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제 2형 당뇨병 치료제의 개발 동향

Trends and Perspectives in the Development of Antidiabetic Drugs for Type 2 Diabetes Mellitus

  • Lee, Soo-Hyun (College of Life Sciences and Biotechnology, Korea University) ;
  • Lee, Jong-Keun (College of Life Sciences and Biotechnology, Korea University) ;
  • Kim, Ik-Hwan (College of Life Sciences and Biotechnology, Korea University)
  • 투고 : 2012.05.11
  • 심사 : 2012.07.02
  • 발행 : 2012.09.28

초록

Type 2 Diabetes Mellitus, a chronic metabolic disorder which results from a high blood glucose level, is one of the most prevalent and costly diseases of our time. Considering increasing rates of obesity and the aging population in Korea, the number of diabetic patients is likely to rise rapidly in the future. There are five conventional diabetic drugs which work through different mechanisms; sulfonylureas, biguanide, meglitinide, alpha-glucosidase inhibitors, and thiazolidinedione. Although they all have antidiabetic effects, some side effects such as hypoglycemia, weight gain and gastrointestinal intolerance are associated with them. Incretin based therapies, utilizing glucagon-like peptide-1 (GLP-1) and dipeptidyl peptidase-4 (DPP-4) inhibitors, which have a lower risk of adverse side effects, have recently been introduced. At present PPAR-targeting drugs are being actively developed. In this research review, particular emphasis has been placed on the current trends and possible biological targets for the new generation of antidiabetic drugs.

