Why a glucagon receptor agonist in a weight-loss compound is not a contradiction

The question in the title: Why a glucagon receptor agonist in a weight-loss compound is not a contradiction I will give what I have already checked below so nobody repeats it.

Comparing LEADER (N Engl J Med, 2016) with SURMOUNT-OSA (N Engl J Med, 2024) 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?

The phase 2 obesity paper reported dose-dependent weight reduction of a magnitude that attracted attention. It also reported dose-dependent heart-rate increases. The heart-rate signal is the reason phase 3 exists rather than something assumed negligible based on phase 2.

Mass and identity: a report on retatrutide should state the mass detected by LC-MS, not assume a theoretical mass. The theoretical mass is not published in peer-reviewed literature for retatrutide at present.

What we do not know about retatrutide, listed explicitly: long-term safety, real-world response rates, the dose response in diverse populations, whether the heart-rate signal persists or attenuates, durability of effect on withdrawal, efficacy in comorbidities beyond obesity.

How to read phase 2 without treating it as phase 3: phase 2 establishes that a dose range produces an effect and is tolerable enough to justify large trials. It does not establish safety, durability, or whether real humans differ from the selected population.

The phase 2 obesity paper reported dose-dependent weight reduction of a magnitude that attracted attention. It also reported dose-dependent heart-rate increases. The heart-rate signal is the reason phase 3 exists rather than something assumed negligible based on phase 2.