81 to —0.04] 0.93 0.620 Lowa,b
TG 10 656/660 —0.10 [—0.32 to 0.11] 0.89 0.441 Moderatea
HDL-C 10 656/630 0.12 [—0.01 to 0.24] 0.96 0.857 Lowa,b

Hesperidin TC 6 149/139 —0.24 [—0.50 to 0.02] 0.37 0.053 Moderatea

LDL-C 6 150/139 —0.15 [—0.30 to 0.01] 0.00 0.018 Moderatea
TG 6 150/139 —0.26 [—0.59 to 0.07] 0.56 0.053 Moderatea
HDL-C 5 137/127 0.04 [—0.11 to 0.19] 0.54 0.307 Moderatea

Isoflavone TC 24 904/924 —0.14 [—0.31 to 0.02] 0.78 0.972 Lowa,b

LDL-C 25 987/1,011 0.10 [—0.15 to 0.35] 0.95 0.363 Moderatea
TG 25 988/1,012 —0.05 [—0.12 to 0.02] 0.30 0.231 Moderatea
HDL-C 26 1,014/1,036 —0.02 [—0.08 to 0.04] 0.80 0.902 Moderatea

Quercetin TC 13 505/499 —0.04 [—0.17 to 0.08] 0.00 0.890 Moderatea

LDL-C 13 505/499 —0.03 [—0.14 to 0.08] 0.00 0.940 Moderatea
TG 13 505/499 —0.06 [—0.21 to 0.08] 0.21 0.163 Moderatea
HDL-C 13 505/499 0.03 [—0.03 to 0.09] 0.22 0.284 Moderatea

Resveratrol TC 13 315/313 —0.19 [—0.51 to 0.13] 0.71 0.818 Moderatea

LDL-C 11 266/265 0.22 [—0.39 to 0.83] 0.94 0.395 Moderatea
TG 15 338/347 —0.18 [—0.52 to 0.17] 0.44 0.895 Moderatea
HDL-C 12 292/290 0.02 [—0.07 to 0.11] 0.52 0.135 Moderatea

–1 –0.5 0 0.5 1 mmol/L

Micronutrient vs Control

Ten polyphenols were assessed for the supplemental effects on TC, LDL-C, TG, and HDL-C. aRated down for imprecision. bRated down for inconsistency.
c
Rated down for risk of bias. See Figures 2 and 3 for abbreviations.
2276 An et al JACC VOL. 80, NO. 24, 2022

Micronutrients to Reduce Cardiovascular Risk DECEMBER 13, 2022:2269–2285

F I G U R E 5 Effects of Antioxidant Micronutrients on Hemoglobin A1C and Fasting Blood Glucose

Micronutrient Study N (Int/Con) WMD [95% CI] Hemoglobin A1c I2 Egger's Test GRADE Score

n-3 fatty acid 21 751/734 —0.03 [—0.15 to 0.08] 0.88 0.571 Lowa,c
L-arginine 7 247/246 —0.15 [—0.32 to 0.01] 0.52 0.843 Lowa,b
Folic acid 6 108/121 —0.06 [—0.27 to 0.15] 0.69 0.000 Moderatea
Vitamin C 15 355/360 —0.25 [—0.51 to 0.02] 0.90 0.053 Lowa,b
Vitamin D 27 1,604/1,591 —0.10 [—0.15 to —0.04] 0.94 0.613 Lowa,b
Vitamin E 9 225/232 —0.43 [—0.72 to —0.14] 0.79 0.081 Lowa,b
α-lipoic acid 7 227/237 —0.30 [—0.66 to 0.06] 0.83 0.781 Moderatea
Coenzyme Q10 8 182/184 —0.18 [—0.29 to —0.07] 0.00 0.324 Moderatea
Selenium 2 54/54 0.45 [—0.49 to 1.40] 0.70 - Moderatea
Magnesium 10 277/303 0.04 [—0.23 to 0.32] 0.51 0.077 Moderatea
Zinc 8 254/270 —0.56 [—0.97 to —0.16] 0.86 0.260 Very lowa,b,c
Anthocyanin 9 291/291 0.00 [—0.09 to 0.10] 0.78 0.711 Moderateb
Catechin 9 315/308 —0.12 [—0.23 to —0.02] 0.71 0.320 Lowb,c
Curcumin 7 266/266 —0.55 [—0.99 to —0.12] 0.81 0.181 Lowb,c
Flavanol 3 92/82 —0.10 [—0.40 to 0.20] 0.68 0.934 Moderateb
Isoflavone 5 73/74 —0.00 [—0.25 to 0.24] 0.26 0.309 Moderateb
Resveratrol 12 314/315 —0.06 [—0.16 to 0.05] 0.63 0.446 Moderateb

–1 –0.5 0 0.5 1 %
Micronutrient vs Control

Micronutrient Study N (Int/Con) WMD [95% CI] Fasting Blood Glucose I2 Egger's Test GRADE Score

n-3 fatty acid 34 987/1,033 0.08 [—1.33 to 1.49] 1.00 0.523 Moderatea
n-6 fatty acid 2 67/67 0.22 [—0.19 to 0.63] 0.74 - Lowa,c
L-arginine 10 362/359 —0.22 [—0.42 to —0.02] 0.80 0.078 Lowa,b
Folic acid 16 6,989/7,033 —0.07 [—0.15 to 0.00] 0 66 0.071 Lowa,b
Vitamin C 16 435/440 —0.45 [—0.96 to 0.05] 0.94 0.613 Lowa,b
Vitamin D 32 2,646/2,512 —0.12 [—0.23 to –0.02] 0.91 0.192 Lowa,b
Vitamin E 12 282/282 0.00 [—0.09 to 0.09] 0.00 - Moderatea
α-lipoic acid 7 223/211 —0.27 [—0.65 to 0.12] 0.96 0.161 Moderatea
Coenzyme Q10 9 216/207 —0.46 [—1.00 to 0.07] 0.86 0.407 Lowa,b
Melatonin 8 218/201 —0.11 [—0.30 to 0.08] 0.45 0.137 Moderatea
Selenium 6 184/184 0.02 [—0.59 to 0.63] 0.84 0.596 Moderatea
Magnesium 10 262/268 —0.22 [—0.52 to 0.07] 0.83 0.840 Moderatea
Zinc 20 598/628 —0.71 [—1.35 to —0.07] 0.99 0.020 Lowa,b
Anthocyanin 30 799/776 —0.09 [—0.17 to —0.02] 0.76 0.173 Lowb,c
Catechin 27 1,020/1,004 —0.10 [—0.17 to —0.03] 0.80 0.233 Lowb,c
Curcumin 12 419/425 —0.44 [—0.70 to —0.18] 0.77 0.147 Lowb,c
Flavanol 14 344/331 —0.19 [—0.33 to —0.05] 0.95 0.884 Lowb,c
Genistein 7 410/426 —0.44 [—0.52 to —0.37] 0.95 0.102 Lowb,c
Hesperidin 6 168/157 0.01 [—0.12 to O.14] 0.45 0.545 Moderateb
Isoflavone 12 496/520 —0.05 [—0.24 to 0.13] 0.76 0.216 Moderateb
Quercetin 10 330/324 —0.02 [—0.14 to 0.09] 0.88 0.791 Moderateb
Resveratrol 20 461/472 —2.66 [—5.54 to 0.22] 1.00 0.139 Lowb,c