키워드

참고문헌

  1. Abbatecola, A. M., S. Maggi, and G. Paolisso. 2008. New approaches to treating type 2 diabetes mellitus in the elderly: Role of incretin therapies. Drugs Aging. 25: 913-925. https://doi.org/10.2165/0002512-200825110-00002
  2. Ahren, B. and J. Foley. 2008. The islet enhancer vildagliptin: Mechanisms of improved glucose metabolism. Int. J. Clin. Pract. 62: 8-14.
  3. Ahren, B. 2011. The future of incretin-based therapy: Novel avenues-novel targets. Diabetes, Obes. Metab. 13: 158-166.
  4. Ahren, B. 2009. Clinical results of treating type 2 diabetic patients with sitagliptin, vildagliptin or saxagliptin - diabetes control and potential adverse events. Best Pract. Res. Clin. Endoc. Metab. 23: 487-498. https://doi.org/10.1016/j.beem.2009.03.003
  5. Ahren, B. 2011. GLP-1 for type 2 diabetes. Exp. Cell Res. 317: 1239-1245. https://doi.org/10.1016/j.yexcr.2011.01.010
  6. Atkins, R. C. 2005. The epidemiology of chronic kidney disease. Kidney Int. 67: S14-S18. https://doi.org/10.1111/j.1523-1755.2005.09403.x
  7. Bagust, A. and S. Beale. 2003. Deteriorating beta-cell function in type 2 diabetes: A long-term model. QJM. 96: 281-288. https://doi.org/10.1093/qjmed/hcg040
  8. Buse, J. B., C. J. Rubin, R. Frederich, K. Viraswami-Appanna, K. C. Lin, R. Montoro, G. Shockey, and J. A. Davidson. 2005. Muraglitazar, a dual ([alpha]/[gamma]) PPAR activator: A randomized, double-blind, placebo-controlled, 24-week monotherapy trial in adult patients with type 2 diabetes. Clin. Ther. 27: 1181-1195. https://doi.org/10.1016/j.clinthera.2005.08.005
  9. Buse, J. B., J. Rosenstock, G. Sesti, W. E. Schmidt, E. Montanya, J. H. Brett, M. Zychma, and L. Blonde. 2009. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: A 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). J. Lancet. 374: 39-47. https://doi.org/10.1016/S0140-6736(09)60659-0
  10. Cariou, B., Y. Zair, B. Staels, and E. Bruckert. 2011. Effects of the new dual $PPAR{\alpha}/{\delta}$ agonist GFT505 on lipid and glucose homeostasis in abdominally obese patients with combined dyslipidemia or impaired glucose metabolism. Diabetes Care 34: 2008-2014. https://doi.org/10.2337/dc11-0093
  11. Choi, J. H., A. S. Banks, J. L. Estall, S. Kajimura, P. Bostrom, D. Laznik, J. L. Ruas, M. J. Chalmers, T. M. Kamenecka, and M. Bluher. 2010. Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPAR [ggr] by Cdk5. Nature 466: 451-456. https://doi.org/10.1038/nature09291
  12. Choi, J. H., A. S. Banks, T. M. Kamenecka, S. A. Busby, M. J. Chalmers, N. Kumar, D. S. Kuruvilla, Y. Shin, Y. He, and J. B. Bruning. 2011. Antidiabetic actions of a non-agonist PPAR [ggr] ligand blocking Cdk5-mediated phosphorylation. Nature 477: 477-481. https://doi.org/10.1038/nature10383
  13. Congdon, N. G., D. S. Friedman, and T. Lietman. 2003. Important causes of visual impairment in the world today. JAMA, J. Am. Med. Assoc. 290: 2057-2060. https://doi.org/10.1001/jama.290.15.2057
  14. Drucker, D. J. and M. A. Nauck. 2006. The incretin system: Glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. J. Lancet. 368: 1696-1705. https://doi.org/10.1016/S0140-6736(06)69705-5
  15. Dunning, B., J. Foley, and B. Ahren. 2005. Alpha cell function in health and disease: Influence of glucagon-like peptide-1. Diabetologia 48: 1700-1713. https://doi.org/10.1007/s00125-005-1878-0
  16. Flegal, K. M., M. D. Carroll, C. L. Ogden, and L. R. Curtin. 2010. Prevalence and trends in obesity among US adults, 1999-2008. J. Am. Vet. Med. Assoc. 303: 235-241. https://doi.org/10.1001/jama.2009.2014
  17. Gilbert, M. P. and R. E. Pratley. 2009. Efficacy and safety of incretin-based therapies in patients with type 2 diabetes mellitus. Eur. J. Intern. Med. 20: S309-S318.
  18. Gomis, R., R. M. Espadero, R. Jones, H. Woerle, and K. Dugi. 2011. Efficacy and safety of initial combination therapy with linagliptin and pioglitazone in patients with inadequately controlled type 2 diabetes: A randomized, double-blind, placebo-controlled study. Diabetes, Obes. Metab. 13: 653-661. https://doi.org/10.1111/j.1463-1326.2011.01391.x
