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Compounds · Tirzepatide

Tirzepatide in type 2 diabetes: the SURPASS programme, summarised honestly

Compounds › Tirzepatidetirzepatide SURPASS programme randomised trial effect size SURMOUNT programme
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Solved by s.cardoso in post #2
Taking the opening post at face value and following it one step further. Tirzepatide's half-life of roughly five days means steady state is approached in about three weeks rather than four. That is a real difference from semaglutide and it is small enough that the weekly schedule is unaffected.

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KH
k.haddadTL21 Jan 2025#1

Tirzepatide in type 2 diabetes: the SURPASS programme, summarised honestly — setting out what I have, and where I think it stops being reliable.

I have spent a fortnight trying to pin tirzepatide in type 2 diabetes down and I want to set out where I have got to, because I suspect the honest answer is duller than the thread this will produce.

What I have: a consistent observation across a small number of cases, collected the same way each time. What I do not have: any controlled comparison, or any reason to think my cases are representative.

The specific question is whether the pattern survives once the obvious confounder is removed. I cannot remove it with what I have.

58 likes 19mo
SC
s.cardosoTL2 Solution6 Jan 2025 · edited#2

Taking the opening post at face value and following it one step further.

Tirzepatide's half-life of roughly five days means steady state is approached in about three weeks rather than four. That is a real difference from semaglutide and it is small enough that the weekly schedule is unaffected.

16 likes 19mo
GI
g.ibarraTL29 Jan 2025#3

Everything in the opening post holds. The case it does not cover is the one I have.

Source for the tirzepatide in type 2 diabetes figure, since it was asked for. It is in the discussion rather than the abstract, which is why the version circulating is stronger than the paper is.

Reading the surrounding paragraph is worth the two minutes. The authors are more careful than their summarisers.

6 likes 19mo
MY
m.yilmazTL211 Jan 2025#4
s.cardoso, post #2: Taking the opening post at face value and following it one step further. Tirzepatide's half-life of roughly five days means steady state is approached in about three weeks rather than four. That is a real difference from semaglutide and it is small enough that the weekly schedule is unaffected. Go to post

Marking my place. If it changes for me I will come back and say so.

1 like in reply to #2 18mo
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GDashwoodTL3Regular14 Jan 2025#5

Worth separating two things that post #3 runs together.

Mass and charge states: tirzepatide is about 4813.5 Da and on an electrospray instrument you would expect to see charge states mostly in the 2+ to 4+ range, the same as semaglutide. A doubly charged species would appear at about (4813.5 + 2 × 1.008) / 2 ≈ 2408.

0 likes 18mo
CH
ca.haddadTL216 Jan 2025#6

This follows post #3 rather than contradicting it.

Storage and stability: published data on licensed tirzepatide formulations exists and is worth reading directly rather than through summarised claims. Reconstituted preparations in different diluents have not been studied and extrapolation from the licensed formulation is the best you can do.

22 likes 18mo
FA
f.abrahamsenTL2Member19 Jan 2025#7

Categorical response thresholds — the proportion reaching ten, fifteen or twenty per cent reduction — are more persuasive and less informative than the mean. They depend entirely on where the threshold was drawn.

Someone will know this better than I do and I hope they say so.

10 likes 18mo
EC
e.coelhoTL221 Jan 2025#8
m.yilmaz, post #4: Marking my place. If it changes for me I will come back and say so. Go to post

Comparisons between the tirzepatide and semaglutide programmes across trials rather than within one are weak. Different populations, different durations, different baseline characteristics; the only fair comparison is a head-to-head one.

That is all the detail I have. Someone else will have more.

3 likes in reply to #4 18mo
GH
g.haalandTL3Regular23 Jan 2025#9
GDashwood, post #5: Worth separating two things that post #3 runs together. Mass and charge states: tirzepatide is about 4813.5 Da and on an electrospray instrument you would expect to see charge states mostly in the 2+ to 4+ range, the same as semaglutide. A doubly charged species would appear at about (4813.5 + 2 × 1.008) / 2 ≈ 2408. Go to post

On post #7 — agreed on the reasoning, with one qualification.

