The Effects of Coenzyme Q10 Supplementation on Blood Pressures Among Patients with Metabolic Diseases: A Systematic Review and Meta-analysis of Randomized Controlled Trials

  • Reza Tabrizi
  • Maryam Akbari
  • Nasrin Sharifi
  • Kamran B. Lankarani
  • Mahmood Moosazadeh
  • Fariba Kolahdooz
  • Mohsen Taghizadeh
  • Zatollah Asemi
Review Article

Abstract

Introduction

Although several trials have assessed the effect of coenzyme Q10 (CoQ10) supplementation on blood pressures among patients with metabolic diseases, findings are controversial.

Aim

This review of randomized controlled trials (RCTs) was performed to summarize the evidence on the effects of CoQ10 supplementation on blood pressures among patients with metabolic diseases.

Methods

Randomized-controlled trials (RCTs) published in PubMed, EMBASE, Web of Science and Cochrane Library databases up to 10 August 2017 were searched. Two review authors independently assessed study eligibility, extracted data, and evaluated risk of bias of included studies. Heterogeneity was measured with a Q-test and with I2 statistics. Data were pooled by using the fix or random-effect model based on the heterogeneity test results and expressed as standardized mean difference (SMD) with 95% confidence interval (CI).

Results

A total of seventeen randomized controlled trials (684 participants) were included. Results showed that CoQ10 supplementation significantly decreased systolic blood pressure (SBP) (SMD − 0.30; 95% CI − 0.52, − 0.08). However, CoQ10 supplementation decreased diastolic blood pressure (DBP), but this was not statistically significant (SMD − 0.08; 95% CI − 0.46, 0.29).

Conclusions

CoQ10 supplementation may result in reduction in SBP levels, but did not affect DBP levels among patients with metabolic diseases. Additional prospective studies regarding the effect of CoQ10 supplementation on blood pressure in patients with metabolic diseases are necessary.

Keywords

Coenzyme Q10 Blood pressure Metabolic diseases Meta-analysis 

1 Introduction

Hypertension is a main risk factor for diseases related to metabolic disorders, including diabetes, dyslipidemia, myocardial infarction, heart failure, stroke, peripheral arterial disease, and chronic kidney disease [1]. Major risk factors of hypertension include, but are not limited to, smoking, sedentary lifestyle, a diet high in sodium, and an inadequate intake of few minerals, including potassium, calcium and magnesium [2]. Hypertension is currently managed by the consumption of a variety of drugs. Blood pressure-lowering agents are effective in reducing blood pressure, but many have undesirable side effects, including renal or cardiac dysfunction, cough and depression [3].

Coenzyme Q10 (CoQ10), also known as ubiquinone due to its ubiquitous distribution in nature, is a vitamin like antioxidant and an integral component of the mitochondrial respiratory chain for energy production [4]. It is found in all tissues and organs of the body but in highest concentrations in the heart. Blood and tissue concentrations of CoQ10 are decreased by aging and cardiovascular disease (CVD) [5]. There is evidence of CoQ10 deficiency in some metabolic diseases, such as hypertension [6], diabetes [7], metabolic syndrome (MetS) [8], heart failure [9] and in statin-treated hypercholesterolemic subjects [10]. Since 1975, several studies have clarified the potential effects of CoQ10 to lower blood pressure in hypertensive patients. In a study of subjects with type 2 diabetes mellitus (T2DM), it was reported that CoQ10 therapy lowered blood pressure and improved glycemic control [11]. In addition, in a meta-analysis study conducted by Rosenfeldt et al. [12] was observed that CoQ10 supplementation among patients with essential hypertension had the beneficial effects on reducing systolic blood pressure (SBP) by up to 17 mmHg and diastolic blood pressure (DBP) by up to 10 mmHg without significant side effects. However, despite these reports, the current function of CoQ10, if any, in the treatment of hypertension is unclear. Numerous RCTs have been conducted to determine whether CoQ10 supplementation has a causal effect on blood pressures among patients with metabolic diseases. We hypothesized to systematically review the current evidence on the effect of CoQ10 supplementation on blood pressures in RCTs and to summarize the available findings in a meta-analysis, if possible.

