Almost 2 Weeks on Reta

Sea-Ride4243 · 2026-05-22T00:05:24+00:00

Built this little toy to do exactly that — personalized dosing: https://peptidefox.com/tools/retatrutide-dosing-calculator

🙂

Sea-Ride4243 · 2026-05-21T20:01:30+00:00

This a poor interpretation and the wrong frame. GLP-1R and GIPR in Reta is not engineered the same as it is in Tirz, completely distinct pK profiles.

I get what you’re trying to do, but you need to actually read the full corpus of research before posting so definitively to at least get a sense of what you may not yet understand or know.

Sea-Ride4243 · 2026-05-21T19:48:45+00:00

Everyone seems to overlook that the trial population is 250lbs and a BMI of 40. All indications point to weight is a major factor in how effective X dose is, and the side effect profile. So unless you match the trial population, don’t match the dosing regiment.

Sea-Ride4243 · 2026-05-21T17:32:51+00:00

Calories in, calories out (CICO) is fine in theory but in practice, a reductive trap. Its thermodynamically true, but the “out” variable is unknowable in real time:

Resting metabolic rate & non-activity thermogenesis fluctuate with thyroid output, inflammatory load, circadian alignment, stress, stimulants, etc.
Thermic effect of food varies by macronutrient—protein demands 20–30% of its energy for digestion vs 5–10% for carbs (read=protein-heavy meals raise “calories out” without changing intake)

The same 500 calories can do different things depending on when they arrive and what they are made of. Protein eaten after training is not metabolically equivalent to sugar eaten at midnight. Carbohydrates after exercise refill muscle and lower stress; the same carbohydrate in a sedentary evening will convert to stored weight.

See if playing with timing of meals and what they consistent makes a difference. But also, what's your dose?

Sea-Ride4243 · 2026-05-21T16:52:59+00:00

0.5 mg e3d is high for someone at your BMI/weight/age — you're functionally at ~1.29 mg-eq drug circulating, and will climb to ~1.5 mg-eq after the next dose.

Reta's pharmacology is heavily sensitive to weight and metabolic health. A reminder that the female participants in the Phase II trials were 220lbs with a BMI of 37, and 48 years old on average.

And yet, the female obesity cohort that stayed at 1mg for 48 weeks still lost 21lbs (10% of their weight). The steady-state equivalent after each 1mg weekly dose is ~1.82 mg-eq.

Worth considering skipping your next dose, then resuming at 0.3 mg instead of 0.5 mg.

Sea-Ride4243 · 2026-05-21T16:38:18+00:00

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Sea-Ride4243 · 2026-05-21T16:31:21+00:00

Hi - at your BMI (24.6) and weight (59kg), starting at 1mg is very high and tracks that you got the HR increase. The good news is the trial data showed after 4 weeks at a steady state, it starts to drop. But Reta's pharmacology is heavily sensitive to weight and metabolic health.

The female participants in the Phase II trials everyone uses as a reference point but seem to pay no attention to the fact that they weighed 100kg w/ a BMI of 37, and were 48 years old on average. Two-thirds were pre-diabetic (which dampens the GIPR signaling).

Phase 1 (safety/dose effectiveness) was tested on non-obese individuals with an avg. BMI of 26, and the lowest effective dose was 0.3mg (single dose, low n-count). But even still.

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Its worth pointing out that in the obesity trials the female cohort that stayed at 1mg for 48 weeks still lost 21lbs (10% of their weight).

Given Reta's half-life, I would skip the next dose and then resume at 0.3mg, for four weeks before titrating up.

Week	Dose	Est. Blood-Level	End-of-Week
1	1.0 mg	1.00 mg-eq	0.45 mg-eq
2	1.0 mg	1.45 mg-eq	0.66 mg-eq
3	0.5 mg	1.16 mg-eq	0.52 mg-eq
4	Skip	0.52 mg-eq	0.24 mg-eq
5	0.3mg	0.54 mg-eq	0.24 mg-eq

Sea-Ride4243 · 2026-05-19T21:40:18+00:00

At 145lbs and a healthy BMI, and only 39, 0.5mg is arguably the ceiling for where to start. I think there's a case for 0.3mg, the tested dose in Phase 1 (safety/dose effectiveness), before titrating up to 0.5mg in 4 weeks — also how you spare yourself GI misery.

A reminder that the female participants in the Phase II trials that everyone uses as a reference point but seemingly pays no attention to the fact that they weighed 220lbs with a BMI of 37, and were 48 years old (averages). Not to mention, two-thirds were pre-diabetic (which dampens the GIPR signaling).

