The importance of glucose-dependent insulinotropic polypeptide receptor activation for the effects of tirzepatide.
GIP
GLP-1
antidiabetic drug
antiobesity drug
insulin secretion
pharmacodynamics
Journal
Diabetes, obesity & metabolism
ISSN: 1463-1326
Titre abrégé: Diabetes Obes Metab
Pays: England
ID NLM: 100883645
Informations de publication
Date de publication:
11 2023
11 2023
Historique:
revised:
22
06
2023
received:
01
05
2023
accepted:
02
07
2023
medline:
4
10
2023
pubmed:
8
8
2023
entrez:
8
8
2023
Statut:
ppublish
Résumé
Tirzepatide is a unimolecular co-agonist of the glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors recently approved for the treatment of type 2 diabetes by the US Food and Drug Administration and the European Medicine Agency. Tirzepatide treatment results in an unprecedented improvement of glycaemic control and lowering of body weight, but the contribution of the GIP receptor-activating component of tirzepatide to these effects is uncertain. In this review, we present the current knowledge about the physiological roles of the incretin hormones GLP-1 and GIP, their receptors, and previous results of co-targeting the two incretin hormone receptors in humans. We also analyse the molecular pharmacological, preclinical and clinical effects of tirzepatide to discuss the role of GIP receptor activation for the clinical effects of tirzepatide. Based on the available literature on the combination of GLP-1 and GIP receptor activation, tirzepatide does not seem to have a classical co-activating mode of action in humans. Rather, in vitro studies of the human GLP-1 and GIP receptors reveal a biased GLP-1 receptor activation profile and GIP receptor downregulation. Therefore, we propose three hypotheses for the mode of action of tirzepatide, which can be addressed in future, elaborate clinical trials.
Substances chimiques
tirzepatide
OYN3CCI6QE
gastric inhibitory polypeptide receptor
D6H00MV7K8
Incretins
0
Glucagon
9007-92-5
Blood Glucose
0
Gastric Inhibitory Polypeptide
59392-49-3
Glucagon-Like Peptide 1
89750-14-1
Glucagon-Like Peptide-1 Receptor
0
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
3079-3092Informations de copyright
© 2023 John Wiley & Sons Ltd.
Références
Dupre J, Ross SA, Watson D, Brown JC. Stimulation of insulin secretion by gastric inhibitory polypeptide in man. J Clin Endocrinol Metab. 1973;37:826-828.
Kreymann B, Ghatei MA, Williams G, Bloom SR. Glucagon-like Peptide-1 7-36: a physiological incretin in man. Lancet. 1987;330(8571):1300-1304.
Gasbjerg LS, Helsted MM, Hartmann B, et al. Separate and combined glucometabolic effects of endogenous glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 in healthy individuals. Diabetes. 2019;68(5):906-917.
Nauck MA, Kleine N, Ørskov C, Hoist 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;36:741-744.
Nauck MA, Heimesaat MM, Orskov C, Holst JJ, Ebert R, Creutzfeldt W. Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Invest. 1993;91(1):301-307.
Vilsbøll T, Knop FK, Krarup T, et al. The pathophysiology of diabetes involves a defective amplification of the late-phase insulin response to glucose by glucose-dependent insulinotropic polypeptide-regardless of etiology and phenotype. J Clin Endocrinol Metab. 2003;88(10):4897-4903.
Chia CW, Carlson OD, Kim W, et al. Exogenous glucose-dependent insulinotropic polypeptide worsens postprandial hyperglycemia in type 2 diabetes. Diabetes. 2009;58(6):1342-1349.
Miyawaki K, Yamada Y, Ban N, et al. Inhibition of gastric inhibitory polypeptide signaling prevents obesity. Nat Med. 2002;8(7):738-742.
Nauck MA, Meier JJ. Incretin hormones: their role in health and disease. Diabetes Obes Metab. 2018;20(October 2017):5-21.
Giugliano D, Scappaticcio L, Longo M, et al. GLP-1 receptor agonists and cardiorenal outcomes in type 2 diabetes: an updated meta-analysis of eight CVOTs. Cardiovasc Diabetol. 2021;20(1):1-11.
