Eli Lilly Discloses Phase 1 Data on Nisotirostide, a Novel NPY2 Receptor Agonist Designed to Add to GLP-1 Therapy

Eli Lilly and Company researchers published the discovery and first clinical data on nisotirostide, an investigational peptide designed to be added to GLP-1 receptor agonist therapy, in a paper posted online October 3, 2026 in the journal Molecular Metabolism. The paper describes nisotirostide as a novel, selective agonist of the neuropeptide Y2 receptor (NPY2R) being developed as adjunctive therapy for people with type 2 diabetes who are already taking a GLP-1 receptor agonist.

The NPY2 receptor is the binding site for peptide YY, a hormone released by the gut after eating that signals fullness. Unlike GLP-1 receptor agonists, which mimic a different gut hormone, nisotirostide works through this separate appetite-regulating pathway, which is the rationale for testing it alongside, rather than instead of, GLP-1 therapy.

In laboratory binding studies, nisotirostide potently and selectively activated NPY2 receptor signaling. In mouse models, nisotirostide reduced body weight by up to 12% when given alone, and by up to 31% when combined with a GLP-1 receptor agonist, an effect the study authors described as synergistic. Mice treated with nisotirostide also showed improved glucose control that the authors said was independent of weight loss.

Those preclinical findings were paired with results from a completed Phase 1 clinical study (ClinicalTrials.gov identifier NCT04641312), a single ascending dose trial in 65 healthy participants and participants with type 2 diabetes who were taking a 1.5 mg once-weekly dose of dulaglutide, an already-approved GLP-1 receptor agonist marketed by Lilly as Trulicity. Participants received single subcutaneous doses of nisotirostide ranging from 0.025 mg to 1 mg. According to the ClinicalTrials.gov registry, the study ran from November 2020 to December 2021; the Molecular Metabolism paper is the first peer-reviewed publication of its results.

Pharmacokinetic data from the Phase 1 study supported a once-weekly dosing regimen for nisotirostide. At the highest dose tested, 1 mg, nisotirostide given alone reduced mean body weight by 0.75 kg compared with placebo, a difference the paper reported was not statistically significant. When added on top of dulaglutide, however, nisotirostide produced a reduction of up to 2.58 kg compared with dulaglutide alone, which was statistically significant (p<0.05). The most commonly reported adverse events with nisotirostide were gastrointestinal, including nausea and vomiting, which the authors described as dose-dependent and mild to moderate in severity.

The study authors concluded that nisotirostide's preclinical metabolic benefits, including glucose improvements that did not depend on weight loss, translated into the clinical setting, and that its pharmacokinetic and tolerability profile supports further development as an add-on therapy to GLP-1 receptor agonists for type 2 diabetes and obesity. Nisotirostide is not approved by the FDA, the European Medicines Agency, Australia's Therapeutic Goods Administration or any other regulator for any indication, and only this single Phase 1 study has been reported to date. This article describes published research findings and is not treatment or dosing guidance.