Treatment potential of the GLP-1 receptor agonists in type 2 diabetes mellitus: A review

Expert Review of Clinical Pharmacology

Volumn 9, Issue 2, 2016, Pages 241-265

  Ostergaard L ^a   Frandsen, Christian S ^a   Madsbad, S ^a  

^a UNIVERSITY OF COPENHAGEN   (Denmark)

Author keywords

albiglutide; dulaglutide; exenatide; GLP 1 receptor agonist; liraglutide; lixisenatide; type 2 diabetes mellitus

Indexed keywords

ALBIGLUTIDE; DULAGLUTIDE; EXENDIN 4; GLUCAGON LIKE PEPTIDE 1 RECEPTOR AGONIST; GLUCOSE; HEMOGLOBIN A1C; INSULIN; LIRAGLUTIDE; LIXISENATIDE; ORAL ANTIDIABETIC AGENT; PLACEBO; ANTIDIABETIC AGENT; GLUCAGON; GLUCAGON LIKE PEPTIDE 1; GLUCAGON LIKE PEPTIDE 1 RECEPTOR; GLUCOSE BLOOD LEVEL;

ANTIDIABETIC ACTIVITY; DOSAGE SCHEDULE COMPARISON; GASTROINTESTINAL SYMPTOM; GLUCAGON RELEASE; GLUCOSE BLOOD LEVEL; GLYCEMIC CONTROL; HORMONE INHIBITION; HUMAN; HYPOGLYCEMIA; INSULIN RELEASE; INSULIN TREATMENT; META ANALYSIS; META ANALYSIS (TOPIC); NAUSEA; NON INSULIN DEPENDENT DIABETES MELLITUS; PHASE 3 CLINICAL TRIAL (TOPIC); RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; SYSTEMATIC REVIEW; WEIGHT REDUCTION; AGONISTS; ANIMAL; DIABETES MELLITUS, TYPE 2; DRUG EFFECTS; METABOLISM; PATHOPHYSIOLOGY; SECRETION (PROCESS);

ANIMALS; BLOOD GLUCOSE; DIABETES MELLITUS, TYPE 2; GLUCAGON; GLUCAGON-LIKE PEPTIDE 1; GLUCAGON-LIKE PEPTIDE-1 RECEPTOR; HUMANS; HYPOGLYCEMIC AGENTS; INSULIN;

EID: 84958663475     PISSN: 17512433     EISSN: 17512441     Source Type: Journal    
DOI: 10.1586/17512433.2016.1121808     Document Type: Review

References (137)

1. American Diabetes Association. 7. Approaches to glycemic treatment. Diabetes Care. 2015 Jan 1;38(Suppl 1):S41-S48
2. Tasyurek HM, Altunbas HA, Balci MK, et al. Incretins: Their physiology and application in the treatment of diabetes mellitus. Diabetes Metab Res Rev. 2014 Jul;30(5):354-371
3. Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev. 2007 Oct;87(4):1409-1439
4. Deacon CF. Circulation and degradation of GIP and GLP-
5. Horm Metab Res. 2004 Dec;36(1112):761-765
6. Holst JJ. Glucagon-like peptide-1: from extract to agent. The Claude Bernard lecture, 2005. Diabetologia. 2006 Feb;49(2):253-260
7. Meier JJ. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat Rev Endocrinol. 2012 Sep 4;8(12):728-742
8. Madsbad S, Kielgast U, Asmar M, et al. An overview of once-weekly glucagon-like peptide-1 receptor agonists -available efficacy and safety data and perspectives for the future. Diabetes Obes Metab. 2011 May;13 (5):394-407
9. Harris KB, McCarty DJ. Efficacy and tolerability of glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes mellitus. Ther Adv Endocrinol Metab. 2015 Feb 1;6(1):3-18
10. Nielsen LL, Young AA, Parkes DG. Pharmacology of exenatide (synthetic exendin-4): A potential therapeutic for improved glycemic control of type 2 diabetes. Regul Pept. 2004 Feb 15;117(2):77-88
11. Kielgast U, Holst JJ, Madsbad S. Treatment of type 1 diabetic patients with glucagon-like peptide-1 (GLP-1) and GLP-1R agonists. Curr Diabetes Rev. 2009 Nov;5 (4):266-275
12. Cho YM, Wideman RD, Kieffer TJ. Clinical application of glucagon-like peptide 1 receptor agonists for the treatment of type 2 diabetes mellitus. Endocrinol Metab (Seoul). 2013 Dec;28(4):262-274
13. Vilsbøll T, Christensen M, Junker AE, et al. Effects of glucagon-like peptide-1 receptor agonists on weight loss: systematic review and meta-analyses of randomised controlled trials. BMJ. 2012;344:d7771
14. Buse JB, Henry RR, Han J, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care. 2004 Nov;27(11):2628-2635
15. Zinman B, Hoogwerf BJ, Durán García S, et al. The effect of adding exenatide to a thiazolidinedione in suboptimally controlled type 2 diabetes: A randomized trial. Ann Intern Med. 2007 Apr 3;146(7):477-485
16. DeFronzo RA, Ratner RE, Han J, et al. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care. 2005 May;28(5):1092-1100
17. Kendall DM, Riddle MC, Rosenstock J, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care. 2005 May;28(5):1083-1091