2 Methods

2.1 Search Strategy

Relevant studies were systematically searched from online databases PubMed, EMBASE, Web of Science and Cochrane Library databases up to 10 July 2017. Search terms included: patients [“diabetes” OR “type 2 diabetes mellitus (T2DM)” OR “type 1 diabetes mellitus (T1DM)” OR “non-alcoholic fatty liver disease (NAFLD)” OR “acute myocardial infarction (AMI)” OR “coronary artery disease (CAD)” OR “metabolic syndrome (MetS)” OR “polycystic ovary syndrome (PCOS)”]; intervention (“Q10” OR “CoQ10” AND “supplementation” OR “intake”) and outcomes [“blood pressure” OR “systolic blood pressure (SBP)” OR “diastolic blood pressure (DBP)”]. Search was conducted by two independent researchers. References cited in the selected studies were manually searched for additional relevant articles. Our search was restricted to studies published in the English language.

2.2 Selection Criteria

The eligibility criteria were: human RCTs, patients with metabolic diseases, and administration of CoQ10 or Q10 supplements. Studies that did not report mean changes of blood pressure, along with standard deviation (SD) for the intervention and control groups, the abstracts of seminars without full text, case reports, and studies that did not obtain the minimum required score of quality assessment process were excluded.

2.3 Quality Assessment

Data extraction and study quality assessment was conducted by two independent reviewers (ZA and MA), according to Cochrane Collaboration Risk of Bias tool. The scale includes 3 domains related to quality of clinical trials: (1) random sequence generation description (0 = no description; 1 = inadequate description; 2 = adequate description); (2) blinding process (2 = double-blinding with adequate description; 1 = double-blinding with inadequate description; 0 = wrong usage of double-blinding), and (3), and withdrawal of patients (1 = the number and reasons of patients withdrawal described; 0 = otherwise). In the event of disagreement, resolved by discussion until consensus was reached.

2.4 Statistical Methods

RevMan software (Cochrane Review Manager, version 5.2) and STATA version 12.0 (Stata Corp., College Station, TX) were used for data analyses. Heterogeneity was evaluated through the Cochran (Q) and I-squared tests (I2). Given the existing heterogeneity between studies, when I2 exceeds 50% or P < 0.05, the random-effect model was used; otherwise, the fixed-effect model was applied. Inverse variance method and Cohen statistics were used for estimation of standardized mean difference (SMD) and 95% CI for verifying the outcomes behavior of each study group (intervention/control). Sensitivity analyses also undertook in the trials one by one to evaluate the reliability of the pooled mean difference. In addition, the Cochrane Collaboration Risk of Bias tool was used to assess the methodological quality of the RCTs. Potential publication bias was assessed through visual inspection of funnel plots and quantitatively assessed using egger’s tests.

3 Results

3.1 Characteristics of Included Studies

17 included primary studies were randomized controlled trials which two used cross-over design and 15 of them used parallel method (Fig. 1). The duration of intervention in included studies was between 4 and 24 weeks. Eight of included primary studies have examined the impact of CoQ10 supplementation on hypertension in patients with diabetic diseases [11, 13, 14, 15, 16, 17, 18, 19]; nine included studies were with other metabolic disease syndromes [20, 21, 22, 23, 24, 25, 26, 27, 28]. Mean difference of SBP and DBP have reported 17 and 16 of included studies, respectively. CoQ10 dosage used in include studies was from 100 to 900 mg/day. Table 1 shows the characteristics of included primary studies.
Fig. 1

Literature search and review flowchart for selection of studies

Table 1

Characteristics of included studies

Author, year

Disease

Participants

Country

Intervention (name and composition) (mg/day)

Duration (weeks)

Age (year)

