Safiglipron meets HbA1c noninferiority endpoint versus dapagliflozin in phase 3 trial

The phase 3 OUTSTAND-2 trial, reported in Nature Medicine, randomized 810 adults at 98 sites in China to once-daily oral safiglipron 30, 60 or 90 mg or dapagliflozin 10 mg. Participants had type 2 diabetes inadequately controlled with metformin and a mean baseline HbA1c of 8.60%. The double-blind, double-dummy trial assessed HbA1c change at 32 weeks, followed by a 20-week active-treatment extension. Safiglipron is a small-molecule GLP-1 receptor agonist administered without fasting or dietary restrictions.

Under the primary noninferiority estimand, HbA1c fell by 1.58, 1.50 and 1.68 percentage points with safiglipron 30, 60 and 90 mg, respectively, versus 1.28 points with dapagliflozin. All doses met the 0.4-point noninferiority margin. Under the treatment-policy estimand, 90 mg established superiority, with a difference of −0.25 points (95% CI −0.45 to −0.05). The 60-mg dose did not establish superiority, stopping fixed-sequence testing; subsequent hypotheses were not confirmatory.

HbA1c below 7.0% was achieved by 54.9–63.5% of safiglipron recipients versus 36.5% with dapagliflozin. Mean weight changes were −2.35%, −3.55% and −4.17% across increasing safiglipron doses versus −3.60% with dapagliflozin.

Gastrointestinal adverse events were more frequent with safiglipron and mostly mild or moderate. Adverse events caused discontinuation in 3.9–4.0% versus 1.5% with dapagliflozin. Findings support glycemic efficacy, but the primary endpoint was a surrogate, not cardiovascular or renal outcomes, and recruitment exclusively in China limits generalizability.