Sattar N, Lee MMY, Kristensen SL, 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.
Femminella GD, Frangou E, Love SB, et al. Evaluating the effects of the novel GLP-1 analogue liraglutide in Alzheimer's disease: study protocol for a randomised controlled trial (ELAD study). Trials. 2019;20(1):1-10.
Newsome PN, Buchholtz K, Cusi K, et al. A placebo-controlled trial of subcutaneous Semaglutide in nonalcoholic steatohepatitis. N Engl J Med. 2021;384(12):1113-1124.
Tadic M, Sala C, Saeed S, et al. New antidiabetic therapy and HFpEF: light at the end of tunnel? Heart Fail Rev. 2022;27(4):1137-1146.
Kårhus ML, Brønden A, Forman JL, et al. Safety and efficacy of liraglutide versus colesevelam for the treatment of bile acid diarrhoea: a randomised, double-blind, active-comparator, non-inferiority clinical trial. Lancet Gastroenterol Hepatol. 2022;7(10):922-931.
Willard FS, Douros JD, Gabe MB, et al. Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. JCI Insight. 2020;5(17):1-16.
Frias JP, Nauck MA, Van J, 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.
Frias JP, Nauck MA, Van J, 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 do. Diabetes Obes Metab. 2020;22(6):938-946.
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 (London, England). 2021;398(10295):143-155.
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):503-515.
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 (London, England). 2021;398(10300):583-598.
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):1811-1824.
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-J Am Med Assoc. 2022;327(6):534-545.
Inagaki N, Takeuchi M, Oura T, Imaoka T, Seino Y. Efficacy and safety of tirzepatide monotherapy compared with dulaglutide in Japanese patients with type 2 diabetes (SURPASS J-mono): a double-blind, multicentre, randomised, phase 3 trial. Lancet Diabetes Endocrinol. 2022;10(9):623-633.
Kadowaki T, Chin R, Ozeki A, Imaoka T, Ogawa Y. Safety and efficacy of tirzepatide as an add-on to single oral antihyperglycaemic medication in patients with type 2 diabetes in Japan (SURPASS J-combo): a multicentre, randomised, open-label, parallel-group, phase 3 trial. Lancet Diabetes Endocrinol. 2022;10(9):634-644.
Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022;387(3):205-216.
Heise T, Mari A, DeVries JH, et al. Effects of subcutaneous tirzepatide versus placebo or semaglutide on pancreatic islet function and insulin sensitivity in adults with type 2 diabetes: a multicentre, randomised, double-blind, parallel-arm, phase 1 clinical trial. Lancet Diabetes Endocrinol. 2022 Jun 1;10(6):418-429.
Sattar N, McGuire DK, Pavo I, et al. Tirzepatide cardiovascular event risk assessment: a pre-specified meta-analysis. Nat Med. 2022;28(3):591-598.
Jorsal T, Rhee NA, Pedersen J, et al. Enteroendocrine K and L cells in healthy and type 2 diabetic individuals. Diabetologia. 2018;61(2):284-294.
Deacon CF. Circulation and degradation of GIP and GLP-1. Horm Metab Res. 2004;36(11-12):761-765.
Nauck MA, Bartels E, Ørskov 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.
Gasbjerg LS, Helsted MM, Hartmann B, et al. GIP and GLP-1 receptor antagonism during a meal in healthy individuals. J Clin Endocrinol Metab. 2020;105(3):1-14.
Elahi D, McAloon-Dyke M, Fukagawa NK, et al. The insulinotropic actions of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (7-37) in normal and diabetic subjects. Regul Pept. 1994;51(1):63-74.
Daousi C, Wilding JPH, Aditya S, et al. Effects of peripheral administration of synthetic human glucose-dependent insulinotropic peptide (GIP) on energy expenditure and subjective appetite sensations in healthy normal weight subjects and obese patients with type 2 diabetes. Clin Endocrinol (Oxf). 2009;71(2):195-201.
Lund A, Vilsbøll T, Bagger JI, Holst JJ, Knop FK. The separate and combined impact of the intestinal hormones, GIP, GLP-1, and GLP-2, on glucagon secretion in type 2 diabetes. Am J Physiol Endocrinol Metab. 2011;300(6):E1038-E1046.
