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Compounds · Semaglutide

Tracking semaglutide's approved indications across jurisdictions, dated — does this still hold?

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Solved by Ridgeway in post #9
post #8 is right about the mechanism and I think understates the practical bit. 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…

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n.serranoTL2 Moderator25 Oct 2024#1

Tracking semaglutide's approved indications across jurisdictions, dated — does this still hold? — that is the question, and I have not found it answered plainly anywhere I have looked.

Comparing SCALE (N Engl J Med, 2015) with STEP 8 (JAMA, 2022) and finding the comparison harder than it looks.

Different populations, different durations, different endpoints defined slightly differently, and in one case a different estimand. People compare the headline percentages anyway, including me until recently.

Is there a defensible way to put these side by side, or is the honest answer that there is not and we should stop?

11 likes 21mo
ZS
z.szaboTL2 Moderator27 Oct 2024#2

Having read the exchange above, I think I was wrong earlier in this topic and I want to say so plainly rather than quietly editing.

The correction was fair and I had been repeating something I had not checked carefully enough.

15 likes 21mo
KR
k.redgraveTL2Member28 Oct 2024#3

This follows post #2 rather than contradicting it.

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.

0 likes 21mo
SI
s.ivaturiTL2 Moderator29 Oct 2024#4

I read the opening post twice before replying, because I had assumed the opposite.

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.

1 like 21mo
UC
unit_conversionTL3Regular30 Oct 2024#5
s.ivaturi, post #4: I read the opening post twice before replying, because I had assumed the opposite. 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… Go to post

Is there a ceiling dose beyond which the effect plateaus? The trials did not study that because they stopped at 2.4 mg. Some people report trying higher doses, but trial data is absent and off-label dosing enters territory this site does not advise on.

9 likes in reply to #4 21mo
ZC
z.cardosoTL2 Moderator31 Oct 2024#6
n.serrano, post #1: Tracking semaglutide's approved indications across jurisdictions, dated — does this still hold? — that is the question, and I have not found it answered plainly anywhere I have looked. Comparing SCALE ( N Engl J Med , 2015) with STEP 8 ( JAMA , 2022) and finding the comparison harder than it looks. Different populations, different… Go to post

On post #2 — agreed on the reasoning, with one qualification.

The 165 to 184 hour range: that is roughly 7 to 7.6 days, which is why the weekly schedule works. Below 4 half-lives you are not approaching steady state yet, which is the pharmacological argument for the four-week step interval.

21 likes in reply to #1 21mo
EN
electrolyte_notesTL2Regular1 Nov 2024 · edited#7

Picking up post #4: that is the part I would want checked first.

For anyone arriving from a search: the marked solution above is the direct answer, and the replies underneath it add the caveats that make it safe to use.

0 likes 21mo
BD
b.dumitruTL22 Nov 2024#8
R
RidgewayTL3Regular Solution2 Nov 2024#9

post #8 is right about the mechanism and I think understates the practical bit.

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.

8 likes 21mo
ID
i.dumitruTL2 Moderator3 Nov 2024#10
k.redgrave, post #3: This follows post #2 rather than contradicting it. 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. Go to post

Gastric emptying delay is the mechanism behind most of the gastrointestinal side effects. Slowing the stomach empties it feeds less food into the intestines at a time, which is part of the satiety mechanism but is also why nausea is dose-dependent and titration-dependent.

6 likes in reply to #3 21mo
GD
glossary_deskTL3Regular4 Nov 2024#11

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.

10 likes 21mo
AV
a.vestergaardTL2 Moderator5 Nov 2024#12

Approved indications differ by jurisdiction and change. As of mid-2026 the weight-management indication is approved in many European jurisdictions but not all, and access is still narrower in others. For your own region, check the regulatory website rather than a forum summary.

3 likes 21mo
NM
n.marsdenTL1Member6 Nov 2024#13
n.serrano, post #1: Tracking semaglutide's approved indications across jurisdictions, dated — does this still hold? — that is the question, and I have not found it answered plainly anywhere I have looked. Comparing SCALE ( N Engl J Med , 2015) with STEP 8 ( JAMA , 2022) and finding the comparison harder than it looks. Different populations, different… Go to post

Worth separating two things that post #9 runs together.

Two things before anyone answers the substance.

First, the context in the first post is clear and specific. Second, the question is framed so that an answer can actually address it. Both are the norm here and both matter more than they sound.

