Orals showdown: GLP-1 tops SGLT2 on A1c in diabetes

Clinical takeaway: An oral GLP-1 that tops dapagliflozin on A1c is worth watching, but the head-to-head measured glucose only, so dapagliflozin's heart and kidney benefits still will decide many second-line calls.

GLP-1 receptor agonists lower glucose sharply but have mostly meant an injection. Orforglipron, a once-daily oral GLP-1 agonist now approved for obesity as Foundayo, could bring that potency to a pill in diabetes too. ACHIEVE-2 tested it head-to-head against dapagliflozin, a widely used oral SGLT2 inhibitor, in adults whose type 2 diabetes was not controlled on metformin.

Choosing what to add after metformin is a routine call, and the choice often splits between injectable incretins and oral agents like SGLT2 inhibitors and sulfonylureas. An oral GLP-1 would blur that line, offering incretin-level control without a needle. Dapagliflozin makes a demanding yardstick: oral, established, and carrying proven cardiovascular and kidney benefit.

All three orforglipron doses were non-inferior to dapagliflozin, and in fact beat it. At week 40, HbA1c fell by 1.23% to 1.56% across the 3 mg, 12 mg, and 36 mg doses, versus 0.81% with dapagliflozin, for treatment differences of 0.42% to 0.75%. Mild-to-moderate GI events hit 47% to 54% of orforglipron patients versus 12% on dapagliflozin, and discontinuations rose with dose to 15% to 20% versus 6%. No severe hypoglycemia events occurred in any arm.

This study, ACHIEVE-2, randomized 962 adults on metformin, 1:1:1:1, to once-daily oral orforglipron 3 mg, 12 mg, or 36 mg, or dapagliflozin 10 mg, across 73 sites in six countries over 40 weeks. The trial was open-label, with orforglipron doses blinded. Baseline HbA1c averaged 8.14% and BMI 32.6. Eli Lilly funded the study.

An oral GLP-1 that beats an SGLT2 inhibitor on glucose is a real option in patients where A1c is the priority and cardiorenal protection is not the deciding factor. Orforglipron is approved only in obesity thus far.

Source: Welch M, et al. Lancet. 2026 Jul 11. Orforglipron compared with dapagliflozin in adults with type 2 diabetes and inadequate glycaemic control with metformin (ACHIEVE-2): a multicentre, randomised, non-inferiority, open-label, phase 3 trial