Happy Thursday!
Lilly dropped the TRIUMPH-1 Phase 3 results yesterday and the internet did what the internet always does.
(You can read the results here: https://investor.lilly.com/news-releases/news-release-details/lillys-triple-agonist-retatrutide-delivered-powerful-weight-loss)
Big number, big headline.
70 pounds of weight loss.
30% bodyweight gone at two years.
All true.
However, in my opinion, none of it is the actual interesting story.
The interesting story is sitting in the 4 mg column, and nobody is talking about it.
4mg
Participants on retatrutide 4 mg lost an average of 47 pounds over 80 weeks.
That's 19% of their bodyweight. To get there, they did one dose escalation.
2 mg to start, then up to four. That's it.
For comparison, that 19% number puts the lowest dose of retatrutide roughly even with the highest dose of semaglutide from STEP-1.
Same ballpark of weight loss, simpler titration, fewer steps for the patient to tolerate along the way.
But here's the part that made me sit up.
The discontinuation rate at 4 mg was lower than that of placebo.
4.1% of people on 4 mg retatrutide stopped the drug due to adverse events. 4.9% of people on the placebo stopped.
Read that again.
The active drug had a lower dropout rate than the saline shot.
That never happens in obesity trials.
At the 9 mg dose, dropouts jumped to 6.9%. At 12 mg, they hit 11.3%. Classic dose-dependent tolerability curve. The higher you go, the more people quit.
So the lowest dose yields nearly 20% weight loss with the cleanest side-effect profile in the trial.
Why It Matters
Most of the patients I talk to do not need 30% weight loss.
They need 15 to 20%.
They need to get out of class 1 obesity.
They need their waist circumference to come down so their lipids and blood pressure follow.
They need to feel better in their body and stop the metabolic slide that started in their thirties.
For that patient, the 4 mg dose looks close to ideal on this data.
Strong efficacy. Lowest GI side effects among retatrutide arms.
Lowest dysesthesia signal.
The instinct in this space, especially in the research world, is to chase the maximum dose.
More is more. The bigger the number on the scale, the bigger the win.
TRIUMPH-1 is a quiet argument against that instinct.
You get 19% at 4 mg and 28% at 12 mg. You triple the dose for an extra 9% of body weight, and you pay for it with a 2.7x higher discontinuation rate and a dysesthesia signal that goes from 5% to 12.5%.
For some patients, that trade is worth it. For most, it probably isn't.
On Microdosing
While we're talking about lower doses being underrated, I want to make something clear.
I am still a huge fan of microdosing retatrutide and have been for a while.
The TRIUMPH-1 lowest arm was 4 mg.
Plenty of people in my world are getting genuinely impressive results at 1 to 2 mg per week and never escalating past that.
You will not see those doses studied in a Phase 3 trial.
There's no commercial reason for Lilly to test them.
But I have watched person after person dial in 1-2 mg weekly, lose 30 to 50 pounds over six to twelve months, and have almost no side effects to speak of.
No GI symptoms. No dysesthesia. No appetite suppression so heavy that they stop eating protein.
If 4 mg is the trial sweet spot for the average obesity patient, 1 to 2 mg is the sweet spot for the person who wants steady recomposition without feeling like they're on a drug. Different goals, different doses. Both work.
Final Thoughts
If retatrutide gets approved next year, I think the 4 mg dose is going to be where most of the action lives in the prescription market.
It's the sweet spot for tolerability and effect on the data we have.
But for the lean-ish person who wants 20 to 30 pounds off and a smoother metabolic ride, 1 to 2 mg per week is still my answer. The Phase 3 trial didn't test it because they didn't have to. We already know it works.
The 9 mg and 12 mg arms are real. People who need that level of weight loss now have an option.
But the headlines are going to drive many patients and providers to default to the top dose, and I don't think the data support that for the average person walking into a clinic.
Sometimes the most useful dose is the one that gives you the most benefit at the lowest cost.
Best,
Hunter Williams