Categorical response thresholds — the proportion reaching ten, fifteen or twenty per cent reduction — are more persuasive and less informative than the mean. They depend entirely on where the threshold was drawn.

I am describing what is, rather than arguing for what should be.

17 likes in reply to #5 18mo
ID
il.dumitruTL225 Jan 2025#10

On tirzepatide in type 2 diabetes, the part that usually goes wrong is that the question is asked as though it has one answer. It has a range, and the width of the range is the interesting bit.

If you can post the two or three numbers you are working from, several people here will check the arithmetic rather than argue about the conclusion.

6 likes 18mo
HF
h.ferrariTL227 Jan 2025#11

Following this. I have the same question and no better information than the first post.

2 likes 18mo
EL
e.lehtinenTL229 Jan 2025#12
LA
l.aguirreTL231 Jan 2025#13
f.abrahamsen, post #7: Categorical response thresholds — the proportion reaching ten, fifteen or twenty per cent reduction — are more persuasive and less informative than the mean. They depend entirely on where the threshold was drawn. Someone will know this better than I do and I hope they say so. Go to post

I have been on both sides of the tirzepatide in type 2 diabetes argument in this category within eighteen months, which should tell you how strong the evidence for either side is.

21 likes in reply to #7 18mo
RF
r.friskTL22 Feb 2025#14

On post #10 — agreed on the reasoning, with one qualification.

Tirzepatide in type 2 diabetes is a good example of a question where the honest answer is boring and the interesting answers are unsupported. I would go with boring.

0 likes 18mo
KV
k.vanheckeTL23 Feb 2025 · edited#15

Post #13 is the version of this I will quote in future. One addition.

Categorical response thresholds — the proportion reaching ten, fifteen or twenty per cent reduction — are more persuasive and less informative than the mean. They depend entirely on where the threshold was drawn.

If that is already documented somewhere, ignore me and link it.

20 likes 18mo
VB
v.baptistaTL25 Feb 2025#16
s.cardoso, post #2: Taking the opening post at face value and following it one step further. Tirzepatide's half-life of roughly five days means steady state is approached in about three weeks rather than four. That is a real difference from semaglutide and it is small enough that the weekly schedule is unaffected. Go to post

The titration schedule has more steps than semaglutide's, which reflects the finer gradation used in the clinical programme rather than a pharmacological requirement for smaller steps.

The strength of my opinion here exceeds the strength of my evidence.

0 likes in reply to #2 18mo
BA
b.aaltoTL27 Feb 2025#17

SURPASS-2's comparator choice is the criticism that survives. Semaglutide 1.0 mg was the licensed diabetes dose at the time and it was not the highest dose available in the class, so the trial answers a narrower question than the headline implies.

The number is defensible. The precision I gave it is not.

0 likes 18mo
KF
k.fonsecaTL29 Feb 2025#18

Posting my tirzepatide in type 2 diabetes numbers with the method attached so they can be discounted properly. Uncontrolled, unblinded, and collected by someone who wanted a particular answer.

0 likes 18mo
ON
o.nybergTL211 Feb 2025#19
MW
m.wanjalaTL1Member12 Feb 2025#20
g.haaland, post #9: On post #7 — agreed on the reasoning, with one qualification. Categorical response thresholds — the proportion reaching ten, fifteen or twenty per cent reduction — are more persuasive and less informative than the mean. They depend entirely on where the threshold was drawn. I am describing what is, rather than arguing for what should be. Go to post

I read post #18 twice before replying, because I had assumed the opposite.

Categorical response thresholds — the proportion reaching ten, fifteen or twenty per cent reduction — are more persuasive and less informative than the mean. They depend entirely on where the threshold was drawn.

That distinction has done more work for me than anything else in this category.

3 likes in reply to #9 17mo
SV
s.vogelTL214 Feb 2025#21

The apnoea-hypopnoea index used in SURMOUNT-OSA is an objective measurement rather than a symptom scale, which is why that trial carries more weight than its size suggests. Two parallel trials with and without positive airway pressure addressed the obvious confounder directly.

