Discovery and development of exenatide: The first antidiabetic agent to leverage the multiple benefits of the incretin hormone, GLP-1

Expert Opinion on Drug Discovery

Volumn 8, Issue 2, 2013, Pages 219-244

  Parkes, David G ^a   MacE, Kenneth F ^b   Trautmann, Michael E ^c  

^a AMYLIN PHARMACEUTICALS INC   (United States)

^b ELI LILLY AND COMPANY   (United States)

^c not available   (Germany)

Author keywords

Exenatide; Exendin 4; GLP 1 receptor agonist; Type 2 diabetes mellitus

Indexed keywords

EXENDIN 4; GLUCAGON LIKE PEPTIDE 1; GLUCOSE; INSULIN; PLACEBO;

ADIPOSE TISSUE; CARCINOGENICITY; DRUG FORMULATION; DRUG METABOLISM; DRUG POTENCY; FOOD INTAKE; GASTROINTESTINAL SYMPTOM; GENOTOXICITY; GLUCAGON RELEASE; HOMEOSTASIS; HUMAN; HYPERGLYCEMIA; HYPOGLYCEMIA; KIDNEY DISEASE; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PANCREAS CANCER; PANCREAS ISLET CELL FUNCTION; PANCREATITIS; PRIORITY JOURNAL; REVIEW; STOMACH EMPTYING; THYROID CANCER; WEIGHT REDUCTION;

EID: 84872700382     PISSN: 17460441     EISSN: 1746045X     Source Type: Journal    
DOI: 10.1517/17460441.2013.741580     Document Type: Review

References (137)

1. Centers for Disease Control and Prevention. Diabetes Data and Trends 2011; Diabetes Fact Sheet 2011. Available from: http://apps.nccd.cdc.gov/DDTSTRS
2. American Diabetes Association. Standards of medical care in diabetes-2012. Diabetes Care 2012;35:S11-63
3. Kotronen A, Yki-Järvinen H. Fatty liver: a novel component of the metabolic syndrome. Arterioscler Thromb Vasc Biol 2008;28:27-38
4. DeFronzo RA. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 2009;58:773-95
5. Goke R, Fehmann HC, Linn T, et al. Exendin-4 is a high potency agonist and truncated exendin-(9-39)-amide an antagonist at the glucagon-like peptide 1-(7-36)-amide receptor of insulin-secreting b-cells. Biol Chem 1993;268:19650-5 (Pubitemid 23270754)
6. Byrne MM, Goke B. Lessons from human studies with glucagon-like peptide-1: potential of the gut hormone for clinical use. In: Fehmann HC, Goke B, editors. Insulinotropic gut hormone glucagon-like peptide 1. Karger; Basel, New York: 1997. p. 219-33
7. Wettergren A, Schjoldager B, Mortensen PE, et al. Truncated GLP-1 (proglucagon 78-107-amide) inhibits gastric and pancreatic functions in man. Digest Dis Sci 1993;38:665-73 (Pubitemid 23121274)
8. Creutzfeldt WOC, Orskov C, Kleine N, et al. Glucagonostatic actions and reduction of fasting hyperglycemia by exogenous glucagon-like peptide I(7-36) amide in type I diabetic patients. Diabetes Care 1996;19:580-6
9. Turton MD, O'Shea D, Gunn I, et al. A role for glucagon-like peptide-1 in the central regulation of feeding. Nature 1996;379:69-72 (Pubitemid 26008136)
10. Elrick H, Stimmler L, Hlad CJ, Arai Y. Plasma insulin response to oral and intravenous glucose administration. J Clin Endocrinol Metab 1964;24:1076-82
11. Holst JJ, Vilsbøll T, Deacon CF. The incretin system and its role in type 2 diabetes. Mol Cell Endocrinol 2009;297:127-36
12. Nauck MA, Heimesaat MM, Ørskov C, et al. Preserved incretin activity of glucagon-like peptide 1[7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Invest 1993;91:301-7 (Pubitemid 23037285)
13. Nauck MA, Wollschläger D, Werner J, et al. Effects of subcutaneous glucagon-like peptide 1 (GLP-1 [7-36 amide]) in patients with NIDDM. Diabetologia 1996;39:1546-53 (Pubitemid 26397366)
14. Nauck MA, Niedereich-Holz U, Ettler R, et al. Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans. Am J Physiol 1997;273:E981-8