18. Moretto TJ, Milton DR, Ridge TD, et al. Efficacy and tolerability of exenatide monotherapy over 24 weeks in antidiabetic drug-naive patients with type 2 diabetes: A randomized, double-blind, placebo-controlled, parallelgroup study. Clin Ther. 2008 Aug;30(8):1448-1460
19. Kadowaki T, Namba M, Yamamura A, et al. Exenatide exhibits dose-dependent effects on glycemic control over 12 weeks in Japanese patients with suboptimally controlled type 2 diabetes. Endocr J. 2009;56(3):415-424
20. Gao Y, Yoon KH, Chuang L-M, et al. Efficacy and safety of exenatide in patients of Asian descent with type 2 diabetes inadequately controlled with metformin or metformin and a sulphonylurea. Diabetes Res Clin Pract. 2009 Jan;83(1):69-76
21. Liutkus J, Rosas Guzman J, Norwood P, et al. A placebocontrolled trial of exenatide twice-daily added to thiazolidinediones alone or in combination with metformin. Diabetes Obes Metab. 2010 Dec;12(12):1058-1065
22. Apovian CM, Bergenstal RM, Cuddihy RM, et al. Effects of exenatide combined with lifestyle modification in patients with type 2 diabetes. Am J Med. 2010;123(5):468.e9-17
23. 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 Jan 18;154(2):103-112
24. Derosa G, Franzetti IG, Querci F, et al. Exenatide plus metformin compared with metformin alone on -cell function in patients with Type 2 diabetes. Diabet Med J Br Diabet Assoc. 2012 Dec;29(12):1515-1523
25. Lu C-H, Wu T-J, Shih K-C, et al. Safety and efficacy of twice-daily exenatide in Taiwanese patients with inadequately controlled type 2 diabetes mellitus. J Formos Med Assoc Taiwan Yi Zhi. 2013 Mar;112(3):144-150
26. Heine RJ, Van Gaal LF, Johns D, et al. Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: A randomized trial. Ann Intern Med. 2005 Oct 18;143(8):559-569
27. Nauck MA, Duran S, Kim D, et al. A comparison of twicedaily exenatide and biphasic insulin aspart in patients with type 2 diabetes who were suboptimally controlled with sulfonylurea and metformin: A non-inferiority study. Diabetologia. 2007 Feb;50(2):259-267
28. Davis SN, Johns D, Maggs D, et al. Exploring the substitution of exenatide for insulin in patients with type 2 diabetes treated with insulin in combination with oral antidiabetes agents. Diabetes Care. 2007 Nov;30 (11):2767-2772
29. Bergenstal R, Lewin A, Bailey T, et al. Efficacy and safety of biphasic insulin aspart 70/30 versus exenatide in subjects with type 2 diabetes failing to achieve glycemic control with metformin and a sulfonylurea. Curr Med Res Opin. 2009 Jan;25(1):65-75
30. Davies MJ, Donnelly R, Barnett AH, et al. Exenatide compared with long-acting insulin to achieve glycaemic control with minimal weight gain in patients with type 2 diabetes: results of the Helping Evaluate Exenatide in patients with diabetes compared with Long-Acting insulin (HEELA) study. Diabetes Obes Metab. 2009 Dec;11 (12):1153-1162
31. Bunck MC, Diamant M, Corner A, et al. One-year treatment with exenatide improves cell function, compared with insulin glargine, in metformin-treated type 2 diabetic patients: A randomized, controlled trial. Diabetes Care. 2009 May 1;32(5):762-768
32. Gallwitz B, Böhmer M, Segiet T, et al. Exenatide twice daily versus premixed insulin aspart 70/30 in metformintreated patients with type 2 diabetes: A randomized 26-week study on glycemic control and hypoglycemia. Diabetes Care. 2011 Mar;34(3):604-606
33. Xu W, Bi Y, Sun Z, et al. Comparison of the effects on glycaemic control and -cell function in newly diagnosed type 2 diabetes patients of treatment with exenatide, insulin or pioglitazone: A multicentre randomized parallel-group trial (the CONFIDENCE study). J Intern Med. 2015 Jan;277(1):137-150
34. Derosa G, Maffioli P, Salvadeo SAT, et al. Exenatide versus glibenclamide in patients with diabetes. Diabetes Technol Ther. 2010 Mar;12(3):233-240
35. Derosa G, Putignano P, Bossi AC, et al. Exenatide or glimepiride added to metformin on metabolic control and on insulin resistance in type 2 diabetic patients. Eur J Pharmacol. 2011 Sep;666(13):251-256
