Dalcetrapib
Review of phase II dalcetrapib data flags its unique CETP-binding mechanism ahead of dal-OUTCOMES (Expert Opin Investig Drugs 2010)
Original title: Dalcetrapib: a review of Phase II data
This review surveys HDL-C-raising compounds, focusing on the CETP inhibitor dalcetrapib. Torcetrapib, despite raising HDL-C by 70%, was halted after excess mortality attributed largely to renin-angiotensin-aldosterone system activation and hypertensive effects, while dalcetrapib and anacetrapib development continued. Unlike other CETP inhibitors, dalcetrapib induces a conformational change in CETP rather than forming a non-productive CETP/HDL-C complex, and although it is the least potent of the three by CETP activity, the 900-mg dose did not raise blood pressure or aldosterone over 48 weeks. The advancing 600-mg dose raises HDL-C by 25% to 30% alone or with a statin, with little LDL-C effect, and the author notes results from the ongoing dal-OUTCOMES trial in over 15,000 high-risk CHD patients, plus the dal-VESSEL, dal-PLAQUE, and dal-PLAQUE 2 surrogate endpoint studies, would be needed before regulatory approval.
Original abstract
Importance Of The Field: While statins reduce the risk of cardiovascular disease by up to 50%, many patients remain at increased risk due to low levels of high-density lipoprotein cholesterol (HDL-C). Whether pharmacologically raising HDL-C per se with drug therapy will reduce cardiovascular events remains to be determined.
Areas Covered In This Review: Review of HDL-C-raising compounds, with a focus on cholesteryl ester transfer protein (CETP) inhibitors.
What The Reader Will Gain: An overview of the CETP inhibitor dalcetrapib. Despite 70% increases in HDL-C, development of the CETP inhibitor torcetrapib was halted due to excess mortality, attributed largely to activation of the renin-angiotensin-aldosterone system resulting in hypertensive effects. Development of the CETP inhibitors dalcetrapib and anacetrapib is ongoing. Dalcetrapib has a unique chemical structure and induces a conformational change in CETP rather than forming a non-productive CETP/HDL-C complex as do the other CETP inhibitors. Although dalcetrapib is the least potent CETP inhibitor of the three in terms of CETP activity, the 900-mg dose did not increase blood pressure or raise aldosterone levels over 48 weeks of follow-up. The 600-mg dose of dalcetrapib is moving forward and raises HDL-C by 25 - 30% when used alone or in combination with a statin, with little effect on low-density lipoprotein cholesterol levels.
Take Home Message: Before regulatory approval is granted, results from the ongoing dal-OUTCOMES trial evaluating the effects of dalcetrapib 600 mg daily over standard statin therapy on mortality and morbidity in > 15,000 high-risk CHD patients will be needed. The Dalcetrapib HDL Evaluation, Atherosclerosis and Reverse Cholesterol Transport (dal-HEART) program also includes three surrogate end point trials, dal-VESSEL, dal-PLAQUE and dal-PLAQUE 2, which will provide further information as to the contribution of CETP to cardiovascular disease.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.