Presented data

Results

Mohseni et al. [20], 2004

Hyperlipidemia and myocardial infarction

52

Iran

Q10, 200

12

35–75

SBP, DBP

Decreased SBP and DBP

Mohammadshahi et al. [21], 2014

NAFLD

41

Iran

Q10, 100

12

19–54

SBP, DBP

Decreased SBP

Moazen et al. [13], 2013

T2DM

52

Iran

Q10, 200

8

50.67 ± 1.43, 52.79 ± 1.56

SBP, DBP

Decreased SBP

Young et al. [22], 2012

Metabolic syndrome

31

New Zealand

Q10, 200

12

25–75

SBP, DBP

No effect

Lee et al. [23], 2011

Obese subjects

51

Korea

Q10, 200

12

42.7 ± 11.3, 42.5 ± 11.2

SBP, DBP

No effect

Dai et al. [24], 2011

Ischaemic left ventricular systolic dysfunction

56

Hong Kong

Q10, 300

8

70.1 ± 9.8, 67.7 ± 9.4

SBP, DBP

No effect

Hamilton et al. [14], 2009

Statin treated T2DM

23

Australia

Q10, 200

12

68 ± 6

SBP, DBP

No effect

Chew et al. [15], 2008

T2DM

25

Australia

Q10, 200

24

40–79

SBP, DBP

No effect

Nukui et al. [25], 2006

Healthy subjects

46

Japan

Q10, 900

4

40 ± 13

SBP, DBP

No effect

Playford et al. [16], 2003

T2DM

38

Australia

Q10, 200

12

54 ± 9

SBP, DBP

Decreased SBP

Hodgson et al. [11], 2002

T2DM

37

Australia

Q10, 200

12

53.2 ± 1.0

SBP, DBP

Decreased SBP and DBP

Burke et al. [26], 2001

Isolated systolic hypertension

71

USA

Q10, 120

12

50–75

SBP, DBP

Decreased SBP

Singh et al. [27], 1999

Coronary artery disease

58

India

Q10, 120

8

48.3 ± 7.2

SBP, DBP

Decreased SBP and DBP

Henriksen et al. [17], 1999

T1DM

34

Denmark

Q10, 100

12

35.5 ± 8.2

SBP, DBP

No effect

Eriksson et al. [18], 1999

T2DM

23

Denmark

Q10, 200

24

65 ± 17

SBP, DBP

No effect

Andersen et al. [19], 1997

T1DM

34

Denmark

Q10, 100

12

35.3 ± 9.8

SBP, DBP

No effect

Kamikawa et al. [28], 1985

Chronicstable angina pectoris

12

Japan

Q10, 150

4

45–66

SBP

No effect

SBP systolic blood pressure, DBP diastolic blood pressure, NAFLD non-alcoholic fatty liver disease, T2DM type 2 diabetes mellitus, T1DM type 1 diabetes mellitus

3.2 Publication Bias, Pooled Standardized Mean Difference and Subgroup Analysis

The statistical Egger test showed that no evidence of publication bias in included studies for SBP (B = − 1.11, P = 0.648), and DBP (B = 2.37, P = 0.58).

Results showed that CoQ10 supplementation significantly decreased SBP (SMD − 0.30; 95% CI − 0.52, − 0.08). However, CoQ10 supplementation decreased DBP, but this was not statistically significant (SMD − 0.08; 95% CI − 0.46, 0.29) (Table 2 and Fig. 2). All meta-analysis based on pre and post changed in intervention and placebo group a among study population shown in Table 2.
Table 2

Estimation of the standardized mean difference of systolic and diastolic blood pressure with CI 95% between the intervention and placebo groups

Variable

Number of study

Standardized mean difference

CI 95%

Heterogeneity

I-squared (%)

Q

P value

SBP

 Intervention group (after vs. before)

16

− 0.66

− 1.15, − 0.17

89.1

137.2

< 0.0001

 Placebo group (after vs. before)

16

− 0.09

− 0.27, 0.08

25.9

20.25

0.163

 Intervention vs. placebo group

16

− 0.30

− 0.52, − 0.08

52.6

31.63

0.007

DBP

 Intervention group (after vs. before)

14

− 0.37

− 0.83, 0.08

86.9

99.33

< 0.0001

 Placebo group (after vs. before)

14

− 0.31

− 0.81, 0.18

88.5

112.77

< 0.0001

 Intervention vs. placebo group

14

− 0.08

− 0.46, 0.29

81.7

71.06

< 0.0001

Fig. 2

Meta-analysis hypertension standardized mean differences estimates for a systolic blood pressure, and b for diastolic blood pressure in CoQ10 supplements and placebo groups (CI = 95%)

Subgroup analysis was performed to evaluate the impact of suspected variables including dosage, type disease, and duration of the study in the heterogeneity of findings. Considering to subgroup analyses, the reduction of heterogeneity was found in some of subgroups that were showed in Fig. 2 and Table 3.
Table 3

The relationship between CoQ10 supplementation and hypertension based on subgroup analysis

 

Variable

Number of SMD included

Subgroups

Pooled OR (random effect)

95% CI

I-squared (%)

overall I-squared (%)

