Comparing tirzepatide and semaglutide is harder than the tables suggest

Posting this under the heading it deserves: Comparing tirzepatide and semaglutide is harder than the tables suggest Everything below is what sits behind that.

Comparing SCALE (N Engl J Med, 2015) with STEP 1 (N Engl J Med, 2021) and finding the comparison harder than it looks.

Different populations, different durations, different endpoints defined slightly differently, and in one case a different estimand. People compare the headline percentages anyway, including me until recently.

Is there a defensible way to put these side by side, or is the honest answer that there is not and we should stop?

Dual agonism versus dose: how much of tirzepatide's effect is the GIP component and how much is simply achieving higher receptor engagement? The honest answer is that the question is not settled. Some of the effect is surely the GIP component, but the trial design does not decompose it.

Titration schedules for tirzepatide have more dose steps than semaglutide partly because the compound is more potent and partly because the clinical programme used a finer gradation. That does not mean you cannot escalate on a coarser schedule if that suits you — the published schedule is not a lower bound.