GAUSS-3 - Evolocumab vs ezetimibe in true muscle-related statin intolerance

Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: The GAUSS-3 randomized clinical trial. JAMA 2016;315:1580-90

Bottom line:

  • ~43% of patients with perceived statin-related muscle symptoms had intolerance reproducible with a N-of-1 trial;

  • In those with muscle-related statin intolerance reproducible with a N-of-1 trial, evolocumab & ezetimibe were similarly tolerated;

  • LDL-C reductions with these agents were consistent with those from other trials with LDL-C reductions of 50-55% for evolocumab & 15-20% for ezetimibe.


Patients (Phase A n=491, Phase B n=218)

  • Included
    • Adults unable to tolerate atorvastatin 10 mg/d & any other statin (any dose) or 3+ statins
    • Baseline LDL-C
      • >2.6 mmol/L + CAD
      • >3.3 mmol/L + 2 CV risk factors
      • >4.1 mmol/L + 1 CV risk factor
      • >4.9 mmol/L (at least possible familial hypercholesterolemia [FH])
  • Baseline characteristics (of Phase B patients)
    • Age 59 y
    • Male 51%
    • CV hx: CAD 31%, cerebrovascular disease/PAD 20%
    • Hx of intolerance to at least 3 statins 82%
    • Worst muscle-related adverse effects: Myalgias 80%, myositis 14%, rhabdomyolysis 6%
    • Mean LDL-C 5.7 mmol/L


  • Phase A (confirming statin-related muscle symptoms)
    • I: Atorvastatin 20 mg/d x10 weeks
    • C: Matching placebo x10 weeks
    • Note: Preceded by 4-week washout without any lipid-lowering therapy
  • Phase B (comparison of non-statin lipid-lowering monotherapy for those with reproducible statin-related muscle symptoms in Phase A)
    • I: Evolocumab 420 mg subcutaneously q1 month (+ ezetimibe placebo)
    • C: Ezetimibe 10 mg daily (+ evolocumab placebo)


Phase A: Muscle symptoms with

  • Atorvastatin but not placebo (truly statin-related muscle symptoms) 43%
  • Placebo but not atorvastatin: 27%
  • Both atorvastatin & placebo 10%
  • Neither 18%

Phase B

  • Total muscle-related events: Evolocumab 20.7%, ezetimibe 28.8%, p=0.23
    • Myalgia: 13.8% vs 21.9%
    • Elevated CK: 2.8% vs 1.4%
  • LDL-C reduction
    • Evolocumab lowered by ~53% (-2.7 mmol/L) from baseline
    • Ezetimibe lowered by 17% (-0.8 mmol/L) from baseline
    • ~37% (1.9 mmol/L) difference between groups
    • Maximal LDL-C reduction achieved at ~4 weeks & maintained during 6-month follow-up


Considerations (generalizability, internal validity, etc)

  • Low risk of bias (allocation, performance, detection, attrition) in both phases due to computer-generated randomization sequence with allocation concealed by centralized allocation and blinding of patients and outcome assessors using matching placebos
  • Phase A of this trial is generalizable to our patients who have a history of perceived intolerance to numerous statins
    • The Phase A results indicate that many of these patients can tolerate a statin with rechallenge, particularly if bias is minimized by way of a N-of-1 double-blind trial design. However, up to 43% of these patients have true statin-related myalgia that is reproducible with a N-of-1 trial;
    • Given the high cost of PCSK9 inhibitors, this raises the question of whether it would be cost-effective to perform N-of-1 trials in patients with history of statin intolerance if it allowed us to get 53% of them back onto a statin rather than a more expensive (and in the case of ezetimibe monotherapy at least, inferior) lipid-lowering therapy?
  • Generalizability of Phase B is limited by the fact that most of us cannot perform N-of-1 trials routinely. Consistent with clinical practice however, it does indicate that some of these of these patients will go on to report muscle symptoms while receiving an alternate lipid-lowering agent and even discontinue these agents. Since Phase B of this trial did not have a placebo group, this cannot show that either of these drugs were truly responsible for the muscle symptoms.