Efficacy and safety of cAMP-biased GLP-1 receptor agonist ecnoglutide versus dulaglutide in patients with type 2 diabetes and elevated glucose concentrations on metformin monotherapy (EECOH-2): a 52-week, multicentre, open-label, non-inferiority, randomised, phase 3 trial.

BACKGROUND: Ecnoglutide is a novel biased GLP-1 receptor agonist that preferentially activates the cAMP pathway over β-arrestin recruitment. We aimed to assess both non-inferiority and superiority of ecnoglutide versus dulaglutide, also a GLP-1 receptor agonist, in patients with type 2 diabetes. METHODS: We conducted a 52-week, open-label, active-controlled, phase 3 trial at 52 hospitals in China. Adults aged 18-75 years with a BMI of 20-35 kg/m, a diagnosis of type 2 diabetes, and elevated glucose concentrations on metformin monotherapy were included. Participants were randomly assigned (1:1:1) to receive subcutaneous ecnoglutide (0·6 mg or 1·2 mg) or dulaglutide (1·5 mg) once weekly. The primary endpoint was mean change from baseline in HbA at week 32 (non-inferiority for ecnoglutide 0·6 mg and 1·2 mg, with a 0·4% non-inferiority margin; superiority for ecnoglutide 1·2 mg) and was assessed in all randomly assigned participants who received at least one dose of study treatment (full analysis set). Safety was assessed in all randomly assigned participants who received at least one dose of study drug and had at least one safety evaluation after starting treatment. This trial is registered with ClinicalTrials.gov (NCT05680129) and has ended. FINDINGS: Between Jan 10 and May 30, 2023, 623 participants were randomly assigned, of whom 621 comprised the full analysis set (mean age 53·9 years [SD 10·1], 347 [56%] males, 274 [44%] females, and mean HbA 8·40% [SD 0·78]; 68·28 mmol/mol [8·56]; 206 in the ecnoglutide 0·6 mg group, 208 in the ecnoglutide 1·2 mg group, and 207 in the dulaglutide 1·5 mg group). At week 32, mean HbA reductions were 1·91% (SE 0·05; -20·86 mmol/mol [0·53]) with ecnoglutide 0·6 mg, 1·89% (0·05; -20·69 mmol/mol [0·54]) with ecnoglutide 1·2 mg, and 1·65% (0·05; -18·02 mmol/mol [0·53]) with dulaglutide. Estimated treatment differences versus dulaglutide were -0·26% (95% CI -0·39 to -0·13; -2·84 mmol/mol [-4·29 to -1·38]) with ecnoglutide 0·6 mg and -0·24% (-0·38 to -0·11; -2·67 mmol/mol [-4·14 to -1·20]; p=0·0002 for superiority) with ecnoglutide 1·2 mg. HbA reductions were sustained to week 52. During the 52 weeks, six (3%) of 206 patients in the ecnoglutide 0·6 mg group, eight (4%) of 208 patients in the ecnoglutide 1·2 mg group, and six (3%) of 207 patients in the dulaglutide group discontinued treatment due to adverse events. INTERPRETATION: Once-weekly ecnoglutide 0·6 mg and 1·2 mg were non-inferior to dulaglutide 1·5 mg in reducing HbA in adults with type 2 diabetes and elevated glucose concentrations on metformin monotherapy. Although the 1·2 mg dose showed statistically significantly greater reductions in HbA from baseline to week 32 than dulaglutide 1·5 mg, the difference was not considered clinically relevant. Both doses of ecnoglutide were well tolerated. These results suggest that ecnoglutide might offer a new treatment option for type 2 diabetes. FUNDING: Hangzhou Sciwind Biosciences.