u/Tiny_Split9436

A new retatrutide analysis has looked at what may be happening inside the kidney.
Researchers analysed blood proteins from two Phase 2 retatrutide trials.

One trial included 281 people with type 2 diabetes. The other included 338 people with obesity and no diabetes.

The new result is for uromodulin, or UMOD.
UMOD is a protein made mainly by kidney tubule cells.

Retatrutide increased UMOD in a clear dose-dependent pattern.

At 12 mg:
• +26.7% at 36 weeks in the diabetes trial
• +47.7% at 24 weeks in the obesity trial
• +42.2% at 48 weeks in the obesity trial

Dulaglutide produced almost no change: -1.5%.

The increases at 8 mg and 12 mg remained significant after adjusting for weight loss, HbA1c, or both.

That matters because it makes a simple explanation of "the kidneys improved because people lost weight and improved their diabetes" less convincing.

There is also an interesting biological clue.
The kidney cells that produce UMOD also express glucagon receptors.

Retatrutide activates the glucagon receptor as well as GLP-1 and GIP receptors.
So one possibility is that the glucagon part of retatrutide has a direct effect on kidney tubule cells.

This was a post-hoc biomarker analysis.
The people did not have established kidney disease.

Higher UMOD is associated with better kidney health, but raising UMOD has not been shown to cause better kidney outcomes.

The older retatrutide findings of lower urine albumin and higher eGFR are also not new.
The new finding is the large dose-dependent UMOD increase and the fact that it remained after adjustment for weight loss and HbA1c.

Source: ASN Kidney Week 2026, abstract FR-PO0500.

The weight-loss numbers from TRIUMPH-Q and TRIUMPH-2 get the most focus, but the blood sugar results are worth looking at separately in TRIUMPH-2.

Everyone in the trial had type 2 diabetes.
Average HbA1c at the start was 7.7%.

An HbA1c below 5.7% is in the normal range.

After 80 weeks:
4 mg:
• HbA1c fell by 1.4 percentage points
• 73.1% reached HbA1c ≤6.5%
• 28.4% reached HbA1c <5.7%
9 mg:
• HbA1c fell by 1.6 percentage points
• 79.2% reached HbA1c ≤6.5%
• 40.0% reached HbA1c <5.7%
12 mg:
• HbA1c fell by 1.5 percentage points
• 79.0% reached HbA1c ≤6.5%
• 39.3% reached HbA1c <5.7%
Placebo:
• HbA1c fell by 0.2 percentage points
• 26.3% reached ≤6.5%
• 4.4% reached <5.7%

The 9 mg result was effectively as strong as 12 mg for glucose control: 40.0% versus 39.3% below 5.7%.

At the same time, average weight loss was 19.1% at 9 mg and 20.8% at 12 mg.

.

The full TRIUMPH-2 results are out.
This is the major Phase 3 retatrutide obesity trial specifically in people with type 2 diabetes.

1,152 people were randomised and followed for 80 weeks.

Average weight loss:
• 4 mg: 12.7%
• 9 mg: 19.1%
• 12 mg: 20.8%
• Placebo: 4.0%

But the new responder numbers are probably more interesting:
At 12 mg:
• 67.0% lost at least 15%
• 52.0% lost at least 20%
• 34.9% lost at least 25%
At 9 mg:
• 62.2% lost at least 15%
• 45.3% lost at least 20%
• 30.6% lost at least 25%

And 59.5% of people on 12 mg no longer met the BMI definition of obesity by week 80.
Among participants who started with a BMI of at least 35, average loss on 12 mg was 23.4%.

The 20.8% average weight-loss result itself isn’t new. Lilly first announced that in July.
What’s new now is the detailed Phase 3 dataset, including the responder rates and subgroup results.

TRIUMPH-1 reached 28.3% at 12 mg, but that trial excluded people with diabetes, so the numbers aren’t directly comparable.

Source: Eli Lilly, detailed TRIUMPH-2 Phase 3 results, 29 September 2026.

Another important Reta trial already underway is TRIUMPH-6.

This one isn't about finding the biggest possible weight-loss number.

I personally think this is biggest thing. Ok we can lose 15%, 20%, 28%, 30%, what about the next 40 years of our extended lifetimes? Ok it’s not that long…

TRIUMPH-6 has enrolled 643 people with obesity.

