The most useful reply I ever got about SELECT was a request to state my units. It sounds like pedantry and it has saved me twice.
Asking directly, because I could not find a straight answer: What SELECT changed about how semaglutide is discussed, and what it did not
I was wrong about SELECT in a thread last spring and I would like to correct it publicly rather than quietly.
The error was in the units, which changed the conclusion by an order of magnitude. Setting out the corrected version, and the way I now check for that class of mistake.
I had written a reply contradicting the opening post and deleted it. Here is what survived.
One more thing on SELECT 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.
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.
If anyone has run this properly I would rather read that than my own guess.
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.
That is a fair summary of where the discussion has got to.
Worth separating two things that post #4 runs together.
STEP 1 and STEP 4 are two different questions. The first asks what happens when treatment is added; the second asks what happens when it is withdrawn after a run-in. Quoting the first as evidence about maintenance is the commonest misreading of the programme.
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.
Filing this under things that are true until someone shows me otherwise.
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.
It took me longer than it should have to see that.
Worth separating two things that post #7 runs together.
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.
Two people can read the same figure differently here and both be reasonable.
Discontinuation rates in the trials are worth reading alongside efficacy and almost never are. A large mean effect in a population where a meaningful fraction stopped early is telling you two things, not one.
One of those cases where knowing the mechanism does not help the decision.
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.
Written quickly, so the reasoning may be tighter than the wording.
Post #12 and I disagree about the size of the effect, not about the direction.
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.
Taking post #15 at face value and following it one step further.
Injection site does not appear to matter much for semaglutide exposure. The published comparisons of abdomen, thigh and upper arm found differences small enough to be clinically unimportant, which is not true of every injectable.
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.
On alcohol: the labelling does not contraindicate it, but it raises gastric irritation risk and semaglutide already does that. There is no published interaction study and the conservative position is to limit it if you are titrating or if gastrointestinal symptoms are troublesome.
On balance I think that is right, and I would not bet much on it.
Checked the SELECT claim against the primary source this morning. It survives, with a narrower scope than the version quoted here. Posting the narrower scope.
Building on post #19 rather than restating it.
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.
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.
What I would want before treating SELECT as settled: the method, the sample, and whether anyone tried to find the opposite result. Two of the three are usually missing.
Post #22 and I disagree about the size of the effect, not about the direction.
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.
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.
Not a strong opinion, just a consistent one.
The question underneath SELECT is usually "how would I tell?" rather than "what is true?", and that one has a method attached to it.
Write down what you would expect to see under each hypothesis before you collect anything. If they predict the same observation, collecting it will not help.
Adding the measurement that post #28 says would settle it.
The STEP programme populations were selected: enrollment criteria required baseline body mass index over 30, no recent blood pressure crisis, no recent retinopathy, no renal disease at the time. Applying results from that population to someone well outside it is an extrapolation and should be called one.
If anyone can point at the primary source I would be grateful.
Post #27 describes the usual case. This is about the unusual one.
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.