OUTSTAND-2 was a multicenter, randomized, double-blind, double-dummy, active-comparator-controlled phase 3 trial conducted at 98 sites in China to evaluate once-daily oral safiglipron (proposed INN; HRS-7535) at doses of 30 mg, 60 mg and 90 mg versus dapagliflozin 10 mg. Eligible adults were aged 18–75 years with type 2 diabetes inadequately controlled on stable metformin monotherapy (baseline HbA1c 7.5–11.0%, BMI 19.0–40.0 kg/m2). The study included a 3-week single-blind run-in, a 32-week core treatment period, a 20-week active-treatment extension and a 2-week safety follow-up.
Between 27 September 2024 and 30 April 2025, 1,431 participants were screened and 810 were randomized: 202 to safiglipron 30 mg, 203 to safiglipron 60 mg, 203 to safiglipron 90 mg and 202 to dapagliflozin 10 mg. The randomized population had a mean HbA1c of 8.60%, a median diabetes duration of 5.0 years and comprised 35.7% women. A total of 809 participants received at least one dose and composed the safety population.
The prespecified primary endpoint was change from baseline in HbA1c at week 32 under a primary non-inferiority estimand (non-inferiority margin 0.4%). Key secondary endpoints included HbA1c target achievement, fasting plasma glucose (FPG) and percentage change in body weight at week 32. Supportive secondary and exploratory endpoints included indices of β cell function and insulin sensitivity (HOMA-β, HOMA-IR), post-prandial responses in a mixed-meal tolerance test, waist circumference, seven-point self-monitored blood glucose (SMBG) profiles, blood pressure, lipids, urinary albumin-to-creatinine ratio (UACR) and patient-reported treatment satisfaction (DTSQs). Safety assessments included adverse events, hypoglycemia, laboratory parameters, ECGs and diabetic retinopathy evaluation.
At week 32, changes from baseline in HbA1c versus dapagliflozin under the primary non-inferiority estimand were reported as follows: safiglipron 30 mg −0.30% (95% CI: −0.51 to −0.09), 60 mg −0.22% (−0.44 to −0.01) and 90 mg −0.40% (−0.62 to −0.19). All three doses met the prespecified non-inferiority criterion versus dapagliflozin (non-inferiority margin 0.4%; all P < 0.0001 for non-inferiority testing).
These results indicate that each tested dose of oral safiglipron produced HbA1c reductions that were not inferior to those achieved with dapagliflozin 10 mg at 32 weeks in this population on background metformin.
A prespecified treatment-policy estimand was used for sequential superiority testing. Under this estimand, safiglipron 90 mg met the prespecified statistical criterion for superiority versus dapagliflozin at week 32, with a treatment difference of −0.25% (95% CI: −0.45 to −0.05; one-sided P = 0.0067). Safiglipron 60 mg did not meet the superiority criterion (P = 0.0789), after which fixed-sequence testing stopped.
Rates of achieving commonly used glycemic targets favored safiglipron across doses. For HbA1c <7.0%, attainment rates were 54.9–63.5% with safiglipron compared with 36.5% with dapagliflozin. For the more stringent target of HbA1c ≤6.5%, rates were 38.9–48.6% with safiglipron versus 16.1% with dapagliflozin.
Rescue therapy use during the trial was low: 0.5–1.5% of participants in the safiglipron groups required rescue therapy versus 0% in the dapagliflozin group over the reported period.
Mean percentage changes in body weight at week 32 were reported as −2.35% (safiglipron 30 mg), −3.55% (60 mg), −4.17% (90 mg) and −3.60% (dapagliflozin). Fasting plasma glucose, seven-point SMBG profiles, waist circumference and indices of β cell function and insulin sensitivity (HOMA-β and HOMA-IR) showed varying degrees of improvement from baseline with both safiglipron and dapagliflozin, although the source provides summary statements rather than detailed numerical results for all of these measures in the text presented here.
Patient-reported treatment satisfaction (DTSQs) demonstrated changes from baseline with both agents; the source indicates varying degrees of improvement but does not report all detailed scores in the excerpt provided.
Exploratory endpoints included blood pressure, lipid parameters and UACR; the source notes these were prespecified exploratory endpoints but detailed outcomes for these measures were not reported in the provided text.
Gastrointestinal adverse events were more frequent with safiglipron than with dapagliflozin and were described as mostly mild or moderate in severity. Adverse-event–related treatment discontinuation occurred in 4.0% of participants in the safiglipron 30 mg and 60 mg groups, 3.9% in the safiglipron 90 mg group and 1.5% in the dapagliflozin group. No detailed safety laboratory or cardiovascular outcome data beyond these summaries are included in the provided excerpt.
Hypoglycemic episodes, laboratory parameters, ECG and diabetic retinopathy assessments were prespecified safety evaluations; the summary presented does not enumerate rates for hypoglycemia or other specific safety laboratory findings.
In adults with type 2 diabetes inadequately controlled with metformin, oral small-molecule GLP-1 receptor agonist safiglipron at doses of 30–90 mg once daily met non-inferiority to dapagliflozin 10 mg for HbA1c reduction at 32 weeks. Under a treatment-policy estimand, the 90 mg dose met a prespecified superiority criterion versus dapagliflozin. HbA1c target attainment rates favored safiglipron, and body-weight reductions were observed with both agents.
Gastrointestinal events were more common with safiglipron and led to higher discontinuation rates than with dapagliflozin, although most GI events were mild or moderate. The trial supports safiglipron as an effective oral non-peptide small-molecule GLP-1 receptor agonist option for this patient population.
Limitations and additional outcomes such as long-term cardiorenal effects, detailed subgroup analyses and comprehensive safety laboratory results are not reported in the excerpt provided and would require consultation of the full article or supplementary materials for complete evaluation.
ClinicalTrials.gov identifier: NCT06589765.