S5 - E20.2 - Drug Development Highlights From EASL Congress 2024: Tirzepatidate and other "Twin-cretins"

Surfing the MASH Tsunami

Mazen Noureddin and Naim Alkhouri join Jörn Schattenberg and Roger Green to discuss the tirzepatide late-breaker at the EASL Congress 2024 and other "Twin-cretins," all of which are GLP-glucagon combinations.
"Twin-cretins" is the name Jörn has coined for agents with a GLP-1 agonist plus another incretin effect. Tirzepatide is a GLP/GIP agent, while survodutide and the agents discussed last year, pemvidutide and efinopegdutide, are GLP/gluagons.
Naim reviews the results of the tirzepatide late-breaker presentation. As expected, it showed high rates of MASH resolution. Naim does not feel it answered the question whether an incretin-agonist can achieve significant fibrosis regression without a direct liver effect, since it relied on a completer analysis that treated 3 of 10 non-completers as a success (in ITT, that would have been 0 out of 10). Again, glucagon has a direct effect; GIP does not.
This takes Naim back to the question of whether a GLP/GOP can have a meaningful effect on fibrosis. He notes that Stephen believed firmly that it could not, but there is a paradox in that bariatric surgery can produce a reduction in fibrosis. Naim notes that conclusive data will arrive later this year, so no one needs to decide now.
Mazen praises tirzepatide's effect on weight loss and safety and could prescribe it now, but the completer analysis has not persuaded him to prescribe to regress fibrosis, particularly given the lack of a dose response. He notes that "while I don't want to compare apples to oranges," he is more confident in the glucagon effect found with survodutide, pemvidutide and efinopegdutide. Jörn agrees.
Roger asks how prescribing decisions will change in a market where a significant share of US patients will have been prescribed semaglutide or tirzepatide before coming to the hepatologist. Naim comments that many of his MASH patients have been on GLP-1 already. He notes that since glucagon increases blood sugar, the ratio of GLP-1:glucagon is a key issue and difference between the three GLP/glucagon agents.