Does Coenzyme Q10 Supplementation Mitigate Statin-Associated Muscle Symptoms?

Pharmacological and Methodological Considerations

Beth A. Taylor

Disclosures

Am J Cardiovasc Drugs. 2018;18(2):75-82. 

In This Article

Methodological Issues With CoQ10 Trials

The discrepancy between published trials of CoQ10 for treating SAMS is not readily explained by the patient population studied, the statins administered, or the duration of therapy (see Table 1). Alternatively, it may be attributable to the imprecise nature of defining SAMS. The major difficulty in diagnosing and treating SAMS is that clinicians lack effective biomarkers and tests to confirm diagnosis. Direct causality of muscle side effects to statin therapy is hard to prove, since other commonly used medications including neuroleptics, fibrates, antiviral agents, immunosuppressants and analgesics can produce myopathy.[10] Indeed, a substantial portion of SAMS appears to be non-specific muscle pain; that is, pain attributable to factors independent of statin therapy. For example, in our The Effect of Statins on Muscle Performance, or STOMP, study, 4.6% of patients receiving placebo had SAMS compared to 9.4% of patients similarly dechallenged and rechallenged with atorvastatin.[7]

In our recently published Coenzyme Q10 in Statin Myopathy study, we used a double-blind, placebo-controlled, cross-over protocol to confirm SAMS in 120 patients with a history of statin-associated muscle complaints.[40] After a 4-week washout period from all cholesterol-lowering drugs, the subjects were randomized to simvastatin 20 mg daily or placebo for 8 weeks, washed out for 4 weeks, and then crossed over to alternative therapy. Only 35.8% of patients (n = 43) experienced myalgia on simvastatin and did not experience myalgia on placebo, what was termed true or confirmed statin myalgia, and 17.5% of patients (n = 21) had no symptoms on simvastatin or placebo. However, 29.2% (n = 35) experienced pain on placebo, but not on simvastatin, and 17.5% (n = 21) experienced pain on both simvastatin and placebo during the confirmation phase. In a similarly designed clinical trial, 209 of 491 patients (42.6%) with a history of muscle-related side effects reported SAMS on 20 mg atorvastatin alone, whereas 130 of the 491 patients (26.5%) reported SAMS on placebo alone.[46] A systematic review of 42 clinical trials found the percentage of muscle problems with statin therapy to be only slightly (and non-significantly) higher than with placebo (12.7 vs 12.4%), again reflecting the high background rate of non-specific muscle problems in these trials.[47] Indeed, some researchers and clinicians have stated that SAMS do not exist and instead are a product of the "nocebo effect",[48] citing recent clinical trial data showing an increase in SAMS only when patients shifted from double-blind to open-label statin administration.[49] These studies suggest that only 30–50% of patients with self-reported SAMS in previous CoQ10 studies actually had muscle pain due to statins and not from other causes. Consequently, both the uncertain diagnosis and causality of SAMS may contribute to the varying results from human CoQ10 trials.

Of note is that several recent publications have begun to address the diagnostic limitation in distinguishing between SAMS and non-specific muscle symptoms. In 2014, the National Lipid Association Statin Muscle Safety Task Force published a proposed Statin Myalgia Clinical Index (SMCI) that attempted to classify the likelihood of true SAMS.[10] The SMCI was updated and revised as the Statin-Associated Muscle Symptoms-Clinical Index (SAMS-CI) based on author interviews and physician feedback.[50] The SAMS-CI scores SAMS as probable (score 9–11), possible (score 7–8), and unlikely (score 2–6) based on four scales of muscle symptom characteristics: location; pattern; timing of onset; and timing of improvement after statin withdrawal. In 2016, a Canadian working group proposed several modifications to the original SMCI, based on the addition of several more decisive factors such as the existence of muscle pain with non-statin cholesterollowering drugs,[43] but to date these proposed modifications have not been incorporated into a published questionnaire. A recent publication validating the SAMS-CI from the Coenzyme Q10 in Statin Myopathy trial[40] reported that patients with confirmed SAMS did indeed exhibit higher scores than patients with muscle symptoms on placebo alone, muscle symptoms on both treatments, or no muscle symptoms on either treatment.[51] While only half of the patients with confirmed SAMS were appropriately classified by the SAMS-CI as having possible or probable SAMS, 65 of 76 (86%) of patients who did not test positive for SAMS were classified as unlikely with the index, such that the negative predictive value (NPV) was 76.5%. Lowering the cutoff for classification as unlikely to 4 from 6 points increased NPV to 90.6%.[51] These preliminary results suggest that the SAMS-CI may be an effective tool to identify patients with self-reported SAMS who are unlikely to have true SAMS, and could be used by clinicians and researchers to ensure that more patients with confirmed SAMS are enrolled in clinical trials assessing effectiveness of CoQ10 to treat statin intolerance.

processing....