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Q&A 46.6

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 published:. November 2016

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 members of the statin group 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. Myopathy risk also increases when certain medicines are used together with statins, either because both medicines can cause myopathy or because the second medicine increases the blood plasma concentration of statin. (2) Statins should be used with cautions in patient 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) It should be noted that there are other causes of elevated creatine kinase levels including in certain ethnic groups e.g. Afro-Caribbean who have higher “normal ranges”.(3) If creatine kinase 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, discontinued (1). Guidance for monitoring creatine kinase levels before and during treatment is detailed in the manufacturers’ summary of product characteristics (3-8). The Medicines and Healthcare products Regulatory Agency (MHRA) advise patients to seek prompt medical attention if they experience muscle problems while taking statins. Myopathy may not be serious to start with, but can rarely progress to fatal rhabdomyolysis.(2)

Statins competitively inhibit HMG-CoA reductase and decrease synthesis of melvalonate, 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) The total amount of the body’s CoQ10 is approximately 2g, and 0.5g must be replaced daily by endogenous synthesis and diet. (10) It plays an important role in oxidative phosphorylation in mitochondria, protects against oxidative stress produced by free radicals and regenerates antioxidants. Statins block an intermediate in the production of coenzyme Q10. This has prompted the hypothesis that, because mitochondria are involved with muscle function, statin-induced coenzyme Q10 deficiency contributes towards statin-associated myopathy. (11) Deficiency of coenzyme Q10 can lead to severe deficits in mitochondrial energy metabolism, which can present as myopathy with exercise intolerance and recurrent episodes of rhabdomyolysis and myoglobinuria (12).

Coenzyme Q10 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. In some cases the deficiency may be a primary one due to an inborn error of coenzyme Q10 biosynthesis. In other cases there may be morphological, biochemical or genetic abnormalities of the mitochondria leading to mitochondrial encephalomyopathies. Other diseases linked to coenzyme Q10 deficiency include cardiovascular disease, phenylketonuria, cancer, neurodegenerative diseases and statin-induced decrease of coenzyme Q10 (13).

Coenzyme Q10 is available as a nutritional supplement and has been used in the treatment of the above conditions in an attempt to correct the deficiency (13). Whilst it is known that exogenous coenzyme Q10 increases the plasma levels of coenzyme Q10 in humans and animals, it seems that tissue levels of coenzyme Q10 are determined by local endogenous synthesis (13).

Based on this rationale, is there any evidence that patients taking statins should use coenzyme Q10 supplementation to reduce the risk of statin-induced myopathy?

Answer

Effects of statins on coenzyme Q10 levels

A study by Bleske et al investigated the effects of coenzyme Q10 levels after 10mg atorvastatin or 20mg pravastatin was administered for 4 weeks in a randomised crossover trial to 12 healthy volunteers (14). The results showed that although there was a significant decrease in low-density lipoprotein levels, there was no decrease in serum coenzyme Q10. This study was the first to show no effect of statins on serum coenzyme Q10 levels and the authors speculated that this might have been due to factors within the group of healthy young volunteers studied, as previous investigations were carried out mainly in patients with cardiac disease or hypercholesterolaemia.

Other studies have shown a decrease in serum coenzyme Q10 levels following statin use but few have investigated the effect on tissue levels (13). In one study, 34 patients with primary hypercholesterolaemia were randomly given 20mg simvastatin or 20 mg simvastatin plus 100mg coenzyme Q10 for 3 months (15). From the 30 patients that completed the study period, a significant reduction in serum coenzyme Q10 levels was reported at 45 and 90 days in the simvastatin group compared to those that received simvastatin plus coenzyme Q10. The authors concluded that simvastatin decreased serum and possibly platelet coenzyme Q10 levels and although coenzyme Q10 supplementation did prevent this reduction there were insufficient data to recommend routine coadministration.

Effects of coenzyme Q10 on muscle symptoms

Several studies have investigated whether supplementation of coenzyme Q10 affects muscle symptoms in patients taking statins for hyperlipidaemia. Only three have shown significant positive outcomes.