Mentis N, Vardarli I, Köthe LD, et al. GIP does not potentiate the antidiabetic effects of GLP-1 in hyperglycemic patients with type 2 diabetes. Diabetes. 2011;60(4):1270-1276.
Holst JJ. The incretin system in healthy humans: the role of GIP and GLP-1. Metabolism. 2019;96:46-55.
Wettergren A, Wøjdemann M, Holst JJ. Glucagon-like peptide-1 inhibits gastropancreatic function by inhibiting central parasympathetic outflow. Am J Physiol-Gastrointest Liver Physiol. 1998;275(5):984-992.
Bremholm L, Andersen UB, Hornum M, et al. Acute effects of glucagon-like peptide-1, GLP-19-36 amide, and exenatide on mesenteric blood flow, cardiovascular parameters, and biomarkers in healthy volunteers. Physiol Rep. 2017;5(4):1-12.
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):3103-3109.
Torekov SS, Harsløf T, Rejnmark L, et al. A functional amino acid substitution in the glucose-dependent insulinotropic polypeptide receptor (GIPR) gene is associated with lower bone mineral density and increased fracture risk. J Clin Endocrinol Metab. 2014;99(4):729-733.
Kizilkaya HS, Sørensen KV, Kibsgaard CJ, et al. Loss of function glucose-dependent insulinotropic polypeptide receptor variants are associated with alterations in BMI, bone strength and cardiovascular outcomes. Front Cell Dev Biol. 2021;9:1-12.
Helsted MM, Gasbjerg LS, Lanng AR, et al. The role of endogenous GIP and GLP-1 in postprandial bone homeostasis. Bone. 2020;140:1-7.
Skov-Jeppesen K, Hepp N, Oeke J, et al. The antiresorptive effect of GIP, but not GLP-2, is preserved in patients with hypoparathyroidism-a randomized crossover study. J Bone Miner Res. 2021;36(8):1448-1458.
Asmar M, Asmar A, Simonsen L, et al. The gluco- and liporegulatory and the vasodilatory effects of glucose-dependent insulinotropic polypeptide (GIP) are abolished by an antagonist of the human GIP receptor. Diabetes. 2017;66(9):2363-2371.
Koffert J, Honka H, Teuho J, et al. Effects of meal and incretins in the regulation of splanchnic blood flow. Endocr Connect. 2017;6(3):179-187.
Wice BM, Reeds DN, Tran HD, et al. Xenin-25 amplifies GIP-mediated insulin secretion in humans with normal and impaired glucose tolerance but not type 2 diabetes. Diabetes. 2012;61(7):1793-1800.
Fredriksson R, Lagerström MC, Lundin L-G, Schiöth HB. The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol Pharmacol. 2003;63(6):1256-1272.
Gabe MBN, van der Velden WJC, Smit FX, Gasbjerg LS, Rosenkilde MM. Molecular interactions of full-length and truncated GIP peptides with the GIP receptor-a comprehensive review. Peptides. 2020;125:1-8.
Mayendraraj A, Rosenkilde MM, Gasbjerg LS. GLP-1 and GIP receptor signaling in beta cells-a review of receptor interactions and co-stimulation. Peptides. 2022;151:1-10.
Yuliantie E, Darbalaei S, Dai A, et al. Pharmacological characterization of mono-, dual- and tri-peptidic agonists at GIP and GLP-1 receptors. Biochem Pharmacol. 2020;177:1-13.
Gabe MBN, Sparre-Ulrich AH, Pedersen MF, et al. Human GIP(3-30)NH2 inhibits G protein-dependent as well as G protein-independent signaling and is selective for the GIP receptor with high-affinity binding to primate but not rodent GIP receptors. Biochem Pharmacol. 2018;150:97-107.
Hilger D, Masureel M, Kobilka BK. Structure and dynamics of GPCR signaling complexes. Nat Struct Mol Biol. 2018;25(1):4-12.
Waldhoer M, Casarosa P, Rosenkilde MM, et al. The carboxyl terminus of human cytomegalovirus-encoded 7 transmembrane receptor US28 camouflages agonism by mediating constitutive endocytosis. J Biol Chem. 2003;278(21):19473-19482.
