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.

Reducing LDL & improving CV outcomes - systematic review

Silverman MG, et al. Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions: A systematic review and meta-analysis. JAMA 2016;316:1289-97.

Clinical question: Does reduction of CV outcomes with lipid-lowering therapy correlate with degree of LDL-lowering?

Bottom line:

  • The value of this study is mechanistic; it does not provide clinical guidance. 

  • The analysis demonstrates that CV outcome reduction of proven lipid-lowering drugs is closely associated with degree of LDL-lowering. This supports the lipid hypothesis, i.e. that lipid-lowering drugs which lower CV risk outcomes (statins, bile acid sequestrants, & ezetimibe) do so primarily by lowering LDL.

  • This study does not validate a particular lipid target, nor does it support using interventions with neutral, harmful or conflicting evidence (fibrates, niacin, or CETP inhibitors) to achieve a lipid target.



  • Databases: MEDLINE, Embase
  • Timeframe: 1966 to July 2016
  • Inclusion criteria:
    • Randomized controlled trials (RCTs)
    • Compared (1) LDL-lowering intervention to control/placebo or (2) more vs less intensive statin therapy
    • Reported cardiovascular outcomes including MI
    • Duration of at least 6 months
    • At least 50 events
  • Exclusion criteria: Trial with populations with "significant competing risks", including heart failure & chronic kidney disease
  • Additional measures for comprehensiveness:
    • References lists of identified studies, review and meta-analyses
    • Reviewed abstracts of major cardiovascular meetings held in past 2 years (no mention of which)
    • Contacted content experts

Results of systematic review

  • Included 49 RCTs (n=312,175)
    • Statin (25 trials)
    • Fibrate (9 trials)
    • Diet (4 trials)
    • CETP inhibitor (3 trials)
    • Niacin (3 trials)
    • Bile acid sequestrants (2 trials)
    • PCSK9 inhibitor (2 trials)
    • Ezetimibe (1 trial)
    • Ileal bypass surgery (1 trial)

Results of the meta-analysis

  • Mean follow-up 4.3 years
  • Mean ~absolute reduction in LDL vs placebo in trials
    • PCSK9 inhibitor -1.85 mmol/L
    • Ileal bypass -1.6 mmol/L
    • Bile acid sequestrant -0.90 mmol/L
    • Statin -0.85 mmol/L (all drugs & doses pooled)
    • Diet -0.75 mmol/L
    • Niacin -0.35 mmol/L
    • Ezetimibe -0.3 mmol/L
    • Fibrate -0.25 mmol/L
  • ~23% relative risk reduction (RRR) in major vascular events per 1 mmol/L reduction in LDL with any interventions except CETP inhibitors

Considerations & limitations

  • Generalizability & internal validity
    • Investigators excluded studies that included patients with "significant competing risk", which includes some of the landmark "negative" statin trials (CORONA, GISSI-HF, 4D, etc)
      • Results of this analysis don't apply to the subpopulations of these studies (primarily heart failure & chronic kidney disease)
      • The analysis may overestimate the true relative risk reduction since this exclusion criterion primarily excluded "negative" studies.
    • Numerous differences in populations between trials, including
      • Era (e.g. 1st fibrate/niacin trial conducted in 60s, most statin trials conducted in 1990s-2000s)
      • Primary vs secondary prevention
      • LDL before initiation of study treatment & background CV therapies
  • Results
    • Although interventions produced comparable RRRs in CV outcomes per 1-mmol/L reduction in LDL, actual achievable LDL reduction & therefore realistic CV reductions with each agent are quite different
    • This study evaluated a composite CV outcome, which bundles together outcomes of different severity & importance to patients. Different interventions may have the same effect on a composite CV outcome, but not specific components. For example, statins reduce every type of CV event (death, MI, stroke, revascularization), whereas fibrates only reduce non-fatal MI, but not death or stroke.

IMPROVE-IT - Ezetimibe added to statin following ACS

Visual abstract - Ezetimibe.png

Bottom line: In patients within 10 days of ACS, ezetimibe lowered LDL by 0.4 mmol/L and reduced the relative risk of CV events by 6% more than placebo when added to simvastatin. At a median 6 years, the addition of ezetimibe had no effect on mortality and reduced the absolute risk of any MI by 1.7% (NNT 59) and stroke by 0.6% (NNT 167).