–1 –0.5 0 0.5 1 mmol/L

Micronutrient vs Control

Twenty-two micronutrients were assessed for the supplemental effects on hemoglobin A1C and fasting blood glucose. aRated down for
imprecision. bRated down for inconsistency. c
Rated down for risk of bias. See Figure 2 for abbreviations.
JACC VOL. 80, NO. 24, 2022 An et al 2277
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F I G U R E 6 Effects of Antioxidant Micronutrients on Fasting Blood Insulin

Micronutrient Study N (Int/Con) WMD [95% CI] Fasting Blood Insulin I2 Egger's Test GRADE Score

n-3 fatty acid 20 708/704 —4.99 [—21.94 to 11.97] 0.99 0.137 Moderatea

L-arginine 4 117/117 —11.33 [—21.65 to —1.02] 0.90 0.021 Moderatea

Folic acid 10 256/254 —25.73 [—36.41 to —15.04] 0.85 0.028 Moderateb

Vitamin C 4 51/48 —9.78 [—39.78 to 20.23] 0.93 0.035 Moderateb

Vitamin D 22 2,206/2,051 —2.96 [—8.23 to 2.32] 0.84 0.828 Moderateb

Vitamin E 6 189/186 —2.62 [—11.35 to 6.11] 0.92 0.022 Moderatea

α-lipoic acid 2 61/53 2.37 [—10.34 to 15.08] 0.00 - Moderatea

Coenzyme Q10 6 133/128 —10.69 [—44.32 to 22.94] 0.97 0.299 Moderatea

Melatonin 5 218/161 —7.81 [—16.78 to 1.15] 0.42 0.125 Moderatea

Selenium 5 154/154 —17.56 [—48.09 to 12.98] 0.87 0.279 Moderatea

Magnesium 11 345/339 —1.94 [—7.25 to 3.36] 0.43 0.061 Moderatea

Zinc 12 305/329 —22.79 [—38.43 to —7.15] 0.82 0.199 Moderateb

Anthocyanin 15 446/451 4.34 [—0.74 to 9.43] 0.80 0.272 Lowb,c

Catechin 19 741/732 0.05 [—1.11 to 1.21] 0.92 0.061 Moderateb

Curcumin 5 149/153 —8.45 [—10.45 to —6.44] 0.00 0.673 High

Flavanol 8 197/187 —14.86 [—21.02 to —8.71] 0.86 0.837 Moderatec

Genistein 7 414/422 —11.61 [—15.40 to —7.82] 0.97 0.306 Moderatec

Hesperidin 5 137/128 0.63 [—5.06 to 6.32] 0.54 0.290 Moderateb

Isoflavone 11 475/500 —1.63 [—10.61 to 7.35] 0.84 0.156 Moderateb

Quercetin 3 115/115 —8.09 [—15.53 to —0.66] 0.09 0.328 Moderateb

Resveratrol 15 324/332 —5.72 [—11.63 to 0.19] 0.90 0.886 Lowb,c

–30 –20 –10 0 10 20 30 pmol/L

Micronutrient vs Control

Twenty-one micronutrients were assessed for the supplemental effects on fasting blood insulin. aRated down for imprecision. bRated down for inconsistency. cRated
down for risk of bias. See Figure 2 for abbreviations.

[95% CI:
0.35% to
0.02%]) and FBG (
0.46 mmol/L to
1.93 mm Hg]). For patients with dyslipidemia, a
[95% CI:
0.67 to
0.25 mmol/L]), blood lipids (TC median dose of 130 mg/d polyphenols (range

0.20 mmol/L [95% CI:
0.33 to
0.07 mmol/L]), TG 45-400 mg/d) improved blood lipids LDL-C
(
0.27 mmol/L [95% CI:
0.46 to
0.07 mmol/L]), and (
0.79 mmol/L [95% CI:
1.17 to
0.40 mmol/L]),
HDL–C (0.12 mmol/L [95% CI: 0.05 to 0.19 mmol/L]), HDL-C (0.19 mmol/L [95% CI: 0.14 to 0.25 mmol/L]),
and blood pressure (SBP
4.54 mm Hg [95% CI:
7.14 TC (
0.77 mmol/L [95% CI:
1.27 to
0.28 mmol/L]),
 2278
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An et al
F I G U R E 7 Effects of Polyphenol Supplementation Among Individuals With Different Cardiometabolic Health Profiles

Median Blood Pressure Blood Lipid Blood Glucose

Median Dose
Cardiometabolic Duration Low–Density High–Density
[Range], Systolic Diastolic Total Fasting Blood
Health Profile [Range], Lipoprotein Lipoprotein Triglyceride Hemoglobin Fasting Blood
mg/d Blood Pressure Blood Pressure Cholesterol Glucose
month Cholesterol Cholesterol A1c Insulin

146.5 1.38 –0.59 –0.61 –0.06 –0.00 0.09 –0.17 –0.13 –0.16 –5.32
Healthy
[6.5 to 20,000] [0.23 to 24] [–1.50 to 0.32] [–1.32 to 0.11] [–0.12 to –0.01] [–0.12 to 0.11] [0.03 to 0.14] [–0.32 to –0.02] [–0.36 to 0.10] [–0.28 to –0.05] [–9.02 to –1.62]

Postmenopausal 70 2.76 –0.85 –0.47 –0.12 –0.09 0.04 0.09 –0.10 –0.15 –4.77
Women [10 to 1,315] [0.92 to 36] [–1.68 to –0.02] [–1.02 to 0.08] [–0.38 to 0.14] [–0.35 to 0.17] [–0.05 to 0.13] [–0.08 to 0.26] [–0.31 to 0.10] [–0.35 to 0.05] [–10.98 to 1.45]

350 1.84 –2.18 –1.10 –0.03 0.03 –0.03 –0.04 0.06 2.21
Hypertension
[54 to 1,024] [0.46 to 6] [–3.78 to –0.57] [–2.10 to –0.10] [–0.17 to 0.10] [–0.07 to 0.13] [–0.08 to 0.03] [–0.17 to 0.10] [–0.20 to 0.31] [–2.96 to 7.39]

