Endocrinol Metab.  2023 Feb;38(1):25-33. 10.3803/EnM.2022.1642.

Glucagon-Like Peptide 1 Therapy: From Discovery to Type 2 Diabetes and Beyond

• Viljoen A
• Bain SC

• KMID: 2539814
• DOI: http://doi.org/10.3803/EnM.2022.1642

Abstract

The therapeutic benefits of the incretin hormone, glucagon-like peptide 1 (GLP1), for people with type 2 diabetes and/or obesity, are now firmly established. The evidence-base arising from head-to-head comparative effectiveness studies in people with type 2 diabetes, as well as the recommendations by professional guidelines suggest that GLP1 receptor agonists should replace more traditional treatment options such as sulfonylureas and dipeptidyl-peptidase 4 (DPP4) inhibitors. Furthermore, their benefits in reducing cardiovascular events in people with type 2 diabetes beyond improvements in glycaemic control has led to numerous clinical trials seeking to translate this benefit beyond type 2 diabetes. Following early trial results their therapeutic benefit is currently being tested in other conditions including fatty liver disease, kidney disease, and Alzheimer’s disease.

Keyword

Glucagon-like peptide 1; Diabetes mellitus, type 2; Renal insufficiency, chronic

Reference

1. Bayliss WM, Starling EH. The mechanism of pancreatic secretion. J Physiol. 1902; 28:325–53.

2. Brown JC, Dryburgh JR. A gastric inhibitory polypeptide. II. The complete amino acid sequence. Can J Biochem. 1971; 49:867–72.

3. Holst JJ, Orskov C, Nielsen OV, Schwartz TW. Truncated glucagon-like peptide I, an insulin-releasing hormone from the distal gut. FEBS Lett. 1987; 211:169–74.

4. Mojsov S, Weir GC, Habener JF. Insulinotropin: glucagonlike peptide I (7-37) co-encoded in the glucagon gene is a potent stimulator of insulin release in the perfused rat pancreas. J Clin Invest. 1987; 79:616–9.

5. Drucker DJ, Philippe J, Mojsov S, Chick WL, Habener JF. Glucagon-like peptide I stimulates insulin gene expression and increases cyclic AMP levels in a rat islet cell line. Proc Natl Acad Sci U S A. 1987; 84:3434–8.

6. Kreymann B, Williams G, Ghatei MA, Bloom SR. Glucagon-like peptide-1 7-36: a physiological incretin in man. Lancet. 1987; 2:1300–4.

7. Pederson RA, Satkunarajah M, McIntosh CH, Scrocchi LA, Flamez D, Schuit F, et al. Enhanced glucose-dependent insulinotropic polypeptide secretion and insulinotropic action in glucagon-like peptide 1 receptor -/- mice. Diabetes. 1998; 47:1046–52.

8. Orskov C, Holst JJ, Nielsen OV. Effect of truncated glucagon-like peptide-1 [proglucagon-(78-107) amide] on endocrine secretion from pig pancreas, antrum, and nonantral stomach. Endocrinology. 1988; 123:2009–13.

9. Hvidberg A, Nielsen MT, Hilsted J, Orskov C, Holst JJ. Effect of glucagon-like peptide-1 (proglucagon 78-107amide) on hepatic glucose production in healthy man. Metabolism. 1994; 43:104–8.

10. Wettergren A, Schjoldager B, Mortensen PE, Myhre J, Christiansen J, Holst JJ. Truncated GLP-1 (proglucagon 78-107-amide) inhibits gastric and pancreatic functions in man. Dig Dis Sci. 1993; 38:665–73.

11. 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.

12. Nauck MA, Kleine N, Orskov C, Holst JJ, Willms B, Creutzfeldt W. Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia. 1993; 36:741–4.

13. Ritzel R, Orskov C, Holst JJ, Nauck MA. Pharmacokinetic, insulinotropic, and glucagonostatic properties of GLP-1 [7-36 amide] after subcutaneous injection in healthy volunteers. Dose-response-relationships. Diabetologia. 1995; 38:720–5.