Everyone gets retatrutide for the first 80 weeks.

After that they enter a 36-week randomised, double-blind maintenance phase.

They either continue retatrutide dose 1, move to retatrutide dose 2, or switch to placebo.

So the trial should give us a much better answer to one of the big long-term questions around Reta.

After someone has lost a large amount of weight, what happens if treatment continues, changes dose, or stops?

That is particularly relevant after TRIUMPH-1 showed average weight loss reaching 28.3% at 80 weeks and over 30% in its selected two-year extension group.

TRIUMPH-6 is specifically designed around maintaining that weight reduction rather than just producing more of it.

Enrolment is already complete.

The trial started in March 2025 and is expected to finish in April 2028.

Total participation is about 125 weeks.

This could end up being one of the more important Reta trials for understanding what long-term treatment actually looks like.

Lilly trial page:

https://trials.lilly.com/en-US/trial/580035

ClinicalTrials.gov:

https://clinicaltrials.gov/study/NCT06859268

Ok, after the massive news today what is next?

The next few big Reta milestones are already fairly close.

First is TRIUMPH-5.

This is the direct Phase 3 comparison of retatrutide against tirzepatide in 800 adults with obesity. Lilly vs Lilly. It’s interesting as placebo patients work out pretty quickly they are on a placebo. It’s not double blind.

The trial has finished recruiting.

Primary completion is expected in November 2026, with the full study expected to finish in December.

This is the comparison we don't have today.

TRIUMPH-1 showed 28.3% average weight loss at 12 mg using the efficacy analysis.

SURMOUNT-1 showed 20.9% with tirzepatide 15 mg.

Those came from separate trials.

TRIUMPH-5 puts Reta and tirzepatide into the same Phase 3 study.

The next big milestone is the US regulatory filing.

Lilly still says it plans to submit retatrutide in Q1 2027.

Its clinical data package is complete and Lilly is finishing the manufacturing and CMC package needed for the application.

There is still a separate court fight over how retatrutide should legally be classified in the US.

Lilly wants to submit it as a biologic. FDA has taken the position that Reta does not meet its definition of a protein.

That case went before the Seventh Circuit Court of Appeals on 24 September and is still unresolved.

So Q1 2027 is Lilly's current submission target, but I wouldn't treat it as a fixed timetable for what happens at FDA after that.

Then there is TRIUMPH-6.

That is a 643-person Phase 3 maintenance study.

Everyone gets retatrutide for the first 80 weeks.

They are then randomised for another 36 weeks to continue one Reta dose, move to another Reta dose, or switch to placebo.

The study is expected to finish in April 2028.

What happens with the planned Q1 2027 US submission and the court case over its regulatory status? I don’t think many expect Q1 anymore and Mounjaro/Zepbound is flying off the shelves.

One thing I hadn't seen written up yet is how many people actually made it through the full 80-week TRIUMPH-1 study.

Across the retatrutide groups, around 89–91% completed the study.

For placebo, it was 75%.

Staying on the assigned treatment all the way through was lower, as you would expect.

Around 75–87% of the retatrutide groups completed the study while still taking treatment.

For placebo, it was about 64%.

That matters when looking at the very large weight-loss numbers.

The 28.3% figure is the efficacy estimate, so it isn't simply "the average of everyone who started the trial no matter what happened".

But the study also reported a treatment-regimen estimate, which was 25.0% at 12 mg and includes treatment discontinuation and other relevant events.

So even using the more conservative analysis, the average loss was still 25%.

The completion numbers also show that most people assigned to retatrutide stayed in the study through 80 weeks, although a smaller proportion stayed on treatment the whole way.

Is there anything not fixed by Reta? Apart from the side effects… here we go

TRIUMPH-1 also included 574 people with obesity and knee osteoarthritis.

Their average WOMAC pain score at the start was 5.97.

By week 80, pain scores had fallen by 2.24 points with placebo, a 38% reduction.

At 4 mg retatrutide, the reduction was 3.66 points, or 61%.

At 9 mg it was 4.19 points, or 70%.

At 12 mg it was 4.30 points, or 73%.