36. Gallwitz B, Guzman J, Dotta F, et al. Exenatide twice daily versus glimepiride for prevention of glycaemic deterioration in patients with type 2 diabetes withmetformin failure (EUREXA): An open-label, randomised controlled trial. Lancet. 2012 Jun 16;379(9833):2270-2278
37. Bunck MC, Cornér A, Eliasson B, et al. One-year treatment with exenatide vs. insulin glargine: effects on postprandial glycemia, lipid profiles, and oxidative stress. Atherosclerosis. 2010;212(1):223-229
38. Eng C, Kramer CK, Zinman B, et al. Glucagon-like peptide-1 receptor agonist and basal insulin combination treatment for the management of type 2 diabetes: A systematic review and meta-analysis. Lancet. 2014Dec 20;384 (9961):2228-2234
39. Ratner RE, Rosenstock J, Boka G DRI6012 Study Investigators. Dose-dependent effects of the once-daily GLP-1 receptor agonist lixisenatide in patients with Type 2 diabetes inadequately controlled with metformin: A randomized, double-blind, placebo-controlled trial. Diabet Med J Br Diabet Assoc. 2010Sep;27(9):1024-1032
40. Lund A, Knop F, Vilsbøll T. Glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes: differences and similarities. Eur J Intern Med. 2014 Mar;25(5):407-414
41. Fonseca VA, Alvarado-Ruiz R, Raccah D, et al. Efficacy and safety of the once-daily GLP-1 receptor agonist lixisenatide in monotherapy: A randomized, double-blind, placebo-controlled trial in patients with type 2 diabetes (GetGoal-Mono). Diabetes Care. 2012 Jun;35(6):1225-1231
42. Pinget M, Goldenberg R, Niemoeller E, et al. Efficacy and safety of lixisenatide once daily versus placebo in type 2 diabetes insufficiently controlled on pioglitazone (GetGoal-P). Diabetes Obes Metab. 2013 Nov;15 (11):1000-1007
43. Ahrén B, Leguizamo Dimas A, Miossec P, et al. Efficacy and safety of lixisenatide once-daily morning or evening injections in type 2 diabetes inadequately controlled on metformin (GetGoal-M). Diabetes Care. 2013 Sep;36 (9):2543-2550
44. Rosenstock J, Hanefeld M, Shamanna P, et al. Beneficial effects of once-daily lixisenatide on overall and postprandial glycemic levels without significant excess of hypoglycemia in type 2 diabetes inadequately controlled on a sulfonylurea with or without metformin (GetGoal-S). J Diabetes Complications. 2014 Jun;28(3):386-392
45. Seino Y, Min KW, Niemoeller E, et al. EFC10887 GETGOAL-L Asia Study Investigators. Randomized, double-blind, placebo-controlled trial of the once-daily GLP-1 receptor agonist lixisenatide in Asian patients with type 2 diabetes insufficiently controlled on basal insulin with or without a sulfonylurea (GetGoal-L-Asia). Diabetes Obes Metab. 2012Oct;14(10):910-917
46. Riddle MC, Aronson R, Home P, et al. Adding once-daily lixisenatide for type 2 diabetes inadequately controlled by established basal insulin: A 24-week, randomized, placebo-controlled comparison (GetGoal-L). Diabetes Care. 2013 Sep;36(9):2489-2496
47. Riddle MC, Forst T, Aronson R, et al. Adding once-daily lixisenatide for type 2 diabetes inadequately controlled with newly initiated and continuously titrated basal insulin glargine: A 24-week, randomized, placebo-controlled study (GetGoal-Duo 1). Diabetes Care. 2013 Sep;36 (9):2497-2503
48. Montanya E, Sesti G. A review of efficacy and safety data regarding the use of liraglutide, a once-daily human glucagon-like peptide 1 analogue, in the treatment of type 2 diabetes mellitus. Clin Ther. 2009 Nov;31 (11):2472-2488
49. Agersø H, Jensen LB, Elbrønd B, et al. The pharmacokinetics, pharmacodynamics, safety and tolerability of NN2211, a new long-acting GLP-1 derivative, in healthy men. Diabetologia. 2002 Feb;45(2):195-202
50. Marre M, Shaw J, Brändle M, et al. Liraglutide, a oncedaily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with Type 2 diabetes (LEAD-1 SU). Diabet Med J Br Diabet Assoc. 2009 Mar;26 (3):268-278
51. Nauck M, Frid A, Hermansen K, et al. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: The LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes Care. 2009 Jan;32(1):84-90
52. Zinman B, Gerich J, Buse JB, et al. Efficacy and safety of the human glucagon-like peptide-1 analog liraglutide in combination with metformin and thiazolidinedione in patients with type 2 diabetes (LEAD-4 Met+TZD). Diabetes Care. 2009;32(7):1224-1230
