Efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib as monotherapy and coadministered with atorvastatin in dyslipidemic patients

• Published in: The American heart journal Vol. 157; no. 2; pp. 352 - 360.e2
• Main Authors: Bloomfield, Daniel, MD, Carlson, Gary L., BS, Sapre, Aditi, PhD, Tribble, Diane, PhD, McKenney, James M., Pharm D, Littlejohn, Thomas W., MD, Sisk, Christine McCrary, BS, Mitchel, Yale, MD, Pasternak, Richard C., MD
• Format: Journal Article
• Language: English
• Published: New York, NY Mosby, Inc 01-02-2009; Mosby; Elsevier Limited
• Subjects: Aged; Anticholesteremic Agents - therapeutic use; Apolipoproteins; Atorvastatin Calcium; Biological and medical sciences; Cardiology. Vascular system; Cardiovascular; Cardiovascular disease; Cholesterol; Cholesterol Ester Transfer Proteins - antagonists & inhibitors; Diabetes; Dose-Response Relationship, Drug; Double-Blind Method; Drug dosages; Drug Therapy, Combination; Dyslipidemias - drug therapy; Female; Heptanoic Acids - therapeutic use; Humans; Hypertension; Low density lipoprotein; Male; Medical sciences; Middle Aged; Oxazolidinones - therapeutic use; Product development; Proteins; Pyrroles - therapeutic use; Treatment Outcome; Ultrasonic imaging; Human; Protein inhibitor; Toxicity; Metabolic diseases; Lipids; Cardiovascular disease; Ester; Efficiency; Atorvastatin; Transfer; Complication; Circulatory system; Safety; Cardiology; Dyslipemia
• ISSN: 0002-8703; 1097-6744
• DOI: 10.1016/j.ahj.2008.09.022

Background High-density lipoprotein cholesterol (HDL-C) levels are inversely associated with cardiovascular risk. Cholesteryl ester transfer protein inhibition is one strategy for increasing HDL-C. This study evaluated the lipid-altering efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib as monotherapy or coadministered with atorvastatin in patients with dyslipidemia. Methods A total of 589 patients with primary hypercholesterolemia or mixed hyperlipidemia (53.8% of the study population had low HDL-C) were randomized equally to one of 10 groups: 5 groups received background statin therapy of atorvastatin 20 mg and 5 did not, and each of these was randomized to placebo, anacetrapib 10, 40, 150, and 300 mg once daily for 8 weeks. An equal proportion of patients had triglycerides >150 mg/dL in each group. Results For placebo and anacetrapib monotherapy (10, 40, 150, and 300 mg), least squares mean percent changes from baseline to week 8 for low-density lipoprotein cholesterol (LDL-C) were 2%, −16%, −27%, −40%, and −39%, respectively, and for HDL-C were 4%, 44%, 86%, 139%, and 133%, respectively ( P < .001 vs placebo for all doses). Coadministration of anacetrapib with atorvastatin produced significant incremental LDL-C reductions and similar HDL-C increases versus atorvastatin monotherapy. For both anacetrapib monotherapy and coadministration with atorvastatin, the LDL-C reductions were similar in patients with baseline triglyceride levels greater than and less than or equal to the median. Anacetrapib was well tolerated, and the incidence of adverse events was similar for placebo and all active treatment groups. There were no increases in systolic or diastolic blood pressure in any treatment arm. Conclusions Anacetrapib, as monotherapy or coadministered with atorvastatin, produced significant reductions in LDL-C and increases in HDL-C; the net result of treatment with anacetrapib + atorvastatin was ∼70% lowering of LDL-C and more than doubling of HDL-C. Anacetrapib was generally well tolerated with no discernable effect on blood pressure.