  • Ezetimibe reduces LDL by ~25%
  • Prior to IMPROVE-IT, none of the available ezetimibe trials enrolled enough patients to adequately evaluate cardiovascular outcomes


    • Multicenter (1147 sites in 39 countries)
    • Inclusion:
      • Men & women 50+ y
      • Hospitalized for ACS within 10 days
      • LDL 1.3-3.2 mmol/L measured <24 hours of ACS onset (1.3-2.6 mmol/L if receiving lipid-lowering therapy at baseline)
    • Exclusion:
      • Clinically unstable (cardiogenic shock, severe decompensated HF, acute MR, acute VSD)
      • Recurrent symptoms of cardiac ischemia
      • Arrhythmias (vfib, sustained VT, 3o AVB, 2o AVB type 2) 
      • Planned CABG
      • CrCl <30 mL/min
      • Active liver disease
      • Statin dose equal to simvastatin >40 mg/d
    • ? screened -> 18,144 randomized
    • "Average" patient @ baseline
      • 64 y
      • Female 24%
      • White 84%, North American 38%
      • Index event: STEMI 29%, NSTEMI 47%, unstable angina 24%
      • PCI 70%
      • Time from event to randomization: 5 days
      • PMHx
        • Current smoker 33%
        • Previous MI 21%, PCI 20%, CABG 9%
        • HTN 61%
        • HF 4%
        • PAD 5%
        • Diabetes 27%
      • LDL: 2.4 mmol/L
      • Meds
        • ASA 97%
        • P2Y12 inhibitor 87%
        • ACEI 75%
        • Beta-blocker 87%

    Interventions & co-interventions

    • I: Ezetimibe 10 mg PO once daily (60% still taking at end of study)
    • C: Placebo
      • Co-interventions:
        • Simvastatin 40 mg PO once daily
          • Before 2011 amendment: If LDL >2.0 mmol/L x2 consecutive measurements: Simvastatin increased to 80 mg daily
        • If LDL >2.6 mmol/L x2 consecutive measurements: Study drug discontinued, started on open-label lipid-lowering therapy (outcomes followed & included in intention-to-treat analysis)

    Results @ median 6 years

    • LDL lowered by ~0.4 mmol/L (24%) more with ezetimibe than placebo
      • @ baseline: 2.4 mmol/L in both groups
      • @ 1 y: 1.4 vs 1.8 mmol/L
    • Statistically significant reduction in primary outcome (CV death, non-fatal MI, unstable angina requiring hospitalization, coronary revascularization occurring >30 days after randomization, or non-fatal stroke) with ezetimibe+simvastatin versus placebo+simvastatin: Hazard ratio (HR) 0.94 (95% confidence interval 0.89-0.99, p=0.016)
      • 32.7% vs 34.7% (NNT 50)
    • Key secondary outcomes
      • Death: 15.4% vs 15.3% (p=0.78)
      • Serious adverse events: Not reported
      • Any MI: 13.1% vs 14.8% (NNT 59, p=0.002)
      • Any stroke: 4.2% vs 4.8% (NNT 167, p=0.05)
    • No statistically significant differences in any adverse events
      • Cancer: 10.2% in both groups (p=0.57)
      • ALT/AST elevated 3x or more above ULN: 2.5% vs 2.3% (p=0.43)
      • Rhabdomyolysis, myopathy, or myalgias with CK elevation 5x or more above ULN: 0.6% in both groups (p=0.90)
    • Subgroups
      • Statistically significant (p<0.10) tests for interaction suggested greater relative risk reduction in primary outcome with OLDER patients (both >65 or >75), and in those with diabetes.

    Issues with internal validity?

    • Randomized, allocation-concealed, all-blind (investigators, clinicians, patients) trial analyzed using intent-to-treat analysis
    • Missing data for ~10% for primary outcome (sensitivity analyses did not show that this made any meaningful difference)
    • Notes:
      • Randomization stratified according to: Prior use of lipid-lowering therapy (yes/no), type of ACS, enrolment in EARLY ACS trial (yes/no)
      • Study continued until each patient followed >2.5 y + occurrence of 5250 events

    Additional publications of IMPROVE-IT

    • The TIMI Risk Score in Secondary Prevention may be useful to identify patients more likely to benefit from adding ezetimibe
      • 9-point risk score, 1 point for each:
        • Prior CVD: HF, prior CABG, prior stroke, PAD
        • CV risk factors: Age 75+ y, smoking, HTN, diabetes, eGFR <60
      • Significant interaction (p=0.01) between TIMI Risk Score for Secondary Prevention & benefit of adding ezetimibe in IMPROVE-IT:
        • Low risk (score 0-1): Simva+ezetimibe 14.0%, simva+placebo 13.1% (no benefit, non-significant 5% relative risk increase)
        • Intermediate risk (score 2): Simva+ezetimibe 19.3%, simva+placebo 21.5% (NNT 46, 11% relative risk reduction [RRR]; similar to overall IMPROVE-IT population)
        • High (score 3+): SImva+ezetimibe 33.9%, simva+placebo 40.2% (NNT 16, RRR 19%)
      • Importantly, baseline LDL not included in this risk score, & absolute LDL reduction was similar in all risk groups (i.e. ~0.4 mmol/L greater than placebo)
        • RRR differed between risk groups & was not proportional to LDL reduction within the range of baseline LDL (1.3-3.2 mmol/L) in IMPROVE-IT. This may represent a fundamental difference from statins (which reduce CV events proportional to LDL reduction), or reflect the low variation in baseline LDL within the study population
    • Achieving an LDL <0.8 mmol/L did not reduce in greater risk of adverse events & was associated with a lower risk of the primary outcome compared to an achieved LDL >1.8 mmol/L