Drug targets beyond HMG-CoA reductase: Why venture beyond the statins?

Abstract

In this review, we aim to convey a brief, select history of the development of cholesterol-lowering therapies. We focus particularly on the highly successful statins as well as setbacks that should serve as cautionary tales. We go on to preview recent developments that may complement, if not one day replace, the statins. Our focus is on pharmacological interventions, particularly those targeting the cholesterol biosynthetic pathway. Also, we examine therapies under current investigation that target the assembly of atherogenic lipoproteins (via apolipoprotein B or microsomal triglyceride transfer protein), the stability of the low-density lipoprotein-receptor (via PCSK9, proprotein convertase subtilisin kexin 9), or are designed to increase high-density lipoprotein-cholesterol (via inhibition of cholesteryl ester transfer protein).

Keywords

statins / cholesterol-lowering drugs / side-effects / adverse reactions / cholesterol synthesis

References

[1] Abe I, Abe T, Lou W, Masuoka T, Noguchi H (2007). Site-directed mutagenesis of conserved aromatic residues in rat squalene epoxidase. Biochem Biophys Res Commun, 352(1): 259–263

[2] Abifadel M, Pakradouni J, Collin M, Samson-Bouma M E, Varret M, Rabès J P, Boileau C (2010). Strategies for proprotein convertase subtilisin kexin 9 modulation: a perspective on recent patents. Expert Opin Ther Pat, 20(11): 1547–1571

[3] Abifadel M, Varret M, Rabès J P, Allard D, Ouguerram K, Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich D, Derré A, Villéger L, Farnier M, Beucler I, Bruckert E, Chambaz J, Chanu B, Lecerf J M, Luc G, Moulin P, Weissenbach J, Prat A, Krempf M, Junien C, Seidah N G, Boileau C (2003). Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet, 34(2): 154–156

[4] Akdim F, Visser M E, Tribble D L, Baker B F, Stroes E S, Yu R, Flaim J D, Su J, Stein E A, Kastelein J J (2010). Effect of mipomersen, an apolipoprotein B synthesis inhibitor, on low-density lipoprotein cholesterol in patients with familial hypercholesterolemia. Am J Cardiol, 105(10): 1413–1419

[5] Anon (2006). Cholesterol: the good, the bad, and the stopped trials. Lancet, 368(9552): 2034

[6] Anon (2008). Discontinuation of Development of TAK-475, A Compound for Treatment of Hypercholesterolemia. (<month>December</month>2010)

[7] Anon (2010). ClinicalTrials.gov. (<month>December</month>2010)

[8] Baigent C, Blackwell L, Emberson J, Holland L E, Reith C, Bhala N, Peto R, Barnes E H, Keech A, Simes J, Collins R, and the Cholesterol Treatment Trialists’ (CTT) Collaboration (2010). Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet, 376(9753): 1670–1681

[9] Barter P J, Caulfield M, Eriksson M, Grundy S M, Kastelein J J, Komajda M, Lopez-Sendon J, Mosca L, Tardif J C, Waters D D, Shear C L, Revkin J H, Buhr K A, Fisher M R, Tall A R, Brewer B, and the ILLUMINATE Investigators (2007). Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med, 357(21): 2109–2122

[10] Bates T R, Connaughton V M, Watts G F (2009). Non-adherence to statin therapy: a major challenge for preventive cardiology. Expert Opin Pharmacother, 10(18): 2973–2985

[11] Britt H, Miller G C, Charles J, Henderson J, Bayram C, Harrison C, Valenti L, Fahridin S, Pan Y, O’Halloran J (2008). General practice activity in Australia 2007-08. Canberra: Australian Institute of Health and Welfare. Report no.

