Coenzyme Q10 supplementation decreases statin-related mild-to-moderate muscle symptoms: A randomized clinical study

Design

Double-blind, randomized, placebo-controlled study

N= 50

Objective

To evaluate the benefit of Coenzyme Q10 (CoQ10) in preventing statin-associated myalgia in a specific group of patients with mild-to-moderate muscle symptoms

Study Groups

CoQ10 (n= 25)

Placebo (n= 25)

Inclusion Criteria

Statin intake for more than 6 months, statin-induced myalgia at least 6 months

Exclusion Criteria

No statin-associated myopathy, serious medical conditions or any other specific disease (e.g., hepatic, vascular, renal, or endocrine) or coagulopathy, coenzyme Q10 supplementation or anticoagulant therapy

Methods

Patients were randomized (1:1) to receive CoQ10 50 or placebo twice daily for 30 days. After the treatment, the Brief Pain Inventory (BPI) questionnaire and blood testing were collected.

Duration

Treatment: 30 days

Outcome Measures

Pain Severity Score (PSS), Pain Interference Score (PIS), laboratory values

Baseline Characteristics

CoQ10 (n= 25)

Age, years

Female/Male

Body mass index, kg/m²

Duration of therapy, years

Duration of symptoms, years

Results

Endpoint

CoQ10 (n= 25)

p-value

Reduction of intensity of myopathic pain

PSS

PIS

-33.1 ± 5.7%

-40.3 ± 7.0%

-0.4 ± 6.3%

-11.5 ± 10.2%

< 0.05

< 0.05

Results for PSS and PIS were presented in a graphical figure. The PSS and PIS scores were both significantly reduced at day 30 compared to day 0 for the CoQ10 group (3.9 to 2.9 and 4.0 to 2.6 for PSS and PIS, respectively; p< 0.001 day 0 vs. day 30 for both comparisons), but not for the placebo group.

There were no differences in any blood lipid levels, liver function enzymes, or muscle enzymes between day 0 and day 30 in either group.

LDL, low-density lipoprotein; AST, aspartate aminotransferase; ALT, alanine aminotransferase; γ-GT, gamma-glutamyl transpeptidase; CK, creatine kinase

Adverse Events

Common Adverse Events: Not disclosed

Serious Adverse Events: Not disclosed

Percentage that Discontinued due to Adverse Events: Not disclosed

Study Author Conclusions

InpharmD Researcher Critique

This study included a small sample size and excluded patients with serious medical conditions, potentially limiting the generalizability of the results as there is a substantial number of patients who take statins and may go on to experience statin-associated myopathy.

A Randomized Trial of Coenzyme Q10 in Patients with Confirmed Statin Myopathy

Design

Double-blind, cross-over trial

N= 120

Objective

To evaluate the effect of coenzyme Q10 (CoQ10) supplementation on simvastatin-associated muscle pain, muscle strength and aerobic performance in patients with confirmed statin myalgia

Study Groups

Myalgia confirmation stage:

Confirmed (n= 43)

Not confirmed (n= 77)

CoQ10 stage:

Simvastatin + CoQ10 (n= 20)

Simvastatin +  placebo (n= 18)

Inclusion Criteria

Age ≥ 20 years, history of muscle complaints during statin treatment

Exclusion Criteria

Cancer within 5 years of entry, hypo- or hyperthyroidism, hepatic disease, renal disease, using medications known to affect skeletal muscle metabolism

Methods

Patients using supplemental CoQ10 discontinued supplementation for 2 months before the study. Additionally, patients' cholesterol medications were discontinued 4 weeks prior. Patients were then randomized (1:1) to simvastatin (20 mg/day) or placebo to confirm statin myalgia for 8 weeks or until muscle symptoms persisted for 1 week or were intolerable. After a 4-week wash-out period, patients crossed over from their initial treatment to receive the alternative treatment. Only patients who experienced muscle pain on simvastatin but not on placebo and whose pain resolved within 4 weeks off treatment were entered into the CoQ10 trial.

After an additional 4-week wash-out period for patients who were eligible to enter into the CoQ10 trial, patients were then loaded for 2 weeks with either CoQ10 600 mg daily or placebo. After loading, patients were randomized again to simvastatin 20 mg/day and CoQ10 600 mg/day or simvastatin and placebo for 8 weeks or until muscle symptoms persisted for 1 week or were intolerable.  A subset of patients who completed the study then entered another 4-week washout period and crossed over from statin/CoQ10 to statin/placebo or vice versa. 

