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Should patients on statins take Coenzyme Q10 supplementation to reduce the risk of statin-induced myopathy?

Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals

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Date prepared: March 2019

Background

The 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors, commonly known as statins are widely used as lipid lowering agents in the primary and secondary prevention of cardiovascular events. There are five statins currently licensed in the UK: atorvastatin, fluvastatin, pravastatin, rosuvastatin and simvastatin (1).

Muscle-related problems are the most frequently reported side effects of statins. The risk of myopathy is increased with all statins and is known to be dose dependent. This risk increases when certain medicines are used together with statins, either because both medicines can cause myopathy or because the second medicine increased the plasma concentration of the statin (2). Statins should be used with caution in patients at increased risk of muscle toxicity, including those with a personal or family history of muscular disorder, previous history of muscular toxicity, a high alcohol intake, renal impairment or hypothyroidism (1). Creatine kinase (CK) is often used to establish muscle damage including myopathy, though it should be noted that there are other causes of elevated CK levels including alcohol and drug use, trauma and hypothyroidism. In addition, certain ethnic groups, such as people of Afro-Caribbean origin are considered to have higher reference ranges (3). If CK levels are markedly elevated (greater than 5 times the upper limit of normal) treatment with a statin should not be started, or in patients already on a statin, it should be discontinued (1). Guidance for monitoring CK levels before and during treatment is detailed in the manufacturers’ summary of product characteristics for each of the individual statins (4-8). The Medicines and Healthcare products Regulatory Agency (MHRA) advises patients to seek prompt medical attention if they experience muscle problems while taking statins. Myopathy may not be serious to start with, but it can, in rare cases, progress to fatal rhabdomyolysis (2).

Statins competitively inhibit the HMG-CoA reductase enzyme and decrease synthesis of mevalonate, which is involved in the cholesterol synthesis pathway (9). The mechanism of statin-induced myopathy is unknown but one possible mechanism suggested is due to mitochondrial dysfunction caused by reduced intramuscular coenzyme Q10 (9). Coenzyme Q10 (CoQ10), also known as ubiquinone, is a fat-soluble antioxidant found in all cell types throughout the body (10, 11). The total amount of the body’s CoQ10 is approximately 2g, and 0.5g must be replaced daily by endogenous synthesis and diet (11). It plays an important role in oxidative phosphorylation in mitochondria, protects against oxidative stress produced by free radicals and regenerates certain antioxidants. Statins block an intermediate in the production of CoQ10, which has prompted the hypothesis that, because mitochondria are involved with muscle function, statin-induced CoQ10 deficiency contributes towards statin-associated myopathy (12).

Deficiency of CoQ10 can lead to severe deficits in mitochondrial energy metabolism, which can present as myopathy with exercise intolerance and recurrent episodes of rhabdomyolysis and myoglobinuria (13). CoQ10 deficiency has been reported in a variety of disorders, although it is unclear whether this deficiency is the cause of the disease or a consequence. It may be a primary deficiency in some cases, such as an inborn error of CoQ10 biosynthesis. In other cases, there may be morphological, biochemical or genetic abnormalities of the mitochondria leading to mitochondrial encephalomyopathies. Other diseases linked to CoQ10 deficiency include cardiovascular disease, phenylketonuria, cancer and neurodegenerative diseases (14).

CoQ10 is available as a nutritional supplement and has been used in the treatment of the above conditions in an attempt to correct the deficiency (11). Whilst it is known that exogenous CoQ10 increases the plasma levels of CoQ10 in humans and animals, it seems that tissue levels of CoQ10 are determined by local endogenous synthesis (14).

Based on this rationale, is there any clinical evidence to indicate that patients taking statins should use CoQ10 supplementation to reduce the risk of statin-induced myopathy?

Answer

Effects of statins on coenzyme Q10 levels

A meta-analysis of twelve randomised controlled trials (RCTs) looked at the effect of statin use on circulating CoQ10 levels and included 1776 participants, with varying indications for statin use (10). Treatment with various statins for durations of between 14 days to 26 weeks significantly decreased circulating CoQ10 levels compared with placebo (p=0.001). The decrease in CoQ10 levels was not associated with the duration of statin treatment nor with the intensity of statin used. Subgroup analysis showed that there was no obvious difference between the effects of lipophilic and hydrophilic statins (p=0.320). Although levels of CoQ10 were statistically significantly lower with statins compared with placebo, the magnitude of effect cannot be assessed from the paper as it is not clear what units the magnitude of the reduction is in (10). In addition, no detail was presented in the manuscript regarding specific statins used, their doses, frequencies and indications.

In a randomised, double blind study, 49 patients in Japan with hypercholesterolemia were given atorvastatin 10mg daily for 16 weeks. Half (n=24) were supplemented with 100mg daily of CoQ10, while the other half (n=25) received matched placebo. In participants in the placebo group, there was a mean decrease in serum CoQ10 levels by 42% compared to baseline (p < 0.0001). Participants supplemented with plasma CoQ10 showed an increase in plasma CoQ10 levels by 127% compared to baseline (p < 0.0001). At the end of the study (week 12), there were no differences between the two groups with respect to levels of total cholesterol, serum low-density lipoprotein (LDL-C), high-density lipoprotein (HDL-C), triglyceride or apolipoprotein A1 levels. Changes in plasma CoQ10 levels appeared to be unrelated to the changes in CK levels (15).

These studies provide some evidence to support the hypothesis that statins may affect the synthesis of CoQ10, resulting in reduced CoQ10 serum levels and that supplementing with CoQ10 can help to increase circulating CoQ10 levels. However they do not address the question of whether or not using CoQ10 supplements alongside statins helps to avoid or reduce any muscle symptoms associated with statin use nor whether CoQ10 supplement use improves adherence to statins.

Effects of coenzyme Q10 on muscle symptoms

The effect of CoQ10 supplementation on muscle symptoms associated with statin use is not well established. Several studies have investigated whether there is any benefit in the use of CoQ10 with respect to muscle symptoms, however the results are conflicting.

A meta-analysis of RCTs evaluated the effects of CoQ10 on statin-induced myopathy. It included results from twelve RCTs, with a total of 575 patients (294 of which were on CoQ10 supplementation and 281 on placebo). The duration of included trials ranged from 30 days to 3 months. All studies included patients being treated with statin and reporting muscle symptoms although the specific statin and doses used were not specified. The manuscript did not detail what doses of CoQ10 were used in the studies either. Despite significant heterogeneity being observed in the included studies, this was found to be independent of the CoQ10 doses used. (16). With respect to statin-associated muscle symptoms reported by patients, use of CoQ10 alongside the statin improved reported muscle pain (p ................
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