15. Flint A, Raben A, Astrup A, Holst JJ. Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans. J Clin Invest 1998;101:515-20 (Pubitemid 28084232)
16. Flint A, Raben A, Ersbøll AK, et al. The effects of physiological levels of glucagon-like peptide-1 on appetite, gastric emptying, energy and substrate metabolism in obesity. Int J Obes 2001;25:781-92 (Pubitemid 32601369)
17. Näslund E, Barkeling B, King N, et al. Energy intake and appetite are suppressed by glucagon-like peptide-1 (GLP-1) in obese men. Int J Obes 1999;23:304-11 (Pubitemid 29118862)
18. Thorens B. Physiology of GLP-1-lessons from glucoincretin receptor knockout mice. Horm Metab Res 2004;36:766-70 (Pubitemid 40115897)
19. Young AA. Glucagon-like peptide-1, exendin and insulin sensitivity. In: Hansen B, Shafrir E, editors. Insulin resistance and insulin resistance syndrome. Harwood Academic; New York: 2002. p. 235-62
20. Edvell A, Linstrom P. Initiation of increased pancreatic islet growth in young normoglycemic mice (Umea°). Endocrin 1999;140:778-83 (Pubitemid 29058212)
21. Stoffers DA, Kieffer TJ, Hussain MA, et al. Insulinotropic glucagon-like peptide 1 agonists stimulate expression of homeodomain protein IDX-1 and increase islet size in mouse pancreas. Diabetes 2000;49:741-8 (Pubitemid 30339989)
22. Farilla L, Hui H, Bertolotto C, et al. Glucagon-like peptide-1 promotes islet cell growth and inhibits apoptosis in Zucker diabetic rats. Endocrin 2002;143:4397-408 (Pubitemid 35239574)
23. Baggio L, Drucker DJ. Therapeutic approaches to preserve islet mass in type 2 diabetes. Annu Rev Med 2006;57:265-81 (Pubitemid 43261991)
24. Wang YH, Perfetti R, Greig NH, et al. Glucagon-like peptide-1 can reverse the age-related decline in glucose tolerance in rats. J Clin Invest 1997;99:2883-9 (Pubitemid 27278664)
25. Deacon CF, Nauck MA, Toft-Nielsen M, et al. Both subcutaneously and intravenously administered glucagon-like peptide I are rapidly degraded from the NH2-terminus in type II diabetic patients and in healthy subjects. Diabetes 1995;44:1126-31
26. Kieffer TJ, McIntosh CH, Pederson RA. Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide-1 in vitro and in vivo by dipeptidyl peptidase IV. Endocrinol 1995;136:3585-96
27. Raufman JP, Singh L, Singh G, Eng J. Truncated glucagon-like peptide-1 interacts with exendin receptors on dispersed acini from guinea pig pancreas. Identification of a mammalian analogue of the reptilian peptide exendin-4. J Biol Chem 1992;267:21432-7
28. Thorens B. Expression cloning of the pancreatic b-cell receptor for the gluco-incretin hormone glucagon-like peptide 1. Proc Natl Acad Sci USA 1992;89:8641-5
29. Brubaker PL, Drucker DJ. Structure-function of the glucagon receptor family of G protein-coupled receptors: the glucagon, GIP, GLP-1, and GLP-2 receptors. Receptors Channels 2002;8:179-88
30. Nielsen LL, Young AA, Parkes DG. Pharmacology of exenatide (synthetic exendin-4): a potential therapeutic for improved glycemic control of type 2 diabetes. Reg Pept 2004;117:77-88 (Pubitemid 38045329)
31. Bullock BP, Heller RS, Habener JF. Tissue distribution of messenger ribonucleic acid encoding the rat glucagon-like peptide-1 receptor. Endocrinology 1996;137:2968-78 (Pubitemid 26192194)
32. Ban K, Noyan-Ashraf MH, Hoefer J, et al. Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide-1 receptor dependent and independent pathways. Circulation 2008;117:2340-50 (Pubitemid 351653542)