Duration

Data collection: October 2009 to 2012

Wash-out periods: 4 weeks

Treatment periods: 8 weeks or until muscle symptoms persisted for 1 week or were intolerable

Outcome Measures

Baseline Characteristics

Confirmed (n= 43)

Not confirmed (n= 77)

Age, years

Female

Body-mass index, kg/m²

Laboratory values

CK, U/L

Total cholesterol, mg/dL

LDL-C, mg/dL

HDL-C, mg/dL

Triglycerides

152

255

166

52

186

117

255

165

55

173

HDL-C, high-density lipoprotein cholesterol

Results

Endpoint

Simvastatin + CoQ10 (n= 20)

Simvastatin + placebo (n= 18)

p-value

Changes from pre-treatment to post-treatment in confirmed statin myalgic subjects who completed both phases of the crossover study

LDL-C, mg/dL

CK, U/L

Serum CoQ10, mcg/mL

VO2max, mL/kg/min

PSS

PIS

-50 ± 25

+22 ± 129

+4 ± 2

-1 ± 6

+2 ± 2

+1 ± 2

-49 ± 19

+33 ± 106

-1 ± 0

0 ± 2

+2 ± 2

+2 ± 5

NS

NS

< 0.05

NS

NS

NS

Time to pain onset, weeks

BPI pain severity and interference scores increased with simvastatin therapy (both p<0.01), irrespective of CoQ10 assignment (p=0.53 and 0.56). 

NS, not significant

Adverse Events

Common Adverse Events: Not disclosed

Serious Adverse Events: Not disclosed

Percentage that Discontinued due to Adverse Events: N/A

Study Author Conclusions

Only 36% of patients complaining of statin myalgia develop symptoms during a randomized, double-blind crossover of statin vs placebo. CoQ10 supplementation does not reduce muscle pain in patients with statin myalgia.

InpharmD Researcher Critique

Effect of coenzyme q10 on myopathic symptoms in patients treated with statins

Design

Double-blind, randomized, controlled pilot study

N= 32

Objective

To determine whether coenzyme Q10 supplementation would reduce the degree of muscle pain associated with statin treatment

Study Groups

Coenzyme Q10 (n= 18)

Vitamin E (n= 14)

Inclusion Criteria

Receiving treatment for hyperlipidemia with a HMG-CoA reductase inhibitor (statin) and reporting myopathic symptoms with no other identifiable cause of myopathy

Exclusion Criteria

Clinical evidence of hepatic, vascular, renal, or endocrine disease; coagulopathy; or other serious medical conditions

Methods

Patients were randomized to receive daily dose of 100 mg coenzyme Q10 or 400 IU of vitamin E for a duration of 30 days. Patients used supplements in addition to daily medications. Compliance was based on pill count remaining at end of treatment period. 

Myopathic symptoms and intereference with patients' daily activities were evaluated using Brief Pain Inventory Questionnaire. The questionnaire uses 4 items to measure pain intensity in previous 24 hours and 7 items measuring pain interference with daily life in the previous 24 hours, each rated on a numeric scale of 0 ("no pain") to 10 ("pain as bad as you can imagine"). Pain intensity was calculated as Pain Severity Score (PSS) and impact of pain on daily living activities and well-being was calculated as a Pain Interference Score (PIS). 

Duration

Intervention: 30 days

Outcome Measures

Baseline Characteristics

Coenzyme Q10 (n= 18)

Vitamin E (n= 14)

Age, years

Female

Body mass index, kg/m²

29.8 ± 1.7

Triglycerides (mg/dL)

Cholesterol (mg/dL)

LDL cholesterol (mg/dL)

Creatine kinase (U/L)

PSS*

PIS*

Statin use between groups was similar; most patients used simvastatin. 

*Difference not significant (NS) between groups

Results

Endpoint

Coenzyme Q10 (n= 18)

Vitamin E (n= 14)

p-Value

PSS at 30 days

% Decrease from baseline

Numeric change in score

Significance compared to baseline

2.97 ± 0.48

40 ± 11%

–2.03 ± 0.44

p< 0.001

4.73 ± 0.68

9 ± 14%

0.34 ± 0.33

NS

PIS at 30 days

% Improvement from baseline

Significance compared to baseline

2.82 ± 0.61

38 ± 14%

p< 0.02

4.25 ± 0.70

N/A

NS

Plasma CK concentrations were similar in the coenzyme Q10 and vitamin E groups at baseline and did not change at the end of the intervention period after either treatment (157 ± 23 and 103 ± 14 U/L).

