From Failure to Promise: Obicetrapib and the Renaissance of Cholesteryl Ester Transfer Protein Inhibition in Atherosclerotic Cardiovascular Disease

Atherosclerotic cardiovascular diseases are a leading global cause of death, driven significantly by elevated low-density lipoprotein cholesterol levels. Despite the emergence of effective lipid-lowering therapies such as statins and other agents, a significant proportion of high-risk patients fail to reach the recommended low-density lipoprotein cholesterol targets. This highlights a critical unmet need for additional lipid-lowering therapies that are not only efficacious and orally administered, but also demonstrate durable safety and cardiovascular benefits. CETP (cholesteryl ester transfer protein) inhibition alters lipid metabolism by preventing the transfer of cholesteryl esters from high-density lipoprotein to apolipoprotein B-containing lipoproteins, thereby reducing atherogenic cholesterol burden. CETP inhibitors have had a challenging development history due to off-target effects observed in early compounds like torcetrapib. However, obicetrapib is a highly selective and hydrophilic CETP inhibitor that heralds a promising new generation of drugs with robust lipid-lowering capabilities and a favorable safety profile. This review presents a comprehensive overview of obicetrapib's mechanism of action, its pharmacokinetic and pharmacodynamic profiles, and a detailed critical assessment of its clinical development through various pivotal trials including TULIP (TA-8995: Its Use in Patients With Mild Dyslipidemia), ROSE (Trial Evaluating Obicetrapib in Combination With Ezetimibe), ROSE2 (Phase 2b ROSE Trial Evaluating Obicetrapib in Combination With Ezetimibe), BROADWAY (Randomized Study to Evaluate the Effect of Obicetrapib on Top of Maximum Tolerated Lipid-Modifying Therapies), BROOKLYN (Obicetrapib on Top of Maximum Tolerated Lipid-Modifying Therapies, TANDEM (Study of Obicetrapib and Ezetimibe Fixed Dose Combination on Top of Maximum Tolerated Lipid-Modifying Therapies), and the ongoing PREVAIL (Cardiovascular Outcome Study to Evaluate the Effect of Obicetrapib in Patients With Cardiovascular Disease) cardiovascular outcomes trial. We compare the efficacy, safety, and tolerability of obicetrapib against prevailing treatment options, positioning it as a potential oral adjunct to maximally tolerated lipid-lowering regimens in the current lipid management landscape.