So there was a substantial improvement even in the placebo group, but the reduction was much larger with retatrutide.

This doesn't tell us how much of the pain improvement came directly from retatrutide and how much came from losing a large amount of weight. Less body weight means less load through the knee, so that is likely part of the story.

But the size of the change is still notable. At the higher doses, average knee pain fell by about 70% over 80 weeks.

This was a randomised Phase 3 comparison, not a small observational study.

TRIUMPH-1 also included 243 people with moderate-to-severe obstructive sleep apnoea.

Sleep apnoea was measured using AHI, the number of breathing pauses or shallow-breathing events per hour of sleep.

The average starting AHI was 58.6 events per hour.

At 80 weeks, AHI fell by 25.7 events per hour at 4 mg.

At 9 mg, it fell by 36.1 events per hour, a 60.6% reduction.

At 12 mg, it fell by 33.8 events per hour, about 58%.

Placebo fell by 11.1 events per hour, about 16%.

So the reduction seen with Reta was much larger than the placebo change.

The 9 mg result was actually slightly larger than the 12 mg result in this group. That doesn't mean 9 mg is the better dose. This was a much smaller basket within the main trial and it wasn't designed to find an ideal dose for an individual.

A fall of 36.1 events per hour is also well above the 15 events per hour threshold Lilly used as a clinically meaningful change.

This doesn't mean people with sleep apnoea should stop CPAP or other treatment. But damn again. Those machines are noisy.

Man, it’s even got waist dimensions. This is what I care about not fitting into 5 out of 7 of my old suits even after scales say 22kg loss.
Work trip tomorrow…

Obviously other non weight metrics matte too.

New data includes:

Waist circumference down 24.1 cm.

Triglycerides down 41.0%.

Non-HDL cholesterol down 24.2%.

Systolic blood pressure down 12.3 mmHg.

They break out every angle in this paper.

I’ve asked beige in here about side effects. Now we have real data. 12mg is a high dose.

At 12 mg, 42.4% reported nausea.

32.0% had diarrhoea.

26.1% had constipation.

25.3% had vomiting.

Dysesthesia was reported by 12.5% and urinary tract infections by 8.4%.

Overall, 11.3% of the 12 mg group stopped treatment because of adverse events. That compares with 4.9% on placebo.

The rates were generally lower at the lower Reta doses.

At 4 mg, nausea was 28.6%, vomiting 10.6%, dysesthesia 5.1%, and 4.1% stopped because of adverse events.

At 9 mg, nausea was 38.4%, vomiting 22.8%, dysesthesia 12.3%, and 6.9% stopped.

That doesn't mean everyone reporting one of these effects had a severe reaction. Lilly reported that dysesthesia and urinary tract infections were generally mild to moderate, most resolved during treatment, and most people continued taking retatrutide.

But there is clearly a tolerability side to the Phase 3 results as well as the weight-loss numbers.

The 12 mg group averaged 28.3% weight loss in the efficacy analysis, but it also had the highest rate of people stopping because of adverse events.

Wow this data is rich. This is even bigger than the headline days. Especially for us folks staying on it a long time.

TRIUMPH-1 also had a two-year extension, and the weight loss was still substantial at 104 weeks.

The extension followed 532 people who had started the trial with a BMI of at least 35 and had completed the first 80 weeks on treatment.

At 104 weeks, average weight loss from the original starting weight was:

27.9% for people originally assigned to the 4 mg pathway.

29.5% for the 9 mg pathway.

30.3% for the 12 mg pathway.

The 30.3% group had lost an average of 38.5 kg from a starting weight of 121.7 kg.

These people continued treatment for another 24 weeks after the main 80-week trial, with doses moved towards their maximum tolerated dose of 9 mg or 12 mg.

So this isn't the same as saying everyone in TRIUMPH-1 would lose 30.3% if they stayed on it for two years.

This was a selected group. They had already completed 80 weeks on treatment, had tolerated their assigned dose, and had started with a BMI of at least 35.

But it does show that weight loss had not simply stopped at the 80-week point in this group.

The main 12 mg result at 80 weeks was 28.3%.

In this extension group, the 12 mg pathway reached 30.3% at 104 weeks.

The % loss is the title, but what was the starting and ending point.

