The mystery of evacetrapib - why are CETP inhibitors failing?

References

• Barter PJ, Chapman MJ, Hennekens CH, et al. Cholesteryl ester transfer protein. A novel target for raising HDL and inhibiting atherosclerosis. Arterioscler Thromb Vasc Biol. 2003;23(2):160–167. .
   PubMed Web of Science ®Google Scholar
• Brousseau ME, Schaefer EJ, Wolfe ML, et al. Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol. N Engl J Med. 2004 Apr 8;350(15):1505–1515.
   PubMed Web of Science ®Google Scholar
• Thompson A, Di Angelantonio E, Sarwar N, et al. 2008 jun18. Association of cholesteryl ester transfer protein genotypes with cetp mass and activity, lipid levels, and coronary risk. Jama 299 (23):2777–2788.
   PubMed Web of Science ®Google Scholar
• Johannsen TH, Frikke-Schmidt R, Schou J, et al. Genetic inhibition of CETP, ischemic vascular disease and mortality, and possible adverse effects. J Am Coll Cardiol. 2012 Nov 13;60(20):2041–2048.
   PubMed Web of Science ®Google Scholar
• Rittershaus CW, Miller DP, Thomas LJ, et al. Vaccine-induced antibodies inhibit CETP activity in vivo and reduce aortic lesions in a rabbit model of atherosclerosis. Arterioscler Thromb Vasc Biol. 2000 Sep;20(9):2106–2112. .
   PubMed Web of Science ®Google Scholar
• Sugano M, Makino N, Sawada S, et al. Effect of antisense oligonucleotides against cholesteryl ester transfer protein on the development of atherosclerosis in cholesterol-fed rabbits. J Biol Chem. 1998 Feb 27;273(9):5033–5036.
   PubMed Web of Science ®Google Scholar
• Okamoto H, Yonemori F, Wakitani K, et al. A cholesteryl ester transfer protein inhibitor attenuates atherosclerosis in rabbits. Nature. 2000 Jul 13;406(6792):203–207.
   PubMed Web of Science ®Google Scholar
• Morehouse LA, Sugarman ED, Bourassa PA, et al. Inhibition of CETP activity by torcetrapib reduces susceptibility to diet-induced atherosclerosis in New Zealand White rabbits. J Lipid Res. 2007 Jun;48(6):1263–1272.
   PubMed Web of Science ®Google Scholar
• HE B. ACP Journal Club: adding niacin plus laropiprant to statins did not reduce vascular events and increased serious adverse events. Ann Intern Med. 2014 Nov 18;161(10):JC8.
   Web of Science ®Google Scholar
• HTC G, MJ L, Haynes R, et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014 Jul 17;371(3):203–212.
   PubMed Web of Science ®Google Scholar
• Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. 2007 Nov 22;357(21):2109–2122.
   PubMed Web of Science ®Google Scholar
• Schwartz GG, Olsson AG, Abt M, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med. 2012 Nov 29;367(22):2089–2099.
   PubMed Web of Science ®Google Scholar
• Lincoff AM, Nicholls SJ, Riesmeyer JS, et al. Evacetrapib and cardiovascular outcomes in high-risk vascular disease. N Engl J Med. 2017 May 18;376(20):1933–1942.
   PubMed Web of Science ®Google Scholar
• Clark RW, Sutfin TA, Ruggeri RB, et al. Raising high-density lipoprotein in humans through inhibition of cholesteryl ester transfer protein: an initial multidose study of torcetrapib. Arterioscler Thromb Vasc Biol. 2004 Mar;24(3):490–497.
   PubMed Web of Science ®Google Scholar
• Nissen SE, Tardif JC, Nicholls SJ, et al. Effect of torcetrapib on the progression of coronary atherosclerosis. N Engl J Med. 2007 Mar 29;356(13):1304–1316.
   PubMed Web of Science ®Google Scholar
• Bots ML, Visseren FL, Evans GW, et al. Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind trial. Lancet. 2007 Jul 14;370(9582):153–160.
   PubMed Web of Science ®Google Scholar
• Kastelein JJ, van Leuven SI, Burgess L, et al. Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia. N Engl J Med. 2007 Apr 19;356(16):1620–1630.
   PubMed Web of Science ®Google Scholar
• Barter P. Lessons learned from the investigation of lipid level management to understand its impact in atherosclerotic events (ILLUMINATE) trial. Am J Cardiol. 2009 Nov 16;104(10 Suppl):10E–5E.
   PubMed Web of Science ®Google Scholar
• Vergeer M, Stroes ES. The pharmacology and off-target effects of some cholesterol ester transfer protein inhibitors. Am J Cardiol. 2009 Nov 16;104(10 Suppl):32E–8E.
   PubMed Web of Science ®Google Scholar
• Forrest MJ, Bloomfield D, Briscoe RJ, et al. Torcetrapib-induced blood pressure elevation is independent of CETP inhibition and is accompanied by increased circulating levels of aldosterone. Br J Pharmacol. 2008 Aug;154(7):1465–1473. .
   PubMed Web of Science ®Google Scholar
• Luscher TF, Taddei S, Kaski JC, et al. Vascular effects and safety of dalcetrapib in patients with or at risk of coronary heart disease: the dal-VESSEL randomized clinical trial. Eur Heart J. 2012 Apr;33(7):857–865. .
   PubMed Web of Science ®Google Scholar
• Fayad ZA, Mani V, Woodward M, et al. Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial. Lancet. 2011 Oct 29;378(9802):1547–1559.
   PubMed Web of Science ®Google Scholar
• Tardif JC, Rheaume E, Lemieux Perreault LP, et al. Pharmacogenomic determinants of the cardiovascular effects of dalcetrapib. Circ Cardiovasc genet. 2015 Jan 11;8(2):372–382.
