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.

Novel screening method for familial hypercholesterolemia: Child-parent screening in primary care

Wald DS, et al. Child-parent familial hypercholesterolemia screening in primary care. N Engl J Med 2016;375:1628-37.

Bottom-line: In the UK, a child-parent FH screening strategy done at the time of routine immunizations by a GP identified FH in 1 child and 1 parent for every 360 children screened.

Lipid or FH mutation testing alone are each inadequate to diagnose FH in this population due to high false-positive rates.



  • Familial hypercholesterolemia (FH) is a genetic dyslipidemia that affects ~1 in 500 Canadians
  • Untreated FH leads to accelerated atherosclerosis;
    • By age 50, almost half of men and 20% of women with untreated FH have experienced a coronary event.
  • Only 5% of individuals with FH are properly diagnosed, often only after experiencing a cardiovascular event
  • Multiple countries have implemented various screening strategies, including screening of all adults +/- children ("universal screening"), to more selective screening of first-degree relatives of individuals identified to have FH ("cascade screening")
  • The goal of screening programs is to identify and treat FH before patients manifest clinical atherosclerosis

Who was involved in this study?

  • Timeframe: 2012-2015
  • Country: UK
  • Setting: 92 GP offices
  • Participants: 11,010 children (10,095 with valid screening test) presenting for their routine immunizations at ~1 year of age
  • Baseline characteristics
    • Median age 12.7 months
    • Family hx of premature MI 11%
    • Lipid panel, median
      • Total cholesterol 3.93 mmol/L
      • LDL 2.20 mmol/L
      • HDL 0.93 mmol/L
      • Triglycerides 0.67 mmol/L
    • Median age of parents: Mother 31 y, father 34 y

What was the screening intervention?

  1. Heel-stick capillary blood sample from the child to measure:
    • Lipid panel (total cholesterol, HDL, triglycerides)
    • Possible FH mutations (48 tested, including mutations of the LDL receptor, ApoB, & PCSK9)
  2. Both parents of a child with a positive screening test for either of the above: Venipuncture for same screening test

What counted as a "positive" screening test?

  • Children
    1. Total cholesterol >5.95 mmol/L (>99th percentile) + at least 1 FH mutation, or
    2.  Total cholesterol >5.95 mmol/L x2 (test repeated 3 months later)
  • Parents of children with a positive screening test
    1. If child had a FH mutation: Same FH mutation, or
    2. Higher cholesterol level of the 2 parents

How many children & parents had a positive screen for FH?

  • Children: Positive screening test = ~0.28% (prevalence & number needed to screen = ~360)
    • False positives:
      • 0.6% (64/10,095) had a single elevated cholesterol level (negative on repeat + no known FH mutation)
      • 0.17% (17/10,095) had a FH mutation without hyperlipidemia
  • Parents: Prevalence 0.28% (based on definition above)

What was the impact of screening?

  • Identified 1 in 360 children with FH. Notably, this likely captured every case of FH in this population based on a previous estimated prevalence of ~1 in 500;
  • Identified parents with FH at an age (31-34 y/o) where they may have already had years of atherosclerotic buildup, but were not likely to have developed a coronary event. These parents could therefore receive therapy early enough to modify their cardiovascular risk and at least delay their first coronary event.

What gaps in our knowledge remain?

  1. How do we treat these children with FH once we've identified them? At what age do we start lipid-lowering therapies?
  2. How do we treat and/or monitor individuals with a FH mutation but normal cholesterol levels?
  3. What is the financial impact of child-parent screening? Considerations include costs to society (cost of lipid + FH mutation screening, lipid-lowering therapies including PCSK9 inhibitors) and to individuals (lipid-lowering therapy and insurance premiums).
  4. Which is most effective and cost-effective between the 3 available screening methods: Cascade, child-parent, or universal screening? Would a hybrid cascade+child-parent screening strategy be best?

OSLER - Evolocumab (PCSK9 inhibitor) for LDL lowering

Sabatine MS, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1500-9.

