N Engl J Med

ADA 2025: Oral GLP-1 significantly lowered A1c and weight in early T2DM

June 24, 2025

Orforglipron offered a potent, once-daily option for early T2DM, with clinically meaningful reductions in both A1c and weight, according to results shared at the American Diabetes Association (ADA) 85^th Scientific Sessions. Its oral formulation may improve accessibility and adherence relative to injectable GLP-1 therapies.

Study details: In the phase 3 ACHIEVE-1 trial (NCT05971940), 559 adults with early T2DM (A1c, 7.0–9.5%) managed by diet and exercise were randomized to receive orforglipron (3 mg, 12 mg, or 36 mg) or placebo once daily for 40 weeks. The primary endpoint was change in A1c; a key secondary endpoint was percent change in body weight.

Results: All orforglipron doses significantly reduced A1c compared with placebo. At week 40, mean A1c reductions were −1.24% (3 mg), −1.47% (12 mg), and −1.48% (36 mg), vs. −0.41% with placebo (p<0.001 for all). Corresponding mean A1c levels were 6.5% to 6.7%. Percent change in weight loss was dose-dependent: −4.5% (3 mg), −5.8% (12 mg), and −7.6% (36 mg), compared with −1.7% with placebo. GI side effects were common but mostly mild-to-moderate and occurred during dose escalation. No severe hypoglycemia was reported.

Source:

Rosenstock J, et al; ACHIEVE-1 Trial Investigators. (2025, June 21). N Engl J Med. Orforglipron, an Oral Small-Molecule GLP-1 Receptor Agonist, in Early Type 2 Diabetes. https://pubmed.ncbi.nlm.nih.gov/40544435/