Dalcetrapib: A Comprehensive Monograph on a CETP Modulator's Journey from Broad Failure to Precision Medicine

Executive Summary

Dalcetrapib (DrugBank ID: DB12181) is an investigational small molecule drug that represents one of the most compelling and complex narratives in modern cardiovascular pharmacology. Initially developed as a broad-application therapy to reduce cardiovascular risk by raising high-density lipoprotein cholesterol (HDL-C), its journey has been marked by a high-profile clinical trial failure, subsequent scientific redemption through a landmark pharmacogenomic discovery, and a pioneering pivot toward precision medicine. As a modulator of Cholesteryl Ester Transfer Protein (CETP), Dalcetrapib was designed to inhibit the transfer of cholesteryl esters from anti-atherogenic HDL to pro-atherogenic lipoproteins. This mechanism reliably produced a significant 30-40% increase in HDL-C levels. However, unlike other potent CETP inhibitors, it had a negligible effect on low-density lipoprotein cholesterol (LDL-C), making it an almost pure pharmacological test of the "HDL hypothesis"—the long-held belief that raising HDL-C levels would directly translate to reduced cardiovascular events.

The definitive test of this hypothesis, the dal-OUTCOMES trial involving over 15,000 patients with recent acute coronary syndrome (ACS), was terminated in 2012 for futility. Despite successfully raising HDL-C, Dalcetrapib demonstrated no clinical benefit, a result that profoundly challenged the prevailing dogma in lipidology and contributed to a paradigm shift away from HDL-C quantity as a primary therapeutic target. The drug's development was halted, and it was considered another casualty in the difficult history of CETP inhibitors.