US Pharm. 2012;37(2):55-59.
From 2006 to 2010, the number of dispensed prescriptions for lipid regulators, which primarily include statins, has continuously increased from 210.4 million to 255 million.1 The 3-hydroxy-3-methyl-glutaryl-
Definition
Myopathy is defined in various ways. The National Lipid Association (NLA) defines myopathy as symptoms of myalgia in addition to an elevation in serum creatine kinase (CK) greater than 10 times the upper limit of normal (CK >10 × ULN). The American College of Cardiology (ACC), American Heart Association (AHA), and National Heart, Lung, and Blood Institute (NHLBI) use myopathy as a general term referring to any disease of the muscles, which is the most common definition.2
Epidemiology
When compared to clinical practice, the number of patients reporting statin-associated myopathy during clinical trials remains low, primarily because patients who are susceptible to, or who have an increased risk for, statin-associated adverse events are often excluded from clinical trials. Another barrier to the reporting of statin-associated myopathy is the lack of a consensual definition and diagnostic criteria. Randomized, controlled trials report about a 1.5% to 5% incidence of statin-associated myopathy.2 In the clinical practice setting, it is harder to obtain rates of statin-associated myopathy because reporting is voluntary and the FDA has its own definition for myopathy (CK ³10 × ULN). The reporting rates through the FDA Adverse Event Reporting System (AERS) from 2002 to 2004 were 0.74, 0.57, and 3.56 cases per 1 million prescriptions written in the United States. The incidence of myopathy was highest for rosuvastatin and lowest for fluvastatin.2
Statin-associated myopathy may be dose related. The Prediction of Muscular Risk in Observational Conditions (PRIMO) study reported a myopathy rate of 10.5% of patients (832 out of 7,924) who were receiving high-dose statin therapy (fluvastatin 80 mg; atorvastatin 40 or 80 mg; pravastatin 40 mg; or simvastatin 40 or 80 mg) with a median onset of 1 month. The highest predictors for myopathy were a previous history of muscle pain during lipid-lowering therapy, unexplained cramps, and an elevation in CK concentrations.
Certain statins are associated with a higher incidence of myopathy. Bruckert et al used pravastatin as a reference and demonstrated that atorvastatin and simvastatin were associated with higher incidences of myopathy, whereas fluvastatin XL was associated with a lower incidence.4 The FDA has recently advised against the use of simvastatin 80 mg (the highest FDA-approved dose) because of its association with myopathy.5 The rates of myopathy are higher in the clinical practice setting when compared to clinical trials; however, the incidence of myopathy remains a rare adverse event.
Proposed Mechanisms of Myotoxicity
The precise mechanisms underlying statin-associated myopathy are not well understood; however, theories do exist. One proposed mechanism suggests that decreased cholesterol concentrations secondary to statin therapy may result in alterations in myocyte membrane cholesterol. A second proposed mechanism involves depletion of isoprenoids that control myofiber apoptosis, and a third mechanism suggests that a depletion of ubiquinone or coenzyme Q10 (CoQ10) may account for the potential myotoxicity of statins.2,3,6,7
Reduced Sarcolemmal Cholesterol: It is proposed that because cholesterol plays a key role in cell membrane fluidity, lowering cholesterol with a statin may possibly disturb the integrity of the myocyte and lead to membrane destabilization.3,8,9 This theory is unlikely to be valid because it has been demonstrated in experimental models that nonstatin lipid-lowering agents, including fibrates, have induced myopathy through different pathways.2 Additionally, a second finding demonstrates that inherited disorders of the distal cholesterol synthetic pathway result in reduced cholesterol levels without occurrence of associated myopathy.9
Isoprenoid Depletion: Isoprenoids are lipids that are by-products of the HMG-CoA reductase pathway and play a key role in the control of myofiber apoptosis or cell death.2,3,6,9 Isoprenoids are linked to proteins by a process called farnesylation or geranyl generation. A reduction in these processes is thought to increase concentrations of cytosolic calcium, which activates a cascade leading to cell death.3,5 In addition, it has been demonstrated that statin-induced apoptosis in the smooth muscle cells is prevented by exogenous supplementation of isoprenoids, with the two most important isoprenoids for the pathway being farnesyl pyrophosphate and geranyl pyrophosphate. The positive results from isoprenoid supplementation provide support to the role of isoprenoids in statin-associated myopathy.3,9,10
