Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: The LAPLACE-2 randomized clinical trial

Jennifer G Robinson, Bettina S Nedergaard, William J Rogers, Jonathan Fialkow, Joel M Neutel, David Ramstad, Ransi Somaratne, Jason C Legg, Patric Nelson, Rob Scott, Scott M Wasserman, Robert Weiss, LAPLACE-2 Investigators

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Abstract

IMPORTANCE: In phase 2 studies, evolocumab, a fully human monoclonal antibody to PCSK9, reduced LDL-C levels in patients receiving statin therapy.

OBJECTIVE: To evaluate the efficacy and tolerability of evolocumab when used in combination with a moderate- vs high-intensity statin.

DESIGN, SETTING, AND PATIENTS: Phase 3, 12-week, randomized, double-blind, placebo- and ezetimibe-controlled study conducted between January and December of 2013 in patients with primary hypercholesterolemia and mixed dyslipidemia at 198 sites in 17 countries.

INTERVENTIONS: Patients (n = 2067) were randomized to 1 of 24 treatment groups in 2 steps. Patients were initially randomized to a daily, moderate-intensity (atorvastatin [10 mg], simvastatin [40 mg], or rosuvastatin [5 mg]) or high-intensity (atorvastatin [80 mg], rosuvastatin [40 mg]) statin. After a 4-week lipid-stabilization period, patients (n = 1899) were randomized to compare evolocumab (140 mg every 2 weeks or 420 mg monthly) with placebo (every 2 weeks or monthly) or ezetimibe (10 mg or placebo daily; atorvastatin patients only) when added to statin therapies.

MAIN OUTCOMES AND MEASURES: Percent change from baseline in low-density lipoprotein cholesterol (LDL-C) level at the mean of weeks 10 and 12 and at week 12.

RESULTS: Evolocumab reduced LDL-C levels by 66% (95% CI, 58% to 73%) to 75% (95% CI, 65% to 84%) (every 2 weeks) and by 63% (95% CI, 54% to 71%) to 75% (95% CI, 67% to 83%) (monthly) vs placebo at the mean of weeks 10 and 12 in the moderate- and high-intensity statin-treated groups; the LDL-C reductions at week 12 were comparable. For moderate-intensity statin groups, evolocumab every 2 weeks reduced LDL-C from a baseline mean of 115 to 124 mg/dL to an on-treatment mean of 39 to 49 mg/dL; monthly evolocumab reduced LDL-C from a baseline mean of 123 to 126 mg/dL to an on-treatment mean of 43 to 48 mg/dL. For high-intensity statin groups, evolocumab every 2 weeks reduced LDL-C from a baseline mean of 89 to 94 mg/dL to an on-treatment mean of 35 to 38 mg/dL; monthly evolocumab reduced LDL-C from a baseline mean of 89 to 94 mg/dL to an on-treatment mean of 33 to 35 mg/dL. Adverse events were reported in 36%, 40%, and 39% of evolocumab-, ezetimibe-, and placebo-treated patients, respectively. The most common adverse events in evolocumab-treated patients were back pain, arthralgia, headache, muscle spasms, and pain in extremity (all <2%).

CONCLUSIONS AND RELEVANCE: In this 12-week trial conducted among patients with primary hypercholesterolemia and mixed dyslipidemia, evolocumab added to moderate- or high-intensity statin therapy resulted in additional LDL-C lowering. Further studies are needed to evaluate the longer-term clinical outcomes and safety of this approach for LDL-C lowering.

TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01763866.

Original languageEnglish
JournalJAMA: The Journal of the American Medical Association
Volume311
Issue number18
Pages (from-to)1870-82
Number of pages13
ISSN0098-7484
DOIs
Publication statusPublished - 14 May 2014
Externally publishedYes

Keywords

  • Aged
  • Antibodies, Monoclonal
  • Anticholesteremic Agents
  • Azetidines
  • Double-Blind Method
  • Drug Therapy, Combination
  • Dyslipidemias
  • Female
  • Fluorobenzenes
  • Heptanoic Acids
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Hypercholesterolemia
  • Male
  • Middle Aged
  • Pyrimidines
  • Pyrroles
  • Simvastatin
  • Sulfonamides
  • Treatment Outcome

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