Mohammad S, Patel RT, Bruno J, Siyab M, Wen J, Mcgraw TE. A naturally occurring GIP receptor variant undergoes enhanced agonist-induced desensitization, which impairs GIP control of adipose insulin sensitivity. Mol Cell Biol. 2014;34(19):3618-3629.
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.
Samms RJ, Zhang GF, He W, et al. Tirzepatide induces a thermogenic-like amino acid signature in brown adipose tissue. Mol Metab. 2022;64:1-6.
Killion EA, Chen M, Falsey JR, et al. Chronic glucose-dependent insulinotropic polypeptide receptor (GIPR) agonism desensitizes adipocyte GIPR activity mimicking functional GIPR antagonism. Nat Commun. 2020;11(1):1-17.
Ussher JR, Campbell JE, Mulvihill EE, et al. Inactivation of the glucose-dependent insulinotropic polypeptide receptor improves outcomes following experimental myocardial infarction. Cell Metab. 2017;27(2):450-460.
Samms RJ, Cosgrove R, Snider BM, et al. GIPR agonism inhibits PYY-induced nausea-like behavior. Diabetes. 2022;71(7):1410-1423.
Bergmann NC, Lund A, Gasbjerg LS, et al. Effects of combined GIP and GLP-1 infusion on energy intake, appetite and energy expenditure in overweight/obese individuals: a randomised, crossover study. Diabetologia. 2019;62(4):665-675.
Edholm T, Degerblad M, Grybäck P, et al. Differential incretin effects of GIP and GLP-1 on gastric emptying, appetite, and insulin-glucose homeostasis. Neurogastroenterol Motil. 2010;22(11):1191-1201.
El K, Douros JD, Willard FS, et al. The incretin co-agonist tirzepatide requires GIPR for hormone secretion from human islets. Nat Metab. 2023;June 5:1-17.
Bergmann NC, Davies MJ, Lingvay I, Knop FK. Semaglutide for the treatment of overweight and obesity: a review. Diabetes, Obesity and Metabolism. Vol 25. John Wiley & Sons, Ltd; 2022:18-35.
Heimbürger SMN, Hoe B, Nielsen CN, et al. The effect of 6-day subcutaneous glucose-dependent insulinotropic polypeptide infusion on time in glycaemic range in patients with type 1 diabetes: a randomised, double-blind, placebo-controlled crossover trial. Diabetologia. 2021;64(11):2425-2431.
Heimbürger SMN, Hoe B, Nielsen CN, et al. GIP affects hepatic fat and brown adipose tissue thermogenesis, but not white adipose tissue transcriptome in T1D. J Clin Endocrinol Metab. 2022;107(12):3261-3274.
NovoNordisk. Financial Report for 1 January 2023 to 31 March 2023. Co Announc; 2023;(May 2023):1-29.
Knop FK, Urva S, Rettiganti M, et al. A long-acting glucose-dependent insulinotropic polypeptide receptor agonist shows weight loss without nausea or vomiting. Diabetes. 2023;72(S1):56-OR.
Aulinger BA, Bedorf A, Kutscherauer G, et al. Defining the role of GLP-1 in the enteroinsulinar axis in type 2 diabetes using DPP-4 inhibition and glp-1 receptor blockade. Diabetes. 2014;63(3):1079-1092.
Stensen S, Gasbjerg LS, Rosenkilde MM, et al. Endogenous glucose-dependent insulinotropic polypeptide contributes to sitagliptin-mediated improvement in β-cell function in patients with type 2 diabetes. Diabetes. 2022;71(10):2209-2221.
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;46:1-26.
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;359:824-830.
Nauck MA, Heimesaat MM, Ørskov C, Holst JJ, Ebert R, Creutzfeldt W. Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. JClinInvest. 1993;91:301-307.
Vilsbøll T, Krarup T, Madsbad S, Holst J. Defective amplification of the late phase insulin response to glucose by GIP in obese type II diabetic patients. Diabetologia. 2002;45(8):1111-1119.
