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.
WHAT CAUSES STATIN MYOPATHY?
The causes of statin-induced myopathy are poorly understood.
Historically, statin-induced toxicity was thought to be caused by inhibition of the synthesis of mevalonate, leading to depletion of its metabolites, such as cholesterol, isoprenoids, and ubiquinone (coenzyme Q10). Depletion of intracellular cholesterol may lead to abnormal membrane behaviors; depletion of isoprenoids may affect intracellular signaling; depletion of coenzyme Q10 may in turn reduce mitochondrial respiratory function. Genetic factors may also play a role, contributing to pharmacokinetics and predisposing metabolic muscle disorders.23,24
Statin-induced myopathy seems to be different in randomized efficacy trials than in the clinical setting. In randomized trials, the mechanism appears to involve abnormal pharmacokinetics. The participants are carefully selected to have a low risk of muscle toxicity, but some develop toxicity when statin levels are elevated because of reduced drug breakdown and metabolism. However, in clinical practice, where a much larger group of unselected patients are exposed to statins, toxicity appears to be more related to a metabolic predisposition.25–27
Multiple minor metabolic abnormalities have been described in the muscles of patients with statin-induced muscle toxicity, suggesting that some patients have a predisposition for muscle complaints.23 About 25% of patients with recurrent rhabdomyolysis irrespective of lipid-lowering therapy have an underlying metabolic muscle disorder.28 In these vulnerable patients, minor metabolic defects are exacerbated by any agent that reduces the delivery of fat substrate to muscle, leading to muscle starvation.
This concept explains why patients may develop the same muscle complaint on different lipid-lowering agents.29,30 It also may explain why rhabdomyolysis can occur after apheresis of lipids, when no drugs have been given.31 In vulnerable patients, muscle toxicity may result from any agent that lessens the lipid substrate available to muscle rather than from the reduction of products downstream from mevalonate by statins.
SOME STATINS MAY BE LESS TOXIC
In the PRIMO study, muscle-related symptoms occurred with the various regimens as follows:
- Fluvastatin XL 40 mg—5.1%
- Pravastatin 40 mg—10.9%
- Atorvastatin 40 to 80 mg—14.9%
- Simvastatin 40 to 80 mg—18.2%.
Others have also shown that fluvastatin contributed to the smallest number of reported cases of rhabdomyolysis among statins: 55 (1.6%) of 3,339 cases.34
More recent studies indicate that rosuvastatin (Crestor), the most hydrophilic statin, may be well tolerated in those who do not tolerate other statins,35–37 though no head-to-head trial has been done.
RISK FACTORS FOR STATIN-INDUCED MYOPATHY
APPROACH TO SUSPECTED STATIN-INDUCED MYOPATHY
The recommendations that follow are based on observations from our statin myopathy clinic in more than 650 patients, of whom more than 60 have suffered rhabdomyolysis. This experience is largely anecdotal, since such patients have not been well studied in controlled trials.
Are the symptoms due to the statin?
In our experience, most patients who develop significant weakness and pain on statin therapy have normal CK levels.40
Since there is as yet no test to confirm or reject the diagnosis of statin toxicity, the first objective is to determine the likelihood that the muscle complaint is being caused by statin therapy. Factors that make statin toxicity more likely must be weighed against any features that are atypical or that favor an alternate diagnosis.
The final decision about future statin treatment depends on the balance between the expected benefit of statin therapy for each individual and the likelihood that the symptoms are due to statin therapy. Below, we provide an algorithmic approach based on history, physical examination, and laboratory findings.
Findings from the history that implicate statins
Many muscle symptoms resolve within 2 weeks of starting statin therapy. Therefore, if patients have a normal CK level and can tolerate the symptoms, we ask them to continue therapy and see if their symptoms resolve with continued use.
Symptoms that persist beyond the first 2 weeks of therapy are likely due to the statin. These include symmetric burning or pain in the large muscles during exercise that was not present before lipid-lowering therapy. Any symptom that reproducibly recurs with statin rechallenge and disappears within 2 weeks of discontinuing therapy is more likely to be caused by the statin.
Findings of the PRIMO study are representative of typical statin-induced symptoms that we see in our clinic.20
- Most patients did not identify a trigger, but the 40% who did had engaged in unusual physical exertion or had received a new drug in addition to the statin.
- Heaviness, stiffness, or cramps predominated in 70%, with only a quarter noting weakness and another quarter suffering myalgias during exercise. Pain was diffuse in 60% and more common in the lower extremities than the upper extremities.
- Physically active patients were more likely to suffer muscle symptoms than sedentary patients, echoing the observation by Sinzinger and O’Grady that athletes are especially intolerant of lipid-lowering therapy.41
- Patients who have had muscle complaints with other drug therapies such as bisphosphonates, 42 raloxifene (Evista),43 or diuretics may be having the same provocation of an underlying muscle predisposition by the statin.
- A personal or family history of muscle complaints predisposed patients to statin-induced myopathy.20
Finally, we have repeatedly found that when dyspnea and fatigue are associated with the muscle complaint, they are more likely to be caused by statins.44