  19. Gregg, E. W., B. L. Cadwell, Y. J. Cheng, C. C. Cowie, D. E. Williams, L. Geiss, M. M. Engelgau, and F. Vinicor. 2004. Trends in the prevalence and ratio of diagnosed to undiagnosed diabetes according to obesity levels in the US. Diabetes Care 27: 2806-2812. https://doi.org/10.2337/diacare.27.12.2806
  20. Home, P. D., S. J. Pocock, H. Beck-Nielsen, P. S. Curtis, R. Gomis, M. Hanefeld, N. P. Jones, M. Komajda, and J. J. V. McMurray. 2009. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): A multicentre, randomised, open-label trial. J. Lancet. 373: 2125-2135. https://doi.org/10.1016/S0140-6736(09)60953-3
  21. Hong, E. G. 2011. Drug therapy of elderly diabetic patients. Korean J. Med. 80: 635-642.
  22. Hundal, R. S., M. Krssak, S. Dufour, D. Laurent, V. Lebon, V. Chandramouli, S. E. Inzucchi, W. C. Schumann, K. F. Petersen, and B. R. Landau. 2000. Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes 49: 2063-2069. https://doi.org/10.2337/diabetes.49.12.2063
  23. Kahn, S. E., B. Zinman, J. M. Lachin, S. M. Haffner, W. H. Herman, R. R. Holman, B. G. Kravitz, D. Yu, M. A. Heise, and R. P. Aftring. 2008. Rosiglitazone-associated fractures in type 2 diabetes. Diabetes Care 31: 845-851. https://doi.org/10.2337/dc07-2270
  24. Kecskemeti, V., Z. Bagi, P. Pacher, I. Posa, E. Kocsis, and K. M. Zs. 2002. New trends in the development of oral antidiabetic drugs. Curr. Med. Chem. 9: 53-71. https://doi.org/10.2174/0929867023371427
  25. Kim, J. H. and M. -. Lee. 2009. Incretin-based combination therapy in type 2 diabetes mellitus RID C-9606-2011. J. Korean Med. Assoc. 52: 1030-1036. https://doi.org/10.5124/jkma.2009.52.10.1030
  26. Kim, S. G. and D. S. Choi. 2008. The present state of diabetes mellitus in korea. J. Korean Med. Assoc. 51: 791-798. https://doi.org/10.5124/jkma.2008.51.9.791
  27. King, H., R. E. Aubert, and W. H. Herman. 1998. Global burden of diabetes, 1995-2025: Prevalence, numerical estimates, and projections. Diabetes Care 21: 1414-1431. https://doi.org/10.2337/diacare.21.9.1414
  28. Knop, F. K., T. Vilsboll, and J. J. Holst. 2009. Incretin-based therapy of type 2 diabetes mellitus. Curr. Protein Pept. Sci. 10: 46-55. https://doi.org/10.2174/138920309787315158
  29. Knudsen, L. 2010. Liraglutide: The therapeutic promise from animal models. Int. J. Clin. Pract. 64: 4-11.
  30. Kokil, G. R., P. V. Rewatkar, A. Verma, S. Thareja, and S. R. Naik. 2010. Pharmacology and chemistry of diabetes mellitus and antidiabetic drugs: A critical review. Curr. Med. Chem. 17: 4405-4423. https://doi.org/10.2174/092986710793361225
  31. Lebovitz, H. 1999. Insulin secretagogues: Old and new. Diabetes Rev. 7: 139-153.
  32. Lipscombe, L. L. and J. E. Hux. 2007. Trends in diabetes prevalence, incidence, and mortality in ontario, canada 1995-2005: A population-based study. J. Lancet. 369: 750-756. https://doi.org/10.1016/S0140-6736(07)60361-4
  33. Luo, J. and F. B. Hu. 2002. Time trends of obesity in preschool children in china from 1989 to 1997. Int. J. Obes. 26: 553-558. https://doi.org/10.1038/sj.ijo.0801944
  34. Masana Marin, L. and R. Gomis Barbera. 2002. Thiazoli-dindiones: Drugs for cardiovascular prevention. Med. Clin. (Barc). 118: 585-586. https://doi.org/10.1016/S0025-7753(02)72459-7
  35. Matthews, D., S. Dejager, B. Ahren, V. Fonseca, E. Ferrannini, A. Couturier, J. Foley, and B. Zinman. 2010. Vildagliptin add-on to metformin produces similar efficacy and reduced hypoglycaemic risk compared with glimepiride, with no weight gain: Results from a 2-year study. Diabetes, Obes. Metab. 12: 780-789. https://doi.org/10.1111/j.1463-1326.2010.01233.x
  36. Nelson, P., T. Poon, X. Guan, C. Schnabel, M. Wintle, and M. Fineman. 2007. The incretin mimetic exenatide as a monotherapy in patients with type 2 diabetes. Diabetes Technol. Ther. 9: 317-326. https://doi.org/10.1089/dia.2006.0024
  37. Nguyen, Q. 2008. Evaluation and management of diabetes mellitus. Am Health and Drug Benefits. 1: 39-48.
  38. Nissen, S. E. and K. Wolski. 2007. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N. Engl. J. Med. 356: 2457-2471. https://doi.org/10.1056/NEJMoa072761
  39. Norris, A. W. and C. D. Sigmund. 2012. A second chance for a PPAR${\gamma}$ targeted therapy? Circ. Res. 110: 8-11. https://doi.org/10.1161/RES.0b013e3182435d88