SBP

Type diseases

4

Diabetic

− 0.34

− 0.60, − 0.08

20.0

52.6

8

Non-diabetic

− 0.26

− 0.63, 0.10

69.1

Duration

4

< 3 months

− 0.33

− 0.57, − 0.08

58.1

8

≥ 3 months

− 0.09

− 0.66, 0.49

0.0

DBP

Type diseases

4

Diabetic

0.10

− 0.63, 0.83

87.0

81.7

8

Non-diabetic

− 0.25

− 0.63, 0.13

70.8

Duration

4

< 3 months

− 0.07

− 0.05, 0.36

84.5

8

≥ 3 months

− 0.15

− 0.73, 0.42

0.0

Sensitivity analysis was calculated after excluding each study from meta-analysis to evaluate the effect of one by one of all included studies on pooled standardizes mean difference. After excluding each included study from the sensitivity analysis, findings showed that no significant difference between the pre-sensitivity and post-sensitivity pooled standardized mean difference. We found that the lower and higher pooled standardizes mean difference in sensitivity analysis for SBP was (SMD − 0.34; 95% CI − 0.56, − 0.011) after omitting the Lee et al. [23] study and (SMD − 0.20; 95% CI − 0.37, 0.045) after omitting Singhet al. [27] study, respectively. The lower and higher pooled standardizes mean difference in sensitivity analysis for DBP were (SMD − 0.25; 95% CI − 0.49, − 0.10) after omitting Moazen et al. [13] and (SMD 0.10; 95% CI − 0.33, 0.36) after omitting Singh et al. [27] study, respectively (Fig. 3).
Fig. 3

Sensitivity analysis hypertension; a systolic blood pressure, and b diastolic blood pressure to assess the effects of every study on pooled standardized mean differences estimates

Figure 4 showed the summary of review authors’ judgments on risk of bias item for each included primary study.
Fig. 4

The summary of review authors’ judgments about each risk of bias item for each included study

Scatters in the funnel plot were almost symmetrical visually, indicating low risks of publication bias (Fig. 5). Therefore, the findings of this report were qualified.
Fig. 5

A funnel plot of meta-analysis hypertension standardized mean differences estimates for a systolic blood pressure, and b for diastolic blood pressure

4 Discussion

To our knowledge, this is the first meta-analysis of RCTs that evaluated the effect of CoQ10 supplementation on blood pressure among patients with metabolic diseases. We found that CoQ10 supplementation may result in an improvement in SBP among patients with metabolic diseases, but did not affect DBP.

The open label observational studies, of which the largest study comprised 109 subjects with symptomatic essential hypertension, were before and after studies without a placebo control group and included the earliest studies dating from 1975 [29]. All these studies demonstrated significant reductions in SBP ranging from 10 to 21 and from 7 to 16 mmHg in DBP that was similar in magnitude to the randomized studies. These represent credible therapeutic effects given that the placebo group in the randomized studies indicated decreases in SBP of only 1–4 and 0–3 mmHg in DBP. In line with our study, in a meta-analysis study conducted by Rosenfeldt et al. [12], it was seen that CoQ10 administration among patients with essential hypertension had the beneficial effects on reducing SBP by up to 17 mmHg and DBP by up to 10 mmHg without significant side effects. In another meta-analysis study, CoQ10 supplementation among patients with and without established cardiovascular disease was associated with significant improvement in endothelial function assessed peripherally by flow-mediated dilatation [30]. In addition, CoQ10 supplementation at a dosage of 60–200 mg/day with treatment periods ranging from 1 to 6 months among patients with heart failure resulted in a 3.7% net improvement in ejection fraction [31].

Dosage of CoQ10 used in the trials reported was varied from 100 to 900 mg/day. In the current meta-analysis study, a dosage of 100–150 mg/day of CoQ10 supplements was significantly beneficial in decreased SBP compared with dosage of ≥ 150 mg/day of CoQ10 supplements. A factor complicating CoQ10 therapy in the current era is the widespread use of lowering-lipid agents, including statins. Statins suppress the synthesis not only of endogen cholesterol but also of CoQ10 because both substances share the mevalonate synthetic pathway beginning with acetyl-CoA and ending with cholesterol, CoQ10 and dolichol. Furthermore, statin therapy has been shown to lower CoQ10 levels in plasma [10], but this effect has not been demonstrated in tissue. However, lipid-soluble statins, including simvastatin have been shown experimentally to decrease myocardial adenosine triphosphate [32] most likely owing to reduced CoQ10-mediated oxidative phosphorylation.

