Article - Effect of mitochondrial-targeted antioxidants on glycaemic control, cardiovascular health, and oxidative stress in humans: A systematic review and meta-analysis of randomized controlled trials.

Expert Review

Reviewer: Ana-Paula Agrela

18th Sep 2023

Conflict of interest

None

Take home message

Mitochondria are a major producer of reactive oxygen species (ROS) in cells. Excess mitochondrial ROS has been implicated in the pathophysiology of various chronic diseases including Parkinson’s disease, cardiovascular disease (CVD), Type 2 diabetes and cancer.
This review reported that there is limited evidence to support the use of mitoAOXs in the management of glycaemic control and cardiovascular health. However, there are promising findings on the effect of mitoAOXs on endothelial function that warrant consideration and further investigation in target clinical population groups.

Evidence category

B: Systematic reviews including RCTs of limited number

Summary review

Background

A systematic review and meta-analysis was conducted to evaluate the current evidence from randomised control trials (RCTs) in humans on the effects of mitochondrial-targeted antioxidant (mitoAOXs) on glycaemic control, cardiovascular health, and oxidative stress.

Methodology

19 Randomised control trials (n= 884 participants) using mitoAOXs (including Elamipretide, MitoQ and MitoTEMPO) were included from MEDLINE-PubMed, Scopus, EMBASE and Cochrane Library databases. A Cochrane Collaboration’s tool was used to assess risk bias and to grade the quality of the trials and their certainty of the evidence.

Results

Primary clinical outcomes were:

A quantitative analysis on glycaemic control found no significant effect for fasting glucose in response to MitoQ supplementation.
A quantitative analysis on cardiovascular health related outcomes found a significant lowering effect of mitoAOXs brachial flow-mediated dilation (FMD) (standardized mean difference: 1.19, 95% CI: 0.28, 2.16; I2: 67%) and an improved blood pressure (standardized mean difference: -0.32, 95% CI:-0.95, 0.30; I2: 0%) in patients with atherosclerosis-related impairment of renal blood flow.
A quantitative analysis on oxidative stress-related outcomes found no significant effect of mitoAOX on malondialdehyde or F2-Isoprostanes.

Clinical practice applications

The findings from this review suggest limited evidence to support the use of mitoAOX in the management of glycaemic control or cardiovascular health.
However, there are some potential promising findings which included improved endothelial function (particularly brachial FMD) and improved blood pressure in patients with atherosclerosis-related impairment of renal blood flow.
Based on this review, practitioners may consider recommending the use of mitoAOXs only in quite specific circumstances, namely to improve endothelial function in patients with a risk of brachial FMD or high blood pressure associated with atherosclerosis-related impairment of renal blood flow.

Considerations for future research

The studies included in this review were mostly one to three months in duration therefore, there is a need for long-term, follow-up studies to be conducted to better investigate these outcomes.
Given the pathogenic factors of elevated mitochondrial ROS and oxidative stress in chronic diseases such as CVD and Type2 diabetes, further investigation is needed into the effects of mitoAOXs on mitochondrial ROS and oxidative stress markers in target clinical population groups.
It appears that mitoAOXs may improve endothelial function, therefore further research is needed to focus on the effect of mitoAOXs on endothelial function in target clinical populations.
Additionally, further reviews are required to provide a more comprehensive review of the safety and adverse effects of mitoAOXs.
Furthermore, only antioxidants specific to microconidia were included in this review. It is possible that other more general acting antioxidants may have redox-related effects in mitochondria. Therefore, a more comprehensive review is needed to include all possible antioxidant compounds that have mitochondrial effect.

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Abstract

AIM

To investigate the effects of mitochondrial-targeted antioxidants (mitoAOXs) on glycaemic control, cardiovascular health, and oxidative stress outcomes in humans.

MATERIALS AND METHODS

Randomized controlled trials investigating mitoAOX interventions in humans were searched for in databases (MEDLINE-PubMed, Scopus, EMBASE and Cochrane Library) and clinical trial registries up to 10 June 2021. The Cochrane Collaboration's tool for assessing risk of bias and Grading of Recommendations, Assessment, Development and Evaluations were used to assess trial quality and evidence certainty, respectively.

RESULTS

Nineteen studies (n = 884 participants) using mitoAOXs (including Elamipretide, MitoQ and MitoTEMPO) were included in the systematic review. There were limited studies investigating the effects of mitoAOXs on glycaemic control; and outcomes and population groups in studies focusing on cardiovascular health were diverse. MitoAOXs significantly improved brachial flow-mediated dilation (n = 3 trials; standardized mean difference: 1.19, 95% CI: 0.28, 2.16; I : 67%) with very low evidence certainty. No significant effects were found for any other glycaemic, cardiovascular or oxidative stress-related outcomes with mitoAOXs in quantitative analyses, with evidence certainty rated mostly as low. There was a lack of serious treatment-emergent adverse events with mitoAOXs, although subcutaneous injection of Elamipretide increased mild-moderate injection site-related events.

CONCLUSION

While short-term studies indicate that mitoAOXs are generally well tolerated, there is currently limited evidence to support the use of mitoAOXs in the management of glycaemic control and cardiovascular health. Review findings suggest that future research should focus on the effects of mitoAOXs on glycaemic control and endothelial function in target clinical population groups.