130 2.76 –2.05 –0.58 –0.77 –0.79 0.19 –0.53 –0.19

Dyslipidemia
[45 to 400] [0.46 to 6] [–7.85 to 3.74] [–2.57 to 1.42] [–1.27 to –0.28] [–1.17 to –0.40] [0.14 to 0.25] [–1.00 to –0.06] [–0.24 to –0.13]

Overweight/ 270 2.76 –1.36 –0.74 –0.11 –0.14 0.05 –0.07 0.00 –0.04 –1.55
Obesity [1.65 to 3,000] [0.46 to 12] [–2.41 to –0.31] [–1.73 to 0.26] [–0.26 to 0.04] [–0.44 to 0.17] [0.00 to 0.09] [–0.17 to 0.03] [–0.06 to 0.06] [–0.08 to 0.00] [–3.19 to 0.08]

261.8 2 –4.54 –1.70 –0.20 –0.01 0.12 –0.27 –0.19 –0.46 –3.04
Pre–T2D/T2D
[25 to 1,344] [0.92 to 48] [–7.14 to –1.93] [–4.35 to 0.95] [–0.33 to –0.07] [–0.23 to 0.21] [0.05 to 0.19] [–0.46 to –0.07] [–0.35 to –0.02] [–0.67 to –0.25] [–7.20 to 1.12]

Metabolic 432 2.76 –1.12 –1.66 –0.15 –0.24 0.06 –0.18 0.04 –0.08 0.42
Syndrome [54 to 2,400] [0.69 to 12] [–3.39 to 1.16] [–3.89 to 0.58] [–0.32 to 0.01] [–0.41 to –0.06] [0.02 to 0.10] [–0.34 to –0.02] [–0.02 to 0.10] [–0.23 to 0.06] [–3.64 to 4.48]

Benefit Neutral GRADE High Moderate Low Very Low

DECEMBER 13, 2022:2269–2285

Subgroup analysis of polyphenol supplementation was performed in healthy persons, postmenopausal women, and persons with hypertension, dyslipidemia, overweight/obesity, pre–type 2 diabetes (T2D)/T2D, or metabolic

JACC VOL. 80, NO. 24, 2022

syndrome.
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F I G U R E 8 Effects of Antioxidant Micronutrients on Clinical CVD and T2D Risks

Micronutrient Event Study N (Int/Con) Relative Risk [95% CI] I 2 Egger's Test GRADE Score

n-3 fatty acid All-cause mortality 23 70,508/70,438 0.97 [0.93 to 1.00] 0.28 0.696 Moderatea
CVD mortality 17 62,914/62,916 0.93 [0.88 to 0.97] 0.48 0.441 Moderatea
Arrhythmia 6 5,555/5,577 0.79 [0.65 to 0.96] 0.48 0.380 Moderatea
Myocardial Infarction 12 45,652/45,639 0.85 [0.78 to 0.92] 0.37 0.948 Moderatea
Stroke 8 41,191/41,181 1.06 [0.96 to 1.18] 0.00 0.013 Moderatea
Coronary heart disease 5 30,111/30,104 0.86 [0.80 to 0.93] 0.00 0.653 Moderatea
Type 2 diabetes 18 38,455/38,356 0.92 [0.85 to 0.99] 0.54 0.682 Moderatea

n-6 fatty acid Type 2 diabetes 2 1,046/1,041 1.99 [0.18 to 21.92] 0.00 - Moderatea

Folic acid All-cause mortality 10 12,792/12,788 0.89 [0.78 to 1.01] 0.23 0.342 Moderatea
CVD mortality 5 11,235/11,233 0.86 [0.65 to 1.13] 0.00 0.004 Moderatea
Myocardial Infarction 6 12,112/12,098 1.29 [0.93 to 1.80] 0.04 0.072 Moderatea
Stroke 7 12,268/12,257 0.84 [0.72 to 0.97] 0.00 0.706 Moderatea

Vitamin C All-cause mortality 4 8,020/7,984 1.02 [0.94 to 1.11] 0.00 0.311 Moderatea
CVD mortality 3 7,870/7,867 1.07 [0.92 to 1.25] 0.00 0.116 Moderatea
Myocardial Infarction 2 7,760/7,737 0.96 [0.81 to 1.14] 0.06 - Moderatea
Stroke 2 7,760/7,737 0.92 [0.78 to 1.09] 0.00 - Moderatea

Vitamin D All-cause mortality 63 34,056/33,909 0.99 [0.95 to 1.04] 0.00 0.281 Moderatea
CVD mortality 9 17,513/17,618 1.00 [0.85 to 1.18] 0.00 0.484 Moderatea
Myocardial Infarction 19 23,135/23,034 0.94 [0.84 to 1.06] 0.00 0.345 Moderatea
Stroke 16 23,172/22,943 1.09 [0.95 to 1.24] 0.00 0.163 Moderatea
Coronary heart disease 10 823/710 0.71 [0.29 to 1.69] 0.00 0.617 Moderatea

Vitamin E All-cause mortality 5 22,967/22,989 1.01 [0.96 to 1.06] 0.00 0.834 Moderatea
CVD mortality 5 22,967/22,956 1.00 [0.92 to 1.08] 0.00 0.076 Moderatea
Myocardial Infarction 5 22,967/22,989 1.00 [0.93 to 1.08] 0.00 0.516 Moderatea
Stroke 5 22,967/22,989 1.05 [0.95 to 1.16] 0.34 0.512 Moderatea
Type 2 diabetes 2 10,159/10,144 1.01 [0.88 to 1.15] 0.47 - Moderatea

β-carotene All-cause mortality 6 82,941/82,941 1.10 [1.05 to 1.15] 0.65 0.680 Lowa,b
CVD mortality 12 151,640/151,640 1.12 [1.06 to 1.18] 0.40 0.380 Lowa,b
Myocardial Infarction 7 93,272/93,272 0.99 [0.93 to 1.05] 0.02 0.428 Moderatea
Stroke 6 105,775/105,775 1.09 [1.01 to 1.17] 0.73 0.065 Lowa,b
Type 2 diabetes 4 22,704/27,736 0.98 [0.87 to 1.09] 0.00 0.205 Moderatea

Coenzyme Q10 All-cause mortality 7 904/923 0.68 [0.49 to 0.94] 0.00 0.347 Moderatea

Selenium All-cause mortality 12 22,118/20,820 0.96 [0.88 to 1.05] 0.00 0.890 Moderatea
CVD mortality 5 18,849/18,620 0.97 [0.83 to 1.14] 0.05 0.916 Moderatea
Myocardial Infarction 3 724/721 0.87 [0.59 to 1.30] 0.36 0.796 Moderatea
Stroke 3 18,444/18,453 1.06 [0.87 to 1.29] 0.00 0.412 Moderatea
Coronary heart disease 3 724/641 0.89 [0.64 to 1.23] 0.34 0.629 Moderatea

