Anacetrapib in Heterozygous Familial Hypercholesterolemia | Journal Scan

Study Questions:

What is the safety and efficacy of anacetrapib, a cholesteryl ester transfer protein inhibitor (CETPi), in patients with heterozygous familial hypercholesterolemia (HeFH)?


REALIZE was a multicenter, randomized, double-blind, placebo-controlled, phase 3 study. Patients were aged 18–80 years with a genotype-confirmed or clinical diagnosis of HeFH, on optimum lipid-lowering treatment for at least 6 weeks, and with a low-density lipoprotein cholesterol (LDL-C) of 98 mg/dl or higher without cardiovascular disease or 68 mg/dl or higher with cardiovascular disease from 26 lipid clinics across nine countries. Participants were allocated (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. The primary outcome was percentage change from baseline in LDL-C concentration.


A total of 204 patients were allocated to anacetrapib and 102 to placebo. At week 52, anacetrapib reduced mean LDL-C concentration from 125 mg/dl (standard deviation, 30.2) to 79.3 mg/dl (30.2 mg/dl; percentage change 36.0% [95% confidence interval, –39.5 to –32.5]) compared with an increase with placebo from 129 mg/dl (45.3 mg/dl) to 132.3 mg/dl (60.5 mg/dl); 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 high-density lipoprotein cholesterol (HDL-C) increased by 105.8% on anacetrapib compared to a 3.7% increase in HDL-C. 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).


In patients with HeFH, 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.


Establishing the benefit of novel lipid-altering agents cannot be determined solely on the surrogate endpoints of change in lipids or lipoproteins. The impact of anacetrapib on events in patients on maximal doses of statins is being studied in a very large outcome trial of high-risk patients (REVEAL). The initial enthusiasm for CETPi was the dramatic rise in HDL-C, the impact of which is not known. Investigation is now focusing on the decrease in LDL-C, for which there has been evidence of efficacy for nearly all LDL-C lowering approaches.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Lipid Metabolism, Nonstatins, Novel Agents, Primary Hyperlipidemia, Statins

Keywords: Biological Markers, Cardiovascular Diseases, Cholesterol, Cholesterol Ester Transfer Proteins, Cholesterol, HDL, Cholesterol, LDL, Double-Blind Method, Dyslipidemias, Follow-Up Studies, Genotype, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hyperlipoproteinemia Type II, Lipids, Lipoproteins, Lipoproteins, HDL, Lipoproteins, LDL, Outcome Assessment (Health Care), Oxazolidinones, Primary Prevention

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