Coenzyme Q10 supplementation for the treatment of statin-associated muscle symptoms (2024)

Abstract

Plain language summary

Statins are medications that help lower cholesterol and treat cardiovascular disease, but muscle pain is the most common side effect of statins. Statins decrease the body's levels of coenzyme Q10 (CoQ10), and thus taking CoQ10 supplements (which are widely available over the counter in pharmacies) may help treat the muscle side effects from statins. However, the results of previous studies are not clear whether CoQ10 is effective for treating statin-associated muscle symptoms. Therefore, the purpose of this study was to analyze whether the use of CoQ10 supplements improved statin-associated muscle side effects in a large group of individuals. When the authors compared the survey responses of 64 CoQ10 users versus those of 447 non-CoQ10 users with statin-associated muscle symptoms, CoQ10 supplements did not improve their muscle symptoms.

Tweetable abstract

Coenzyme Q10 supplements do not improve statin-associated muscle symptoms or the continuation of statin therapy in patients with a history of statin-associated muscle symptoms.

Patients & methods

Results

Of the original sample of 634 in the study who had SAMS [15], 511 participants met the inclusion criteria for this study. The baseline characteristics of all participants and stratified by CoQ10 usage are presented in Table1. The mean (± standard deviation) age of the participants was 58±11 years, with 54% males and 100% Caucasian. The participants had been on a wide range of statin types in the past, with the most common being atorvastatin (n=261; 51.1%). At the time of the survey, about half ofthe participants had discontinued cholesterol-lowering therapy (50.3%) or were taking a non-statin (16.2%). Overall, 29.9% of the participants had a resolution of SAMS (n=153), and overall, 64 participants were using CoQ10 (12.5%). CoQ10 users were significantly more likely to be smokers, to be obese and to have a family history of muscle disease compared with non-users of CoQ10. Table2 shows the baseline characteristics of all participants and stratified by whether or not the participants had a resolution of SAMS. There were no significant differences among the participants that did and did not have SAMS resolved, except for the specific statin used in the past (p=0.018) and their current cholesterol-lowering therapy (p<0.001).

The results for the logistic regression models for the primary outcome of SAMS resolution are presented in Table3. CoQ10 was not significantly associated with the resolution of SAMS in any model. The only variable that was significantly associated with the resolution of SAMS was when a participant took lovastatin compared with atorvastatin. The odds of SAMS resolving were higher with lovastatin than atorvastatin (OR: 4.50 [95% CI: 1.77–11.43]; p=0.011). However, those results should be interpreted with caution because of the extremely small sample size (only two CoQ10 users were taking lovastatin) and multiple comparisons. The results for the secondary outcome of statin continuation despite a history of SAMS are presented in Table4. Of the 511 total participants that had experienced SAMS in the past, only 171 (33%) were still taking a statin currently. CoQ10 use was not significantly associated with the continuation of statin therapy in any model, nor were any of the other variables.

Discussion

In this observational, multicenter study, CoQ10 use was not significantly associated with the resolution of SAMS or the continuation of statin therapy despite a past history of SAMS. This study adds to the current body of literature because it is one of the largest studies to date. These findings are important because even though the current AHA/ACC guideline recommends against the use of CoQ10 for the treatment of SAMS [2], CoQ10 is widely available over the counter and still used by many patients. Several randomized, controlled trials (RCTs) have tested the effectiveness of CoQ10 in treating SAMS [17–24], but the interpretation is unclear because some of the CoQ10 RCTs found significant benefit but others did not. Four meta-analyses of those individual RCTs have attempted to yield clarity on this issue [10–13]. One of those meta-analyses showed a significant benefit of CoQ10 for treating SAMS [11], whereas the other three did not [10,12,13]. These meta-analyses all used different methods, but the authors believe that the most likely explanation for the differences in the results of these meta-analyses are differences in power. The meta-analysis that found significant benefit for CoQ10 had the largest sample size (total n=575) [11]. The other three meta-analyses all trended toward benefit for CoQ10, but they failed to find a significant association with much smaller sample sizes (total n=253, n=220 and n=321) [10,12,13]. The findings of the present study could contribute to future meta-analyses.

Several possible explanations for the lack of benefit associated with CoQ10 for the treatment of SAMS, in this study and in previous studies, are worth noting. First, even though the sample size of this study is larger or comparable to previous studies, it still had low power to detect small beneficial effects of CoQ10 because only 64 participants reported using CoQ10. The authors estimated that SAMS would need to resolve in 2.5 times more CoQ10 users than non-users to be detectable in this study, which is an extremely large effect size. However, it does not appear that the lack of association in this study is due to low power, as none of the ORs for CoQ10 were >1 for an association with resolution of SAMS. Second, true SAMS is extremely difficult to diagnose. In order to overcome that difficulty, some previous studies restricted enrollment to only patients that passed a run-in period. For example, Taylor et al. utilized a randomized, double-blind and crossover run-in period prior to their RCT of CoQ10 for SAMS [23]. Only participants that experienced muscle pain on simvastatin, but not on placebo, were entered into the CoQ10 RCT. Only 36% of the participants passed the run-in period, demonstrating that most patients may not have true SAMS but only a nocebo effect. In the present study, the relationship between statin use and muscle symptoms must have been clear to the participants and their physician, but the study did not have a placebo run-in period like the aforementioned study by Taylor et al. However, a disadvantage of a placebo run-in period would be that it would only include participants that had an acute onset of SAMS; it would exclude participants with a more delayed onset of SAMS.

