Authors : Balasukula Rachana; R. L. Manisha; Muvvala Sudhakar

Volume/Issue : Volume 11 - 2026, Issue 5 - May

Google Scholar : https://tinyurl.com/2p9t6mdx

Scribd : https://tinyurl.com/2p9t6mdx

DOI : https://doi.org/10.38124/ijisrt/26May1659

Note : A published paper may take 4-5 working days from the publication date to appear in PlumX Metrics, Semantic Scholar, and ResearchGate.

Abstract : The therapeutic landscape of obesity and type 2 diabetes mellitus has been transformed by the discovery and clinical translation of multi-agonist incretin peptides. Once-weekly semaglutide established glucagon-like peptide-1 (GLP1) receptor agonism as the benchmark pharmacological intervention, producing approximately 15% body weight reduction. Tirzepatide, the first approved dual GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptor co-agonist, has produced weight reductions exceeding 22%. Retatrutide, a triple agonist of GLP-1, GIP, and glucagon receptors, has demonstrated phase 2 weight reductions approaching 24%, while amylin co-agonist combinations such as cagrilintide– semaglutide (CagriSema) extend the polypharmacological frontier further. This review provides a comprehensive analysis of the molecular pharmacology, receptor biology, clinical trial evidence, and emerging pipeline of multi-agonist incretins. We examine landmark trials including STEP, SURMOUNT, SURPASS, SELECT, FLOW, and the retatrutide and survodutide programs; discuss the expanding indications beyond weight loss in cardiovascular disease, chronic kidney disease, metabolic dysfunction-associated steatohepatitis, and neurodegeneration; and address the unique adverse effect profile including gastrointestinal tolerability, gallbladder disease, pancreatitis surveillance, and emerging concerns regarding sarcopenia and lean mass preservation. The review highlights particular relevance for India, where the projected diabetes burden, obesity prevalence, and cost-access considerations make this drug class strategically important. Future directions include oral peptide and small-molecule incretin agonists, gene therapy approaches, and combination strategies with amylin, glucagon, and other gut hormones.

Keywords : Amylin; CagriSema; Cagrilintide; GLP-1 Receptor Agonists; Incretin; Mazdutide; Multi-Agonist; Obesity; Retatrutide; Semaglutide; Survodutide; Tirzepatide; Type 2 Diabetes.

References :

