Evolution of glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes

Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) are a class of antidiabetic drugs developed over the past 15 years. GLP-1, a gastrointestinal peptide hormone that contributes to the postprandial “incretin effect”, stimulates glucose-dependent insulin secretion. The incretin effect is greatly diminished in type 2 diabetes, but can be restored by GLP-1RAs. These drugs also exert other GLP-1 effects, including reducing glucagon secretion, delaying gastric emptying, reducing food intake, improving cardiac ventricular function, and lowering blood pressure. Short-acting GLP-1RAs are administered once daily (lixisenatide) or twice daily (exenatide); long-acting GLP 1RAs are administered once daily (liraglutide) or once weekly (slow-release exenatide, dulaglutide, albiglutide). All GLP-1RAs significantly reduce glycated hemoglobin (HbA1c) in patients with type 2 diabetes whose glycemic control is inadequate with oral antidiabetic drugs. Compared with other antidiabetic medications, GLP-1RAs provide better glycemic control with the additional benefit of weight loss. Within this class, long-acting GLP-1RAs are more efficacious than short-acting GLP-1RAs, with similar or lower risk of hypoglycemia and lower incidence of gastrointestinal adverse effects. Head-to-head trials and a network meta-analysis suggest that once daily liraglutide is the most effective GLP-1RA in reducing HbA1c. Dulaglutide is the only once-weekly GLP 1RA demonstrated to be noninferior to liraglutide. The once-weekly GLP-1RAs offer additional advantages to patients, including fewer injections and easy-to-use, single-dose pen devices. Despite the relatively recent development of GLP-1RAs, international diabetes guidelines recognize the benefits of this class of drugs and recommend them as a treatment option for patients with type 2 diabetes.

1. American Diabetes Association. Pharmacologic approaches to glycemic treatment. Diabetes Care. 2017;40(Suppl 1):64-74. doi: 10.2337/dc17-S011

2. Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm--2016 executive summary. Endocr Pract. 2016;22(1):84-113. doi: 10.4158/EP151126.CS

3. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38(1):140-149. doi: 10.2337/dc14-2441

4. Дедов И.И., Шестакова М.В., Майоров А.Ю., и др. Алгоритмы специализированной медицинской помощи больным сахарным диабетом / Под редакцией И.И. Дедова, М.В. Шестаковой, А.Ю. Майорова. – 8-й выпуск // Сахарный диабет. – 2017. – Т. 20. – №1S. – C. 1-121. [Dedov II, Shestakova MV, Mayorov AY, et al. Standards of specialized diabetes care. Edited by Dedov II, Shestakova MV, Mayorov AY. 8th edition. Diabetes mellitus. 2017;20(1S):1-121. (in Russ.)] doi: 10.14341/DM20171S8

5. D'Alessio DA, Vahl TP. Utilizing the GLP-1 signaling system to treat diabetes: sorting through the pharmacologic approaches. Curr Diab Rep. 2005;5(5):346-352. doi: 10.1007/s11892-005-0092-2

6. Kieffer TJ, Habener JF. The glucagon-like peptides. Endocr Rev. 1999;20(6):876-913. doi: 10.1210/edrv.20.6.0385

7. Nauck M. Incretin therapies: highlighting common features and differences in the modes of action of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Diabetes Obes Metab. 2016;18(3):203-216. doi: 10.1111/dom.12591

8. Schwartz SS, Epstein S, Corkey BE, et al. The time is right for a new classification system for diabetes: rationale and implications of the beta-cell-centric classification schema. Diabetes Care. 2016;39(2):179-186. doi: 10.2337/dc15-1585

9. de Graaf C, Donnelly D, Wootten D, et al. Glucagon-like peptide-1 and its class B G protein-coupled receptors: a long march to therapeutic successes. Pharmacol Rev. 2016;68(4):954-1013. doi: 10.1124/pr.115.011395

10. Buteau J. GLP-1 signaling and the regulation of pancreatic β-cells mass/function. Avances en Diabetología. 2015;31(3):3-8. doi: 10.1016/S1134-3230(11)70002-3

11. Cryer PE. Minireview: Glucagon in the pathogenesis of hypoglycemia and hyperglycemia in diabetes. Endocrinology. 2012;153(3):1039-1048. doi: 10.1210/en.2011-1499

12. Nauck MA, Kemmeries G, Holst JJ, Meier JJ. Rapid tachyphylaxis of the glucagon-like peptide 1-induced deceleration of gastric emptying in humans. Diabetes. 2011;60(5):1561-1565. doi: 10.2337/db10-0474

13. Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev. 2007;87(4):1409-1439. doi: 10.1152/physrev.00034.2006

14. Drucker DJ. The cardiovascular biology of glucagon-like peptide-1. Cell Metab. 2016;24(1):15-30. doi: 10.1016/j.cmet.2016.06.009

15. Aldiss P, Davies G, Woods R, et al. ‘Browning’ the cardiac and peri-vascular adipose tissues to modulate cardiovascular risk. Int J Cardiol. 2017;228:265-274. doi: 10.1016/j.ijcard.2016.11.074

16. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. New Engl J Med. 2016;375(19):1834-1844. doi: 10.1056/NEJMoa1607141

17. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. New Engl J Med. 2016;375(4):311-322. doi: 10.1056/NEJMoa1603827

18. Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. New Engl J Med. 2015;373(23):2247-2257. doi: 10.1056/NEJMoa1509225

19. Liu SC, Tu YK, Chien MN, Chien KL. Effect of antidiabetic agents added to metformin on glycaemic control, hypoglycaemia and weight change in patients with type 2 diabetes: a network meta-analysis. Diabetes Obes Metab. 2012;14(9):810-820. doi: 10.1111/j.1463-1326.2012.01606.x

20. Zhang Q, Dou J, Lu J. Combinational therapy with metformin and sodium-glucose cotransporter inhibitors in management of type 2 diabetes: systematic review and meta-analyses. Diabetes Res Clin Pract. 2014;105(3):313-321. doi: 10.1016/j.diabres.2014.06.006

21. Lorenzi M, Ploug UJ, Langer J, et al. Liraglutide versus SGLT-2 inhibitors in people with type 2 diabetes: a network meta-analysis. Diabetes Ther. 2017;8(1):85-99. doi: 10.1007/s13300-016-0217-4

22. Karagiannis T, Liakos A, Bekiari E, et al. Efficacy and safety of once-weekly glucagon-like peptide 1 receptor agonists for the management of type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2015;17(11):1065-1074. doi: 10.1111/dom.12541

23. Maruthur NM, Tseng E, Hutfless S, et al. Diabetes medications as monotherapy or metformin-based combination therapy for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med. 2016;164(11):740-751. doi: 10.7326/M15-2650

24. 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;375(9724):1447-1456. doi: 10.1016/S0140-6736(10)60307-8

25. Guo X, Yang Q, Dong J, et al. Tumour risk with once-weekly glucagon-like peptide-1 receptor agonists in type 2 diabetes mellitus patients: a systematic review. Clin Drug Investig. 2016;36(6):433-441. doi: 10.1007/s40261-016-0389-8

26. Azoulay L, Filion KB, Platt RW, et al. Association between incretin-based drugs and the risk of acute pancreatitis. JAMA Intern Med. 2016;176(10):1464-1473. doi: 10.1001/jamainternmed.2016.1522

27. Azoulay L, Filion KB, Platt RW, et al. Incretin based drugs and the risk of pancreatic cancer: international multicentre cohort study. BMJ. 2016;352:i581. doi: 10.1136/bmj.i581

28. Monami M, Dicembrini I, Nardini C, et al. Effects of glucagon-like peptide-1 receptor agonists on cardiovascular risk: a meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2014;16(1):38-47. doi: 10.1111/dom.12176

29. Bhavsar S, Mudaliar S, Cherrington A. Evolution of exenatide as a diabetes therapeutic. Curr Diabetes Rev. 2013;9(2):161-193. doi: 10.2174/1573399811309020007

30. State Register of Medicinal Products. Available at: http://grls.rosminzdrav.ru/Default.aspx. Accessed 21 Mar 2017.

31. Bydureon (exenatide extended-release) [summary of product characteristics]: Södertälje, Sweden: AstraZeneca AB, 2016.Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002020/WC500108241.pdf. Accessed 28 Mar 2017.

32. Madsbad S. Review of head-to-head comparisons of glucagon-like peptide-1 receptor agonists. Diabetes Obes Metab. 2016;18(4):317-332. doi: 10.1111/dom.12596

33. Jendle J, Grunberger G, Blevins T, et al. Efficacy and safety of dulaglutide in the treatment of type 2 diabetes: a comprehensive review of the dulaglutide clinical data focusing on the AWARD phase 3 clinical trial program. Diabetes Metab Res Rev. 2016;32(8):776-790. doi: 10.1002/dmrr.2810

34. Eperzan (albiglutide) [summary of product information]: Cork, Ireland: GlaxoSmithKline, 2015. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002735/WC500165117.pdf. Accessed 4 Jan 2017.

35. Trujillo JM, Nuffer W, Ellis SL. GLP-1 receptor agonists: a review of head-to-head clinical studies. Ther Adv Endocrinol Metab. 2015;6(1):19-28. doi: 10.1177/2042018814559725

36. 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;36(10):2945-2951. doi: 10.2337/dc12-2709

37. 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;381(9861):117-124. doi: 10.1016/S0140-6736(12)61267-7

38. 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;2(4):289-297. doi: 10.1016/S2213-8587(13)70214-6

39. Dungan KM, Povedano ST, Forst T, et al. Once-weekly dulaglutide versus once-daily liraglutide in metformin-treated patients with type 2 diabetes (AWARD-6): a randomised, open-label, phase 3, non-inferiority trial. Lancet. 2014;384(9951):1349-1357. doi: 10.1016/S0140-6736(14)60976-4