14. Deacon CF, Nauck MA, Toft-Nielsen M, Pridal L, Willms B, Holst JJ. 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.

15. Deacon CF, Pridal L, Klarskov L, Olesen M, Holst JJ. Glucagon-like peptide 1 undergoes differential tissue-specific metabolism in the anesthetized pig. Am J Physiol. 1996; 271(3 Pt 1):E458–64.

16. Deacon CF, Knudsen LB, Madsen K, Wiberg FC, Jacobsen O, Holst JJ. Dipeptidyl peptidase IV resistant analogues of glucagon-like peptide-1 which have extended metabolic stability and improved biological activity. Diabetologia. 1998; 41:271–8.

17. Zander M, Madsbad S, Madsen JL, Holst JJ. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet. 2002; 359:824–30.

18. Eng J, Kleinman WA, Singh L, Singh G, Raufman JP. 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.

19. Buse JB, Rosenstock J, Sesti G, Schmidt WE, Montanya E, Brett JH, et al. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallelgroup, multinational, open-label trial (LEAD-6). Lancet. 2009; 374:39–47.

20. Nauck M, Rizzo M, Johnson A, Bosch-Traberg H, Madsen J, Cariou B. Once-daily liraglutide versus lixisenatide as add-on to metformin in type 2 diabetes: a 26-week randomized controlled clinical trial. Diabetes Care. 2016; 39:1501–9.

21. Hernandez I, Zhang Y. Comparing adoption of breakthrough and “me-too” drugs among medicare beneficiaries: a case study of dipeptidyl peptidase-4 inhibitors. J Pharm Innov. 2017; 12:105–9.

22. Green AR, Aronson JK, Haddad PM. Examining the ‘psychopharmacology revolution’ (1950-1980) through the advertising of psychoactive drugs in the British Medical Journal. J Psychopharmacol. 2018; 32:1056–66.

23. Drucker DJ, Buse JB, Taylor K, Kendall DM, Trautmann M, Zhuang D, et al. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet. 2008; 372:1240–50.

24. Buse JB, Nauck M, Forst T, Sheu WH, Shenouda SK, Heilmann CR, et al. Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes (DURATION-6): a randomised, open-label study. Lancet. 2013; 381:117–24.

25. Dungan KM, Povedano ST, Forst T, Gonzalez JG, Atisso C, Sealls W, 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; 384:1349–57.

26. Pratley RE, Nauck MA, Barnett AH, Feinglos MN, Ovalle F, Harman-Boehm I, 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; 2:289–97.

27. Lau J, Bloch P, Schaffer L, Pettersson I, Spetzler J, Kofoed J, et al. Discovery of the once-weekly glucagon-like peptide-1 (GLP-1) analogue semaglutide. J Med Chem. 2015; 58:7370–80.

28. Pratley RE, Aroda VR, Lingvay I, Ludemann J, Andreassen C, Navarria A, et al. Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): a randomised, open-label, phase 3b trial. Lancet Diabetes Endocrinol. 2018; 6:275–86.

29. Ahmann AJ, Capehorn M, Charpentier G, Dotta F, Henkel E, Lingvay I, et al. Efficacy and safety of once-weekly semaglutide versus exenatide er in subjects with type 2 diabetes (SUSTAIN 3): a 56-week, open-label, randomized clinical trial. Diabetes Care. 2018; 41:258–66.

30. Capehorn MS, Catarig AM, Furberg JK, Janez A, Price HC, Tadayon S, et al. Efficacy and safety of once-weekly semaglutide 1.0mg vs once-daily liraglutide 1.2mg as add-on to 1-3 oral antidiabetic drugs in subjects with type 2 diabetes (SUSTAIN 10). Diabetes Metab. 2020; 46:100–9.

31. Ahren B, Masmiquel L, Kumar H, Sargin M, Karsbol JD, Jacobsen SH, et al. Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): a 56-week, double-blind, phase 3a, randomised trial. Lancet Diabetes Endocrinol. 2017; 5:341–54.

