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CC BY-NC-ND 4.0 · Diabetologie und Stoffwechsel 2023; 18(06): 461-474
DOI: 10.1055/a-2078-9491
Übersicht

Tirzepatid: GIP-/GLP-1-Rezeptoragonist zur Therapie des Typ-2-Diabetes – SURPASS-Studienprogramm

Tirzepatide, a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, in the management of type 2 diabetes: the SURPASS trials
Jens Aberle
1   Endokrinologie und Diabetologie, Ambulanzzentrum des UKE GmbH, Hamburg, Germany
,
Thomas Forst
2   Medical, CRS Clinical Research Services Mannheim GmbH, Mannheim, Germany (Ringgold ID: RIN217310)
,
Elke Heitmann
3   Medizinische Abteilung - Diabetes, Lilly Deutschland GmbH, Bad Homburg, Germany (Ringgold ID: RIN35059)
,
Sven W Görgens
3   Medizinische Abteilung - Diabetes, Lilly Deutschland GmbH, Bad Homburg, Germany (Ringgold ID: RIN35059)
,
Jochen Seufert 
4   Klinik für Innere Medizin II, Abteilung Endokrinologie und Diabetologie, Universitätsklinikum Freiburg, Freiburg, Germany (Ringgold ID: RIN35059)
› Author AffiliationsFinanzielle Unterstützung für die klinischen SURPASS-Studien und die Erstellung dieses Manuskripts wurde von Eli Lilly and Company bereitgestellt.
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Zusammenfassung

Innovative therapeutische Ansätze zur Behandlung des Typ-2-Diabetes (T2D) sollten idealerweise sowohl zur Senkung des glykierten Hämoglobins (HbA1c) als auch zur Gewichtsabnahme beitragen und eine überlegene Wirksamkeit gegenüber derzeit verfügbaren Behandlungsoptionen zeigen. Der Inkretinrezeptor-Agonist Tirzepatid (LY3298176) – entwickelt, um sowohl die Rezeptoren des Glukose-abhängigen insulinotropen Polypeptids (GIP) als auch des Glukagon-ähnlichen Peptids 1 (GLP-1) zu aktivieren – ist inzwischen in zahlreichen Ländern, einschließlich den USA und EU-Ländern, für die Behandlung des T2D zugelassen. Wirksamkeit und Sicherheit von Tirzepatid wurden im SURPASS-Programm klinischer Phase-3-Studien untersucht und hier zusammengefasst. Tirzepatid 5, 10 und 15 mg wurde als Monotherapie und in Kombination mit zugelassenen oralen Antidiabetika und/oder Insulin bei Patienten:innen mit T2D untersucht (in SURPASS 1 vs. Placebo; in SURPASS 2 vs. Semaglutid; in SURPASS 3 vs. Insulin degludec; in SURPASS 4 vs. Insulin glargin bei Patienten:innen mit erhöhtem kardiovaskulären Risiko; in SURPASS 5 vs. Placebo). Dabei waren über die SURPASS-1–5-Studien hinweg jegliche Tirzepatid-Behandlungsarme in Woche 40 oder 52 mit mittleren Senkungen des HbA1c von 1,87–2,59 % verbunden, die durchgehend signifikant größer waren als in den Vergleichsgruppen. Außerdem wirkte sich Tirzepatid in diesen Studien im Vergleich zu allen aktiven Vergleichspräparaten und Placebo überlegen auf die Körpergewichtsreduktion aus. Insgesamt weisen die verfügbaren Daten auf eine gute Verträglichkeit hin. Gastrointestinale Nebenwirkungen sind vergleichbar mit denen anderer Inkretin-Agonisten und Tirzepatid zeigte außerdem eine sehr geringe Rate hypoglykämischer Ereignisse, was aufgrund seines Wirkmechanismus zu erwarten ist. Dank des neuartigen Wirkmechanismus und den damit verbundenen zusätzlichen klinischen Vorteilen konnte sich Tirzepatid als erster GIP/GLP-1-Rezeptoragonist seiner Klasse etablieren. Ebenfalls von großem Interesse werden die Ergebnisse der laufenden SURPASS-CVOT-Studie sein, die zum Verständnis möglicher kardiovaskulärer Vorteile von Tirzepatid – angesichts verbesserter glykämischer Kontrolle und Gewichtsreduktion – beitragen werden.

