Trivalent chromium is an essential micronutrient that participates in the regulation of insulin receptor signal transduction as well as carbohydrate and lipid metabolism.1 Circulating levels of chromium decrease with age,2 and in patients with insulin resistance and type 2 diabetes (T2D).3 Previous studies have shown that intravenous chromium infusion can reduce insulin requirement and improve hyperglycemia in patients with severe insulin resistance.4 However, findings from randomized controlled trials (RCTs) investigating the efficacy of oral chromium supplementation in reducing cardiometabolic risk factors have been inconsistent. To reconcile the inconsistencies in the literature regarding the role of chromium in the development of health outcomes and the contradictory recommendations for the optimal intake of chromium, we conducted a systematic review and meta-analysis of relevant RCTs via a novel dose-response approach to investigate and clarify the impact and sources of heterogeneities in relation to chromium supplementation on cardiometabolic risk factors.
The study protocol was registered in PROSPERO database (CRD42022363706), and RCTs included in this meta-analysis had ethics approval from their respective institutional review boards. The PubMed, Web of Science, and the Cochrane databases were searched for RCTs through October 10th, 2022. RCTs that investigated the effect of oral chromium supplementation rather than intravenous injection chromium on measures of glycemic control (fasting blood glucose [FBG], hemoglobin A1c [A1C], and fasting blood insulin [FBI]), blood lipids (low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], total cholesterol [TC], and triglyceride [TG]), or blood pressure (systolic blood pressure [SBP] and diastolic blood pressure [DBP]) were included.
Weighted mean differences of specific cardiometabolic risk factors between intervention and control groups and the standard deviations were used as the basis for each trial comparison. A random-effects model was used to calculate summary weighted mean differences and 95% CIs. In addition, when 10 or more comparison groups were available, we employed a novel 1-stage random-effects dose-response model to evaluate the dose-response relationship between chromium supplementation and changes in cardiometabolic paraments, where chromium supplementation was included as a continuous variable. Restricted cubic splines were used to pool the data from included studies into continuous dose-response curves. RevMan (version 5.4) and Stata/SE (version 17.0) were used to conduct all analyses, including the 1-stage approach for dose-response meta-analysis, based on the drmeta module of Stata/SE.5
A total of 64 studies consisting of 3,004 participants aged 18 to 90 years (median 54.2 years) were included, of which 34 RCTs were done in T2D patients and 30 in participants without T2D. There were 40 RCTs from Western countries and 24 from non-Western countries. The chromium intervention dose ranged from 7 to 1,000 μg/d (median 200 μg/d) with the median intervention duration was 12 weeks (ranged from 8 to 32 weeks).
Chromium supplementation lowered all the glycemic parameters (FBG, A1C, and FBI), all blood lipid parameters (LDL-C, HDL-C, TC, and TG), and SBP in the total population (Figure 1A). When subdivided according to T2D status, chromium improved all glycemic markers, HDL-C and TG in T2D participants. In non-T2D participants, chromium improved FBG and all blood lipid parameters except LDL-C. In the subgroup analysis divided by geographic/cultural background, chromium lowered all glycemic markers in Westerners and non-Westerners, except for FBG in non-Western participants. TC and TG were significantly reduced in non-Westerners, while only HDL-C was significantly improved in Westerners. SBP was significantly reduced in Westerners, while no significant effect was observed for both SBP and DBP in those non-Westerners. Chromium supplementation displayed no effect on DBP in the total population or in any subgroup.
Figure 1.
A Comprehensive Summary of Chromium Supplementation on Cardiometabolic Health
(A) An evidence map summarizing chromium supplementation on cardiometabolic risk factors. Results were presented as weighted mean difference and 95% CIs. (B) Dose-response meta-analysis of chromium supplementation on cardiometabolic risk factors in diverse populations. Marginal average dose-response curve (solid red line) with 95% CIs (dashed lines) estimated by a 1-stage random-effects restricted cubic spline model, using 0 μg/d as the referent (solid gray horizontal line).
To explore if any dose-response effect existed between chromium and cardiometabolic risk factors, dose-response meta-analyses were performed in different subgroups (Figure 1B). A chromium dose of 400 μg/d or higher appears to be appropriate for FBG reduction in participants with T2D. In participants without T2D, an inverted U-shaped chromium-HDL-C association was detected, with a threshold of 300 μg/d of chromium showing an appropriate dose. In participants from Western countries, only a significantly inverted U-shaped chromium-HDL-C relationship was detected, with an appropriate chromium dose of 400 μg/d. In participants from non-Western countries, nonlinear J-shaped dose-response relationships were observed in chromium-A1C, chromium-FBI, and chromium-TC associations. A chromium dose of 200 μg/d appeared to be an appropriate dose for lowering these glycemic and blood lipid parameters.
These findings indicated that chromium supplementation improved cardiometabolic risk factors, although pre-existing cardiometabolic disorders and study location were the sources of heterogeneity that influenced the effects of chromium supplementation on cardiometabolic health. For the first time, we identified appropriate doses of chromium supplementation to improve blood glucose in T2D participants, which were not reported in previous studies.
Based on a novel method—the 1-stage restricted cubic splines—to assess dose-response relationships between chromium supplementation and cardiometabolic risk factors, this study shows the importance of adequate and different chromium intakes for cardiometabolic health that appear to be dependent on T2D status and ethnicity. However, considering the heterogeneity and short-term nature of existing RCTs, additional large and high-quality RCTs with long-term prospective followup are still warranted to determine the optimal balance of benefits and risks associated with chromium supplementation in diverse populations.
Footnotes
This work was partially supported by the Beijing Advanced Innovation Center for Food Nutrition and Human Health. This work was supported by research grants from National High-Level Hospital Clinical Research Funding (bj-2023-72). This work was made possible with support from Washington University in St. Louis CDTR (Grant Number P30DK092950 from the NIDDK). The content is solely the responsibility of the authors and does not necessarily represent the official views of the CDTR or NIDDK. Dr Liu has received consulting payments and honoraria or promises of the same for scientific presentations or reviews at numerous venues, including but not limited to Fred Hutchinson Cancer Center, Harvard University, University of Buffalo, Guangdong General Hospital and Academy of Medical Sciences, Twin Health, and the National Institutes of Health; is a member of the Data Safety and Monitoring Board for several trials, including the SELECT (Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity) trial sponsored by Novo Nordisk and a trial of pulmonary hypertension in diabetes patients sponsored by at Massachusetts General Hospital; and has received royalties from UpToDate; and an honorarium from the American Society for Nutrition for his duties as Associate Editor. Dr Mechanick has received honoraria from Abbott Nutrition for lectures and serves on the Advisory Boards of Aveta.Life, L-Nutra, and Twin Health. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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.
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