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Compounds · Secretagogues & GH axis

Revisiting: What a well-designed human trial of a secretagogue would look like

HB
h.brandtTL2 Moderator21 Dec 2024#1

On the subject in the title: Revisiting: What a well-designed human trial of a secretagogue would look like Working notes rather than a conclusion.

Session topic: SELECT (N Engl J Med, 2023). Please read it before posting; the discussion is much better when everyone has.

The question I would like us to start with is what the trial set out to estimate, rather than what it found. Once that is on the table we can talk about whether the design could have answered it, and only then about the numbers.

Specific things I would like covered: the population and how far it generalises, how discontinuation was handled, whether the comparator was a fair one, and what the absolute rather than relative effect looks like.

I will summarise at the end and the summary will feed the relevant digest page.

3 likes 19mo
SB
s.beaulieuTL2 Moderator23 Dec 2024 · edited#2

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

Tesamorelin has an approved indication in HIV-associated lipodystrophy. That is the only compound in this class with a registration-quality evidence base from a proper trial programme. Generalising from that narrow population to healthy adults is a substantial extrapolation.

7 likes 19mo
O
OkaforTL3Regular24 Dec 2024#3

Pulsatile secretion matters because growth hormone is secreted in pulses, not continuously. A single post-dose growth hormone level is nearly uninterpretable. Assessing this class properly requires serial sampling or an integrated measure like IGF-1, and almost nothing published online does either.

17 likes 19mo
ID
il.dumitruTL2 Moderator25 Dec 2024#4

IGF-1 as a surrogate: it is a better integrated measure than a spot growth hormone level and it is still a surrogate, with all the caveats that come with surrogates. Stable or rising IGF-1 is not the same as "this is working" in any health-related sense.

0 likes 19mo
AS
a.salcedoTL3Regular26 Dec 2024#5
il.dumitru, post #4: IGF-1 as a surrogate: it is a better integrated measure than a spot growth hormone level and it is still a surrogate, with all the caveats that come with surrogates. Stable or rising IGF-1 is not the same as "this is working" in any health-related sense. Go to post

CJC-1295 with and without DAC: the version with a drug affinity complex binds albumin covalently and persists for days. The version without it does not persist. Supplier labelling frequently does not distinguish them clearly, so confirming which you have is important.

3 likes in reply to #4 19mo
MY
m.yilmazTL2 Moderator27 Dec 2024#6
h.brandt, post #1: On the subject in the title: Revisiting: What a well-designed human trial of a secretagogue would look like Working notes rather than a conclusion. Session topic: SELECT ( N Engl J Med , 2023). Please read it before posting; the discussion is much better when everyone has. The question I would like us to start with is what the trial set… Go to post

Coming back to post #4, because the follow-up matters more than the original answer.

Ipamorelin selectivity claims originate in preclinical characterisation and are reasonably well supported for what they claim: less effect on cortisol and prolactin than earlier GHRPs. Whether that translates to something clinically meaningful is a different question from whether the selectivity is real.

11 likes in reply to #1 19mo
FA
f.abrahamsenTL2Member28 Dec 2024#7

Reading a rodent study on a secretagogue without over-extrapolating: rodent studies can show a mechanism is plausible. They cannot show magnitude of effect in humans or safety profile in humans. That gap is larger for secretagogues than for incretin agonists because the human evidence is thinner.

24 likes 19mo
KH
ka.haddadTL2 Moderator29 Dec 2024#8

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 19mo
JD
j.dahlbergTL2 Moderator30 Dec 2024#9

What a well-designed human trial of a secretagogue would look like: randomised, placebo-controlled, adequate sample size, IGF-1 as primary outcome, muscle and strength as secondary outcomes, adequate follow-up duration. Very few secretagogue trials meet that description.

0 likes 19mo
TW
t.wojcikTL2 Moderator31 Dec 2024#10

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.

1 like 19mo
MM
m.marchettiTL2 Moderator31 Dec 2024#11

Practical note that does not fit anywhere else. Whatever you conclude from this topic, write down what you did and when. The single most useful thing in your own records is not any individual result; it is that they are dated and consecutive.

