Dalcetrapib: a review of Phase II data.

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.