Meier JJ, Hucking K, Holst JJ, Deacon CF, Schmiegel WH, Nauck MA. Reduced insulinotropic effect of gastric inhibitory polypeptide in first-degree relatives of patients with type 2 diabetes. Diabetes. 2001;50(11):2497-2504.
Højberg PV, Vilsbøll T, Rabøl R, et al. Four weeks of near-normalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes. Diabetologia. 2009;52(2):199-207.
Hoe B, Lynggaard MB, Gasbjerg LS, et al. Improved glycemic control in patients with type 2 diabetes improves beta cell actions of endogenous glucose-dependent insulinotropic polypeptide. Diabetes. 2022;71(Supplement 1):1.
Bergmann NC, Gasbjerg LS, Heimbürger SM, et al. No acute effects of exogenous glucose-dependent insulinotropic polypeptide on energy intake, appetite, or energy expenditure when added to treatment with a Long-acting glucagon-like peptide 1 receptor agonist in men with type 2 diabetes. Diabetes Care. 2020;43(3):588-596.
Shah M, Vella A. Effects of GLP-1 on appetite and weight. Rev Endocr Metab Disord. 2014;15(3):181-187.
Adriaenssens AE, Gribble FM, Reimann F. The glucose-dependent insulinotropic polypeptide signaling axis in the central nervous system. Peptides. 2020;125(November 2019):170-194.
Thondam SK, Daousi C, Wilding JPHH, et al. Glucose-dependent insulinotropic polypeptide promotes lipid deposition in subcutaneous adipocytes in obese type 2 diabetes patients : a maladaptive response. Am J Physiol-Endocrinol Metab. 2017;312:224-233.
Wu T, Ma J, Bound MJ, et al. Effects of sitagliptin on glycemia, incretin hormones, and antropyloroduodenal motility in response to intraduodenal glucose infusion in healthy lean and obese humans and patients with type 2 diabetes treated with or without metformin. Diabetes. 2014;63(8):2776-2787.
Stensen S, Gasbjerg LS, Krogh LL, et al. Effects of endogenous GIP in patients with type 2 diabetes. Eur J Endocrinol. 2021;185(1):33-45.
Møller CL, Vistisen D, Faerch K, et al. Glucose-dependent insulinotropic polypeptide is associated with lower low-density lipoprotein but unhealthy fat distribution, independent of insulin: the addition-pro study. J Clin Endocrinol Metab. 2016;101(2):485-493.
Meier JJ, Nauck MA. Glucose-dependent insulinotropic polypeptide/gastric inhibitory polypeptide. Best Pract Res Clin Endocrinol Metab. 2004;18(4):587-606.
Carbone LJ, Angus PW, Yeomans ND. Incretin-based therapies for the treatment of non-alcoholic fatty liver disease: a systematic review and meta-analysis. J Gastroenterol Hepatol. 2016;31(1):23-31.
Sun F, Wu S, Guo S, et al. Impact of GLP-1 receptor agonists on blood pressure, heart rate and hypertension among patients with type 2 diabetes: a systematic review and network meta-analysis. Diabetes Res Clin Pract. 2015;110(1):26-37.
Baggio LL, Yusta B, Mulvihill EE, et al. GLP-1 receptor expression within the human heart. Endocrinology. 2018;159(4):1570-1584.
Kanie T, Mizuno A, Takaoka Y, et al. Dipeptidyl peptidase-4 inhibitors, glucagon-like peptide 1 receptor agonists and sodium-glucose co-transporter-2 inhibitors for people with cardiovascular disease: a network meta-analysis. Cochrane Database Syst Rev. 2021;10(10):1-175.
Bray JJH, Foster-Davies H, Salem A, et al. Glucagon-like peptide-1 receptor agonists improve biomarkers of inflammation and oxidative stress: a systematic review and meta-analysis of randomised controlled trials. Diabetes Obes Metab. 2021;23(8):1806-1822.
Góralska J, Raźny U, Polus A, et al. Pro-inflammatory gene expression profile in obese adults with high plasma GIP levels. Int J Obes (Lond). 2018;42(4):826-834.
Gögebakan Ö, Osterhoff MA, Schüler R, et al. GIP increases adipose tissue expression and blood levels of MCP-1 in humans and links high energy diets to inflammation: a randomised trial. Diabetologia. 2015;58:1759-1768.
