Discussion
obesity, steatosis, nausea, insulin-naive type 2 diabetes, fibrosis, NASH, GI disorders, reductions in HbAAnother GCGR/GLP-1R dual agonist
OBESITY, FIBROSIS, GI DISORDERS, TYPE 2 DIABETES, STEATOSIS, COMPLICATIONS
GLP-1R agonists such as semaglutide have been approved for the treatment of type 2 diabetes and obesity [In addition to semaglutide, other GLP-1R agonists now approved for the treatment of type 2 diabetes have been investigated in combination with background metformin therapy. In the LEAD-2 study, liraglutide treatment for 26 weeks produced HbAFurthermore, a Phase II dose-finding study of the weekly GIPR/GLP-1R dual agonist tirzepatide found reductions in HbAAnother GCGR/GLP-1R dual agonist, cotadutide, has been developed for the treatment of type 2 diabetes and obesity. In a Phase IIa trial in participants receiving metformin background therapy, cotadutide treatment for 49 days led to a significant reduction in blood glucose (The overall tolerability profile of survodutide was as expected for an incretin dual agonist. Most of the reported TEAEs with survodutide treatment were GI disorders such as nausea; drug-related AEs were reported by 58.6% of those receiving survodutide, with half of these participants reporting drug-related GI disorders. The occurrence of GI disorders is common in people treated with GLP-1R agonists [The observed changes in plasma alanine and glucagon concentrations with survodutide but not placebo or semaglutide indicate target engagement at both the GCGR and the GLP-1R, highlighting that survodutide is a GCGR/GLP-1R dual agonist and its effects are exerted at both receptors. Amino acids are sensitive biomarkers for assessing GCGR activity of GCGR/GLP-1R dual agonists, as plasma amino acid levels are reduced independently of insulin and glucose levels and GLP-1R activity [GCGR/GLP-1R dual agonism is also a focus in the treatment of NASH as it can potentially ameliorate hepatic fat accumulation, steatosis and fibrosis, alongside reductions in bodyweight [The 16 week duration of this trial meant that rapid dose escalation of survodutide over 6 weeks was required to allow for 10 weeks of treatment and drug exposure with the maintenance dose in each DG. This escalation most likely led to a higher incidence of AEs and treatment discontinuations due to AEs during the dose-escalation phase. In future studies, more gradual dose escalations over a longer escalation phase and treatment duration may help to mitigate the occurrence of dose-related GI AEs. In addition, future studies are expected to include participants with a higher baseline bodyweight than in the current study, as discontinuations due to AEs were more frequent in participants with a baseline bodyweight of <100 kg. As a proof-of-concept, first-in-patient trial in people with type 2 diabetes, the inclusion/exclusion criteria were more restrictive and therefore the results may not be generalisable to the entire insulin-naive type 2 diabetes population. In addition, the majority of the participants were White, which may also impact the generalisability of the results. Following the promising results of this study, future studies of survodutide will allow for the use of additional concomitant medications (in addition to metformin) and include participants with additional complications.