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.
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Compounds · Retatrutide · continued
What we do not know about retatrutide, listed explicitly posts 61–90
This is a continuation of a long topic, addressed by post number rather than by page. Start at post 1.
This follows post #59 rather than contradicting it.
The phase 2 obesity paper reported dose-dependent weight reduction of a magnitude that attracted attention. It also reported dose-dependent heart-rate increases. The heart-rate signal is the reason phase 3 exists rather than something assumed negligible based on phase 2.
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SHermansen, post #25: I read post #23 twice before replying, because I had assumed the opposite. Triple agonism: is the effect additive, synergistic, or neither? A phase 2 comparison of tirzepatide (dual) to retatrutide (triple) would answer that question. The published data does not include such a direct comparison. Go to post
Retatrutide is investigational. Anything obtained outside a trial is by definition research-use-only material with no human-use authorisation. This site will state that plainly rather than winking at it.
taper_table, post #11: Mass and identity: a report on retatrutide should state the mass detected by LC-MS, not assume a theoretical mass. The theoretical mass is not published in peer-reviewed literature for retatrutide at present. Go to post
Phase 2 sample sizes are not adequate for safety characterisation of a novel triple agonist. Phase 3 is where that question gets answered. Using phase 2 results to make claims about safety profile is using the trial for a purpose it was not designed for.
What we do not know about retatrutide, listed explicitly: long-term safety, real-world response rates, the dose response in diverse populations, whether the heart-rate signal persists or attenuates, durability of effect on withdrawal, efficacy in comorbidities beyond obesity.
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Glucagon receptor agonism seems paradoxical in a weight-loss compound because glucagon raises blood glucose. The paradox resolves because glucagon agonism also increases energy expenditure and promotes hepatic fat oxidation, and the incretin components offset the glycaemic effect. In diabetes trials, HbA1c improved rather than worsened.
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Collapsed as off-topic by two members at trust level 3 or above
On post #63 — agreed on the reasoning, with one qualification.
TRIUMPH is phase 3 and it is ongoing. No phase 3 results exist. Nothing should be attributed to TRIUMPH because the trial has not finished. When it does, this page will update.
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.
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Dose escalation in the published trials: the protocols started at lower doses and escalated by defined steps. The step sizes are documented and they may or may not match what someone self-prescribing would choose.
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post #70 answers the question as asked. The question underneath it is different.
Why this subcategory is more cautious than elsewhere: retatrutide is investigational, phase 3 is ongoing, and the heart-rate signal in phase 2 is not negligible. Caution is proportionate to the evidence status.
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pe.onwuka, post #14: On post #10 — agreed on the reasoning, with one qualification. Mass and identity: a report on retatrutide should state the mass detected by LC-MS, not assume a theoretical mass. The theoretical mass is not published in peer-reviewed literature for retatrutide at present. Go to post
Mass and identity: a report on retatrutide should state the mass detected by LC-MS, not assume a theoretical mass. The theoretical mass is not published in peer-reviewed literature for retatrutide at present.
m.marchetti, post #30: The phase 2 obesity paper reported dose-dependent weight reduction of a magnitude that attracted attention. It also reported dose-dependent heart-rate increases. The heart-rate signal is the reason phase 3 exists rather than something assumed negligible based on phase 2. Go to post
Triple agonism: is the effect additive, synergistic, or neither? A phase 2 comparison of tirzepatide (dual) to retatrutide (triple) would answer that question. The published data does not include such a direct comparison.
Coming back to post #72, because the follow-up matters more than the original answer.
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.
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post #74 is right about the mechanism and I think understates the practical bit.
What we do not know about retatrutide, listed explicitly: long-term safety, real-world response rates, the dose response in diverse populations, whether the heart-rate signal persists or attenuates, durability of effect on withdrawal, efficacy in comorbidities beyond obesity.
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Worth separating two things that post #72 runs together.
Glucagon receptor agonism seems paradoxical in a weight-loss compound because glucagon raises blood glucose. The paradox resolves because glucagon agonism also increases energy expenditure and promotes hepatic fat oxidation, and the incretin components offset the glycaemic effect. In diabetes trials, HbA1c improved rather than worsened.