53. Russell-Jones D, Vaag A, Schmitz O, et al. Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met+SU): A randomised controlled trial. Diabetologia. 2009 Oct;52(10):2046-2055
54. Forst T, Michelson G, Ratter F, et al. Addition of liraglutide in patients with Type 2 diabetes well controlled on metformin monotherapy improves several markers of vascular function. Diabet Med J Br Diabet Assoc. 2012;29(9):1115-1118
55. De Wit HM, Vervoort GMM, Jansen HJ, et al. Liraglutide reverses pronounced insulin-associated weight gain, improves glycaemic control and decreases insulin dose in patients with type 2 diabetes: A 26 week, randomised clinical trial (ELEGANT). Diabetologia. 2014 Sep;57(9):1812-1819
56. Garber A, Henry R, Ratner R, et al. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): A randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet. 2009 Feb 7;373 (9662):473-481
57. Seino Y, Rasmussen MF, Nishida T, et al. Efficacy and safety of the once-daily human GLP-1 analogue, liraglutide, vs glibenclamide monotherapy in Japanese patients with type 2 diabetes. Curr Med Res Opin. 2010 May;26 (5):1013-1022
58. Li C, Li J, Zhang Q, et al. Efficacy and safety comparison between liraglutide as add-on therapy to insulin and insulin dose-increase in Chinese subjects with poorly controlled type 2 diabetes and abdominal obesity. Cardiovasc Diabetol. 2012;11:142
59. Pratley RE, Nauck M, Bailey T, et al. Liraglutide versus sitagliptin for patients with type 2 diabetes who did not have adequate glycaemic control with metformin: A 26-week, randomised, parallel-group, open-label trial. Lancet. 2010 Apr 24;375(9724):1447-1456
60. Yang W, Chen L, Ji Q, et al. Liraglutide provides similar glycaemic control as glimepiride (both in combination with metformin) and reduces body weight and systolic blood pressure in Asian population with type 2 diabetes from China, South Korea and India: A 16-week, randomized, double-blind, active control trial(∗). Diabetes Obes Metab. 2011 Jan;13(1):81-88
61. Charbonnel B, Steinberg H, Eymard E, et al. Efficacy and safety over 26 weeks of an oral treatment strategy including sitagliptin compared with an injectable treatment strategy with liraglutide in patients with type 2 diabetes mellitus inadequately controlled on metformin: A randomised clinical trial. Diabetologia. 2013 Jul;56 (7):1503-1511
62. Mathieu C, Rodbard HW, Cariou B, et al. A comparison of adding liraglutide versus a single daily dose of insulin aspart to insulin degludec in subjects with type 2 diabetes (BEGIN: VICTOZA ADD-ON). Diabetes Obes Metab. 2014 Jul;16(7):636-644
63. Brady EM, Davies MJ, Gray LJ, et al. A randomized controlled trial comparing the GLP-1 receptor agonist liraglutide to a sulphonylurea as add on to metformin in patients with established type 2 diabetes during Ramadan: The Treat 4 Ramadan Trial. Diabetes Obes Metab. 2014;16(6):527-536
64. Kaku K, Rasmussen MF, Clauson P, et al. Improved glycaemic control with minimal hypoglycaemia and no weight change with the once-daily human glucagonlike peptide-1 analogue liraglutide as add-on to sulphonylurea in Japanese patients with type 2 diabetes. Diabetes Obes Metab. 2010 Apr;12(4):341-347
65. Vilsbøll T, Zdravkovic M, Le-Thi T, et al. Liraglutide, a long-acting human glucagon-like peptide-1 analog, given as monotherapy significantly improves glycemic control and lowers body weight without risk of hypoglycemia in patients with type 2 diabetes. Diabetes Care. 2007 Jun;30(6):1608-1610
66. Seino Y, Rasmussen MF, Zdravkovic M, et al. Dose-dependent improvement in glycemia with once-daily liraglutide without hypoglycemia or weight gain: A doubleblind, randomized, controlled trial in Japanese patients with type 2 diabetes. Diabetes Res Clin Pract. 2008 Aug;81(2):161-168
67. Madsbad S, Schmitz O, Ranstam J, et al. NN2211-1310 International Study Group. Improved glycemic control with no weight increase in patients with type 2 diabetes after once-daily treatment with the long-acting glucagon-like peptide 1 analog liraglutide (NN2211): A 12-week, double-blind, randomized, controlled trial. Diabetes Care. 2004Jun;27(6):1335-1342