This one actually disappoints me. Only 37.5% of bmi 40 got below 30. I started my weight loss at about 38. I haven’t looked yet how that compares to the other Mounjaro and Wegovy trial data.

At the start of the trial, average BMI was around 40.

By week 80, 65.3% of people in the 12 mg retatrutide group had a BMI below 30.

That means nearly two thirds had moved below the BMI threshold used to define obesity.

The change was also seen in people starting with much higher BMI.

Among those who started with a BMI of 40 or above, 37.5% finished below BMI 30.

So some people moved from class 3 obesity all the way to below the obesity threshold during the trial.

BMI obviously doesn't tell you everything about someone's health, and the 37.5% result comes from a subgroup analysis, so I wouldn't treat the exact percentage as a guarantee for anyone.

But it gives another way of looking at the scale of the weight loss in TRIUMPH-1 rather than just quoting the 28.3% average.

The peer reviewed journal is unusually deep on detail and I’m keeping these coming…

The 28.3% average weight loss gets most of the attention, but the responder numbers from TRIUMPH-1 are just as striking.

At 12 mg, 62.5% of people lost at least 25% of their starting weight.

45.3% lost at least 30%.

27.2% lost at least 35%.

So more than one in four people in the 12 mg group lost over a third of their starting body weight.

The numbers were lower at the other doses, but still substantial.

At 9 mg, 52.9% lost at least 25%, 37.9% lost at least 30%, and 20.8% lost at least 35%.

At 4 mg, 27.8% lost at least 25%, 15.3% lost at least 30%, and 5.9% lost at least 35%.

These are group results from the Phase 3 trial, not a prediction of what any individual person would lose.

Retatrutide is still investigational and is not yet an approved treatment.

Full TRIUMPH-1 paper:

https://www.nejm.org/doi/full/10.1056/NEJMoa2604169

The 28.3% headline gets the shoutout, but the different doses in TRIUMPH-1 are worth looking at.

At 4 mg, average weight loss was 19.0%. About 4.1% of people stopped treatment because of side effects.

At 9 mg, average weight loss was 25.9%. About 6.9% stopped because of side effects.

At 12 mg, average weight loss was 28.3%. About 11.3% stopped because of side effects.

So the jump from 4 mg to 9 mg added 6.9 percentage points of average weight loss, while side-effect discontinuation increased by 2.8 percentage points.

The jump from 9 mg to 12 mg added another 2.4 percentage points of weight loss, while side-effect discontinuation increased by 4.4 percentage points.

The side effects also became more common as the dose increased.

Nausea was reported by 28.6% at 4 mg, 38.4% at 9 mg and 42.4% at 12 mg.

Vomiting was 10.6%, 22.8% and 25.3%.

Dysesthesia was reported by 5.1%, 12.3% and 12.5%.

That doesn't mean 9 mg is the "best" dose, or that anyone should choose a dose based on these numbers. TRIUMPH-1 wasn't designed to work out the ideal dose for an individual person.

But it does show that the 28.3% result at 12 mg came with a fairly clear trade-off.

The 9 mg result is also pretty remarkable on its own: 25.9% average weight loss at 80 weeks.

And even 4 mg averaged 19.0%.

These are the efficacy estimates, so the numbers describe the treatment effect under the trial's efficacy analysis rather than what happened to everyone regardless of treatment discontinuation.

How does chime with real work experience of doses given Reta is unique in its pre FDA greyness?

Full TRIUMPH-1 paper:

https://www.nejm.org/doi/full/10.1056/NEJMoa2604169

Now that the full TRIUMPH-1 paper is out, I wanted to put the retatrutide result next to tirzepatide and Wegovy.

The headline numbers make Reta look miles ahead, but they aren't quite apples to apples.

In TRIUMPH-1, retatrutide 12 mg produced 28.3% average weight loss at 80 weeks using the efficacy estimate. That basically asks what the effect would look like if people stayed on treatment without starting other weight-loss treatment.

The more conservative treatment-regimen result was 25.0%. That includes people regardless of whether they stopped treatment or needed other weight-management treatment.

That 25.0% is probably the better number to use when making a rough comparison.

Tirzepatide 15 mg produced 20.9% average weight loss at 72 weeks in SURMOUNT-1.

