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.

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