Safiglipron Noninferior to Dapagliflozin for HbA1c Lowering in Phase 3 OUTSTAND-2

The oral small-molecule glucagon-like peptide-1 (GLP-1) receptor agonist safiglipron (HRS-7535) was noninferior to dapagliflozin for lowering hemoglobin A1C (HbA1c) at all 3 doses tested in adults with type 2 diabetes inadequately controlled with metformin, according to phase 3 results published in Nature Medicine. The 90mg dose also met the prespecified criterion for superiority.

Safiglipron is taken without fasting or dietary restrictions. The investigators said OUTSTAND-2 is, to their knowledge, the first double-blind phase 3 trial to compare an oral small-molecule GLP-1 receptor agonist with a sodium-glucose cotransporter 2 (SGLT2) inhibitor.

The multicenter, double-dummy trial ran at 98 sites in China. It randomized 810 adults with a mean baseline HbA1c of 8.60% to once-daily oral safiglipron 30mg, 60mg, or 90mg or to dapagliflozin 10mg for 32 weeks, followed by a 20-week extension. At week 32, least-squares mean HbA1c fell by 1.58%, 1.50%, and 1.68% with the 3 safiglipron doses, respectively, compared with 1.28% with dapagliflozin (noninferiority margin, 0.4%). Under the treatment policy estimand, safiglipron 90mg was superior to dapagliflozin (difference, −0.25%; 95% CI, −0.45 to −0.05). The 60mg dose was not, so fixed-sequence testing stopped.

Under the efficacy estimand, 54.9% to 63.5% of safiglipron recipients reached HbA1c <7.0%, compared with 36.5% of dapagliflozin recipients. Mean body weight fell by 2.35% to 4.17% with safiglipron and by 3.60% with dapagliflozin. Weight loss was smaller with 30mg than with dapagliflozin, and the differences for 60mg and 90mg were not statistically significant. Gastrointestinal adverse events, including nausea, vomiting, and diarrhea, were more frequent with safiglipron and were mostly mild to moderate. Adverse events led to permanent treatment discontinuation in 3.9% to 4.0% of safiglipron recipients and 1.5% of dapagliflozin recipients. No severe hypoglycemia was reported.

The authors wrote that testing stopped at the 60mg superiority comparison, so later key secondary findings should be read as supportive rather than confirmatory. They also noted that enrolling only Chinese participants may limit generalizability. Long-term cardiovascular and kidney outcomes remain undetermined and are being studied in the ongoing RENEW-CKD trial.

Source: Guo L, Yu D, Xu Y, et al. Oral small-molecule GLP-1RA safiglipron versus dapagliflozin in type 2 diabetes: a randomized, double-blind, active-comparator-controlled phase 3 trial. Nat Med. Published online October 5, 2026. doi:10.1038/s41591-026-04713-y