REVIEW

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

  • Ingrid C. GELISSEN 1 ,
  • Andrew J. BROWN , 2
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  • 1. Faculty of Pharmacy, The University of Sydney, Sydney NSW 2006, Australia
  • 2. BABS, School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney NSW 2052, Australia

Received date: 14 Dec 2010

Accepted date: 07 Jan 2011

Published date: 01 Jun 2011

Copyright

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg

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).

Cite this article

Ingrid C. GELISSEN , Andrew J. BROWN . Drug targets beyond HMG-CoA reductase: Why venture beyond the statins?[J]. Frontiers in Biology, 2011 , 6(3) : 197 -205 . DOI: 10.1007/s11515-011-1130-x

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.
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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

PMID

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

DOI PMID

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

PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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