Evaluating biased agonism of glucagon-like peptide-1 (GLP-1) receptors to improve cellular bioenergetics: A systematic review.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are highly effective antidiabetic and anti-obesity agents. Recent development and optimisation of these agents includes biased agonism (selective activation of a downstream signalling pathway) of the GLP-1 receptor, which has demonstrated greater weight-lowering effects and improved insulin response in treated persons relative to other GLP-1 RAs. We aim to synthesise current literature reporting on the effects of biased GLP-1 RAs and compare their effects on cellular-level bioenergetics compared to non-biased GLP-1 RAs. A systematic search was conducted on PubMed, Ovid, and Scopus databases from inception to April 2025 for studies reporting on the effects of GLP-1 receptor biased agonists on cellular bioenergetics. Primary studies reporting on the effects of biased GLP-1 RAs on cellular signal transduction and bioenergetic outcomes were sought for inclusion. Current literature to date suggests that GLP-1 receptor biased agonism contributes to improved bioenergetic outcomes. Biased agonism of the GLP-1 receptor was associated with increased cAMP production and accumulation, increased ERK1/2 phosphorylation, and decreased GLP-1 receptor internalisation and recycling. In addition, improved glucose control and insulin response were observed. GLP-1 receptor biased agonism may be associated with greater weight-lowering and glucose-lowering effects as well as improved safety and tolerability. Notwithstanding, additional studies are needed to parse the contributory effects of GLP-1 receptor biased agonism compared to agonism of GIP and glucagon receptors on anti-obesity and glucose-lowering effects as well as tolerability. Moreover, their effects on other metabolic outcomes are future research vistas.