A possible mechanism of CoQ10 action on blood pressures levels is a decrease in oxidative stress by CoQ10. An increase in oxidative stress is well observed in patients with essential hypertension [33]. In blood vessels, increased oxidative stress would result in an increase in the production of the superoxide radical, which in turn rapidly reacts with endothelial nitric oxide (NO) to form peroxynitrite, thus decreasing NO availability [34]. Reducing NO availability impairs the ability of endothelium to induce NO-mediated relaxation of underlying smooth muscle with resultant vasoconstriction and elevated blood pressure. CoQ10 is a potent chain breaking lipid-soluble antioxidant with the ability to counteract this vasoconstriction and thus can decrease blood pressure. The primary function of CoQ10 in cardiac disease and hypertension is vasodilatation through a direct impact on the endothelium and vascular smooth muscle [35]. In subjects with diabetes or dyslipidemia, it was documented that CoQ10 improves endothelial function and lowers blood pressures [36]. In addition, few studies have showed that CoQ10 supplementation in hypertensive patients significantly decreased peripheral resistance accompanying lowered blood pressure and unchanged cardiac output [35, 37]. It must be kept in mind that in normal animals or humans, CoQ10 supplementation has no direct vasodilating or hypotensive effect. This confirms that the hypotensive impact of CoQ10 is specific to the state of enhanced oxidative stress occurring in metabolic disorders, including diabetic, CVD and hypertensive patients. It must be kept in mind that bioavailability assessments are crucial for interpreting supplementation studies, monitoring concentrations of CoQ10 in blood and tissues. A study on the bioavailability of ubiquinol-10 and ubiquinone-10 in aged humans found that ubiquinol-10 reached higher concentrations in plasma than ubiquinone-10 [38]. In addition, another study showed that ubiquinol-10 reached higher concentrations than ubiquinone-10 in the pancreas and liver [39]. The above-mentioned study demonstrated that ubiquinone-10 treated rats had a significant reduction in blood pressure, while ubiquinol-10 treated rats showed no significant reduction in blood pressure [39].

A major limitation in our meta-analysis study, lack of data on dietary intake was in most of the studies, which would have had major implications for all studies. It would also have been beneficial if trials had looked at pre-trial serum and/or CoQ10 concentrations and then looked at this again after supplementation; this would also have given a better understanding of absorption over a range of CoQ10 intakes. Differences were seen between trials with cross-over and non-crossover design and this would exaggerate inter-individual dietary habits in both design groups. Those who had the higher-CoQ10 diet may demonstrate less of a response to CoQ10 supplement than those who had a lower intake, with a non-crossover design being more greatly influenced by diet than a crossover design.

CoQ10 supplementation may result in reduction in SBP levels, but did not affect DBP levels among patients with metabolic diseases. Additional prospective studies regarding the effect of CoQ10 supplementation on blood pressure in patients with metabolic diseases are necessary.

Notes

Compliance with Ethical Standards

Funding

The current study was founded by a grant from the Vice-chancellor for Research, Shiraz University of Medical Sciences, Shiraz, and Iran.

Conflict of interest

None.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Reza Tabrizi
    • 1
  • Maryam Akbari
    • 1
  • Nasrin Sharifi
    • 2
  • Kamran B. Lankarani
    • 3
  • Mahmood Moosazadeh
    • 4
  • Fariba Kolahdooz
    • 5
  • Mohsen Taghizadeh
    • 2
  • Zatollah Asemi
    • 2
  1. 1.Health Policy Research Center, Institute of Health, Student Research CommitteeShiraz University of Medical SciencesShirazIslamic Republic of Iran
  2. 2.Research Center for Biochemistry and Nutrition in Metabolic DiseasesKashan University of Medical SciencesKashanIslamic Republic of Iran
  3. 3.Health Policy Research CenterShiraz University of Medical SciencesShirazIslamic Republic of Iran
  4. 4.Health Sciences Research Center, Faculty of HealthMazandaran University of Medical SciencesSariIslamic Republic of Iran
  5. 5.Indigenous and Global Health Research, Department of MedicineUniversity of AlbertaEdmontonCanada

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