Inhibition of CoQ10 or Ubiquinone: Ubiquinone or CoQ10 is a product of the HMG-CoA reductase pathway. This coenzyme is an isoprenoid that plays a key role in the electron transport chain, and reduction in CoQ10 could cause abnormal mitochondrial respiratory function, leading to impaired energy production and induce myopathy. However, changes in both plasma and intramuscular CoQ10 concentrations with statin therapy are inconsistent.2 Human and animal studies have demonstrated that statin treatment may reduce serum CoQ10 concentrations; however, myocyte CoQ10 concentrations have not consistently decreased with statin treatment and therefore a direct association between decreased CoQ10 and myopathy has not been conclusively proven.3,9,11,12 Furthermore, randomized, double-blind clinical trials have failed to show that CoQ10 supplementation decreases statin-associated myopathy.8,13
Clinical Presentation
The most common symptoms displayed with statin-associated myopathies include fatigue, flulike symptoms, and nocturnal cramping.3,14,15 Other symptoms may include unintentional weight loss, tachycardia, nausea, and brown urine from myoglobin breakdown.15 In general, patients may tolerate statin therapy for up to 1 year before statin myopathies occur.16 Nevertheless, statin therapy in combination with fibrates, particularly gemfibrozil, may induce reactions in a little over 30 days.16
Risk Factors
Patient-Dependent: Many risk factors have been identified for statin-associated myopathy, including female gender, advanced age, and low body mass index.3 Patients with diabetes mellitus, hypertension, untreated hypothyroidism, and renal or hepatic disease have also been shown to be at increased risk.3,7,17,18 Additionally, heavy alcohol use, crack cocaine use, increased exercise, and a diet rich in grapefruit juice may predispose patients to muscle breakdown.17-19
Drug-Dependent: The risk of statin-associated myopathy has been shown to increase as a patient’s statin dose increases.7 Several statins are metabolized through the CYP450 system (TABLE 1).6,9,20-26 Therefore, drugs that are inhibitors or substrates of CYP450, especially the 3A4 isoenzyme, will potentiate the risk of toxicity (TABLE 2). Cyclosporine and fluconazole are among the many agents that potentiate myopathy risk.7,14,19,27
Screening and Monitoring
Two methods to monitor for statin-associated myopathy have been proposed, including recommendations from the ACC/AHA/NHLBI and the NLA. These two proposed methods have several similarities, but also have some noteworthy and significant differences.
The ACC/AHA/NHLBI recommendations include baseline monitoring of CK levels for all patients being initiated on statin therapy. Monitoring is important at the time of initiation, as baseline elevations in CK levels are not uncommon and the knowledge of this prior to starting statin therapy may be helpful should a patient develop muscle symptoms while on statin therapy.28 Alternatively, the NLA does not recommend baseline monitoring of CK levels for all patients, as they report that this is not cost-effective. The NLA does recommend obtaining baseline CK levels only in patients at high risk for myopathy, such as older patients or those requiring combination therapy with another agent known to increase myotoxicity.29
Neither the ACC/AHA/NHLBI nor the NLA recommends routine CK level monitoring in all patients after beginning statin therapy, but instead recommends obtaining CK level only in patients who develop muscle symptoms while on statin therapy.28,29 The ACC/AHA/NHLBI recommends discontinuation of statin therapy if the CK level obtained in a symptomatic patient is >10 × ULN. If the CK level obtained in a symptomatic patient is <10 × ULN, CK levels should be monitored weekly until there is no longer a medical concern or until CK levels rise to >10 × ULN, at which point statin therapy should be discontinued. If weekly CK levels obtained in a symptomatic patient progressively increase, statin dose reduction or temporary discontinuation may be considered.28
Alternatively, according to the NLA, statin therapy should be discontinued in patients who develop intolerable muscle symptoms regardless of CK level. If the CK level obtained in a symptomatic patient is <10 × ULN but muscle symptoms are tolerable, statin therapy can be continued with or without a dose reduction and symptoms can be used as a clinical guide to stop or continue statin therapy from that point forward. If a patient develops rhabdomyolysis, defined as a CK level >10 × ULN or >10,000 IU/L with an elevation in serum creatinine or a requirement for IV hydration therapy, statin therapy should be discontinued immediately.29
Both the ACC/AHA/NHLBI and the NLA emphasize the importance of counseling patients who are beginning statin therapy to report muscle discomfort and/or weakness to a health care professional immediately, as well as the need to rule out other causes of myopathy should muscle symptoms occur while on statin therapy.28,29
Management of Myopathy
