Oral safiglipron versus dapagliflozin in type 2 diabetes: phase 3 trial in China

The study

Safiglipron is an oral, small-molecule GLP-1 receptor agonist. It can be taken without fasting or dietary restrictions. OUTSTAND-2 was a phase 3, multicentre, randomised, double-blind, double-dummy trial with an active comparator. It ran at 98 sites in China.

The trial enrolled 810 adults with type 2 diabetes. Mean HbA1c was 8.60%, median diabetes duration was 5.0 years and 35.7% of participants were women. The abstract does not describe background metformin therapy in its methods.

Participants received safiglipron 30 mg (n = 202), 60 mg (n = 203), 90 mg (n = 203) or dapagliflozin 10 mg (n = 202). Treatment lasted 32 weeks, followed by a 20-week active-treatment extension. The primary endpoint was change in HbA1c from baseline at week 32, tested for non-inferiority against dapagliflozin with a margin of 0.4%.

What they found

All three safiglipron doses met non-inferiority. Differences versus dapagliflozin in HbA1c change were -0.30% (95% CI -0.51 to -0.09) for 30 mg, -0.22% (-0.44 to -0.01) for 60 mg and -0.40% (-0.62 to -0.19) for 90 mg.

Superiority was tested under the treatment policy estimand. The 90 mg dose met the prespecified criterion (difference -0.25%; 95% CI -0.45 to -0.05; one-sided P = 0.0067). The 60 mg dose did not (P = 0.0789). Fixed-sequence testing then stopped. The abstract does not report a superiority result for 30 mg.

More participants reached HbA1c targets with safiglipron than with dapagliflozin:

• HbA1c below 7.0%: 54.9-63.5% versus 36.5%.
• HbA1c 6.5% or lower: 38.9-48.6% versus 16.1%.

Mean body weight changes were -2.35% (30 mg), -3.55% (60 mg), -4.17% (90 mg) and -3.60% (dapagliflozin). Fasting plasma glucose, self-monitored glucose profiles, waist circumference, HOMA-β, HOMA-IR and treatment satisfaction improved to varying degrees with both drugs. Rescue therapy was used by 0.5-1.5% of safiglipron participants and by 0% on dapagliflozin.

Gastrointestinal adverse events were more frequent with safiglipron and were mostly mild or moderate. Adverse events led to discontinuation in 4.0%, 4.0% and 3.9% of the 30 mg, 60 mg and 90 mg groups, and in 1.5% on dapagliflozin.

How much weight to give it

The design is strong: randomised, double-blind and double-dummy, with an active comparator, in a fairly large sample. The primary result is clear for non-inferiority.

Some limits matter:

• The main outcome is HbA1c, a surrogate. The abstract reports no cardiovascular, kidney or other hard outcomes.
• Only the 90 mg dose met the superiority criterion. The 60 mg dose did not, and testing stopped there, so the evidence for a clear advantage over dapagliflozin is limited.
• All sites were in China. Results may not carry over directly to other populations.
• The abstract does not report results from the 20-week extension, the funding source, or rates of specific gastrointestinal events.
• Weight loss on dapagliflozin was within the range seen across the safiglipron doses, so weight is not a clear point of difference in this abstract.

For your clinic

This trial suggests that an oral GLP-1 receptor agonist taken without fasting rules could become an option after metformin. It is not a reason to change current prescribing. The abstract does not report whether safiglipron is approved or available anywhere.

If safiglipron becomes available, clinicians should weigh the HbA1c and target-attainment gains against more gastrointestinal adverse events and a higher discontinuation rate than with dapagliflozin. Read the full paper first for gastrointestinal event rates, extension-phase results, the safety profile and the baseline characteristics of participants. Wait for evidence on longer-term and hard outcomes before drawing wider conclusions.