Oral Safiglipron Demonstrates Glycemic Efficacy in Phase 3 Trial of Early Type 2 Diabetes

A Phase 3 trial published in Nature Medicine evaluated safiglipron (HRS-7535), developed by Jiangsu Hengrui Pharmaceuticals Co., Ltd. (Hengrui Pharma), an oral small-molecule glucagon-like peptide-1 (GLP-1) receptor agonist, in adults with type 2 diabetes inadequately controlled with diet and exercise alone. The OUTSTAND-1 study (NCT06672172) assessed three once-daily doses of safiglipron over 32 weeks, followed by a 20-week active-treatment extension.

Phase 3 Study Evaluated Three Doses

OUTSTAND-1 was a multicenter, randomized, double-blind, placebo-controlled Phase 3 trial conducted at 46 sites in China. Between October 2024 and March 2025, 475 individuals were screened and 284 were randomized to receive safiglipron 30 mg, 60 mg or 90 mg once daily, or placebo.

The treatment groups included 70 participants receiving 30 mg, 70 receiving 60 mg, 72 receiving 90 mg and 72 receiving placebo. Participants were 18 to 75 years of age, had an HbA1c of 7.0% to 10.0%, and were managed with diet and exercise without glucose-lowering medication for at least two months before screening. Most participants had relatively early disease, with a median diabetes duration of 1.6 years. The mean baseline HbA1c was 7.95% and mean body mass index was 27.8 kg/m². Approximately one-third of participants had previously received glucose-lowering medication but had discontinued treatment before entering the study.

The primary endpoint was the change in HbA1c from baseline to Week 32. Safiglipron was administered once daily, with dose escalation used for participants assigned to the 60-mg and 90-mg groups.

Significant Reduction in HbA1c

At Week 32, all three safiglipron doses produced greater reductions in HbA1c than placebo. Under the treatment-policy estimand, the least-squares mean changes from baseline were −1.40% with 30 mg, −1.38% with 60 mg and −1.63% with 90 mg, compared with −0.18% with placebo.

The corresponding placebo-adjusted treatment differences were −1.22%, −1.20% and −1.45%, respectively, with all three comparisons reaching statistical significance at P<0.0001. The primary endpoint findings remained consistent across prespecified sensitivity analyses.

Glycemic target attainment also favored safiglipron. At Week 32, 71.4%, 77.1% and 77.8% of participants receiving 30 mg, 60 mg and 90 mg, respectively, achieved HbA1c below 7.0%, compared with 25.0% receiving placebo. HbA1c of 6.5% or below was achieved by 58.6%, 64.3% and 68.1% of participants in the respective safiglipron groups, compared with 16.7% with placebo.

Fasting Glucose and Body Weight

Safiglipron also reduced fasting plasma glucose compared with placebo. The placebo-adjusted differences at Week 32 were −1.58 mmol/L with 30 mg, −1.68 mmol/L with 60 mg and −2.08 mmol/L with 90 mg, with all comparisons reaching P<0.0001.

Changes in body weight were more pronounced at the higher doses. Placebo-adjusted percentage changes were −0.65%, −2.23% and −3.56% with 30 mg, 60 mg and 90 mg, respectively. The difference with 30 mg was not statistically significant, whereas the 60-mg and 90-mg doses produced significant reductions compared with placebo.

Other outcomes generally favored safiglipron, including postprandial glucose, measures of β-cell function and insulin sensitivity, disposition index and waist circumference. No participants receiving safiglipron required rescue therapy for persistent hyperglycemia during the 32-week placebo-controlled period, compared with 9.7% of participants receiving placebo.

Gastrointestinal Adverse Events Were Most Common

Gastrointestinal adverse events represented the most frequently reported safety findings. During the 32-week core treatment period, gastrointestinal events occurred in 44.3% of participants receiving 30 mg, 60.0% receiving 60 mg and 73.6% receiving 90 mg, compared with 15.3% receiving placebo. Most events were mild or moderate and occurred predominantly during dose titration.

Adverse events leading to treatment discontinuation occurred in 1.4%, 2.9% and 6.9% of participants receiving 30 mg, 60 mg and 90 mg, respectively, compared with none in the placebo group. One case of acute pancreatitis occurred in the 30-mg group. Serious adverse events were reported across the treatment groups, although no deaths occurred during the trial. No severe hypoglycemia was reported during the 32-week core treatment period.

Outcomes Through Week 52

The trial continued for a further 20 weeks after the placebo-controlled period. Participants who remained on safiglipron continued their assigned treatment, while those initially assigned to placebo switched to safiglipron 30 mg from Week 33.

A total of 243 participants completed the 52-week treatment period and 261 completed trial follow-up. Improvements in glycemic control and body weight remained evident at Week 52, although the investigators reported some attenuation of HbA1c reduction and partial weight regain during the extension period. Because the placebo group switched to active treatment after Week 32, the extension period did not provide a continued placebo-controlled comparison.

Study Population and Clinical Context

The findings provide Phase 3 evidence for once-daily oral safiglipron in Chinese adults with relatively early type 2 diabetes managed with diet and exercise alone. However, all participants were Asian and the study was conducted exclusively in China. The findings therefore may not directly represent populations with different ethnic characteristics, longer diabetes duration, higher body mass index or more advanced diabetes-related complications.

The study was designed primarily to assess glycemic efficacy and safety. Its sample size and follow-up duration do not establish the effects of safiglipron on uncommon adverse events or long-term cardiovascular and renal clinical outcomes.

OUTSTAND-1 demonstrated significant improvements in glycemic control across all three evaluated safiglipron doses, while the higher doses were associated with greater reductions in body weight. Gastrointestinal adverse events were the predominant safety finding. The results add Phase 3 clinical evidence for an oral small-molecule GLP-1 receptor agonist in adults with relatively early type 2 diabetes.

Reference

Yu, M., Peng, L., Jiang, C. et al. Oral small-molecule GLP-1 receptor agonist safiglipron in early type 2 diabetes: a randomized, double-blind, placebo-controlled trial. Nat Med (2026). https://doi.org/10.1038/s41591-026-04651-9

A Study of HRS-7535 Compared with Placebo in Adult Participants with Type 2 Diabetes and Inadequately Controlled with Diet and Exercise (OUTSTAND-1), ClinicalTrials.gov ID NCT06672172