Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects 3 - GAUSS-3

Contribution To Literature:

The GAUSS-3 trial showed that evolocumab safely and reliably reduces low-density lipoprotein cholesterol (LDL-C) at 24 weeks compared with ezetimibe in a well-phenotyped group of patients with muscle-related statin intolerance.


The goal of the trial was to assess the safety and efficacy of evolocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, in patients with muscle-related statin intolerance.

Study Design

Patients with a history of intolerance to multiple statin agents were first enrolled in a run-in phase and challenged with atorvastatin or placebo for 10 weeks. Patients with intolerable symptoms only to atorvastatin (i.e., documented statin intolerance) or creatine kinase (CK) ≥10 upper limit of normal (ULN) were then randomized in a 2:1 fashion to either evolocumab (n = 145) or ezetimibe (n = 73). Evolocumab was administered as an open-label, subcutaneous injection of 420 mg monthly. Ezetimibe was given as a 10 mg oral dose daily.

  • Total number of enrollees: 218
  • Duration of follow-up: 24 weeks
  • Mean patient age: 59 years
  • Percentage female: 50%

Other salient features/characteristics:

  • Coronary artery disease: 31%
  • LDL-C: 220 mg/dl
  • Intolerance to ≥3 statin agents: 82%

Inclusion criteria:

  • LDL-C ≥100 mg/dl with coronary disease or ≥130 mg/dl with ≥2 risk factors, ≥160 mg/dl with ≥1 risk factor, or ≥190 mg/dl with no additional risk factors
  • Inability to tolerate atorvastatin 10 mg plus any other statin, or ≥3 statins with one at the lowest daily starting dose

Exclusion criteria:

  • New York Heart Association (NYHA) class III or IV heart failure
  • Uncontrolled cardiac arrhythmia
  • Uncontrolled hypertension
  • Type 1 diabetes
  • Poorly controlled type 2 diabetes
  • Uncontrolled hypothyroidism or hyperthyroidism

Principal Findings:

Co-primary endpoint #1: Mean % change in LDL-C at week 24 for evolocumab vs. ezetimibe: -52.8% vs. -16.7%, p < 0.001

Co-primary endpoint #2: Mean % change in LDL-C at weeks 22 and 24 for evolocumab vs. ezetimibe: -54.5% vs. -16.7%, p < 0.001

Secondary outcomes (evolocumab vs. ezetimibe):

  • Change in lipoprotein (a) at 24 weeks for evolocumab vs. ezetimibe: -21.1% vs. +0.2%, p < 0.001
  • Change in high-density lipoprotein cholesterol (HDL-C) at 24 weeks: +7.4% vs. 2.9%, p = 0.008
  • Change in triglycerides at 24 weeks: -2.9% vs. -1.1%, p > 0.05
  • % achieving LDL-C <70 mg/dl at 24 weeks: 27.4% vs. 0%, p < 0.001
  • Total muscle-related events: 20.7% vs. 28.8%, p > 0.05
  • CK increase > ULN: 2.8% vs. 1.4%, p > 0.05
  • Drug discontinuation for muscle symptoms: 0.7% vs. 6.8%

In an exploratory genome-wide association study (GWAS) analysis to identify genes related to statin-associated muscle symptoms (SAMS), 147 patients with confirmed SAMS were compared with 622 controls from three different trials and the screen fail patients of GAUSS-3. This identified two loci with an increased risk of SAMS: MGAT5 gene and KCNJ2/SOX9 loci; and one with a lower risk: MRPS6/ATP5O. These seemed to be related to mitochondrial energy production. Interestingly, genes reported to influence plasma statin concentration were not significantly associated with SAMS.


The results of this trial indicate that evolocumab safely and reliably reduces LDL-C at 24 weeks compared with ezetimibe in a well-phenotyped group of patients with muscle-related statin intolerance. Although >25% of patients reported muscle-related events, the rate of drug discontinuation with evolocumab was very low. There were also favorable effects on other lipoproteins. This trial adds to the growing body of evidence with PCSK9 inhibitors. Other outcomes-based trials with this and other PCSK9 inhibitors are ongoing. Longer-term safety and efficacy data are also awaited, especially for neurocognitive effects.


Presented by Dr. Erik Stroes at the American Heart Association Annual Scientific Sessions (AHA 2016), New Orleans, LA, November 15, 2016.

Nissen SE, Stroes E, Dent-Acosta RE, et al., on behalf of the GAUSS-3 Investigators. Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance: The GAUSS-3 Randomized Clinical Trial. JAMA 2016;Apr 3:[Epub ahead of print].

Editorial: Waters DD, Hsue PY, Bangalore S. PCSK9 Inhibitors for Statin Intolerance? JAMA 2016;Apr 3:[Epub ahead of print].

Presented by Dr. Steven E. Nissen at the American College of Cardiology Annual Scientific Session, Chicago, IL, April 3, 2016.

Keywords: ACC Annual Scientific Session, AHA Annual Scientific Sessions, Antibodies, Monoclonal, Cholesterol, HDL, Cholesterol, LDL, Creatine Kinase, Dyslipidemias, Genome-Wide Association Study, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Injections, Subcutaneous, Lipoprotein(a), Metabolic Syndrome, Primary Prevention, Proprotein Convertases, Risk Factors, Subtilisins, Triglycerides

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