Bottom line: In patients previously enrolled in a phase 2/3 trial of evolocumab due to elevated LDL in the context of HeFH, statin intolerance, or maximum-tolerated statin therapy, addition of evolocumab lowered LDL by ~60% versus standard therapy alone. This LDL reduction resulted in a reduction in CV events (NNT 82 at 11 months), which may be an inaccurate estimate due to high risk of performance and detection bias.


    Patients (n=4465)

    • Inclusion
      • Patients who completed one of the 12 phase 2 & 3 RCTs of evolocumab without discontinuation due to an adverse event
      • No unstable medical condition
      • Basic patient populations enrolled in phase 2 & 3 trials:
        • MENDEL-1 & 2: LDL 2.6-4.9 mmol/L without background lipid lowering
        • GAUSE-1: LDL >2.6 mmol/L, statin intolerant
        • GAUSE-2: LDL 2.6-4.9 mmol/L, statin intolerant
        • DESCARTES, THOMAS1&2: LDL >1.9 mmol/L with statin (DESCARTES: +/- ezetimibe)
        • LAPLACE-TIMI 57: LDL >2.1 mmol/L with statin +/- ezetimibe
        • LAPLACE-2: LDL >2.0 mmol/L with "intensive" statin, >2.6 mmol/L on "non-intensive" statin, or >3.9 mmol/L without statin at baseline, added to statin +/- ezetimibe
        • RUTHERFORD-1 & 2: HeFH with LDL >2.6 mmol/L with statin +/- ezetimibe
        • YUKAWA-1: "High-risk" Japanese patients with LDL 3.0 mmol/L or greater while receiving statin
    • 4465 randomized (74.1% of eligible from phase 2 & 3 trials)
    • "Average" patients (baseline of phase 2 & 3 trials)
      • 58 y
      • Male 51%
      • White 85%
      • North American 47%
      • CV risk factors
        • Smoker 15%
        • Known CAD 20%, MI 9%, PCI 11%, CABG 7%
        • Cerebrovascular or peripheral-artery disease 9%
        • Family hx of premature CAD 24%
        • HTN 52%
        • Diabetes 13%
        • Known FH 10%
      • Lipids: Total cholesterol 5.1, LDL 3.1, HDL 1.3, trig 1.35 mmol/L
      • Meds
        • Statin 70%, high-intensity 27%
        • Ezetimibe 14%

    Issues with generalizability (external validity)?

    • Yes: The patients in OSLER 1 & 2 represent a highly-selected patient population enrolled into early phase 2/3 mechanistic efficacy trials who were adherent and tolerant to their allocated therapy in the phase 2/3 trial
      • In care of real-world patients with greater likelihood of comorbid conditions and frailty, we'd expect lower eficacy, adherence, tolerability and safety than estimated from these trials.


    • I: Evolocumab x56 weeks + standard of care lipid-lowering therapy per local guidelines
      • OSLER-1: 420 mg q1 month
      • OSLER-2: Patient's choice of 140 mg q2weeks or 420 mg q1month
      • In-person clinic visit q3 months
    • C: No evolocumab x48 weeks + standard of care lipid-lowering therapy per local guidelines
      • Telephone contact only
    • After trial: Open-label evolocumab for all patients completing OSLER-1&2

    Results @ median ~11 months

    • LDL reduction
      • Change from baseline to week 12 of OSLER for evolocumab+standard therapy vs standard therapy alone = 61%
        • @ baseline: Median 3.1 mmol/L in both groups
        • @ week 12 of OSLER trial (variable time from baseline): Median 1.2 vs 3.1 mmol/L
      • <1.8 mmol/L target: 73.6% vs 3.8%
    • Statistically significant reduction in composite CV outcome (death, MI, unstable angina requiring hospitalization, coronary revascularization, stroke/TIA, or HF requiring hospitalization): Hazard ratio 0.47 (0.28-0.78)
      • 0.95% vs 2.18% (NNT 82)
      • Not clearly driven by any single component of the composite outcome (e.g. MI or stroke)
    • No patients developed neutralizing antibodies against evolocumab

    Issues with internal validity?

