Glucagon-like peptide-1 receptor (GLP-1R) agonists are approved for the treatment of type 2 diabetes and obesity and elicit robust improvements in glycemic control and weight loss, coupled with cardioprotection in individuals at risk for or with pre-existing cardiovascular disease. These attributes make GLP-1 a preferred partner for next generation therapies exhibiting improved efficacy yet retained safety for the treatment of diabetes, obesity, non-alcoholic steatohepatitis and related cardiometabolic disorders. The available clinical data demonstrates the best GLP-1R agonists are not yet competitive with bariatric surgery, emphasizing the need to further improve the efficacy of current medical therapy.

Here we discuss data highlighting the physiological and pharmacological attributes of potential peptide and non-peptide partners, exemplified by amylin, glucose-dependent insulinotropic polypeptide (GIP), and steroid hormones. We review progress, limitations and future considerations for translating findings from preclinical experiments to competitive efficacy and safety in humans with type 2 diabetes and obesity.

Multiple co-agonist combinations exhibit promising efficacy in the clinic, notably tirzepatide, and investigational amylin combinations. Simultaneously, increasing doses of GLP-1R agonists such as semaglutide produces substantial weight loss, raising the bar for development of new unimolecular co-agonists. Collectively, the available data suggests that new co-agonists with robust efficacy should prove superior to GLP-1R agonists alone for the treatment of metabolic disorders.