Studies showing benefits

In the first study, 32 patients taking a statin according to cholesterol treatment guidelines and reporting myopathic symptoms were randomly assigned to receive a daily supplement of either 100mg of coenzyme Q10 (n=18) or 400 IU vitamin E (n=14) for 30 days (16). The study aim was to determine whether coenzyme Q10 supplementation improved muscle symptoms in patients using statins. Myopathic symptoms and interference with daily activities were assessed using the Brief Pain Inventory questionnaire before supplementation was started and then again after 30 days. All patients completed the study and compliance was reported to be 100%.

Results showed that 16 out of the 18 patients that received coenzyme Q10 reported a decrease in pain and this pain intensity decreased by 40% (p<0.001). Interference of pain with daily activities significantly improved by 38% (p<0.02). In the vitamin E group, 3 out of 14 patients reported a decrease in pain but no change in pain intensity was reported. Similarly, no improvement in interference of pain in daily activities was reported in the vitamin E group. The authors describe this as a small pilot study showing that coenzyme Q10 may be beneficial in patients using statins by ameliorating muscle symptoms, and suggest that due to its positive findings larger scale studies are now warranted. Another interesting finding from this study was that no correlation between pain score and plasma creatine kinase level was found suggesting that this may not be a sensitive marker of statin-induced myopathy.

The second pilot study evaluated the possible benefits of coenzyme Q10 and selenium in patients with statin-associated myopathy with or without increased plasma levels of creatine kinase not leading to statin withdrawal (17). A total of 60 patients with mild to moderate myalgia were randomised to one of four groups; active groups, coenzyme Q10 200mg + selenium 200micrograms, coenzyme Q10 200mg + placebo, selenium 200micrograms + placebo, and an entirely placebo group. Selenium supplementation showed no beneficial effects so data was only presented for the active (n=22) and placebo coenzyme Q10 groups only (n=18). After 3 months of treatment, statin-related effects were measured using visual analogue scale (VAS) scoring systems. In the coenzyme Q10 group, intensity of muscle pain improved in 17/22 patients (77%, p<0.001), with VAS scores decreased from 6.7±1.72 to 3.2±2.1 (p<0.01); muscle weakness improved in 12/13 patients (92%, p=0.011), with VAS scores decreased from 7.0±1.63 to 2.8±2.34 (p<0.01); muscle cramps improved in 11/13 patients (85%, p=0.024) with VAS scores decreased from 5.33±2.06 to 1.86±2.42 (p<0.01) and tiredness improved in 10/10 patients (100%, p=0.005) with VAS scores decreased from 6.7±1.34 to 1.2±1.32 (p<0.01). No significant changes in the placebo group were observed. Based on these positive results the authors speculate that coenzyme Q10 supplementation may decrease the need to withdraw these drugs if adverse effects appear.

In a more recent double blind, placebo-controlled study, 50 patients treated with statins and reporting muscle pain were recruited (18). Patients were randomised to receive 50mg twice daily coenzyme Q10 (n=25) or placebo (n=25) over a period of 30 days. The Brief Pain Inventory questionnaire was used and at the end of the study period the intensity of muscle pain, measured as the Pain Severity Score (PSS), in the coenzyme Q10 group reduced from 3.9±0.4 to 2.9±0.4 (p<0.001). The Pain Interference Score (PIS), measuring interference of pain with daily activities, also reduced from 4.0±0.4 to 2.6±0.4 (p<0.001). In the placebo group, PSS and PIS did not change significantly. The relative values of PSS and PIS significantly decreased in the Q10 group compared to the placebo group (-33.1 and -40.3%, respectively; both p<0.05). Coenzyme Q10 supplementation decreased statin-related muscle symptoms in 75% of patients. The authors concluded that coenzyme Q10 supplementation effectively reduced statin-related mild-to-moderate muscular symptoms.

Studies showing no benefits

The majority of the studies did not show a significantly beneficial effect with the use of coenzyme Q10 on statin induced myopathies. In one study, 44 patients with self-reported myalgia, who were unable to continue with adequate doses of statin therapy, were randomly assigned to treatment with either coenzyme Q10 200mg/day (n=22), or placebo (n=22), for 12 weeks (19). The study aim was to evaluate whether coenzyme Q10 could improve statin tolerance and reduce myalgic symptoms in patients with previous statin-induced myalgia. Open-label simvastatin was titrated up from a dose of 10-20mg/day to 40mg/day at 4-weekly intervals. Myalgia was assessed using a 100mm VAS. Primary outcomes were the number of patients taking simvastatin 40mg at 12 weeks, the number remaining on simvastatin therapy and the change in myalgia score. The study was powered (80%) to detect a 9-mm difference in the myalgia score between treatment groups.

