Anacetrapib as lipid-modifying therapy in patients with heterozygous familial hypercholesterolaemia (REALIZE): a randomised, double-blind, placebo-controlled, phase 3 study.
BACKGROUND
Present guidelines emphasise the importance of low concentrations of LDL cholesterol (LDL-C) in patients with familial hypercholesterolaemia. In most patients with the disease, however, these concentrations are not achieved with present treatments, so additional treatment is therefore warranted. Inhibition of cholesteryl ester transfer protein has been shown to reduce LDL-C concentrations in addition to regular statin treatment in patients with hypercholesterolaemia or at high risk of cardiovascular disease. We aimed to investigate the safety and efficacy of anacetrapib, a cholesteryl ester transfer protein inhibitor, in patients with heterozygous familial hypercholesterolaemia.


METHODS
In this multicentre, randomised, double-blind, placebo-controlled, phase 3 study, patients aged 18-80 years with a genotype-confirmed or clinical diagnosis of heterozygous familial hypercholesterolaemia, on optimum lipid-lowering treatment for at least 6 weeks, and with an LDL-C concentration of 2·59 mmol/L or higher without cardiovascular disease or 1·81 mmol/L or higher with cardiovascular disease from 26 lipid clinics across nine countries were eligible. We randomly allocated participants with a computer-generated allocation schedule (2:1; block size of six; no stratification) to oral anacetrapib 100 mg or placebo for 52 weeks, with a 12 week post-treatment follow-up afterwards. We masked patients, care providers, and those assessing outcomes to treatment groups throughout the study. The primary outcome was percentage change from baseline in LDL-C concentration. We did analysis using a constrained longitudinal repeated measures model. This trial is registered with ClinicalTrials.gov, number NCT01524289.


RESULTS
Between Feb 10, 2012, and Feb 12, 2014, we randomly allocated 204 patients to anacetrapib and 102 to placebo. One patient in the anacetrapib group did not receive the drug. At week 52, anacetrapib reduced mean LDL-C concentration from 3·3 mmol/L (SD 0·8) to 2·1 mmol/L (0·8; percentage change 36·0% [95% CI -39·5 to -32·5] compared with an increase with placebo from 3·4 mmol/L (1·2) to 3·5 mmol/L (1·6; percentage change 3·7% [-1·2 to 8·6], with a difference in percentage change between anacetrapib and placebo of -39·7% (95% CI -45·7 to -33·7; p<0·0001). The number of cardiovascular events was increased in patients given anacetrapib compared with those given placebo (4 [2%] of 203 vs none [0%] of 102; p=0·1544), but the proportion with adverse events leading to discontinuation was similar (12 [6%] of 203 vs five [5%] of 102).


CONCLUSIONS
In patients with heterozygous familial hypercholesterolaemia, treatment with anacetrapib for 1 year was well tolerated and resulted in substantial reductions in LDL-C concentration. Whether this change leads to a reduction of cardiovascular events will be answered in an outcome study.


BACKGROUND
Merck & Co, Inc.
Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Electronic address: j.j.kastelein@amc.uva.nl.
John J P
JJ
Kastelein
Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Joost
J
Besseling
Clinical Research, Merck & Co, Inc, Kenilworth, NJ, USA.
Sukrut
S
Shah
Endocrinology and Nephrology Unit, Centre Hospitalier Universitaire de Québec Research Centre, Laval University, Quebec City, QC, Canada.
Jean
J
Bergeron
Lipid Clinic, Medical Department, Oslo University Hospital, Oslo, Norway.
Gisle
G
Langslet
Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
G Kees
GK
Hovingh
Cardiovascular Metabolic, Covance, Sydney, Australia.
Naab
N
Al-Saady
Project Management, Covance, Rotterdam, Netherlands.
Michiel
M
Koeijvoets
Biostatistics, Covance, Madison, WI, USA.
John
J
Hunter
Scientific Affairs, Merck & Co, Inc, Kenilworth, NJ, USA.
Amy O
AO
Johnson-Levonas
Clinical Research, Merck & Co, Inc, Kenilworth, NJ, USA.
Jennifer
J
Fable
Biostatistics, Merck & Co, Inc, Kenilworth, NJ, USA.
Aditi
A
Sapre
Clinical Research, Merck & Co, Inc, Kenilworth, NJ, USA.
Yale
Y
Mitchel
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000924:Anticholesteremic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002318:Cardiovascular Diseases / Q000150:complications; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors; D008078:Cholesterol, LDL / Q000097:blood / Q000187:drug effects; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000150:complications / Q000188:drug therapy*; D000960:Hypolipidemic Agents / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D023303:Oxazolidinones / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
D000924:Anticholesteremic Agents; D053480:Cholesterol Ester Transfer Proteins; D008078:Cholesterol, LDL; D000960:Hypolipidemic Agents; D023303:Oxazolidinones; C530884:anacetrapib