32. Aroda VR, Bain SC, Cariou B, Piletic M, Rose L, Axelsen M, et al. Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): a randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial. Lancet Diabetes Endocrinol. 2017; 5:355–66.

33. Lingvay I, Catarig AM, Frias JP, Kumar H, Lausvig NL, le Roux CW, et al. Efficacy and safety of once-weekly semaglutide versus daily canagliflozin as add-on to metformin in patients with type 2 diabetes (SUSTAIN 8): a double-blind, phase 3b, randomised controlled trial. Lancet Diabetes Endocrinol. 2019; 7:834–44.

34. Frias JP, Auerbach P, Bajaj HS, Fukushima Y, Lingvay I, Macura S, et al. Efficacy and safety of once-weekly semaglutide 2·0 mg versus 1·0 mg in patients with type 2 diabetes (SUSTAIN FORTE): a double-blind, randomised, phase 3B trial. Lancet Diabetes Endocrinol. 2021; 9:563–74.

35. Davies M, Faerch L, Jeppesen OK, Pakseresht A, Pedersen SD, Perreault L, et al. Semaglutide 2·4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebocontrolled, phase 3 trial. Lancet. 2021; 397:971–84.

36. Frias JP, Bonora E, Nevarez Ruiz L, Li YG, Yu Z, Milicevic Z, et al. Efficacy and safety of dulaglutide 3.0 mg and 4.5 mg versus dulaglutide 1.5 mg in metformin-treated patients with type 2 diabetes in a randomized controlled trial (AWARD11). Diabetes Care. 2021; 44:765–73.

37. Buckley ST, Baekdal TA, Vegge A, Maarbjerg SJ, Pyke C, Ahnfelt-Ronne J, et al. Transcellular stomach absorption of a derivatized glucagon-like peptide-1 receptor agonist. Sci Transl Med. 2018; 10:e. aar7047.

38. Pratley R, Amod A, Hoff ST, Kadowaki T, Lingvay I, Nauck M, et al. Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial. Lancet. 2019; 394:39–50.

39. Rodbard HW, Rosenstock J, Canani LH, Deerochanawong C, Gumprecht J, Lindberg SO, et al. Oral semaglutide versus empagliflozin in patients with type 2 diabetes uncontrolled on metformin: the PIONEER 2 Trial. Diabetes Care. 2019; 42:2272–81.

40. Rosenstock J, Allison D, Birkenfeld AL, Blicher TM, Deenadayalan S, Jacobsen JB, et al. Effect of additional oral semaglutide vs sitagliptin on glycated hemoglobin in adults with type 2 diabetes uncontrolled with metformin alone or with sulfonylurea: the PIONEER 3 Randomized Clinical Trial. JAMA. 2019; 321:1466–80.

41. Bettge K, Kahle M, Abd El Aziz MS, Meier JJ, Nauck MA. 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; 19:336–47.

42. Nauck MA, Quast DR, Wefers J, Meier JJ. GLP-1 receptor agonists in the treatment of type 2 diabetes: state-of-the-art. Mol Metab. 2021; 46:101102.

43. Pfeffer MA, Claggett B, Diaz R, Dickstein K, Gerstein HC, Kober LV, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015; 373:2247–57.

44. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016; 375:311–22.

45. Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jodar E, Leiter LA, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016; 375:1834–44.

46. Hernandez AF, Green JB, Janmohamed S, D’Agostino RB Sr, Granger CB, Jones NP, et al. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial. Lancet. 2018; 392:1519–29.

47. Husain M, Birkenfeld AL, Donsmark M, Dungan K, Eliaschewitz FG, Franco DR, et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2019; 381:841–51.

48. Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomized placebo-controlled trial. Lancet. 2019; 394:121–30.

49. Aroda VR, Bauer R, Christiansen E, Haluzik M, Kallenbach K, Montanya E, et al. Efficacy and safety of oral semaglutide by subgroups of patient characteristics in the PIONEER phase 3 programme. Diabetes Obes Metab. 2022; 24:1338–50.