33. Meloni AR, DeYoung MB, Lowe C, Parkes DG. GLP-1 receptor activated insulin secretion from pancreatic betacells: mechanism and glucose-dependence. Diab Obes Metab 2012;doi: 10.1111/j.1463-1326.2012.01663.x
34. Scrocchi LA, Brown TJ, MaClusky N, et al. Glucose intolerance but normal satiety in mice with a null mutation in the glucagon-like peptide receptor gene. Nat Med 1996;2:1254-8 (Pubitemid 26375413)
35. Flamez D, Van Breusegem A, Scrocchi LA, et al. Mouse pancreatic b-cells exhibit preserved glucose competence after disruption of the glucagon-like peptide-1 receptor gene. Diabetes 1998;47:646-52 (Pubitemid 28160457)
36. Pederson RA, Satkunarajah M, McIntosh CH, et al. Enhanced glucose-dependent insulinotropic polypeptide secretion and insulinotropic action in glucagon-like peptide-1 receptor-/-mice. Diabetes 1998;47:1046-52 (Pubitemid 28294546)
37. Scrocchi LA, Marshall BA, Cook SM, et al. Identification of glucagon-like peptide 1 (GLP-1) actions essential for glucose homeostasis in mice with disruption of GLP-1 receptor signaling. Diabetes 1998;47:632-9 (Pubitemid 28160455)
38. Scrocchi LA, Drucker DJ. Effects of aging and a high fat diet on body weight and glucose tolerance in glucagon-like peptide-1 receptor-/-mice. Endocrinol 1998;139:3127-32 (Pubitemid 28512341)
39. Flamez D, Gilon P, Moens K, et al. Altered cAMP and Ca2+ signaling in mouse pancreatic islets with glucagon-like peptide-1 receptor null phenotype. Diabetes 1999;48:1979-86 (Pubitemid 29458360)
40. Burcelin R, Da Costa A, Drucker D, Thorens B. Glucose competence of the heptoportal vein sensor requires the presence of an activated glucagon-like peptide-1 receptor. Diabetes 2001;50:1720-8 (Pubitemid 33641588)
41. De Leon DD, Deng S, Madani R, et al. Role of endogenous glucagon-like peptide-1 in islet regeneration after partial pancreatectomy. Diabetes 2003;52:365-71 (Pubitemid 36173191)
42. Eng J, Kleinman WA, Singh L, et al. Isolation and characterization of exendin-4, an exendin-3 analogue from Heloderma suspectum venom: further evidence for an exendin receptor on dispersed acini from guinea pig pancreas. J Biol Chem 1992;267:7402-5
43. Freeman JS. Role of the incretin pathway in the pathogenesis of type 2 diabetes mellitus. Cleve Clin J Med 2009;76(Suppl 5):S12-19
44. Chen YE, Drucker DJ. Tissue-specific expression of unique mRNAs that encode proglucagon-derived peptides or exendin 4 in the lizard. J Biol Chem 1997;272:4108-15 (Pubitemid 27078475)
45. Thorens B, Porret A, Buühler L, et al. Cloning and functional expression of the human islet GLP-1 receptor. Demonstration that exendin-4 is an agonist and exendin-(9-39) an antagonist of the receptor. Diabetes 1993;42:1678-82 (Pubitemid 23318127)
46. Raufman JP. Bioactive peptides from lizard venoms. Regul Pept 1996;61:1-18
47. Fehmann HC, Jiang J, Schweinfurth J, et al. Stable expression of the rat GLP-I receptor in CHO cells: activation and binding characteristics utilizing GLP-I(7-36)-amide, oxyntomodulin, exendin-4, and exendin(9-39). Peptides 1994;15:453-6 (Pubitemid 24223320)
48. Schepp W, Schmidtler J, Riedel T, et al. Exendin-4 and exendin-(9-39)NH2: agonist and antagonist, respectively, at the rat parietal cell receptor for glucagon-like peptide-1-(7-36)NH2. Eur J Pharmacol 1994;269:183-91
49. Montrose-Rafizadeh C, Yang H, Wang Y, et al. Novel signal transduction and peptide specificity of glucagon-like peptide receptor in 3T3-L1 adipocytes. J Cell Physiol 1997;172:275-83 (Pubitemid 27376193)
