Orforglipron added to titrated insulin glargine significantly reduces HbA1c in type 2 diabetes

Achieving optimal glycemic control in type 2 diabetes (T2DM) remains a significant challenge, particularly for patients already on insulin therapy. Many individuals struggle with inadequate control despite standard-of-care treatments, leading to increased risk of complications. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are highly effective, but most are injectable, posing adherence barriers. There's a critical need for convenient, oral non-peptide GLP-1 RAs that can effectively complement existing insulin regimens, offering improved glycemic outcomes and potentially weight management without the burden of injections.

This was a randomized, double-blind, phase 3 study (ACHIEVE-5) conducted across 72 sites globally, enrolling 546 adults with type 2 diabetes who had inadequate glycemic control despite taking insulin glargine (with or without metformin/SGLT2 inhibitors). Participants were randomized (1:1:1:1) to receive once-daily Orforglipron at 3 mg (n=137), 12 mg (n=132), or 36 mg (n=136) dosages, or placebo (n=141), for 40 weeks. All groups continued titrated insulin glargine. The primary outcome measured was the mean change in hemoglobin A1c (HbA1c) from baseline to week 40 for the 12 mg and 36 mg doses.

Among the 546 randomized participants, 507 (92.9%) completed the 40-week trial. At week 40, all Orforglipron dosages demonstrated superior reductions in HbA1c compared to placebo. The mean HbA1c changes from baseline were -1.58% with Orforglipron 3 mg, -1.88% with 12 mg, and -1.82% with 36 mg once daily, versus -0.79% with placebo.

Each dosage of Orforglipron was statistically superior to placebo, with estimated treatment differences of -0.78% (95% CI, -1.02% to -0.55%) for 3 mg once daily, and -1.08% (95% CI, -1.33% to -0.83%) for 12 mg once daily. The 36 mg dose also showed significant superiority, with its estimated treatment difference reported as -1.03% (95% CI, -1.28% to -0.78%). Baseline mean HbA1c was 8.50% (SD, 0.95%), indicating a population with substantial glycemic burden.