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 completion rate deserves as much attention as the headline, because a large effect among those who finished is a different claim from a large effect among those enrolled.
What would genuinely help is knowing whether the amylin component adds anything beyond what a higher GLP-1 dose would achieve. I have searched first, so if this is covered somewhere point me at it and I will read it.
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.
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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.
JessicaH_TX said:Agreed, and subgroup analyses deserve particular suspicion.
Same pattern here, and in the same order. I had assumed I was the exception until I read this.