BBramley, post #5: That is a fair summary of where the discussion has got to. Go to post
SELECT is worth one more sentence than it usually gets, and the sentence is the one about how the number was arrived at.
Compounds · Semaglutide · continued
What SELECT changed about how semaglutide is discussed, and what it did not posts 91–120
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.
Post #91 answers the question as asked. The question underneath it is different.
The C-cell question: semaglutide triggered medullary thyroid carcinoma in rodent toxicology studies. A signal in rodents does not automatically appear in humans, but it is the reason the compound is contraindicated in people with personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2.
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Worth separating two things that post #91 runs together.
On the injection-day question: the labelling for licensed semaglutide allows the day to be changed provided at least two days separate the two injections. That interval is not arbitrary — it is what stops two doses stacking inside one absorption window.
Worth one more sentence than it usually gets.
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Appetite effects and gastrointestinal effects are frequently reported together and are not the same mechanism reported twice. Slowed gastric emptying contributes to both, but central satiety signalling accounts for effects that persist after emptying has normalised.
Small point, but it is the one that usually catches people.
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Post #95 and I disagree about the size of the effect, not about the direction.
Cardiovascular data in people without diabetes is the specific contribution of SELECT, and it is worth being precise that the enrolled population had established cardiovascular disease. That is not the same as the general population and the result should not be quoted as though it were.
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l.chevalier, post #17: On dose steps: the four-week interval in the pivotal programme was a trial design choice, and slower escalation was not studied. That means the evidence supports not going faster and says nothing at all about going slower. I would treat that as a working assumption and revisit it. Go to post
Taking post #95 at face value and following it one step further.
The 2.4 mg maintenance dose in the weight-management programme and the 1.0 mg diabetes dose are frequently discussed as though they were the same drug at different strengths. They are, but the trials behind them enrolled different populations for different endpoints, so the evidence does not transfer sideways.
The part I am sure of is shorter than the part I have written.
ambient_review, post #26: No notes. Posting so the count is not one. Go to post
I had written a reply contradicting post #95 and deleted it. Here is what survived.
Semaglutide's structure is a modified backbone with a C18 diacid attached through a spacer. The acylation is the reason for the long half-life and it is also the reason a plain sequence comparison against native GLP-1 is misleading about how the molecule behaves.
The evidence for this is thinner than the way I have phrased it suggests.
e.mensa, post #4: The 2.4 mg maintenance dose in the weight-management programme and the 1.0 mg diabetes dose are frequently discussed as though they were the same drug at different strengths. They are, but the trials behind them enrolled different populations for different endpoints, so the evidence does not transfer sideways. Go to post
SELECT would be much easier to settle if anyone reported the denominator. Almost nobody reports the denominator.
On post #99 — agreed on the reasoning, with one qualification.
Solutions of semaglutide can look faintly opalescent without anything being wrong. Visible particulate, fibres or frank cloudiness are a different observation entirely and are worth raising with the supplier rather than reasoning about.
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Picking up post #99: that is the part I would want checked first.
On identity confirmation: a mass close to 4113.6 Da on the intact molecule is consistent with semaglutide and is also consistent with several closely related species. Mass narrows the field; it does not close it, and no certificate should be read as though it did.
Marking that as an opinion rather than a finding.
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The opalescent appearance in semaglutide solutions is occasionally noted and the mechanism is unclear. It does not appear to correlate with product failure in practice. Visible particles or frank cloudiness is different and would be reason to contact the supplier.
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e.mensa, post #4: The 2.4 mg maintenance dose in the weight-management programme and the 1.0 mg diabetes dose are frequently discussed as though they were the same drug at different strengths. They are, but the trials behind them enrolled different populations for different endpoints, so the evidence does not transfer sideways. Go to post
This follows post #104 rather than contradicting it.
Research-use-only semaglutide is not a licensed medicine, is not manufactured to pharmaceutical standards, and is not approved for human use. That is a statement about what it is, not a coded opinion about anything.
I read post #104 twice before replying, because I had assumed the opposite.
Two sentences on SELECT and then I will stop, because the rest is speculation and the thread is better without mine.
What is documented is narrow. What is inferred from it is broad. The gap between them is where every argument here lives.
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Semaglutide versus liraglutide in STEP 8: semaglutide produced greater weight reduction and the discontinuation rates differed. But the trial was open-label for the dosing schedule, which admits expectation effects. Weekly versus daily itself is part of the comparison, not a confounding variable to be removed.
I would want a second opinion before relying on that.
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Albumin binding is not a unique structural feature and nothing in the class lacks it, but the reversibility matters. Semaglutide binds albumin covalently through a fatty side chain, which creates a very long half-life at the cost of sequestering the free form. That is a trade-off and it is the trade-off that allows weekly dosing.
The answer changed when I changed how I was measuring, which was informative.
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Bookmarking this. I will come back when I have something worth adding.
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s.karlsen_rph, post #70: Answering the question post #66 raises rather than the one it answers. SELECT: I have looked for the primary source twice and failed twice. Either it does not exist or it is somewhere I do not know to look, and I would like to know which. Go to post
The arithmetic in post #109 is right; the assumption feeding it is the part to check.
The SELECT trial changed the positioning because it was the first cardiovascular outcome trial in people without diabetes. That decoupled the cardiovascular argument from glycaemic control, which is why it mattered beyond its own numbers.
A qualification I should have led with rather than closed on.
h.fonseca, post #96: An update on my earlier SELECT post: the pattern held for another six weeks and then stopped, which I did not predict and cannot explain. Go to post
Answering the question post #108 raises rather than the one it answers.
Where I have landed on SELECT, having got it wrong once in public: the direction is clear, the magnitude is not, and anyone quoting a precise magnitude has borrowed it from somewhere that did not measure it.
Research-use-only semaglutide is not a licensed medicine, is not manufactured to pharmaceutical standards, and is not approved for human use. That is a statement about what it is, not a coded opinion about anything.
The rule of thumb is fine; the edge cases are where it earns its keep.
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p.ostergaard, post #61: On the injection-day question: the labelling for licensed semaglutide allows the day to be changed provided at least two days separate the two injections. That interval is not arbitrary — it is what stops two doses stacking inside one absorption window. A single observation, in a thread that deserves better than single observations. Go to post
Narrowing post #114, because the general version has more than one answer.
Two things can be true about SELECT at once: the mechanism is plausible and the evidence for the size of the effect is thin. Most of the argument here is people defending the first against attacks on the second.
Before the thread moves on from SELECT — what is the sample size behind the claim? I am not being difficult; I have seen the same figure quoted from an n of four and from an n of four hundred.
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Albumin binding is not a unique structural feature and nothing in the class lacks it, but the reversibility matters. Semaglutide binds albumin covalently through a fatty side chain, which creates a very long half-life at the cost of sequestering the free form. That is a trade-off and it is the trade-off that allows weekly dosing.
I have no interest in any supplier named above.
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I disagree with the framing of SELECT above, and I think it is a substantive disagreement rather than a terminological one. Setting out why, so it can be checked.
The reasoning depends on an assumption that is doing a lot of work and is never stated. If the assumption holds, the conclusion follows. I do not think it holds generally.
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Collapsed as off-topic by two members at trust level 3 or above
The C-cell question: semaglutide triggered medullary thyroid carcinoma in rodent toxicology studies. A signal in rodents does not automatically appear in humans, but it is the reason the compound is contraindicated in people with personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2.
That matches what I was told, which is not the same as knowing it.