Statin myopathy: A common dilemma not reflected in clinical trials
ABSTRACTAlthough statins are remarkably effective, they are still underprescribed because of concerns about muscle toxicity. We review the aspects of statin myopathy that are important to the primary care physician and provide a guide for evaluating patients on statins who present with muscle complaints. We outline the differential diagnosis, the risks and benefits of statin therapy in patients with possible toxicity, and the subsequent treatment options.
KEY POINTS
- There is little consensus on the definition of statin-induced myopathy, and it is underdiagnosed. The incidence of statin-induced muscle toxicity in randomized controlled trials is lower than in clinical practice.
- Abnormal pharmacokinetic activity contributes to toxicity, but some patients may be predisposed by underlying metabolic muscle disorders.
- A focused history and neuromusculoskeletal examination are important in the evaluation of muscle complaints that may be induced by statins.
- In patients with possible statin-induced myopathy, assessing the risks and benefits of statin therapy is essential.
- For patients who cannot tolerate statin therapy, alternatives include a “statin holiday” followed by a rechallenge with a different statin, intermittent rosuvastatin (Crestor), or resin therapy. Sometimes the best alternative is a compromise between the goal level for low-density-lipoprotein cholesterol and the level achievable with alternative therapy.
Prescribe a 6-week ‘statin holiday’ and see if symptoms resolve
In patients whose evaluation suggests statin myopathy, we stop all lipid-lowering therapy for 6 weeks and see if symptoms resolve and if grip and hip strength increase by dynamometry.
We often give these patient supplements of 600 mg daily of a bioavailable source of coenzyme Q10 and fish oil during this statin holiday. The data supporting the use of these supplements are mixed but the risks are minimal.5 In patients whose evaluation suggests a primary disorder in fatty acid oxidation, we add a trial of l-carnitine supplementation if symptoms do not resolve after a 6-week course of the coenzyme Q10 and fish oil.
If symptoms persist or if resolution is unclear at 6 weeks, we extend the holiday for an additional 6 weeks, except in patients with recent unstable coronary disease: for these patients, unless there is evidence of rhabdomyolysis, we believe that the benefits of continued statin therapy exceed the risks.
If the initial evaluation is consistent with statin myopathy and the neuromuscular symptoms (myalgias and weakness) do not respond within a few months of statin withdrawal, neurologic consultation is indicated to evaluate for an underlying neurologic disorder that has become symptomatic during statin therapy but whose existence is independent of the statin therapy. In some cases, the preexisting neurologic disorder may become symptomatic because of the statin therapy and remain symptomatic despite discontinuation of the statin therapy.
Restarting lipid-lowering therapy
Once the myopathy symptoms have abated or are controlled, a rechallenge of statin therapy is in order for those whose risk profile suggests greater benefit from statin therapy.
We consider the complete statin exposure history and any concomitant therapy that may have been competing with cytochrome P450 (CYP) metabolism of statins in designing an alternate lipid-lowering plan.
For patients with known coronary or vascular disease, in whom the survival benefit of statins is greatest, we generally try to find a statin regimen that is tolerable. Long-acting fluvastatin or a statin with less CYP dependence, such as pravastatin, is often successful.59 For patients whose myopathy has recurred with multiple statin rechallenges or whose lipid-lowering goal requires a more potent therapy, rosuvastatin in alternate-day or once- or twice-a-week schedules is efficacious and well tolerated in many patients.36,37,60 Of note, however, although such alternate-day therapies may produce excellent reductions in cholesterol levels, these regimens have not been proven to reduce cardiovascular end points.
Alternative lipid-lowering therapy. Occasionally, a patient cannot tolerate even intermittent rosuvastatin. In these cases, we prescribe resin therapy, which is well tolerated in those with recurrent statin myopathy.61
Although some believe that ezetimibe (Zetia) is an option for these patients, we do not agree, since it often causes similar muscle complaints in the most sensitive statin myopathy patients.30 Furthermore, ezetimibe has not been shown to improve cardiac end points.
Red yeast rice is also not a safe alternative in these patients, in whom muscle complaints and CK elevations frequently develop anew on this unregulated supplement despite its low lovastatin equivalence, 6 mg a day.62 A recent study showed that there is wide variability in the amount of lovastatin in over-the-counter red yeast rice; the median dose was 6 mg, and the maximum dose was 14.5 mg.63
The ultimate lipid-lowering plan for most of these patients will require a compromise between the ideal LDL-C goal and the LDL-C level that is achievable with these alternate attempts at lipid lowering.
While combination therapy may be attractive in patients with combined lipid disorders and no muscle complaints, fibrates are more likely to cause muscle toxicity per dose prescribed than statins, and the addition of fibrates to statin therapy increases the risks of muscle reactions.64,65 The evidence that fibrates reduce cardiovascular end points is much less robust than that for statins, which further reduces enthusiasm for combination therapy in patients with statin muscle toxicity.66,67