68. Feinglos MN, Saad MF, Pi-Sunyer FX, et al. Liraglutide Dose-Response Study Group. Effects of liraglutide (NN2211), a long-acting GLP-1 analogue, on glycaemic control and bodyweight in subjects with Type 2 diabetes. Diabet Med J Br Diabet Assoc. 2005Aug;22(8):1016-1023
69. Vilsbøll T, Brock B, Perrild H, et al. Liraglutide, a oncedaily human GLP-1 analogue, improves pancreatic B-cell function and arginine-stimulated insulin secretion during hyperglycaemia in patients with Type 2 diabetes mellitus. Diabet Med J Br Diabet Assoc. 2008 Feb;25(2):152-156
70. Robinson LE, Holt TA, Rees K, et al. Effects of exenatide and liraglutide on heart rate, blood pressure and body weight: systematic review and meta-analysis. BMJ Open. 2013;3(1):e001986
71. Hermansen K, Bækdal TA, Düring M, et al. Liraglutide suppresses postprandial triglyceride and apolipoprotein B48 elevations after a fat-rich meal in patients with type 2 diabetes: A randomized, double-blind, placebo-controlled, cross-over trial. Diabetes Obes Metab. 2013 Nov;15(11):1040-1048
72. Mann KV, Raskin P. Exenatide extended-release: A once weekly treatment for patients with type 2 diabetes. Diabetes Metab Syndr Obes Targets Ther. 2014;7:229-239
73. Drucker DJ, Buse JB, Taylor K, et al. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: A randomised, open-label, non-inferiority study. Lancet. 2008 Oct 4;372(9645):1240-1250
74. Diamant M, Van Gaal L, Stranks S, et al. Once weekly exenatide compared with insulin glargine titrated to target in patients with type 2 diabetes (DURATION-3): An open-label randomised trial. Lancet. 2010 Jun 26;375 (9733):2234-2243
75. Inagaki N, Atsumi Y, Oura T, et al. Efficacy and safety profile of exenatide once weekly compared with insulin once daily in Japanese patients with type 2 diabetes treated with oral antidiabetes drug(s): results from a 26-week, randomized, open-label, parallel-group, multicenter, noninferiority study. Clin Ther. 2012 Sep;34(9):1892-908.e1
76. Davies M, Heller S, Sreenan S, et al. Once-weekly exenatide versus once-or twice-daily insulin detemir: randomized, open-label, clinical trial of efficacy and safety in patients with type 2 diabetes treated with metformin alone or in combination with sulfonylureas. Diabetes Care. 2013 May;36(5):1368-1376
77. Bergenstal RM, Wysham C, Macconell L, et al. Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): A randomised trial. Lancet. 2010 Aug 7;376(9739):431-439
78. Russell-Jones D, Cuddihy RM, Hanefeld M, et al. Efficacy and safety of exenatide once weekly versus metformin, pioglitazone, and sitagliptin used as monotherapy in drug-naive patients with type 2 diabetes (DURATION-4): A 26-week double-blind study. Diabetes Care. 2012 Feb;35(2):252-258
79. Home PD, Shamanna P, Stewart M, et al. Efficacy and tolerability of albiglutide versus placebo or pioglitazone over 1 year in people with type 2 diabetes currently taking metformin and glimepiride: HARMONY 5. Diabetes Obes Metab. 2015 Feb;17(2):179-187
80. Madsbad S. The role of glucagon-like peptide-1 impairment in obesity and potential therapeutic implications. Diabetes Obes Metab. 2014 Jan;16(1):9-21
81. Baggio LL, Huang Q, Brown TJ, et al. A recombinant human glucagon-like peptide (GLP)-1-albumin protein (albugon) mimics peptidergic activation of GLP-1 receptor-dependent pathways coupled with satiety, gastrointestinal motility, and glucose homeostasis. Diabetes. 2004 Sep;53(9):2492-2500
82. Woodward HN, Anderson SL. Once-weekly albiglutide in the management of type 2 diabetes: patient considerations. Patient Prefer Adherence. 2014;8:789-803
83. Blair HA, Keating GM Albiglutide: A review of its use in patients with type 2 diabetes mellitus. Drugs. [Internet]. 2015 Mar 17; [cited 2015 Apr 11]. Available from: http:// link.springer.com/10.1007/s40265-015-0370-5
84. Rosenstock J, Reusch J, Bush M, et al. Albiglutide Study Group. Potential of albiglutide, a long-acting GLP-1 receptor agonist, in type 2 diabetes: A randomized controlled trial exploring weekly, biweekly, and monthly dosing. Diabetes Care. 2009Oct;32(10):1880-1886