1. World Health Organization. Obesity and overweight: key facts. Geneva: WHO; 2024.
2. Anjana RM, Unnikrishnan R, Deepa M, Pradeepa R, Tandon N, Das AK, et al. Metabolic non-communicable disease health report of India: the ICMR-INDIAB national cross-sectional study (ICMR-INDIAB-17). Lancet Diabetes Endocrinol. 2023;11(7):474–489.
3. Wadden TA, Bartlett SJ, Foster GD, Greenway FL, Magkos F, Mantzoros CS, et al. Obesity: an overview of pathogenesis, comorbidities, and treatment. Postgrad Med. 2023;135(4):343–352.
4. Pi-Sunyer X. The medical risks of obesity. Postgrad Med. 2009;121(6):21–33.
5. Apovian CM, Aronne LJ, Bessesen DH, McDonnell ME, Murad MH, Pagotto U, et al. Pharmacological management of obesity: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2015;100(2):342–362.
6. Buse JB, Wexler DJ, Tsapas A, Rossing P, Mingrone G, Mathieu C, et al. 2019 update to: management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2020;43(2):487–493.
7. Wilding JPH, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021;384(11):989–1002.
8. Davies M, Færch 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, placebo-controlled, phase 3 trial. Lancet. 2021;397(10278):971–984.
9. Wadden TA, Bailey TS, Billings LK, Davies M, Frias JP, Koroleva A, et al. Effect of subcutaneous semaglutide vs placebo as an adjunct to intensive behavioral therapy on body weight in adults with overweight or obesity: the STEP 3 randomized clinical trial. JAMA. 2021;325(14):1403–1413.
10. Knop FK, Brønden A, Vilsbøll T. Exenatide: pharmacokinetics, clinical use, and future directions. Expert Opin Pharmacother. 2017;18(6):555–571.
11. Drucker DJ, Holst JJ. The expanding incretin universe: from basic biology to clinical translation. Diabetologia. 2023;66(10):1765–1779.
12. Drucker DJ. Mechanisms of action and therapeutic application of glucagon-like peptide-1. Cell Metab. 2018;27(4):740–756.
13. Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev. 2007;87(4):1409–1439.
14. Andersen A, Lund A, Knop FK, Vilsbøll T. Glucagon-like peptide 1 in health and disease. Nat Rev Endocrinol. 2018;14(7):390–403.
15. Müller TD, Finan B, Bloom SR, D'Alessio D, Drucker DJ, Flatt PR, et al. Glucagon-like peptide 1 (GLP-1). Mol Metab. 2019;30:72–130.
16. Yusta B, Baggio LL, Asadi A, Kim JG, Mojibian M, Lam TKT, et al. GIP and GLP-1 receptor antagonism during a meal in healthy individuals. J Clin Endocrinol Metab. 2017;102(5):1568–1576.
17. Nauck MA, Bartels E, Orskov C, Ebert R, Creutzfeldt W. Additive insulinotropic effects of exogenous synthetic human gastric inhibitory polypeptide and glucagon-like peptide-1-(7-36) amide infused at near-physiological insulinotropic hormone and glucose concentrations. J Clin Endocrinol Metab. 1993;76(4):912–917.
18. Samms RJ, Coghlan MP, Sloop KW. How may GIP enhance the therapeutic efficacy of GLP-1? Trends Endocrinol Metab. 2020;31(6):410–421.
19. Bagger JI, Holst JJ, Hartmann B, Andersen B, Knop FK, Vilsbøll T. Effect of oxyntomodulin, glucagon, GLP-1, and combined glucagon + GLP-1 infusion on food intake, appetite, and resting energy expenditure. J Clin Endocrinol Metab. 2015;100(12):4541–4552.
20. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JFE, Nauck MA, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes (LEADER). N Engl J Med. 2016;375(4):311–322.
21. Pi-Sunyer X, Astrup A, Fujioka K, Greenway F, Halpern A, Krempf M, et al. A randomized, controlled trial of 3.0 mg of liraglutide in weight management (SCALE Obesity and Prediabetes). N Engl J Med. 2015;373(1):11–22.
22. Knudsen LB, Lau J. The discovery and development of liraglutide and semaglutide. Front Endocrinol (Lausanne). 2019;10:155.
23. Christou GA, Katsiki N, Blundell J, Fruhbeck G, Kiortsis DN. Semaglutide as a promising antiobesity drug. Obes Rev. 2019;20(6):805–815.
24. Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes (SUSTAIN-6). N Engl J Med. 2016;375(19):1834–1844.
25. 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 (PIONEER 6). N Engl J Med. 2019;381(9):841–851.
