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

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

Publikationsverlauf

Eingereicht: 01. Februar 2023

Angenommen nach Revision: 13. April 2023

Artikel online veröffentlicht:
06. Juni 2023

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