85. Reinhardt R, Nauck MA, Stewart M, et al. HARMONY 2 results at week 52 primary endpoint: once-weekly albiglutide monotherapy for patients with type 2 diabetes mellitus inadequately controlled with diet and exercise [Abstract no. 903]. 49th Annual Meeting of the European Association for the study of diabetes; 2013 Sep 23-27; Barcelona
86. Reusch J, Stewart MW, Perkins CM, et al. Efficacy and safety of once-weekly glucagon-like peptide 1 receptor agonist albiglutide (HARMONY 1 trial): 52-week primary endpoint results from a randomized, double-blind, placebo-controlled trial in patients with type 2 diabetes mellitus not controlled on pioglitazone, with or without metformin. Diabetes Obes Metab. 2014 Dec;16(12):1257-1264
87. Seino Y, Inagaki N, Miyahara H, et al. A randomized dosefinding study demonstrating the efficacy and tolerability of albiglutide in Japanese patients with type 2 diabetes mellitus. Curr Med Res Opin. 2014;30(6):1095-1106
88. Ahrén B, Johnson SL, Stewart M, et al. HARMONY 3: 104-week randomized, double-blind, placebo-and activecontrolled trial assessing the efficacy and safety of albiglutide compared with placebo, sitagliptin, and glimepiride in patients with type 2 diabetes taking metformin. Diabetes Care. 2014 Aug;37(8):2141-2148
89. Weissman PN, Carr MC, Ye J, et al. HARMONY 4: randomised clinical trial comparing once-weekly albiglutide and insulin glargine in patients with type 2 diabetes inadequately controlled with metformin with or without sulfonylurea. Diabetologia. 2014 Dec;57(12):2475-2484
90. Leiter LA, Carr MC, Stewart M, et al. Efficacy and safety of the once-weekly GLP-1 receptor agonist albiglutide versus sitagliptin in patients with type 2 diabetes and renal impairment: A randomized phase III study. Diabetes Care. 2014 Aug;37(10):2723-2730
91. Rosenstock J, Reusch J, Bush M, et al. Albiglutide Study Group. Potential of albiglutide, a long-acting GLP-1 receptor agonist, in type 2 diabetes: A randomized controlled trial exploring weekly, biweekly, and monthly dosing. Diabetes Care. 2009Oct;32(10):1880-1886
92. Rosenstock J, Fonseca VA, Gross JL, et al. Advancing basal insulin replacement in type 2 diabetes inadequately controlled with insulin glargine plus oral agents: A comparison of adding albiglutide, a weekly GLP-1 receptor agonist, versus thrice-daily prandial insulin lispro. Diabetes Care. 2014 Aug;37(8):2317-2325
93. Thompson AM, Trujillo JM. Dulaglutide: The newest glp-1 receptor agonist for the management of type 2 diabetes. Ann Pharmacother. 2015 Mar 1;49 (3):351-359
94. Wysham C, Blevins T, Arakaki R, et al. Efficacy and safety of dulaglutide added onto pioglitazone and metformin versus exenatide in type 2 diabetes in a randomized controlled trial (AWARD-1). Diabetes Care. 2014 Aug;37 (8):2159-2167
95. Umpierrez GE, Blevins T, Rosenstock J, et al. The effects of LY2189265, a long-acting glucagon-like peptide-1 analogue, in a randomized, placebo-controlled, double-blind study of overweight/obese patients with type 2 diabetes: The EGO study. Diabetes Obes Metab. 2011 May;13 (5):418-425
96. Grunberger G, Chang A, Garcia Soria G, et al. Monotherapy with the once-weekly GLP-1 analogue dulaglutide for 12 weeks in patients with Type 2 diabetes: dose-dependent effects on glycaemic control in a randomized, double-blind, placebo-controlled study. Diabet Med J Br Diabet Assoc. 2012 Oct;29(10):1260-1267
97. Terauchi Y, Satoi Y, Takeuchi M, et al. Monotherapy with the once weekly GLP-1 receptor agonist dulaglutide for 12 weeks in Japanese patients with type 2 diabetes: dose-dependent effects on glycaemic control in a randomised, double-blind, placebo-controlled study. Endocr J. 2014;61(10):949-959
98. Nauck M, Weinstock RS, Umpierrez GE, et al. Efficacy and safety of dulaglutide versus sitagliptin after 52 weeks in type 2 diabetes in a randomized controlled trial (AWARD-5). Diabetes Care. 2014 Aug;37(8):2149-2158
