Oral Orforglipron Noninferior, Superior to Oral Semaglutide for T2DM

THURSDAY, March 5, 2026 (HealthDay News) — For adults with type 2 diabetes inadequately controlled with metformin, oral orforglipron, a glucagon-like peptide-1 (GLP-1) receptor agonist, is noninferior and superior to oral semaglutide for mean change in hemoglobin A1c (HbA1c), according to a study published online Feb. 26 in The Lancet.

Julio Rosenstock, M.D., from the University of Texas in Dallas, and colleagues conducted a 52-week randomized trial involving adults with type 2 diabetes inadequately controlled with metformin, HbA1c between 7.0 and 10.5 percent, and body mass index at least 25 kg/m² from 131 medical research centers. Participants were randomly assigned to oral orforglipron (12 mg or 36 mg) or oral semaglutide (7 mg or 14 mg; 424, 423, 426, and 425 participants, respectively).

The researchers found that for the treatment regimen estimand, the mean changes at week 52 from a baseline HbA1c of 8.3 percent were −1.71, −1.91, −1.23, and −1.47 percent with orforglipron 12 mg, orforglipron 36 mg, semaglutide 7 mg, and semaglutide 14 mg, respectively. The primary objective of noninferiority was met; superiority was demonstrated for both orforglipron doses versus both semaglutide doses, including orforglipron 12 mg versus semaglutide 14 mg. Gastrointestinal events were the most frequent adverse events, which were mainly mild to moderate in severity. Study treatment was discontinued for more participants in the orforglipron groups than in the semaglutide groups (9 and 10 versus 4 and 5 percent, respectively); the orforglipron groups also had a greater mean increase in pulse rate.

“Orforglipron represents a potential new therapeutic option for individuals with type 2 diabetes considering initiation of GLP-1 receptor agonist therapy who might prefer an alternative to the subcutaneous route of administration,” the authors write.

Several authors disclosed ties to biopharmaceutical companies, including Eli Lilly, which is developing orforglipron and funded the study.

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