50. Nishizawa M, Nakabayashi H, Kawai K, et al. The hepatic vagal reception of intraportal GLP-1 is via receptor different from the pancreatic GLP-1 receptor. J Auton Nerv Syst 2000;80:14-21 (Pubitemid 30160722)
51. Yang H, Egan JM, Wang Y, et al. GLP-1 action in L6 myotubes is via a receptor different from the pancreatic GLP-1 receptor. Am J Physiol 1998;273:C675-83
52. Young AA, Gedulin BR, Bhavsar S, et al. Glucose-lowering and insulin-sensitizing actions of exendin-4: studies in obese diabetic (ob/ob, db/db) mice, diabetic fatty Zucker rats, and diabetic rhesus monkeys (Macaca mulatta). Diabetes 1999;48:1026-34 (Pubitemid 29226349)
53. Szayna M, Doyle ME, Betkey JA, et al. Exendin-4 decelerates food intake, weight gain, and fat deposition in Zucker rats. Endocrinology 2000;141:1936-41 (Pubitemid 32274340)
54. Parkes DG, Pittner R, Jodka C, et al. Insulinotropic actions of exendin-4 and glucagon-like peptide-1 in vivo and in vitro. Metabolism 2001;50:583-9 (Pubitemid 32433049)
55. Egan JM, Clocquet AR, Elahi D. The insulinotropic effect of acute exendin-4 administered to humans: comparison of nondiabetic state to type 2 diabetes. J Clin Endocrinol Metab 2002;87:1282-90 (Pubitemid 36121100)
56. Greig NH, Holloway HW, De Ore KA, et al. Once daily injection of exendin-4 to diabetic mice achieves long-term beneficial effects on blood glucose concentrations. Diabetologia 1999;42:45-50 (Pubitemid 29039736)
57. Gedulin B, Jodka C, Hoyt J. Exendin-4 (AC2993) decreased glucagon secretion during hyperglycemic clamps in Diabetic Fatty Zucker rats [abstract 0864]. Diabetes 1999;48(Suppl 1):A199
58. Rayner CK, Samsom M, Jones KL, Horowitz M. Relationships of upper gastrointestinal motor and sensory function with glycemic control. Diabetes Care 2001;24:371-81 (Pubitemid 32119141)
59. Mack CM, Moore CX, Jodka CM, et al. Antiobesity action of peripheral exenatide (exendin-4) in rodents: effects on food intake, body weight, metabolic status and side-effect measures. Int J Obes (Lond) 2006;30:1332-40 (Pubitemid 44306514)
60. Xu G, Stoffers DA, Habener JF, Bonner-Weir S. Exendin-4 stimulates both b-cell replication and neogenesis, resulting in increased b-cell mass and improved glucose tolerance in diabetic rats. Diabetes 1999;48:2270-6 (Pubitemid 30395416)
61. Tourrel C, Bailbé D, Meile M-J, et al. Glucagon-like peptide-1 and exendin-4 stimulate b-cell neogenesis in streptozotocin-treated newborn rats resulting in persistently improved glucose homeostasis at adult age. Diabetes 2001;50:1562-70 (Pubitemid 33639596)
62. Tourrel C, Bailbé D, Lacorne M, et al. Persistent improvement of type 2 diabetes in the Goto-Kakizaki rat model by expansion of the b-cell mass during the prediabetic period with glucagon-like peptide-1 or exendin-4. Diabetes 2002;51:1443-52 (Pubitemid 34826610)
63. Gedulin BR, Nikoulina SE, Smith PA, et al. Exenatide (exendin-4) improves insulin sensitivity and b-cell mass in insulin-resistant obese fa/fa Zucker rats independent of glycemia and body weight. Endocrinology 2005;146:2069-76 (Pubitemid 40396918)
64. Parkes D, Jodka C, Smith P, et al. Pharmacokinetic actions of exendin-4 in the rat: comparison with glucagon-like peptide-1. Drug Dev Res 2001;53:260-7 (Pubitemid 33029654)
65. Eng J. Prolonged effect of exendin-4 on hyperglycemia of db/db mice [abstract 554]. Diabetes 1996;45:152A