A third possible explanation for the lack of effectiveness of CoQ10 in this study and previous studies is that the dose of CoQ10 was too low. The adult human body contains approximately 2 g of CoQ10, of which 500mg must be replaced daily, either through diet or endogenous production [25]. All of the previous RCTs used doses less than 500mg per day [17–24], except for the RCT by Taylor et al., which used 600mg per day. Moreover, it is postulated that the supplement should be taken a number of weeks before starting a statin, so that the muscle stores are replete. However, the aforementioned Taylor et al. study utilized a 2-week loading period, in which the participants were treated with either placebo or CoQ10 for 2 weeks prior to the start of statin use, but they still did not detect a significant benefit with CoQ10. Some of the previous RCTs also measured plasma levels of CoQ10 [17,19,20,22–24]. In the present study, the participants did not report their dose or duration of CoQ10 use, only whether or not they were taking it. Therefore, the authors were unable to assess whether or not the participants were taking a sufficient replacement dose of CoQ10. On the other hand, the dose of CoQ10 may not make a difference in SAMS. Studies in rats showed that although dietary CoQ10 increases serum levels, it does not increase the levels of CoQ10 in muscle [26].

A fourth potential explanation for a lack of benefit is that CoQ10 supplementation may only be effective in participants with an established CoQ10 deficiency [27]. SAMS has multiple suspected etiologies, including pre-existing underlying neuromuscular disorders, auto-immune reactions and vitamin D deficiency [28]. However, this study did not measure CoQ10 serum levels in participants upon enrollment. Thus, the authors cannot confirm that all participants had a CoQ10 deficiency secondary to statin therapy, nor can they confirm that CoQ10 plasma levels significantly increased with CoQ10 use. Finally, the lack of association in this study could simply mean that CoQ10 is not effective for the treatment of SAMS. Some point out that a direct causal link between CoQ10 deficiency and SAMS has still not been well established [29–31].

This study has several limitations in addition to those described above. The major limitation is that it was not an RCT, which is the gold standard for evaluating effectiveness of an intervention. As with any observational study, cause-and-effect could not be determined – for example, did the patients stop taking the CoQ10 because it either did or did not work? The duration of CoQ10 therapy was unknown, and there was no information on whether CoQ10 had been used prophylactically or only for treatment. The bioavailability of CoQ10 is dependent on the formulation [32], but the formulation was unknown as well. The outcome of this study is subjective and reported by the participants, and thus it is subject to recall bias. Another limitation is that the survey did not collect either the participants' dietary intake or physical activity data [33]. The survey also did not collect the participants' BMI. However, the questionnaire did include whether or not the participants had obesity, and the authors adjusted both models 2 and 3 for obesity as a covariate. The authors do not expect that using obesity instead of BMI would have impacted the results in a major way because obesity was not statistically significant in either model, and the association of CoQ10 was similar regardless of which covariates were included in the models. Finally, the sample consisted entirely of Caucasian participants, and thus it is unknown whether these findings apply to other racial/ethnic groups.

Conclusion & future directions

In this multicenter, observational study of 511 Caucasians with a history of SAMS, the addition of CoQ10 for 64 participants was not significantly associated with either the resolution of SAMS or the continuation of statin therapy. The lack of association was consistent in multiple different logistic regression models, regardless of the covariates used (e.g., risk factors for SAMS or baseline differences among CoQ10 users and non-users). There are several potential explanations for this lack of CoQ10 benefit (e.g., insufficient dose, duration or formulation of CoQ10). This supports the current AHA/ACC recommendation against the use of CoQ10 in the treatment of SAMS.

Based on these and others' findings, and for several other reasons, the authors do not believe that future research should continue to investigate CoQ10 for the treatment of SAMS. The ideal clinical trial that is needed to definitively determine the effectiveness of CoQ10 for the treatment of SAMS would have an excessive number of design requirements, such as a run-in period to distinguish participants with true SAMS versus those with only nocebo effect; screening for enrollment of only participants with known CoQ10 deficiency; a loading period to ensure sufficient CoQ10 levels prior to the start of the statin; treatment with high doses of CoQ10 (at least 500mg per day); and treatment with a CoQ10 formulation with maximal bioavailability. Finally, it would need to be a randomized, placebo-controlled trial with sufficient power to detect only small benefit (and thus a very large sample size). Given the high cost of such a clinical trial, the expected small benefit of CoQ10 (based on the results of the meta-analyses) and the availability of new, alternative agents (i.e., PCSK9 inhibitors), such a trial for CoQ10 is not necessary. Future research should focus more on the prevention instead of the treatment of SAMS. For example, there are now clinical practice guidelines on the use of patients' genetics to decrease the risk of SAMS [34].

Footnotes

References

Papers of special note have been highlighted as: • of interest; •• of considerable interest