TOPLINE

Once-daily oral HRS-7535, a novel nonpeptide GLP-1 receptor agonist (RA), added to metformin led to significant improvements in glycemic control and modest weight reduction in patients with type 2 diabetes (T2D) inadequately controlled with metformin, according to a 16-week phase 2 trial. The treatment also showed a safety profile consistent with that of other GLP-1 RAs.

METHODOLOGY

• Currently, the only approved oral GLP-1 RA for T2D is semaglutide, but it is less effective than the injectable form and requires a gastric permeation enhancer as well as strict fasting for optimal absorption. These limitations highlight the need for once-daily, nonpeptide oral GLP-1 RAs without such constraints.
• Researchers conducted a phase 2 trial to evaluate the efficacy and safety of HRS-7535, a novel oral nonpeptide GLP-1 RA as add-on therapy to metformin in 194 patients with T2D (A1c levels, 7.5%-11.0%; mean age, 52.3 years; 40.7% women) inadequately controlled with stable metformin therapy.
• Participants were randomly assigned to receive once-daily oral HRS-7535 at doses of 15 mg (n = 39), 30 mg (n = 39), 60 mg (n = 38), or 90 mg (n = 39) or a matching placebo (n = 39) for 16 weeks.
• Patients in the 60-mg and 90-mg groups underwent dose-escalation regimens initiated at 30 mg — the dose was increased by 15 mg weekly for 2 weeks in to reach 60 mg, and increased by 30 mg every 4 weeks to reach 90 mg.
• The primary endpoint was the change in A1c levels from baseline to week 16.

TAKEAWAY

• At week 16, the HRS-7535 groups showed greater reductions in A1c levels than the placebo group, with placebo-adjusted least squares mean (LSM) differences of -0.94% for 15 mg, -1.34% for 30 mg, -1.57% for 60 mg, and -1.39% for 90 mg (P < .001 for all).
• The percentages of patients achieving A1c levels < 7.0% at week 16 were 48.7%-63.2% in the HRS-7535 groups vs 15.4% in the placebo group (P ≤ .002 for all).
• The 90-mg HRS-7535 group showed a greater reduction in body weight than the placebo group (LSM difference, -2.04 kg vs -1.06 kg) at week 16.
• Overall, adverse events occurred in 71.8%-84.6% of patients in the HRS-7535 groups and 71.8% of patients in the placebo group, mainly as mild-to-moderate gastrointestinal symptoms.

IN PRACTICE

“As a nonpeptide oral GLP-1 RA that does not require fasting administration or injection, HRS-7535 may provide a convenient treatment option, pending confirmation in phase 3 trials,” the authors wrote.

“[This study] demonstrates statistically significant effects of HRS-7535 in this population with this study design. It will depend on other study designs, other population selection criteria, and quite possibly selection of other racial and ethnic groups to put the drug through its paces,” an expert wrote in an accompanying editorial.

SOURCE

This study was led by Lixin Guo, MD, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China. It was published online in JAMA Network Open.

LIMITATIONS

The double-blind treatment period was limited to 16 weeks, with exposure to target HRS-7535 doses (60 mg or 90 mg) lasting only 8-12 weeks. Additionally, the trial population consisted of adults in China with generally lower baseline body weight and BMI compared with populations in many global T2D trials, potentially limiting generalizability. 

DISCLOSURES

This study was supported by Jiangsu Hengrui Pharmaceuticals. Three authors declared being employees of Jiangsu Hengrui Pharmaceuticals during the conduct of the trial.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.