Introduction:
Anacetrapib, a cholesteryl ester transfer protein inhibitor, has been shown to robustly reduce atherogenic lipoproteins including low-density lipoprotein cholesterol (LDL-C), Apo B and raise high-density lipoprotein cholesterol (HDL-C) as well as ApoA1.
Hypothesis:
This 1-year, Phase 3, multicenter, randomized, double-blind, placebo-controlled study assessed the lipid-modifying efficacy and safety profile of anacetrapib added to optimized LDL-C lowering therapy in patients with heterozygous familial hypercholesterolemia (HeFH).
Methods:
Patients with a genotype-confirmed or clinical diagnosis of HeFH, treated with an optimal dose of statin ± other lipid-modifying medication(s) and having an LDL-C ≥100 mg/dL without history of cardiovascular disease or LDL-C ≥70 mg/dL with a history of CVD were randomized in a ratio of 2:1 to anacetrapib 100 mg (n=204) or placebo (n=102) for 52 weeks followed by a 12-week reversal phase. The primary end points were the percent change from baseline in LDL-C (beta-quantification method) and the safety profile of anacetrapib. This trial is registered in ClinicalTrials.gov, #NCT01524289.
Results:
A total of 306 patients were enrolled at 25 sites in 9 countries. At baseline, most patients were on high-dose statin therapy and >70% also were on ezetimibe. Baseline LDL-C and HDL-C were 129.4 and 53.3 mg/dL, respectively. At Week 52, anacetrapib vs. placebo significantly reduced LDL-C by 39.7% and increased HDL-C by 102.1% (p<0.001 for both). Significant placebo-adjusted reductions in Apo B (24.8%) and increases in Apo A-I (32.9%) also were observed. Significantly more patients in the anacetrapib vs. placebo group achieved LDL-C <100 (82% vs. 18%; p<0.001) and <70 mg/dL (44% vs. 5%; p<0.001). Sustained effects on LDL-C (21.9%; p<0.001) and HDL-C (53.0%; p<0.001) were seen 12-weeks after cessation of anacetrapib therapy. No clinically important between-group differences were seen in the proportions of patients with abnormalities in liver enzymes, CK, blood pressure, electrolytes, adverse experiences and adjudicated CV events.
Conclusion:
In patients with HeFH, treatment with anacetrapib for 1 year was generally well tolerated and resulted in substantial reductions in LDL-C and increases in HDL-C.
Lp (a) >50 mg/dl predicts atherosclerotic cardiovascular events in patients with heterozygous familial hypercholesterolemia who achieved LDL-C <2.6 mmol/l
