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.