[12] Brown A J (2009). 24(S),25-epoxycholesterol: a messenger for cholesterol homeostasis. Int J Biochem Cell Biol, 41(4): 744–747

[13] Brown A J (2010). Does upsizing statins have a downside? Drug Saf, 33(5): 435–436, author reply 436-437

[14] Bruckert E, Hayem G, Dejager S, Yau C, Bégaud B (2005). Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients—the PRIMO study. Cardiovasc Drugs Ther, 19(6): 403–414

[15] Bucher N L, Overath P, Lynen F (1960). beta-Hydroxy-beta-methyl-glutaryl coenzyme A reductase, cleavage and condensing enzymes in relation to cholesterol formation in rat liver. Biochim Biophys Acta, 40: 491–501

[16] Cannon C P, Shah S, Dansky H M, Davidson M, Brinton E A, Gotto A M, Stepanavage M, Liu S X, Gibbons P, Ashraf T B, Zafarino J, Mitchel Y, Barter P (2010). Safety of Anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med, 363: 2406–2415

[17] Chan J C, Piper D E, Cao Q, Liu D, King C, Wang W, Tang J, Liu Q, Higbee J, Xia Z, Di Y, Shetterly S, Arimura Z, Salomonis H, Romanow W G, Thibault S T, Zhang R, Cao P, Yang X P, Yu T, Lu M, Retter M W, Kwon G, Henne K, Pan O, Tsai M M, Fuchslocher B, Yang E, Zhou L, Lee K J, Daris M, Sheng J, Wang Y, Shen W D, Yeh W C, Emery M, Walker N P, Shan B, Schwarz M, Jackson S M (2009). A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates. Proc Natl Acad Sci USA, 106(24): 9820–9825

[18] Chugh A, Ray A, Gupta J B (2003). Squalene epoxidase as hypocholesterolemic drug target revisited. Prog Lipid Res, 42(1): 37–50

[19] Clarke G A, Bouchard G, Paigen B, Carey M C (2004). Cholesterol synthesis inhibition distal to squalene upregulates biliary phospholipid secretion and counteracts cholelithiasis in the genetically prone C57L/J mouse. Gut, 53(1): 136–142

[20] Cuchel M, Bloedon L T, Szapary P O, Kolansky D M, Wolfe M L, Sarkis A, Millar J S, Ikewaki K, Siegelman E S, Gregg R E, Rader D J (2007). Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia. N Engl J Med, 356(2): 148–156

[21] Dang H, Liu Y, Pang W, Li C, Wang N, Shyy J Y, Zhu Y (2009). Suppression of 2,3-oxidosqualene cyclase by high fat diet contributes to liver X receptor-alpha-mediated improvement of hepatic lipid profile. J Biol Chem, 284(10): 6218–6226

[22] Daskalopoulou S S (2009). When statin therapy stops: implications for the patient. Curr Opin Cardiol, 24(5): 454–460

[23] DeBose-Boyd R A (2008). Feedback regulation of cholesterol synthesis: sterol-accelerated ubiquitination and degradation of HMG CoA reductase. Cell Res, 18(6): 609–621

[24] Dubuc G, Chamberland A, Wassef H, Davignon J, Seidah N G, Bernier L, Prat A (2004). Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol, 24(8): 1454–1459

[25] Eisele B, Budzinski R, Müller P, Maier R, Mark M (1997). Effects of a novel 2,3-oxidosqualene cyclase inhibitor on cholesterol biosynthesis and lipid metabolism in vivo. J Lipid Res, 38(3): 564–575

[26] Endo A (2010). A historical perspective on the discovery of statins. Proc Jpn Acad, Ser B, Phys Biol Sci, 86(5): 484–493

[27] Frank-Kamenetsky M, Grefhorst A, Anderson N N, Racie T S, Bramlage B, Akinc A, Butler D, Charisse K, Dorkin R, Fan Y, Gamba-Vitalo C, Hadwiger P, Jayaraman M, John M, Jayaprakash K N, Maier M, Nechev L, Rajeev K G, Read T, Röhl I, Soutschek J, Tan P, Wong J, Wang G, Zimmermann T, de Fougerolles A, Vornlocher H P, Langer R, Anderson D G, Manoharan M, Koteliansky V, Horton J D, Fitzgerald K (2008). Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates. Proc Natl Acad Sci USA, 105(33): 11915–11920

[28] Frantz I D Jr, Moore R B (1969). The sterol hypothesis in atherogenesis. Am J Med, 46(5): 684–690

[29] Funk J, Landes C (2005). Histopathologic findings after treatment with different oxidosqualene cyclase (OSC) inhibitors in hamsters and dogs. Exp Toxicol Pathol, 57(1): 29–38

