Dalcetrapib, a CETP inhibitor, does not increase aldosterone production

A report from researchers at the University Hospital Geneva, Switzerland showed that the effects of the cholesteryl ester transfer protein (CETP) inhibitors on aldosterone production differ. Unlike torcetrapib, dalcetrapib is not a steroidogenic agent. Neither in vitro production of aldosterone or expression of the aldosterone synthase gene CYP11B2 was increased with dalcetrapib. The results were reported at the American Heart Association Annual Scientific Sessions, New Orleans 2008.

Capponi AM, Clerc RG, Campos L et al. No increase in the in vitro production of aldosterone or the expression of CYP11B2 with the CETP modulator dalcetrapib (RO4607381/JTT-705), in contrast with torcetrapib. Circulation 2008;118:S_452. [Abstract 3618].

In this study, researchers used the human adrenocortical carcinoma cell line H295R to investigate the effects of torcetrapib and dalcetrapib on aldosterone secretion and expression of CYP11B2. Aldosterone was measured by direct radioimmunoassay. Quantitative real-time PCR was used to measure CYP11B2 messenger RNA. Angiotensin II (100 nM) was used as a positive control, and 0.1% DMSO as control.

Torcetrapib increased 24-hour aldosterone secretion in a concentration-dependent manner to a maximum of 396 ± 87.8% of control values, whereas dalcetrapib (up to 10 µM) had no effect. Addition of 25-OH cholesterol, a membrane permeant precursor of steroidogenesis, led to a further increase in aldosterone secretion in torcetrapib-treated cells. Torcetrapib also increased CYP11B2 mRNA by about 11-fold compared with control, and this effect was maintained over 24 hours, whereas dalcetrapib had no effect. The effects of torcetrapib were independent of CETP.

These findings add to data from a previous report,1 which showed that administration of torcetrapib was associated with the release of aldosterone and corticosterone from primary adrenocortical cells in both in vivo and in vitro models. In contrast, another CETP inhibitor anacetrapib, was not associated with adrenal steroid release in either model. Additionally, administration of torcetrapib but not anacetrapib led to an acute increase in blood pressure, a response shown to be dependent on intact adrenal glands.

While these results indicate that the pharmacological effects of torcetrapib are compound-specific and not evident with the newer CETP inhibitors, it remains to be seen whether either dalcetrapib or anacetrapib can provide clinical benefit. Results from outcomes studies are not expected until 2012 or 2013 earliest./p>

Reference

1. Forrest MJ, Bloomfield D, Briscoe RJ et al. Torcetrapib-induced blood pressure elevation is independent of CETP inhibition and is accompanied by increased circulating levels of aldosterone. Br J Pharmacol 2008;154:1465-73.