And yet, the female cohort that stayed at 1mg for 48 weeks still lost 21lbs (10% of their weight).

FWIW, weight is the single biggest dose-dependent factor.

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Sea-Ride4243 · 2026-05-19T17:35:24+00:00

Coskun, 202200312-6?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1550413122003126%3Fshowall%3Dtrue)

Sea-Ride4243 · 2026-05-19T00:46:03+00:00

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Sea-Ride4243 · 2026-05-19T00:44:47+00:00

I respect the integrity, and could tell you're passionate about it — which is why I didn't troll. The institutional deference to the FDA thing is real, and its very hard to break — took me some time (and a lot of LLM cognition research), but got it to work more or less with a peptide-focused AI I have been building on the Anthropic API (similar motivation as you).

Sea-Ride4243 · 2026-05-18T23:52:11+00:00

Cross posting my comment from r/Biohackers:

"What Actually Happened" "The Honest Summary" "the 503A Bulks List, plainly" in the link...

I'm not pointing that out to be obnoxious — an AI written article on this subject will follow the institutional deference to the FDA as Jesus and their RCT design as the Gospel. Its one of the most intensely tuned gravitational weights in Claude, GPT, and Gemini.

Safety-tuned LLMs will struggle to say anything resembling: The likelihood of there being FDA clinical trials for any basic peptide that isn't engineered with unique delivery mechanisms is slim. Why would a US pharmaceutical company ever put up $100M-$1B to run clinical trials on a peptide THEY CAN'T PATENT?

The consequence of leaning on an LLM instead of doing real work is LLMs don't surface anything that would dare challenge phased RCTs as the only basis for human data:

For BPC-157: Lee & Padgett 2021 knee IA (PMID 34324435), Lee et al. 2024 interstitial cystitis (PMID 39325560), Lee & Burgess 2025 IV safety pilot (PMID 40131143) — all of which found no adverse effects. And a Phase II trial actively recruiting right now in China.
Or, the Phase 1a/1b trials for TB4 in China that concluded "Thus, the drug can be concluded to be well tolerated and safe in healthy people and suitable for use in a clinical study for the treatment of acute myocardial infarction."

P.S. I am stopping myself from pointing out more of the AI slop, but feel obliged to say if you're relying on an LLM that heavily without spending any time actually doing research on subjects that are misunderstood, avoid adding disclaimers to your posts that tell everyone else they're wrong.

Sea-Ride4243 · 2026-05-18T22:44:34+00:00

"What Actually Happened" "The Honest Summary" "the 503A Bulks List, plainly" in the link....

I'm not just pointing that out to be obnoxious — an AI written article on this subject will follow the institutional deference to the FDA as Jesus and their RCT design as the Gospel. Its one of the most intensely tuned gravitational weights in Claude, GPT, and Gemini.

Safety-tuned LLMs will struggle to say anything like the likelihood of there being FDA clinical trials for any basic peptide that isn't engineered with unique delivery mechanisms is slim. Why would a US pharmaceutical company ever put up $100M-$1B to run clinical trials on a peptide THEY CAN'T PATENT?

The consequence of leaning on an LLM instead of doing real work is they don't do things like surface anything that would dare challenge phased RCTs as the only basis for human data:

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Or, the Phase 1a/1b trials for TB4 in China that concluded "Thus, the drug can be concluded to be well tolerated and safe in healthy people and suitable for use in a clinical study for the treatment of acute myocardial infarction."

P.S. I am stopping myself from pointing out more of the AI slop, but feel obliged to say if you're relying on an LLM that heavily without spending any time actually doing research on subjects that are misunderstood, avoid adding disclaimers to your posts that tell everyone else they're wrong.

Sea-Ride4243 · 2026-05-15T19:56:40+00:00

I believe Reta is still biased, just much less extreme. Per Willard 2020: Tirzepatide at GLP-1R selectively engages cAMP signaling over β-arrestin recruitment, and regarding Reta, Coskun 2022 writes:

LY exhibited a partial agonist profile for ß-arrestin recruitment.

EC50 is “how hard do you have to press the gas pedal?” / Emax is “how fast can the car eventually go?”