99. Umpierrez G, Tofé Povedano S, Pérez Manghi F, et al. Efficacy and safety of dulaglutide monotherapy versus metformin in type 2 diabetes in a randomized controlled trial (AWARD-3). Diabetes Care. 2014 Aug;37(8):2168-2176
100. Giorgino F, Benroubi M, Sun J-H, et al. Efficacy and safety of once-weekly dulaglutide versus insulin glargine in patients with type 2 diabetes on metformin and glimepiride (AWARD-2). Diabetes Care. 2015 Dec;38(12):2241-2249
101. Blonde L, Jendle J, Gross J, et al. Once-weekly dulaglutide versus bedtime insulin glargine, both in combination with prandial insulin lispro, in patients with type 2 diabetes (AWARD-4): A randomised, open-label, phase 3, non-inferiority study. Lancet. 2015 May 23;385 (9982):2057-2066
102. Dungan KM, Povedano ST, Forst T, et al. Once-weekly dulaglutide versus once-daily liraglutide in metformintreated patients with type 2 diabetes (AWARD-6): A randomised, open-label, phase 3, non-inferiority trial. Lancet. 2014 Oct 11;384(9951):1349-1357
103. Blevins T, Pullman J, Malloy J, et al. DURATION-5: exenatide once weekly resulted in greater improvements in glycemic control compared with exenatide twice daily in patients with type 2 diabetes. J Clin Endocrinol Metab. 2011 May;96(5):1301-1310
104. 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 Jul 4;374 (9683):39-47
105. Buse JB, Nauck M, Forst T, et al. Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes (DURATION-6): A randomised, open-label study. Lancet. 2013 Jan 12;381(9861):117-124
106. Pratley RE, Nauck MA, Barnett AH, et al. Once-weekly albiglutide versus once-daily liraglutide in patients with type 2 diabetes inadequately controlled on oral drugs (HARMONY 7): A randomised, open-label, multicentre, non-inferiority phase 3 study. Lancet Diabetes Endocrinol. 2014 Apr;2(4):289-297
107. Rosenstock J, Raccah D, Korányi L, et al. Efficacy and safety of lixisenatide once daily versus exenatide twice daily in type 2 diabetes inadequately controlled on metformin: A 24-week, randomized, open-label, active-controlled study (GetGoal-X). Diabetes Care. 2013 Oct;36 (10):2945-2951
108. Kapitza C, Forst T, Coester H-V, et al. Pharmacodynamic characteristics of lixisenatide once daily versus liraglutide once daily in patients with type 2 diabetes insufficiently controlled on metformin. Diabetes Obes Metab. 2013 Jul;15(7):642-649
109. Fineman MS, Cirincione BB, Maggs D, et al. GLP-1 based therapies: differential effects on fasting and postprandial glucose. Diabetes Obes Metab. 2012 Aug;14(8):675-688
110. Madsbad S. Treatment of type 2 diabetes with incretinbased therapies. Lancet. 2009 Feb 7;373(9662):438-439
111. Nauck MA, Kemmeries G, Holst JJ, et al. Rapid tachyphylaxis of the glucagon-like peptide 1-induced deceleration of gastric emptying in humans. Diabetes. 2011 May;60 (5):1561-1565
112. Umapathysivam MM, Lee MY, Jones KL, et al. Comparative effects of prolonged and intermittent stimulation of the glucagon-like peptide 1 receptor on gastric emptying and glycemia. Diabetes. 2014 Feb 1;63 (2):785-790
113. Marathe CS, Rayner CK, Jones KL, et al. Relationships between gastric emptying, postprandial glycemia, and incretin hormones. Diabetes Care. 2013;36(5):1396-1405
114. Jones AG, McDonald TJ, Shields BM, et al. Markers of -cell failure predict poor glycemic response to glp-1 receptor agonist therapy in type 2 diabetes. Diabetes Care. 2015 Aug 4. pii: dc150258. [Epub ahead of print]
115. Meier JJ, Rosenstock J, Hincelin-Méry A, et al. Contrasting effects of lixisenatide and liraglutide on postprandial glycemic control, gastric emptying, and safety parameters in patients with type 2 diabetes on optimized insulin glargine with or without metformin: A randomized, open-label trial. Diabetes Care. 2015;38(7):1263-1273
116. Monnier L, Colette C, Owens D. Postprandial and basal glucose in type 2 diabetes: Assessment and respective impacts. Diabetes Technol Ther. 2011 Jun;13(S1):S-25-S-32
117. Horowitz M, Vilsbøll T, Zdravkovic M, et al. Patientreported rating of gastrointestinal adverse effects during treatment of type 2 diabetes with the once-daily human GLP-1 analogue, liraglutide. Diabetes Obes Metab. 2008 Jul;10(7):593-596