26. Lincoff AM, Brown-Frandsen K, Colhoun HM, Deanfield J, Emerson SS, Esbjerg S, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes (SELECT). N Engl J Med. 2023;389(24):2221–2232.
27. Perkovic V, Tuttle KR, Rossing P, Mahaffey KW, Mann JFE, Bakris G, et al. Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes (FLOW). N Engl J Med. 2024;391(2):109–121.
28. Kosiborod MN, Abildstrøm SZ, Borlaug BA, Butler J, Rasmussen S, Davies M, et al. Semaglutide in patients with heart failure with preserved ejection fraction and obesity (STEP-HFpEF). N Engl J Med. 2023;389(12):1069–1084.
29. Aroda VR, Rosenstock J, Terauchi Y, Altuntas Y, Lalic NM, Morales Villegas EC, et al. PIONEER 1: randomized clinical trial of the efficacy and safety of oral semaglutide monotherapy in comparison with placebo in patients with type 2 diabetes. Diabetes Care. 2019;42(9):1724–1732.
30. Knop FK, Aroda VR, do Vale RD, Holst-Hansen T, Laursen PN, Rosenstock J, et al. Oral semaglutide 25 mg and 50 mg compared with 14 mg in adults with type 2 diabetes (PIONEER PLUS): a multicentre, randomised, phase 3b trial. Lancet. 2023;402(10403):705–719.
31. 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(10192):39–50.
32. Coskun T, Sloop KW, Loghin C, Alsina-Fernandez J, Urva S, Bokvist KB, et al. LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes. Mol Metab. 2018;18:3–14.
33. Bossart M, Wagner M, Elvert R, Evers A, Hübschle T, Kloeckener T, et al. Effects on weight loss and glycemic control with SAR441255, a potent unimolecular peptide GLP-1/GIP/glucagon receptor triagonist. Cell Metab. 2022;34(1):59–74.
34. Frías JP, Davies MJ, Rosenstock J, Pérez Manghi FC, Fernández Landó L, Bergman BK, et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes (SURPASS-2). N Engl J Med. 2021;385(6):503–515.
35. Ludvik B, Giorgino F, Jódar E, Frias JP, Fernández Landó L, Brown K, et al. Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3). Lancet. 2021;398(10300):583–598.
36. Del Prato S, Kahn SE, Pavo I, Weerakkody GJ, Yang Z, Doupis J, et al. Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4). Lancet. 2021;398(10313):1811–1824.
37. Jastreboff AM, Aronne LJ, Ahmad NN, Wharton S, Connery L, Alves B, et al. Tirzepatide once weekly for the treatment of obesity (SURMOUNT-1). N Engl J Med. 2022;387(3):205–216.
38. Garvey WT, Frias JP, Jastreboff AM, le Roux CW, Sattar N, Aizenberg D, et al. Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2). Lancet. 2023;402(10402):613–626.
39. Wadden TA, Chao AM, Machineni S, Kushner R, Ard J, Srivastava G, et al. Tirzepatide after intensive lifestyle intervention in adults with overweight or obesity (SURMOUNT-3). Nat Med. 2023;29(11):2909–2918.
40. Aronne LJ, Sattar N, Horn DB, Bays HE, Wharton S, Lin WY, et al. Continued treatment with tirzepatide for maintenance of weight reduction in adults with obesity (SURMOUNT-4). JAMA. 2024;331(1):38–48.
41. Aronne LJ, Horn DB, le Roux CW, Ho W, Falcon BL, Gomez Valderas E, et al. Tirzepatide as compared with semaglutide for the treatment of obesity. N Engl J Med. 2025;392(8):729–740.
42. Jastreboff AM, le Roux CW, Stefanski A, Aronne LJ, Halpern B, Wharton S, et al. Tirzepatide for obesity treatment and diabetes prevention. N Engl J Med. 2025;392(10):958–971.
43. Malhotra A, Grunstein RR, Fietze I, Weaver TE, Redline S, Azarbarzin A, et al. Tirzepatide for the treatment of obstructive sleep apnea and obesity (SURMOUNT-OSA). N Engl J Med. 2024;391(13):1193–1205.
44. Packer M, Zile MR, Kramer CM, Baum SJ, Litwin SE, Menon V, et al. Tirzepatide for heart failure with preserved ejection fraction and obesity (SUMMIT). N Engl J Med. 2025;392(5):427–437.
45. Jastreboff AM, Kaplan LM, Frias JP, Wu Q, Du Y, Gurbuz S, et al. Triple-hormone-receptor agonist retatrutide for obesity — a phase 2 trial. N Engl J Med. 2023;389(6):514–526.
46. Rosenstock J, Frias J, Jastreboff AM, Du Y, Lou J, Gurbuz S, et al. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial. Lancet. 2023;402(10401):529–544.
47. Sanyal AJ, Kaplan LM, Frias JP, Brouwers B, Wu Q, Thomas MK, et al. Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2 trial. Nat Med. 2024;30(7):2037–2048.
48. Lau DCW, Erichsen L, Francisco AM, Satylganova A, le Roux CW, McGowan B, et al. Once-weekly cagrilintide for weight management in people with overweight and obesity: a multicentre, randomised, double-blind, placebo-controlled and active-controlled, dose-finding phase 2 trial. Lancet. 2021;398(10317):2160–2172.
49. Frias JP, Deenadayalan S, Erichsen L, Knop FK, Lingvay I, Macura S, et al. Efficacy and safety of co-administered once-weekly cagrilintide 2.4 mg with once-weekly semaglutide 2.4 mg in type 2 diabetes: a multicentre, randomised, double-blind, active-controlled, phase 2 trial. Lancet. 2023;402(10403):720–730.
50. Garvey WT, Blüher M, Osorto Contreras CK, et al. CagriSema (cagrilintide 2.4 mg/semaglutide 2.4 mg) in adults with overweight or obesity (REDEFINE-1): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2025; (in press).
51. Hjuler ST, Andreassen KV, Gydesen S, Karsdal MA, Henriksen K. KBP-042 improves bodyweight and glucose homeostasis with indices of increased insulin sensitivity irrespective of route of administration. Eur J Pharmacol. 2015;762:229–238.
52. Le Roux CW, Steen O, Lucas KJ, Startseva E, Unseld A, Hennige AM. Glucagon and GLP-1 receptor dual agonist survodutide for obesity: a randomised, double-blind, placebo-controlled, dose-finding phase 2 trial. Lancet Diabetes Endocrinol. 2024;12(3):162–173.
53. Sanyal AJ, Bedossa P, Fraessdorf M, Neff GW, Lawitz E, Bugianesi E, et al. A phase 2 randomized trial of survodutide in MASH and fibrosis. N Engl J Med. 2024;391(4):311–322.
54. Ji L, Jiang H, Bi Y, Chen H, Chen W, Cheng Z, et al. Efficacy and safety of mazdutide in Chinese participants with overweight or obesity (DREAMS-2): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Diabetes Endocrinol. 2024;12(8):538–549.
55. Nahra R, Wang T, Gadde KM, Oscarsson J, Stumvoll M, Jermutus L, et al. Effects of cotadutide on metabolic and hepatic parameters in adults with overweight or obesity and type 2 diabetes. Diabetes Care. 2021;44(6):1433–1442.
56. Sattar N, Lee MMY, Kristensen SL, Branch KRH, 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(10):653–662.
57. Drucker DJ. The cardiovascular biology of glucagon-like peptide-1. Cell Metab. 2016;24(1):15–30.
58. 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(12):1113–1124.
59. Loomba R, Hartman ML, Lawitz EJ, Vuppalanchi R, Boursier J, Bugianesi E, et al. Tirzepatide for metabolic dysfunction-associated steatohepatitis with liver fibrosis. N Engl J Med. 2024;391(4):299–310.
60. Athauda D, Maclagan K, Skene SS, Bajwa-Joseph M, Letchford D, Chowdhury K, et al. Exenatide once weekly versus placebo in Parkinson's disease (Exenatide-PD): a randomised, double-blind, placebo-controlled trial. Lancet. 2017;390(10103):1664–1675.
61. Wharton S, Davies M, Dicker D, Lingvay I, Mosenzon O, Rubino DM, et al. Managing the gastrointestinal side effects of GLP-1 receptor agonists in obesity: recommendations for clinical practice. Postgrad Med. 2022;134(1):14–19.
62. Monami M, Nreu B, Scatena A, Cresci B, Andreozzi F, Sesti G, et al. Safety issues with glucagon-like peptide-1 receptor agonists (pancreatitis, pancreatic cancer and cholelithiasis): data from randomized controlled trials. Diabetes Obes Metab. 2017;19(9):1233–1241.
63. Conte C, Hall KD, Klein S. Is weight loss-induced muscle mass loss clinically relevant? JAMA. 2024;332(1):9–10.
64. Pradeepa R, Mohan V. Epidemiology of type 2 diabetes in India. Indian J Ophthalmol. 2021;69(11):2932–2938.
65. Misra A, Jayawardena R, Anoop S. Obesity in South Asia: phenotype, morbidities, and mitigation. Curr Obes Rep. 2019;8(1):43–52.
66. Mohan V, Khunti K, Chan SP, Filho FF, Tran NQ, Ramaiya K, et al. Management of type 2 diabetes in developing countries: balancing optimal glycaemic control and outcomes with affordability and accessibility to treatment. Diabetes Ther. 2020;11(1):15–35.