    • Yes: Randomized, allocation-concealed, open-label (participants, clinicians and investigators aware of allocated treatment) non-placebo controlled trial with ? lost-to-follow-up analyzed using intention-to-treat population
      • High risk of performance and detection bias, particularly relating to "soft" CV outcomes such as hospitalizations and decision to revascularize
    • Notably, this is actually a pooled report of 2 RCTs: OSLER-1 is an extension of 5 phase-2 trials, and OSLER-2 is an extension of 7 phase-3 trials

    ODYSSEY LONG TERM - Alirocumab (PCSK9 inhibitor) in heterozygous FH or with established ASCVD

    Robinson JG, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1489-99.

    Bottom line: In patients at high risk of ASCVD, alirocumab lowered LDL by 62% more than placebo when added to maximum-tolerated statin therapy. This trial provides weak and mixed statistical evidence that additional LDL reduction with alirocumab may reduce CV events, primarily from reduction in non-fatal MI (NNT 72 over 78 weeks). This underpowered trial also suggests that alirocumab increases the risk of myalgia (NNH 40), and cannot rule out an increased risk of neurocognitive and ophthalmic events.

    The ongoing ODYSSEY OUTCOMES trial should provide definitive CV and safety outcome data.



      • Multicenter (320 sites in 27 countries in Africa, Europe, & North/South America)
      • Inclusion
        • Adults at high risk of ASCVD, defined as
          • HeFH (diagnosed based on clinical criteria or genotyping)
          • Established coronary artery disease (CAD), defined as history of
            • MI, silent MI or unstable angina
            • PCI or CABG
            • CAD diagnosed by invasive (coronary angiography) or non-invasive testing (treadmill stress test, stress echo, nuclear imaging)
          • "Coronary heart disease equivalent"
            • Peripheral artery disease (PAD; current intermittent claudication with ABI <0.9 in either leg, history of intermitent claudication treated with endovascular or surgical procedure, or history of critical limb ischemia treated with thrombolysis or procedure)
            • Ischemic stroke
            • eGFR <60 for at least 3 months
            • Type 2 diabetes + 1 more risk factor (HTN, ABI <0.90, albuminuria, retinopathy, family hx of premature CAD)
        • LDL 1.8 mmol/L or more at screening (on maximum-tolerated statin dose)
      • Exclusion
        • Recent cardiovascular event leading to hospitalization or intervention
        • Planned revascularization (carotid, coronary or peripheral) during study
        • HF NYHA III-IV in past year
        • SBP/DBP >180/110 mm Hg at screening/randomization visit
        • PMHx
          • Hemorrhagic stroke
          • Optic nerve disease
          • Hep B or C, or ALT/AST >3x ULN
          • CKD with eGFR <30 mL/min
          • Homozygous FH
          • Trigs >4.5 mmol/L on 2 tests
          • HbA1c >10%
          • Known loss-of-function of PCSK9
          • CK >3x ULN
          • HIV
          • Other major systemic disease that may preclude ability to complete study
          • Meds
            • Taking statin other than atorvastatin, rosuvastatin or simvastatin
            • Not taking statin daily
              • Use of systemic steroids (unless for pituitary/adrenal replacement stable for at least 6 weeks)
              • Use of HRT (unless stable x6 weeks & no plan to change regimen during study)
        • Involved in any previous PCSK9 inhibitor trial
      • 5142 screened -> 2341 randomized
      • "Average" patient
        • 60.5 y
        • Male 62%
        • White 93%
        • CV risk factors
          • HeFH 18%
          • CAD ~70%
          • CAD-risk equivalent 41%
          • Smoker 20%
          • T2 diabetes 34%
        • Meds
          • Statin ~100%, high-dose 47%
          • Other lipid-lowering therapy 28%
            • Ezetimibe 15%
        • Lipid panel: LDL 3.2, HDL 1.29, fasting trig 1.52 mmol/L


      • I: Alirocumab 150 mg subcutaneously (1 mL) q2 weeks administered at home
        • Mean exposure 70 weeks (max 78)
        • Mean adherence 98% of doses
      • C: Matching placebo
      • Co-intervention: Maximum-tolerated statin, diet per NCEP ATP III guidelines

      Issues with generalizability (external validity)?

