Efficacy and safety of high‐dose GLP ‐1, GLP ‐1/ GIP and GLP ‐1/glucagon receptor agonists in type 2 diabetes

Background GLP-1 receptor agonists (GLP-1 RAs) have become agents of choice for people with type 2 diabetes (T2D) with established cardiovascular disease or in high-risk individuals. With currently available GLP-1 RA 51-79% of subjects achieve an HbA1c target <7.0% and 4-27% lose 10% of bodyweight, illustrating the need for more potent agents. Methods Three databases (PubMed, Cochrane, Web of Science) were searched using MESH terms “glucagon-like peptide-1 receptor agonist”, “glucagon receptor agonist”, “glucose-dependent insulinotropic peptide”, “dual or co-agonist” and “tirzepatide”. Quality of papers was scored using PRISMA guidelines. Risk of bias was evaluated using the Cochrane assessment tool. Results An HbA1c target <7.0% was attained by up to 80% with high-dose GLP-1 RAs and up to 97% with tirzepatide, with even up to 62% of people with T2D reaching HbA1c<5.7%. A ≥10% bodyweight loss was obtained by up to 50% and up to 69% with high-dose GLP-1 RAs or tirzepatide respectively. The glucose- and weight-lowering effects of GLP-1/glucagon RA cotadutide equal those of liraglutide 1.8 mg. Gastrointestinal side effects of high dose GLP-1 RAs and coagonists occurred in 30-70% of patients, mostly arising within the first 2 weeks of the first dose, being mild or moderate in severity, and transient. Conclusions The development of high-dose GLP-1 RAs and dual GLP-1/GIP-RA tirzepatide resulted in increasing numbers of people reaching HbA1c and bodyweight targets, with up to 62% attaining normoglycaemia with 15 mg tirzepatide. Whether this will also translate in better cardiovascular outcomes and will affect treatment guidelines remains to be studied. This article is protected by copyright. All rights reserved.