Wegovy 2.4 mg produced 14.9% at 68 weeks in STEP 1.

So, very roughly:

Wegovy: 14.9%

Tirzepatide: 20.9%

Retatrutide: 25.0%

Reta's more idealised efficacy estimate was 28.3%.

The placebo groups lost 2.4% in STEP 1, 3.1% in SURMOUNT-1 and 3.9% in the retatrutide treatment-regimen analysis.

That gives placebo-adjusted differences of roughly 12.5 percentage points for Wegovy, 17.8 points for tirzepatide and 21.1 points for retatrutide.

It is tempting to look at those numbers and say Reta definitely beats tirzepatide.

We can't say that yet.

These were separate trials, done at different times, in different people, for different lengths of time. Retatrutide was studied for 80 weeks, tirzepatide for 72 and Wegovy for 68.

We do have a proper head-to-head trial for tirzepatide against Wegovy.

In SURMOUNT-5, people taking the maximum tolerated dose of tirzepatide lost 20.2% at 72 weeks compared with 13.7% on Wegovy. So the advantage of tirzepatide over Wegovy has actually been tested directly.

There is no equivalent retatrutide vs tirzepatide trial yet.

The mechanism is also worth looking at.

Wegovy acts on GLP-1.

Tirzepatide acts on GLP-1 and GIP.

Retatrutide acts on GLP-1, GIP and glucagon.

The weight-loss results have moved upwards as those extra pathways have been added, but that doesn't prove the glucagon part is responsible for the difference. A head-to-head trial would be needed to properly answer that.

There is also a trade-off in the Reta data.

At 12 mg, 11.3% of people stopped retatrutide because of adverse events.

In the separate SURMOUNT-1 trial, 6.2% stopped tirzepatide 15 mg because of adverse events.

In STEP 1, about 7% stopped Wegovy because of adverse events.

Those figures shouldn't be directly compared as if they came from one trial, but the 12 mg Reta dose clearly isn't side-effect free.

The lower Reta dose is quite interesting too.

At 4 mg, average weight loss was 19.0% using the efficacy estimate and discontinuation because of adverse events was 4.1%.

Again, that doesn't mean 4 mg Reta is equivalent to high-dose tirzepatide. Different trials. But it suggests the eventual discussion around Reta may not simply be "everyone needs 12 mg".

The biggest result for me is probably the proportion reaching very large losses.

At 12 mg, 62.5% of TRIUMPH-1 participants lost at least 25% of their starting weight, 45.3% lost at least 30%, and 27.2% lost at least 35%.

That is well beyond what we were used to seeing from obesity medication a few years ago.

So my reading of the evidence at the moment is fairly simple.

Wegovy established that drug treatment could produce around 15% average weight loss.

Tirzepatide pushed that to around 20%, and has directly beaten Wegovy.

Retatrutide has now pushed the Phase 3 result into roughly the 25% range when using the more conservative analysis, and close to 30% under the efficacy estimate.

But until Reta is tested directly against tirzepatide, "Reta beats Mounjaro" is still an inference from separate trials, not a demonstrated result.

And retatrutide remains investigational rather than an approved treatment.

Sources:

TRIUMPH-1, NEJM:
https://www.nejm.org/doi/full/10.1056/NEJMoa2604169

SURMOUNT-1, tirzepatide:
https://www.nejm.org/doi/10.1056/NEJMoa2206038

STEP 1, semaglutide:
https://www.nejm.org/doi/full/10.1056/NEJMoa2032183

SURMOUNT-5, tirzepatide vs semaglutide:
https://www.nejm.org/doi/full/10.1056/NEJMoa2416394

The full Phase 3 TRIUMPH-1 obesity trial has now been published in the New England Journal of Medicine.

We already knew the headline results from Lilly in May and the ADA presentation in June, so the 28.3% figure itself isn't new today.

What is new is that the full trial is now peer reviewed and published.

TRIUMPH-1 included 2,339 adults with obesity, or overweight with a weight-related condition, without diabetes. Treatment lasted 80 weeks.

At 12 mg, average weight loss was 28.3% using the efficacy estimate.

At 9 mg it was 25.9%, at 4 mg 19.0%, and placebo 2.2%.

