Anacetrapib promotes reverse cholesterol transport and bulk cholesterol excretion in Syrian golden hamsters

Abstract

Despite therapies such as statins, which reduce circulating levels of low density lipoprotein cholesterol (LDL-C), cardiovascular event rates remain high. Numerous epidemiological studies (e.g., the Framingham Heart Study) indicate that high density lipoprotein cholesterol (HDL-C) levels are inversely correlated with cardiovascular risk ( 1-6 ). Therefore, therapies that increase HDL-C have gained recent attention as possible treatments for dyslipidemia and atherosclerosis.Cholesteryl ester transfer protein (CETP) mediates transfer of cholesteryl ester (CE) and triglyceride (TG) between HDL and apoB-containing lipoproteins such as LDL and therefore, represents an attractive target for increasing HDL-C and reducing LDL-C. Indeed, initial clinical trials with torcetrapib established the validity of CETP inhibition as a mechanism for elevation of HDL-C ( 7, 8 ). However, the phase III outcome trial ILLUMINATE demonstrated that torcetrapib treatment was associated with an increase in cardiovascular events and overall mortality, possibly due to off-target effects on blood pressure and circulating adrenal hormones ( 9 ). A series of preclinical studies further corroborated that torcetrapib had compoundspecifi c off-target activity that was unrelated to CETP inhibition ( 10-12 ).Anacetrapib (ANA) is a potent CETP inhibitor that has not demonstrated the off-target activities of torcetrapib in preclinical or clinical studies ( 10,(13)(14)(15). ANA treatment increases HDL-C by over 100% and lowers LDL-C by 30-40% as a monotherapy and when coadministered with statins ( 13-15 ). In a recent 1.5 year safety study in ‫ف‬ 1,600 patients with cardiovascular disease ( 15 ) Cardiovascular disease continues to be a major contributor to morbidity and mortality throughout the world. 29 July 2011. Published, JLR Papers in Press, August 14, 2011 DOI 10.1194 Manuscript received 13 April 2011 and in revised form

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

“…169 These results are consistent with the stimulatory effects of anacetrapib on macrophage-to-feces reverse cholesterol transport in both normolipidemic and dyslipidemic hamsters. 217,220 Anacetrapib treatment in dyslipidemic hamsters and healthy human volunteers had no effect on the ability of HDL to blunt cytokineinduced expression of adhesion molecules and monocyte chemotactic protein-1 in endothelial cells. 221 Overall these data indicate that CETP inhibition improves cholesterol efflux capacity of plasma but does not alter anti-inflammatory or endothelium-protective activities of HDL.…”

Glucagon receptor antagonism induces increased cholesterol absorption

“…The plasma level of proprotein convertase subtilisin/kexin type 9 (PCSK9) was determined by PCSK9 dissociation-enhanced lanthanide fl uorescence immunoassay, as described elsewhere ( 14 ). The plasma or serum lipoprotein profi le was assayed by fastprotein LC, as described previously ( 15 ). Fecal cholesterol was measured by extracting lipids using the Folch method ( 16 ), whereby fecal samples were homogenized with 5 ml of chloroform:methanol (2:1, v:v).…”

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

“…Feces were collected for a 24 h period prior to compound treatment and again after 14 days of compound treatment. On day 14, 2 h after the fi nal dose, hamsters received an intravenous dose of 13 C-cholesterol and an oral dose of D 6 -cholesterol, both at 15 mg/kg. Intravenous 13 C-cholesterol was injected as a fi ltered solution (3 mg/ml in a vehicle containing 10% ethanol and 90% Intralipid, 5 ml/kg iv dose).…”