      • High-risk CV population: Doesn't apply to "primary prevention" population without HeFH
        • Excluded patients with any significant comorbidity who would be expected to have competing risks for death and hospitalization, as well as a greater absolute risk of adverse effects and intolerability with these drugs
          • We'd expect overestimation of benefit and underestimation of harm in frail patients and in those with significant comorbid conditions (including those with heart failure)


      • LDL reduction
        • Change from baseline to 24 weeks for alirocumab vs placebo = 62% difference
          • @ baseline: 3.2 mmol/L in both groups
          • @ 24 weeks: 1.2 vs 3.1 mmol/L
        • Achieved goal <1.8 mmol/L @ week 24: 79.3% vs 8% 
        • Highlights:
          • Differences in LDL remained consistent between groups through to week 78 among patients continuing study treatment
          • Similar % reduction in LDL in patients with & without HeFH
      • Uncertain effect on CV outcomes
        • No statistically significant difference in composite CV outcome (death due to CAD or from unknown cause, non-fatal MI, ischemic stroke, unstable angina requiring hospitalization, HF hospitalization, ischemia-driven coronary revascularization)
          • 4.6% vs 5.1% (p=0.68)
        • Statistically significant reduction in post-hoc analysis of components of above non-significant outcome
          • "Major adverse CV event" (coronary death, non-fatal MI, ischemic stroke, unstable angina requiring hospitalization): 1.7% vs 3.3% (NNT 63, p=0.02)
            • Driven by difference in non-fatal MI: 0.9% vs 2.3% (NNT 72, p=0.01)
      • Safety
        • Serious adverse event: 18.7% vs 19.5% (p=0.40)
        • Discontinued study drug: 28.2% vs 24.5% (NNH 27)
          • Discontinued due to adverse event: 7.2% vs 5.8% (p=0.26)
        • Select adverse events
          • Neurocognitive disorder: 1.2% vs 0.5% (p=0.17)
          • Ophthalmic event: 2.9% vs 1.9% (p=0.65)
          • Myalgia: 5.4% vs 2.9% (NNH 40, p=0.006)
          • No statistically significant difference in new diabetes (1.8% vs 2.0%) or worsening of existing diabetes (12.9% vs 13.6%)
          • No statistically significant difference in AST/ALT or CK elevations

      Issues with internal validity?

      • Randomized, allocation-concealed, triple-blind (patients, clinicians & investigators) trial with ~27% drop-out rate analyzed using the intention-to-treat population
        • The high drop-out rate does not necessarily introduce between-group bias, but may have led to underestimation of CV and safety outcome events
      • Stratified based on (1) HeFH status, (2) hx of MI or stroke, (3) background statin of atorva 40-80/rosuva 20-40 vs simvastatin at any dose or atorva <40/rosuva <20, (4) geography.

      ODYSSEY ESCAPE - PCSK9 inhibitor alirocumab for heterozygous familial hypercholesterolemia requiring lipid apheresis (short)

      Moriarty PM, et al. Alirocumab in patients with heterozygous familial hypercholesterolaemia undergoing lipoprotein apheresis: the ODYSSEY ESCAPE trial.


      In HeFH patients previously requiring lipoprotein apheresis for LDL-lowering, a PCSK9 inhibitor further lowered LDL by ~55%. LDL-lowering with a PCSK9 inhibitor allowed for a 75% reduction in the rate of apheresis sessions (e.g. from once-weekly to once-monthly), and allowed up to two-thirds of patients to completely stop apheresis during a 3-month period (NNT <2). Although apheresis is an intermediate outcome, the high cost and burden to quality of life associated with this procedure make it an important clinical outcome to reduce.

      This 62-patient trial was too small to accurately assess safety and tolerability of alirocumab, so clinicians should monitor for neurocognitive decline, ophthalmologic events, myalgias and injection-site reactions as previously reported to occur more commonly with PCSK9 inhibitors.


