SURMOUNT-5 Results — Tirzepatide vs Semaglutide Head-to-Head
The full results from SURMOUNT-5 are published and they're pretty definitive. This was the trial everyone's been waiting for — direct comparison of tirzepatide (max 15mg) vs semaglutide (max 2.4mg) for weight management in adults with obesity.
Key topline results (72 weeks):
| Endpoint | Tirzepatide 15mg | Semaglutide 2.4mg | Difference |
|---|---|---|---|
| Mean % body weight change | -20.2% | -13.7% | -6.5% (p<0.001) |
| ≥5% weight loss | 94.4% | 85.0% | — |
| ≥10% weight loss | 82.8% | 67.1% | — |
| ≥15% weight loss | 68.8% | 50.2% | — |
| ≥20% weight loss | 51.5% | 30.0% | — |
| ≥25% weight loss | 35.0% | 15.4% | — |
The GI side effect profiles were comparable between groups. Discontinuation due to AEs was actually slightly lower in the tirz arm (4.3% vs 5.0%).
Thoughts?
The ≥25% threshold is the headline for me. More than DOUBLE the proportion reaching that level of weight loss (35% vs 15.4%). That's surgical territory without surgery.
Worth noting this was an open-label trial though, which is a legitimate methodological limitation. Participants knew which drug they were on, which could influence behavioral adherence and self-reporting. That said, body weight is a pretty objective endpoint.
A few things bother me about how this is being reported:
- The semaglutide arm used max 2.4mg. We know higher-dose sema (like the 7.2mg cagrisema component trials) narrows this gap considerably. So this is really "current max dose tirz vs current max dose sema" — not a permanent verdict.
- The cost difference is enormous. If your insurance covers one but not the other, a 6.5% difference in average weight loss may not be worth thousands out of pocket.
- Individual variation was HUGE in both arms. Some people lost more on sema than the average tirz patient, and vice versa. These are population-level statistics.
I'm not anti-tirz at all (I'm on it myself), but I think the "tirz DESTROYS sema" narrative is oversimplistic.
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View Resultsingrid_STO said:A few things bother me about how this is being reported: The semaglutide arm used max 2.4mg. We know higher-dose sema (like the 7.2mg cagrisema compon…
Fair points, but I'd push back on #1 — we have to compare what's actually available and approved. Hypothetical future doses of semaglutide aren't relevant to treatment decisions today. And cagrisema is a different drug (sema + cagrilintide), not just "higher dose sema."
The pharmacology matters. Tirzepatide's GIP agonism isn't just "more GLP-1" — it's a mechanistically distinct pathway that affects glucose-dependent insulin secretion, lipid metabolism in adipose tissue, and potentially central appetite regulation through different neuronal populations.
SURPASS-2 showed similar separation in T2D populations. This isn't a fluke finding.
Good discussion, keeping this pinned. Let's remember to be respectful of both "camps" — lots of people have done very well on semaglutide and the goal here isn't to make anyone feel bad about their medication choice. Both are excellent drugs. 👍