Adverse Events

Study Author Conclusions

In conclusion, results suggest that coenzyme Q10 supplementation may decrease muscle pain associated with statin treatment. Thus, coenzyme Q10 supplementation may offer an alternative to stopping treatment with these vital drugs

InpharmD Researcher Critique

This was a small pilot study with an extremely limited sample size. Results may be considered exploratory. 

Effect of coenzyme Q10 supplementation on statin-induced myalgias

Design

Randomized, controlled, double-blind trial

N= 76

Objective

To assess the effect of coenzyme Q10 (CoQ10) supplementation on myalgias presumed to be caused by statins

Study Groups

CoQ10 (n= 40)

Placebo (n= 36)

Inclusion Criteria

Patients currently receiving statin therapy and experiencing myalgias that were generalized or present in ≥ 2 extremities with pain starting within 60 days of initiation of the drug or a dosage increase lasting for ≥ 2 weeks with no other cause determined

Exclusion Criteria

Serum creatine kinase level > 300 U/L, a diagnosis of fibromyalgia, and a recent traumatic injury to the affected areas

Methods

Patients were randomized to CoQ10 60 mg twice daily or placebo. Patients were paired based on visual analog scale (VAS) score. The 10-cm VAS and Short-Form McGill Pain Questionnaire were repeated with each follow-up visit. Adherence to study drug was assessed based on remaining pill count. 

Duration

3 months

Outcome Measures

Difference in 1-month VAS score

Baseline Characteristics

CoQ10 (n= 40)

Placebo (n= 36)

Age, years

Female

Race

White

Black

Other

31

8

1 

24

10

2

Recurrence

Statin

Simvastatin

Pravastatin

Atorvastatin

Rosuvastatin

22

10

7

1

22

5

7

2

Myalgia location

Calves

Thighs

Arms

Shins

33

25

13

17

31

18

16

11

No significant difference between groups

Results

Endpoint

CoQ10

Placebo

p-Value

Mean VAS score, cm

Baseline

1 month*

2 months

3 months

6.0 ± 2.2 (n= 40)

3.9 ± 2.2 (n= 34)

3.8 ± 2.2 (n= 31)

3.2 ± 2.3 (n= 27)

5.9 ± 2.0 (n= 36)

4.0 ± 2.2 (n= 32)

3.8 ± 2.7 (n= 30)

3.1 ± 2.2 (n= 26)

0.94

0.97

0.96

0.94 

At 1 month, both the CoQ10- and placebo-treated patients had a significant decrease to a mean VAS score of approximately 4 cm (p< 0.01). However, no significant difference was found between the 2 groups. 

Adverse Events

Study Author Conclusions

In conclusion, CoQ10 did not produce a greater response than placebo in the treatment of presumed statin-induced myalgias.

InpharmD Researcher Critique

A subgroup analysis revealed mean baseline VAS was significantly greater in female patients (6.5 vs. 5.3; p= 0.01), however no differences in outcomes were seen in the post hoc analysis when analyzed by gender. 

Coenzyme Q10 Liquid Supplementation in Dyslipidemic Subjects with Statin-related Clinical Symptoms: a double-blind, randomized, placebo-controlled study

Design

Double-blind, randomized, placebo-controlled trial

N= 60

Objective

To evaluate the effect of a Coenzyme Q10 (CoQ10) liquid formulation on statin-associated muscle symptoms in dyslipidemic patients with intolerance to statins and uncontrolled cholesterol levels

Study Groups

CoQ10 (n= 30)

Placebo (n= 30)

Inclusion Criteria

Aged ≥ 18 years old; caucasian; uncontrolled low-density lipoprotein cholesterol (LDL-C) level; statin intolerance

Exclusion Criteria

Secondary dyslipidemia; type 2 diabetes; impaired renal function; endocrine disorders, gastrointestinal disorders; ischemic heart disease; heart failure or stroke; malignancy; significant neurologic or psychiatric disturbances; pregnant or lactating women 

