The current trial sought to study the safety and efficacy of alirocumab, a PCSK9 inhibitor, compared with placebo in heterozygous familial hypercholesterolemia (HeFH) patients who were on maximal tolerated doses of a statin, but had low-density lipoprotein cholesterol (LDL-C) levels ≥160 mg/dl.


Alirocumab would be superior to placebo in reducing LDL-C levels in HeFH patients with suboptimal LDL-C control despite being on maximal tolerated doses of a statin with or without other lipid-lowering therapy.

Study Design

  • Randomized
  • Blinded
  • Parallel

Patient Populations:

  • HeFH patients on maximally tolerated statin ± other lipid-lowering agent
  • LDL-C ≥160 mg/dl

    Number of enrollees: 107
    Duration of follow-up: 24 weeks
    Mean patient age: 51 years
    Percentage female: 45%

Primary Endpoints:

  • Percent LDL-C change from baseline at 24 weeks

Secondary Endpoints:

  • Percent LDL-C change from baseline at 52 weeks

Drug/Procedures Used:

Patients were randomized in a 2:1 fashion to either self-administered alirocumab 150 mg subcutaneous Q2W or matching placebo.

Principal Findings:

A total of 107 patients were randomized, 72 to alirocumab and 35 to placebo. Baseline characteristics were fairly similar between the two arms. A genotypic diagnosis of HeFH was present in 17%, and the rest met clinical criteria. About 15% had diabetes, and 50% had a history of coronary heart disease. Nearly 80% of patients were on a high-dose statin at enrollment, and 27% were on ezetimibe. The mean baseline LDL-C was ~200 mg/dl, non–HDL-C was 227 mg/dl, and Lp(a) was 26 mg/dl.

Alirocumab significantly reduced LDL-C at 24 weeks compared with placebo at 24 weeks; percent decrease from baseline was 45.7% vs. 6.6%, difference 39.1, p < 0.0001. The absolute values of LDL-C at 24 weeks were also significantly lower (107 vs. 182 mg/dl). 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 (57% vs. 11%, p < 0.0001).

Injection-site reactions were higher in the alirocumab arm (8.3% vs. 2.9). On safety analysis, adjudicated cardiovascular (CV) events were similar (8.3% vs. 0%). Transaminitis (4.2% vs. 2.9%) and creatine kinase >3 x upper limit of normal (2.8% vs. 0%) were similar.


The results of this trial indicate that alirocumab is superior to placebo in lowering LDL-C levels and achieving target levels in HeFH patients already on maximal tolerated doses of statins (with or without other lipid-lowering therapy). These results are smaller than those of the smaller phase 2 ODYSSEY LONG TERM trial, and add to the growing body of literature with PCSK9 inhibitors. Other large outcomes-based trials are ongoing. The higher CV event rate in this trial with alirocumab has also been observed in a few other phase 2/3 trials (none individually significant), and needs careful attention in the outcomes trials.


Presented by Dr. Henry N. Ginsberg at the American Heart Association Scientific Sessions, Chicago, IL, November 19, 2014.

Keywords: Lipoproteins, LDL, Creatine Kinase, Cholesterol, LDL, Azetidines, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hyperlipoproteinemia Type II, Coronary Disease, Maximum Tolerated Dose, Diabetes Mellitus, AHA Annual Scientific Sessions

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