118. Egan AG, Blind E, Dunder K, et al. Pancreatic safety of incretin-based drugs-FDA and EMA assessment. N Engl J Med. 2014 Feb 27;370(9):794-797
119. Monami M, Dicembrini I, Nardini C, et al. Glucagon-like peptide-1 receptor agonists and pancreatitis: A metaanalysis of randomized clinical trials. Diabetes Res Clin Pract. 2014 Feb;103(2):269-275
120. Meier JJ, Nauck MA. Risk of pancreatitis in patients treated with incretin-based therapies. Diabetologia. 2014 Jul;57(7):1320-1324
121. Nauck MA, Friedrich N. Do GLP-1-based therapies increase cancer risk? Diabetes Care. 2013 Aug;36(Suppl 2):S245-S252
122. Butler PC, Elashoff M, Elashoff R, et al. A critical analysis of the clinical use of incretin-based therapies: Are the GLP-1 therapies safe? Diabetes Care. 2013 Jul;36(7):2118-2125
123. Suarez EA, Koro CE, Christian JB, et al. Incretin-mimetic therapies and pancreatic disease: A review of observational data. Curr Med Res Opin. 2014 Dec;30(12):2471-2481
124. Ferdinand KC, White WB, Calhoun DA, et al. Effects of the once-weekly glucagon-like peptide-1 receptor agonist dulaglutide on ambulatory blood pressure and heart rate in patients with type 2 diabetes mellitus. Hypertension. 2014 Oct;64(4):731-737
125. Pyke C, Heller RS, Kirk RK, et al. GLP-1 receptor localization in monkey and human tissue: novel distribution revealed with extensively validated monoclonal antibody. Endocrinology. 2014 Apr;155(4):1280-1290
126. No CV benefit with lixisenatide in ELIXA, but results reassure [Internet]. Medscape. [cited 2015 Sep 16]. Available from: http://www.medscape.com/viewarticle/ 846074
127. Meier JJ, Nauck MA. Incretin-based therapies: where will we be 50 years from now? Diabetologia. 2015 Aug;58 (8):1745-1750
128. Gough SCL, Bode B, Woo V, et al. Efficacy and safety of a fixed-ratio combination of insulin degludec and liraglutide (IDegLira) compared with its components given alone: results of a phase 3, open-label, randomised, 26-week, treat-to-target trial in insulin-naive patients with type 2 diabetes. Lancet Diabetes Endocrinol. 2014 Nov;2 (11):885-893
129. Buse JB, Vilsbøll T, Thurman J, et al. Contribution of liraglutide in the fixed-ratio combination of insulin degludec and liraglutide (IDegLira). Diabetes Care. 2014 Nov;37(11):2926-2933
130. Barnett AH. Complementing insulin therapy to achieve glycemic control. Adv Ther. 2013 Jun;30(6):557-576
131. Dirksen C, Bojsen-Møller KN, Jørgensen NB, et al. Exaggerated release and preserved insulinotropic action of glucagon-like peptide-1 underlie insulin hypersecretion in glucose-tolerant individuals after Roux-en-Y gastric bypass. Diabetologia. 2013 Dec;56 (12):2679-2687
132. Hjøllund KR, Deacon CF, Holst JJ. Dipeptidyl peptidase-4 inhibition increases portal concentrations of intact glucagon-like peptide-1 (GLP-1) to a greater extent than peripheral concentrations in anaesthetised pigs. Diabetologia. 2011 Aug;54(8):2206-2208
133. Marbury T, Flint A, Segel S, et al. Pharmacokinetics and tolerability of a single dose of semaglutide, a onceweekly human GLP-1 analog, in subjects with and without renal impairment. [Abstract no. 882]. 50th Annual Meeting of the European Association for the Study of Diabetes; 2013 Sep 16-19; Vienna
134. Ueno H, Mizuta M, Shiiya T, et al. Exploratory trial of intranasal administration of glucagon-like peptide-1 in Japanese patients with type 2 diabetes. Diabetes Care. 2014 Jul;37(7):2024-2027
135. Henry RR, Rosenstock J, Logan D, et al. Continuous subcutaneous delivery of exenatide via ITCA 650 leads to sustained glycemic control and weight loss for 48 weeks in metformin-treated subjects with type 2 diabetes. J Diabetes Complications. 2014 Jun;28(3):393-398
136. Day JW, Gelfanov V, Smiley D, et al. Optimization of coagonism at GLP-1 and glucagon receptors to safely maximize weight reduction in DIO-rodents. Biopolymers. 2012;98(5):443-450
137. De Silva A, Salem V, Long CJ, et al. The gut hormones PYY 3-36 and GLP-1 7-36 amide reduce food intake and modulate brain activity in appetite centers in humans. Cell Metab. 2011 Nov 2;14(5):700-706.