The interest in combining it with semaglutide is that two different satiety mechanisms might add. Whether they do, and by how much, is exactly what the combination trials were designed to find out rather than something to be assumed.
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Compounds · Cagrilintide & amylin analogues · continued
Amylin analogue mechanism: satiety signalling separate from GLP-1 posts 61–90
This is a continuation of a long topic, addressed by post number rather than by page. Start at post 1 · go to the accepted answer.
r.aldana_pharmd, post #16: Is synergy the right word for the combination data? A phase 2 trial cannot establish whether effects are synergistic or additive. Synergy is a mechanistic claim that requires a designed experiment to support it. The combination works, but the mechanism is unsettled. The answer changed when I changed how I was measuring, which was… Go to post
Native amylin has awkward physical properties — it aggregates readily, which is why a stable analogue is a pharmaceutical achievement rather than a formulation detail.
blank_injection, post #2: Narrowing the opening post, because the general version has more than one answer. For anyone arriving from searches on "amylin agonist": this subcategory discusses published clinical evidence and what it does and does not establish. It does not endorse or recommend the compounds discussed. Someone should write this up properly, and it… Go to post
Worth separating two things that post #60 runs together.
The phase 3 combination programme is where the clinically interesting numbers will come from. Phase 2 established that the combination does something; the size of it in a larger population is a separate question.
I am not the right person to answer the follow-up to this.
Reconstitution at higher concentrations is worth avoiding for aggregation-prone material. The published formulation work generally uses lower concentrations than people reconstitute to at home, and there is a reason for that.
None of the above is medical advice and I am not qualified to give any.
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f.haddad, post #9: If someone has run amylin analogue mechanism properly I would rather read that than my own reconstruction of it. Posting mine only because the thread has gone quiet. Go to post
Post #63 and I disagree about the size of the effect, not about the direction.
Amylin analogues affect gastric emptying as well, so the mechanism overlaps the incretins in at least one place. That overlap is part of why the combination's tolerability profile is not simply the sum of the two.
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.
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Where I part company with post #67, and it is a narrow parting.
Is synergy the right word for the combination data? A phase 2 trial cannot establish whether effects are synergistic or additive. Synergy is a mechanistic claim that requires a designed experiment to support it. The combination works, but the mechanism is unsettled.
Two sources, same conclusion, and I could not rule out that one copied the other.
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Post #70 is the version of this I will quote in future. One addition.
The interest in combining it with semaglutide is that two different satiety mechanisms might add. Whether they do, and by how much, is exactly what the combination trials were designed to find out rather than something to be assumed.
That is what I would do. It may not be what is correct.
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ni.kravchenko, post #59: Useful. I had the fact and not the reason, which turns out to be the important half. Go to post
Where I part company with post #68, and it is a narrow parting.
An update on my earlier amylin analogue mechanism post: the pattern held for another six weeks and then stopped, which I did not predict and cannot explain.
Collapsed as off-topic by two members at trust level 3 or above
Building on post #73 rather than restating it.
What I would tell a new member reading about amylin analogue mechanism for the first time: the confident posts are not the reliable ones, and the reliable ones are longer.
i.balogun, post #70: Post #67 is the version of this I will quote in future. One addition. The version of amylin analogue mechanism that I was taught turned out to be a teaching simplification. Useful, and not true in the way I had assumed it was. Go to post
Amylin analogue mechanism would be much easier to settle if anyone reported the denominator. Almost nobody reports the denominator.
Everything in post #76 holds. The case it does not cover is the one I have.
The phase 3 combination programme is where the clinically interesting numbers will come from. Phase 2 established that the combination does something; the size of it in a larger population is a separate question.
Take the reasoning and check the arithmetic; I do not always get it right.
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m.ekstrom, post #31: Careful with the language on amylin analogue mechanism. "Not detected" and "not present" are different findings and the first is a statement about the method. Go to post
Thank you for taking the time. That was more work than a reply usually is.
Nausea profile of amylin analogues: the historical agent pramlintide required multiple daily doses and had a difficult tolerability profile. A weekly formulation is a substantially different proposition and data from that is more relevant than data from pramlintide.
That is the version I use. It may not be the version that is correct.
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Gastric emptying: both amylin and GLP-1 slow it, through partly overlapping but distinct mechanisms. Whether the slowing at a higher magnitude produces disproportionate nausea or is tolerable is a question phase 3 exists to answer.
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h.delgado, post #26: Confirming post #23 from a second method, which matters more than confirming it from a second person. Amylin analogues affect gastric emptying as well, so the mechanism overlaps the incretins in at least one place. That overlap is part of why the combination's tolerability profile is not simply the sum of the two. Written quickly, so… Go to post
Adding a reference point for amylin analogue mechanism. Mine is a single case, collected without controls, and I am posting the method alongside it so it can be discounted appropriately.
Everything in post #81 holds. The case it does not cover is the one I have.
Cagrilintide is a long-acting amylin analogue, which puts it in a different mechanistic family from the incretin agonists it is usually discussed alongside. Amylin signalling contributes to satiety through a distinct pathway.
A weak preference rather than a position.
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Narrowing post #81, because the general version has more than one answer.
Comparing an amylin analogue to an incretin agonist on weight change alone misses that they were developed to be used together rather than instead of each other.
Noting that I have skin in this question and have tried to discount for it.
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coldchain_liu, post #54: One more thing on amylin analogue mechanism that took me far too long to see: the two figures people quote are not measuring the same quantity. Once you notice that, the apparent contradiction disappears. Go to post
Second this, and I would have said it less carefully.
Thibodeau, post #36: The thing about amylin analogue mechanism that took me longest to accept is that a plausible mechanism is not evidence of an effect. It is a reason to look, not a result. Go to post
Taking post #84 at face value and following it one step further.
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.
Happy to be the one who is wrong here if it settles the question.
I read post #86 twice before replying, because I had assumed the opposite.
The monoisotopic mass sits near 3749.9 Da, and the same caveat applies as everywhere else: a mass consistent with the proposed structure is a necessary condition and not a sufficient one.
That is where I would start, not where I would stop.
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On analysis: an amylin analogue and its aggregates are not equally detectable by a standard reversed-phase method, because a large aggregate may not elute at all. Area percent cannot see what stays on the column.
This is the version I would want a new member to read first.
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d.ferreira, post #66: Reconstitution at higher concentrations is worth avoiding for aggregation-prone material. The published formulation work generally uses lower concentrations than people reconstitute to at home, and there is a reason for that. None of the above is medical advice and I am not qualified to give any. Go to post
I had written a reply contradicting post #86 and deleted it. Here is what survived.
Agreed on amylin analogue mechanism, with one qualification that I think matters. The reasoning holds for the case as described. Change the starting assumption and it does not, and the starting assumption is the part nobody states.
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.
Reporting the observation and leaving the explanation open deliberately.
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