ACHIEVE-2: Oral Orforglipron Outperformed Dapagliflozin on Blood Sugar in Phase 3 Diabetes Trial, Lancet Reports

The Lancet published results on July 11, 2026 from ACHIEVE-2, a phase 3 trial comparing the oral GLP-1 receptor agonist orforglipron with the SGLT2 inhibitor dapagliflozin in adults with type 2 diabetes whose blood sugar was not adequately controlled on metformin alone. The trial was funded by Eli Lilly and Company, which developed orforglipron, and its results were reported by the ACHIEVE-2 Trial Investigators led by corresponding author Yanyun Chen of Eli Lilly.

Orforglipron is a non-peptide small molecule that activates the GLP-1 receptor, taken as a once-daily tablet rather than an injection. The FDA approved it under the brand name Foundayo in 2026 for chronic weight management in adults with obesity, or overweight with weight-related conditions, based on a separate obesity trial program. It does not yet hold FDA approval for type 2 diabetes; ACHIEVE-2 is part of the ACHIEVE program of phase 3 trials evaluating that indication.

The study enrolled adults using at least 1,500 mg of metformin daily who had HbA1c between 7.0% and 10.5%, stable body weight, and a BMI of 23 kg/m2 or higher. Between January 10, 2024 and September 26, 2025, investigators at 73 sites in six countries randomly assigned 962 participants in equal groups to once-daily oral orforglipron at 3 mg, 12 mg, or 36 mg, or to once-daily oral dapagliflozin 10 mg, an already-approved SGLT2 inhibitor. The study was open-label, though the orforglipron dose itself was blinded. At baseline, participants averaged 56.1 years of age, had type 2 diabetes for a mean of 8.0 years, an HbA1c of 8.14%, and a BMI of 32.6 kg/m2.

The primary endpoint was the change in HbA1c from baseline to week 40, tested against a non-inferiority margin of 0.3 percentage points relative to dapagliflozin. Mean HbA1c fell by 1.23% with orforglipron 3 mg, 1.50% with 12 mg, and 1.56% with 36 mg, compared with 0.81% for dapagliflozin. Every orforglipron dose met the non-inferiority margin, and the estimated treatment differences, ranging from -0.42 to -0.75 percentage points versus dapagliflozin, were statistically significant at each dose (p<0.0001 for all three comparisons).

Adverse events followed the pattern seen in other GLP-1 receptor agonist trials. Gastrointestinal events, mostly mild to moderate, occurred in 47% of participants on orforglipron 3 mg, 46% on 12 mg, and 54% on 36 mg, compared with 12% on dapagliflozin. Discontinuation of the assigned study drug was also more frequent with orforglipron, ranging from 15% to 20% across the three doses, versus 6% with dapagliflozin. The investigators reported no severe episodes of hypoglycemia in either arm.

The authors concluded that orforglipron demonstrated superior glycemic control compared with dapagliflozin, with a tolerability profile consistent with the GLP-1 receptor agonist class, including higher rates of discontinuation due to adverse events. The trial is registered on ClinicalTrials.gov as NCT06192108 and is listed as completed.

ACHIEVE-2 measured a single glucose-control endpoint over 40 weeks in a trial funded and staffed in part by orforglipron's manufacturer, and it does not by itself establish an approved diabetes indication for the drug. The findings describe average effects in a defined trial population rather than guidance for any individual patient, and orforglipron remains approved in the United States only for chronic weight management as of this trial's publication.