Oral glucagon-like peptide-1 receptor agonists and combinations of entero-pancreatic hormones as treatments for adults with type 2 diabetes: where are we now?

Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) have changed the landscape of type 2 diabetes (T2D) management due to their cardio-renal benefits, their glucose-lowering efficacy and weight loss (WL) maintenance. However, the response to GLP-1 RA monotherapy is heterogeneous. Additionally, the majority of GLP-1 RAs are injectable treatments. Oral GLP-1 RAs and injectable combinations of GLP-1 with other entero-pancreatic hormones [glucose-dependent insulinotropic polypeptide (GIP), glucagon and amylin] are under development for T2D and obesity management. Herein, we review the data on i) oral GLP-1 RAs (oral semaglutide 25/50 mg and orforglipron) and ii) dual/triple agonists (tirzepatide, cagrilintide 2.4 mg/semaglutide 2.4 mg, survodutide, mazdutide, retatrutide) that have recently completed phase 3 trials for T2D or are currently in phase 3 clinical trials. Tirzepatide is the first approved dual agonist (GLP-1/GIP) for T2D and obesity management. We are in a new era in T2D management where entero-pancreatic hormone based treatments can result in ≥ 15% WL and euglycaemia for many people with T2D. Multiple molecules with different mechanisms of action are under development for T2D, obesity and other metabolic complications. Data on their cardio-renal benefits, long-term efficacy and safety as well as their cost-effectiveness will better inform their position in treatment algorithms.