50. Ahren B, Atkin SL, Charpentier G, Warren ML, Wilding JPH, Birch S, et al. Semaglutide induces weight loss in subjects with type 2 diabetes regardless of baseline BMI or gastrointestinal adverse events in the SUSTAIN 1 to 5 trials. Diabetes Obes Metab. 2018; 20:2210–19.

51. Lingvay I, Hansen T, Macura S, Marre M, Nauck MA, de la Rosa R, et al. Superior weight loss with once-weekly semaglutide versus other glucagon-like peptide-1 receptor agonists is independent of gastrointestinal adverse events. BMJ Open Diabetes Res Care. 2020; 8:e001706.

52. Butler PC, Elashoff M, Elashoff R, Gale EA. A critical analysis of the clinical use of incretin-based therapies: are the GLP-1 therapies safe? Diabetes Care. 2013; 36:2118–25.

53. Abd El Aziz M, Cahyadi O, Meier JJ, Schmidt WE, Nauck MA. Incretin-based glucose-lowering medications and the risk of acute pancreatitis and malignancies: a meta-analysis based on cardiovascular outcomes trials. Diabetes Obes Metab. 2020; 22:699–704.

54. Nauck MA, Quast DR, Wefers J, Pfeiffer AF. The evolving story of incretins (GIP and GLP-1) in metabolic and cardiovascular disease: a pathophysiological update. Diabetes Obes Metab. 2021; 23 Suppl 3:5–29.

55. Holst JJ, Jepsen SL, Modvig I. GLP-1: incretin and pleiotropic hormone with pharmacotherapy potential: increasing secretion of endogenous GLP-1 for diabetes and obesity therapy. Curr Opin Pharmacol. 2022; 63:102189.

56. Pedrosa MR, Franco DR, Gieremek HW, Vidal CM, Bronzeri F, de Cassia Rocha A, et al. GLP-1 agonist to treat obesity and prevent cardiovascular disease: what have we achieved so far? Curr Atheroscler Rep. 2022; 24:867–84.

57. Taha MB, Yahya T, Satish P, Laird R, Agatston AS, CainzosAchirica M, et al. Glucagon-like peptide 1 receptor agonists: a medication for obesity management. Curr Atheroscler Rep. 2022; 24:643–54.

58. Drucker DJ. GLP-1 physiology informs the pharmacotherapy of obesity. Mol Metab. 2022; 57:101351.

59. Davies MJ, Aroda VR, Collins BS, Gabbay RA, Green J, Maruthur NM, et al. Management of hyperglycemia in type 2 diabetes, 2022: a consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2022; 45:2753–86.

60. Sattar N, Lee MM, Kristensen SL, Branch KR, Del Prato S, Khurmi NS, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials. Lancet Diabetes Endocrinol. 2021; 9:653–62.

61. Berndt J, Ooi SL, Pak SC. What is the mechanism driving the reduction of cardiovascular events from glucagon-like peptide-1 receptor agonists?: a mini review. Molecules. 2021; 26:4822.

62. ClinicalTrials.gov. Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity (SELECT) [Internet]. Bethesda; U.S. National Library of Medicine; 2022 [cited 2022 Dec 29]. Available from: https://clinicaltrials.gov/ct2/show/NCT03574597.

63. Kristensen SL, Rorth R, Jhund PS, Docherty KF, Sattar N, Preiss D, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol. 2019; 7:776–85.

64. van Baar MJ, van der Aart AB, Hoogenberg K, Joles JA, Heerspink HJL, van Raalte DH. The incretin pathway as a therapeutic target in diabetic kidney disease: a clinical focus on GLP-1 receptor agonists. Ther Adv Endocrinol Metab. 2019; 10:2042018819865398.

65. Williams DM, Nawaz A, Evans M. Renal outcomes in type 2 diabetes: a review of cardiovascular and renal outcome trials. Diabetes Ther. 2020; 11:369–86.

