Glucagon-like peptide-1 (GLP-1) receptor agonists improve glycemic control, promote weight loss and have demonstrated cardiorenal benefits in large outcome trials. Many approved GLP-1 receptor agonists are injectable; oral peptide formulations require fasting or fluid restrictions, which can limit convenience. Safiglipron (HRS-7535) is a structurally distinct, once-daily oral small-molecule GLP-1 receptor agonist developed to avoid peptide-related dosing constraints. Phase 2 studies showed reductions in HbA1c, body weight and albuminuria, supporting progression to phase 3 evaluation.
OUTSTAND-1 was a multicenter, randomized, double-blind, placebo-controlled phase 3 trial conducted at 46 sites in China. Adults aged 18–75 years with type 2 diabetes managed with diet and exercise alone (no glucose-lowering medication for at least 2 months), HbA1c 7.0–10.0% and BMI 19.0–40.0 kg m−2 were eligible. The core study included a 32-week placebo-controlled period followed by a 20-week active-treatment extension.
Between 21 October 2024 and 31 March 2025, 475 individuals were screened; 375 entered a single-blind placebo run-in and 284 participants were randomized to once-daily safiglipron 30 mg (n=70), 60 mg (n=70), 90 mg (n=72) or placebo (n=72). Dose titration occurred in 30-mg increments every 4 weeks. Mean baseline HbA1c was 7.95% and median diabetes duration was 1.6 years; 33.1% of randomized participants were women.
The primary endpoint was the change in HbA1c from baseline to week 32. Placebo-adjusted treatment differences (treatment policy estimand) in HbA1c change at week 32 were:
All three doses achieved statistical significance versus placebo (P < 0.0001). These results indicate robust glycemic lowering across the tested dose range in this population with early type 2 diabetes.
Secondary outcomes generally favoured safiglipron over placebo. Proportions achieving prespecified glycemic targets at week 32 were substantially higher with safiglipron:
Placebo-adjusted fasting plasma glucose differences at week 32 were −1.58, −1.68 and −2.08 mmol L−1 for 30 mg, 60 mg and 90 mg respectively (all P < 0.0001). Other secondary measures that favoured safiglipron included attainment of HbA1c <5.7%, improvements in postprandial glycaemia, HOMA-β (a marker of β cell function), HOMA-IR (insulin resistance), disposition index and waist circumference. Use of rescue therapy was reduced in safiglipron groups. Insulin and C-peptide responses varied by dose. Changes in treatment satisfaction were limited.
Body weight changes versus placebo were modest and showed a dose-related pattern: −0.65% (30 mg), −2.23% (60 mg) and −3.56% (90 mg). The trial also reported favourable effects on postprandial glycaemia and measures related to β cell function and insulin resistance, as noted above. Specific numerical results for all secondary metabolic markers beyond those summarized here were reported in the source article.
Gastrointestinal adverse events were the most commonly reported safety events and were mostly mild or moderate in severity. Adverse-event–related discontinuation during the treatment period occurred in 1.4% of participants receiving safiglipron 30 mg, 2.9% receiving 60 mg, 6.9% receiving 90 mg and 0% receiving placebo. Overall reasons for treatment discontinuation across the 52-week period most commonly included participant withdrawal and adverse events. The authors reported that the overall safety profile supported once-daily oral safiglipron as an acceptable treatment option in this population.
Among the 284 randomized participants, 243 (85.6%) completed the 52-week treatment period: 64 (91.4%) in the 30-mg group, 60 (85.7%) in the 60-mg group, 60 (83.3%) in the 90-mg group and 59 (81.9%) in the placebo group. Trial follow-up was completed by 261 participants (91.9%). Across the 52-week period, reasons for discontinuation were most commonly participant withdrawal (22 participants, 7.7%) and adverse events (12 participants, 4.2%).
In OUTSTAND-1, once-daily oral safiglipron produced clinically meaningful and statistically significant reductions in HbA1c and fasting plasma glucose compared with placebo in adults with early type 2 diabetes managed with diet and exercise alone. A high proportion of participants attained standard glycemic targets, and metabolic secondary endpoints generally favoured safiglipron. Weight reductions were modest and dose-related. The safety profile was characterized predominantly by gastrointestinal events that were mostly mild or moderate, with low rates of discontinuation at the lower doses and higher discontinuation at the 90-mg dose.
These phase 3 results support the efficacy of oral safiglipron as a monotherapy option in this population. Details on longer-term outcomes, broader populations and comparative effectiveness versus other GLP-1 receptor agonists were not reported in this source and would be needed to further define the clinical role of safiglipron.