A recent study comparing dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, with orforglipron, an oral nonpeptide glucagon-like peptide-1 (GLP-1) receptor agonist (RA), has found superior glycaemic control and weight loss with the latter.
The use of orforglipron among adults with type 2 diabetes (T2D) inadequately controlled with metformin also results in improved cardiometabolic parameters and demonstrates a safety profile similar to other GLP-1 RAs. [ADA 2026, abstract 1254-OR]
“Orforglipron demonstrated superior glycaemic control compared with dapagliflozin, with a tolerability profile consistent with the GLP-1 RA class, including increased rates of discontinuation due to adverse events (AEs), positioning it as a potential effective oral treatment option for T2D,” said the authors led by Dr Michelle D Welch, Consano Clinical Research, San Antonio, Texas, US.
Welch and her team assessed a total of 1,404 adults between 10 January 2024 and 26 September 2025. Of these, 962 (mean age at baseline 56 years) with T2D (HbA1c ≥7.0 percent to ≤10.5 percent; duration 8.0 years) taking metformin (≥1,500 mg/day) with a BMI ≥23.0 kg/m2 were included in ACHIEVE-2, a 40-week, phase 3, open-label, randomized study.
Eligible patients were randomly assigned in a 1:1:1:1 ratio to receive once-daily orforglipron 3 (n=240), 12 (n=241), 36 mg (n=241) or dapagliflozin 10 mg (n=240). The primary endpoint was the change in HbA1c at week 40 from baseline.
Superiority
At week 40, the change in mean HbA1c from baseline was ‒1.23 percent, ‒1.50 percent, and ‒1.56 percent with orforglipron 3, 12, and 36 mg, respectively, compared with ‒0.82 percent with dapagliflozin 10 mg, demonstrating superiority. [Lancet 2026;doi:10.1016/S0140-6736(26)00800-7]
The estimated difference of orforglipron with dapagliflozin was ‒0.42 percent (95 percent confidence interval [CI], ‒0.62 to ‒0.23), ‒0.70 percent (95 percent CI, ‒0.90 to ‒0.49), and ‒0.75 percent (95 percent CI, ‒0.96 to ‒0.55) with the 3-, 12-, and 36-mg doses, respectively (p<0.0001 for all).
“At week 40, all orforglipron doses were superior to dapagliflozin in reducing HbA1c,” said Welch, noting that the 12- and 36-mg doses were superior for weight loss, while orforglipron 36 mg was superior for reductions in triglycerides, nonhigh-density lipoprotein cholesterol, and systolic blood pressure.
Safety profile
Mild to moderate gastrointestinal events were the most common AEs, occurring in 112 of 240 patients (47 percent) receiving orforglipron 3 mg, 112 of 241 (46 percent) receiving 12 mg, and 130 of 241 (54 percent) taking 36 mg compared with 29 of 240 (12 percent) on dapagliflozin.
Notably, more treatment discontinuations occurred with orforglipron 3 mg (35 of 240, 15 percent), 12 mg (44 of 241, 18 percent), and 36 mg (47 of 241, 20 percent) than with dapagliflozin (14 of 240, 6 percent). On the other hand, severe episodes of hypoglycaemia did not occur in either group.
“The most frequent AEs associated with orforglipron were mild to moderate gastrointestinal AEs occurring mostly during dose escalation,” said Welch.