Effectiveness of Coenzyme Q10 Supplementation for Reducing Fatigue: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Coenzyme Q10 (CoQ10) is a popular nutritional supplement, an antioxidant and an essential component of the mitochondrial electron transport chain. Several clinical studies have suggested that fatigue can be reduced by antioxidant supplementation. However, the data on this topic has been sparse to date. Hence, we conducted this meta-analysis with the aim of investigating the effectiveness of fatigue reduction via CoQ10 supplementation. More specifically, we searched electronic databases for randomized controlled trials (RCTs) published from the database inception to January 2022. A random effects model was implemented to conduct the meta-analysis among 13 RCTs (with a total of 1,126 participants). As compared with the placebo groups evaluated in each RCT, the CoQ10 group showed a statistically significant reduction in fatigue scores (Hedges’ g = −0.398, 95% confidence interval = −0.641 to −0.155, p = 0.001). The directions of the treatment effects were consistent between the healthy and diseased participants. Compared with the placebo group, the effect of reducing fatigue was statistically significant in the subgroup using the CoQ10-only formulation but not in the subgroup using CoQ10 compounds. The results of our meta-regression demonstrate that increases in the daily dose (coefficient = −0.0017 per mg, p < 0.001) and treatment duration (coefficient = −0.0042 per day, p = 0.007) of CoQ10 supplementation were correlated with greater fatigue reduction. There was only one adverse (gastrointestinal) event in the 602 participants who underwent the CoQ10 intervention. Based on the results of this meta-analysis, we conclude that CoQ10 is an effective and safe supplement for reducing fatigue symptoms. Systematic Review Registration: https://inplasy.com/inplasy-2022-1-0113/, identifier INPLASY202210113


Eligibility criteria 5
Specify the inclusion and exclusion criteria for the review and how studies were grouped for the syntheses. Methods Information sources 6 Specify all databases, registers, websites, organisations, reference lists and other sources searched or consulted to identify studies. Specify the date when each source was last searched or consulted.

Methods
Search strategy 7 Present the full search strategies for all databases, registers and websites, including any filters and limits used. Methods, Table S2 Selection process 8 Specify the methods used to decide whether a study met the inclusion criteria of the review, including how many reviewers screened each record and each report retrieved, whether they worked independently, and if applicable, details of automation tools used in the process.

Methods
Data collection process 9 Specify the methods used to collect data from reports, including how many reviewers collected data from each report, whether they worked independently, any processes for obtaining or confirming data from study investigators, and if applicable, details of automation tools used in the process.
Methods, Table S4 Data items 10a List and define all outcomes for which data were sought. Specify whether all results that were compatible with each outcome domain in each study were sought (e.g., for all measures, time points, analyses), and if not, the methods used to decide which results to collect.
Methods, Table S4 10b List and define all other variables for which data were sought (e.g., participant and intervention characteristics, funding sources). Describe any assumptions made about any missing or unclear information.
Methods Table 1-2, Table S4 Study risk of bias assessment 11 Specify the methods used to assess risk of bias in the included studies, including details of the tool(s) used, how many reviewers assessed each study and whether they worked independently, and if applicable, details of automation tools used in the process.

Effect measures 12
Specify for each outcome the effect measure(s) (e.g., risk ratio, mean difference) used in the synthesis or presentation of results. Methods Synthesis methods 13a Describe the processes used to decide which studies were eligible for each synthesis (e.g., tabulating the study intervention characteristics and comparing against the planned groups for each synthesis (item #5)).
Methods, Figure 1, Table 1-2, Table S3 13b Describe any methods required to prepare the data for presentation or synthesis, such as handling of missing summary statistics, or data conversions. Methods, Table S4 13c Describe any methods used to tabulate or visually display results of individual studies and syntheses. Methods 13d Describe any methods used to synthesize results and provide a rationale for the choice(s). If meta-analysis was performed, describe the model(s), method(s) to identify the presence and extent of statistical heterogeneity, and software package(s) used.

Methods
13e Describe any methods used to explore possible causes of heterogeneity among study results (e.g., subgroup analysis, meta-regression). Methods 13f Describe any sensitivity analyses conducted to assess robustness of the synthesized results.

Methods
Reporting bias assessment 14 Describe any methods used to assess risk of bias due to missing results in a synthesis (arising from reporting biases). Methods, Figure 2, Table 3 Certainty assessment 15 Describe any methods used to assess certainty (or confidence) in the body of evidence for an outcome. Methods

Study selection
16a Describe the results of the search and selection process, from the number of records identified in the search to the number of studies included in the review, ideally using a flow diagram.
Results, Figure 1, 16b Cite studies that might appear to meet the inclusion criteria, but which were excluded, and explain why they were excluded. Results, Table S3 Study characteristics 17 Cite each included study and present its characteristics. Results, Table 1-2 Risk of bias 18 Present assessments of risk of bias for each included study. Figure 2, Table 3 Results of individual studies 19 For all outcomes, present, for each study: (a) summary statistics for each group (where appropriate) and (b) an effect estimates and its precision (e.g., confidence/credible interval), ideally using structured tables or plots.  Table 3 20b Present results of all statistical syntheses conducted. If meta-analysis was done, present for each the summary estimate and its precision (e.g., confidence/credible interval) and measures of statistical heterogeneity. If comparing groups, describe the direction of the effect.
Results, Figure 3-8, Figure   S1-S2 20c Present results of all investigations of possible causes of heterogeneity among study results. Results, Figure 3-8, Figure   S1-S2 20d Present results of all sensitivity analyses conducted to assess the robustness of the synthesized results. Results, Figure 4 Reporting biases 21 Present assessments of risk of bias due to missing results (arising from reporting biases) for each synthesis assessed. Figure 2, Table 3 Certainty of evidence 22 Present assessments of certainty (or confidence) in the body of evidence for each outcome assessed.

OTHER INFORMATION
Registration and protocol 24a Provide registration information for the review, including register name and registration number, or state that the review was not registered. Methods 24b Indicate where the review protocol can be accessed, or state that a protocol was not prepared. Methods, Table S2-S3 24c Describe and explain any amendments to information provided at registration or in the protocol. Methods,    Used 'no intervention' as control group, rather than matching placebo.  Overlapping participants with the author's another publication (18), which is already enrolled in our meta-analysis.