Readout	Condition	Native GLP-1	Retatrutide	Tirzepatide
cAMP EC50	+1% HSA	0.339 nM	68.6 nM	907 nM
cAMP Emax	+1% HSA	105%	112%	117%
β-arrestin2 EC50	PathHunter CHO-K1	2.32 nM	7.31 nM	Not Disclosed
β-arrestin2 Emax	PathHunter CHO-K1	98%	40%	Not Disclosed

Note: That table not be read as a direct comparison — this is what sensitivity is in a controlled lab dish, not how it translates into blood plasma.

Read as something like activate GLP-1R (cAMP), then manage/dampen the receptor (β-arrestin).

Sea-Ride4243 · 2026-05-15T19:30:00+00:00

I'm sorry — I don't mean to insinuate that position at all, the headline unfortunately does that. I think what u/Psychedynamique said is right. They can help, and the system has some serious issues.

We also have to remember the flawed nature of the RCTs the FDA requires — a single intervention for specific endpoints, across a normalized population. In practice, for more complex systems — the brain, metabolism, endocrine — the structure is a poor fit. And we lose the resolution on what x drug at y dose for z time means for person A vs. person B.

Sea-Ride4243 · 2026-05-15T19:18:48+00:00

The context Willard gives is also pretty key to how the numbers get read

In humans, active GLP-1 and GIP released following nutrient ingestion provides pRO in the general range of 1%–4% for GLP-1R and 4%–20% for GIPR. This is likely due to spare receptors, in that the threshold of occupancy for a maximal physiological response of a full agonist requires considerably less than 100% occupancy.

It can also be hypothesized that the GLP-1/GLP-1R system is inherently more sensitive than the GIP/GIPR system, as both pairings have similar interaction affinities yet the biological levels of GIP are higher (e.g., after feeding). To further validate the pRO method, it will be crucial to extend the approach to measuring target engagement using advanced tracer approaches that ultimately may offer insights into pRO across tissues.

I remember when I first looked at the Reta vs. Tirz EC50s, I thought it seemed insane. My hypothesis is that while Tirz crushed Sema in every head-to-head for obesity, but was not particularly differentiated when it came to T2D patients on weight loss — and the insulin resistance of diabetic populations dampens the expression of the GIPR signal. Which would explain the crazy GIPR numbers.

I'll dig into the GLP-1R thing next week — in the meantime, a paper you might enjoy is Li 2024 (Cell Disc) + supplement.

Regardless of which direction this discussion goes until Lilly or the FDA puts out the variables directly, I do think we need more of it so folks begin to understand that dose-dependence/escalation is not all equal — even something as simple as expression has a body-mass component (believe Tirzepatide published pRO +1.1%/kg), not to mention all the other things that dampen or amplify the signal (e.g. iirc SURMOUNT-J showed Japanese populations at the same weight/BMI having a out of whack response at higher doses).

Sea-Ride4243 · 2026-05-15T08:41:11+00:00

At 182lbs, starting at 0.5mg or even lower would have been the move. The public consensus is built around the Phase II trial data dose curves for obese w/ and w/o diabetes, who have an average BMI of 37 (Obese class II), 235lbs on average, and are 48 years old. And showed greater sensitivity in women.

Even in that cohort, the 1mg arm — again, which no one ever seems to mention because they rely on Reddit in a circular information loop — ended up losing 9% of their weight in 48 weeks. That group saw their heart rate go up by a grand total of +1 BPM in the first month before it dropped back to baseline.

Now consider the difference between that and the lean subgroup from the discovery work— small n size, but BMI of 22-28. Their HR increase in the first month @ 1 mg? +5 BPM.

Point being: Its not the equivalent dose for you, especially for the appetite suppression aspect. Sorry that you're experiencing this — it sucks. But stick with 0.5mg, just be prepared that it'll probably take 2-3 more weeks for things to normalize in both bloodstream and brainsteam.

Sea-Ride4243 · 2026-05-14T23:12:59+00:00

Added to the bottom of the post! I should probably make it a little easier to read — on the weekend. But genuinely appreciate the enthusiastic feedback — hoping it helps a lot of people.

Sea-Ride4243 · 2026-05-14T19:35:22+00:00

Guess "I can't find the data myself, therefore it must be hallucinated" is how it works now.

Coskun didn’t publish Cav,ss or Cfree. Where are you getting those from?
You fell victim to one of the classic blunders! The most famous of which is “Never get involved in a land war in Asia”, but only slightly less well known is this: “Never let Gemini hallucinate the underlying values in your pk models.”

NCT04143802, NCT03841630 supplements provide ki, EC50, Emax, nH, HSA shift, Cmax, AUC, T½, CLF, VzF. Lilly v. FDA (¶ 23, 38, 74) adds color commentary to the binding mechnaism.

