Dalcetrapib: a review of Phase II data.
BACKGROUND
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.


METHODS
Review of HDL-C-raising compounds, with a focus on cholesteryl ester transfer protein (CETP) inhibitors.


RESULTS
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.


CONCLUSIONS
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.
Robinson
Jennifer G
JG
Lipid Research Clinic, University of Iowa, Iowa City, IA 52242, USA. jennifer-g-robinson@uiowa.edu
D000577:Amides; D000818:Animals; D000924:Anticholesteremic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D002318:Cardiovascular Diseases / Q000517:prevention & control; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors; D008076:Cholesterol, HDL / Q000097:blood / Q000187:drug effects*; D017322:Clinical Trials, Phase II as Topic; D004952:Esters; D006801:Humans; D013438:Sulfhydryl Compounds / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*
D000577:Amides; D000924:Anticholesteremic Agents; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D004952:Esters; D013438:Sulfhydryl Compounds; C411602:dalcetrapib