Ahlqvist E, Osmark P, Kuulasmaa T, et al. Link between GIP and osteopontin in adipose tissue and insulin resistance. Diabetes. 2013;62(6):2088-2094.
Breier NC, Paranjape SY, Scudder S, et al. Worsening postural tachycardia syndrome is associated with increased glucose-dependent insulinotropic polypeptide secretion. Hypertension. 2022;79(5):e89-e99.
Brandt SJ, Götz A, Tschöp MH, Müller TD. Gut hormone polyagonists for the treatment of type 2 diabetes. Peptides. 2018;100:190-201.
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):343-352.
Coskun T, Sloop KW, Loghin C, et al. LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: from discovery to clinical proof of concept. Mol Metab. 2018;18:3-14.
Knerr PJ, Mowery SA, Douros JD, et al. Next generation GLP-1/GIP/glucagon triple agonists normalize body weight in obese mice. Mol Metab. 2022;63(101533):1-12.
Olsen MB, Hövelmann U, Griffin J, Knudsen KM, Eriksson P-O, Agersnap MA. Dapiglutide, a once-weekly GLP-1R/GLP-2R dual agonist, was safe and well tolerated and showed dose-dependent body weight loss over four weeks in healthy subjects. Diabetes. 2022;71(Supplement_1).
Gabe MBN, Skov-Jeppesen K, Gasbjerg LS, et al. GIP and GLP-2 together improve bone turnover in humans supporting GIPR-GLP-2R co-agonists as future osteoporosis treatment. Pharmacol Res. 2022;176(106058):1-14.
NovoNordisk. NNC0519-0130 phase 1 [Internet]. ClinicalTrials.gov Identifier: NCT05363774 2023. Available from: https://clinicaltrials.gov/ct2/show/NCT05363774
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(3):336-347.
EMEA/H/C/005620/0000. Assessment Report. Eur Med Agency; 2022;EMA/791310:21 July 2022.
Ravussin E, Sanchez-Delgado G, Martin CK, et al. The effect of Tirzepatide during weight loss on metabolic adaption, fat oxidation, and food intake in people with obesity. Diabetes. 2023;72(S1):127-OR.
Wang Y, Yang D, Wang M. Signaling profiles in HEK 293T cells co-expressing GLP-1 and GIP receptors. Acta Pharmacol Sin. 2021;43(6):1453-1460.
Zhao F, Zhang C, Zhou Q, et al. Structural insights into hormone recognition by the human glucose-dependent insulinotropic polypeptide receptor. Elife. 2021;10(e68719):1-20.
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):1-16.
Sun B, Willard FS, Feng D, et al. Structural determinants of dual incretin receptor agonism by tirzepatide. PNAS. 2022;119(13):1-11.
Furihata K, Mimura H, Shweta U, et al. A phase 1 multiple-ascending dose study of tirzepatide in Japanese participants with type 2 diabetes. Diabetes Obes Metab. 2022;24(2):239-246.
Urva S, Quinlan T, Landry J, et al. Effects of hepatic impairment on the pharmacokinetics of the dual GIP and GLP-1 receptor agonist tirzepatide. Clin Pharmacokinet. 2022;61:1057-1067.
Jones B, Buenaventura T, Kanda N, et al. Targeting GLP-1 receptor trafficking to improve agonist efficacy. Nat Commun. 2018;9(1):1-17.
Oduori OS, Murao N, Shimomura K, et al. Gs/Gq signaling switch in β cells defines incretin effectiveness in diabetes. J Clin Invest. 2020;130(12):6639-6655.
Nichols CG, York NW, Remedi MS. Preferential Gq signaling in diabetes: an electrical switch in incretin action and in diabetes progression? J Clin Invest. 2020;130(12):6235-6237.
Finan B, Ma T, Ottaway N, et al. Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans. Sci Transl Med. 2013;5(209):1-18.
Schmitt C, Portron A, Jadidi S, Sarkar N, DiMarchi R. Pharmacodynamics, pharmacokinetics and safety of multiple ascending doses of the novel dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 agonist RG7697 in people with type 2 diabetes mellitus. Diabetes Obes Metab. 2017;19(10):1436-1445.