0 likes in reply to #1 21mo
VS
v.stanescuTL2 Moderator6 Nov 2024#14

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.

30 likes 21mo
AL
aliquot_lineTL3Regular7 Nov 2024#15

The mass figure differs between sources because of how the different entities report it. The monoisotopic mass of the bare peptide is one number; the mass including the acylation is another. Different sources emphasise different details.

15 likes 21mo
EN
e.nilsenTL2 Moderator8 Nov 2024#16
z.cardoso, post #6: On post #2 — agreed on the reasoning, with one qualification. The 165 to 184 hour range: that is roughly 7 to 7.6 days, which is why the weekly schedule works. Below 4 half-lives you are not approaching steady state yet, which is the pharmacological argument for the four-week step interval. Go to post

Picking up post #13: that is the part I would want checked first.

Is there a ceiling dose beyond which the effect plateaus? The trials did not study that because they stopped at 2.4 mg. Some people report trying higher doses, but trial data is absent and off-label dosing enters territory this site does not advise on.

5 likes in reply to #6 21mo
FT
fr.translation_moTL2Translator · FR9 Nov 2024 · edited#17

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.

1 like 21mo
AT
a.teixeiraTL2 Moderator9 Nov 2024#18

For anyone arriving from a search: the marked solution above is the direct answer, and the replies underneath it add the caveats that make it safe to use.

0 likes 21mo
RF
resistance_firstTL2Regular10 Nov 2024#19

I read post #17 twice before replying, because I had assumed the opposite.

Two things before anyone answers the substance.

First, the context in the first post is clear and specific. Second, the question is framed so that an answer can actually address it. Both are the norm here and both matter more than they sound.

3 likes 21mo
AD
a.delgadoTL2 Moderator11 Nov 2024#20

This follows post #17 rather than contradicting it.

The 165 to 184 hour range: that is roughly 7 to 7.6 days, which is why the weekly schedule works. Below 4 half-lives you are not approaching steady state yet, which is the pharmacological argument for the four-week step interval.

0 likes 21mo
AI
a.ilungaTL2 Moderator11 Nov 2024#21

For anyone arriving from a search: the marked solution above is the direct answer, and the replies underneath it add the caveats that make it safe to use.

22 likes 21mo
LE
logbook_erinTL3Regular12 Nov 2024#22
i.dumitru, post #10: Gastric emptying delay is the mechanism behind most of the gastrointestinal side effects. Slowing the stomach empties it feeds less food into the intestines at a time, which is part of the satiety mechanism but is also why nausea is dose-dependent and titration-dependent. Go to post

I read post #20 twice before replying, because I had assumed the opposite.

Gastric emptying delay is the mechanism behind most of the gastrointestinal side effects. Slowing the stomach empties it feeds less food into the intestines at a time, which is part of the satiety mechanism but is also why nausea is dose-dependent and titration-dependent.

0 likes in reply to #10 20mo
MN
m.nascimentoTL2 Moderator13 Nov 2024 · edited#23

post #22 is right about the mechanism and I think understates the practical bit.

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.

3 likes 20mo
CL
coldchain_liuTL3Regular13 Nov 2024#24

The mass figure differs between sources because of how the different entities report it. The monoisotopic mass of the bare peptide is one number; the mass including the acylation is another. Different sources emphasise different details.

10 likes 20mo
FD
f.danquahTL2 Moderator14 Nov 2024#25

Picking up post #22: that is the part I would want checked first.

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.

30 likes 20mo
CC
crossref_checkTL3Wiki editor15 Nov 2024#26
v.stanescu, post #14: 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. Go to post

Coming back to post #24, because the follow-up matters more than the original answer.

Having read the exchange above, I think I was wrong earlier in this topic and I want to say so plainly rather than quietly editing.

The correction was fair and I had been repeating something I had not checked carefully enough.

0 likes in reply to #14 20mo
SG
s.girardTL2 Moderator15 Nov 2024#27
m.nascimento, post #23: post #22 is right about the mechanism and I think understates the practical bit. 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… Go to post

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.

6 likes in reply to #23 20mo
CO
c.okaforTL3Regular16 Nov 2024#28

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.

15 likes 20mo
VB
v.bergstromTL2 Moderator17 Nov 2024#29

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.

0 likes 20mo
RJ
r.jhannsdttirTL3Regular17 Nov 2024#30

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.

1 like 20mo