A reference post rather than a discussion. Corrections are the point; I would rather this be right than mine. It is about tirzepatide, and it is deliberately narrow — everything I am not confident about is marked as such.
What is actually established
The GIP arm is doing real work rather than padding the label. GIP receptor agonism appears to improve adipose insulin sensitivity and lipid handling, and — counter-intuitively — GIP signalling in the CNS reduces nausea rather than adding to it, which is why tolerability at high total agonism is better than the GLP-1-only comparison would predict. SURPASS-2 is the cleanest head-to-head: tirzepatide beat semaglutide 1mg at every dose tier.
The condition it depends on
The caveat that the head-to-head used semaglutide 1mg, not 2.4mg. It is still the best direct evidence available, but it is not the comparison most people think they are citing.
The practical version
Practical numbers: half-life about 5 days, steady state 3 to 4 weeks, ladder 2.5 / 5 / 7.5 / 10 / 12.5 / 15mg, and the maintenance doses with published data behind them are 5, 10 and 15mg.
What I am not sure about
What I am after is whether anyone has held 10mg long term rather than climbing, and what happened over the following year. I would rather have one careful answer than five confident ones.
Dr.EM_Chicago said:The GIP arm is doing real work rather than padding the label.
Agreeing with Dr.EM_Chicago, and the qualification matters more than the agreement. Steady state is faster than people expect: half-life about five days, so you are at plateau in roughly three to four weeks rather than five. That matters when you are deciding whether a dose step has finished expressing itself.
Dr.EM_Chicago said:The GIP arm is doing real work rather than padding the label.
This is where I part company with the consensus forming above. The "tirzepatide is simply better" summary irritates me. It is better on mean weight loss, and the cardiovascular outcome evidence is far thinner than semaglutide's. If the reason for treating is cardiovascular risk rather than weight, the evidence base points the other way.
If somebody has the primary source to hand I would rather cite it than paraphrase it.
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View ResultsThis one has a reasonably settled answer, so here it is. SURMOUNT-1 landed around 20.9% mean weight loss at 15mg over 72 weeks, against roughly 15% for semaglutide 2.4mg in STEP 1. Different trials, different populations, so the comparison is indicative rather than decisive — but SURPASS-2 was a genuine head-to-head and it pointed the same way.
Dr.SleepRoch said:Steady state is faster than people expect: half-life about five days, so you are at plateau in roughly three to four weeks rather than five.
Agreed, and the adaptation point cuts both ways: tachyphylaxis to gastric emptying is why tolerability improves, and it is also why people who were relying on physical fullness feel the effect fade while the appetite effect is still working.