This gets cited here weekly, usually second-hand, so it is worth setting out what it does and does not establish.
Amylin analogues act on a different satiety circuit — area postrema and dorsal raphe — rather than the arcuate pathway GLP-1 agonists use. Because the mechanisms are complementary rather than additive on the same receptor, the combination gets more effect without the tolerability cost of simply pushing GLP-1 higher. REDEFINE-2 put cagrisema near 22.7% against about 15.8% for semaglutide alone.
Where I think it is weakest: the population was selected and supported in ways a real cohort is not, so I would read the effect size as a ceiling rather than an expectation.
The question I want answered is whether the amylin component adds anything beyond what a higher GLP-1 dose would achieve. If the honest answer is that nobody knows, that is a useful answer and I would rather have it.
Figures above are from the primary publication rather than the press summary. If a number here disagrees with one you have, post yours and we will work out which of us is reading a secondary source.
TrialTracker_MD said:Amylin analogues act on a different satiety circuit — area postrema and dorsal raphe — rather than the arcuate pathway GLP-1 agonists use.
Agreed, and subgroup analyses deserve particular suspicion. With enough subgroups something is significant by chance, and pre-registered subgroups are a different animal from ones found afterwards.
TrialTracker_MD said:Amylin analogues act on a different satiety circuit — area postrema and dorsal raphe — rather than the arcuate pathway GLP-1 agonists use.
I read this differently from TrialTracker_MD, on substance rather than tone. Two drugs, two side-effect profiles, one price. The efficiency argument only works if the tolerability really is better than dose-escalating a single agent, and I have not seen that demonstrated head to head.
I would rather be corrected than agreed with, if it comes to it.
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View ResultsShort answer first, then the reasoning. Relative and absolute effects need reading together. A 20% relative reduction on a high baseline risk is a large absolute benefit; the same relative figure on a low baseline risk is a small one, and press summaries almost always quote the relative number because it is bigger.
I would rather be corrected than agreed with, if it comes to it.