Mechanisms implicating statins in other drug interactions include inhibition of CYP2C9, glucuronidation, and organic anion transporting polypeptide (OATP).31 Concomitant treatment with gemfibrozil and a statin produces a significant interaction, as this combination inhibits CYP2C9 and glucuronidation, resulting in marked increases in statin exposure. Similarly, the coadministration of a statin with cyclosporine is clinically relevant. Cyclosporine blocks another key step in statin metabolism, OATP, resulting in elevated concentrations of nearly all statins. The concomitant use of cyclosporine with lovastatin, simvastatin, or pitavastatin is contraindicated, whereas most other agents require dose limitations.18,23,25,31
Do statins possess a dose-dependent threshold for adverse events?
A general dose-dependent threshold for AEs has been observed with statin therapy. This upper limit is more apparent with certain statins and primarily manifests as myotoxicity or increased hepatic transaminase levels. High-dose simvastatin has shown the most evidence regarding increased myopathy. In the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trial, 53 patients (0.9%) in the simvastatin 80-mg group experienced myopathy, including 7 cases (0.1%) of rhabdomyolysis, over a mean of 6.7 years of follow-up.34 By comparison, there were 2 reports of myopathy (0.03%) in the 20-mg group. Similarly, in Phase Z of the A to Z trial, 9 reports (0.4%) of myopathy, including 3 cases of rhabdomyolysis (0.13%), were reported with simvastatin 80 mg over a median of 2 years of follow-up, compared to none with lower doses.35 Lower rates of myopathy and rhabdomyolysis (0.0%-0.3% and 0.0%-0.1%, respectively) were found with atorvastatin 80 mg, fluvastatin 80 mg, and rosuvastatin 40 mg in major trials.36 These data prompted the FDA to publish an advisory on simvastatin dose limitations, including restricting the 80-mg dose.18 A threshold also has been observed with other statins, as an approximate 3-fold higher incidence of creatine kinase (CK) and hepatic transaminase elevations occur when titrating from moderate to maximal doses.37
Should ethnicity be a factor in selecting a statin?
While no specific recommendations presently exist regarding the selection of statin therapy based on ethnicity, rosuvastatin doses, including the 5-mg starting dose, should be reduced in patients of Asian ancestry because of a 2-fold increase in pharmacokinetic parameters compared to whites.38 Otherwise, the few studies evaluating individual agents among various ethnic groups generally suggest similar effects on pharmacokinetic parameters, lipid changes, and CV outcomes.
One study compared pharmacokinetic parameters of pitavastatin between healthy Caucasian and Japanese men.39 Pitavastatin demonstrated pharmacokinetic bioequivalence between the 2 groups with no clinically relevant differences. A substudy of ASCOT assessed the lipid effects of atorvastatin among whites, blacks, and South Asians.40 No significant differences were observed in the reductions in total cholesterol, LDL-C, or triglycerides. Lastly, outcomes were evaluated among different ethnicities in the JUPITER study.41 Similar reductions in major CV events were noted for whites versus non-whites with Hispanics and blacks experiencing comparable risk reductions.
How should statin-associated myalgia be managed?
Approximately 11% of patients receiving moderate- to high-dose statin therapy experience muscle symptoms.42 This common AE can greatly affect therapy by reducing quality of life and adherence and limiting treatment outcomes. A step-wise approach can be implemented to minimize the risk of myotoxicity.
The first step is to avoid critical drug interactions that increase statin exposure. The statins most susceptible to interactions are those metabolized by CYP3A4—simvastatin, lovastatin, and atorvastatin. Medications commonly used that inhibit CYP3A4 include macrolide antibiotics and azole antifungals.42
Second, establishing a firm diagnosis of statin- associated myalgia is critical. This is often challenging given that many comorbid conditions (eg, arthritis) are associated with muscle symptoms. Ruling out other possible contributors, such as thyroid dysfunction, electrolyte abnormalities, and recent muscle injury, also should be considered. Temporary discontinuation of the statin to determine if symptoms improve is suggested. Monitoring the CK level is prudent in symptomatic patients to gauge potential myotoxicity and determine if therapy should be discontinued. The National Lipid Association recommends stopping statin therapy when signs and symptoms of rhabdomyolysis are present, including CK >10,000 IU/L or >10 times the upper limit of normal with elevated serum creatinine or requiring intravenous hydration.42
Other steps include switching to a different statin, reducing the statin dose, or using intermittent dosing (eg, every other day or twice weekly) with an extended half-life statin (eg, atorvastatin or rosuvastatin).42 Lastly, a bile acid resin or the cholesterol absorption inhibitor ezetimibe can be used. These classes produce only moderate reductions in LDL-C (~20%) but are unlikely to cause muscle symptoms.
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