A Novel Oral Nonpeptide GLP-1 Agonist (HRS-7535) Improves Glycemic Control in Type 2 Diabetes: JAMA Network Open | August 2026
Introduction:
Oral GLP-1 receptor agonists could overcome the inconvenience of injections, but currently available oral semaglutide requires specific fasting and administration conditions. HRS-7535 is a novel once-daily nonpeptide oral GLP-1 receptor agonist designed to provide effective glucose control without these restrictions. This Phase II trial evaluated HRS-7535 as add-on therapy to metformin in patients with inadequately controlled type 2 diabetes.
Why was this study needed?
Injectable GLP-1 therapies can limit treatment acceptance and adherence.
Current oral semaglutide requires strict administration conditions.
Small-molecule nonpeptide GLP-1 agonists could provide simpler oral therapy.
Dose-ranging clinical evidence for HRS-7535 was needed before Phase III development.
Results:
Among 194 patients, all HRS-7535 doses produced significantly greater HbA1c reductions than placebo after 16 weeks.
Approximately 49–63% achieved HbA1c <7%, compared with 15% receiving placebo.
Higher doses produced modest additional weight loss, although glucose lowering appeared to be the stronger treatment effect.
Safety was consistent with the GLP-1 class, with predominantly mild-to-moderate gastrointestinal adverse effects.
Clinical Impact:
HRS-7535 represents a promising new generation of small-molecule oral GLP-1 therapy that could eliminate both injections and the restrictive administration requirements of current peptide-based oral formulations. Phase III trials will need to establish durability, cardiovascular safety, weight-loss efficacy, and performance across broader populations.
Bottom Line:
Once-daily oral HRS-7535 produced substantial glucose lowering with modest weight reduction and familiar GLP-1–related gastrointestinal effects. If Phase III studies confirm these findings, nonpeptide oral GLP-1 agonists could significantly simplify incretin-based therapy for type 2 diabetes.
