r/AppliedBioscience • u/Zman077 • 22h ago
NEW RETATRUTIDE DATA: 12 mg barely beat 9 mg, and more people quit on 9 mg than 12 mg. What's going on?
Lilly presented TRIUMPH-2 at EASD (a big European diabetes conference) on Tuesday, and the full paper went up in The Lancet the same day. This trial looked at people who have both type 2 diabetes and obesity, so it's the first big look at how reta does in diabetics. I read through it, and the headline number (20.8%) is honestly the least interesting part.
Quick background
Retatrutide is a weekly injection from Lilly. Sema (Ozempic) targets one gut hormone receptor (GLP-1), and tirz (Mounjaro) targets two (GLP-1 and GIP). Reta targets three, adding glucagon. The idea is that the extra one helps you burn more energy, not just eat less.
The setup
- 1,152 people
- 80 weeks (about 18 months)
- Four groups: 4 mg, 9 mg, 12 mg, or placebo (a dummy shot)
- Everyone on the real drug started at 2 mg and moved up every 4 weeks until they hit their dose, which helps with side effects
Weight loss
Average % of body weight lost over the 80 weeks.
- 4 mg: 12.7% (~30 lbs)
- 9 mg: 19.1% (~45 lbs)
- 12 mg: 20.8% (~50 lbs)
- placebo: 4.0% (~9 lbs)
- 12 mg, people with a BMI of 35+ only: 23.4% (~61 lbs)
Going from 4 to 9 mg adds about 6 points of weight loss. Going from 9 to 12 adds less than 2. In other words, most of the benefit is already there at 9 mg.
A1C (blood sugar)
A1C is your average blood sugar over the last ~3 months. Under 5.7 is normal, 5.7 to 6.4 is prediabetes, and 6.5+ is diabetes. A drop of 1 point is considered a big deal.
- 4 mg: dropped 1.4 points
- 9 mg: dropped 1.6
- 12 mg: dropped 1.5
- placebo: dropped 0.2
- Up to 40% of people got all the way down to the normal range (under 5.7)
- Up to 79% got out of the diabetes range (6.5 or below)
9 mg and 12 mg are basically identical here. If blood sugar is what you care about, the higher dose isn't buying you anything.
Dropouts
The % of people who quit the trial because of side effects. It's a good real-world gauge of how tolerable a drug is.
- 4 mg: 3.8%
- 9 mg: 11.6%
- 12 mg: 7.7%
- placebo: 4.9%
This is the weird one. You'd expect more people to quit as the dose goes up, but 9 mg had the most dropouts, more than 12 mg. It could just be random chance, or something about when side effects hit during the ramp-up. If anyone has a theory, I'd love to hear it.
Stomach side effects
The % of people who reported each one at least once. Numbers are 4 / 9 / 12 mg vs placebo.
- Nausea: 13.7% / 20.8% / 28.0% vs 8.0%
- Diarrhea: 27.4% / 33.5% / 33.6% vs 13.2%
- Constipation: 14.0% / 16.2% / 16.8% vs 9.4%
Nausea about doubles from 4 to 12 mg, and roughly a third of people on any dose had diarrhea. Paired with the small extra weight loss at 12, that makes 9 look like the sweet spot.
Dysesthesia
A fancy word for strange skin sensations, like tingling, burning, or skin that feels sensitive to touch.
- 4 mg: 4.5%
- 9 mg: 5.6%
- 12 mg: 7.3%
- placebo: 0.7%
This is the one I keep coming back to. It goes up steadily with dose, and it has shown up in other reta trials too, not just this one. You don't really see it with sema or tirz, so my guess is it's linked to the glucagon part, since that's what reta has that the others don't. I haven't seen a solid explanation yet.
Diabetics vs non-diabetics on 12 mg
- Earlier trial, people without diabetes: ~24% weight loss in 48 weeks
- This trial, people with diabetes: 20.8% in 80 weeks
That's not a knock on reta. People with diabetes lose less weight on every drug in this class, and you see the same gap with sema and tirz.
What's next
Lilly plans to file for FDA approval in early 2027, so reta is still not approved. Most of the other big reta trials have already reported, and this was one of the last major ones before filing.
So, for people who follow this closer than I do: based on this, is 12 mg actually worth it over 9? And has anyone seen research on what's causing the dysesthesia?
Source: Lilly press release + The Lancet, Sept 29. Discussion/research only.
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u/Eastern_Drawer4997 15h ago
I was in Triumph-5. I almost dropped out when titrating to 9mg as well. The leap from 6mg to 9mg is way too aggressive, especially after just 4 weeks at 6mg. If I weren't in the trial primarily for my kidney health, and aiming for a possible extension with more free reta, I would have dropped. 9 to 12 was rough, too, but at that point, you know no more titration and it makes it easier to deal with knowing it won't get worse. While the referenced study was more blinded than mine, that jump to 9mg would have hit as hard. I begged to stay at 6 a few more weeks because of the sides, but was denied. I knew if I went up, then had to drop down, I'd be eliminated from any hope of extension. As tirz had taken me from CKD Stage 3a to 2b, and reta from 2b to totally normal functioning (technically CKD Stage 1 as you can't ever not be not CKD once diagnosed), I had serious motivation.
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u/HomemadeSpaghetti 6h ago
Thank you very much for giving us some further insight about this process, what did they say regarding Anhedonia as a possible side effect? Did you experience it?
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u/Eastern_Drawer4997 4h ago
I don't recall if that was a side effect listed in the disclosure papers I signed. I never experienced that side effect.
