Safety and tolerability of dalcetrapib

Area of Science:

• Cardiovascular Pharmacology
• Drug Development
• Lipid Metabolism

Background:

• Previous cholesteryl ester transfer protein inhibitors, like torcetrapib, showed safety concerns including increased mortality and hypertension.
• Concerns arose from torcetrapib's off-target effects on the renin-angiotensin-aldosterone system.
• Dalcetrapib was developed as a potentially safer alternative.

Purpose of the Study:

• To evaluate the efficacy and clinical safety of dalcetrapib.
• To compare dalcetrapib's effects with placebo and statin combinations.
• To assess nonclinical safety regarding aldosterone production.

Main Methods:

• Pooled analysis of 4-week phase IIa trials (n=838) and a 12-week phase IIb trial (n=292).
• Doses of dalcetrapib (300, 600, 900 mg) were tested as monotherapy and in combination with statins.
• Nonclinical safety assessed via aldosterone production and CYP11B2 mRNA in H295R cells exposed to dalcetrapib or torcetrapib.

Main Results:

• Dalcetrapib increased high-density lipoprotein cholesterol by up to 36% and apolipoprotein A-I by up to 16%.
• Adverse event incidence was similar between placebo and lower dalcetrapib doses (300, 600 mg); higher incidence at 900 mg (p <0.05).
• No clinically relevant changes in blood pressure, ECG, or cardiovascular adverse events were observed; torcetrapib increased aldosterone in vitro, but dalcetrapib did not.

Conclusions:

• Dalcetrapib is effective in increasing HDL-C and ApoA-I, alone or with statins.
• Dalcetrapib was well-tolerated, with a safety profile distinct from torcetrapib.
• Nonclinical data showed no adverse effects on aldosterone production, supporting dalcetrapib's safety.