66. Ahren B, Pacini G. Importance of quantifying insulin secretion in relation to insulin sensitivity to accurately assess b-cell function in clinical studies. Eur J Endocrinol 2004;150:97-104 (Pubitemid 38312800)
67. Parkes D, Gedulin B, Smith P, Young A. Effect of exendin-4 on glucagon secretion in lean and obese Zucker (ZDF) rats [abstract 1298-P]. Diabetes 2001;50(Suppl 2):A313
68. Stoffers DA, Desai BM, DeLeon DD, Simmons RA. Neonatal exendin-4 prevents the development of diabetes in the intrauterine growth retarded rat. Diabetes 2003;52:734-40 (Pubitemid 36323581)
69. Rolin B, Larsen MO, Gotfredsen CF, et al. The long-acting GLP-1 derivative NN2211 ameliorates glycemia and increases b-cell mass in diabetic mice. Am J Physiol Endocriol Metab 2002;283:E745-52
70. Wang Q, Brubaker PL. Glucagon-like peptide-1 treatment delays the onset of diabetes in 8 week-old db/db mice. Diabetologia 2002;45:1263-73
71. Li Y, Hansotia T, Yusta B, et al. Glucagon-like peptide-1 receptor signaling modulates cell apoptosis. J Biol Chem 2003;278:471-8 (Pubitemid 36043598)
72. Jodka C, Gedulin B, Young A. Exendin-4 potently regulates gastric emptying in rats [abstract 1543]. Diabetes 1998;47(Suppl 1):A403
73. Dickson SL, Shirazi RH, Hansson C, et al. The glucagon-like peptide 1 (GLP-1) analogue, exendin-4, decreases the rewarding value of food: a new role for mesolimbic GLP-1 receptors. J Neurosci 2012;32:4812-20
74. Kinzig KP, D'Alessio DA, Seeley RJ. The diverse roles of specific GLP-1 receptors in the control of food intake and the response to visceral illness. J Neurosci 2002;22:10470-6 (Pubitemid 35416883)
75. Egan JM, Montrose-Rafizadeh C, Want Y, et al. Glucagon-like peptide-1 (7-36) amide (GLP-1) enhances insulin-stimulated glucose metabolism in 3T3-L1 adipocytes: one of several potential extrapancreatic sites of GLP-1 action. Endocrinology 1994;135:2070-5 (Pubitemid 24363904)
76. Wang Y, Kole HK, Montrose-Rafizadeh C, et al. Regulation of glucose transporters and hexose uptake in 3T3-L1 adipocytes: glucagon-like peptide-1 and insulin interactions. J Molec Endocrinol 1997;19:241-8 (Pubitemid 28023159)
77. Laugero KD, Stonehouse AH, Guss S, et al. Exenatide improves hypertension in a rat model of the metabolic syndrome. Metab Syndr Relat Disord 2009;7:327-34
78. Hirata K, Kume S, Araki S, et al. Exendin-4 has an anti-hypertensive effect in salt-sensitive mice model. Biochem Biophys Res Commun 2009;380:44-9
79. Liu Q, Adams L, Broyde A, et al. The exenatide analogue AC3174 attenuates hypertension, insulin resistance, and renal dysfunction in Dahl salt-sensitive rats. Cardiovasc Diabetol 2010;9:32
80. Timmers L, Henriques JPS, de Kleijn DPV, et al. Exenatide reduces infarct size and improves cardiac function in a porcine model of ischemia and reperfusion injury. J Am Coll Cardiol 2009;53:501-10
81. Liu Q, Anderson C, Broyde A, et al. Glucagon-like peptide-1 and the exenatide analogue AC3174 improve cardiac function, cardiac remodeling, and survival in rats with chronic heart failure. Cardiovasc Diabetol 2010;9:76
82. Arakawa M, Mita T, Azuma K, et al. Inhibition of monocyte adhesion to endothelial cells and attenuation of atherosclerotic lesion by a glucagon-like peptide-1 receptor agonist, exendin-4. Diabetes 2010;59:1030-7
83. Hsieh J, Longuet C, Baker CL, et al. The glucagon-like peptide 1 receptor is essential for postprandial lipoprotein synthesis and secretion in hamsters and mice. Diabetologia 2010;53:552-61
84. Harkavyi A, Whitton PS. Glucagon-like peptide 1 receptor stimulation as a means of neuroprotection. Br J Pharmacol 2010;159:495-501