Methods

There was an initial run-in period in which patients underwent a washout period of one month and statins were stopped. Statins were started again at half of the previously taken dose if clinical symptoms were mitigated and creatinine phosphokinase (CPK) and/or transaminase levels had returned to below 3 times the upper limit of normal (ULN). Patients were then randomized (1:1) to receive either a liquid CoQ10 supplement at 100 mg or placebo daily for three months. Placebo group patients received statin at half dose of previous therapy and placebo. The CoQ10 supplement and placebo were self-administered as oral drops 1 mL once daily before, with, or after meals. The clinical index score for myalgia assessment and visual analogue scale (VAS) for pain were assessed at baseline, 1 and 3 months.

The liquid CoQ10 formulation used was a liquid formulation based on micro-sphere dispersion technology at a relatively low dosage. The authors report previous studies show that this formulation has a 3-fold higher bioavailability than other CoQ10 formulations.

Duration

Treatment: 3 months

Outcome Measures

Primary: detection of clinical symptoms (assessed using clinical index score for myalgia) and the perception of pain (assessed using VAS)

Secondary outcome: variation in lipid profile and variation in safety parameters (transaminases, CPK, and creatinine)

Baseline Characteristics

CoQ10 (n= 30)

Age, years

Female

Body-mass index, kg/m²

Laboratory values

CoQ10, mcg/L

Total cholesterol, mg/dL

LDL-C, mg/dL

HDL-C, mg/dL

TG, mg/dL

AST, IU/L

ALT, IU/L

Creatinine, mg/dL

CPK, IU/L

759.4 ± 93.8

196.4 ± 21.4

127.5 ± 11.8

44.1 ± 3.9

124.2 ± 25.8 

68.1 ± 57.2 

74.5 ± 52.1 

0.9 ± 0.4

528.6 ± 113.7

764.1 ± 95.7 

199.3 ± 22.2 

129.8 ± 12.4

43.8 ± 3.7

128.3 ± 27.5 

65.9 ± 53.1 

70.3 ± 50.2 

1.0 ± 0.5 

542.2 ± 111.9 

Scales

VAS score

Clinical index score

5.3 ± 2.4 

10.3 ± 2.1

5.6 ± 2.7 

10.9 ± 2.6 

HDL-C, high-density lipoprotein cholesterol; TG, triglycerides; AST, aspartate aminotransferase; ALT, alanine aminotransferase

Results

Endpoint 

Placebo (n= 30)

p-value

Clinical index score at 3 months

VAS Score at 3 months

Total cholesterol at 3 months, mg/dL

LDL-C at 3 months, mg/dL

No variation in the lipid profile was recorded for CoQ10 group, while there was an increase in both total cholesterol (215.7 ± 24.9 mg/dL at 1 month; 232.7± 28.1 mg/dL at 3 months) and LDL-C (144.9 ± 19.1 mg/dL at 1 month; 162.1± 25.7 at 3 months) with the placebo at 1 month (p< 0.05 vs baseline) and 3 months (p< 0.01 vs baseline).

Transaminases (AST 41.9 ± 28.1 IU/L; ALT 52.7 ± 41.3 IU/L) and CPK (265.1 ± 41.4) were significantly lower with CoQ10 after 3 months compared to placebo (AST 54.3 ± 39.5; ALT 58.8 ± 42.9; CPK 398.6 ± 90.7; p< 0.05).

Adverse Events

Not disclosed

Study Author Conclusions

The addition of CoQ10 with half dosage statin in patients with previous intolerance to statins improves the perception of clinical symptoms such as asthenia, myalgia or pain. CoQ10 was safe and effective in preventing the worsening of the lipid profile that would be expected with a reduced dosage of statin.

InpharmD Researcher Critique

The study was well designed; however, only Caucasian participants were included, which limits the generalizability of results to other race groups. The study also did not specify what type of liquid was used as a placebo; if an oil was used, it could have contributed to the increase in lipid profile parameters observed in the placebo group. Treatment-related adverse events were not reported in the study. For some results, the authors compared 3-month CoQ10 group results to 1-month placebo results which can create bias in result interpretation. Overall, the use of the specific liquid formulation of CoQ10 in the study could have contributed to increasing its efficacy; the authors reported the formulation has a bioavailability three times higher than other formulations available on the market.