The impact of coenzyme Q10 on metabolic and cardiovascular disease profiles in diabetic patients: A systematic review and meta‐analysis of randomized controlled trials

Abstract Aims Coenzyme Q10 (CoQ10) is well known for its beneficial effects in cardiovascular disease (CVD); however, reported evidence has not been precisely synthesized to better inform on its impact in protecting against cardiovascular‐related complications in diabetic patients. Materials and Methodology The current meta‐analysis included randomized controlled trials published in the past 5 years reporting on the effect of CoQ10 on metabolic and CVD‐related risk profiles in individuals with diabetes or metabolic syndrome. We searched electronic databases such as MEDLINE, Cochrane Library, Scopus and EMBASE for eligible studies. In addition to assessing the risk of bias and quality of evidence, the random and fixed‐effect models were used to calculate the standardized mean difference and 95% confidence intervals for metabolic parameters and CVD outcomes. Results Overall, 12 studies met the inclusion criteria, enrolling a total of 650 patients. Although CoQ10 supplementation did not statistically affect all metabolic profiles measured, it significantly reduced CVD‐risk‐related indexes such as total cholesterol and low‐density lipoprotein (LDL) levels in diabetic patients when compared to those on placebo [SMD = 0.13, 95% CI (0.03; 0.23), Chi2 = 43.62 and I 2 = 29%, P = .07]. Conclusions The overall results demonstrated that supplementation with CoQ10 shows an enhanced potential to lower CVD risk in diabetic patients by reducing total cholesterol and LDL. Moreover, the beneficial effects of CoQ10 in lowering the CVD risk are associated with its ameliorative properties against oxidative stress and improving endothelial health.


| INTRODUC TI ON
Heart failure remains the leading cause of death in diabetic patients, when compared to their nondiabetic counterparts. 1 A combination of metabolic abnormalities is acknowledged to be responsible for enhanced susceptibility of diabetic individuals to myocardial damage. For example, in type 2 diabetes (T2D), the predominant form of diabetes that is associated with dyslipidaemia and enhanced arterial atherosclerotic buildup has been directly connected with endothelial dysfunction and subsequent increased risk of heart failure. 1-4 The characteristic features of diabetic dyslipidaemia include elevated plasma triglyceride and low-density lipoprotein (LDL) concentrations, and reduced high-density lipoprotein (HDL) levels. Such complications may arise due to increased free fatty acid flux secondary to insulin resistance and can greatly impair myocardial contractility, which eventually leads to reduced cardiac efficiency. 5,6 Currently, of major concern has been the limited capacity of available therapies to protect diabetic patients against the rising cardiovascular disease (CVD)-related comorbidities.
Although currently used therapies like statins can control dyslipidaemic complications, their long-term use has been associated with reduced endogenous levels of ubiquinone or coenzyme Q 10 (CoQ10). 7,8 In fact, it has been established that a diabetic heart already displays significantly reduced endogenous CoQ10 levels, when compared to the nondiabetic counterpart. 9 This may further explain the continued rise in CVD-related deaths in diabetic patients since CoQ10 is known to act as an important antioxidant to protect against dyslipidaemia-induced oxidative stress and inflammation, 10,11 some of the major consequences implicated in enhanced diabetes-induced myocardial damage. Beyond its antioxidant properties, CoQ10 remains a crucial component of the mitochondrial electron transport chain that plays an essential role in facilitating the production of adenosine triphosphate through its involvement in redox reactions. 12 Consistently, administration of CoQ10 has been correlated with improved endothelial function in patients with and without established CVDs. 10 Despite an increase in the number of studies reporting on the beneficial effects of CoQ10 supplementation in improving endothelial function in humans, 10 available evidence remains inconclusive regarding its impact on improving CVD outcomes in those with diabetes. Thus, this systematic review and meta-analysis updates our current understanding on the cardio-protective effects of CoQ10, using data from randomized controlled trials (RCTs) published in the last five years.

| ME THODS
This systematic review and meta-analysis was prepared in agreement with the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) guidelines. 13 Accordingly, File S1 provides a PRISMA checklist for this systematic review and meta-analysis. Furthermore, to deliver transparency in the review process and avoid publication bias, this meta-analysis, the International prospective register of systematic reviews (PROSPERO), was thoroughly searched and found no similar review registered on the current topic.

| Inclusion and exclusion criteria
The systematic review and meta-analysis included RCTs evaluating the impact of CoQ10 on CVD-related outcomes in adults (>18 years) with diabetes or metabolic syndrome. Briefly, included studies were those that assessed the use of CoQ10 as an intervention, contained the comparison group on placebo, and reported on measurable CVD-related outcomes in individuals with diabetes or metabolic syndrome. Animal studies were excluded since the main objective was to establish the impact of CoQ10 supplementation on of Research Capacity Development under the Intra-Mural Postdoctoral Fellowship Programme from funding received from the South African Treasury. The content hereof is the sole responsibility of the authors and does not necessarily represent the official views of the SAMRC or the funders.