20 likes 19mo
MD
methods_draftTL2Member1 Jan 2025#12

Secretagogues and glucose tolerance: there is a mechanistic concern that sustained growth hormone elevation might impair glucose tolerance. The clinical relevance of this concern in practice is not well established.

8 likes 19mo
BW
br.wikstromTL2 Moderator2 Jan 2025#13
il.dumitru, post #4: IGF-1 as a surrogate: it is a better integrated measure than a spot growth hormone level and it is still a surrogate, with all the caveats that come with surrogates. Stable or rising IGF-1 is not the same as "this is working" in any health-related sense. Go to post

I read post #11 twice before replying, because I had assumed the opposite.

Evidence quality in the secretagogue literature is honestly weaker than in the incretin literature. Large randomised controlled trials are rare. Most evidence is mechanistic or from small studies. This is why this subcategory has higher sourcing standards than most.

0 likes in reply to #4 19mo
GR
gradient_reviewTL2Member3 Jan 2025 · edited#14

This follows post #11 rather than contradicting it.

Development history is more informative than speculation: ipamorelin was investigated clinically for post-operative ileus and was not taken forward to registration. That it was not brought to market tells you something about the cost-benefit calculation that any amount of forum enthusiasm does not.

0 likes 19mo
PL
p.lindqvistTL2 Moderator3 Jan 2025#15

Why this subcategory is stricter about sourcing than most: the evidence base is weaker and that is precisely why documentation quality matters more. A supplier page that clearly identifies the compound and the purity is more valuable for secretagogues than for incretin agonists where the evidence base is stronger.

14 likes 19mo
CE
crossover_entryTL3Regular4 Jan 2025#16

post #15 answers the question as asked. The question underneath it is different.

Thank you for the correction. I have edited my earlier post with a note rather than silently, so the thread still makes sense to read. The error was mine and it was the kind that comes from remembering a figure instead of looking it up.

5 likes 19mo
KA
k.adeyemiTL2 Moderator5 Jan 2025#17
m.yilmaz, post #6: Coming back to post #4, because the follow-up matters more than the original answer. Ipamorelin selectivity claims originate in preclinical characterisation and are reasonably well supported for what they claim: less effect on cortisol and prolactin than earlier GHRPs. Whether that translates to something clinically meaningful is a… Go to post

Coming back to post #15, because the follow-up matters more than the original answer.

GHRH analogues versus ghrelin mimetics are often conflated but they are different mechanisms. GHRH analogues (like CJC-1295) cause the pituitary to release growth hormone. Ghrelin mimetics (like GHRPs) act on the ghrelin receptor directly. The effect on growth hormone secretion is similar but the mechanisms are distinct.

0 likes in reply to #6 19mo
EK
e.kjeldsenTL2Member6 Jan 2025#18
Okafor, post #3: Pulsatile secretion matters because growth hormone is secreted in pulses, not continuously. A single post-dose growth hormone level is nearly uninterpretable. Assessing this class properly requires serial sampling or an integrated measure like IGF-1, and almost nothing published online does either. Go to post

Reading a rodent study on a secretagogue without over-extrapolating: rodent studies can show a mechanism is plausible. They cannot show magnitude of effect in humans or safety profile in humans. That gap is larger for secretagogues than for incretin agonists because the human evidence is thinner.

28 likes in reply to #3 19mo
JS
j.sandvikTL2 Moderator6 Jan 2025#19

Tesamorelin has an approved indication in HIV-associated lipodystrophy. That is the only compound in this class with a registration-quality evidence base from a proper trial programme. Generalising from that narrow population to healthy adults is a substantial extrapolation.

9 likes 19mo
AT
a.thorneTL2Wiki editor7 Jan 2025#20

post #19 is right about the mechanism and I think understates the practical bit.

GHRH analogues versus ghrelin mimetics are often conflated but they are different mechanisms. GHRH analogues (like CJC-1295) cause the pituitary to release growth hormone. Ghrelin mimetics (like GHRPs) act on the ghrelin receptor directly. The effect on growth hormone secretion is similar but the mechanisms are distinct.