Abstract

Ideally, innovative therapeutic approaches for the treatment of type 2 diabetes (T2D) should contribute to both reduction in glycated haemoglobin (HbA1c) and weight loss, and demonstrate superior efficacy over currently available treatment options. Tirzepatide (LY3298176) is an incretin hormone agonist that was developed to activate both glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 (GIP/GLP-1) receptors and is approved in a number of countries, including the US and EU, for the treatment of T2D. The efficacy and safety of tirzepatide are being investigated in the SURPASS phase 3 clinical trial programme and are summarised herein. Tirzepatide 5, 10 and 15 mg was evaluated as monotherapy and in combination with accepted oral antidiabetes drugs and/or insulin in patients with T2D (SURPASS 1, versus placebo; SURPASS 2, versus semaglutide; SURPASS 3, versus insulin degludec; SURPASS 4, versus insulin glargine in patients with high cardiovascular risk; SURPASS 5, versus placebo). Across the SURPASS-1 to -5 studies, all dose regimens of tirzepatide were associated with mean reductions in HbA1c of 1.87–2.59% at either week 40 or 52 that were consistently significantly greater than changes seen in comparator groups. Tirzepatide showed superior effects on body weight reduction compared to all active comparators and placebo in these trials. Overall, available data indicate that tirzepatide is well tolerated with a gastrointestinal tolerability profile comparable to other incretin agonists, and a very low rate of hypoglycaemic events, which can be expected based on its mechanism of action. The novel dual mechanism of action and associated added clinical benefits has established tirzepatide as a first-in-class GIP/GLP-1 receptor agonist. It will also be of interest to see outcomes from the ongoing SURPASS-CVOT trial, which will assist understanding of what cardiovascular benefits tirzepatide may offer, given its benefits for improved glycaemic control and weight reduction.

Schlüsselwörter

Glukagon-ähnliches Peptid 1 - Glukose-abhängiges insulinotropes Polypeptid - Inkretin - Tirzepatid - Typ 2 Diabetes

Keywords

Glucagon-like peptide 1 - glucose-dependent insulinotropic polypeptide - incretin - tirzepatide - type 2 diabetes


