Barter - Figure 20 - More off-target effects - The Current Status and Future Development of CETP Inhibitors - Translating HDL Science to Clinical Practice

Barter - Figure 20 - More off-target effects Text

This Figure summarizes 3 considerations from 2 pre-clinical studies[21][22] that should be borne in mind when looking for whether the explanation for the negative results in ILLUMINATE were caused by pharmacologically off-target effects of torcetrapib.

First, and very interestingly, torcetrapib increases blood pressure in rats, a species that does not have CETP.
Secondly, analogues of torcetrapib that do not inhibit CETP raise blood pressure to an extent similar to that observed with torcetrapib.
Finally, more recently developed CETP inhibitors such as dalcetrapib and anacetrapib do not raise blood pressure.

This serves as very powerful evidence that the adverse effects of CETP on blood pressure were unrelated to CETP inhibition.

Barter P. J Clin Lipidol. 2011; 5(6).

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References

[21]Forrest MJ, Bloomfield D, Briscoe RJ, Brown PN, Cumiskey AM, Ehrhart J, Hershey JC, Keller WJ, Ma X, McPherson HE, Messina E, Peterson LB, Sharif-Rodriguez W, Siegl PK, Sinclair PJ, Sparrow CP, Stevenson AS, Sun SY, Tsai C, Vargas H, Walker M III, West SH, White V, Woltmann RF. Torcetrapib-induced blood pressure elevation is independent of CETP inhibition and is accompanied by increased circulating levels of aldosterone. Br J Pharmacol. 2008; 154: 1465–1473.

[22]Hu X, Dietz JD, Xia C, et al. Torcetrapib Induces Aldosterone and Cortisol Production by an Intracellular Calcium-Mediated Mechanism Independently of Cholesteryl Ester Transfer Protein Inhibition. Endocrinology 2009:150:2211-2219.