Oral small-molecule GLP-1RA safiglipron versus dapagliflozin in type 2 diabetes: a randomized, double-blind, active-comparator-controlled phase 3 trial
- Design
- Randomized trial · 810 participants · Biomarker outcome
- Match to healthy normal-weight adults aged 55–75
- Different populationINDIRECT: all participants had type 2 diabetes inadequately controlled with metformin (mean HbA1c 8.60%); age and BMI are not reported.
- Could weight loss explain it?
- Not applicableNot applicable: the primary outcome is HbA1c change, which is glycaemic control itself; body weight fell in all arms (-2.35% to -4.17% with safiglipron, -3.60% with dapagliflozin).
- Study tier
- Study tier 2MODERATE: an 810-participant double-blind phase 3 randomized trial with an active comparator; held below HIGH because the primary endpoint is a 32-week glycaemic measure, not a clinical event.
- Assessment
- Version 3 · Two independent AI reviews agreed · Oct 19, 2026
Study facts come from the paper. Population match, weight-loss explanation and study tier are our judgments, made against the reference group of healthy normal-weight adults aged 55–75.
This double-blind randomized trial in China gave 810 adults with type 2 diabetes on metformin one of three doses of oral safiglipron or dapagliflozin for 32 weeks. All three doses lowered HbA1c at least as well as dapagliflozin and the 90 mg dose did better, but the 60 mg dose did not reach superiority. Weight loss was similar to or smaller than with dapagliflozin, and gut side effects and stopping for side effects were more common with safiglipron.
01Findings
What the study reported
- Drugs
- Safiglipron
- Dose
- safiglipron 30 mg, 60 mg or 90 mg
- Comparator
- dapagliflozin 10 mg
- Treatment duration
- 32 weeks, followed by a 20-week active-treatment extension
- Route
- oral
- Primary outcome
- change from baseline in HbA1c at week 32 (non-inferiority versus dapagliflozin)
- Effect
- HbA1c differences versus dapagliflozin -0.30%, -0.22% and -0.40% for 30, 60 and 90 mg (non-inferior for all); superiority met for 90 mg (-0.25%) but not 60 mg (P = 0.0789); weight change -2.35%, -3.55%, -4.17% versus -3.60% with dapagliflozin
- 95% confidence interval
- 95% CI: -0.51 to -0.09 (30 mg), -0.44 to -0.01 (60 mg), -0.62 to -0.19 (90 mg)
- P value
- all P < 0.0001 for non-inferiority; 90 mg superiority one-sided P = 0.0067; 60 mg P = 0.0789
- Follow-up
- week 32 (primary endpoint), followed by a 20-week active-treatment extension
- Adverse events
- Gastrointestinal adverse events were more frequent with safiglipron and mostly mild or moderate; adverse events led to discontinuation in 4.0%, 4.0%, 3.9% versus 1.5% with dapagliflozin; rescue therapy 0.5-1.5% versus 0%
- Limitations
- Conducted only in China against an active comparator rather than placebo, with a 32-week glycaemic primary endpoint; superiority was shown for the 90 mg dose only, after which fixed-sequence testing stopped, and several authors were employees of the developer.
Who was studied
- Sex distribution
- 35.7% women
- Obesity status
- not reported in abstract
- Diabetes status
- type 2 diabetes required (inadequately controlled with metformin)
- Cvd status
- not reported in abstract
- Ckd status
- not reported in abstract
- Baseline condition
- type 2 diabetes inadequately controlled with metformin
- Sample size
- 810
- Inclusion exclusion
- adults with type 2 diabetes inadequately controlled with metformin, at 98 sites in China
Study quality details
- Study design
- Randomized controlled trial
- Sample size
- 810
- Randomization
- yes
- Blinding
- double-blind
- Comparator
- dapagliflozin 10 mg
- Follow up duration
- week 32 (primary endpoint), followed by a 20-week active-treatment extension
- Outcome type
- biomarker
- Replication
- not assessed
- Consistency with other evidence
- not assessed
- Population applicability
- INDIRECT
- Statistical precision
- CI reported: 95% CI: -0.51 to -0.09 (30 mg), -0.44 to -0.01 (60 mg), -0.62 to -0.19 (90 mg)
- Risk of bias
- not assessed
- Funding conflicts
- unclear
- Peer review status
- yes
02Funding
Funding and conflicts
- Funding
- not reported in abstract
- Industry funded
- Unclear
- Manufacturer
- not stated in source
- Sponsor role
- not reported in abstract
- Author conflicts
- Five authors were Jiangsu Hengrui Pharmaceuticals employees at the time of the study, and three declare a patent pending relating to safiglipron.
- Independent replication
- unknown
- Notes
- Authors declare relationships with the drug's manufacturer: Jiangsu Hengrui Pharmaceuticals (five employees; three with a patent pending relating to safiglipron).
Funding is shown on every study and never used to score it.
04Source
The source, as retrieved
Abstract
Safiglipron is an oral small-molecule glucagon-like peptide-1 (GLP-1) receptor agonist administered without fasting or dietary restrictions. We evaluated its efficacy and safety versus dapagliflozin in OUTSTAND-2, a phase 3, multicenter, randomized, double-blind, double-dummy, active-comparator-controlled trial conducted at 98 sites in China. We randomized 810 adults (mean hemoglobin A1C (HbA1c) 8.60%, median diabetes duration 5.0 years, 35.7% women) to safiglipron 30 mg (n = 202), safiglipron 60 mg (n = 203), safiglipron 90 mg (n = 203) or dapagliflozin 10 mg (n = 202) for 32 weeks, followed by a 20-week active-treatment extension. For the primary endpoint, treatment differences versus dapagliflozin in change from baseline in HbA1c at week 32 under the primary non-inferiority estimand were -0.30% (95% confidence interval (CI): -0.51 to -0.09), -0.22% (-0.44 to -0.01) and -0.40% (-0.62 to -0.19) for safiglipron 30 mg, 60 mg and 90 mg, respectively, establishing non-inferiority for all three doses (all P < 0.0001; non-inferiority margin 0.4%). Under the treatment policy estimand, 90 mg met the prespecified statistical criterion for superiority (difference -0.25%; 95% CI: -0.45 to -0.05; one-sided P = 0.0067), whereas 60 mg did not (P = 0.0789), after which fixed-sequence testing stopped. HbA1c target attainment rates with safiglipron versus dapagliflozin were 54.9-63.5% versus 36.5% for HbA1c <7.0% and 38.9-48.6% versus 16.1% for HbA1c ≤6.5%. Mean body weight changes were -2.35%, -3.55%, -4.17% and -3.60% for safiglipron 30 mg, safiglipron 60 mg, safiglipron 90 mg and dapagliflozin, respectively. Fasting plasma glucose, seven-point self-monitored blood glucose profiles, waist circumference, HOMA-β, HOMA-IR and changes in treatment satisfaction showed varying degrees of improvement from baseline with both safiglipron and dapagliflozin. Rescue therapy was used by 0.5-1.5% versus 0% of participants, respectively. Gastrointestinal adverse events were more frequent with safiglipron and mostly mild or moderate; adverse events led to treatment discontinuation in 4.0%, 4.0%, 3.9% and 1.5% of participants, respectively. Safiglipron provides an effective oral treatment option for adults with type 2 diabetes inadequately controlled with metformin. ClinicalTrials.gov identifier: NCT06589765 .