Contemporary Classification of Glucagon-Like Peptide 1 Receptor Agonists (GLP1RAs)

Sanjay Kalra, Saptarshi Bhattacharya, Nitin Kapoor, Sanjay Kalra, Saptarshi Bhattacharya, Nitin Kapoor

Abstract

This communication provides a contemporary classification of glucagon-like peptide 1 receptor agonists (GLP1RAs) based on indication, route, and frequency of administration, which could support a person-centric approach to treatment choice. It includes all recently developed GLP1RAs as well as those in advanced stages of clinical study. Keeping pace with current trends in pharmacology and metabolic medicine, it attempts to bring clarity and simplicity to a complex spread of information.

Keywords: Danuglipron; Dulaglutide; Exenatide; Exenatide LAR; GLP1RA; IDegLira; IcoSema; Liraglutide; LixiLan; Person-centric care; Semaglutide; Tirzepatide.

© 2021. The Author(s).

References

    1. Gupta Y, Kalra S. Choice of glucose-lowering therapy—a metabolic fulcrum-based approach. US Endocrinol. 2015;11(02):79. doi: 10.17925/USE.2015.11.02.79.
    1. Aroda VR. A review of GLP-1 receptor agonists: evolution and advancement, through the lens of randomised controlled trials. Diabetes Obes Metab. 2018;20(Suppl 1):22–33. doi: 10.1111/dom.13162.
    1. Sheahan KH, Wahlberg EA, Gilbert MP. An overview of GLP-1 agonists and recent cardiovascular outcomes trials. Postgrad Med J. 2020;96(1133):156–161. doi: 10.1136/postgradmedj-2019-137186.
    1. Szayna M, Doyle ME, Betkey JA, Holloway HW, Spencer RGS, Greig NH, Egan JM. Exendin-4 decelerates food intake, weight gain, and fat deposition in Zucker rats. Endocrinology. 2000;141(6):1936–41.
    1. McCormack PL. Exenatide twice daily: a review of its use in the management of patients with type 2 diabetes mellitus. Drugs. 2014;74(3):325–351. doi: 10.1007/s40265-013-0172-6.
    1. Norris SL, Lee N, Thakurta S, Chan BK. Exenatide efficacy and safety: a systematic review. Diabet Med. 2009;26(9):837–846. doi: 10.1111/j.1464-5491.2009.02790.x.
    1. Jose B, Tahrani AA, Piya MK, Barnett AH. Exenatide once weekly: clinical outcomes and patient satisfaction. Patient Prefer Adherence. 2010;4:313–324.
    1. Fineman MS, Mace KF, Diamant M, Darsow T, Cirincione BB, Booker Porter TK, et al. Clinical relevance of anti-exenatide antibodies: safety, efficacy and cross-reactivity with long-term treatment. Diabetes Obes Metab. 2012;14(6):546–554. doi: 10.1111/j.1463-1326.2012.01561.x.
    1. Ratner RE, Rosenstock J, Boka G. 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. 2010;27(9):1024–32.
    1. Lorenz M, Pfeiffer C, Steinstrasser A, Becker RH, Rutten H, Ruus P, et al. Effects of lixisenatide once daily on gastric emptying in type 2 diabetes—relationship to postprandial glycemia. Regul Pept. 2013;185:1–8.
    1. Barnett AH. Lixisenatide: evidence for its potential use in the treatment of type 2 diabetes. Core Evid. 2011;6:67–79. doi: 10.2147/CE.S15525.
    1. Madsen K, Knudsen LB, Agersoe H, Nielsen PF, Thøgersen H, Wilken M, Johansen NL. Structure–activity and protraction relationship of long-acting glucagon-like peptide-1 derivatives: importance of fatty acid length, polarity, and bulkiness. J Med Chem. 2007;50:6126–32.
    1. Buse JB, Garber A, Rosenstock J, Schmidt WE, Brett JH, Videbaek N, et al. Liraglutide treatment is associated with a low frequency and magnitude of antibody formation with no apparent impact on glycemic response or increased frequency of adverse events: results from the Liraglutide Effect and Action in Diabetes (LEAD) trials. J Clin Endocrinol Metab. 2011;96(6):1695–1702. doi: 10.1210/jc.2010-2822.
    1. Rigato M, Fadini GP. Comparative effectiveness of liraglutide in the treatment of type 2 diabetes. Diabetes Metab Syndr Obes. 2014;7:107–120.
    1. 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(4):311–322. doi: 10.1056/NEJMoa1603827.
    1. Knudsen LB, Lau J. The discovery and development of liraglutide and semaglutide. Front Endocrinol (Lausanne) 2019;10:155. doi: 10.3389/fendo.2019.00155.
    1. Goldenberg RM, Steen O. Semaglutide: review and place in therapy for adults with type 2 diabetes. Can J Diabetes. 2019;43(2):136–145. doi: 10.1016/j.jcjd.2018.05.008.
    1. 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(19):1834–1844. doi: 10.1056/NEJMoa1607141.
    1. Vilsboll T, Bain SC, Leiter LA, Lingvay I, Matthews D, Simo R, et al. Semaglutide, reduction in glycated haemoglobin and the risk of diabetic retinopathy. Diabetes Obes Metab. 2018;20(4):889–897. doi: 10.1111/dom.13172.
    1. Glaesner W, Vick AM, Millican R, Ellis B, Tschang SH, Tian Y, et al. Engineering and characterization of the long-acting glucagon-like peptide-1 analogue LY2189265, an Fc fusion protein. Diabetes Metab Res Rev. 2010;26(4):287–296. doi: 10.1002/dmrr.1080.
    1. Zhang L, Zhang M, Zhang Y, Tong N. Efficacy and safety of dulaglutide in patients with type 2 diabetes: a meta-analysis and systematic review. Sci Rep. 2016;6:18904. doi: 10.1038/srep18904.
    1. Kugler AJ, Thiman ML. Efficacy and safety profile of once-weekly dulaglutide in type 2 diabetes: a report on the emerging new data. Diabetes Metab Syndr Obes. 2018;11:187–197. doi: 10.2147/DMSO.S134960.
    1. Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P, Probstfield J, Riesmeyer JS, Riddle MC, Rydén L, Xavier D, Atisso CM, Dyal L, Hall S, Rao-Melaci P. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. 2019;394:121–130. doi: 10.1016/S0140-6736(19)31149-3.
    1. Rendell MS. Albiglutide: a unique GLP-1 receptor agonist. Expert Opin Biol Ther. 2016;16(12):1557–1569. doi: 10.1080/14712598.2016.1240780.
    1. Lund A, Knop FK, Vilsboll T. Glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes: differences and similarities. Eur J Intern Med. 2014;25(5):407–414. doi: 10.1016/j.ejim.2014.03.005.
    1. Avgerinos I, Michailidis T, Liakos A, Karagiannis T, Matthews DR, Tsapas A, et al. Oral semaglutide for type 2 diabetes: a systematic review and meta-analysis. Diabetes Obes Metab. 2020;22(3):335–345. doi: 10.1111/dom.13899.
    1. . Novo Nordisk A/S. Identifier NCT04707469. Research study to compare three doses of semaglutide tablets taken once daily in people with type 2 diabetes (PIONEER PLUS). 13 Jan 2021. Available from: . Accessed 2 May 2021.
    1. Griffith DA, Edmonds DJ, Fortin J-P, Kalgutkar AS, Kuzmiski JB, Loria PM, et al. A small-molecule oral agonist of the human glucagon-like peptide-1 receptor. bioRxiv. 2020:319483.
    1. Businesswire. Pfizer Investor Day features significant number of pipeline advances for COVID-19 programs and across numerous therapeutic areas. 2020. Available from: . Accessed 15 Sept 2020.
    1. Kalra S, Saboo B. Exenatide implant therapy in diabetes. Recent Adv Endocrinol. 2018;68(10):1538–1540.
    1. Schwartz SS, Epstein S, Corkey BE, Grant SF, Gavin JR, 3rd, Aguilar RB. 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.
    1. Abdul-Ghani MA, Puckett C, Triplitt C, Maggs D, Adams J, Cersosimo E, et al. Initial combination therapy with metformin, pioglitazone and exenatide is more effective than sequential add-on therapy in subjects with new-onset diabetes. Results from the Efficacy and Durability of Initial Combination Therapy for Type 2 Diabetes (EDICT): a randomized trial. Diabetes Obes Metab. 2015;17(3):268–275. doi: 10.1111/dom.12417.
    1. Anderson SL, Trujillo JM. Basal insulin use with GLP-1 receptor agonists. Diabetes Spectr. 2016;29(3):152–160. doi: 10.2337/diaspect.29.3.152.
    1. Blonde L, Anderson JE, Chava P, Dendy JA. Rationale for a titratable fixed-ratio co-formulation of a basal insulin analog and a glucagon-like peptide 1 receptor agonist in patients with type 2 diabetes. Curr Med Res Opin. 2019;35(5):793–804. doi: 10.1080/03007995.2018.1541790.
    1. Rosenstock J, Diamant M, Aroda V, Silvestre L, Souhami E, Zhou T, et al. Efficacy and safety of LixiLan, a titratable fixed-ratio combination of lixisenatide and insulin glargine, versus insulin glargine in type 2 diabetes inadequately controlled on metformin monotherapy: the LixiLan proof-of-concept randomized trial. Diabetes Care. 2016;39:1579–1586. doi: 10.2337/dc16-0046.
    1. Price H, Bluher M, Prager R, Phan TM, Thorsted BL, Schultes B, et al. Use and effectiveness of a fixed-ratio combination of insulin degludec/liraglutide (IDegLira) in a real-world population with type 2 diabetes: results from a European, multicentre, retrospective chart review study. Diabetes Obes Metab. 2018;20(4):954–962. doi: 10.1111/dom.13182.
    1. Greig SL, Scott LJ. Insulin degludec/liraglutide: a review in type 2 diabetes. Drugs. 2015;75(13):1523–1534. doi: 10.1007/s40265-015-0448-0.
    1. DoctoRx. Seeking Alpha: Novo Nordisk's insulin products, pipeline may energize the stock. 2020. Available from: . Accessed 2 May 2021.
    1. . Eli Lilly and Company. Identifier: NCT03954834. A study of tirzepatide (LY3298176) in participants with type 2 diabetes not controlled with diet and exercise alone (SURPASS-1). May 17, 2019. Available from: . Accessed 2 May 2021.
    1. . Eli Lilly and Company. Identifier: NCT04255433. A study of tirzepatide (LY3298176) compared with dulaglutide on major cardiovascular events in participants with type 2 diabetes (SURPASS-CVOT). 5 Feb 2020. Available from: . Accessed 2 May 2021.
    1. Fruhbeck G, Busetto L, Dicker D, Yumuk V, Goossens GH, Hebebrand J, et al. The ABCD of obesity: an EASO position statement on a diagnostic term with clinical and scientific implications. Obes Facts. 2019;12(2):131–136. doi: 10.1159/000497124.
    1. Acosta A, Abu Dayyeh BK, Port JD, Camilleri M. Recent advances in clinical practice challenges and opportunities in the management of obesity. Gut. 2014;63(4):687–695. doi: 10.1136/gutjnl-2013-306235.
    1. Bray GA, Frühbeck G, Ryan DH, Wilding JPH. Management of obesity. Lancet. 2016;387(10031):1947–1956. doi: 10.1016/S0140-6736(16)00271-3.
    1. Kushner RF, Calanna S, Davies M, Dicker D, Garvey WT, Goldman B, et al. Semaglutide 2.4 mg for the treatment of obesity: key elements of the STEP trials 1 to 5. Obesity (Silver Spring) 2020;28(6):1050–1061. doi: 10.1002/oby.22794.
    1. 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):971–84.
    1. 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. doi: 10.1001/jama.2021.1831.
    1. 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. N Engl J Med. 2015;373(1):11–22. doi: 10.1056/NEJMoa1411892.
    1. Scott LJ. Liraglutide: a review of its use in the management of obesity. Drugs. 2015;75(8):899–910. doi: 10.1007/s40265-015-0408-8.
    1. Mehta A, Marso SP, Neeland IJ. Liraglutide for weight management: a critical review of the evidence. Obes Sci Pract. 2017;3(1):3–14. doi: 10.1002/osp4.84.
    1. Novo Nordisk. Novo Nordisk to initiate phase 3a development in obesity with oral semaglutide. Company announcement no. 25/2021. Bagsværd: Novo Nordisk; 2021.
    1. Wilding JP. Combination therapy for obesity. J Psychopharmacol. 2017;31(11):1503–1508. doi: 10.1177/0269881117737401.
    1. Aronne L, Fujioka K, Aroda V, Chen K, Halseth A, Kesty NC, et al. Progressive reduction in body weight after treatment with the amylin analog pramlintide in obese subjects: a phase 2, randomized, placebo-controlled, dose-escalation study. J Clin Endocrinol Metab. 2007;92(8):2977–2983. doi: 10.1210/jc.2006-2003.
    1. Liberini CG, Koch-Laskowski K, Shaulson E, McGrath LE, Lipsky RK, Lhamo R, et al. Combined Amylin/GLP-1 pharmacotherapy to promote and sustain long-lasting weight loss. Sci Rep. 2019;9(1):8447. doi: 10.1038/s41598-019-44591-8.
    1. John LM, Kruse T, Raun K. Preclinical weight loss efficacy of AM833 in combination with semaglutide in rodent models of obesity. In: ENDO 2021—103rd Annual Meeting of the Endocrine Society, 2021 Mar 20–23.
    1. Enebo LB. Safety and tolerability of concomitant administration of multiple dose AM833 with semaglutide 2.4 mg for weight management. ENDO 2021—103rd Annual Meeting of the Endocrine Society, 2021 Mar 20–23.
    1. Novo Nordisk Inc. Novo Nordisk Inc. successfully completes AM833 phase 2 trial and phase 1 combination trial with AM833 and semaglutide in obesity. Press release from 18 Jun 2020. Available from: .>. Accessed 2 May 2021.
    1. Sanchez-Garrido MA, Brandt SJ, Clemmensen C, Muller TD, DiMarchi RD, Tschop MH. GLP-1/glucagon receptor co-agonism for treatment of obesity. Diabetologia. 2017;60(10):1851–1861. doi: 10.1007/s00125-017-4354-8.
    1. Clemmensen C. GLP-1/glucagon coagonism restores leptin responsiveness in obese mice chronically maintained on an obesogenic diet. Diabetes. 2014;63:1422–7.
    1. Habegger KM, Heppner KM, Geary N, Bartness TJ, DiMarchi R, Tschop MH. The metabolic actions of glucagon revisited. Nat Rev Endocrinol. 2010;6(12):689–697. doi: 10.1038/nrendo.2010.187.
    1. Habegger KM, Stemmer K, Cheng C, Müller TD, Heppner KM, Ottaway N, Holland J, Hembree JL, Smiley D, Gelfanov V, Krishna R. Fibroblast growth factor 21 mediates specific glucagon actions. Diabetes. 2013;62:1453–1463. doi: 10.2337/db12-1116.
    1. Quarta C, Clemmensen C, Zhu Z, Yang B, Joseph SS, Lutter D, et al. Molecular integration of incretin and glucocorticoid action reverses immunometabolic dysfunction and obesity. Cell Metab. 2017;26(4):620–632.e6. doi: 10.1016/j.cmet.2017.08.023.
    1. NamKoong C, Kim MS, Jang BT, Lee YH, Cho YM, Choi HJ. Central administration of GLP-1 and GIP decreases feeding in mice. Biochem Biophys Res Commun. 2017;490(2):247–252. doi: 10.1016/j.bbrc.2017.06.031.
    1. . Eli Lilly and Company. Identifier: NCT04184622. A study of tirzepatide (LY3298176) in participants with obesity or overweight (SURMOUNT-1). 19 Dec 2019. Available from: . Accessed 2 May 2021.
    1. Frias JP, Nauck MA, Van J, Kutner ME, Cui X, Benson C, et al. Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial. Lancet. 2018;392(10160):2180–2193. doi: 10.1016/S0140-6736(18)32260-8.
    1. Finan B, Yang B, Ottaway N, Smiley DL, Ma T, Clemmensen C, et al. A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents. Nat Med. 2015;21(1):27–36. doi: 10.1038/nm.3761.
    1. Gault VA, Bhat VK, Irwin N, Flatt PR. A novel glucagon-like peptide-1 (GLP-1)/glucagon hybrid peptide with triple-acting agonist activity at glucose-dependent insulinotropic polypeptide, GLP-1, and glucagon receptors and therapeutic potential in high fat-fed mice. J Biol Chem. 2013;288(49):35581–35591. doi: 10.1074/jbc.M113.512046.
    1. . Hanmi Pharmaceutical Company Limited. Identifier: NCT03374241. A first-in-human study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of HM15211. 15 Dec 2017. Available from: . Accessed 2 May 2021.
    1. Fahrbach JL, Fu H, Shurzinske L, Skrivanek Z, Martin S. Network meta-analysis accurately predicted the outcome of a subsequent randomised trial comparing once weekly dulaglutide 1.5 mg and once daily liraglutide 1.8 mg. Int J Clin Pract. 2016;70(3):218–221. doi: 10.1111/ijcp.12775.
    1. Schmidt LJ. A systematic review and meta-analysis of the efficacy of lixisenatide in the treatment of patients with type 2 diabetes. Diabetes Obes Metab. 2014;16:769–779. doi: 10.1111/dom.12269.
    1. Karagiannis T. 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;17:1065–1074. doi: 10.1111/dom.12541.
    1. 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;31(11):2472–2488. doi: 10.1016/j.clinthera.2009.11.034.
    1. Kalra S, Sahay R. A review on semaglutide: an oral glucagon-like peptide 1 receptor agonist in management of type 2 diabetes mellitus. Diabetes Ther. 2020;11(9):1965–1982. doi: 10.1007/s13300-020-00894-y.
    1. Andreadis P, Karagiannis T, Malandris K, Avgerinos I, Liakos A, Manolopoulos A, et al. Semaglutide for type 2 diabetes mellitus: a systematic review and meta-analysis. Diabetes Obes Metab. 2018;20(9):2255–2263. doi: 10.1111/dom.13361.
    1. 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. doi: 10.1056/NEJMoa2032183.
    1. Yamada Y, Katagiri H, Hamamoto Y, Deenadayalan S, Navarria A, Nishijima K, et al. Dose-response, efficacy, and safety of oral semaglutide monotherapy in Japanese patients with type 2 diabetes (PIONEER 9): a 52-week, phase 2/3a, randomised, controlled trial. Lancet Diabetes Endocrinol. 2020;8(5):377–391. doi: 10.1016/S2213-8587(20)30075-9.
    1. 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(15):1466–1480. doi: 10.1001/jama.2019.2942.
    1. 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(12):2272–2281. doi: 10.2337/dc19-0883.
    1. 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. The Lancet. 2019;394(10192):39–50. doi: 10.1016/S0140-6736(19)31271-1.
    1. 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. doi: 10.2337/dc19-0749.
    1. Frias JP, Nauck MA, Van J, Benson C, Bray R, Cui X, et al. Efficacy and tolerability of tirzepatide, a dual glucose-dependent insulinotropic peptide and glucagon-like peptide-1 receptor agonist in patients with type 2 diabetes: a 12-week, randomized, double-blind, placebo-controlled study to evaluate different dose-escalation regimens. Diabetes Obes Metab. 2020;22(6):938–946. doi: 10.1111/dom.13979.
    1. Soni H. Peptide-based GLP-1/glucagon co-agonists: a double-edged sword to combat diabesity. Med Hypotheses. 2016;95:5–9. doi: 10.1016/j.mehy.2016.08.005.

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