title: Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance: The GAUSS-3 Randomized Clinical Trial.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  Phase A: atorvastatin (20 mg) vs placebo. Phase B: randomization 2:1 to subcutaneous evolocumab (420 mg monthly) or oral ezetimibe (10 mg daily).
  
  
  METHODS
  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
  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.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT01984424.
authors.affiliation: Cleveland Clinic, Cleveland, Ohio.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Nissen
authors.affiliation: University of Amsterdam Faculty of Medicine, Amsterdam, the Netherlands.
authors.forename: Erik
authors.initials: E
authors.lastname: Stroes
authors.affiliation: Amgen Inc, Thousand Oaks, California.
authors.forename: Ricardo E
authors.initials: RE
authors.lastname: Dent-Acosta
authors.affiliation: School of Medicine at Mount Sinai, New York, New York.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Rosenson
authors.affiliation: Flinders University, Bedford Park, SA, Australia.
authors.forename: Sam J
authors.initials: SJ
authors.lastname: Lehman
authors.affiliation: University of Glasgow, Glasgow, United Kingdom.
authors.forename: Naveed
authors.initials: N
authors.lastname: Sattar
authors.affiliation: Clinical Trial Service Unit, University of Oxford, Oxford, United Kingdom8Epidemiological Services Unit, University of Oxford, Oxford, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Preiss
authors.affiliation: University Hospital of Paris 6, Paris, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Bruckert
authors.affiliation: Charles University in Prague, Prague, Czech Republic11General University Hospital in Prague, Prague, Czech Republic.
authors.forename: Richard
authors.initials: R
authors.lastname: Ceška
authors.affiliation: David Geffen School of Medicine at the University of California, Los Angeles.
authors.forename: Norman
authors.initials: N
authors.lastname: Lepor
authors.affiliation: Baylor College of Medicine, Houston, Texas.
authors.forename: Christie M
authors.initials: CM
authors.lastname: Ballantyne
authors.affiliation: Center for Endocrinology, Diabetes and Preventive Medicine, University of Cologne, Cologne, Germany.
authors.forename: Ioanna
authors.initials: I
authors.lastname: Gouni-Berthold
authors.affiliation: Amgen Inc, Thousand Oaks, California.
authors.forename: Mary
authors.initials: M
authors.lastname: Elliott
authors.affiliation: Cleveland Clinic, Cleveland, Ohio.
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Brennan
authors.affiliation: Amgen Inc, Thousand Oaks, California.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Wasserman
authors.affiliation: Amgen Inc, Thousand Oaks, California.
authors.forename: Ransi
authors.initials: R
authors.lastname: Somaratne
authors.affiliation: Amgen Inc, Thousand Oaks, California.
authors.forename: Rob
authors.initials: R
authors.lastname: Scott
authors.affiliation: Metabolic and Atherosclerosis Research Center, Cincinnati, Ohio.
authors.forename: Evan A
authors.initials: EA
authors.lastname: Stein
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000924:Anticholesteremic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000069059:Atorvastatin / Q000009:adverse effects; D015415:Biomarkers / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood*; D003402:Creatine Kinase / Q000097:blood; D018592:Cross-Over Studies; D004311:Double-Blind Method; D000069438:Ezetimibe / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009135:Muscular Diseases / Q000097:blood / Q000139:chemically induced / Q000517:prevention & control*; D063806:Myalgia / Q000097:blood / Q000139:chemically induced / Q000517:prevention & control; D009220:Myositis / Q000097:blood / Q000139:chemically induced / Q000517:prevention & control; D012206:Rhabdomyolysis / Q000097:blood / Q000139:chemically induced / Q000517:prevention & control; D013997:Time Factors
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000924:Anticholesteremic Agents; D015415:Biomarkers; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000069059:Atorvastatin; D003402:Creatine Kinase; D000069438:Ezetimibe; C577155:evolocumab