Committee ADAPP. 9. Pharmacologic approaches to glycemic treatment: standards of medical Care in diabetes-2022. Diabetes Care. 2022;45(Suppl 1):S125-S143.
Mari A, Sallas WM, He YL, et al. Vildagliptin, a dipeptidyl peptidase-IV inhibitor, improves model-assessed β-cell function in patients with type 2 diabetes. J Clin Endocrinol Metab. 2005;90(8):4888-4894.
Gilbert MP, Pratley RE. GLP-1 analogs and DPP-4 inhibitors in type 2 diabetes therapy: review of head-to-head clinical trials. Front Endocrinol. 2020;11:1-13.
Andersen ES, Deacon CF, Holst JJ. Do we know the true mechanism of action of the DPP-4 inhibitors? Diabetes Obes Metab. 2018;20(1):34-41.
Amgen. AMG 133 is a first-in-class investigational bispecific molecule that activates GLP-1R and inhibits GIPR. Press Release; 2022;Dec 1st.
Lu SC, Chen M, Atangan L, et al. GIPR antagonist antibodies conjugated to GLP-1 peptide are bispecific molecules that decrease weight in obese mice and monkeys. Cell Reports Med. 2021;2(5):1-9.
Killion EA, Wang J, Yie J, et al. Anti-obesity effects of GIPR antagonists alone and in combination with GLP-1R agonists in preclinical models. Sci Transl Med. 2018;10(472):1-11.
Lynggaard MB, Gasbjerg LS, Christensen MB, Knop FK. GIP(3-30)NH2-a tool for the study of GIP physiology. Curr Opin Pharmacol. 2020;55:31-40.
Hansen LS, Sparre-Ulrich AH, Christensen M, et al. N-terminally and C-terminally truncated forms of glucose-dependent insulinotropic polypeptide are high-affinity competitive antagonists of the human GIP receptor. Br J Pharmacol. 2016;173(5):826-838.
Stensen S, Krogh LL, Sparre-Ulrich AH, et al. Acute concomitant GIP receptor antagonism during GLP-1 receptor agonism does not affect appetite, resting energy expenditure or food intake in patients with type 2 diabetes and overweight/obesity. Diabetes Obes Metab. 2022;24:1882-1887.
Frías JP, Auerbach P, Bajaj HS, 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(9):563-574.
Vadher K, Patel H, Mody R, et al. Efficacy of tirzepatide 5, 10 and 15 mg versus semaglutide 2 mg in patients with type 2 diabetes: an adjusted indirect treatment comparison. Diabetes Obes Metab. 2022;24:1-8.
Irwin N, Montgomery IA, Flatt PR. Evaluation of the long-term effects of gastric inhibitory polypeptide-ovalbumin conjugates on insulin resistance, metabolic dysfunction, energy balance and cognition in high-fat-fed mice. Br J Nutr. 2012;108(1):46-56.
Fulurija A, Lutz TA, Sladko K, et al. Vaccination against GIP for the treatment of obesity. PloS ONE. 2008;3(9):1-11.
Pathak V, Gault VA, Flatt PR, Irwin N. Antagonism of gastric inhibitory polypeptide (GIP) by palmitoylation of GIP analogues with N- and C-terminal modifications improves obesity and metabolic control in high fat fed mice. Mol Cell Endocrinol. 2015;401:120-129.
Samms RJ, Christe ME, Collins KAL, et al. GIPR agonism mediates weight-independent insulin sensitization by tirzepatide in obese mice. J Clin Invest. 2021;131(12):1-14.
Larsen AT, Gydesen S, Sonne N, Karsdal MA, Henriksen K. The dual amylin and calcitonin receptor agonist KBP-089 and the GLP-1 receptor agonist liraglutide act complimentarily on body weight reduction and metabolic profile. BMC Endocr Disord. 2021;21(1):1-9.
Bergmann NC, Lund A, Gasbjerg LS, et al. Separate and combined effects of GIP and GLP-1 infusions on bone metabolism in overweight men without diabetes. J Clin Endocrinol Metab. 2019;104(7):2953-2960.