After 24 weeks, patients with a history of muscle-related statin intolerance and high levels of low-density lipoprotein (LDL) cholesterol who received evolocumab had significant reductions in LDL cholesterol compared with patients who received ezetimibe.
In addition, 42.6 percent of patients with muscle-related statin intolerance experienced symptoms after taking 20 mg of atorvastatin.
Lead researcher Steven E. Nissen, MD, chairman of cardiovascular medicine at the Cleveland Clinic, presented the results in a late-breaking abstract session at the ACC scientific session on April 3. Results were simultaneously published online in JAMA.
Amgen, the manufacturer of evolocumab, funded the study.
“These findings provide unique insights into the challenging clinical problem of muscle symptoms in statin treated patients,” Nissen said in a news release. “Evolocumab significantly lowered LDL cholesterol with few patients experiencing muscle symptoms. The study has implications for both guidelines and regulatory policy, because it provides strong evidence that muscle-related statin intolerance is a real and reproducible phenomenon.”
In August, the FDA approved evolocumab to lower LDL cholesterol in adults with heterozygous familial hypercholesterolemia, homozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease. Ezetimibe and atorvastatin are also FDA-approved to lower cholesterol.
In the GAUSS-3 (Goal Achievement after Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-3) trial, the researchers enrolled patients with elevated LDL cholesterol levels who could not tolerate statins because of muscle-related adverse effects.
During the first phase of the study, 491 patients were randomly assigned in a 1:1 ratio to receive 20 mg of atorvastatin per day or matching placebo for the first 10 weeks. They then underwent a two-week washout period and then crossed over to the other therapy for another 10 weeks. Patients who had muscle symptoms in the first period did not continue taking the medication. Instead, they entered a two-week washout period before proceeding to the second 10-week period.
The second phase included 218 patients who had muscle-related adverse effects while taking atorvastatin but not placebo. During this period, patients were randomized in a 2:1 ratio to receive evolocumab or ezetimibe for 24 weeks. All patients also received placebo.
The mean age in the first phase was 60.7 years old, while the mean LDL cholesterol level was 212.3 mg/DL. In addition, 50.1 percent of patients were women and 34.6 percent had coronary heart disease. Of the patients, 42.6 percent experienced muscle symptoms while taking atorvastatin but not placebo.
Of the 218 patients in the second phase, the mean LDL cholesterol level at baseline was 219.9 mg/dL. After 24 weeks, patients who received evolocumab had a mean LDL cholesterol reduction of 54.5 percent, while patients who received ezetimibe had a mean LDL cholesterol reduction of 16.7 percent.
In addition, 20.7 percent of patients in the evolocumab group and 28.8 percent of patients in the ezetimibe group had muscle symptoms. Meanwhile, 0.7 percent and 6.8 percent, respectively, discontinued their medications due to muscle symptoms.
The researchers noted a few limitations of the study, including its modest size. The study also did not permit administering small doses of statins one to three times per week, which is a common management strategy for patients with muscle-related symptoms. In addition, they noted that 24 weeks was a relatively short study for patients who require lifetime treatment, although most patients who had statin-associated muscle-related adverse events had them within three months of initiating therapy.
Further, the researchers mentioned that many of the patients with high LDL cholesterol levels at baseline did not achieve optimal LDL cholesterol levels and needed additional therapies that may be associated with muscle symptoms. Finally, they noted that cardiovascular outcomes related to evolocumab have not been established.