Using the more conservative treatment-regimen estimate, which includes what happened after treatment discontinuation and other relevant events, the 12 mg result was 25.0%.

At 12 mg, 62.5% of participants lost at least 25% of their starting weight.

45.3% lost at least 30%.

27.2% lost at least 35%.

And 65.3% ended the trial with a BMI below 30.

The safety results are important alongside those numbers.

At 12 mg, nausea was reported by about 42%, diarrhoea by 32%, constipation by 26% and vomiting by 25%.

About 11% of people in the 12 mg group stopped treatment because of adverse events.

There was also a separate 104-week extension for people who started with a BMI of at least 35. Those continuing 12 mg reached 30.3% average weight loss.

That 30.3% figure shouldn't be treated as the result for the whole TRIUMPH-1 population though, because the extension involved a selected subgroup.

So the main news today isn't that Phase 3 suddenly showed 28.3% weight loss. We've known that for months.

It's that the full Phase 3 obesity trial has now made it through peer review and is published in NEJM.

Retatrutide is still investigational and is not yet an approved obesity treatment.

Paper: Retatrutide, a Triple Hormone Receptor Agonist, for Treatment of Obesity (TRIUMPH-1)

New England Journal of Medicine, 29 September 2026

DOI: 10.1056/NEJMoa2604169

Hi all,

Thanks to the mods for letting me share this.

I’m the creator of OneGLP, previously called GLPzy. I originally built it because I wanted one place to keep track of the practical side of being on a GLP-1, and it has grown quite a lot since then.

It’s iPhone and iPad only for now. I want to add Android later on and will offer a founding user offer when I do also.

It’s one of the trackers covered on monj if you want to read more about it from an independent website:

https://monj.co.uk/oneglp/

It supports Wegovy / semaglutide and lets you track things including:

• doses, reminders and injection sites
• weight, BMI and body measurements
• symptoms and appetite
• progress photos, photo comparison sliders with auto adjust and manual adjustments, frames to align new photos, different angles and video reels - I gets loads of users saying they love these 📷
• medication supply
• nutrition
• Apple Health
• estimated medication exposure
• reports and data exports

There’s no OneGLP account to create. Your records stay on your device unless you choose to export or share them.

I’ve also just renamed the app from GLPzy to OneGLP. It’s still exactly the same app and App Store listing, so existing users keep their data and Premium access.

The Founding User Lifetime Premium offer is still free to claim until 31 December 2026. Once claimed, it stays unlocked permanently. There’s no subscription or renewal afterwards.

I’m still developing it pretty actively and feedback is genuinely useful, so if you try it and find something missing or something that could work better, let me know.

Hope you enjoy it and I look forward to any feedback.

App Store:
https://apps.apple.com/gb/app/oneglp-glp-1-tracker-glpzy/id6761775005

Website:
https://oneglp.app/

So a family member just has a multiple bypass so this chimes with me. There’s more going on with GLPs than just the weight loss.

A new analysis of the SELECT trial has looked at why semaglutide reduced heart attacks, strokes and cardiovascular deaths.

SELECT included 17,604 people with existing cardiovascular disease who were overweight or obese but did not have diabetes.

The original trial found that semaglutide reduced major cardiovascular events by 20% compared with placebo.

This new paper tried to work out how much of that benefit could be explained by changes we already know semaglutide causes, including weight, waist size, blood pressure, blood sugar, cholesterol, inflammation and kidney function.

Weight loss on its own did not explain much of the effect in the main analysis. The best estimate was that changes in body weight accounted for about 20% of the cardiovascular benefit.

Inflammation, measured using hsCRP, accounted for about 42% in the same analysis.

Waist circumference gave a higher estimate of 64%, although the researchers found problems with the reliability of the weight and waist calculations.

When several of the measured risk factors were considered together, the estimated amount explained was about 31%.

Those numbers need some caution. The uncertainty around them was very wide, in some cases wide enough that the study cannot rule out a much larger contribution from these factors.

So I don't think the result is "80% of the heart benefit has nothing to do with weight loss".

It's more that the researchers could not clearly explain semaglutide's cardiovascular benefit using weight loss and the other usual risk factors they measured.

That leaves open the possibility that other effects are involved.

