Efficacy and Safety of HD-6277, a Novel G Protein-Coupled Receptor 40 Agonist, in Individuals with Type 2 Diabetes Mellitus: A Double-Blind, Randomized, Placebo-Controlled, Parallel-Group, Multicenter Phase 2 Clinical Trial

Abstract

Background: This study assessed the efficacy and safety of HD-6277, a novel oral G protein-coupled receptor 40 (GPR40) agonist in adults with inadequate control of type 2 diabetes mellitus (T2DM). Methods: This double-blind, randomized, placebo-controlled phase 2 trial recruited 112 individuals aged 18-75 years with T2DM and glycosylated hemoglobin (HbA1c) levels between 7.0% and 10.0% while on diet and exercise alone for at least 8 weeks before screening. Parallel-group randomized trials of HD-6277 (50 and 100 mg groups vs. placebo) were conducted for 12 weeks. The primary outcome was the change in HbA1c levels from baseline to week 12. Secondary outcomes included changes in HbA1c, fasting plasma glucose (FPG), postprandial glucose, insulin, glycoalbumin, and C-peptide at weeks 4, 8, and 12. Results: At week 12, HD-6277 at 50 and 100 mg demonstrated statistically significant reductions in HbA1c compared to placebo, with least square (LS) mean differences of-0.73% (95% confidence interval [CI], -1.11 to-0.35; P= 0.0002) and-0.85% (95% CI, -1.21 to-0.50; P<0.0001), respectively. Both doses also produced clinically meaningful reductions in FPG. Additionally, HD-6277 at 100 mg significantly increased the insulinogenic index compared to placebo, with an LS mean difference of 1.91 (95% CI, 0.34 to 3.48; P= 0.0175). No clinically relevant treatment-related adverse events were observed. Conclusion: HD-6277 at 50 and 100 mg improved glycemic control and was well-tolerated in adults with T2DM inadequately managed with diet and exercise. GPR40 agonists may offer a promising new therapeutic option for T2DM.