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Statins are considered to be a cornerstone of pharmacologic approaches to cholesterol reduction.1 However, between 5% and 20% of patients who meet the requirements for statin treatment are unable to tolerate the recommended doses of these agents, due to muscle-related adverse effects.2,3 While a small percentage of patients have elevated serum creatine kinase (CK) levels, most do not and therefore the diagnosis of muscle-related statin intolerance must be made on the basis of subjective self-report. Patients who discontinue statin treatment as a result of these symptoms often receive treatment with ezetimibe or with subtherapeutic doses of statins, but these approaches typically do not result in the 50% reduction recommended by current guidelines.1,3,4,5
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have shown efficacy in lowering LDL-C levels without causing increasing muscle-related adverse events, even in patients who have experienced these symptoms in the past, making them a promising alternative therapy for this population.3
A recent study—the GAUSS-3 (Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-3) trial3—was designed to “first identify patients with statin-induced muscular symptoms during a placebo-controlled statin rechallenge procedure” and subsequently to “compare the effectiveness and tolerability of two nonstatin therapies—ezetimibe and evolocumab, a PCSK9 inhibitor.” The researchers conducted a two-stage randomized clinical trial of patients aged 18 to 80 years (n=511) with uncontrolled LDL-C levels and an inability to tolerate atorvastatin at 10 mg and any other statin at any dose, or ≥3 statins, with one at the lowest average daily starting dose and two other statins at any dose.
A Two-Phase Study
Phase A: After an initial four-week washout period, in which all lipid-lowering agents were eliminated, participants were enrolled in phase A—a double-blind, placebo-controlled crossover procedure, in which patients received atorvastatin (20 mg daily) or placebo for a 10-week period, followed by a two-week washout (Period 1).
In Period 2, patients crossed over to the alternative therapy for a second 10-week period. Patients who experienced intolerable muscle symptoms during the first period were not required to completed the full 10 weeks but immediately entered the two-week washout period.
Phase B: Patients who experienced muscle-related adverse effects while taking atorvastatin, but not while taking placebo, were eligible for phase B, in which they were randomized to 24 weeks of either ezetimibe or evolocumab.
Patients with a documented history of CK elevation >10 times the upper limit of normal, accompanied by muscle symptoms while taking statins, and whose symptoms resolved upon discontinuation, were eligible to enter directly into phase B.