Publication History

Received: 01 February 2023

Accepted after revision: 13 April 2023

Article published online:
06 June 2023

© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • Literatur

  • 1 Akil L, Ahmad HA. Relationships between obesity and cardiovascular diseases in four southern states and Colorado. J Health Care Poor Underserved 2011; 22 (Suppl. 04) 61-72
    CrossrefPubMedSearch in Google Scholar
  • 2 Al-Goblan AS, Al-Alfi MA, Khan MZ. Mechanism linking diabetes mellitus and obesity. Diabetes Metab Syndr Obes 2014; 7: 587-591
    CrossrefPubMedSearch in Google Scholar
  • 3 Bhupathiraju SN, Hu FB. Epidemiology of obesity and diabetes and their cardiovascular complications. Circ Res 2016; 118: 1723-1735
    CrossrefPubMedSearch in Google Scholar
  • 4 Kivimäki M, Strandberg T, Pentti J. et al. Body-mass index and risk of obesity-related complex multimorbidity: an observational multicohort study. Lancet Diabetes Endocrinol 2022; 10: 253-263
    CrossrefPubMedSearch in Google Scholar
  • 5 Zheng Y, Ley SH, Hu FB. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol 2018; 14: 88-98
    CrossrefPubMedSearch in Google Scholar
  • 6 IDF Diabetes Atlas. Online. Accessed February 10, 2022 at: https://diabetesatlas.org
  • 7 Caleyachetty R, Barber TM, Mohammed NI. et al. Ethnicity-specific BMI cutoffs for obesity based on type 2 diabetes risk in England: a population-based cohort study. Lancet Diabetes Endocrinol 2021; 9: 419-426
    CrossrefPubMedSearch in Google Scholar
  • 8 Hartmann B, Lanzinger S, Bramlage P. et al. Lean diabetes in middle-aged adults: A joint analysis of the German DIVE and DPV registries. PLoS One 2017; 12: e0183235
    CrossrefPubMedSearch in Google Scholar
  • 9 Lean ME, Leslie WS, Barnes AC. et al. Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial. Lancet 2018; 391: 541-551
    Search in Google Scholar
  • 10 Stratton IM, Adler AI, Neil HA. et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000; 321: 405-412
    CrossrefPubMedSearch in Google Scholar
  • 11 Van Gaal L, Scheen A. Weight management in type 2 diabetes: current and emerging approaches to treatment. Diabetes Care 2015; 38: 1161-1172
    CrossrefPubMedSearch in Google Scholar
  • 12 Ryan DH, Yockey SR. Weight loss and improvement in comorbidity: differences at 5%, 10%, 15%, and over. Curr Obes Rep 2017; 6: 187-194
    CrossrefPubMedSearch in Google Scholar
  • 13 Gregg EW, Jakicic JM, Blackburn G. Look AHEAD Research Group. et al. Association of the magnitude of weight loss and changes in physical fitness with long-term cardiovascular disease outcomes in overweight or obese people with type 2 diabetes: a post-hoc analysis of the Look AHEAD randomised clinical trial. Lancet Diabetes Endocrinol 2016; 4: 913-921
    CrossrefPubMedSearch in Google Scholar
  • 14 Nauck MA, Meier JJ. Management of endocrine disease: Are all GLP-1 agonists equal in the treatment of type 2 diabetes?. Eur J Endocrinol 2019; 181: R211-R234
    CrossrefPubMedSearch in Google Scholar
  • 15 Samms RJ, Coghlan MP, Sloop KW. How may GIP enhance the therapeutic efficacy of GLP-1?. Trends Endocrinol Metab 2020; 31: 410-421
    CrossrefPubMedSearch in Google Scholar
  • 16 Krarup T, Saurbrey N, Moody AJ. et al. Effect of porcine gastric inhibitory polypeptide on beta-cell function in type I and type II diabetes mellitus. Metabolism 1987; 36: 677-682
    CrossrefPubMedSearch in Google Scholar
  • 17 Nauck MA, Heimesaat MM, Orskov C. et al. 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: 301-307
    CrossrefPubMedSearch in Google Scholar
  • 18 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: 63-74
    CrossrefPubMedSearch in Google Scholar
  • 19 Nauck MA, Bartels E, Orskov C. et al. 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: 912-917
    CrossrefPubMedSearch in Google Scholar
  • 20 Finan B, Ma T, Ottaway N. et al. Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans. Sci Transl Med 2013; 5: 209ra151
    CrossrefPubMedSearch in Google Scholar
  • 21 Brandt SJ, Kleinert M, Tschop MH. et al. Are peptide conjugates the golden therapy against obesity?. J Endocrinol 2018; 238: R109-R119
    CrossrefPubMedSearch in Google Scholar
  • 22 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
    CrossrefPubMedSearch in Google Scholar
  • 23 Ohwaki K, Furihata K, Mimura M. et al. Poster 1024-P: effect of tirzepatide, a dual GIP and GLP-1 receptor agonist, on glycemic control and body weight in Japanese patients with T2DM. Diabetes 2019;68(1).
  • 24 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 dose-escalation regimens. Diabetes Obes Metab 2020; 22: 938-946
    CrossrefPubMedSearch in Google Scholar
  • 25 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: 2180-2193
    CrossrefPubMedSearch in Google Scholar
  • 26 Eli Lilly & Company. Press release. Online. Accessed March 04, 2022 at: https://investor.lilly.com/news-releases/news-release-details/lillys-tirzepatide-led-greater-improvements-liver-fat-content
  • 27 Jastreboff AM, Aronne LJ, Ahmad NN. et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med 2022; 387: 205-216
    CrossrefPubMedSearch in Google Scholar
  • 28 Rosenstock J, Wysham C, Frias 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: 143-155
    CrossrefPubMedSearch in Google Scholar
  • 29 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: 534-545
    CrossrefPubMedSearch in Google Scholar
  • 30 Frias JP, Davies MJ, Rosenstock J. et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med 2021; 385: 503-515
    Search in Google Scholar
  • 31 Ludvik B, Giorgino F, Jodar 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 2021; 398: 583-598
    CrossrefPubMedSearch in Google Scholar
  • 32 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: 1811-1824
    CrossrefPubMedSearch in Google Scholar
  • 33 Inagaki N, Takeuchi M, Oura T. et al. 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: 623-633
    CrossrefPubMedSearch in Google Scholar
  • 34 Kadowaki T, Chin R, Ozeki A. et al. 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: 634-644
    CrossrefPubMedSearch in Google Scholar
  • 35 Gastaldelli A, Cusi K, Fernández Landó L. et al. Effect of tirzepatide versus insulin degludec on liver fat content and abdominal adipose tissue in people with type 2 diabetes (SURPASS-3 MRI): a substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial. Lancet Diabetes Endocrinol 2022; 10: 393-406
    CrossrefPubMedSearch in Google Scholar
  • 36 Battelino T, Bergenstal RM, Rodriguez A. et al. Efficacy of once-weekly tirzepatide versus once-daily insulin degludec on glycaemic control measured by continuous glucose monitoring in adults with type 2 diabetes (SURPASS-3 CGM): a substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial. Lancet Diabetes Endocrinol 2022; 10: 407-417
    CrossrefPubMedSearch in Google Scholar
  • 37 Urva S, Quinlan T, Landry J. et al. Effects of Renal impairment on the pharmacokinetics of the dual gip and glp-1 receptor agonist tirzepatide. Clin Pharmacokinet 2021; 60: 1049-1059
    CrossrefPubMedSearch in Google Scholar
  • 38 Sattar N, McGuire DK, Pavo I. et al. Tirzepatide cardiovascular event risk assessment: a pre-specified meta-analysis. Nat Med 2022; 28: 591-598
    CrossrefPubMedSearch in Google Scholar