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):

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:

1. 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.
2. 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.
3. 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.

sean_dublin said:

A few things bother me about how this is being reported: The semaglutide arm used max 2.4mg. We know higher-dose sema (...

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. 👍