2 likes 19mo
QZ
q.zhao_qaTL3Quality assurance8 Jan 2025#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.

0 likes 19mo
RL
r.lundgrenTL2 Moderator8 Jan 2025#22

On post #18 — agreed on the reasoning, with one qualification.

Why this subcategory is stricter about sourcing than most: the evidence base is weaker and that is precisely why documentation quality matters more. A supplier page that clearly identifies the compound and the purity is more valuable for secretagogues than for incretin agonists where the evidence base is stronger.

0 likes 19mo
DM
d.moreauTL2Regular9 Jan 2025#23

Development history is more informative than speculation: ipamorelin was investigated clinically for post-operative ileus and was not taken forward to registration. That it was not brought to market tells you something about the cost-benefit calculation that any amount of forum enthusiasm does not.

4 likes 19mo
KB
ka.batistaTL2 Moderator10 Jan 2025#24
a.salcedo, post #5: CJC-1295 with and without DAC: the version with a drug affinity complex binds albumin covalently and persists for days. The version without it does not persist. Supplier labelling frequently does not distinguish them clearly, so confirming which you have is important. Go to post

Evidence quality in the secretagogue literature is honestly weaker than in the incretin literature. Large randomised controlled trials are rare. Most evidence is mechanistic or from small studies. This is why this subcategory has higher sourcing standards than most.

12 likes in reply to #5 19mo
SF
sterile_fileTL3Regular10 Jan 2025#25
t.wojcik, post #10: 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. Go to post

Pulsatile secretion matters because growth hormone is secreted in pulses, not continuously. A single post-dose growth hormone level is nearly uninterpretable. Assessing this class properly requires serial sampling or an integrated measure like IGF-1, and almost nothing published online does either.

0 likes in reply to #10 19mo
NC
n.chowdhuryTL2 Moderator11 Jan 2025 · edited#26

IGF-1 as a surrogate: it is a better integrated measure than a spot growth hormone level and it is still a surrogate, with all the caveats that come with surrogates. Stable or rising IGF-1 is not the same as "this is working" in any health-related sense.

1 like 19mo
AS
a.stephanopoulosTL3Regular12 Jan 2025#27

This follows post #24 rather than contradicting it.

CJC-1295 with and without DAC: the version with a drug affinity complex binds albumin covalently and persists for days. The version without it does not persist. Supplier labelling frequently does not distinguish them clearly, so confirming which you have is important.

7 likes 18mo
FP
f.petrovTL2 Moderator12 Jan 2025#28
Okafor, post #3: Pulsatile secretion matters because growth hormone is secreted in pulses, not continuously. A single post-dose growth hormone level is nearly uninterpretable. Assessing this class properly requires serial sampling or an integrated measure like IGF-1, and almost nothing published online does either. Go to post

Practical note that does not fit anywhere else. Whatever you conclude from this topic, write down what you did and when. The single most useful thing in your own records is not any individual result; it is that they are dated and consecutive.

18 likes in reply to #3 18mo
VM
v.milanoviTL3Regular13 Jan 2025#29
j.dahlberg, post #9: What a well-designed human trial of a secretagogue would look like: randomised, placebo-controlled, adequate sample size, IGF-1 as primary outcome, muscle and strength as secondary outcomes, adequate follow-up duration. Very few secretagogue trials meet that description. Go to post

post #28 answers the question as asked. The question underneath it is different.

Ipamorelin selectivity claims originate in preclinical characterisation and are reasonably well supported for what they claim: less effect on cortisol and prolactin than earlier GHRPs. Whether that translates to something clinically meaningful is a different question from whether the selectivity is real.

19 likes in reply to #9 18mo
PF
p.friskTL2 Moderator13 Jan 2025#30

What a well-designed human trial of a secretagogue would look like: randomised, placebo-controlled, adequate sample size, IGF-1 as primary outcome, muscle and strength as secondary outcomes, adequate follow-up duration. Very few secretagogue trials meet that description.

0 likes 18mo