By Rakesh Calton, MD, and Nancy Selfridge, MD

Dr. Calton is Associate Professor, Clinical Foundations, Ross University School of Medicine, Barbados, West Indies.
Dr. Selfridge is Professor, Clinical Foundations Department, Ross University School of Medicine, Barbados, West Indies.

SYNOPSIS: A meta-analysis of systematic reviews and randomized, controlled trials to analyze the role of commonly used dietary supplements for prevention and treatment of cardiovascular disease suggests no significant effect on cardiovascular outcomes or all-cause mortality, although some B vitamins appear to reduce stroke incidence, and B3 appears to increase all-cause mortality.

SOURCE: Jenkins DJA, Spence JD, Giovannucci EL, et al. Supplemental vitamins and minerals for cardiovascular disease prevention and treatment: JACC focus seminar. J Am Coll Cardiol 2021;77:423-436.

The use of dietary supplements, such as vitamins B, C, and D and calcium, is on the rise throughout North America, Europe, and other countries.1-3 However, there is a lack of consensus on the use of these supplements for the prevention and treatment of cardiovascular disease (CVD), although various health authorities and advisories recommend consumption of a well-balanced, plant-based diet to meet daily requirements for these nutrients.4,5 To analyze the role of dietary supplements in the prevention and treatment of CVD, Jenkins et al conducted a meta-analysis of recent systematic reviews and randomized, controlled trials (RCTs) in an update to their previous 2018 systematic review and meta-analysis on the same topic.6

For this updated meta-analysis, the authors included the systematic reviews and RCTs identified in their 2018 review along with recent studies published up to May 2020. The literature search was conducted according to protocols recommended in the Cochrane Handbook for systematic reviews and meta-analyses. Only meta-analyses and single RCTs were included if they focused on those individual vitamin and mineral supplements previously reported by the authors as commonly used and those supplements that had a significant finding for CVD outcomes or total mortality. Out of 2,999 papers identified in the literature search, 156 total and 35 new RCTs met the inclusion criteria and were added for this updated meta-analysis.

Data analysis was conducted using Review Manager 5.3, a software application for meta-analyses created by Cochrane Collaboration. The heterogeneity of the studies was assessed and reported as an I2 statistic, with an I2 value > 50% indicating substantial heterogeneity. Publication bias was analyzed on meta-analyses > 10 trials, using STATA software. P < 0.05 was considered evidence of a small study effect. The number needed to treat (NNT) and number needed to harm were calculated using the inverse of the respective absolute risk reduction (ARR) values: NNT = 1/ARR, number needed to harm = 1/ARR. Risk bias was addressed for randomization, blinding and allocation concealment, thoroughness of follow-up, and intention-to-treat using the Cochrane Risk of Bias tool. The Grading of Recommendations Assessment, Development, and Evaluation tool was used to assess and categorize the quality and strength of evidence as high, moderate, low, and very low. All RCTs were graded as high-quality evidence, and other studies were downgraded based on identification of limitations using the aforementioned risk of bias tool, high interstudy heterogeneity, imprecision reflected in reported 95% confidence intervals, and publication bias represented by significantly small study effects.

Supplements assessed included vitamin D, vitamin C, calcium, multivitamin formulations, B-complex formulations (at least two of the following: B6, folate, and B12), and antioxidant mixtures (at least two of the following: vitamin A, C, E, and beta-carotene). Vitamin D, vitamin C, calcium, and multivitamins did not significantly affect cardiovascular outcomes or all-cause mortality. Vitamin B-complex and folic acid significantly affected stroke reduction. Niacin increased the all-cause mortality rate. Antioxidant mixtures did not affect CVD outcomes or all-cause mortality.


This well-designed meta-analysis has some significant strengths, including the use of Cochrane Collaboration Handbook protocols and tools for their systematic review and statistical analyses, and the thoroughness of the literature review. A weakness of this systematic review is that it included no cohort studies, which, because of their longer study duration, may be better for identifying chronic disease risk factors. In this analysis, the authors did not find any beneficial effects of micronutrient supplementation on CVD prevention or mortality. Of supplements most used by patients, multivitamins, vitamin C, vitamin D, calcium, and antioxidants do not show any consistent benefit for the prevention of CVD, including myocardial infarction and stroke, nor a reduction in all-cause mortality. Thus, in general, there is no evidence to support patient use of these supplements for these purposes, and clinicians should refrain from recommending them. The authors cited a potential exception, considering some research evidence suggesting patients on statins may tolerate statins better when they are vitamin D-replete.

Vitamin B-complex and folic acid are shown to be associated with a reduction in stroke incidence, but niacin is associated with increased all-cause mortality. It is reasonable for clinicians to consider recommending daily supplementation with B-complex and folate for patients with increased risk of stroke based on these study results, although caution should be exercised with niacin supplementation. A plant-based diet rich in B vitamins and folic acid currently is supported by United States Preventive Services Task Force recommendations and may be appropriate for patients who do not wish to take supplements.


  1. Kantor ED, Rehm CD, Du M, et al. Trends in dietary supplement use among U.S. adults from 1999-2012. JAMA 2016;316:1464-1474.
  2. Haspel T. Most dietary supplements don’t do anything. Why do we spend $35 billion a year on them? The Washington Post. Published Jan. 27, 2020.
  3. Skeie G, Braaten T, Hjartåker A, et al. Use of dietary supplements in the European Prospective Investigation into Cancer and Nutrition calibration study. Eur J Clin Nutr 2009;63 (Suppl 4):S226-S238.
  4. Government of Canada. Canada’s food guide. Updated Aug. 20, 2021.
  5. United States Department of Agriculture and United States Department of Health and Human Services. Scientific report of the 2015 Dietary Guidelines Advisory Committee.
  6. Jenkins DJA, Spence JD, Giovanucci EL, et al. Supplemental vitamins and minerals for CVD prevention and treatment. J Am Coll Cardiol 2018;71:2570-2584.