85. Perry T, Lahiri DK, Chen D, et al. A novel neurotrophic property of glucagon-like peptide 1: a promoter of nerve growth factor-mediated differentiation in PC12 cells. J Pharmacol Exp Ther 2002;300:958-66 (Pubitemid 34165002)
86. Perry T, Haughey NJ, Mattson MP, et al. Protection and reversal of excitotoxic neuronal damage by glucagon-like peptide-1 and exendin-4. J Pharmacol Exp Ther 2002;302:881-8 (Pubitemid 34920207)
87. Perry T, Holloway HW, Weerasuriya A, et al. Evidence of GLP-1-mediated neuroprotection in an animal model of pyridoxine-induced peripheral sensory neuropathy. Exp Neurol 2007;203:293-301 (Pubitemid 46157226)
88. Li Y, Perry T, Kindy MS, et al. GLP-1 receptor stimulation preserves primary cortical and dopaminergic neurons in cellular and rodent models of stroke and Parkinsonism. Proc Natl Acad Sci USA 2009;106:1285-90
89. Li Y, Chigurupati S, Holloway HW, et al. Exendin-4 ameliorates motor neuron degeneration in cellular and animal models of amyotrophic lateral sclerosis. PLoS ONE 2012;7:e32008
90. Byrd R, Flanagan S, Kothare P, et al. Pharmacokinetics of exenatide long acting release (LAR) in monkeys. Presented at the 2006 annual meeting of the Amer Assoc Pharm Sci 2006
91. Copley K, McCowen K, Hiles R, et al. Investigation of exenatide elimination and its in vivo and in vitro degradation. Curr Drug Metab 2006;7:367-74
92. Gao W, Jusko WJ. Target-mediated pharmacokinetic and pharmacodynamic model of exendin-4 in rats, monkeys, and humans. Drug Metab Dispos 2012;40:990-7
93. Hiles RA, Bawdon RE, Petrella EM. Ex vivo human placental transfer of the peptides pramlintide and exenatide (synthetic exendin-4). Human Exper Toxicol 2003;22:623-8 (Pubitemid 38239781)
94. Tatarkiewicz K, Smith PA, Sablan EJ, et al. Exenatide does not evoke pancreatitis and attenuates chemically induced pancreatitis in normal and diabetic rodents. Am J Physiol Endocrinol Metab 2010;299:E1076-86
95. Nachnani JS, Bulchandani DG, Nookala A, et al. Biochemical and histological effects of exendin-4 (exenatide) on the rat pancreas. Diabetologia 2010;53:153-9
96. Koehler JA, Baggio LL, Lamont BJ, et al. Glucagon-like peptide-1 receptor activation modulates pancreatitis-associated gene expression but does not modify the susceptibility to experimental pancreatitis in mice. Diabetes 2009;58:2148-61
97. Tatarkiewicz K, Belanger P, Gu G, et al. Long-term exposure of exenatide does not adversely affect exocrine pancreas structure and function in Zucker diabetic fatty (ZDF) rats. Diabetologia (Abstract 818-P) 2011;54(Suppl 1):185
98. Vrang N, Jelsing J, Simonsen L, et al. The effects of 13 weeks of liraglutide treatment on endocrine and exocrine pancreas in male and female ZDF-rats: a quantitative and qualitative analysis revealing no evidence of drug induced pancreatitis. Am J Physiol Endocrinol Metab 2012;303:E253-64
99. BYETTA (exenatide) injection prescribing information. Revised December 2011. Available from: http://www.byetta.com
100. BYDUREON (exenatide extended-release for injectable suspension) prescribing information. Revised January 2012. Available from: http://www.bydureon. com
101. Bhavsar S, Mudaliar S, Cherrington A. Evolution of exenatide as a diabetes therapeutic. Curr Diab Rev 2012;In press
102. Aroda V, Henry R, Han J, et al. Efficacy of GLP-1 receptor agonists and DPP-4 inhibitors: meta-analysis and systematic review. Clin Ther 2012;34:1247-58.e22
