Summary: In a 2-year pragmatic open-label trial in US adults with type 2 diabetes needing treatment intensification, once-weekly semaglutide got modestly more patients to an HbA1c below 7% than physician-chosen alternatives, with a small added HbA1c reduction and a weight advantage at year 1 that did not persist to year 2.
PICO Summary
| Element | Detail |
|---|---|
| Population | 1,278 US adults with type 2 diabetes inadequately controlled on 1–2 oral agents; 2-year, randomised, open-label pragmatic trial (SEPRA), industry-funded. |
| Intervention | Once-weekly subcutaneous semaglutide as add-on (n=644). |
| Comparison | Alternative add-on treatment chosen by the treating physician (n=634). |
| Outcome | HbA1c below 7% was reached by more on semaglutide at year 1 (53.1% vs 45.5%; OR 1.36; p=0.033) and year 2 (49.9% vs 38.9%; OR 1.56; p=0.007). HbA1c fell slightly more with semaglutide (year 1 ETD -0.20%; year 2 -0.31%). Weight fell more at year 1 (ETD -1.65%; p=0.010) but not significantly at year 2 (p=0.175). No new safety concerns. |
Semaglutide vs physician-chosen alternatives (SEPRA)
Pragmatic RCT · type 2 diabetes · 2 years
Once-weekly semaglutide got modestly more patients to HbA1c below 7% than physician-chosen alternatives at both years. The HbA1c edge was small (about 0.2 to 0.3 points) and the year-1 weight advantage faded by year 2.
Expert Commentary
This is a useful pragmatic trial whose real-world design is its strength, since randomising against whatever a clinician would otherwise prescribe tells us how semaglutide performs against the genuine next-best option rather than placebo. The direction is positive and consistent, with more patients reaching target at both years and fewer needing further treatment changes, which fits semaglutide’s established efficacy. I would, however, keep the effect sizes in proportion against the headline word outperforms: the between-group HbA1c differences were modest at roughly 0.2 to 0.3 percentage points, and the weight advantage seen at year 1 was no longer statistically significant by year 2, which tempers any claim of large or durable separation. Two design features also warrant restraint, the trial was open-label, which can bias behaviour and reporting, and it was industry-funded, while the heterogeneous comparator makes it impossible to say which specific alternatives were bettered. Can I use this with my patients? Yes, comfortably. It supports semaglutide as a strong choice for intensification beyond metformin, especially where weight loss is desirable, while I frame the glycaemic edge over good alternatives as real but modest, mind cost and gastrointestinal tolerability, and keep cardiorenal indications central to the choice.
References
Buse JB, Nordahl Christensen H, Harty BJ, Cziraky MJ, Willey VJ, Skibsted S. Long-term comparative effectiveness of once-weekly semaglutide versus alternative treatments in a real-world US adult population with type 2 diabetes: a randomized pragmatic clinical trial. BMJ Open Diabetes Res Care. 2025;13(5):e005161. doi:10.1136/bmjdrc-2025-005161