Summary
In a 810-person phase 3 trial in China, all three safiglipron doses were non-inferior to dapagliflozin for HbA1c reduction at 32 weeks. The 90 mg dose also met a prespecified superiority criterion in a separate analysis, while gastrointestinal events and treatment discontinuations were more frequent with safiglipron.
A phase 3 trial in China found that once-daily oral safiglipron lowered HbA1c at least as much as dapagliflozin in adults whose type 2 diabetes was inadequately controlled with metformin. All three tested doses met the trial’s primary non-inferiority criterion at 32 weeks; 90 mg also met a prespecified superiority criterion in a separate analysis.
Safiglipron is a small-molecule glucagon-like peptide-1 (GLP-1) receptor agonist. Unlike oral peptide-based GLP-1 treatment, it can be taken without restrictions on food or dosing time, according to the study. The trial, OUTSTAND-2, was randomized, double-blind and active-comparator-controlled, and was conducted at 98 sites.
Glucose control and weight results
Researchers randomized 810 adults to safiglipron 30 mg, 60 mg or 90 mg, or dapagliflozin 10 mg; all participants continued metformin. The average starting HbA1c was 8.60%. The primary comparison assessed change in HbA1c at week 32 against a prespecified non-inferiority margin of 0.4 percentage points. The estimated differences versus dapagliflozin were −0.30 percentage points for 30 mg, −0.22 for 60 mg and −0.40 for 90 mg. The upper confidence limit for each difference was below the margin, meeting the non-inferiority criterion.
In an analysis that included outcomes irrespective of treatment discontinuation or use of additional glucose-lowering medication, the 90 mg dose had an estimated HbA1c difference of −0.25 percentage points versus dapagliflozin (95% confidence interval −0.45 to −0.05; one-sided P = 0.0067), meeting the prespecified criterion for superiority. The 60 mg dose did not meet that criterion (P = 0.0789), so the trial’s fixed-sequence testing stopped and subsequent comparisons were not confirmatory. These results distinguish the primary non-inferiority finding from the separate superiority analysis.
Body weight also fell in each group. At week 32, estimated changes were −2.35%, −3.55% and −4.17% with safiglipron 30 mg, 60 mg and 90 mg, respectively, compared with −3.60% with dapagliflozin. The estimated difference for 90 mg was −0.56 percentage points, with a 95% confidence interval from −1.37 to 0.24; that interval includes no difference.
Tolerability and study boundaries
The study followed participants for 52 weeks, including a 20-week extension after the primary 32-week period. Gastrointestinal adverse events, including nausea, vomiting and diarrhoea, were more frequent with safiglipron and were mostly mild or moderate. Permanent treatment discontinuation due to adverse events occurred in 4.0%, 4.0% and 3.9% of participants in the three safiglipron groups, compared with 1.5% receiving dapagliflozin. No severe hypoglycaemia was reported; level 1 hypoglycaemia occurred in 6.4–9.4% of participants across the safiglipron doses and 2.5% with dapagliflozin.
The findings apply directly to the Chinese adults enrolled, and longer-term cardiovascular and kidney outcomes were not assessed in this trial. The study was sponsored and funded by Jiangsu Hengrui Pharmaceuticals, which collaborated on its design, data collection, analysis, interpretation and preparation of the paper.