[30] Goldstein J L, DeBose-Boyd R A, Brown M S (2006). Protein sensors for membrane sterols. Cell, 124(1): 35–46

[31] Golomb B A, Evans M A (2008). Statin adverse effects : a review of the literature and evidence for a mitochondrial mechanism. Am J Cardiovasc Drugs, 8(6): 373–418

[32] Hirano K, Yamashita S, Nakajima N, Arai T, Maruyama T, Yoshida Y, Ishigami M, Sakai N, Kameda-Takemura K, Matsuzawa Y (1997). Genetic cholesteryl ester transfer protein deficiency is extremely frequent in the Omagari area of Japan. Marked hyperalphalipoproteinemia caused by CETP gene mutation is not associated with longevity. Arterioscler Thromb Vasc Biol, 17(6): 1053–1059

[33] Li J J (2009). Triumph of the heart: The story of the statin. Oxford: Oxford University Press

[34] McGinnis B, Olson K L, Magid D, Bayliss E, Korner E J, Brand D W, Steiner J F (2007). Factors related to adherence to statin therapy. Ann Pharmacother, 41(11): 1805–1811

[35] Mera Y, Odani N, Kawai T, Hata T, Suzuki M, Hagiwara A, Katsushima T, Kakutani M (2010). Pharmacological characterization of diethyl-2-({3-dimethylcarbamoyl-4-[(4'-trifluoromethylbiphenyl-2-carbonyl) amino] phenyl} acetyloxymethyl)-2-phenylmalonate, JTT-130, an intestine-specific inhibitor of microsomal triglyceride transfer protein. J Pharmacol Exp Ther, 336(2): 321–327

[36] Morand O H, Aebi J D, Dehmlow H, Ji Y H, Gains N, Lengsfeld H, Himber J (1997). Ro 48-8.071, a new 2,3-oxidosqualene:lanosterol cyclase inhibitor lowering plasma cholesterol in hamsters, squirrel monkeys, and minipigs: comparison to simvastatin. J Lipid Res, 38(2): 373–390

[37] Raal F J, Santos R D, Blom D J, Marais A D, Charng M J, Cromwell W C, Lachmann R H, Gaudet D, Tan J L, Chasan-Taber S, Tribble D L, Flaim J D, Crooke S T (2010). Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet, 375(9719): 998–1006

[38] Ridker P M, Danielson E, Fonseca F A, Genest J, Gotto A M Jr, Kastelein J J, Koenig W, Libby P, Lorenzatti A J, Macfadyen J G, Nordestgaard B G, Shepherd J, Willerson J T, Glynn R J, and the JUPITER Trial Study Group (2009). Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet, 373(9670): 1175–1182

[39] Robinson J G (2010). Dalcetrapib: a review of Phase II data. Expert Opin Investig Drugs, 19(6): 795–805

[40] Robinson J G, Smith B, Maheshwari N, Schrott H (2005). Pleiotropic effects of statins: benefit beyond cholesterol reduction? A meta-regression analysis. J Am Coll Cardiol, 46(10): 1855–1862

[41] Rozman D, Monostory K (2010). Perspectives of the non-statin hypolipidemic agents. Pharmacol Ther, 127(1): 19–40

[42] Ruckenstuhl C, Lang S, Poschenel A, Eidenberger A, Baral P K, Kohút P, Hapala I, Gruber K, Turnowsky F (2007). Characterization of squalene epoxidase of Saccharomyces cerevisiae by applying terbinafine-sensitive variants. Antimicrob Agents Chemother, 51(1): 275–284

[43] Sankatsing R R, Fouchier S W, de Haan S, Hutten B A, de Groot E, Kastelein J J, Stroes E S (2005). Hepatic and cardiovascular consequences of familial hypobetalipoproteinemia. Arterioscler Thromb Vasc Biol, 25(9): 1979–1984

[44] Sattar N, Preiss D, Murray H M, Welsh P, Buckley B M, de Craen A J, Seshasai S R, McMurray J J, Freeman D J, Jukema J W, Macfarlane P W, Packard C J, Stott D J, Westendorp R G, Shepherd J, Davis B R, Pressel S L, Marchioli R, Marfisi R M, Maggioni A P, Tavazzi L, Tognoni G, Kjekshus J, Pedersen T R, Cook T J, Gotto A M, Clearfield M B, Downs J R, Nakamura H, Ohashi Y, Mizuno K, Ray K K, Ford I (2010). Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet, 375(9716): 735–742