0.5 0.7 1 1.5 2

Micronutrient vs Control

Eight micronutrients studied were assessed for the supplemental effects on all-cause mortality, CVD mortality, coronary heart disease, arrhythmia, myocardial
infarction, stroke, and T2D events. aRated down for imprecision. bRated down for inconsistency. See Figures 1, 2, and 7 for other abbreviations.

and TG (
0.53 mmol/L [95% CI:
1.00 to
0.06 mmol/
L]) and blood glucose (FBG
0.19 mmol/L [95% CI:

0.24 to
0.13 mmol/L]). For patients with hyper-
tension, a median dose of 350 mg/d polyphenols
(range 54-1,024 mg/d) decreased blood pressure (SBP

2.18 mm Hg [95% CI:
3.78 to
0.57 mm Hg] and DBP

1.10 mm Hg [95% CI:
2.10 to
0.10 mm Hg]). Lastly,
a median dose of 432 mg/d polyphenols (range
54-2,400 mg/d) improved the blood lipid profile of
patients with metabolic syndrome (LDL-C
0.24
 2280
F I G U R E 9 An Evidence-Based Map of Micronutrient Supplementation on Cardiometabolic Health

Randomized Controlled Trials on Randomized Controlled Trials on

Blood Pressure Blood Lipid Blood Glucose

Micronutrients to Reduce Cardiovascular Risk

An et al
CVD Risk Factors CVD and Type 2 Diabetes Events
Coronary
Antioxidant All-Cause CVD Myocardial Type 2
Stroke Heart Arrhythmia
Micronutrient Systolic Diastolic Low-Density High-Density Fasting Fasting Mortality Mortality Infarction Diabetes
Median Duration Total Hemoglobin Median Duration Disease
Median Dose [Range] Blood Blood Lipoprotein Lipoprotein Triglyceride Blood Blood Median Dose [Range]
[Range], Month Cholesterol Cholesterol Cholesterol A1c [Range], Year
Pressure Pressure Glucose Insulin

n-3 2 g/d [0.28-9.50 g/d] 3 [0.69-60] 1.8 g/d [0.27-5.5 g/d] 2 [0.5-7.4]

Fatty Acid n-6 4.25 g/d [1-20 g/d] 2.07 [0.69-24] 2 g/d [1.9-5.5 g/d] 3.33 [1-3.33]

n-9 1.38 [0.46-1.84]

L-arginine 6 g/d [1.3-30 g/d] 1.50 [0.23-30]

Amino Acid
L-citrulline 6 g/d [2-6 g/d] 1.15 [0.23-1.84]

Folic Acid 5 mg [0.25-15 mg] 1.84 [0.23-53.85] 3 mg/d [0.5-15 g/d] 3.25 [1-8]

Vitamin C 500 mg/d [50-3,000 mg/d] 1.84 [0.33-60] 500 mg/d [500-500 mg/d] 7.6 [3.0-9.4]

1,400 mg/d
Vitamin Vitamin C + E 3 [1.84-5.52]
[300-1,400 mg/d]

Vitamin D 3,410 IU/d 3 [1.38-84] 1,350 IU/d

1.75 [0.46-5.5]
[40-120,000 IU/d] [10-100,000 IU/d]

Vitamin E 400 mg/d [3-1,800 mg/d] 2 [0.69-72] 400 mg/d [50-600 mg/d] 7.5 [3.6-10]

Magnesium 400 mg/d [200-729 mg/d] 2.76 [1-6]

Mineral Selenium 200 μg/d [100-960 μg/d] 2.76 [1.38-6] 200 μg/d [100-200 μg/d] 3.5 [0.5-7.6]

Zinc 30 mg/d [5-200 mg/d] 2 [0.92-12]

α-Lipoic Acid 600 mg/d

2.96 [1.84-16.57]
[100-2,400 mg/d]
β-carotene 20 mg/d [6-50 mg/d] 6.1 [2-19]
Antioxidant 2.76 [0.56- 6] 50 mg/d [33.3-100 mg/d]
Coenzyme Q10 300 mg/d [60-1,200 mg/d] 0.25 [0.25-10]
Supplement
Lycopene 15 mg/d [5-30 mg/d] 2 [1.38-6]

Melatonin 5 mg/d [1-24 mg/d] 1.84 [0.46-12]

Anthocyanin 160 mg/d

1.84 [0.46-6]
[1.65-1,024 mg/d]
Catechin 456 mg/d [20-1,344 mg/d] 2.76 [0.46-12]

Curcumin 500 mg/d

2.76 [2.38-5.52]
[80-2,400 mg/d]

Flavanol 805 mg/d

1.18 [0.46-11.97]
[6.5-20,000 mg/d]

Flavonoid 4.14 [0.46-12]

Polyphenol
Genistein 54 mg/d [50-90 mg/d] 6 [2.76-36]

Hesperidin 500 mg/d [290-500 mg/d] 2.76 [0.69-3]

Isoflavone 66 mg/d [10-165 mg/d] 2.76 [0.46-48]

Quercetin 150 mg/d [50-1,000 mg/d] 1.38 [0.23-2.76]

Resveratrol 390 mg/d [75-3,000 mg/d] 2.76 [0.92-6.44]

Cardiometabolic
Direction Evidence Quality
Health
Decrease Benefit High Quality

Increase Benefit Moderate Quality

DECEMBER 13, 2022:2269–2285

JACC VOL. 80, NO. 24, 2022
Increase Harm Low Quality
Unchanged Neutral Very Low Quality

The effects of 27 antioxidants on blood pressure, blood lipids, blood glucose, all-cause mortality, CVD risks, and type 2 diabetes risk were summarized. Specific micronutrient supplementation doses and intervention durations
based on the evidence were provided. See Figures 1 and 2 for abbreviations.
JACC VOL. 80, NO. 24, 2022 An et al 2281
DECEMBER 13, 2022:2269–2285 Micronutrients to Reduce Cardiovascular Risk

C ENTR AL I LL U STRA T I O N A Comprehensive Heat Map Summarizing Micronutrient Supplementation on

Cardiometabolic Health

Effects of Antioxidant Micronutrient on Cardiovascular Disease Risk Factors

Blood Pressure Blood Lipid Blood Glucose

Micronutrient Low-Density High-Density

Systolic Diastolic Total Hemoglobin Fasting Fasting
Lipoprotein Lipoprotein Triglyceride
Blood Pressure Blood Pressure Cholesterol A1c Blood Glucose Blood Insulin
Cholesterol Cholesterol
n-3
Fatty acid n-6
n-9
L-arginine
Amino acid
L-citrulline
Folic acid
Vitamin C
Vitamin Vitamin C+E
Vitamin D
Vitamin E
Magnesium
Mineral Selenium
Zinc
α-lipoic acid
Antioxidant Coenzyme Q10
supplement Lycopene
Melatonin
Anthocyanin
Catechin
Curcumin
Flavanol
Flavonoid
Polyphenol
Genistein
Hesperidin
Isoflavone
Quercetin
Resveratrol

