Oral small-molecule glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may address limitations associated with injectable and peptide-based therapies for type 2 diabetes mellitus (T2DM). A phase 2 randomized clinical trial published in JAMA Network Open evaluated the efficacy and safety of oral HRS-7535, a nonpeptide GLP-1 RA, as add-on therapy in adults with T2DM inadequately controlled with metformin.

The 16-week, double-blind, placebo-controlled trial enrolled 194 adults aged 18 to 75 years across 44 centers in China. Participants with HbA1c levels between 7.5% and 11.0% receiving stable metformin therapy were randomized to once-daily oral HRS-7535 at doses of 15 mg, 30 mg, 60 mg, or 90 mg, or matching placebo. The primary outcome was change in HbA1c from baseline to week 16, while secondary outcomes included fasting plasma glucose, 2-hour postprandial glucose, body weight, and achievement of HbA1c below 7.0%.

Findings

• Mean HbA1c reductions at week 16 ranged from −1.19% with 15 mg to −1.82% with 60 mg, compared with −0.25% with placebo (all P < .001).
• Placebo-adjusted HbA1c reductions ranged from −0.94% to −1.57% across HRS-7535 dose groups.
• HbA1c below 7.0% was achieved in 48.7% to 63.2% of HRS-7535-treated participants versus 15.4% with placebo.
• The 90-mg dose demonstrated greater body weight reduction than placebo (−2.63% vs −1.30%).
• Adverse events occurred in 71.8% to 84.6% of HRS-7535 groups and 71.8% of placebo-treated participants, with gastrointestinal events being predominantly mild to moderate.
• Level 1 hypoglycemia occurred in 9 HRS-7535-treated participants, while no level 2 or 3 hypoglycemia, pancreatitis, or significant liver enzyme elevations were reported.

The trial demonstrated improved glycemic control with oral HRS-7535 in adults with T2DM inadequately controlled with metformin, along with modest body weight reduction and a safety profile consistent with GLP-1 RAs. Further phase 3 studies are needed to confirm long-term efficacy and safety outcomes.