[45] Schedlbauer A, Schroeder K, Peters T J, Fahey T (2004). Interventions to improve adherence to lipid lowering medication. Cochrane Database Syst Rev, (4): CD004371

[46] Seiki S, Frishman W H (2009). Pharmacologic inhibition of squalene synthase and other downstream enzymes of the cholesterol synthesis pathway: a new therapeutic approach to treatment of hypercholesterolemia. Cardiol Rev, 17(2): 70–76

[47] Silva M, Matthews M L, Jarvis C, Nolan N M, Belliveau P, Malloy M, Gandhi P (2007). Meta-analysis of drug-induced adverse events associated with intensive-dose statin therapy. Clin Ther, 29(2): 253–260

[48] Sposito A C, Carvalho L S, Cintra R M, Araújo A L, Ono A H, Andrade J M, Coelho O R, Quinaglia e Silva J C, and the Brasilia Heart Study Group (2009). Rebound inflammatory response during the acute phase of myocardial infarction after simvastatin withdrawal. Atherosclerosis, 207(1): 191–194

[49] Staffa J A, Chang J, Green L (2002). Cerivastatin and reports of fatal rhabdomyolysis. N Engl J Med, 346(7): 539–540

[50] Steinberg D, Witztum J L (2009). Inhibition of PCSK9: a powerful weapon for achieving ideal LDL cholesterol levels. Proc Natl Acad Sci USA, 106(24): 9546–9547

[51] Stone B G, Evans C D, Prigge W F, Duane W C, Gebhard R L (1989). Lovastatin treatment inhibits sterol synthesis and induces HMG-CoA reductase activity in mononuclear leukocytes of normal subjects. J Lipid Res, 30(12): 1943–1952

[52] Telford D E, Lipson S M, Barrett P H, Sutherland B G, Edwards J Y, Aebi J D, Dehmlow H, Morand O H, Huff M W (2005). A novel inhibitor of oxidosqualene:lanosterol cyclase inhibits very low-density lipoprotein apolipoprotein B100 (apoB100) production and enhances low-density lipoprotein apoB100 catabolism through marked reduction in hepatic cholesterol content. Arterioscler Thromb Vasc Biol, 25(12): 2608–2614

[53] Thompson A, Di Angelantonio E, Sarwar N, Erqou S, Saleheen D, Dullaart R P, Keavney B, Ye Z, Danesh J (2008). Association of cholesteryl ester transfer protein genotypes with CETP mass and activity, lipid levels, and coronary risk. JAMA, 299(23): 2777–2788

[54] Visser M E, Kastelein J J, Stroes E S (2010). Apolipoprotein B synthesis inhibition: results from clinical trials. Curr Opin Lipidol, 21(4): 319–323

[55] Webster R J, Heeley E L, Peiris D P, Bayram C, Cass A, Patel A A (2009). Gaps in cardiovascular disease risk management in Australian general practice. Med J Aust, 191(6): 324–329

[56] Wenner Moyer M (2010). The search beyond statins. Nat Med, 16(2): 150–153

[57] Wong J, Quinn C M, Brown A J (2004). Statins inhibit synthesis of an oxysterol ligand for the liver x receptor in human macrophages with consequences for cholesterol flux. Arterioscler Thromb Vasc Biol, 24(12): 2365–2371

[58] Wong J, Quinn C M, Brown A J (2007). Synthesis of the oxysterol, 24(S), 25-epoxycholesterol, parallels cholesterol production and may protect against cellular accumulation of newly-synthesized cholesterol. Lipids Health Dis, 6(1): 10

[59] Yeshurun D, Slobodin G, Keren D, Elias N (2005). Statin escape phenomenon: Does it really exist? Eur J Intern Med, 16(3): 192–194

Acknowledgments

Our laboratories are supported by grants from the National Health and Medical Research Council and the Prostate Cancer Foundation of Australia. We thank members of the Brown Laboratory for providing critical feedback.

RIGHTS & PERMISSIONS

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg