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Diabetes Therapy
Published in: Diabetes Therapy 5/2024

Open Access 04-04-2024 | Obesity | Review

Dual and Triple Incretin-Based Co-agonists: Novel Therapeutics for Obesity and Diabetes

Authors: Robert M. Gutgesell, Rubén Nogueiras, Matthias H. Tschöp, Timo D. Müller

Published in: Diabetes Therapy | Issue 5/2024

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Abstract

The discovery of long-acting incretin receptor agonists represents a major stride forward in tackling the dual epidemic of obesity and diabetes. Here we outline the evolution of incretin-based pharmacotherapy, from exendin-4 to the discovery of the multi-incretin hormone receptor agonists that look set to be our next step toward curing diabetes and obesity. We discuss the multiagonists currently in clinical trials and the improvement in efficacy each new generation of these drugs bring. The success of these agents in preclinical models and clinical trials suggests a promising future for multiagonists in the treatment of metabolic diseases, with the most recent glucose-dependent insulinotropic peptide receptor:glucagon-like peptide 1 receptor:glucagon receptor (GIPR:GLP-1R:GCGR) triagonists rivaling the efficacy of bariatric surgery. However, further research is needed to fully understand how these therapies exert their effect on body weight and in the last section we cover open questions about the potential mechanisms of multiagonist drugs, and the understanding of how gut–brain communication can be leveraged to achieve sustained body weight loss without adverse effects.
Literature
1.
Murray CJL, Aravkin AY, Zheng P, et al. Global burden of 87 risk factors in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020;396(10258):1223–49.CrossRef
2.
3.
Kinlen D, Cody D, O’Shea D. Complications of obesity. QJM Mon J Assoc Physicians. 2018;111(7):437–43.CrossRef
4.
5.
Müller TD, Blüher M, Tschöp MH, DiMarchi RD. Anti-obesity drug discovery: advances and challenges. Nat Rev Drug Discov. 2022;21(3):201–23.PubMedCrossRef
6.
Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994;372(6505):425–32.PubMedCrossRef
7.
Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402(6762):656–60.PubMedCrossRef
8.
Tschöp M, Smiley DL, Heiman ML. Ghrelin induces adiposity in rodents. Nature. 2000;407(6806):908–13.PubMedCrossRef
9.
Maes HH, Neale MC, Eaves LJ. Genetic and environmental factors in relative body weight and human adiposity. Behav Genet. 1997;27(4):325–51.PubMedCrossRef
10.
11.
Yeo GSH, Farooqi IS, Aminian S, Halsall DJ, Stanhope RG, O’Rahilly S. A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nat Genet. 1998;20(2):111–2.PubMedCrossRef
12.
Farooqi IS, Jebb SA, Langmack G, et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med. 1999;341(12):879–84.PubMedCrossRef
13.
Heymsfield SB, Greenberg AS, Fujioka K, et al. Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA. 1999;282(16):1568–75.PubMedCrossRef
14.
Khatib MN, Shankar AH, Kirubakaran R, et al. Ghrelin for the management of cachexia associated with cancer. Cochrane Database Syst Rev. 2018;2018(2):CD012229.PubMedCentral
15.
Hagemann CA, Jensen MS, Holm S, et al. LEAP2 reduces postprandial glucose excursions and ad libitum food intake in healthy men. Cell Rep Med. 2022;3(4):100582.PubMedPubMedCentralCrossRef
16.
17.
18.
Tschöp MH, Friedman JM. Seeking satiety: from signals to solutions. Sci Transl Med. 2023;15(723):eadh4453.PubMedCrossRef
19.
Murlin JR, Clough HD, Gibbs CBF, Stokes AM. Aqueous extracts of pancreas: I. influence on the carbohydrate metabolism of depancreatized animals. J Biol Chem. 1923;56(1):253–96.CrossRef
20.
Svoboda M, Tastenoy M, Vertongen P, Robberecht P. Relative quantitative analysis of glucagon receptor mRNA in rat tissues. Mol Cell Endocrinol. 1994;105(2):131–7.PubMedCrossRef
21.
Svendsen B, Larsen O, Gabe MBN, et al. Insulin secretion depends on intra-islet glucagon signaling. Cell Rep. 2018;25(5):1127–34.e2.PubMedCrossRef
22.
Habegger KM, Heppner KM, Geary N, Bartness TJ, DiMarchi R, Tschöp MH. The metabolic actions of glucagon revisited. Nat Rev Endocrinol. 2010;6(12):689–97.PubMedPubMedCentralCrossRef
23.
Müller TD, Finan B, Clemmensen C, DiMarchi RD, Tschöp MH. The new biology and pharmacology of glucagon. Physiol Rev. 2017;97(2):721–66.PubMedCrossRef
24.
Samols E, Marri G, Marks V. Interrelationship of glucagon, insulin and glucose: the insulinogenic effect of glucagon. Diabetes. 1966;15(12):855–66.PubMedCrossRef
25.
D’Alessio DA, Marks V. Glucagon as the first incretin: objects (in the rearview mirror) are closer than they appear. Diabetes. 2023;72(12):1739–40.PubMedCrossRef
26.
27.
Farahani RA, Egan AM, Welch AA, et al. The effect of glucagon-like peptide 1 receptor blockade on glucagon-induced stimulation of insulin secretion. Diabetes. 2023;72(4):449–54.PubMedCrossRef
28.
29.
Brown JC, Pederson RA, Jorpes E, Mutt V. Preparation of highly active enterogastrone. Can J Physiol Pharmacol. 1969;47(1):113–4.PubMedCrossRef
30.
Dupre J, Ross SA, Watson D, Brown JC. Stimulation of insulin secretion by gastric inhibitory polypeptide in man. J Clin Endocrinol Metab. 1973;37(5):826–8.PubMedCrossRef
31.
Meier JJ, Goetze O, Anstipp J, et al. Gastric inhibitory polypeptide does not inhibit gastric emptying in humans. Am J Physiol Endocrinol Metab. 2004;286(4):E621–5.PubMedCrossRef
32.
Nauck MA, Bartels E, Orskov C, Ebert R, Creutzfeldt W. Lack of effect of synthetic human gastric inhibitory polypeptide and glucagon-like peptide 1 [7-36 amide] infused at near-physiological concentrations on pentagastrin-stimulated gastric acid secretion in normal human subjects. Digestion. 1992;52(3–4):214–21.PubMedCrossRef
33.
Christensen M, Vedtofte L, Holst JJ, Vilsbøll T, Knop FK. Glucose-dependent insulinotropic polypeptide: a bifunctional glucose-dependent regulator of glucagon and insulin secretion in humans. Diabetes. 2011;60(12):3103–9.PubMedPubMedCentralCrossRef
34.
Kim SJ, Nian C, McIntosh CHS. Activation of lipoprotein lipase by glucose-dependent insulinotropic polypeptide in adipocytes. A role for a protein kinase B, LKB1, and AMP-activated protein kinase cascade. J Biol Chem. 2007;282(12):8557–67.PubMedCrossRef
35.
Kim SJ, Nian C, McIntosh CHS. Resistin is a key mediator of glucose-dependent insulinotropic polypeptide (GIP) stimulation of lipoprotein lipase (LPL) activity in adipocytes. J Biol Chem. 2007;282(47):34139–47.PubMedCrossRef
36.
Kim SJ, Nian C, McIntosh CHS. GIP increases human adipocyte LPL expression through CREB and TORC2-mediated trans-activation of the LPL gene. J Lipid Res. 2010;51(11):3145–57.PubMedPubMedCentralCrossRef
37.
Ebert R, Creutzfeldt W. Metabolic effects of gastric inhibitory polypeptide. In: Blazquez E, editor. Gut regulatory peptides: their role in health and disease. Berlin: S. Karger AG; 1988.
38.
McIntosh CH, Bremsak I, Lynn FC, et al. Glucose-dependent insulinotropic polypeptide stimulation of lipolysis in differentiated 3T3-L1 cells: wortmannin-sensitive inhibition by insulin. Endocrinology. 1999;140(1):398–404.PubMedCrossRef
39.
Heimburger SMN, Nielsen CN, Calanna S, et al. Glucose-dependent insulinotropic polypeptide induces lipolysis during stable basal insulin substitution and hyperglycaemia in men with type 1 diabetes: a randomized, double-blind, placebo-controlled, crossover clinical trial. Diabetes Obes Metab. 2022;24(1):142–7.PubMedCrossRef
40.
Xie D, Zhong Q, Ding KH, et al. Glucose-dependent insulinotropic peptide-overexpressing transgenic mice have increased bone mass. Bone. 2007;40(5):1352–60.PubMedCrossRef
41.
Sachs S, Götz A, Finan B, et al. GIP receptor agonism improves dyslipidemia and atherosclerosis independently of body weight loss in preclinical mouse model for cardio-metabolic disease. Cardiovasc Diabetol. 2023;22(1):217.PubMedPubMedCentralCrossRef
42.
Nagashima M, Watanabe T, Terasaki M, et al. Native incretins prevent the development of atherosclerotic lesions in apolipoprotein E knockout mice. Diabetologia. 2011;54(10):2649–59.PubMedPubMedCentralCrossRef
43.
Nogi Y, Nagashima M, Terasaki M, Nohtomi K, Watanabe T, Hirano T. Glucose-dependent insulinotropic polypeptide prevents the progression of macrophage-driven atherosclerosis in diabetic apolipoprotein E-null mice. PLoS ONE. 2012;7(4):e35683.PubMedPubMedCentralCrossRef
44.
Ji C, Xue GF, Li G, Li D, Hölscher C. Neuroprotective effects of glucose-dependent insulinotropic polypeptide in Alzheimer’s disease. Rev Neurosci. 2016;27(1):61–70.PubMedCrossRef
45.
Holscher C. Incretin analogues that have been developed to treat type 2 diabetes hold promise as a novel treatment strategy for Alzheimer’s disease. Recent Patents CNS Drug Discov. 2010;5(2):109–17.CrossRef
46.
Zhang Q, Delessa CT, Augustin R, et al. The glucose-dependent insulinotropic polypeptide (GIP) regulates body weight and food intake via CNS-GIPR signaling. Cell Metab. 2021;33(4):833-844.e5.PubMedPubMedCentralCrossRef
47.
Liskiewicz A, Khalil A, Liskiewicz D, et al. Glucose-dependent insulinotropic polypeptide regulates body weight and food intake via GABAergic neurons in mice. Nat Metab. 2023;5(12):2075–85.PubMedPubMedCentralCrossRef
48.
Lund PK, Goodman RH, Habener JF. Pancreatic pre-proglucagons are encoded by two separate mRNAs. J Biol Chem. 1981;256(13):6515–8.PubMedCrossRef
49.
Lund PK, Goodman RH, Dee PC, Habener JF. Pancreatic preproglucagon cDNA contains two glucagon-related coding sequences arranged in tandem. Proc Natl Acad Sci. 1982;79(2):345–9.PubMedPubMedCentralCrossRef
50.
Lund PK, Goodman RH, Montminy MR, Dee PC, Habener JF. Anglerfish islet pre-proglucagon II: nucleotide and corresponding amino acid sequence of the cDNA. J Biol Chem. 1983;258(5):3280–4.PubMedCrossRef
51.
Kreymann B, Williams G, Ghatei MA, Bloom SR. Glucagon-like peptide-1 7–36: a physiological incretin in man. Lancet. 1987;2(8571):1300–4.PubMedCrossRef
52.
53.
Adriaenssens AE, Biggs EK, Darwish T, et al. Glucose-dependent insulinotropic polypeptide receptor-expressing cells in the hypothalamus regulate food intake. Cell Metab. 2019;30(5):987–96.e6.PubMedPubMedCentralCrossRef
54.
Dowsett GKC, Lam BYH, Tadross JA, et al. A survey of the mouse hindbrain in the fed and fasted states using single-nucleus RNA sequencing. Mol Metab. 2021;53:101240.PubMedPubMedCentralCrossRef
55.
Steuernagel L, Lam BYH, Klemm P, et al. HypoMap—a unified single-cell gene expression atlas of the murine hypothalamus. Nat Metab. 2022;4(10):1402–19.PubMedPubMedCentralCrossRef
56.
Campbell JE, Drucker DJ. Pharmacology, physiology, and mechanisms of incretin hormone action. Cell Metab. 2013;17(6):819–37.PubMedCrossRef
57.
Deacon CF, Johnsen AH, Holst JJ. Degradation of glucagon-like peptide-1 by human plasma in vitro yields an N-terminally truncated peptide that is a major endogenous metabolite in vivo. J Clin Endocrinol Metab. 1995;80(3):952–7.PubMed
58.
Kieffer TJ, McIntosh CH, Pederson RA. Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV. Endocrinology. 1995;136(8):3585–96.PubMedCrossRef
59.
Mentlein R, Gallwitz B, Schmidt WE. Dipeptidyl-peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon-like peptide-1(7–36)amide, peptide histidine methionine and is responsible for their degradation in human serum. Eur J Biochem. 1993;214(3):829–35.PubMedCrossRef
60.
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(11):7402–5.PubMedCrossRef
61.
Gedulin BR, Nikoulina SE, Smith PA, et al. Exenatide (exendin-4) improves insulin sensitivity and {beta}-cell mass in insulin-resistant obese fa/fa Zucker rats independent of glycemia and body weight. Endocrinology. 2005;146(4):2069–76.PubMedCrossRef
62.
Göke R, Fehmann HC, Linn T, et al. Exendin-4 is a high potency agonist and truncated exendin-(9–39)-amide an antagonist at the glucagon-like peptide 1-(7–36)-amide receptor of insulin-secreting beta-cells. J Biol Chem. 1993;268(26):19650–5.PubMedCrossRef
63.
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;28(5):1083–91.PubMedCrossRef
64.
Pi-Sunyer X, Astrup A, Fujioka K, et al. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N Engl J Med. 2015;373(1):11–22.PubMedCrossRef
65.
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):1447–56.PubMedCrossRef
66.
Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834–44.PubMedCrossRef
67.
Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021;384(11):989–1002.PubMedCrossRef
68.
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;35(6):1225–31.PubMedPubMedCentralCrossRef
69.
Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373(23):2247–57.PubMedCrossRef
70.
71.
Holman RR, Bethel MA, Mentz RJ, et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2017;377(13):1228–39.PubMedPubMedCentralCrossRef
72.
Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. 2019;394(10193):121–30.PubMedCrossRef
73.
Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med. 2023;389:2221–32.PubMedCrossRef
74.
Del Prato S, Kang J, Trautmann ME, et al. Efficacy and safety of once-monthly efpeglenatide in patients with type 2 diabetes: results of a phase 2 placebo-controlled, 16-week randomized dose-finding study. Diabetes Obes Metab. 2020;22(7):1176–86.PubMedPubMedCentralCrossRef
75.
Gerstein HC, Sattar N, Rosenstock J, et al. Cardiovascular and renal outcomes with efpeglenatide in type 2 diabetes. N Engl J Med. 2021;385(10):896–907.PubMedCrossRef
76.
Knop FK, Aroda VR, do Vale RD, et al. Oral semaglutide 50 mg taken once per day in adults with overweight or obesity (OASIS 1): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2023;402(10403):705–19.PubMedCrossRef
77.
Buchwald H, Estok R, Fahrbach K, et al. Weight and type 2 diabetes after bariatric surgery: systematic review and meta-analysis. Am J Med. 2009;122(3):248–56.e5.PubMedCrossRef
78.
Chang SH, Stoll CRT, Song J, Varela JE, Eagon CJ, Colditz GA. The effectiveness and risks of bariatric surgery: an updated systematic review and meta-analysis, 2003–2012. JAMA Surg. 2014;149(3):275–87.PubMedPubMedCentralCrossRef
79.
Arterburn DE, Telem DA, Kushner RF, Courcoulas AP. Benefits and risks of bariatric surgery in adults: a review. JAMA. 2020;324(9):879–87.PubMedCrossRef
80.
Bomholt AB, Johansen CD, Christensen JB, et al. Evaluation of commercially available glucagon receptor antibodies and glucagon receptor expression. Commun Biol. 2022;5(1):1–13.CrossRef
81.
Day JW, Ottaway N, Patterson JT, et al. A new glucagon and GLP-1 co-agonist eliminates obesity in rodents. Nat Chem Biol. 2009;5(10):749–57.PubMedCrossRef
82.
Nahra R, Wang T, Gadde KM, et al. Effects of cotadutide on metabolic and hepatic parameters in adults with overweight or obesity and type 2 diabetes: a 54-week randomized phase 2b study. Diabetes Care. 2021;44(6):1433–42.PubMedPubMedCentralCrossRef
83.
le Roux CW, Steen O, Lucas KJ, Startseva E, Unseld A, Hennige AM. A phase 2, randomized, double-blind, placebo-controlled, dose-finding study of BI 456906 in people with overweight/obesity, San Diego, CA, USA; 2023 (51-OR).
84.
Ji L, Gao L, Jiang H, et al. Safety and efficacy of a GLP-1 and glucagon receptor dual agonist mazdutide (IBI362) 9 mg and 10 mg in Chinese adults with overweight or obesity: a randomised, placebo-controlled, multiple-ascending-dose phase 1b trial. EClinicalMedicine. 2022;54:101691.PubMedPubMedCentralCrossRef
85.
Campbell JE. Targeting the GIPR for obesity: to agonize or antagonize? Potential mechanisms. Mol Metab. 2021;46:101139.PubMedCrossRef
86.
Mroz PA, Finan B, Gelfanov V, et al. Optimized GIP analogs promote body weight lowering in mice through GIPR agonism not antagonism. Mol Metab. 2019;20:51–62.PubMedCrossRef
87.
Sparre-Ulrich AH, Hansen LS, Svendsen B, et al. Species-specific action of (Pro3)GIP—a full agonist at human GIP receptors, but a partial agonist and competitive antagonist at rat and mouse GIP receptors. Br J Pharmacol. 2016;173(1):27–38.PubMedCrossRef
88.
Ji L, Gao L, Jiang H, et al. Safety and efficacy of a GLP-1 and glucagon receptor dual agonist mazdutide (IBI362) 9 mg and 10 mg in Chinese adults with overweight or obesity: a randomised, placebo-controlled, multiple-ascending-dose phase 1b trial. EClinicalMedicine. 2022;54:101691.PubMedPubMedCentralCrossRef
89.
90.
Frias JP, Bastyr EJ, Vignati L, et al. The sustained effects of a dual GIP/GLP-1 receptor agonist, NNC0090-2746, in patients with type 2 diabetes. Cell Metab. 2017;26(2):343–52.e2.PubMedCrossRef
91.
Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022;387(3):205–16.PubMedCrossRef
92.
Garvey WT, Frias JP, Jastreboff AM, et al. Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2023;402(10402):613–26.PubMedCrossRef
93.
Dahl D, Onishi Y, Norwood P, et al. Effect of subcutaneous tirzepatide vs placebo added to titrated insulin glargine on glycemic control in patients with type 2 diabetes: the SURPASS-5 randomized clinical trial. JAMA. 2022;327(6):534–45.PubMedPubMedCentralCrossRef
94.
Del Prato S, Kahn SE, Pavo I, et al. Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase 3 trial. Lancet. 2021;398(10313):1811–24.CrossRef
95.
Ludvik B, Giorgino F, Jódar E, 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): a randomised, open-label, parallel-group, phase 3 trial. Lancet Lond Engl. 2021;398(10300):583–98.CrossRef
96.
Rosenstock J, Wysham C, Frías JP, et al. Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial. Lancet. 2021;398(10295):143–55.PubMedCrossRef
97.
Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med. 2021;385(6):503–15.PubMedCrossRef
98.
Borner T, Geisler CE, Fortin SM, et al. GIP receptor agonism attenuates GLP-1 receptor agonist-induced nausea and emesis in preclinical models. Diabetes. 2021;70(11):2545–53.PubMedPubMedCentralCrossRef
99.
Finan B, Yang B, Ottaway N, et al. A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents. Nat Med. 2015;21(1):27–36.PubMedCrossRef
100.
101.
Abdelmalek MF, Suzuki A, Sanchez W, et al. A phase 2, adaptive randomized, double-blind, placebo-controlled, multicenter, 52-week study of HM15211 in patients with biopsy-confirmed non-alcoholic steatohepatitis—study design and rationale of HM-TRIA-201 study. Contemp Clin Trials. 2023;130:107176.PubMedCrossRef
102.
Jastreboff AM, Kaplan LM, Frías JP, et al. Triple-hormone-receptor agonist retatrutide for obesity—a phase 2 trial. N Engl J Med. 2023;389(6):514–26.PubMedCrossRef
103.
Rosenstock J, Frias J, Jastreboff AM, 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 conducted in the USA. Lancet. 2023;402(10401):529–44.PubMedCrossRef
104.
105.
Campbell JE, Müller TD, Finan B, DiMarchi RD, Tschöp MH, D’Alessio DA. GIPR/GLP-1R dual agonist therapies for diabetes and weight loss—chemistry, physiology, and clinical applications. Cell Metab. 2023;35(9):1519–29.PubMedCrossRef
106.
Hammoud R, Drucker DJ. Beyond the pancreas: contrasting cardiometabolic actions of GIP and GLP1. Nat Rev Endocrinol. 2023;19(4):201–16.PubMedCrossRef
107.
Nogueiras R, Nauck MA, Tschöp MH. Gut hormone co-agonists for the treatment of obesity: from bench to bedside. Nat Metab. 2023;5(6):933–44.PubMedCrossRef
108.
El K, Douros JD, Willard FS, et al. The incretin co-agonist tirzepatide requires GIPR for hormone secretion from human islets. Nat Metab. 2023;5(6):945–54.PubMedPubMedCentralCrossRef
109.
Décarie-Spain L, Fisette A, Zhu Z, et al. GLP-1/dexamethasone inhibits food reward without inducing mood and memory deficits in mice. Neuropharmacology. 2019;151:55–63.PubMedCrossRef
110.
Wilding JPH, Batterham RL, Davies M, et al. Weight regain and cardiometabolic effects after withdrawal of semaglutide: the STEP 1 trial extension. Diabetes Obes Metab. 2022;24(8):1553–64.PubMedPubMedCentralCrossRef
111.
Sargeant JA, Henson J, King JA, Yates T, Khunti K, Davies MJ. A review of the effects of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors on lean body mass in humans. Endocrinol Metab (Seoul). 2019;34(3):247–62.PubMedCrossRef
112.
Li R, Xia J, Zhang X, et al. Associations of muscle mass and strength with all-cause mortality among US older adults. Med Sci Sports Exerc. 2018;50(3):458–67.PubMedPubMedCentralCrossRef
113.
Ji L, Jiang H, Cheng Z, et al. A phase 2 randomised controlled trial of mazdutide in Chinese overweight adults or adults with obesity. Nat Commun. 2023;14(1):8289.PubMedPubMedCentralCrossRef
114.
115.
Romero-Gómez M, Lawitz E, Shankar RR, et al. A phase IIa active-comparator-controlled study to evaluate the efficacy and safety of efinopegdutide in patients with non-alcoholic fatty liver disease. J Hepatol. 2023;79(4):888–97.PubMedCrossRef
116.
Palani A, Nawrocki AR, Orvieto F, et al. Discovery of MK-1462: GLP-1 and glucagon receptor dual agonist for the treatment of obesity and diabetes. ACS Med Chem Lett. 2022;13(8):1248–54.PubMedPubMedCentralCrossRef
117.
Zhao F, Zhou Q, Cong Z, et al. Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors. Nat Commun. 2022;13(1):1057.PubMedPubMedCentralCrossRef
Metadata
Title
Dual and Triple Incretin-Based Co-agonists: Novel Therapeutics for Obesity and Diabetes
Authors
Robert M. Gutgesell
Rubén Nogueiras
Matthias H. Tschöp
Timo D. Müller
Publication date
04-04-2024
Publisher
Springer Healthcare
Keywords
Obesity
Obesity
Published in
Diabetes Therapy / Issue 5/2024
Print ISSN: 1869-6953
Electronic ISSN: 1869-6961
DOI
https://doi.org/10.1007/s13300-024-01566-x

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Keynote webinar | Spotlight on medication adherence

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Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

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A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine
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