Cardiometabolic
Effects of Antioxidant Micronutrient on Cardiovascular Disease and Type 2 Diabetes Events Direction Health
Cardiovascular Decrease Benefit
All-Cause Disease Myocardial Coronary Type 2
Micronutrient Mortality Infarction Stroke Heart Disease Arrhythmia Diabetes
Mortality Increase Benefit
n-3 Increase Harm
Fatty acid
n-6
Unchanged Neutral
Folic acid

Vitamin C Evidence Quality

Vitamin
Vitamin D High Quality
Vitamin E
Moderate Quality
Mineral Selenium

β-carotene
Low Quality
Antioxidant
supplement
Coenzyme Q10 Very Low Quality

An P, et al. J Am Coll Cardiol. 2022;80(24):2269–2285.

Evidence-based maps summarizing 256 meta-analyses of 884 randomized controlled trials investigating the interventional effects of 27 antioxidant micronutrients on
cardiovascular disease risk factors (top) and cardiovascular disease and type 2 diabetes events (bottom) according to the direction of causation, effect, and evidence
quality.

[95% CI:
0.41 to
0.06 mmol/L], HDL-C 0.06 mmol/L
[95% CI: 0.02 to 0.10 mmol/L], and TG
0.18 mmol/L
[95% CI:
0.34 to
0.02 mmol/L]).
EFFECTS OF MICRONUTRIENT SUPPLEMENTATION
ON CLINICAL CVD AND T2D EVENTS. Eight micro-
nutrients studied were assessed for effects of
supplementation on CVD events (Figure 8). In a me-
dian duration of 3-year intervention, 27,823 all-cause
mortality events, 15,593 CVD mortality events, 11,202
MIs, 8,276 strokes, 2,656 coronary heart disease
events, and 409 arrhythmia events were recorded in
804,955 individuals. Supplementation of coenzyme
2282 An et al
Micronutrients to Reduce Cardiovascular Risk
Q10 (median dose 50 mg/d; range 33.3-100 mg/d)
reduced all-cause mortality (RR: 0.68; 95% CI: 0.49-
0.94) in 7 trials performed in heart failure patients.
A median dose of 1.8 g/d (range 0.27-5.5 g/d) n-3 fat-
ty acid reduced the risks of CVD mortality (RR: 0.93;
95% CI: 0.88-0.97), MI (RR: 0.85; 95% CI: 0.78-0.92),
and coronary heart disease (RR: 0.86; 95% CI: 0.80-
0.93). Folic acid supplementation (median dose 3 mg/
d; range 0.5-15 mg/d) reduced the risk of stroke (RR:
0.84; 95% CI: 0.72-0.97). Vitamin C, vitamin D,
vitamin E, and selenium supplementation showed no
effect on CVD events. In contrast, a median dose of
20 mg/d b-carotene (range 6-50 mg/d) increased the
risk of all-cause mortality (RR: 1.10; 95% CI: 1.05-1.15),
CVD mortality (RR: 1.12; 95% CI: 1.06-1.18), and stroke
(RR: 1.09; 95% CI: 1.01-1.17).
n-3 fatty acid, n-6 fatty acid, vitamin E, and
b-carotene were assessed for the effects of supple-
mentation on T2D risk reduction. A total of 4,058
cases of T2D occurred in 134,368 individuals during a
median 2-year intervention; however, there was no
clinically significant effect on T2D incidence.
A COMPREHENSIVE EVIDENCE-BASED MAP. We
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 (Figure 9). The evidence was graded as high for
3.13% (n ¼ 8), moderate for 74.61% (n ¼ 191), low for
21.09% (n ¼ 54), and very low for 1.17% (n ¼ 3) of all
meta-analyses. According to the benefits on CVD
events and risk factors, n-3 fatty acid (3 events and
2 risk factors), folic acid (1 event and 7 risk factors),
and coenzyme Q10 (1 event and 3 risk factors) ranked
top for CVD prevention. Improved effects on multiple
CVD risk factors were observed in genistein (6 risk
factors), zinc (5 risk factors), anthocyanin (5 risk
factors), curcumin (5 risk factors), flavanol (4 risk
factors), L-arginine (4 risk factors), magnesium (4 risk
factors), n-6 fatty acid (3 risk factors), and a -lipoic
acid (3 risk factors). In contrast, b-carotene supple-
mentation increased the risks of 3 CVD events, and
n-9 fatty acid increased the level of TG.
DISCUSSION
Our systematic assessment and quantification of mul-
tiple differential effects of a wide variety of micro-
nutrients and phytochemicals on cardiometabolic
health indicate that an optimal nutritional strategy to
promote cardiometabolic health will likely involve
JACC VOL. 80, NO. 24, 2022
DECEMBER 13, 2022:2269–2285
personalized combinations of these nutrients (Central
Illustration).
Previously, several systematic reviews have re-
ported inconsistent findings regarding the effects of
different nutrients on clinical outcomes such as
mortality or major cardiovascular events.23-26 The
current study represents the first attempt in
providing a comprehensive and most up-to-date evi-
dence map that systematically assessed the quality
and quantity of all RCTs linking the effects of a wide
variety of micronutrients on CVD risk factors, and
clinical CVD and T2D outcomes. The pooled effects of
polyphenol intake on individuals with various car-
diometabolic health profiles were also assessed, with
special emphasis on the quality of evidence that
could guide their clinical application for the preven-
tion and control of CVD risk. For high-risk in-
dividuals, supplementation of n-3 fatty acid and folic
acid seemed to have significant benefits for reducing
both CVD risk factors and CVD risks,25,27,28 and evi-
dence from a meta-analysis study favors the supple-
mentation of eicosapentaenoic acid alone rather than
the combination with docosahexaenoic acid for CVD
prevention.27 The current updated meta-analysis
supports the notion that a median dose of 1.8 g/d n-
3 fatty acid may have the optimal benefit in lowering
risk of MI, coronary heart disease, and CVD mortality,
probably through improving TG and HDL levels.
Similarly, n-6 fatty acid supplementation improved
TC, LDL-C, and HDL-C, but there were insufficient
data to assess an effect on the risk of CVD. Because
folic acid, L -arginine, and L -citrulline are directly
involved in nitric oxide production, these micro-
nutrients have been shown to help maintain vaso-
dilation and/or redox balance in the cardiovascular
system.15 Consistent with previous reports linking
folic acid supplementation to decreased stroke and
total CVD risk in high-risk populations, 24-26 the cur-
rent meta-analysis also indicated that folic acid
supplementation improved blood pressure, blood
lipids, and blood glucose and reduced MI risk in
diverse populations. These and other published re-
sults support the recommendation of folic acid
supplementation for CVD prevention, particularly in
countries or regions where folic acid fortification is
not implemented.
In 7 trials of coenzyme Q10 supplementation in
heart failure patients, there seemed to be some ben-
efits in reducing total mortality. However, there were
insufficient data to assess its effect on CVD events.
Further trials directly assessing its clinical efficacy on
lipids, glucose, and blood pressures along with clin-
ical CVD outcomes are warranted. In contrast,
b -carotene supplementation was found to increase
JACC VOL. 80, NO. 24, 2022
DECEMBER 13, 2022:2269–2285
stroke and CVD mortality risks in this analysis,
consistent with previous work linking supplementa-
tion of $30 mg/d b -carotene to increased all-cause
mortality.29 The harmful effect of serum b-carotene
levels on CVD risk was recently reported in patients
with T2D, in whom higher serum b-carotene levels
were associated with increased CVD mortality in a
dose-dependent manner during an average 14 years
of follow-up. 30 In several trials investigating the
interventional effect of b-carotene, vitamin E and/or
vitamin C were investigated in parallel with b-caro-
tene. Vitamin E seemed to decrease A1C but showed
no effect on CVD and T2D risk. Vitamin C supple-
mentation seemed to increase HDL-C, but no effect
was found on CVD risks. Although there were insuf-
ficient data to assess the effect of vitamin C on T2D,
results from the Women’s Antioxidant Cardiovascular
Study indicated that vitamin C supplementation had
no effect on T2D risk during a median follow-up of
9.2 years.31
Very few studies investigated polyphenol supple-
mentation for the prevention of CVDs or T2D. In
the COSMOS trial, flavanol-enriched cocoa extract
was shown to reduce CVD mortality during 3.6 years’
follow-up (HR: 0.73; 95% CI: 0.54-0.98). 21 The cur-
rent meta-analysis supports the cardiometabolic
benefits of polyphenol supplementation. Others have
also found cardiometabolic improvement effects of
anthocyanin, 32 catechin,33,34 curcumin,35 flavanol,36
genistein,37 and quercetin.38,39 We observed that
resveratrol supplementation decreased SBP and DBP
in the current meta-analysis, which was inconclusive
in a previously published meta-analysis that
included patients with severe cardiometabolic-based
chronic diseases. 40 In contrast to previous meta-an-
alyses,41,42 isoflavone supplementation was shown
to have no influence on blood pressure or blood
lipids.
STUDY LIMITATIONS. First, some of the intervention
trials had short durations (eg, <1 month), chal-
lenging any simple inference for a long-term impact
on CVD risk factors. Second, low-quality evidence
accounted for >20% of the meta-analyses included,
highlighting the importance for better design and
execution of future trials; after excluding those
studies, however, much of the main findings per-
sisted, affirming the robustness of the evidence.
Third, there was a relative paucity of trial data
investigating the effects of micronutrients on the
incidence of CVDs or T2D, especially for poly-
phenols. Fourth, several inconsistencies existed in
the updated results with previous meta-analysis due
to different inclusion criteria. This inconsistency
may simply be due to the different inclusion criteria
An et al 2283
Micronutrients to Reduce Cardiovascular Risk
and the diversity of intervention substances used in
these trials. In the current study, intervention sub-
stances were restricted to relatively pure phyto-
chemical supplements. Nevertheless, we urge
caution regarding the interpretation of findings
linking the cardiovascular benefits of isoflavones
from polyphenol-rich foods as we cannot separate
the influences of other co-ingested substances in fi-
bers, proteins, or minerals. Fourth, the effect of
antioxidant mixture was not assessed. Some micro-
nutrients may be needed in combination to be
effective, such as selenium. In contrast to antioxi-
dant mixture without selenium, supplementation of
antioxidant mixture with selenium reduced CVD and
all-cause mortality risks.43 Fifth, due to insufficient
RCTs, some micronutrients were not included in
current analysis. For example, copper and manga-
nese, which form part of the endogenous antioxi-
dant system together with zinc and selenium (ie,
superoxide dismutases and glutathione peroxi-
dases), were not included. Finally, the median dose
of included RCTs does not correspond to an optimal
dose for clinical effects. For instance, the median
intervention dose of folic acid (5 mg/d) in included
trials is much higher than the recommended dose of
0.4 mg/d, which could reach 90% of folic acid’s
maximal reduction effect on plasma homocysteine.44
In certain situations, antioxidant micronutrients
may be harmful (eg, b-carotene supplementation
increased lung cancer risk in smokers).45 Thus, spe-
cific antioxidant supplementation doses and inter-
vention durations are another important
consideration before generalizing these results to
other populations in which different dietary patterns
predominantly exist in various populations globally.
Any whole food–based recommendations regarding
dietary patterns that incorporate these evidence-
based micronutrient supplementation doses
will need proper cultural adaptation and
then validation.46
CONCLUSIONS
Supplementation of some but not all micronutrients
may benefit cardiometabolic health outcomes in
diverse populations. The comprehensive evidence
map presented here 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, which
may require cultural adaptations to apply globally.
The micronutrients identified require further valida-
tion in large, high-quality interventional trials to
establish clinical efficacy (eg, the COSMOS trial20,21,47)
2284 An et al JACC VOL. 80, NO. 24, 2022

