The current trial sought to study the safety and efficacy of alirocumab, a PCSK9 inhibitor, compared with ezetimibe in patients who were statin intolerant and had an indication for statin use.


Alirocumab would be superior to ezetimibe in reducing low-density lipoprotein cholesterol (LDL-C) levels in statin-intolerant patients.

Study Design

  • Randomized
  • Blinded
  • Parallel

Patient Populations:

  • Statin-intolerant patients (at least two statins, including one at the lowest dose, due to muscle-related side effects by medical history) with LDL-C ≥70 mg/dl (very-high CV risk) or ≥100 mg/dl (moderate/high risk)

    Number of enrollees: 314
    Duration of follow-up: 24 weeks
    Mean patient age: 64 years
    Percentage female: 45%

Primary Endpoints:

  • Percent LDL-C change from baseline

Drug/Procedures Used:

Statin-intolerant patients underwent a 4-week run-in phase with placebo. If they had muscle-related side effects, they were excluded. The rest were randomized in a 2:2:1 fashion to either self-administered alirocumab 75 mg subcutaneously Q2W, ezetimibe 10 mg daily, or atorvastatin 20 mg daily. All arms received matching placebo as well. At week 12, nearly 50% had their alirocumab uptitrated to 150 mg.

Principal Findings:

A total of 314 patients were randomized, 126 to alirocumab, 125 to ezetimibe, and 63 to atorvastatin. Baseline characteristics were fairly similar between the three arms. About 15% had heterozygous familial hypercholesterolaemia, 22% had diabetes, and more than one third had already been on another lipid-lowering agent other than ezetimibe prior to enrollment. The mean baseline LDL-C was 190 mg/dl, triglycerides were 160 mg/dl, and high-density lipoprotein cholesterol (HDL-C) 50 mg/dl.

Alirocumab significantly reduced LDL-C at 24 weeks compared with ezetimibe; % decrease was 45% vs. 14.6%, difference 30.4, p < 0.0001. The absolute decrease in LDL was 84 vs. 33 mg/dl from baseline. LDL-C lowering with alirocumab reached peak efficacy around 4 weeks, and was sustained thereafter. Patients in the alirocumab arm were more likely to achieve a target LDL-C <100 mg/dl (61% vs. 10%, p < 0.0001). There were also significant reductions in Apo B (36.3% vs. 11.2%, p < 0.0001) and Lp(a) (25.9% vs. 7.3%, p < 0.0001) with alirocumab.

Muscle-related side effects were lower in the alirocumab arm (32.5%) compared with the ezetimibe (41.1%, p = 0.096) and atorvastatin arms (46%, p = 0.042). On safety analysis, ischemia-driven revascularization (2.4% vs. 0.8% vs. 1.6%) and nonfatal myocardial infarction (0.8% vs. 0 vs. 0) were numerically higher in the alirocumab arm.


The results of this trial indicate that alirocumab is superior to ezetimibe in lowering LDL-C levels and achieving target levels in statin-intolerant patients, with a lower risk of muscle-related side effects. Clinical events were numerically higher with alirocumab, but not statistically significant. This trial adds to the growing body of literature with PCSK9 inhibitors. Other large outcomes-based trials are ongoing.


Presented by Dr. Patrick M. Moriarty at the American Heart Association Scientific Sessions, Chicago, IL, November 17, 2014.

Keywords: Pyrroles, Myocardial Infarction, Cholesterol, LDL, Azetidines, Hyperlipoproteinemia Type II, Cholesterol, HDL, Heptanoic Acids, Triglycerides, Diabetes Mellitus, Apolipoproteins B, AHA Annual Scientific Sessions

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