Anacetrapib (DB06630): A Comprehensive Pharmacological and Clinical Review of a Promising yet Abandoned CETP Inhibitor

Executive Summary

Anacetrapib represents a significant paradox in modern cardiovascular drug development. As a potent inhibitor of cholesteryl ester transfer protein (CETP), it achieved unprecedented success in modifying lipid profiles, most notably by more than doubling high-density lipoprotein cholesterol (HDL-C). In the landmark REVEAL trial, it became the only drug in its class to demonstrate a statistically significant, albeit modest, reduction in major coronary events. However, this clinical success was overshadowed by a complex profile: the therapeutic benefit was attributed not to its primary HDL-raising mechanism but to a secondary reduction in non-HDL cholesterol. This, combined with its unique and concerning pharmacokinetic property of long-term accumulation in adipose tissue, created a challenging risk-benefit and commercial proposition. Ultimately, in October 2017, its developer, Merck & Co., abandoned the program, closing a tumultuous chapter for the CETP inhibitor hypothesis. This report provides an exhaustive analysis of Anacetrapib's journey, dissecting its scientific basis, clinical trial evidence, and the strategic factors that led to its discontinuation, offering critical lessons for the future of lipid-modifying therapies.

1.0 Chemical and Pharmacological Profile

1.1 Identification and Physicochemical Properties

Anacetrapib is a small molecule drug developed as an orally administered agent for the treatment of dyslipidemia.[1] It is identified by the Chemical Abstracts Service (CAS) Number 875446-37-0 and the DrugBank accession number DB06630.[1] During its development, it was also referred to by the code MK-0859 and the non-proprietary name anacetrapibum.[1]