103. MacConell L, Brown C, Gurney K, Han J. Safety and tolerability of exenatide twice daily in patients with type 2 diabetes: integrated analysis of 5594 patients from 19 placebo-and comparator-controlled clinical trials. Diabetes Metab Syndr Obes 2012;5:29-41
104. MacConell L, Gurney K, Malloy J, et al. Safety and tolerability of exenatide once weekly in patients with type 2 diabetes: an integrated analysis of 4328 patients. Diabetes 2012;61(Suppl 1):A598; 2372-PO
105. Blevins T, Han J, Nicewarner D, et al. Exenatide non-inferior to insulin in reducing HbA1c: an integrated analysis of 1423 patients with type 2 diabetes. Postgrad Med 2010;122:118-28
106. Buse JB, Bergenstal RM, Glass LC, et al. Use of twice-daily exenatide in basal insulin-treated patients with type 2 diabetes: a randomized, controlled trial. Ann Intern Med 2011;154:103-12
107. Klonoff DC, Buse JB, Nielsen LL, et al. Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 2 years. Curr Med Res Opin 2008;24:275-86 (Pubitemid 351160260)
108. DeYoung MB, MacConell L, Sarin V, et al. Encapsulation of exenatide in poly-(D,L-lactide-co-glycolide) microspheres produced an investigational long-acting once-weekly formulation for type 2 diabetes. Diabetes Technol Ther 2011;13:1145-54
109. Garg R, Chen W, Pendergrass M. Acute pancreatitis in type 2 diabetes treated with exenatide or sitagliptin: a retrospective observational pharmacy claims analysis. Diabetes Care 2010;33:2349-54
110. Elashoff M, Matveyenko AV, Gier B, et al. Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies. Gastroenterology 2011;141:150-6
111. Wenton M, Gaebler JA, Hussein M, et al. Relative risk of acute pancreatitis in initiators of exenatide twice daily compared with other antidiabetic medication: a follow-up study. Diabet Med 2012;29:1412-18
112. Linnebjerg H, Kothare PA, Park S, et al. Effect of renal impairment on the pharmacokinetics of exenatide. Br J Clin Pharmacol 2007;64:317-27 (Pubitemid 47283860)
113. Okerson T, Yan P, Stonehouse A, Brodows R. Effects of exenatide on systolic blood pressure in subjects with type 2 diabetes. Am J Hyperten 2010;23:334-9
114. Lønborg J, Vejlstrup N, Kelbæk H, et al. Exenatide reduces reperfusion injury in patients with ST-segment elevation myocardial infarction. Eur Heart J 2012;33:1491-9
115. Lønborg J, Kelbæk H, Vejlstrup N, et al. Exenatide reduces final infarct size in patients with ST-segment-elevation myocardial infarction and short-duration of ischemia. Circ Cardiovasc Interv 2012;5:288-95
116. Gejl M, Søndergaard HM, Stecher C, et al. Exenatide alters myocardial glucose transport and uptake depending on insulin resistance and increases myocardial blood flow in patients with type 2 diabetes. J Clin Endocrinol Metab 2012;97:E1165-9
117. Nathanson D, Ullman B, Lofstrom U, et al. Effects of intravenous exenatide in type 2 diabetic patients with congestive heart failure: a double-blind, randomised controlled clinical trial of efficacy and safety. Diabetologia 2012;55:926-35
118. Dupré J, Behme MT, McDonald TJ. Exendin-4 normalized postcibal glycemic excursions in type 1 diabetes. J Clin Endocrinol Metab 2004;89:3469-73 (Pubitemid 38951922)
119. Varanasi A, Bellini N, Rawal D, et al. Liraglutide as additional treatment for type 1 diabetes. Eur J Endocrinol 2011;165:77-84
120. Kielgast U, Krarup T, Holst JJ, Madsbad S. Four weeks of treatment with liraglutide reduces insulin dose without loss of glycemic control in type 1 diabetic patients with and without residual b-cell function. Diabetes Care 2011;34:1463-8
