Oral HRS-7535 Lowers HbA1c in Metformin-Treated Type 2 Diabetes

Key Takeaways

• All active HRS-7535 doses were associated with greater HbA1c reduction than placebo at week 16, with placebo-adjusted differences ranging from -0.94% to -1.57%.
• Higher proportions reached HbA1c below 7.0%, fasting and 2-hour postprandial glucose declined more, and the 90-mg group had greater body weight reduction than placebo.
• Adverse events were common and mainly mild to moderate gastrointestinal events, level 1 hypoglycemia was reported, prespecified adverse events of special interest were lipase elevations greater than 3 times the upper limit of normal in 5 HRS-7535-treated patients, and no level 2 or 3 hypoglycemia, pancreatitis, or ALT or AST elevations greater than 3 times the upper limit of normal were reported.

Once-daily oral HRS-7535 added to stable metformin lowered HbA1c more than placebo across all tested doses by week 16 in adults with type 2 diabetes in China. In the phase 2, randomized, double-blind, placebo-controlled trial, placebo-adjusted HbA1c differences ranged from -0.94% to -1.57%, according to JAMA Network Open. The study evaluated oral add-on therapy rather than metformin replacement in adults with HbA1c values of 7.5% to 11.0%. Broader glycemic measures also improved at week 16.

The 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, HbA1c 7.5% to 11.0%, and stable metformin therapy were enrolled in the HRS-7535 trial. A total of 194 participants were randomized 1:1:1:1:1 to placebo or HRS-7535 at 15, 30, 60, or 90 mg once daily, and the 60-mg and 90-mg groups followed prespecified titration regimens. Mean age was 52.3 years, 59.3% were men, mean baseline HbA1c was 8.5%, and 177 of 194 patients completed treatment.

For the primary endpoint, placebo-adjusted HbA1c differences at week 16 were -0.94%, -1.34%, -1.57%, and -1.39% with 15, 30, 60, and 90 mg, respectively, with all P values below .001. HbA1c below 7.0% was reached by 15.4% of placebo recipients and by 48.7% to 63.2% across active-dose groups. Fasting plasma glucose and 2-hour postprandial glucose also fell more with HRS-7535 than with placebo, and body weight changed by -2.63% with 90 mg versus -1.30% with placebo. Rescue antihyperglycemic therapy was used less often with HRS-7535 than with placebo.

Adverse events were frequent in all groups and were predominantly mild to moderate gastrointestinal events. Overall event rates were 71.8% with placebo and 79.5%, 71.8%, 76.3%, and 84.6% with 15, 30, 60, and 90 mg, respectively. Documented hypoglycemia occurred in 0%, 2.6%, 5.1%, 10.5%, and 5.1%, and all reported episodes were level 1 events. Prespecified adverse events of special interest occurred in 5 HRS-7535-treated patients and consisted of lipase elevations greater than 3 times the upper limit of normal. No level 2 or 3 hypoglycemia, pancreatitis, or ALT or AST elevations greater than 3 times the upper limit of normal were reported.

The authors noted several limits on interpretation. The treatment period lasted 16 weeks, and exposure to target 60-mg or 90-mg doses lasted only 8 to 12 weeks. They also noted that the relatively low baseline body weight and BMI in this China cohort may limit generalizability to broader populations. Longer-term studies are needed to define durability, long-term safety, and broader applicability.