Micronutrients to Reduce Cardiovascular Risk DECEMBER 13, 2022:2269–2285

to determine their long-term balance of risks and the advisory boards of Aveta.Life, L-Nutra, and Twin Health. All other
authors have reported that they have no relationships relevant to the
benefits. Future trials that adopt emerging novel
contents of this paper to disclose.
cardiovascular biomarkers that reflect the whole
spectrum of lipid oxidation, endothelial function, and
ADDRESS FOR CORRESPONDENCE: Dr Simin Liu,
cardiovascular risk are also warranted to improve
Department of Epidemiology, Brown University, Box
mechanistic understandings.
G-S121-2, 121 South Main Street, Providence, Rhode
Island 02912, USA. E-mail: simin_liu@brown.edu. OR
FUNDING SUPPORT AND AUTHOR DISCLOSURES Dr Fazheng Ren, Department of Nutrition and Health,
China Agricultural University, No. 10 Tianxiu Road,
This work was partly supported by the United States’ Fulbright Pro-
Haidian District, Beijing 100193, China. E-mail:
gram where S.L. was a Fulbright Distinguished Chair in Global Health
2019-2020, and this work was supported by the Beijing Advanced renfazheng@cau.edu.cn.
Innovation Center for Food Nutrition and Human Health, the Na-
tional Natural Science Foundation of China (31970717, 82170429), the PERSPECTIVES
Chinese Universities Scientific Fund (2020TC015), and the Beijing
Municipal Natural Science Foundation (7222111). Dr Liu has received
consulting payments and honoraria or promises of the same for sci- COMPETENCY IN MEDICAL KNOWLEDGE:
entific presentations or reviews at numerous venues, including but Micronutrients confer differential effects on cardio-
not limited to Johns Hopkins University, Fred Hutchinson Cancer
metabolic outcomes, but dietary therapies incorpo-
Center, Harvard University, University of Buffalo, Guangdong Gen-
eral Hospital, Fuwai Hospital, Chinese Academy of Medical Sciences, rating micronutrients must balance benefits and risks.
and the National Institutes of Health; is a member of the Data Safety
and Monitoring Board for several trials, including the SELECT (Sem- TRANSLATIONAL OUTLOOK: Whole food–based
aglutide Effects on Cardiovascular Outcomes in People with Over- diets to promote cardiometabolic health require
weight or Obesity) trial sponsored by Novo Nordisk and a trial of
personalized combinations of a variety of micronu-
pulmonary hypertension in diabetes patients sponsored by Massa-
chusetts General Hospital; and has received royalties from UpToDate; trients that require validation in clinical trials to
and has received an honorarium from the American Society for establish long-term efficacy in diverse populations.
Nutrition for his duties as Associate Editor. Dr Mechanick has
received honoraria from Abbott Nutrition for lectures; and serves on