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y.adeyemi, post #24: The phase 2 obesity paper reported dose-dependent weight reduction of a magnitude that attracted attention. It also reported dose-dependent heart-rate increases. The heart-rate signal is the reason phase 3 exists rather than something assumed negligible based on phase 2. Go to post
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.
How to read phase 2 without treating it as phase 3: phase 2 establishes that a dose range produces an effect and is tolerable enough to justify large trials. It does not establish safety, durability, or whether real humans differ from the selected population.
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f.espinoza, post #60: How to read phase 2 without treating it as phase 3: phase 2 establishes that a dose range produces an effect and is tolerable enough to justify large trials. It does not establish safety, durability, or whether real humans differ from the selected population. Go to post
The phase 2 obesity paper reported dose-dependent weight reduction of a magnitude that attracted attention. It also reported dose-dependent heart-rate increases. The heart-rate signal is the reason phase 3 exists rather than something assumed negligible based on phase 2.
eire_reader, post #78: How to read phase 2 without treating it as phase 3: phase 2 establishes that a dose range produces an effect and is tolerable enough to justify large trials. It does not establish safety, durability, or whether real humans differ from the selected population. Go to post
TRIUMPH is phase 3 and it is ongoing. No phase 3 results exist. Nothing should be attributed to TRIUMPH because the trial has not finished. When it does, this page will update.
On post #77 — agreed on the reasoning, with one qualification.
Retatrutide is investigational. Anything obtained outside a trial is by definition research-use-only material with no human-use authorisation. This site will state that plainly rather than winking at it.
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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.
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Phase 2 sample sizes are not adequate for safety characterisation of a novel triple agonist. Phase 3 is where that question gets answered. Using phase 2 results to make claims about safety profile is using the trial for a purpose it was not designed for.
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Okafor, post #3: On the opening post — agreed on the reasoning, with one qualification. Dose escalation in the published trials: the protocols started at lower doses and escalated by defined steps. The step sizes are documented and they may or may not match what someone self-prescribing would choose. Go to post
Dose escalation in the published trials: the protocols started at lower doses and escalated by defined steps. The step sizes are documented and they may or may not match what someone self-prescribing would choose.
gradient_file, post #59: Hepatic effects: glucagon receptor agonism promotes hepatic fat oxidation, which is mechanistically plausible for benefit in metabolic liver disease. Whether that translates to improved clinical outcomes is being tested in phase 2 work. Go to post
Worth separating two things that post #81 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.
post #85 is right about the mechanism and I think understates the practical bit.
Hepatic effects: glucagon receptor agonism promotes hepatic fat oxidation, which is mechanistically plausible for benefit in metabolic liver disease. Whether that translates to improved clinical outcomes is being tested in phase 2 work.
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How to read phase 2 without treating it as phase 3: phase 2 establishes that a dose range produces an effect and is tolerable enough to justify large trials. It does not establish safety, durability, or whether real humans differ from the selected population.
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au.pereira, post #81: On post #77 — agreed on the reasoning, with one qualification. Retatrutide is investigational. Anything obtained outside a trial is by definition research-use-only material with no human-use authorisation. This site will state that plainly rather than winking at it. Go to post
Hepatic effects: glucagon receptor agonism promotes hepatic fat oxidation, which is mechanistically plausible for benefit in metabolic liver disease. Whether that translates to improved clinical outcomes is being tested in phase 2 work.
Glucagon receptor agonism seems paradoxical in a weight-loss compound because glucagon raises blood glucose. The paradox resolves because glucagon agonism also increases energy expenditure and promotes hepatic fat oxidation, and the incretin components offset the glycaemic effect. In diabetes trials, HbA1c improved rather than worsened.
0 likes 18mo
What we do not know about retatrutide, listed explicitly: long-term safety, real-world response rates, the dose response in diverse populations, whether the heart-rate signal persists or attenuates, durability of effect on withdrawal, efficacy in comorbidities beyond obesity.
0 likes 18mo