66. ClinicalTrials.gov. A Research Study to See How Semaglutide Works Compared to Placebo in People with Type 2 Diabetes and Chronic Kidney Disease (FLOW) [Internet]. Bethesda: U.S. National Library of Medicine; 2022 [cited 2022 Dec 29]. Available from: https://clinicaltrials.gov/ct2/show/NCT03819153.

67. ClinicalTrials.gov. Effect of Subcutaneous Semaglutide on Kidney Transplant Candidacy (RAISE-KT) [Internet]. Bethesda: U.S. National Library of Medicine; 2022 [cited 2022 Dec 29]. Available from: https://clinicaltrials.gov/ct2/show/NCT04741074.

68. Cariou B. The metabolic triad of non-alcoholic fatty liver disease, visceral adiposity and type 2 diabetes: implications for treatment. Diabetes Obes Metab. 2022; 24 Suppl 2:15–27.

69. Yabut JM, Drucker DJ. Glucagon-like peptide-1 receptorbased therapeutics for metabolic liver disease. Endocr Rev. 2022 Jul 30 [Epub]. https://doi.org/10.1210/endrev/bnac018.

70. Patel Chavez C, Cusi K, Kadiyala S. The emerging role of glucagon-like peptide-1 receptor agonists for the management of NAFLD. J Clin Endocrinol Metab. 2022; 107:29–38.

71. Cusi K, Sattar N, Garcia-Perez LE, Pavo I, Yu M, Robertson KE, et al. Dulaglutide decreases plasma aminotransferases in people with type 2 diabetes in a pattern consistent with liver fat reduction: a post hoc analysis of the AWARD programme. Diabet Med. 2018; 35:1434–9.

72. Petit JM, Cercueil JP, Loffroy R, Denimal D, Bouillet B, Fourmont C, et al. Effect of liraglutide therapy on liver fat content in patients with inadequately controlled type 2 diabetes: the Lira-NAFLD Study. J Clin Endocrinol Metab. 2017; 102:407–15.

73. Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D, Parker R, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet. 2016; 387:679–90.

74. Newsome PN, Buchholtz K, Cusi K, Linder M, Okanoue T, Ratziu V, et al. A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis. N Engl J Med. 2021; 384:1113–24.

75. Muscogiuri G, DeFronzo RA, Gastaldelli A, Holst JJ. Glucagon-like peptide-1 and the central/peripheral nervous system: crosstalk in diabetes. Trends Endocrinol Metab. 2017; 28:88–103.

76. Aviles-Olmos I, Dickson J, Kefalopoulou Z, Djamshidian A, Ell P, Soderlund T, et al. Exenatide and the treatment of patients with Parkinson’s disease. J Clin Invest. 2013; 123:2730–6.

77. Edison P, Femminella GD, Ritchie CW, Holmes C, Walker Z, Ridha BH, et al. Evaluation of liraglutide in the treatment of Alzheimer’s disease. Alzheimers Dement. 2021; 17:e057848.

78. ClinicalTrials.gov. A Research Study Investigating Semaglutide in People With Early Alzheimer’s Disease (EVOKE) [Internet]. Bethesda: U.S. National Library of Medicine; 2022 [cited 2022 Dec 29]. Available from: https://clinicaltrials.gov/ct2/show/NCT04777396?cond=EVOKE&draw=2&rank=1.

79. ClinicalTrials.gov. A Research Study Investigating Semaglutide in People With Early Alzheimer’s Disease (EVOKE Plus) [Internet]. Bethesda: U.S. National Library of Medicine; 2022 [cited 2022 Dec 29]. Available from: https://clinicaltrials.gov/ct2/show/NCT04777409?cond=EVOKE&draw=2&rank=2.

80. Reich N, Holscher C. The neuroprotective effects of glucagon-like peptide 1 in Alzheimer’s and Parkinson’s disease: an in-depth review. Front Neurosci. 2022; 16:970925.