Puredutide

Puredutide is an investigational dual GLP-1/glucagon receptor agonist developed by Eli Lilly. Unlike tirzepatide which targets GIP/GLP-1, puredutide combines GLP-1 receptor agonism with glucagon receptor agonism — aiming to enhance energy expenditure through glucagon's thermogenic and lipolytic effects while providing GLP-1-mediated appetite suppression and glycemic control. The glucagon component differentiates puredutide from pure GLP-1RAs by promoting hepatic fat oxidation, increasing energy expenditure, and enhancing amino acid catabolism. This dual mechanism addresses both energy intake (GLP-1) and energy expenditure (glucagon), similar to retatrutide's approach but without the GIP component. Puredutide is in Phase 2 clinical development for obesity and MASH/NASH.

Puredutide activates both GLP-1R and GCGR. GLP-1R agonism provides glucose-dependent insulin secretion, appetite suppression, and delayed gastric emptying. GCGR agonism enhances hepatic fat oxidation, increases energy expenditure through thermogenesis, and promotes lipolysis. The balance between these agonisms is carefully tuned to maximize metabolic benefit while preventing hyperglycemia.

Obesity Phase 2 trials in progress. Targets dual energy balance mechanism. MASH/NASH Glucagon-mediated hepatic fat reduction combined with GLP-1 anti-inflammatory effects make this a promising NASH candidate. Type 2 Diabetes Being studied with careful monitoring of glycemic balance between GLP-1 (glucose-lowering) and glucagon (glucose-raising) effects.

GLP-1R/cAMP for appetite and insulin. GCGR/cAMP/PKA for hepatic lipid oxidation and energy expenditure. AMPK activation. FGF21 upregulation via glucagon signaling.

GI effects (nausea, vomiting, diarrhea) expected based on GLP-1R agonism. Potential for hyperglycemia from glucagon component, though balanced by GLP-1 effects. Full safety profile pending clinical trial completion.

Investigational compound. Once-weekly subcutaneous injection in clinical trials. Stability data not publicly available.

Investigational — Phase 2 clinical trials. Not approved by any regulatory authority. Early-stage development by Eli Lilly.