40. Zaccardi F, Htike ZZ, Webb DR, et al. Benefits and harms of once-weekly glucagon-like peptide-1 receptor agonist treatments: a systematic review and network meta-analysis. Ann Intern Med. 2016;164(2):102-113. doi: 10.7326/M15-1432

41. 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;96(5):1301-1310. doi: 10.1210/jc.2010-2081

42. 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;372(9645):1240-1250. doi: 10.1016/S0140-6736(08)61206-4

43. 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(9683):39-47. doi: 10.1016/S0140-6736(09)60659-0

44. 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;37(8):2159-2167. doi: 10.2337/dc13-2760

45. Bettge K, Kahle M, Abd El Aziz MS, et al. Occurrence of nausea, vomiting and diarrhoea reported as adverse events in clinical trials studying glucagon-like peptide-1 receptor agonists: a systematic analysis of published clinical trials. Diabetes Obes Metab. 2017;19(3):336-347. doi: 10.1111/dom.12824

46. Abd El Aziz MS, Kahle M, Meier JJ, Nauck MA. A meta-analysis comparing clinical effects of short- or long-acting GLP-1 receptor agonists versus insulin treatment from head-to-head studies in type 2 diabetic patients. Diabetes Obes Metab. 2017;19(2):216-227. doi: 10.1111/dom.12804

47. Xue X, Ren Z, Zhang A, et al. Efficacy and safety of once-weekly glucagon-like peptide-1 receptor agonists compared with exenatide and liraglutide in type 2 diabetes: a systemic review of randomised controlled trials. Int J Clin Pract. 2016;70(8):649-656. doi: 10.1111/ijcp.12847

48. Byetta (exenatide) [prescribing information]: Wilmington, DE, USA: AstraZeneca Pharmaceuticals, 2015. Available at: http://www.azpicentral.com/byetta/pi_byetta.pdf#page=1. Accessed 4 Jan 2017.

49. Lyxumia (lixisenatide) [summary of product characteristics]: Paris, France: sanofi-aventis, 2016. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002445/WC500140401.pdf. Accessed 4 Jan 2017.

50. Victoza (liraglutide) [prescribing information]: Plainsboro, NJ, USA: Novo Nordisk Inc., 2016. Available at: http://www.novo-pi.com/victoza.pdf. Accessed 4 Jan 2017.

51. Trulicity (dulaglutide) [prescribing information]: Indianapolis, IN, USA: Eli Lilly and Company, 2015. Available at: http://pi.lilly.com/us/trulicity-uspi.pdf. Accessed 4 Jan 2017.

52. Anderson BJ, Redondo MJ. What can we learn from patient-reported outcomes of insulin pen devices? J Diabetes Sci Technol. 2011;5(6):1563-1571. doi: 10.1177/193229681100500633

53. DiBonaventura MD, Wagner J-S, Girman CJ, et al. Multinational Internet-based survey of patient preference for newer oral or injectable type 2 diabetes medication. Patient Prefer Adherence. 2010;4:397-406. doi: 10.2147/PPA.S14477

54. Evans M, McEwan P, O'Shea R, George L. A retrospective, case-note survey of type 2 diabetes patients prescribed incretin-based therapies in clinical practice. Diabetes Ther. 2013;4(1):27-40. doi: 10.1007/s13300-012-0015-6

55. Lüdemann J, Dütting ED, Dworak M. Patient preference and tolerability of a DPP-4 inhibitor versus a GLP-1 analog in patients with type 2 diabetes mellitus inadequately controlled with metformin: a 24-week, randomized, multicenter, crossover study. Ther Adv Endocrinol Metab.2015;6(4):141-148. doi: 10.1177/2042018815595584

56. Stauder U, Enginee D, Elton H, et al. Comparative assessment of lixisenatide, exenatide, and liraglutide pen devices: a pilot user-based study. J Diabetes Sci Technol. 2014;8(1):123-131. doi: 10.1177/1932296813511733

57. Matfin G, Van Brunt K, Zimmermann AG, et al. Safe and effective use of the once weekly dulaglutide single-dose pen in injection-naive patients with type 2 diabetes. J Diabetes Sci Technol. 2015;9(5):1071-1079. doi: 10.1177/1932296815583059

58. Gelhorn HL, Poon JL, Davies EW, et al. Evaluating preferences for profiles of GLP-1 receptor agonists among injection-naive type 2 diabetes patients in the UK. Patient Prefer Adherence. 2015;9:1611-1622. doi: 10.2147/PPA.S90842

59. Johnston SS, Nguyen H, Felber E, et al. Retrospective study of adherence to glucagon-like peptide-1 receptor agonist therapy in patients with type 2 diabetes mellitus in the United States. Adv Ther. 2014;31(11):1119-1133. doi: 10.1007/s12325-014-0166-0

60. Qiao Q, Ouwens MJNM, Grandy S, et al. Adherence to GLP-1 receptor agonist therapy administered by once-daily or once-weekly injection in patients with type 2 diabetes in Germany. Diabetes Metab Syndr Obes. 2016;9:201-205. doi: 10.2147/DMSO.S99732