For most patients, myopathy symptoms induced by statin therapy resolve relatively quickly; however, the results of the PRIMO study showed that it may take up to 2 months for resolution of symptoms.4 There is limited evidence regarding the treatment of statin-associated myopathy. While myopathy caused by statins can be mild and can be reversed when the medication is discontinued, it may present as rhabdomyolysis or severe muscle damage. The mainstay of myopathy management is cessation of therapy; however, it is prudent for clinicians to rule out other conditions that can cause myopathy and/or CK elevations, such as hypothyroidism, overt physical activity, and alcohol abuse.28 Patients who present with clinically significant rhabdomyolysis require hospitalization and IV hydration to prevent renal damage.3
Once the patient’s muscle symptoms have resolved, clinicians have several options to treat that patient’s dyslipidemia, including the use of a lower dose of the same statin, initiation of a different statin, and/or utilization of nonstatin lipid-lowering agents.3 The decision to resume statin therapy should be carefully considered in those patients at high risk of cardiovascular disease.6 Recently, studies have evaluated safety and efficacy when switching from one statin to another. These studies have shown that in patients with a prior statin intolerance, the use of another statin is both well tolerated and efficacious.30,31 If the patient is rechallenged with statin therapy and the target LDL goal cannot be achieved, nonstatin lipid-lowering agents, such as ezetimibe and bile-acid binding resins, can be added. An alternative option is the use of nonstatin lipid-lowering agents in place of statin therapy. The use of fibrates and niacin as monotherapy has been associated with myopathy. Therefore, bile acid resins may be the optimal choice in those patients without triglyceride abnormalities who cannot tolerate statin therapy.32
Alternatives with a lower potential to induce myopathy have been explored, including the use of fluvastatin extended release, low-dose rosuvastatin, every-other-day dosing of atorvastatin or rosuvastatin, and twice weekly rosuvastatin, though these regimens are not approved by the FDA.7
There has also been interest in the use of CoQ10, Chinese red rice yeast, and vitamin D as prevention and/or management of statin-associated myopathy. Studies have not shown a correlation between intramuscular CoQ10 levels and statin-induced myopathy. Additionally, randomized, controlled trials evaluating the use of CoQ10 as prevention have yielded equivocal results.3 The NLA does not endorse the use of CoQ10 as treatment.12,13 Chinese red rice yeast has been used for its LDL-lowering effects. This agent contains lovastatin and has been tolerated in those patients with an aversion to standard statin treatment. Clinical studies have not yielded significant results.33
Additionally, the role of vitamin D has been somewhat controversial, as low levels are associated with both myalgia and poor muscle function. Studies evaluating vitamin D supplementation as prevention have been limited in their design and require validation through a larger randomized, double-blind, placebo-controlled trial.34
Educating the patient on the warning signs and risks of myopathy can prevent serious complications. While many patients may self-treat their symptoms with analgesics or pain relievers, any sudden unexplained muscle weakness or other symptoms should be conveyed to their physician.
Conclusion
Statins play a vital role in the prevention of atherosclerotic cardiovascular complications, and statin therapy continues to be a mainstay in treating patients with dyslipidemia. However, statin-associated myopathy affects up to 10% of patients receiving statin therapy.6 Although considered a minor adverse effect, it may have a significant effect on patient adherence to statin therapy. While some patients may elect to discontinue therapy after consulting their health care provider, many patients may be able to continue statins with proper management of the adverse effects.
Pharmacists in the inpatient and outpatient setting may be directly involved in the monitoring of medication therapy and tolerability, and therefore should be aware of the signs and symptoms of statin-associated myopathy. Proper assessment of patients will assist in the recognition of patients at risk. Knowledge of the currently available statins and their properties will enable pharmacists to provide appropriate recommendations for individualized treatment regimens. Once patients are initiated on statin therapy, pharmacists have the opportunity to monitor patient adherence, treatment response, and medication safety, in addition to providing ongoing patient education on statin therapy and its adverse effects. Pharmacists should continue to counsel patients on the risk and warning signs of statin-associated myopathy, as the incidence underscores the need for pharmacists to play a direct role in the monitoring of statin therapy in the inpatient and outpatient setting.
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