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.
OBJECTIVE
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.


METHODS
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.


METHODS
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.


METHODS
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
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.


BACKGROUND
clinicaltrials.gov Identifier: NCT01763866.
Department of Epidemiology, College of Public Health, University of Iowa, Iowa City2Department of Medicine, College of Public Health, University of Iowa, Iowa City.
Jennifer G
JG
Robinson
Center for Clinical and Basic Research, Aalborg, Denmark.
Bettina S
BS
Nedergaard
Division of Cardiovascular Disease, University of Alabama Medical Center, Birmingham.
William J
WJ
Rogers
Department of Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami.
Jonathan
J
Fialkow
Orange County Research Center, Tustin, California.
Joel M
JM
Neutel
Hampton Roads Center for Clinical Research, Suffolk, Virginia.
David
D
Ramstad
Amgen Inc, Thousand Oaks, California.
Ransi
R
Somaratne
Amgen Inc, Thousand Oaks, California.
Jason C
JC
Legg
Amgen Inc, Thousand Oaks, California.
Patric
P
Nelson
Amgen Inc, Thousand Oaks, California.
Rob
R
Scott
Amgen Inc, Thousand Oaks, California.
Scott M
SM
Wasserman
Maine Research Associates, Auburn.
Robert
R
Weiss
D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000924:Anticholesteremic Agents / Q000008:administration & dosage; D000069059:Atorvastatin; D001384:Azetidines / Q000627:therapeutic use*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D050171:Dyslipidemias / Q000188:drug therapy; D000069438:Ezetimibe; D005260:Female; D005464:Fluorobenzenes / Q000008:administration & dosage; D006538:Heptanoic Acids / Q000008:administration & dosage; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage*; D006937:Hypercholesterolemia / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D011743:Pyrimidines / Q000008:administration & dosage; D011758:Pyrroles / Q000008:administration & dosage; D000068718:Rosuvastatin Calcium; D019821:Simvastatin / Q000008:administration & dosage; D013449:Sulfonamides / Q000008:administration & dosage; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000924:Anticholesteremic Agents; D001384:Azetidines; D005464:Fluorobenzenes; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; D000069059:Atorvastatin; D019821:Simvastatin; D000069438:Ezetimibe; C577155:evolocumab