HRS-7535 for Type 2 Diabetes Inadequately Controlled With Metformin: A Randomized Clinical Trial.

Importance: Oral small-molecule glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may address limitations of injectable and peptide-based agents for type 2 diabetes. Objective: To evaluate the efficacy and safety of HRS-7535, an oral nonpeptide GLP-1 RA, as add-on therapy among adults with type 2 diabetes inadequately controlled with metformin. Design, Setting, and Participants: This 16-week, phase 2, double-blind, placebo-controlled randomized clinical trial was conducted at 44 centers in China. Adults aged 18 to 75 years with type 2 diabetes, hemoglobin A1c (HbA1c) levels ranging from 7.5% to 11.0%, and receiving stable metformin therapy were enrolled between May 10 and December 18, 2023. Data were analyzed from May 8 to 22, 2024. Interventions: Participants were randomized (1:1:1:1:1) to once-daily oral HRS-7535 (15, 30, 60, or 90 mg) or matching placebo. The 60- and 90-mg treatment groups used dose-escalation regimens. Main Outcomes and Measures: The primary outcome was change in HbA1c level from baseline to week 16. Secondary outcomes included changes in fasting plasma glucose level, 2-hour postprandial glucose level, body weight, and the proportion of patients achieving HbA1c levels less than 7.0%. Safety outcomes included adverse events (AEs), hypoglycemia, and AEs of special interest. Results: Of 194 randomized patients (mean [SD] age, 52.3 [11.0] years; 115 [59.3%] men; mean [SD] HbA1c level, 8.5% [0.7]), 177 (91.2%) completed treatment. The mean changes in HbA1c level at week 16 were -1.19% (95% CI, -1.54% to -0.84%) with the 15-mg dose, -1.59% (95% CI, -1.94% to -1.24%) with the 30-mg dose, -1.82% (95% CI, -2.16% to -1.48%) with the 60-mg dose, and -1.64% (95% CI, -1.97% to -1.30%) with the 90-mg dose compared with -0.25% (95% CI, -0.60% to 0.09%) with placebo; placebo-adjusted differences ranged from -0.94% (95% CI, -1.43% to -0.45%) to -1.57% (95% CI, -2.05% to -1.08%) (all P < .001). HbA1c level less than 7.0% was achieved in proportions ranging from 48.7% (95% CI, 32.4%-65.2%) to 63.2% (95% CI, 46.0%-78.2%) of HRS-7535-treated patients vs 15.4% (95% CI, 5.9%-30.5%) with placebo. The 90-mg group had greater body weight reduction than placebo (-2.63% [95% CI, -3.72% to -1.54%] vs -1.30% [95% CI, -2.46% to -0.15%]). AEs occurred in 28 of 39 (71.8%) to 33 of 39 (84.6%) HRS-7535-treated patients and 28 of 39 (71.8%) placebo-treated patients and were predominantly mild to moderate gastrointestinal events. Level 1 hypoglycemia occurred in 9 HRS-7535-treated patients; no level 2 or 3 hypoglycemia, pancreatitis, or elevations of alanine aminotransferase or aspartate aminotransferase levels greater than 3 times the upper limit of normal occurred. Conclusions and Relevance: In this randomized clinical trial of adults with type 2 diabetes inadequately controlled with metformin, oral HRS-7535 improved glycemic control and was associated with modest weight reduction, with a safety profile consistent with that of GLP-1 RAs. Because HRS-7535 is a nonpeptide oral GLP-1 RA that does not require fasting administration or injection, it may be a viable treatment option, pending confirmation in phase 3 trials. Trial Registration: ClinicalTrials.gov Identifier: NCT05759897.