Nausea profile of amylin analogues compared with GLP-1 agonists

Nausea profile of amylin analogues compared with GLP-1 agonists Writing it up because I had to work it out twice and would rather nobody else did.

Session topic: SURPASS-4 (Lancet, 2021). Please read it before posting; the discussion is much better when everyone has.

The question I would like us to start with is what the trial set out to estimate, rather than what it found. Once that is on the table we can talk about whether the design could have answered it, and only then about the numbers.

Specific things I would like covered: the population and how far it generalises, how discontinuation was handled, whether the comparator was a fair one, and what the absolute rather than relative effect looks like.

I will summarise at the end and the summary will feed the relevant digest page.

Worth separating two things that the opening post runs together.

Reading the phase 2 paper: it establishes tolerability and efficacy in a selected population on a defined dose escalation. It does not establish the lowest effective dose or the durability over years.

The CagriSema phase 2 paper: a fixed combination of the two components in one weekly injection. The trade-off of a fixed combination is that you cannot titrate the components independently and you cannot attribute effect to one component from a combination trial.

Amylin signalling is distinct from GLP-1 signalling. Amylin slows gastric emptying and promotes satiety through a different receptor and different neural pathways. The hypothesis behind combination is two complementary satiety mechanisms with one injection.

This follows post #32 rather than contradicting it.

Cagrilintide alone is discussed less than in combination because the published data is almost entirely from combination trials. The phase 2 combination data was consistent with more effect than either component alone, but phase 2 cannot establish whether that is synergy or simply additivity.

Cagrilintide molecular characteristics: it is a synthetic amylin analogue, substituted to prevent the amyloidogenicity of human amylin. The sequence is short and analytically straightforward to confirm by LC-MS.

Worth separating two things that post #52 runs together.

The dosing interval: cagrilintide's half-life is roughly 7 to 8 days, suitable for weekly dosing. The pharmacokinetics are the reason the dosing schedule makes sense.

What is genuinely unknown about long-term amylin agonism: real-world response rates, whether effect is durable with continued use, whether satiety adaptation occurs over months or years, safety profile in populations not enrolled in the trials.

Thank you for the correction. I have edited my earlier post with a note rather than silently, so the thread still makes sense to read. The error was mine and it was the kind that comes from remembering a figure instead of looking it up.