I would be interested in a counterexample if anyone has one.

22 likes 17mo
K
KStephanopoulosTL3Regular16 Feb 2025#22

Confirming post #20 from a second method, which matters more than confirming it from a second person.

A note on how tirzepatide in type 2 diabetes gets discussed rather than on tirzepatide in type 2 diabetes itself: the confident posts get the replies and the careful ones get ignored, and the careful ones have been right more often.

10 likes 17mo
AK
ar.kravchenkoTL217 Feb 2025#23

Heart rate rises modestly across this class, tirzepatide included. It is consistent, small, and worth knowing about rather than worth alarm — and it is one of the reasons the trials monitored it explicitly.

That is the version I use. It may not be the version that is correct.

1 like 17mo
FE
footnote_entryTL3Regular19 Feb 2025#24
il.dumitru, post #10: On tirzepatide in type 2 diabetes, the part that usually goes wrong is that the question is asked as though it has one answer. It has a range, and the width of the range is the interesting bit. If you can post the two or three numbers you are working from, several people here will check the arithmetic rather than argue about the… Go to post

The GIP component: GIP receptor agonism is thought to amplify the GLP-1 effect on satiety and energy expenditure, but how much of tirzepatide's effect is that and how much is simply achieving higher receptor occupancy remains genuinely open. The mechanistic literature is active.

That holds for the case as described. Change the assumptions and it may not.

0 likes in reply to #10 17mo
MO
m.oyelaranTL221 Feb 2025#25

SURPASS-2 compared tirzepatide with semaglutide 1.0 mg, the licensed diabetes dose at that time. It did not compare with semaglutide 2.4 mg, the highest approved dose. That is the central and legitimate criticism of the head-to-head evidence and it is worth remembering when people quote the trial.

The mechanism is plausible, which is not the same as established.

15 likes 17mo
CI
citation_indexTL2Member22 Feb 2025#26

Nausea profile: some people report tirzepatide as less nausea-prone than semaglutide, others report it as more. The trial reported gastrointestinal effects broadly comparable in character. Individual variation is the largest factor.

I am not the right person to answer the follow-up to this.

6 likes 17mo
PF
p.fontaineTL224 Feb 2025#27
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BirkelandTL3Regular26 Feb 2025#28
g.haaland, post #9: On post #7 — agreed on the reasoning, with one qualification. Categorical response thresholds — the proportion reaching ten, fifteen or twenty per cent reduction — are more persuasive and less informative than the mean. They depend entirely on where the threshold was drawn. I am describing what is, rather than arguing for what should be. Go to post

On tirzepatide in type 2 diabetes I would separate what is worth knowing from what is worth acting on. The first list is long and the second is short, and conflating them is how threads get heated.

10 likes in reply to #9 17mo
TV
to.vargaTL227 Feb 2025#29
m.oyelaran, post #25: SURPASS-2 compared tirzepatide with semaglutide 1.0 mg, the licensed diabetes dose at that time. It did not compare with semaglutide 2.4 mg, the highest approved dose. That is the central and legitimate criticism of the head-to-head evidence and it is worth remembering when people quote the trial. The mechanism is plausible, which is… Go to post

Where I part company with post #28, and it is a narrow parting.

Dual agonism versus dose: how much of tirzepatide's effect is the GIP component and how much is simply achieving higher receptor engagement? The honest answer is that the question is not settled. Some of the effect is surely the GIP component, but the trial design does not decompose it.

I looked this up rather than remembered it, which is the right order.

1 like in reply to #25 17mo
CD
cohort_driftTL3Regular1 Mar 2025#30

The five maintenance doses in the tirzepatide programme give a genuine dose-response curve, which is unusual. Most trials in this space compare one or two doses against placebo and cannot say anything about the shape of the relationship.

If it helps: the failure mode here is usually boring rather than dramatic.

0 likes 17mo
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