This is a continuation of a long topic, addressed by post number rather than by page. Start at post 1 · go to the accepted answer.
Everything in post #30 holds. The case it does not cover is the one I have.
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.
Triple agonism at GLP-1, GIP and glucagon receptors is the defining feature and the glucagon limb is the one people find counter-intuitive. It raises energy expenditure and promotes hepatic fat oxidation, and the incretin limbs offset the glycaemic consequence.
I would treat that as a working assumption and revisit it.
Distinguishing three things in the Triple agonism discussion that keep getting used interchangeably: the observation, the proposed mechanism, and the recommendation that gets attached to both.
A note on scope: what I am saying about Triple agonism applies to the case in the first post and I would not extend it further without checking.
The hepatic-steatosis rationale follows directly from glucagon receptor agonism promoting fat oxidation in the liver. Mechanistic plausibility in this field has a poor record of predicting clinical outcomes, which is why the trials matter more than the mechanism.
One of those cases where knowing the mechanism does not help the decision.
Heart rate increased in a dose-dependent way in the phase 2 work. That is not a footnote — it is one of the specific things phase 3 exists to characterise, and it is why this subcategory is written more cautiously than the others.
Building on post #35 rather than restating it.
Adding a null result on Triple agonism. I looked, carefully, and found nothing, and null results deserve posting precisely because they never are.
The hepatic-steatosis rationale follows directly from glucagon receptor agonism promoting fat oxidation in the liver. Mechanistic plausibility in this field has a poor record of predicting clinical outcomes, which is why the trials matter more than the mechanism.
The number is defensible. The precision I gave it is not.
Nausea and vomiting were dose-related in the phase 2 work, as they are throughout this class. What is not established is whether the tolerability profile differs from the dual agonists at equipotent effect, because equipotence has not been established either.
Building on post #40 rather than restating it.
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.
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.
Posting my Triple agonism numbers with the method attached so they can be discounted properly. Uncontrolled, unblinded, and collected by someone who wanted a particular answer.
Heart rate increased in a dose-dependent way in the phase 2 work. That is not a footnote — it is one of the specific things phase 3 exists to characterise, and it is why this subcategory is written more cautiously than the others.
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.
The evidence for this is thinner than the way I have phrased it suggests.
The arithmetic in post #45 is right; the assumption feeding it is the part to check.
On Triple agonism the community has more anecdote than the confidence in this thread implies, and I include my own contribution in that.
Following this. I have the same question and no better information than the first post.
I had written a reply contradicting post #46 and deleted it. Here is what survived.
Nausea and vomiting were dose-related in the phase 2 work, as they are throughout this class. What is not established is whether the tolerability profile differs from the dual agonists at equipotent effect, because equipotence has not been established either.
If it helps: the failure mode here is usually boring rather than dramatic.
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.
If anyone has run this properly I would rather read that than my own guess.
Confirming post #50 from a second method, which matters more than confirming it from a second person.
Triple agonism at GLP-1, GIP and glucagon receptors is the defining feature and the glucagon limb is the one people find counter-intuitive. It raises energy expenditure and promotes hepatic fat oxidation, and the incretin limbs offset the glycaemic consequence.
Adding what did not work for me on Triple agonism, since the failures never get written up and they are half the useful information.
Same experience here, different supplier, so it is at least not unique to one of them.
Where I part company with post #53, and it is a narrow parting.
Nausea and vomiting were dose-related in the phase 2 work, as they are throughout this class. What is not established is whether the tolerability profile differs from the dual agonists at equipotent effect, because equipotence has not been established either.
Something worth flagging about Triple agonism: the strongest-sounding claims in this thread are the ones with no source attached, which is the usual pattern and not a coincidence.
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.
Where the Triple agonism discussion usually stalls is that nobody wants to say "I do not know" and everyone is willing to say "it varies". Those are the same sentence with different clothes on.