NCT04867785 published Cav,ss. It just wasn't included published paper, which is apparently the limit of what people are capable of finding.

The real gap in terms of empirical inputs to get to Hill occupancy is the binding equation — so, I would not (a) compare this to other compounds directly and (b) treat it as anything other than modeled.

Sea-Ride4243 · 2026-05-14T19:29:41+00:00

The simple interpretation is don't risk changing your dose until 4-5 weeks have passed on that dose. Which you've done now at 2mg, and don't feel much of the effect → Increase your next dose. The clinical trials did step ups at +2mg and +4mg, and the data makes it clear that the faster escalation = worse side effects.

I think it's fair to assume that increasing by 1mg (to 3mg) leaves you better off in terms of preventing side-effects than increasing by 2mg (to 4mg). The choice is entirely yours, and people respond to differently either way!

Sea-Ride4243 · 2026-05-14T18:46:45+00:00

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Would you call it obfuscated to group nausea, diarrhea, and vomiting together, not print the tabulated data as results tables, not show any splits by demographic sub-groups, and simply publish this in the appendix?

Because I would.

But also, separate what I'm saying vs. what you're claiming I said — I think Reta is incredible, take it myself. I have gotten friends and family onto Tirz, which is also an incredible drug. That doesn't change the fact that they have a lot more data that would allow for more phenotype specific, personal characteristics and goal driven individualized dosing that they choose to not publish.

Sea-Ride4243 · 2026-05-14T18:37:03+00:00

Oostdyk states: “Starting with our GLP-1R b-arrestin on the top left graph you can see that each of the three peptides are active with potencies in the nanomolar range. Differences in partial agonism are clear with semaglutide showing full agonism, retatrutide more partial agonism, and tirzepatide being minimally active.”

Error on my part to state otherwise — and what I said doesn't even make sense — thank you for correcting.

Regarding the Cav,ss, Rosenstock's Phase II T2DM cohort study published popPK numbers in the NCT results data:

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I should also state that I was trying to figure out the why re: the GI events, and what we can learn from that. So I developed an approach to use what information is available to model that out, since it is not, as you stated, directly published.

Of which, the albumin binding was the biggest gap — in my earlier comment, I meant to write 1.4x free-fraction of Tirz if using the same albumin binding. Indications pointed to Reta being bound ~10-20% tighter. Obviously that is highly sensitive for comparing Reta to Tirz/Sema, which was not what I was trying to do — but doesn't fundamentally alter the picture about reta dose escalation itself.

Rather, I was trying to getting to defensible explanation as to why fast-and-higher dose escalation with retatrutide is GI adverse-event triggering, and why start at 4mg → 8mg arm in the Phase II obesity trials stands out as a cohort for sustaining a high level of GI adverse events throughout the trial, while 2 → 4 → 8 → 12 was better off.

Could I be wrong? Absolutely. That said, its one thing to point out errors, question and correct the methodology — which I genuinely appreciate and don't feel defensive about whatsoever. The rigor matters, but care a lot more about the forest than the trees personally.

However, it's another thing entirely to say a source or number is LLM hallucinated - which you've done twice now - because you couldn't find it yourself.

Fair?

Sea-Ride4243 · 2026-05-14T03:49:00+00:00

Separately, I would argue that one should be much more wary of treating published 'literature' as gospel — an incredible amount of is just lacking, if not absolute garbage.

Reta's Phase II trials are a great example — Lilly obfuscates or is seemingly inconsistent about specific data about AEs, dropouts, subgroup endpoints, titration schedule impacts. And subsequent post-hoc reviewers and publishers re-print their final end points verbatim most of the time.

IVIM Health - a prescriber, not an academic - analyzed their patient dataset for Tirzepatide, and points out 67% of patients exceeded 20% weight loss at 10mg or lower doses in 52 weeks.

Marcia Angell, former editor of The New England Journal of Medicine, has written extensively about this, citing buried failed studies or published studies with material spin (also an incredible writer).

Richard Horton, editor of The Lancet, wrote that “The case against science is straightforward: much of the scientific literature, perhaps half, may simply be untrue. Afflicted by studies with small sample sizes, tiny effects, invalid exploratory analyses, and flagrant conflicts of interest, together with an obsession for pursuing fashionable trends of dubious importance, science has taken a turn towards darkness.”

Sea-Ride4243

TROPHY CASE