Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab

J Am Coll Cardiol. 2014 Jun 17;63(23):2531-2540. doi: 10.1016/j.jacc.2014.03.018. Epub 2014 Mar 29.


Objectives: The aim of this study was to compare biweekly and monthly evolocumab with placebo and oral ezetimibe in patients with hypercholesterolemia in a phase III trial.

Background: Evolocumab, a fully human monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly reduced LDL-C in phase II trials.

Methods: Patients 18 to 80 years of age with fasting low-density lipoprotein cholesterol (LDL-C) ≥100 and <190 mg/dl and Framingham risk scores ≤10% were randomized (1:1:1:1:2:2) to oral placebo and subcutaneous (SC) placebo biweekly; oral placebo and SC placebo monthly; ezetimibe and SC placebo biweekly; ezetimibe and SC placebo monthly; oral placebo and evolocumab 140 mg biweekly; or oral placebo and evolocumab 420 mg monthly.

Results: A total of 614 patients were randomized and administered doses. Evolocumab treatment reduced LDL-C from baseline, on average, by 55% to 57% more than placebo and 38% to 40% more than ezetimibe (p < 0.001 for all comparisons). Evolocumab treatment also favorably altered other lipoprotein levels. Treatment-emergent adverse events (AEs), muscle-related AEs, and laboratory abnormalities were comparable across treatment groups.

Conclusions: In the largest monotherapy trial using a PCSK9 inhibitor to date, evolocumab yielded significant LDL-C reductions compared with placebo or ezetimibe and was well tolerated in patients with hypercholesterolemia. (Monoclonal Antibody Against PCSK9 to Reduce Elevated LDL-C in Subjects Currently Not Receiving Drug Therapy for Easing Lipid Levels-2 [MENDEL-2]; NCT01763827).

Keywords: PCSK9 inhibition; dyslipidemia; evolocumab; monotherapy.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Administration, Oral
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Antibodies, Monoclonal / administration & dosage*
  • Antibodies, Monoclonal, Humanized
  • Apoptosis
  • Cholesterol, LDL / blood*
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Drug Administration Schedule
  • Female
  • Follow-Up Studies
  • Humans
  • Hypercholesterolemia / blood
  • Hypercholesterolemia / drug therapy*
  • Injections, Subcutaneous
  • Male
  • Middle Aged
  • Proprotein Convertase 9
  • Proprotein Convertases / antagonists & inhibitors*
  • Proprotein Convertases / blood
  • Retrospective Studies
  • Serine Endopeptidases / blood
  • Treatment Outcome
  • Young Adult


  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Cholesterol, LDL
  • PCSK9 protein, human
  • Proprotein Convertase 9
  • Proprotein Convertases
  • Serine Endopeptidases
  • evolocumab

Associated data