No significant differences were seen between the two groups in the number of patients tolerating simvastatin 40mg (p=0.34) or in the number of patients remaining on any simvastatin dose (p=0.47). When the groups were stratified according to the severity of previous statin-induced myopathy, again no significant differences between the two groups in tolerating simvastatin (p≥0.32) or remaining on simvastatin (p≥0.32) were seen. There was a small but significant increase in the myalgia from baseline after the two therapies (p<0.001) but no difference between the change in myalgia scores (overall, p=0.63, adjusted for number of affected sites, p=0.73). No significant beneficial effect of coenzyme Q10 on simvastatin tolerability and myalgic symptoms in patients with a history of statin-related myalgia could be demonstrated. The increase in coenzyme Q10 plasma concentration (+131%) achieved with supplementation does not necessarily reflect tissue concentrations and subsequent increases in muscle or mitochondrial levels. The study had several limitations: only small increases in myalgia scores were seen so it is possible that the patients did not suffer with severe enough myalgia to observe a benefit from coenzyme Q10; there was no evidence of statin-induced mitochondrial dysfunction; and both coenzyme Q10 and simvastatin was initiated at the same time, but the statin could be discontinued if myalgia occurred. The authors highlight the need for larger, randomised, placebo-controlled trials.

In the second study, 76 patients receiving statin therapy and experiencing myalgias, either generalised or in ≥2 extremities, were randomised to either coenzyme Q10 60mg twice daily (n=40) or placebo (n=36) for three months (20). The study aimed to evaluate the benefits of coenzyme Q10 in patients with presumed statin-induced myalgias and improvement was measured using a 10cm VAS. The primary outcome was difference of the 1 month VAS score between the groups and the study was powered 90% to detect a 15mm difference. The mean VAS score was approximately 6cm in both groups at baseline; at 1 month there was a significant decrease to a mean score of approximately 4cm in both groups (p<0.01), but no significant difference was found between the groups at 1 month (p=0.58), or at 2 or 3 months. Similar results were obtained for the secondary outcome, The Short-Form McGill Pain Questionnaire which measures both sensory and affective domains; a significant decrease was seen in the median total score at the 1 month visit but no significant difference was seen between the groups at either 1 or 2 months. There were more patients meeting the definition of recurrence in the coenzyme Q10 group but post-hoc analysis of these patients showed similar results i.e. no significant difference between groups at all time-points for both the VAS score and median total scores of the Short-Form McGill Pain Questionnaire.

The authors concluded that there was a substantial placebo effect and coenzyme Q10 supplementation was not more effective than placebo at decreasing muscle pain that was presumed to be statin induced. Limitations of the study included the short duration and small sample size, although larger than the two other studies described (16;19), and the fact that causality of the myalgias was not determined so potentially it was not associated with statin therapy.

A further two studies confirm the lack of effect of coenzyme Q10 on muscle pain. One study, only published in abstract form, included 37 patients with statin induced myalgia who were randomised to coenzyme Q10 120mg/day (n=17) or placebo (n=20) for 12 weeks. Over the 12 weeks of treatment myalgia scores, using a visual analogue scale, gradually decreased in both groups (coenzyme Q10, 6.2 to 3.3; placebo, 5.9 to 3.1) but there was no significant differences between the groups (21). Another pilot study evaluated the possible effects of coenzyme Q10 and selenium supplementation in patients who had previous or ongoing experience of statin induced myopathy. Patients followed a 6 week washout period during which no statins were administered, then re-challenged to 10mg atorvastatin and only those who experienced further myopathy continued the study. Those patients that continued atorvastatin were randomised to receive 12 weeks of either coenzyme Q10 400mg/daily and selenium 200mcg daily (n=20) or matching placebo (n=21). No statistically significant changes were seen in the VAS score or other muscle function tests between the two groups throughout the study (22).