  40. Oh, I. H., S. J. Yoon, and E. J. Kim. 2011. The burden of disease in korea. J. Korean Med. Assoc. 54: 646-652. https://doi.org/10.5124/jkma.2011.54.6.646
  41. Paton, C. M. and J. M. Ntambi. 2009. Biochemical and physiological function of stearoyl-CoA desaturase. Endocrino Metab. 297: E28-E37.
  42. Pavankuamr, V. V., C. Vinu, R. Mullangi, and N. R. Srinivas. 2007. Preclinical pharmacokinetics and interspecies scaling of ragaglitazar, a novel biliary excreted PPAR dual activator. Eur. J. Drug Metab. Pharmacokinet. 32: 29-37. https://doi.org/10.1007/BF03190987
  43. Perfetti, R. and H. Hui. 2004. The role of GLP-1 in the life and death of pancreatic beta cells. Horm. Metab. Res. 36: 804-810. https://doi.org/10.1055/s-2004-826167
  44. Porte Jr, D. 2001. Clinical importance of insulin secretion and its interaction with insulin resistance in the treatment of type 2 diabetes mellitus and its complications. Diabetes Metab. Res. 17: 181-188. https://doi.org/10.1002/1520-7560(200105/06)17:3<181::AID-DMRR197>3.0.CO;2-1
  45. Punthakee, Z., J. Bosch, G. Dagenais, R. Diaz, R. Holman, J. L. Probstfield, A. Ramachandran, M. C. Riddle, L. E. Ryden, B. Zinman, R. Afzal, S. Yusuf, H. C. Gerstein, and TIDE Trial Investigators. 2012. Design, history and results of the thiazolidinedione intervention with vitamin D evaluation (TIDE) randomised controlled trial. Diabetologia 55: 36-45. https://doi.org/10.1007/s00125-011-2357-4
  46. Schafer, S., K. Mussig, H. Staiger, F. Machicao, N. Stefan, B. Gallwitz, H. Haring, and A. Fritsche. 2009. A common genetic variant in WFS1 determines impaired glucagon-like peptide-1-induced insulin secretion. Diabetologia 52: 1075-1082. https://doi.org/10.1007/s00125-009-1344-5
  47. Schafer, S., O. Tschritter, F. Machicao, C. Thamer, N. Stefan, B. Gallwitz, J. Holst, J. Dekker, L. t'Hart, and G. Nijpels. 2007. Impaired glucagon-like peptide-1-induced insulin secretion in carriers of transcription factor 7-like 2 (TCF7L2) gene polymorphisms. Diabetologia 50: 2443-2450. https://doi.org/10.1007/s00125-007-0753-6
  48. Shulman, G. I. 2000. Cellular mechanisms of insulin resistance. J. Clin. Invest. 106: 171-176. https://doi.org/10.1172/JCI10583
  49. Sun, K., C. M. Kusminski, and P. E. Scherer. 2011. Adipose tissue remodeling and obesity. J. Clin. Invest. 121: 2094- 2101. https://doi.org/10.1172/JCI45887
  50. Tavani, A., M. Bertuzzi, S. Gallus, E. Negri, and C. La Vecchia. 2002. Diabetes mellitus as a contributor to the risk of acute myocardial infarction. J. Clin. Epidemiol. 55: 1082-1087. https://doi.org/10.1016/S0895-4356(02)00486-9
  51. Truscheit, E., I. Hillebrand, B. Junge, L. Muller, W. Puls, and D. Schmidt. 1988. Microbial alpha-glucosidase inhibitors: Chemistry, biochemistry and therapeutic potential. Prog. Clin. Biochem. Med. 7: 17-99.
  52. Wild, S. H., G. Roglic, A. Green, R. Sicree, and H. King. 2004. Global prevalence of diabetes: Estimates for the year 2000 and projections for 2030. Diabetes Care 27: 2569-2569.
  53. Wilding, J. P. H., I. Gause-Nilsson, and A. Persson. 2007. Tesaglitazar, as add-on therapy to sulphonylurea, dose-dependently improves glucose and lipid abnormalities in patients with type 2 diabetes. Diab. Vasc. Dis. Res. 4: 194-203.
  54. Williams-Herman, D., A. Swern, M. Davies, H. Katzeff, and P. Stein. 2008. In patients with type 2 diabetes, sitagliptin effectively lowers A1c regardless of patient age, gender, or body mass index. Diabetes 57: A148-A148.
  55. Zhao, G., A. J. Souers, M. Voorbach, H. D. Falls, B. Droz, S. Brodjian, Y. Y. Lau, R. R. Iyengar, J. Gao, and A. S. Judd. 2008. Validation of diacyl glycerolacyltransferase I as a novel target for the treatment of obesity and dyslipidemia using a potent and selective small molecule inhibitor. J. Med. Chem. 51: 380-383. https://doi.org/10.1021/jm7013887
  56. Zimmet, P., K. G. Alberti, and J. Shaw. 2001. Global and societal implications of the diabetes epidemic. Nature 414: 782-787. https://doi.org/10.1038/414782a
  57. Zolotov, S., D. B. Yosef, N. D. Rishe, Y. Yesha, and E. Karnieli. 2011. Metabolic profiling in personalized medicine: Bridging the gap between knowledge and clinical practice in type 2 diabetes. Pers. Med. 8: 445-456. https://doi.org/10.2217/pme.11.36

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