K E Y W O R D S
cardiovascular diseases, coenzyme Q 10 , diabetes mellitus, heart failure, metabolic syndrome, oxidative stress CVD outcomes in individuals with diabetes or metabolic syndrome.
Other exclusions included books, cohort or observational studies, letters and case reports, whilst reviews were only scanned for RCTs.
Furthermore, studies not reporting on measurable CVD outcome or contained limited information on the methodology or results from the article were excluded.

| Data extraction and assessment of quality
Two investigators, PVD and TMN, independently evaluated all pertinent articles and carefully selected those that were relevant. Incongruities were resolved by consulting a third investigator, BBN. The main outcome of the study was to establish the impact of CoQ10 supplementation on CVD-related outcomes in diabetes or metabolic syndrome. Another important objective of the study was to establish whether CoQ10 supplementation affected diabetes and metabolic syndrome-related markers such as fasting blood glucose (FPG) or insulin levels, glycated haemoglobin (Hb1Ac) and body mass index (BMI). To accomplish this, relevant data items, from each article, such as name and year of publication, the country where the study was conducted, sample and gender distribution, as well as CoQ10 dosage used and duration of intervention, were extracted by two independent investigators (VM and KM).

| Statistical analysis
The meta-analysis and statistical analyses was performed using and Higgin's I 2 statistics were applied. 19 Furthermore, to generate pooled effect estimates when substantial heterogeneity existed (I 2 > 50%), the random-effects model was used, as previously discussed. 20 Cohen's method was further used to interpret effect sizes, whereby a standardized mean difference of 0.2, 0.5 and 0.8 was equated to small, medium and large, respectively. 21 Likewise, a P-value < .05 was considered statistically significant, whilst interrater reliability was evaluated for both the included studies

| Study characteristics
All included articles were published in peer-reviewed journals within the last five years, and in detail characteristic features of encompassed studies are displayed in Table 1

| Risk of bias assessment
The use of funnel plots showed perfect symmetry distribution which is indicative of no publication bias in the included studies ( Figure 2). The risk of bias and quality of sixteen included studies was assessed by VM and KM, using a modified Downs and Black's checklist. 16 The overall median score range of the 12 in- and adipolin levels. 27 Table 3.

| D ISCUSS I ON
T2D and its interconnected metabolic complications such as obesity are of clinical significance because of their epidemic prevalence and contribution to the rapid rise of noncommunicable-related deaths. 31,32 Dyslipidaemia remains the major characteristic feature of T2D, and its prevalence among diabetic patients may be high as 70% in some populations. 33 Even worse, enhanced lipid deposits on the arterial wall in patients presenting with dyslipidaemia have been associated with the development and worsening of atherosclerosis. 34 The latter is known to be the causal factor for virtually 80% of all deaths among diabetic patients. 35 At present, complex mechanisms implicated in the development of atherosclerosis in a diabetic state have been described. For example, nonenzymatic glycosylation of lipids can interfere with normal physiological function by promoting the generation of oxidative stress, which is one of the major consequences associated with deteriorated cardiac function.
Oxidative stress, through enhanced production of reactive oxygen species, can affect endothelial nitric oxide (NO) availability, and thus in the process compromise vascular function. 36 NO is broadly considered as one of the most vital molecules produced in the human body, and its acts as an essential regulator in a vast array of crucial physiological functions, especially the maintenance of vascular tone. 36,37 Research over the years has led to the identification of several ROS generating systems that could potentially be modulated in conditions of hyperglycaemia. 35  Nevertheless, consistent with other pharmacological compounds like n-acetyl cysteine and resveratrol, although could not significantly affect some metabolic parameters, their capacity to substantially enhance antioxidant capacity within the human system is important for attenuating oxidative stress and in the process show potential to protect the diabetic heart. [45][46][47] Consistently, alpha-lipoic acid, an organosulphur compound derived from caprylic acid that is increasingly explored for its beneficial effects as a dietary supplement with abundant properties, has been shown to provide limited amelioration against metabolic disturbances, but instead may protect against atherosclerosis and development of CVD when used in combination with exercise. 48 Further, suggesting that perhaps the combination use of CoQ10 with exercise may provide even better protective effects against heart failure and associated complications, an aspect that is also increasingly explored elsewhere. 49,50 Nevertheless, presented data also showed that CoQ10 significantly reduced the overall CVD risk with a small effect size, with most studies reporting on the intervention between 8 and 12 weeks. In terms of effect measures for CVD, there was a significant reduction in only total cholesterol and LDL. It is important to note that although a previous study showed an effect in CVD risk measure such as systolic and diastolic blood pressure, 25   tients. This is consistent with the identified limitations, like assessing its synergistic effect when combined with current anti-diabetic agents, as well as testing its overall impact on broader spectrum of CVD-risk-related outcomes such as ejection fraction.

CO N FLI C T O F I NTE R E S T
The authors declare no conflict of interest.

DATA AVA I L A B I L I T Y S TAT E M E N T
All data used to support the findings of this study are included within the article. Raw data can be available on request after publication. High certainty: We are very confident that the true effect lies close to that of the estimate of the effect.

O RCI D
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect.
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.
a The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).