Inflammation is one possibility. There could also be effects on blood vessels, the heart or other pathways that weren't captured properly in this analysis. This study doesn't prove what those mechanisms are.

One thing I found useful is that this was not a new small observational study. It was a pre-planned analysis using data from the 17,604-person randomised SELECT trial.

It also helps explain why the cardiovascular results from GLP-1 drugs are increasingly interesting in their own right rather than just being treated as a side effect of people losing weight.

Paper: Colhoun HM et al. Semaglutide and cardiovascular risk reduction: a mediation analysis of the SELECT trial. European Heart Journal. Published 23 September 2026.

https://doi.org/10.1093/eurheartj/ehag524

Lilly and the FDA are back in court on Thursday, 24 September, over whether retatrutide should legally be treated as a drug or a biological product in the US.

A large part of the case comes down to whether retatrutide counts as having 40 or 41 amino acids under an FDA rule.

Retatrutide has 41 amino-acid residues in total. That isn't really the disagreement.

The FDA rule says a protein is an "alpha amino acid polymer" that is greater than 40 amino acids in size.

FDA says one of retatrutide's 41 residues is not an alpha amino acid. On FDA's reading of the rule, only the alpha amino acids count towards the limit.

That leaves 40.

And 40 is not greater than 40, so FDA says retatrutide does not meet the legal definition of a protein.

Lilly reads the wording differently.

Lilly says the regulation first describes the molecule as an "alpha amino acid polymer", but when it gives the size test it just says "greater than 40 amino acids". It doesn't say "greater than 40 alpha amino acids".

On Lilly's reading, all 41 residues count.

So FDA says the relevant number is 40, which fails a rule requiring more than 40.

Lilly says the relevant number is 41, which passes it.

The district court sided with FDA on this part of the case last year. It agreed that the rule should be read as requiring more than 40 alpha amino acids.

But that wasn't the whole case.

US law also allows something to be treated as a biological product if it is "analogous" to a protein.

Lilly argued that even if retatrutide doesn't meet the strict protein definition, it should still qualify through that route.

The district court found problems with FDA's reasoning on that question and sent it back to FDA to reconsider.

That did not mean the court decided retatrutide was analogous to a protein. FDA could reconsider it and still decide that it isn't.

Lilly has appealed the part of the case it lost, which is why it is now before the Seventh Circuit Court of Appeals.

Thursday is oral argument. The judges do not have to give their decision that day.

There will be three appeals judges and each side has only 15 minutes to make its case and answer questions. The written decision will come later.

Even that decision may not be the final chapter.

Once the three-judge panel rules, the losing side can ask the panel to reconsider. It can also ask for the full Seventh Circuit to rehear the case, although full-court rehearings are uncommon.

After that, either side could ask the US Supreme Court to hear the case. The Supreme Court would decide whether to take it.

There is also still the separate question the district court sent back to FDA: whether retatrutide could be considered analogous to a protein.

So the appeals court could settle the 40-versus-41 argument and there could still be more to come from FDA. Depending on what FDA decides, that decision could potentially end up in court again.

Lilly also has an argument about timing. Federal law normally gives FDA 60 days to respond to a formal request to classify a product.

Lilly argues that FDA has now missed the relevant deadline and that Lilly's proposed classification should therefore take effect. FDA disagrees.

The appeals court may deal with that issue too.

There was also a late filing from the US government on 21 September.

The government pointed the judges to a recent Seventh Circuit case called Franco v Chobani. In that case, the court said judges still decide what a regulation means, but FDA's scientific view can be useful when its reasoning is thorough and consistent.

The government is arguing that the same approach should be used here when deciding what FDA's definition of a protein means.

It helps FDA's argument, but it doesn't decide the case.

So Thursday matters, but it probably isn't the final answer on retatrutide's legal classification.

Retatrutide has 41 residues in total.

FDA says only 40 count under its definition.

Lilly says all 41 count.

The legal threshold is more than 40.

That single-residue difference is now one of the main issues before a US federal appeals court.

Sources: Eli Lilly and Company v FDA, Seventh Circuit No. 26-1301; Eli Lilly and Company v Kennedy, Southern District of Indiana; 21 CFR §600.3(h)(6); 21 USC §360bbb-2; US government supplemental filing dated 21 September 2026.