REFERENCES

1. GBD 2017 Diet Collaborators. Health effects of
dietary risks in 195 countries, 1990-2017: a sys-
tematic analysis for the Global Burden of Disease
Study 2017. Lancet. 2019;393:1958–1972.
2. Mechanick JI, Farkouh ME, Newman JD,
Garvey WT. Cardiometabolic-based chronic dis-
ease, adiposity and dysglycemia drivers: JACC
State-of-the-Art Review. J Am Coll Cardiol.
2020;75:525–538.
3. Mechanick JI, Farkouh ME, Newman JD,
Garvey WT. Cardiometabolic-based chronic dis-
ease, addressing knowledge and clinical practice
gaps: JACC State-of-the-Art Review. J Am Coll
Cardiol. 2020;75:539–555.
4. Mechanick JI, Kushner RF. Lifestyle Medicine, A
Manual for Clinical Practice. In: Mechanick JI,
Kushner RF, eds. Lifestyle Medicine, A Manual for
Clinical Practice. Springer; 2016:1–8.
5. Lichtenstein AH, Appel LJ, Vadiveloo M, et al.
2021 Dietary guidance to improve cardiovascular
health: a scientific statement from the American
Heart Association. Circulation. 2021;144:e472–
e487.
6. Belardo D, Michos ED, Blankstein R, et al.
Practical, evidence-based approaches to nutri-
tional modifications to reduce atherosclerotic
cardiovascular disease: an American Society for
Preventive Cardiology Clinical Practice Statement.
Am J Prev Cardiol. 2022;10:100323.
7. Huang Q, Braffett BH, Simmens SJ, Young HA,
Ogden CL. Dietary polyphenol intake in US adults
and 10-year trends: 2007-2016. J Acad Nutr Diet.
2020;120:1821–1833.
8. Brauchla M, Dekker MJ, Rehm CD. Trends in
Vitamin C consumption in the United States: 1999-
2018. Nutrients. 2021;13:420.
9. Kim K, Vance TM, Chun OK. Estimated intake
and major food sources of flavonoids among US
adults: changes between 1999-2002 and 2007-
2010 in NHANES. Eur J Nutr. 2016;55:833–843.
10. Blasbalg TL, Hibbeln JR, Ramsden CE,
Majchrzak SF, Rawlings RR. Changes in consump-
tion of omega-3 and omega-6 fatty acids in the
United States during the 20th century. Am J Clin
Nutr. 2011;93:950–962.
11. Kim K, Vance TM, Chun OK. Greater total
antioxidant capacity from diet and supplements is
associated with a less atherogenic blood profile in
U.S. adults. Nutrients. 2016;8:15.
12. Yang M, Chung S-J, Chung CE, et al. Estimation
of total antioxidant capacity from diet and sup-
plements in US adults. Br J Nutr. 2011;106:254–
263.
13. Michos ED, Cainzos-Achirica M, Heravi AS,
Appel LJ. Vitamin D, calcium supplements, and
implications for cardiovascular health: JACC Focus
Seminar. J Am Coll Cardiol. 2021;77:437–449.
14. Aune D, Keum N, Giovannucci E, et al. Dietary
intake and blood concentrations of antioxidants
and the risk of cardiovascular disease, total cancer,
and all-cause mortality: a systematic review and
dose-response meta-analysis of prospective
studies. Am J Clin Nutr. 2018;108:1069–1091.
15. Varadharaj S, Kelly OJ, Khayat RN, Kumar PS,
Ahmed N, Zweier JL. Role of dietary antioxidants
in the preservation of vascular function and the
modulation of health and disease. Front Cardiovasc
Med. 2017;4:64.
16. de Baaij JHF, Hoenderop JGJ, Bindels RJM.
Magnesium in man: implications for health and
disease. Physiol Rev. 2015;95:1–46.
17. Tribble DL, AHA Science Advisory. Antioxidant
consumption and risk of coronary heart disease:
emphasis on vitamin C, vitamin E, and beta-
carotene: a statement for healthcare pro-
fessionals from the American Heart Association.
Circulation. 1999;99:591–595.
18. Beckman JA, Paneni F, Cosentino F,
Creager MA. Diabetes and vascular disease:
pathophysiology, clinical consequences, and
medical therapy: part II. Eur Heart J. 2013;34:
2444–2452.
19. Levitan EB, Song Y, Ford ES, Liu S. Is nondia-
betic hyperglycemia a risk factor for cardiovascu-
lar disease?: a meta-analysis of prospective
studies. Arch Intern Med. 2004;164:2147–2155.
JACC VOL. 80, NO. 24, 2022
DECEMBER 13, 2022:2269–2285
20. Sesso HD, Rist PM, Aragaki AK, et al. Multivi-
tamins in the prevention of cancer and cardio-
vascular disease: the COcoa Supplement and
Multivitamin Outcomes Study (COSMOS) ran-
domized clinical trial. Am J Clin Nutr. 2022;115:
1501–1510.
21. Sesso HD, Manson JE, Aragaki AK, et al. Effect
of cocoa flavanol supplementation for the pre-
vention of cardiovascular disease events: the CO-
coa Supplement and Multivitamin Outcomes Study
(COSMOS) randomized clinical trial. Am J Clin Nutr.
2022;115:1490–1500.
22. Shamseer L, Moher D, Clarke M, et al.
Preferred Reporting Items for Systematic Review
and Meta-Analysis Protocols (PRISMA-P) 2015:
elaboration and explanation. BMJ. 2015;349:
g7647.
23. O’Connor EA, Evans CV, Ivlev I, et al. Vitamin
and mineral supplements for the primary preven-
tion of cardiovascular disease and cancer: updated
evidence report and systematic review for the US
Preventive Services Task Force. JAMA. 2022;327:
2334.
24. Jenkins DJA, Spence JD, Giovannucci EL, et al.
Supplemental vitamins and minerals for cardiovas-
cular disease prevention and treatment: JACC Focus
Seminar. J Am Coll Cardiol. 2021;77:423–436.
25. Khan SU, Khan MU, Riaz H, et al. Effects of
