Efficacy and tolerability of evolocumab vs. ezetimibe in patients with muscle-related statin intolerance: the GAUSS-3 randomized clinical trial

Nissen, S. E. et al. (2016) Efficacy and tolerability of evolocumab vs. ezetimibe in patients with muscle-related statin intolerance: the GAUSS-3 randomized clinical trial. JAMA: Journal of the American Medical Association, 315(15), pp. 1580-1590. (doi: 10.1001/jama.2016.3608) (PMID:27039291)

Abstract

Importance: Muscle-related statin intolerance is reported by 5% to 20% of patients. Objective: To identify patients with muscle symptoms confirmed by statin rechallenge and compare lipid-lowering efficacy for 2 nonstatin therapies, ezetimibe and evolocumab. Design, Setting, and Participants: Two-stage randomized clinical trial including 511 adult patients with uncontrolled low-density lipoprotein cholesterol (LDL-C) levels and history of intolerance to 2 or more statins enrolled in 2013 and 2014 globally. Phase A used a 24-week crossover procedure with atorvastatin or placebo to identify patients having symptoms only with atorvastatin but not placebo. In phase B, after a 2-week washout, patients were randomized to ezetimibe or evolocumab for 24 weeks. Interventions: Phase A: atorvastatin (20 mg) vs placebo. Phase B: randomization 2:1 to subcutaneous evolocumab (420 mg monthly) or oral ezetimibe (10 mg daily). Main Outcome and Measures: Coprimary end points were the mean percent change in LDL-C level from baseline to the mean of weeks 22 and 24 levels and from baseline to week 24 levels. Results: Of the 491 patients who entered phase A (mean age, 60.7 [SD, 10.2] years; 246 women [50.1%]; 170 with coronary heart disease [34.6%]; entry mean LDL-C level, 212.3 [SD, 67.9] mg/dL), muscle symptoms occurred in 209 of 491 (42.6%) while taking atorvastatin but not while taking placebo. Of these, 199 entered phase B, along with 19 who proceeded directly to phase B for elevated creatine kinase (N = 218, with 73 randomized to ezetimibe and 145 to evolocumab; entry mean LDL-C level, 219.9 [SD, 72] mg/dL). For the mean of weeks 22 and 24, LDL-C level with ezetimibe was 183.0 mg/dL; mean percent LDL-C change, −16.7% (95% CI, −20.5% to −12.9%), absolute change, −31.0 mg/dL and with evolocumab was 103.6 mg/dL; mean percent change, −54.5% (95% CI, −57.2% to −51.8%); absolute change, −106.8 mg/dL (P < .001). LDL-C level at week 24 with ezetimibe was 181.5 mg/dL; mean percent change, −16.7% (95% CI, −20.8% to −12.5%); absolute change, −31.2 mg/dL and with evolocumab was 104.1 mg/dL; mean percent change, −52.8% (95% CI, −55.8% to −49.8%); absolute change, −102.9 mg/dL (P < .001). For the mean of weeks 22 and 24, between-group difference in LDL-C was −37.8%; absolute difference, −75.8 mg/dL. For week 24, between-group difference in LDL-C was −36.1%; absolute difference, –71.7 mg/dL. Muscle symptoms were reported in 28.8% of ezetimibe-treated patients and 20.7% of evolocumab-treated patients (log-rank P = .17). Active study drug was stopped for muscle symptoms in 5 of 73 ezetimibe-treated patients (6.8%) and 1 of 145 evolocumab-treated patients (0.7%). Conclusions and Relevance: Among patients with statin intolerance related to muscle-related adverse effects, the use of evolocumab compared with ezetimibe resulted in a significantly greater reduction in LDL-C levels after 24 weeks. Further studies are needed to assess long-term efficacy and safety.

• Item Type: Articles
• Additional Information: This study was funded by Amgen, Inc. Thousand Oaks, CA
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Preiss, Dr David and Sattar, Professor Naveed
• Authors: Nissen, S. E., Stroes, E., Dent-Acosta, R. E., Rosenson, R. S., Lehman, S. J., Sattar, N., Preiss, D., Bruckert, E., Češka, R., Lepor, N., Ballantyne, C. M., Gouni-Berthold, I., Elliott, M., Brennan, D. M., Wasserman, S. M., Somaratne, R., Scott, R., and Stein, E. A.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: JAMA: Journal of the American Medical Association
• Publisher: American Medical Association
• ISSN: 0098-7484
• ISSN (Online): 1538-3598
• Published Online: 03 April 2016