Cholesteryl ester transfer protein inhibition and endothelial function: enough with the surrogates

EDITORIAL European Heart Journal (2012) 33, 819–821 doi:10.1093/eurheartj/ehs040 Cholesteryl ester transfer protein inhibition and endothelial function: enough with the surrogates Prediman K. Shah* Division of Cardiology and Oppenheimer Atherosclerosis Research Center, Cedars Sinai Heart Institute, Cedars Sinai Medical Center and UCLA School of Medicine, Los Angeles, CA, USA Online publish-ahead-of-print 20 February 2012 This paper was guest edited by Prof. Bernard Gersh, Mayo Clinic, Rochester, USA This editorial refers to ‘Vascular effects and safety of dalcetrapib in patients with or at risk of coronary heart disease: the dal-VESSEL randomized clinical trial’†, by T.F. Lüscher et al., on page 857 Statins significantly reduce cardiovascular events in a broad category of patients at risk for or with established atherosclerotic cardiovascular disease; however, a substantial residual risk remains even when LDL-cholesterol (LDL-C) levels are lowered to 70 mg/dL.1 A part of this residual risk is related to low HDL-C levels.1 Epidemiological studies, the known favourable biological actions of HDL and its key constituents, as well as experimental studies have suggested beneficial athero-protective effects of HDL, making HDL a suitable therapeutic target.2 However, unlike LDL-C lowering, HDL-C-raising interventions with currently available agents, such as niacin, fibrates, or peroxisome proliferator-activated receptor g agonists, have not been conclusively or consistently demonstrated to reduce cardiovascular events.3 In the last several years, inhibition of a key enzyme, CETP (cholesteryl ester transfer protein), involved in HDL metabolism, has become a focus of attention since CETP inhibition leads to increases in HDL-C levels.4 CETP is a glycoprotein, present in humans, rabbits, primates, and hamsters, but absent in rodents, dogs, horses, cows, and pigs, that facilitates transfer of cholesterol ester from HDL particles to LDL/ very low-density lipoprotein (VLDL) particles in exchange for triglycerides, thereby participating in reverse cholesterol transport and regulating circulating HDL-C levels.4 Recent observations have also highlighted the fact that CETP remodels HDL particles to generate pre-b-HDL particles that participate as initial acceptors of ABCA-1-mediated cholesterol transfer from peripheral tissues.5 Despite the inverse relationship between CETP activity and HDL-C levels, epidemiological and genetic association studies have provided somewhat conflicting and inconsistent results with respect to the relationship between CETP activity and coronary heart disease (CHD) risk.4,6 Therefore, to date it remains uncertain whether CETP is a foe or a friend in atherosclerosis. Torcetrapib, the first oral CETP inhibitor to advance to phase III clinical trials, unexpectedly increased cardiovascular and noncardiovascular mortality (cancer and infection related) despite marked increases in HDL-C and additional reductions in LDL-C, leading to abandonment of torectrapib as a viable drug candidate in 2006.7 Torcetrapib also failed to reduce carotid intima-media thickness and coronary plaque in several phase II clinical trials.8 – 10 The precise reasons for the failure of torcetrapib remain to be fully defined, but off-target (non-CETP-dependent) toxicity resulting from increases in blood pressure and endothelial dysfunction from increased vascular endothelin expression may have played a role.11,12 Torcetrapib was shown to elevate arterial blood pressure by a non-CETP-related mechanism, most probably by stimulating aldosterone synthesis by activating L-type calcium channels in adrenal cells.3 However, modest blood pressure elevation by torcetrapib is unlikely to have accounted for all of the adverse cardiac and non-cardiac complications of torectrapib, and other speculations have included torcetrapib generating non-functional/ dysfunctional HDL and producing adverse effects on innate immunity.13 Unlike torcetrapib, dalcetrapib is a weaker CETP antagonist that acts as a CETP modulator, inhibiting cholesterol ester transfer between HDL and LDL/VLDL without inhibiting CETP-mediated transfer of cholesterol ester between HDL particles; the latter effect thus preserves the generation of pre-b-HDL particles that are believed to be important in initiating reverse cholesterol transport.5 Dalcetrapib has been shown to raise HDL-C by 30% The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology. This editorial has been guest edited by Prof. Bernard Gersh, Mayo Clinic, Division of Cardiovascular Diseases, 200 First Street, S.W., Rochester, MN 55905-0001, USA. * Corresponding author. Division of Cardiology and Oppenheimer Atherosclerosis Research Center, Cedars Sinai Heart Institute, Cedars Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA. Tel: +1 310 423 3884, Fax: +1 310 423 0144, Email: doi:10.1093/eurheartj/ehs019. † Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2012. For permissions please email: 820 without a significant effect on LDL-C.3 Dalcetrapib has no adverse effects on aldosterone pathway or arterial blood pressure.3 Experimental studies with dalcetrapib in rabbits have yielded mixed results, with favourable effects in rabbits with mild hyperlipidaemia and lack of favourable effects in rabbits with severe hyperlipidaemia.4 The favourable vascular effects of HDL-C have been attributed to its ability to stimulate reverse cholesterol transport, antioxidant and anti-inflammatory actions, as well as favourable effects on various aspects of endothelial function.2 Recent studies have shown that HDL stimulates endothelial nitric oxide production, activates endothelial nitric oxide synthase (eNOS), and promotes endothelial repair through involvement of SR-B1, the sphingosine pathway, and other potential cellular effects.2 Lüscher et al. have now reported the results of the dal-VESSEL trial, a randomized double blind placebo-controlled trial of dalcetrapib on brachial artery reactivity as an index of endothelial function.14 In this study, 476 patients with known CHD or CHD equivalent status, with baseline LDL-C ,100 mg/dL (with statin or ezetimibe use) and HDL-C ,50 mg/dL were randomized to placebo or dalcetrapib 600 mg/day, and the endotheliumdependent vasodilator response in the brachial artery was assessed by ultrasound following a 5 min occlusion. Compared with placebo, there was no significant change in brachial artery reactivity with dalcetrapib at 12 weeks (primary endpoint) or at 36 weeks (secondary endpoint). Furthermore, ambulatory blood pressure measurement showed no significant changes with dalcetrapib compared with placebo at 12 or 36 weeks. Dalcetrapib reduced CETP activity by 50%, increased HDL-C by 30%, and increased apolipoprotein A-1 levels by 10%. Dalcetrapib had no effect on LDL-C, plasma biom (...truncated)