   Google Scholar
• Tardif J-C, Dube M-P, Pfeffer MA, et al. Study design of Dal-GenE, a pharmacogenetic trial targeting reduction of cardiovascular events with dalcetrapib. Am Heart J. 2020;222:157–165.
   PubMed Web of Science ®Google Scholar
• Nicholls SJ, Brewer HB, Kastelein JJP, et al. Effects of the CETP inhibitor evacetrapib administered as monotherapy or in combination with statins on HDL and LDL cholesterol: a randomized controlled trial. JAMA. 2011 Nov 16;306(19):2099–2109.
   PubMed Web of Science ®Google Scholar
• Nicholls SJ, Ray KK, Ballantyne CM, et al. Comparative effects of cholesteryl ester transfer protein inhibition, statin or ezetimibe on lipid factors: the ACCENTUATE trial. Atherosclerosis. 2017 Jun;261:12–18.
   PubMed Web of Science ®Google Scholar
• Cannon CP, Shah S, Dansky HM, et al. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med. 2010 Dec 16;363(25):2406–2415.
   PubMed Web of Science ®Google Scholar
• Kastelein JJ, Besseling J, Shah S, et al. Anacetrapib as lipid-modifying therapy in patients with heterozygous familial hypercholesterolaemia (REALIZE): a randomised, double-blind, placebo-controlled, phase 3 study. Lancet. 2015 May 30;385(9983):2153–2161.
   PubMed Web of Science ®Google Scholar
• HTRC. Effects of anacetrapib in patients with atherosclerotic vascular disease. N Engl J Med. 2017 Sep 28;377(13):1217-1227.
   Google Scholar
• Gotto AM Jr., Kher U, Chatterjee MS, et al. Lipids, safety parameters, and drug concentrations after an additional 2 years of treatment with anacetrapib in the DEFINE study. J Cardiovasc Pharmacol Ther. 2014 Nov;19(6):543–549. .
   PubMed Web of Science ®Google Scholar
• Hovingh GK, Kastelein JJ, van Deventer SJ, et al. Cholesterol ester transfer protein inhibition by TA-8995 in patients with mild dyslipidaemia (TULIP): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet. 2015 Aug 1;386(9992):452–460.
   PubMed Web of Science ®Google Scholar
• Barter PJ. CETP and atherosclerosis. Arterioscler Thromb Vasc Biol. 2000;20(9):2029–2031.
   PubMed Web of Science ®Google Scholar
• Hopewell JC, Ibrahim M, Hill M, et al. Impact of ADCY9 genotype on response to anacetrapib. Circulation. 2019 Jul 23;140(11):891–898.
   Web of Science ®Google Scholar
• Nissen SE, Pillai SG, Nicholls SJ, et al. ADCY9 genetic variants and cardiovascular outcomes with evacetrapib in patients with high-risk vascular disease: a nested case-control study. JAMA Cardiol. 2018 May 1;3(5):401–408.
   PubMed Web of Science ®Google Scholar
• Ference BA, Kastelein JJP, Ginsberg HN, et al. Association of genetic variants related to CETP inhibitors and statins with lipoprotein levels and cardiovascular risk. JAMA. 2017 Sep 12;318(10):947–956. .
   PubMed Web of Science ®Google Scholar
• Millar JS, Reyes-Soffer G, Jumes P, et al. Anacetrapib lowers LDL by increasing ApoB clearance in mildly hypercholesterolemic subjects. J Clin Invest. 2015 Jun;125(6):2510–2522. .
   PubMed Web of Science ®Google Scholar
• Masson W, Lobo M, Siniawski D, et al. Therapy with cholesteryl ester transfer protein (CETP) inhibitors and diabetes risk. Diabetes Metab. 2018 Feb 20;44(6):508–513.
   PubMed Web of Science ®Google Scholar
• Barter PJ, Rye KA, Tardif JC, et al. Effect of torcetrapib on glucose, insulin, and hemoglobin A1c in subjects in the investigation of lipid level management to understand its impact in atherosclerotic events (ILLUMINATE) trial. Circulation. 2011 Aug 2;124(5):555–562. .
   PubMed Web of Science ®Google Scholar
• Barter PJ, Cochran BJ, Rye KA. CETP inhibition, statins and diabetes. Atherosclerosis. 2018 Sep;26(278):143–146.
   Google Scholar
• von Eckardstein A, Widmann C. High-density lipoprotein, beta cells, and diabetes. Cardiovasc Res. 2014 Aug 1;103(3):384–394.
   PubMed Web of Science ®Google Scholar
• Barter PJ, Nicholls S, Rye KA, et al. Antiinflammatory properties of HDL. Circ Res. 2004 Oct 15;95(8):764–772.
   PubMed Web of Science ®Google Scholar
• SJ N, GJ D, Cutri B, et al. Reconstituted high density lipoproteins inhibit the acute pro-oxidant and proinflammatory vascular changes induced by a periarterial collar in normocholesterolemic rabbits. Circulation. 2005;111(12):1543–1550. .
   PubMed Web of Science ®Google Scholar
• Blauw LL, Wang Y, Willems van Dijk K, et al. A novel role for CETP as immunological gatekeeper: raising HDL to cure sepsis? Trends Endocrinol Metab. 2020 Feb 4. DOI:10.1016/j.tem.2020.01.003.
   PubMedGoogle Scholar
• Bhattacharyya T, Nicholls SJ, Topol EJ, et al. Relationship of paraoxonase 1 (pon1) gene polymorphisms and functional activity with systemic oxidative stress and cardiovascular risk. Jama. 2008 Mar 19;299(11):1265–1276.
   PubMed Web of Science ®Google Scholar