In vivo effects of anacetrapib on preβ HDL: improvement in HDL remodeling without effects on cholesterol absorption

Abstract

This article is available online at http://www.jlr.org between HDL and apoB-containing lipoproteins such as LDL, and is currently a target for increasing HDL cholesterol (HDL-C) and reducing LDL cholesterol (LDL-C). Small molecule inhibitors have been developed to inhibit CETP, including torcetrapib (Pfi zer), dalcetrapib (Roche), evacetrapib (Eli Lilly), and anacetrapib (ANA) (Merck). While initial clinical trials with torcetrapib established the validity of CETP inhibition as a statin-additive mechanism for reduction of LDL-C and elevation of HDL-C ( 1, 2 ), the phase III outcome trial ILLUMINATE demonstrated that torcetrapib treatment was associated with an increase in cardiovascular events, and overall mortality ( 3 ). A series of preclinical studies indicated that torcetrapib had compound-specifi c off-target activity that was unrelated to CETP inhibition ( 4-6 ). Dalcetrapib was evaluated in a large phase III clinical program (dal-HEART), however the phase III outcomes study (dal-OUTCOMES) was stopped early due to futility/lack of effi cacy ( 7,8 ). While a possible reason for a lack of effect on outcomes benefi t with dalcetrapib might be related to its weaker inhibition of CETP (manifest as an insuffi cient elevation of HDL-C or lack of an effect on LDL-C), the precise answer for why dalcetrapib was ineffective remains unknown.ANA is a potent CETP inhibitor which has not demonstrated the off-target activities of torcetrapib in both preclinical and clinical studies ( 9-11 ). In a recent 1.5 year safety study in ‫ف‬ 1,600 patients with cardiovascular disease ( 11 ), ANA treatment had no effect on blood pressure, electrolytes, or aldosterone, and the distribution of cardiovascular events suggested that ANA treatment would not be associated with the type of adverse effects on outcomes that were observed with torcetrapib. ANA treatment increases HDL-C by over 100% and lowers LDL-C by 30-40% as monotherapy and when coadministered with statins ( 9-11 ). In combination with the lack of any off-target, torcetrapib-like effects, Abstract Cholesteryl ester transfer protein (CETP) transfers cholesteryl ester and triglyceride between HDL and apoB-containing lipoproteins. Anacetrapib (ANA), a reversible inhibitor of CETP, raises HDL cholesterol and lowers LDL cholesterol in dyslipidemic patients. We previously demonstrated that ANA increases macrophage-to-feces reverse cholesterol transport and fecal cholesterol excretion in hamsters, and increased pre ␤ HDL-dependent cholesterol effl ux via ABCA1 in vitro. However, the effects of ANA on in vivo pre ␤ HDL have not been characterized. In vitro, ANA inhibited the formation of pre ␤ , however in ANA-treated dyslipidemic hamsters, pre ␤ HDL levels (measured by twodimensional gel electrophoresis) were increased, in contrast to in vitro fi ndings. Because changes in plasma pre ␤ HDL have been proposed to potentially affect markers of cholesterol absorption with other CETP inhibitors, a dual stable isotope method was used to directly measure cholesterol absorption in hamster...

CETP Deficiency and Concerns in CETP Inhibitor Development

“…The preβ1HDL level was increased in the anacetrapib treatment of dyslipidemic hamsters (25), which is compatible with findings in human with homozygous CETP deficiency but not in heterozygotes. Evacetrapib increased cholesterol efflux capacity and preβ1HDL levels in dyslipidemic patients (26).…”

Glucagon receptor antagonism induces increased cholesterol absorption

“…by guest, on www.jlr.org their synthesis ( 28 ). As a positive pharmacological comparator for the assays of palmitate and cholesterol synthesis, T0901317, an LXR ␣ and ␤ agonist, was used ( 29 ).…”

“…An in vivo study performed in hGCGR mice on chow diet was adapted from a study design previously published ( 28 ). Cholesterol absorption was measured using a stable on chow diet and treated with GRA1 at 30 mpk once daily (QD) for 5 days.…”

Is Cholesteryl Ester Transfer Protein Inhibition an Effective Strategy to Reduce Cardiovascular Risk?

“…40,41 CETPis should also inhibit homotypic transfer of cholesterol esters between HDL subclasses resulting in an increase in lipid-poor pre-β HDL. 42 This was not observed with dalcetrapib in humans, and, consequently, there was no observed increase in ABCA1-mediated efflux, because pre-β HDL is the major acceptor of cholesterol via the ABCA1-mediated pathway. 40 Although dalcetrapib had no effect on ABCA1-mediated efflux, anacetrapib and evacetrapib have been shown to increase ABCA1-mediated efflux, as well as non-ABCA1 efflux, which may be a function of the potency of CETPis.…”