121. VICTOZA liraglutide (rDNA origin) injection prescribing information. Revised April 2012. Available from: http://www.victoza.com
122. Buse JB, Rosenstock J, Sesti G, et al. 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). Lancet 2009;374:39-47
123. Buse JB, Nauck MA, Forst T, et al. Exenatide once weekly versus liraglutide in patients with type 2 diabetes (DURATION-6): a randomised, open-label study. Lancet 2012;In press
124. Best JH, Lavillotti K, DeYoung MB, Garrison LP. The effects of exenatide bid on metabolic control, medication use and hospitalization in patients with type 2 diabetes mellitus in clinical practive: a systematic review. Diab Obes Metab 2012;14:387-98
125. Anderson SL, Trujillo JM. Association of pancreatitis with glucagon-like peptide-1 agonist use. Ann Pharmacother 2010;44:904-9
126. Dore DD, Seeger JD, Chan KA. Use of a claims-based active drug safety surveillance system to assess the risk of acute pancreatitis with exenatide or sitagliptin compared with metformin or glyburide. Curr Med Res Opin 2009;25:1019-27
127. Dore DD, Bloomgren GL, Wenten M, et al. A cohort study of acute pancreatitis in relation to exenatide use. Diabetes Obes Metab 2011;13:559-66
128. Raufman JP, Jensen RT, Sutliff VE, et al. Actions of Gila monster venom on dispersed acini from guinea pig pancreas. Am J Physiol 1982;242:G470-4 (Pubitemid 12099993)
129. Navarro M, Rodriguez de Fonseca F, Alvarez E, et al. Colocalization of glucagon-like peptide-1 (GLP-1) receptors, glucose transporter GLUT-2, and glucokinase mRNAs in rat hypothalamic cells: evidence for a role of GLP-1 receptor agonists as an inhibitory signal for food and water intake. J Neurochem 1996;67:1982-91 (Pubitemid 26349672)
130. Rodriquez de Fonseca F, Navarro M, Alvarez E, et al. Peripheral versus central effects of glucagon-like peptide-1 receptor agonists on satiety and body weight loss in Zucker obese rats. Metabolism 2000;49:709-17 (Pubitemid 30354576)
131. Thum A, Hupe-Sodmann K, Goke R, et al. Endoproteolysis by isolated membrane peptidases reveal metabolic stability of glucagon-like peptide-1 analogs, exendins-3 and-4. Exp Clin Endocrinol Diabetes 2002;110:113-18 (Pubitemid 34461416)
132. Gedulin BR, Smith P, Prickett KS, et al. Dose-response for glycaemic and metabolic changes 28 days after single injection of long-acting release exenatide in diabetic fatty Zucker rats. Diabetologia 2005;48:1380-5 (Pubitemid 41186105)
133. Ding X, Saxena NK, Lin S, et al. Exendin-4, a glucagon-like protein-1 (GLP-1) receptor agonist, reverses hepatic steatosis in ob/ob mice. Hepatology 2006;43:173-81 (Pubitemid 43733604)
134. Simonsen L, Holst JJ, Deacon CF. Exendin-4, but not glucagon-like peptide-1, is cleared exclusively by glomerular filtration in anaesthetised pigs. Diabetologia 2006;49:706-12 (Pubitemid 43357544)
135. Gedulin BR, Smith P, Jodka CM, et al. Pharmacokinetics and pharmacodynamics of exenatide following alternate routes of administration. Int J Pharm 2008;356:231-8
136. U.S. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 21-773 Pharmacology review. Available at: http://www.accessdata.fda.gov/drugsatfda-docs/nda/2005/021773-Byetta-pharmr.PDF
137. U.S. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 022200Orig1s000 Pharmacology review (s). Available from: http://www. accessdata.fda.gov/drugsatfda-docs/nda/2012/ 022200Orig1s000PharmR.pdf