Can co-enzyme Q10 supplementation prevent or treat statin-associated muscle symptoms?

• Co-enzyme Q10 (CoQ10) is an antioxidant produced by the cholesterol biosynthesis pathway.
  
• Treatment with statins has been associated with reduced plasma CoQ10 levels, and it has been hypothesised that supplementation with CoQ10 may assist with management of statin-associated muscle symptoms (SAMS).
  
• Evidence supporting the use of CoQ10 supplements to prevent or treat SAMs in clinical practice is inconsistent.
  
• If a patient chooses to take a CoQ10 supplement, exercise caution in those taking oral anticoagulants such as warfarin due to potential for interactions.
  
• Promptly assess suspected SAMS and implement appropriate management strategies to minimise the risk of compromising patient adherence to statins.
  

With highly effective LDL-C lowering potential, statins are recommended as the first-line lipid-lowering medicine for patients at moderate or high absolute CV risk, in addition to healthy lifestyle changes.^1,2

However, despite their efficacy, muscle symptoms are widely perceived to be a common side effect of statins in clinical practice, and this can compromise adherence.³ Although the prevalence of muscle symptoms in patients taking statins is reported to be 7%-29% based on registries and observational studies,^3,4 randomised controlled trials have revealed a high background rate of patients reporting muscle symptoms on placebo.^5,6 More specifically, a systematic review of 26 randomised controlled trials reported the incidence of muscle symptoms in patients taking statins was 12.7% compared to 12.4% in the placebo group,⁵ and a double-blinded randomised controlled trial reported incidence of predefined myalgia as 9.4% in patients taking statins compared to 4.6% on placebo.⁶

While the precise mechanism of statin-associated muscle symptoms is not known, the association between statin treatment and reduced levels of CoQ10⁷ led to the hypothesis that statin-induced CoQ10 deficiency may play a key role in SAMS.⁸

CoQ10, also known as ubiquinone or 2-methyl-5, 6-dimethoxy-1, 4-benzoquinone, is an end-product of the cholesterol biosynthesis (mevalonate) pathway.^7-9 It acts as an antioxidant, is involved in electron transport in mitochondria, and may play a role in energy transfer in skeletal muscle.^7,8

In observational case studies, CoQ10 deficiency has been associated with encephalomyopathy, severe infantile multisystemic disease, cerebellar ataxia, nephrotic syndrome and isolated myopathy.^10,11-16

In addition to the well-known effect of statins on low-density lipoprotein cholesterol (LDL-C) via inhibition of HMG-CoA reductase,^17,18 a meta-analysis of 6 RCTs demonstrated that statin treatment is also associated with significant reductions in plasma CoQ10 concentrations.⁷ This may be due to statin-induced inhibition of farnesyl pyrophosphate production.¹⁹ To visualise the cholesterol biosynthesis pathway, see Figure 2 in Deichmann et al, 2010.²⁰

It is also worth noting that, as serum CoQ10 is transported by lipoproteins such as LDL, the reduction in plasma CoQ10 levels after treatment with statins may be at least partly attributed to reduced levels of LDL.⁹

Is statin treatment associated with reduction in intramuscular CoQ10?

Although reductions in plasma CoQ10 levels have been observed after treatment with statins,⁷ it is unclear whether this is accompanied by a reduction in intramuscular CoQ10 levels.²¹ Studies investigating intramuscular CoQ10 levels pre- and post-statin treatment have reported inconsistent (increased or decreased) or non-significant differences.²¹ 

Although CoQ10 deficiency has been associated with various conditions and disorders, the consequences of reduced plasma CoQ10 levels in individuals following statin treatment remain unclear. As CoQ10 deficiency has been associated with myopathies,²⁰ multiple studies have investigated whether CoQ10 supplementation can improve muscle symptoms associated with statin use.^22-27

To date, there have been mixed results across trials on the effect of CoQ10 supplementation on muscle symptoms in patients taking statins. Although some small studies have reported a significant reduction in muscle symptoms with CoQ10 supplementation,^22-24 others have shown no significant benefit.^25-27

A 2015 meta-analysis²⁸ concluded there was no significant benefit of CoQ10 on SAMS when considered across these trials, and noted significant interstudy heterogeneity (I2 = 89%, p < 0.001), with methodological limitations, particularly due to small numbers of patients (mostly < 60) in each study.²⁸ These studies used CoQ10 doses of between 100 mg and 400 mg per day, and the authors of the meta-analysis concluded that larger studies using higher doses of CoQ10 may be required to confirm their findings.²⁸

Subsequently, a randomised double-blind crossover study in which patients with confirmed SAMS (n = 38) on simvastatin 20 mg daily received either higher doses of CoQ10 (600 mg/day; n = 20) or placebo (n = 18) for 8 weeks did not report a significant difference in muscle pain.²⁹

A meta-analysis performed in 2020 assessed outcomes from 7 RCTs with 321 people included in total. Overall, the authors concluded that CoQ10 did not have a significant effect on reducing muscle pain compared with placebo.³⁰

“While there is limited clinical trial evidence showing CoQ10 supplementation can improve SAMS, a few patients in my experience do report benefit. If all else fails, CoQ10 can be trialled at a dose of at least 100 mg/day for 8 weeks with no guarantee of benefit. If improvement in symptoms is reported, a trial of stopping and restarting CoQ10 therapy could be considered to establish causality.”

Professor Gerald Watts (DSc PhD DM FRACP FRCP)

Consultant physician, Royal Perth Hospital
Winthrop Professor, School of Medicine and Pharmacy, University of Western Australia.

It is important to promptly assess the signs and symptoms of all patients who present with suspected SAMS. This can help to minimise the risk of compromising adherence to statins, and to differentiate symptoms that may be suggestive of rarer and more severe myopathies.³ This involves using a systematic approach to investigate the nature and characteristics of muscle symptoms, to determine if they are truly statin-related (see the SAMS assessment guide).^3,34

If the muscle symptoms are indeed associated with statin use, confirm there is an appropriate indication for statin use before proceeding to trial management strategies as listed in the SAMS management algorithm. Consider strategies such as reducing statin dose, intermittent dosing or switching the type of statin before making a change in cholesterol-lowering medicine, to ensure patients are not left without the benefits of statins for primary or secondary prevention of CVD.^2,3,35