Use of the once-daily oral HRS-7535, an investigational small-molecule GLP-1 receptor agonist (RA) for type 2 diabetes (T2D) and weight management, demonstrates noninferiority to dapagliflozin for glycated haemoglobin (HbA1c) reduction in Chinese adults with T2D, results of the OUTSTAND-2 phase III trial have shown. Treatment differences are also in favour of HRS-7535, with superiority at the 90-mg dose.
“OUTSTAND-2 assessed HRS-7535 vs dapagliflozin in Chinese adults with T2D inadequately controlled with metformin,” said lead author Dr Lixin Guo, Beijing Hospital; National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing, China.
Guo and colleagues randomized 810 adults with T2D to once-daily oral HRS-7535 30/60/90 mg or dapagliflozin 10 mg for 32 weeks plus a 20-week extension. Treatment with HRS-7535 was initiated at 30 mg and uptitrated by 30 mg every 4 weeks. The change in HbA1c at week 32 served as the primary endpoint, with results using the efficacy estimand.
Most trial participants (86.5 percent) completed treatment. At baseline, the mean age was 52.2 years, HbA1c 8.6 percent, body weight 74.7 kg, BMI 27.1 kg/m2, and the median T2D duration was 5 years. The majority (97.7 percent) used metformin ≥1,500 mg/day prior to screening. [EASD 2026, LBA 10]
At week 32, changes in HbA1c were ‒1.58 percent with HRS-7535 30 mg, ‒1.50 percent with 60 mg, and ‒1.68 percent with 90 mg compared with ‒1.28 percent with dapagliflozin. The estimated difference from dapagliflozin were ‒0.30 percent (95 percent confidence interval [CI], ‒0.51 to ‒0.09), ‒0.22 percent (95 percent CI, ‒0.44 to ‒0.01), and ‒0.40 percent (95 percent CI, ‒0.62 to ‒0.19), respectively.
“All HRS-7535 doses met the prespecified 0.4-percent margin, with p<0.0001 for noninferiority,” wrote Guo and colleagues. “[T]reatment differences favoured HRS-7535 across doses.”
Furthermore, HbA1c <7.0 percent and ≤6.5 percent were reached by 55.7 percent and 41.4 percent of participants in the HRS-7535 30-mg group, by 54.9 percent and 38.9 percent of those in the 60-mg group, and by 63.5 percent and 48.6 percent of those in the 90-mg group compared with 36.5 percent and 16.1 percent of those in the dapagliflozin group, respectively.
Notably, “HRS-7535 reduced body weight and improved fasting plasma glucose, systolic blood pressure, lipid profile, and urine albumin-creatinine ratio at week 32,” according to Guo and colleagues.
Safety profile
The most common adverse events (AEs) associated with the use of HRS-7535 over 52 weeks were mostly gastrointestinal, including nausea, vomiting, and diarrhoea. These AEs were generally mild-to-moderate in intensity and transient.
Additionally, AEs that led to treatment discontinuation occurred in 4.0 percent of participants treated with HRS-7535 30 mg, 3.9 percent with 60 mg, and 3.9 percent with 90 mg compared with 1.0 percent of those who received dapagliflozin. No grade 3 hypoglycaemia events and liver safety signals were reported, consistent with prior HRS-7535 trials. [https://www.hengrui.com/en/media/detail-986.html]
“HRS-7535 improved HbA1c target attainment and multiple cardiometabolic measures, with a GLP-1 RA-consistent safety profile,” Guo said. “Without fasting restrictions, HRS-7535 may provide a convenient oral option for this population.”