nutritional supplements and dietary interventions
on cardiovascular outcomes: an umbrella review
and evidence map. Ann Intern Med. 2019;171:190.
26. Jenkins DJA, Spence JD, Giovannucci EL, et al.
Supplemental vitamins and minerals for CVD pre-
vention and treatment. J Am Coll Cardiol. 2018;71:
2570–2584.
27. Khan SU, Lone AN, Khan MS, et al. Effect of
omega-3 fatty acids on cardiovascular outcomes: a
systematic review and meta-analysis. EClini-
calMedicine. 2021;38:100997.
28. Hu Y, Hu FB, Manson JE. Marine omega-3
supplementation and cardiovascular disease: an
updated meta-analysis of 13 randomized
controlled trials involving 127 477 participants.
J Am Heart Assoc. 2019;8:e013543.
29. Schwingshackl L, Boeing H, Stelmach-
Mardas M, et al. Dietary supplements and risk of
cause-specific death, cardiovascular disease, and
cancer: a systematic review and meta-analysis of
primary prevention trials. Adv Nutr. 2017;8:27–
39.
30. Qiu Z, Chen X, Geng T, et al. Associations of
serum carotenoids with risk of cardiovascular
mortality among individuals with type 2 diabetes:
results from NHANES. Diabetes Care. 2022;45:
1453–1461.
31. Song Y, Cook NR, Albert CM, Denburgh MV,
Manson JE. Effects of vitamins C and E and b-
carotene on the risk of type 2 diabetes in women
at high risk of cardiovascular disease: a random-
ized controlled trial. Am J Clin Nutr. 2009;90:
429–437.
32. Yang L, Ling W, Du Z, et al. Effects of antho-
cyanins on cardiometabolic health: a systematic
review and meta-analysis of randomized
controlled trials. Adv Nutr. 2017;8:684–693.
33. Zheng X-X, Xu Y-L, Li S-H, Hui R, Wu Y-J,
Huang X-H. Effects of green tea catechins with or
without caffeine on glycemic control in adults: a
meta-analysis of randomized controlled trials. Am
J Clin Nutr. 2013;97:750–762.
34. Khalesi S, Sun J, Buys N, Jamshidi A, Nikbakht-
Nasrabadi E, Khosravi-Boroujeni H. Green tea
catechins and blood pressure: a systematic review
and meta-analysis of randomised controlled trials.
Eur J Nutr. 2014;53:1299–1311.
35. Altobelli E, Angeletti PM, Marziliano C,
Mastrodomenico M, Giuliani AR, Petrocelli R. Po-
tential therapeutic effects of curcumin on glyce-
mic and lipid profile in uncomplicated type 2
diabetes—a meta-analysis of randomized
controlled trial. Nutrients. 2021;13:404.
36. Lin X, Zhang I, Li A, et al. Cocoa flavanol intake
and biomarkers for cardiometabolic health: a sys-
tematic review and meta-analysis of randomized
controlled trials. J Nutr. 2016;146:2325–2333.
37. Amerizadeh A, Asgary S, Vaseghi G,
Farajzadegan Z. Effect of genistein intake on some
cardiovascular risk factors: an updated systematic
review and meta-analysis. Curr Prob Cardiol. 2021:
100902.
38. Serban M, Sahebkar A, Zanchetti A, et al. Ef-
fects of quercetin on blood pressure: a systematic
review and meta-analysis of randomized
controlled trials. J Am Heart Assoc. 2016;5:
e002713.
39. Tabrizi R, Tamtaji OR, Mirhosseini N, et al. The
effects of quercetin supplementation on lipid
An et al 2285
Micronutrients to Reduce Cardiovascular Risk
profiles and inflammatory markers among patients
with metabolic syndrome and related disorders: a
systematic review and meta-analysis of random-
ized controlled trials. Crit Rev Food Sci. 2019;60:
1855–1868.
40. Fogacci F, Tocci G, Presta V, Fratter A,
Borghi C, Cicero AFG. Effect of resveratrol on
blood pressure: a systematic review and meta-
analysis of randomized, controlled, clinical trials.
Crit Rev Food Sci. 2018;59:1–14.
41. Qin Y, Niu K, Zeng Y, et al. Isoflavones for
hypercholesterolaemia in adults. Cochrane Data-
base Syst Rev. 2013;6:CD009518.
42. Liu XX, Li SH, Chen JZ, et al. Effect of soy
isoflavones on blood pressure: a meta-analysis of
randomized controlled trials. Nutr Metab Car-
diovasc Dis. 2012;22:463–470.
43. Jenkins DJA, Kitts D, Giovannucci EL, et al.
Selenium, antioxidants, cardiovascular disease,
and all-cause mortality: a systematic review and
meta-analysis of randomized controlled trials. Am
J Clin Nutr. 2020;112:1642–1652.
44. Homocysteine Lowering Trialists’ Collabora-
tion. Dose-dependent effects of folic acid on
blood concentrations of homocysteine: a meta-
analysis of the randomized trials. Am J Clin Nutr.
2005;82:806–812.
45. Tanvetyanon T, Bepler G. Beta-carotene in
multivitamins and the possible risk of lung cancer
among smokers versus former smokers. Cancer.
2008;113:150–157.
46. Mechanick JI, Marchetti AE, Apovian C, et al.
Diabetes-specific nutrition algorithm: a trans-
cultural program to optimize diabetes and pre-
diabetes Care. Curr Diabetes Rep. 2012;12:180–
194.
47. Liu S, Sesso HD. Flavonoid consumption and
cardiometabolic health: potential benefits due to
foods, supplements, or biomarkers? Am J Clin
Nutr. 2021;114:9–11.
KEY WORDS cardiovascular disease,
meta-analysis, micronutrient, minerals,
randomized controlled trial, type 2 diabetes
A PP END IX For supplemental appendices,
please see the online version of this paper.