Efficacy and safety of oral orforglipron in patients with type 2 diabetes: a multicentre, randomised, dose-response, phase 2 study

This phase 2 clinical trial, published in the Lancet, evaluated the efficacy and safety of orforglipron, an oral non-peptide GLP-1 receptor agonist, in 383 patients with type 2 diabetes inadequately controlled with metformin. The multicenter, randomized, dose-response study compared multiple doses of orforglipron with placebo and dulaglutide 1.5 mg subcutaneous as an active comparator over 26 weeks.

The results demonstrated significant dose-dependent reductions in key parameters:

• HbA1c: Reductions of up to -2.1 percentage points with the highest orforglipron doses, comparable or superior to the -1.1% reduction with dulaglutide
• Body weight: Loss of up to -10.1 kg with orforglipron versus -3.9 kg with dulaglutide
• Fasting glucose: Significant reduction across all active doses

The revolutionary aspect of this study is that orforglipron is a small non-peptide molecule that can be administered orally once daily, unlike traditional GLP-1 agonists which are peptides requiring subcutaneous injection. This overcomes one of the main barriers to treatment adherence with GLP-1 agonists.

Adverse events were predominantly gastrointestinal (nausea, vomiting, diarrhea), consistent with the class, and were attenuated by gradual dose escalation. These data positioned orforglipron as a potentially transformative advance in the treatment of type 2 diabetes, combining the efficacy of injectable GLP-1 agonists with the convenience of oral administration.