Unimolecular Dual Incretins Maximize Metabolic Benefits in Rodents, Monkeys, and Humans

Compared to best-in-class GLP-1 mono-agonists, unimolecular co-agonists of GLP-1 and GIP with optimized pharmacokinetics enhance glycemic and metabolic benefits in mammals. “Twincretins”: Two Is Better than One Despite obesity-linked diabetes approaching worldwide epidemic proportions and the growing recognition of it as a global health challenge, safe and effective medicines have remained largely elusive. Pharmacological options targeting multiple obesity and diabetes signaling pathways offer greater therapeutic potential compared to molecules targeting a single pathway. Finan et al. now report the discovery, characterization, and translational efficacy of a single molecule that acts equally on the receptors for the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). In rodent models of obesity and diabetes, this dual incretin co-agonist more effectively lowered body fat and corrected hyperglycemia than selective mono-agonists for the GLP-1 and GIP receptors. An enhanced insulinotropic effect translated from rodents to monkeys and humans, with substantially improved levels of glycosylated hemoglobin A1c (HbA1c) in humans with type 2 diabetes. The dual incretin was engineered with selective chemical modifications to enhance pharmacokinetics. This, in combination with its inherent mixed agonism, lowered the drug dose and ameliorated the dose-limiting nausea that has plagued selective GLP-1 therapies. These dual incretin co-agonists signify a new direction for unimolecular combination therapy and represent a new class of drug candidates for the treatment of metabolic diseases. We report the discovery and translational therapeutic efficacy of a peptide with potent, balanced co-agonism at both of the receptors for the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). This unimolecular dual incretin is derived from an intermixed sequence of GLP-1 and GIP, and demonstrated enhanced antihyperglycemic and insulinotropic efficacy relative to selective GLP-1 agonists. Notably, this superior efficacy translated across rodent models of obesity and diabetes, including db/db mice and ZDF rats, to primates (cynomolgus monkeys and humans). Furthermore, this co-agonist exhibited synergism in reducing fat mass in obese rodents, whereas a selective GIP agonist demonstrated negligible weight-lowering efficacy. The unimolecular dual incretins corrected two causal mechanisms of diabesity, adiposity-induced insulin resistance and pancreatic insulin deficiency, more effectively than did selective mono-agonists. The duration of action of the unimolecular dual incretins was refined through site-specific lipidation or PEGylation to support less frequent administration. These peptides provide comparable pharmacology to the native peptides and enhanced efficacy relative to similarly modified selective GLP-1 agonists. The pharmacokinetic enhancement lessened peak drug exposure and, in combination with less dependence on GLP-1–mediated pharmacology, avoided the adverse gastrointestinal effects that typify selective GLP-1–based agonists. This discovery and validation of a balanced and high-potency dual incretin agonist enables a more physiological approach to management of diseases associated with impaired glucose tolerance.