Anacetrapib & HDL-C: Hope for CETP Inhibitors?Literature - Ronen Gurfinkel & Tisha R. Joy
Anacetrapib: Hope for CETP Inhibitors?REVIEW
Ronen Gurfinkel & Tisha R. Joy, Cardiovascular Therapeutics 29 (2011) 327–339
Inhibition of cholesteryl ester transfer protein (CETP), a key protein involved in reverse cholesterol transport, can lead to increases in high-density lipoprotein cholesterol (HDL-C) levels and thus, is under evaluation as an antiatherogenic strategy. Several CETP inhibitors have been under development including anacetrapib, dalcetrapib, and torcetrapib. To date, anacetrapib demonstrates the greatest HDL-C raising and low-density lipoprotein cholesterol (LDL-C) lowering potential. Phase I and phase II trials with anacetrapib have revealed that anacetrapib is well-tolerated and does not seem to possess the pressor effects associated with torcetrapib. This article will briefly review the HDL-C raising through CETP inhibition as an antiatherogenic strategy with a specific focus on anacetrapib.
Despite advances in the management of blood lipid abnormalities using statins, a high incidence of cardiovascular morbidity and mortality still remains (1). The inverse relationship between HDL-C levels and cardiovascular risk has initiated pharmacologic efforts to raise HDL-C to lower cardiovascular risk (2). CETP is a glycoprotein , which circulates largely bound to HDL (3). CETP levels may be 70-80% higher in people with hyperlipidemia. Inhibitors of cholesteryl ester transfer protein (CETP) that have been shown to raise HDL-C have been under development and include torcetrapib, dalcetrapib and anacetrapib.
From the mentioned CETP inhibitors, the development of torcetrapib has been seized due to adverse clinical outcomes, which are thought to be caused by the induction of both cortisole and aldosterone. Newer drugs such as anacetrapib are understandably evaluated on their effect on safety.
CETP inhibition and anacetrapib
Compared to torcetrapib or dalcetrapib, anacetrapib seems to be a potent CETP inhibitor with regard to both HDL-C raising and LDL-C lowering capability. Preclinical data did not indicate that anacetrapib shares the adverse off target effects seen with torcetrapib (4). Clinical data has shown that both dalcetrapib and anacetrapib do not increase blood pressure, as seen with torcetrapib. Anacetrapib seems to be well tolerated (5,6,7).
Direct evidence however of an antiatherogenic effect of CETP inhibition, and the impact of CETP inhibition on reverse cholesterol transport and on atherogenesis has yet to be delivered. Moreover, completion of long-term phase III studies with populations at risk for CVD events is underway to establish the clinical significance of anacetrapib through its modification of the lipid profile. The effect on HDL increase must also been evaluated in tems of HDL functionality and HDL particles and ultimately hard cardiovascular endpoints.
The HDL raising capacity demonstrated by anacetrapib has been clearly demonstrated. Adverse effects, especially the pressor effects seen with torcetrapib have not been reproduced in anacetrapib trials. Results of clinical trials are underway to assess the effect of anacetrapib in hard cardiovascular outcomes.
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