口服小分子GLP-1受体激动剂HRS-7535治疗二甲双胍和SGLT2抑制剂控制不佳的2型糖尿病：多中心随机双盲安慰剂对照II期试验

原文

AIMS/HYPOTHESIS: This study aimed to evaluate the efficacy and safety of HRS-7535, an oral small-molecule glucagon-like peptide-1 receptor agonist (GLP-1RA), in Chinese participants with type 2 diabetes mellitus inadequately managed by metformin and sodium-glucose co-transporter 2 inhibitors (SGLT2i).

METHODS: This multicentre, randomised, double-blind, placebo-controlled, Phase II study included participants aged 18-75 years with type 2 diabetes, HbA1c 58-97 mmol/mol (7.5-11.0%) and BMI 20.0-35.0 kg/m2 and on stable-dose metformin and sodium-glucose co-transporter 2 (SGLT2) inhibitor therapy for ≥8 weeks prior to screening. Participants were assigned in a 1:1:1 ratio to receive HRS-7535 30 mg, HRS-7535 60 mg or visually matching placebo tablets once daily using a stratified block randomisation method, with treatment assignments concealed until study completion. The primary endpoint was the change in HbA1c from baseline to week 16. Secondary efficacy outcomes included the proportions of participants achieving HbA1c targets of <53 mmol/mol (7.0%) and ≤48 mmol/mol (6.5%), and changes from baseline in fasting body weight to week 16.

RESULTS: A total of 155 participants with a mean baseline HbA1c of 69 mmol/mol (8.5%) were randomly assigned to HRS-7535 30 mg (n=51), HRS-7535 60 mg (n=53) or placebo (n=51). At week 16, the least‑squares mean differences in HbA1c from baseline for the HRS-7535 30 mg, HRS-7535 60 mg and placebo groups were -16 mmol/mol (95% CI -19, -14) (-1.5% [95% CI -1.7, -1.3]), -20 mmol/mol (95% CI -22, -17) (-1.8% [95% CI -2.0, -1.6]) and -4 mmol/mol (95% CI -7, -2) (-0.4% [95% CI -0.6, -0.2]), respectively (p<0.0001 for both HRS-7535 doses vs placebo). The proportions of participants achieving HbA1c <53 mmol/mol (7.0%) were 51.0% in the HRS‑7535 30 mg group, 66.0% in the HRS‑7535 60 mg group, and 9.8% in the placebo group; the corresponding proportions for HbA1c ≤48 mmol/mol (6.5%) were 35.3%, 37.7% and 3.9%, respectively. Body weight loss was -2.4% in the HRS-7535 60 mg group vs -0.7% in the placebo group. Most treatment-emergent adverse events (TEAEs) were mild to moderate, and gastrointestinal adverse events were the most common. No severe hypoglycaemia was reported. The only TEAE that led to treatment discontinuation occurred in the placebo group.

CONCLUSIONS/INTERPRETATION: Treatment with HRS-7535 resulted in significant improvements in glycaemic management in participants with type 2 diabetes, and the drug exhibited a favourable safety profile. To address a significant clinical data void, this research focused on the addition of HRS‑7535 to the background regimen of metformin and SGLT2i for glycaemic management in participants with type 2 diabetes. Trial registration ClinicalTrials.gov NCT06393348. Funding This study was funded by Jiangsu Hengrui Pharmaceuticals.