      Context (from our review of FH)

      • Heterozygous familial hypercholesterolemia (HeFH) is genetic dyslipidemia that affects ~1/500 Canadians
      • HeFH presents clinically with an LDL 5-13 mmol/L +/- physical stigmata of elevated cholesterol, and increased risk of atherosclerotic cardiovascular disease (ASCVD)
        • Patients with untreated HeFH experience a coronary event 20+ years earlier than the general population
        • The cumulative risk of coronary events by age 50 is 44% in men and 20% in women
      • The treatment goal in patients with HeFH is to reduce LDL by >50% from baseline, generally with a max-tolerated statin dose and other lipid-lowering therapies
        • ipoprotein apheresis is an expensive last-line therapeutic procedure involving extracorporeal filtering of apoB-containing lipoproteins (i.e. LDL) from the blood
      • PCSK9 inhibitors, including alirocumab and evolocumab, lower LDL by ~60% in addition to diet, exercise and other lipid-lowering therapies
        • Mega-trials evaluating clinically-important outcomes are underway


        • Multicenter (14 centers in Germany & USA, enrollment March-September 2015)
        • Inclusion criteria:
          • HeFH diagnosed by clinical criteria (Simon Broome or Dutch Lipid Network criteria) or genotyping
          • Consistently received lipoprotein apheresis q1week x4+ weeks or q2weeks x8+ weeks
          • Stable background lipid-lowering therapy, diet, exercise x8+ weeks
        • Exclusion criteria: Homozygous FH
        • Screened 76 patients -> randomized 62 (41 to alirocumab, 21 to placebo)
        • "Average" patient @ baseline
          • 58 y
          • Male 58%
          • LDL: Alirocumab 4.5 mmol/L, placebo 5.0 mmol/L
          • Median apheresis duration before study: 4.9 y (range: 0.5-32.9 y)
          • Lipid-lowering therapies:
            • Statin ~55% (~half on max dose)
            • Others unknown (only reported "ever taken")
          • Apheresis regimen: q1w (43.5%), q2w (56.5%)

        Interventions & Co-Interventions

        • I: Alirocumab 150 mg (as 1 mL volume) subcutaneously q2weeks x18 weeks, administered at study site
          • # of injections: Mean 8.6 (SD 1.3)
        • C: Placebo as per above regimen
          • # of injections: Mean 8.4 (SD 1.7)
        • Co-i: Apheresis continued unless LDL measured as reduced by >30% from baseline


        • LDL
          • Baseline: 4.5 vs 5.0 mmol/L
          • @ week 6 (when pre-study apheresis regimen was maintained): 2.3 vs 4.8 mmol/L (55% greater reduction from baseline with alirocumab vs placebo)
          • @ week 18 (when apheresis sessions were omitted if LDL >30% lower than baseline): 2.9 vs 4.9 mmol/L
        • Apheresis
          • Difference in apheresis rate in weeks 7-18: 75% fewer apheresis sessions with alirocumab vs placebo
            • % of apheresis sessions required, median (range): 0% (0-100) vs 83% (42-100)
          • % of patients requiring no apheresis in weeks 7-18: 63.4% vs 0% (NNT 2)
        • Safety
          • Serious adverse events: 9.8% vs 9.5% 
          • Adverse event leading to study drug discontinuation: 4.9% vs 4.8%
          • Any adverse event: 75.6% vs 76.2%
            • Fatigue: 14.6% vs 9.5%
            • Myalgia: 9.8% vs 4.8%
            • CK >3x ULN: 7.3% vs 0%

        Issues with internal validity?

        • No: 2:1 randomization, allocation-concealed, double-blind (patients & apheresis site personnel blinded to LDL values) RCT with intention-to-treat analysis that accounted for drop-outs (8%)
        • Design involved 2 intervals:
          • Weeks 0-6: Apheresis contined as per established pre-study regimen
          • Weeks 7-18: Apheresis frequency adjusted based on LDL response to treatment; not performed if LDL decreased 30% or more from baseline LDL