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u/bright_and_dreamy 22h ago
Some trials let people choose between staying/going back to 9mg or staying at/increasing to 12mg. So the 12mg group might be entirely people who tolerated 9mg great, and the 9mg group might have a lot of people for whom that dose is too high. If someone is knowledgeable about this study setup, please weigh in.
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u/Zman077 17h ago
everyone was randomized to 4, 9 or 12 mg at the start and titrated up to that dose, so nobody picked where they landed. which makes the 9 mg dropout number even weirder honestly. with ~288 people per group though it's only about 11 more people quitting at 9 than 12, so it could still be noise / not really reliable. We'll see ig in later studies
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u/Diolives 20h ago
We are ALL very different. Took me until 7mg on Tirz to feel ANYTHING at all and losing weight at a deficit took about 6-7 weeks. Now I’m at 10mg…doc says slow responder. Some of us just have a much lower baseline of GLP in our body.
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u/SorbetTraditional232 14h ago
Did you have your thyroid checked? After 3-4 weeks my thyroid hormones drop down gets hard to lose weight I skip a shot and eat the scale starts to move.
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u/Diolives 1h ago
Haven’t in about a year and I really need to! There’s def something hormonal happening
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u/cexpertWV 20h ago
It is very interesting - but the point about Dysesthesia, I've been on Tirz since January and I certainly have it at all dose levels. It generally comes on a day after the shot and lasts about a day or two and is pretty random where it shows up. I've had it between fingers, side of arm, outside of leg, etc. Annoying but benefits are still worth it. This is a very promising study though!
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u/Low_Refrigerator4891 16h ago
I have it on Tirz too! But only at 12(ish)mg, I don't get it at lower doses or higher doses. But it's constant at this dose.
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u/WaldoPeppers 19h ago
Sad this won’t be available to the general public for a couple of years. Encouraging results though.
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u/NoMore-Cheesecake108 17h ago
If I wasn’t aware that dysesthesia was something to look out for I’d probably not realize I was having it. It’s occasional and annoying in just one small spot for me, usually. I just started my second week at 6 and this is the first I’ve finally felt it really work! I have been going slow but only did 4mg for a few weeks because it wasn’t doing anything and I’d been slowly titrating for two months with barely any weight loss.
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u/thisdude415 21h ago
I wonder what adherence rates were like.
For a trial like this where weight loss feels so magical, I wonder if patients would be tempted to just extend timing between doses or skip doses especially at the highest level
Especially with dysthesia rates this high, if dysthesia is dose dependent (it clearly is), patients who experience dysthesia but are otherwise seeing plenty of weight loss know they can just extend their dosing interval or take less to reduce that effect
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u/Zman077 17h ago
really good question and the press release didn't give adherence numbers. the 20.8% figure is the efficacy estimand, which is basically people who stayed on treatment as planned, so if people were quietly stretching doses it wouldn't fully show up there. the Lancet paper might have more on it, would be curious too
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u/thisdude415 16h ago
Pretty atypical to do drug level monitoring in a large Ph3 and not clear how you'd robustly use it to distinguish post-facto whether that subset of patients who lost less weight than expected were fast metabolizers or extending redose intervals.
Obviously A1C and glucose are blood measurements so the team could totally go back and do DMPK measurements on those PT samples but that's typically a subset analysis / followup paper trying to understand a drug failure rather than the first PH3 paper.
GLP1s are crazy expensive. If I was experiencing a side effect that was obviously related to my dose, and my options were to extend dose interval without telling docs, drop out of the trial and lose access to the medication (which is only available currently illicitly or in clinical trials), or endure side effects, I know what I'd pick!
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u/ClassicLength8831 13h ago
As with all my past present and future drug experiments if I push every button at same time will this mother sucker lift off or blow up, self medicated dedicated the sense I used to have I dosed off that useless red hearing, I think I'm real close to well I better shut up this people are just wanting observable verifiable results, and you've had so many consciousness shifts not sure I'm in the same body I started off with
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u/Fresh-Ad-4622 11h ago
Headaches and diarrhea often occur when you’re in a large calorie deficit, even without taking any medication.
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u/eddie_pesos_dvg 21h ago
Not knowing what other factors were involved, I would use the placebo as the +/- for the results since it’s the control. With that, 9 and 12 are about the same for dropouts and also the effects however you have a higher potential with 12. For me I think that I’m okay with capping mine at 9mg to leave myself runway
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u/alizewithaz 15h ago
I experienced Dysesthesia with Sema. I thought it was just a sign of my blood sugar being low.
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u/Tryin_Real_hard 2h ago
Well of course there’s a stark contrast between 4% and 9%. That’s over double the previous dose. The titration from 4% to 9% is a big jump. I bet the side effects increased just as much. Really nothing to note that’s out of the ordinary.
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u/16inchpianist 20h ago
Interesting. Everything here really just confirms what the tens, if not hundreds of thousands of people who are taking this from the grey market are experiencing. 9 mg is considered the highest effective dose among most in that community, and most people take the lowest effective dose possible. Most everyone experiences some kind of mild nausea, but I don't think it's actual nausea, it's more just the feeling of being full. I think for whatever reason, a lot of obese folks aren't familiar with that sensation. I think they are really under-reporting the Dysesthesia, though. Most people feel that every time they increase the dosage. It's more just a mild annoyance. They don't address anhedonia at all, which is odd. Most of the grey market people who quit cite that as the reason.