For adults with early type 2 diabetes, a once-daily pill may soon offer the benefits of injectable GLP-1 therapies—without the needle.
New results from the phase 3 ACHIEVE-1 trial, presented at the American Diabetes Association’s 85th Scientific Sessions, showed that orforglipron, an oral small-molecule GLP-1 receptor agonist, significantly lowered blood sugar and body weight in adults whose diabetes was not yet treated with medication. The study, led by Julio Rosenstock, MD, and colleagues, demonstrated these findings.
The 40-week trial enrolled 559 participants whose type 2 diabetes was inadequately controlled with diet and exercise alone. Patients were randomized to receive one of three daily doses of orforglipron (3 mg, 12 mg, or 36 mg) or placebo.
All doses of orforglipron led to significantly greater reductions in glycated hemoglobin (HbA1c) compared with placebo. HbA1c decreased by 1.24 percentage points with 3 mg, 1.47 with 12 mg, and 1.48 with 36 mg, versus 0.41 with placebo. Most participants receiving orforglipron achieved HbA1c levels less than 7%, with many reaching 6.5% or lower.
Orforglipron also resulted in weight loss. The 36 mg group lost an average of 7.2 kg (7.6%), the 12 mg group 5.2 kg (5.8%), and the 3 mg group 4.2 kg (4.5%), compared to 1.5 kg (1.7%) with placebo. Over 40% of participants on orforglipron lost at least 5% of their body weight; up to 30% lost at least 10%.
Additional improvements included reductions in fasting glucose (31 to 37 mg/dL with orforglipron compared with 11 mg/dL with placebo), triglycerides, and non-HDL cholesterol, particularly at higher doses. Systolic blood pressure also declined modestly following treatment.
No cases of severe hypoglycemia were reported. The most common adverse events were gastrointestinal—nausea, diarrhea, constipation, and vomiting—mostly during dose escalation. These were generally mild to moderate. Fewer than 6% of participants discontinued treatment due to adverse events.
Participants were enrolled from the United States, Mexico, Japan, India, and China. The average duration of diabetes was 4.4 years, with a baseline HbA1c of 8.0%.
Orforglipron may offer a convenient oral treatment option for early type 2 diabetes, delivering both glycemic and weight benefits without injections. Longer-term studies are underway to evaluate sustained outcomes and safety.
The trial was funded by Eli Lilly (ClinicalTrials.gov identifier NCT05971940).
Full disclosures can be found in the published study.
