Retatrutide 24.2% vs 28.7%: what explains the gap?

The 24.2% is Phase 2 at 48 weeks, efficacy estimand. The 28.7% is company-reported Phase 3 and not peer-reviewed. That alone keeps me from calling them apples-to-apples.

Estimand is part of it, but sample size isn' tthe main lever. NCT05882045 and NCT05929066 are huge; population and discontinuation handling can move the estimate.

Agree on estimand. Efficacy estimand can look better because it isn't a plain all-participants snapshot. Need the SAP to know what's really being estimated.

What do you mean by not plain? Estimand definitions get messy.

The glucagon arm is what I keep circling. Retatrutide is a once-weekly triple agonist of GLP-1, GIP, and glucagon receptors, so energy expenditure could differ from pure GLP-1/GIP drugs.

But without the peer-reviewed Phase 3 tables, I can't tell whether up to 28.7% is a real step up or just a different estimand and population mix. The Phase 2 24.2% at 48 weeks is still the cleanest number we have.

I'd love to see discontinuation rates, baseline BMI, and whether the four trials had different titration schedules. Until then, the spread is interesting but not conclusive.

On the sample-size point, the small completed trials don't help much either. NCT05548231=32 and NCT06039826=46 are too small to settle effect size; NCT05931367=445 is better but knee osteoarthritis.

Can we keep sourcing out of this one? I want estimand definitions and raw Phase 3 tables, not access chat.

The thing I keep circling back to is that these aren't even the same timepoint — 48 weeks in Phase 2 vs 68 weeks in Phase 3. I lot about 1.3 lb a week for the first four months, then it tapered to maybe 0.3-0.5 lb a week from month five on, and it honestly never hit zero.

That slow tail over an extra 20 weeks is roughly 8-10 lbs on me, which on a 240 start is about 4%. That eats most of the 4.5 point gap before anyone even starts arguing about estimands.

The later trials also let stalled participants escalate while the earlier design was more locked in, and with way more sites you get more flexibility in how that played out. So my read: duration does most of the work, estimand does some, leftover is noise from 'up to' reporting.

What I actually want to see is which estimand the 28.7% sits on. If it's treatment-regimen with dropouts carried forward, comparing it to a completer-flavored 24.2% from Phase 2 undersells the drug and the gap is bigger than it looks.

If both are the same estimand then it's purely duration and population. Either way, real life with missed weeks and half-hearted logging lands under both, and that's still a win.

My scale swung 3.8 lbs between Tuesday and Wednesday, so I have zero faith in anyone nailing a 4.5 point gap.

Enrollment size cuts the other way too, in my experience — 1946 people across a pile of sites means more baseline BMI spread and more folks who never stuck with a plan before, which usually drags a mean down rather than up. My own non-scale win: down two belt notches and one shirt size since March while the scale only moved about 6% of my starting weight.

Quick follow-up for anyone who's dug into the protocols: did any of the four Phase 3 trials use a run-in period that filtered out non-adherent people before the measurement clock even started?

@luisCarter630 said:

did any of the four Phase 3 trials use a run-in period that filtered out non-adherent people...

Something that gets lost in these comparisons: the timepoint itself. My own loss graph is flat for weeks, then drops, then flat again, and it definitely didn't stop at week 48 — the last 3 lbs came off between months 13 and 15.

If those bigger trials run longer than 48 weeks, you're partly comparing a snapshot to a later snapshot. And "up to 28.7%" reads like a best-case arm, not a central estimate; if one trial hit that and the others landed at 25-26%, the real gap is a rounding argument, not a biology one.

I'd want per-trial numbers with the week each was measured at before concluding the compound behaves differently in a bigger population.

I mostly quit weighing daily — my waist is the number I actually trust. Down 4.5 inches since I started, and two of those inches showed up during a moth where the scale didn't move at all.

If trials only report scale weight, they're blind to whatever's happening with body comp, and that alone could explain part of any gap.

Sleep is my biggest lever and nobody adjusts for it. Four nights under 6 hours and my weekly loss went from about 1.5 lbs to 0.2 — same food, same walks, same everything.

Cortisol and water retention alone can paper over a genuinely good week. Any trial averaging that chaos away is going to understate what people actually experience.

Honestly the mean is the least useful number here. Responder spread is enormous — some folks drop 40%, some lose single digits — so 24 vs 28 tells you nothing about which bucket you land in. I'd rather see the distribution and the dropout rate than a headline percentage that no individual person ever actually lives.

The 48-week cutoff is doing more of the work here than the estimand. Curves in these trials are usually still descending at week 48 — a lot of the phase 3 readouts ran noticeably longer, and "up to 28.7% across four trials" means someone picked the best of four.

If the range bottoms out in the low 20s, most of your gap evaporates and it's not estimand vs population at all, it's stopwatch vs stopwatch. My guess: estimand explains maybe one or two points, duration explains a few, and the rest is headline selection.

Which is annoying, because it means neither number is wrong, they're just answering different questions, and we won't know which one is "the" number until the full phase 3 tables drop.

Up to" is doing an enormous amount of unpaid labor in that sentence.

Retention is the boring explanation nobody wants to hear. The efficacy estimand is basically a what-if for people who stopped early, and if phase 3 kept more of those folks in the trial, the completers look better without the drug behaving differently at all.

I've watched two coworkers bail in month two and neither was ever going to see 25%.

The calendar could be most of it and I say that from my own chart. Started at 214, dropped 14 lbs in the first six weeks — pure water and inflammation, I was up twice a night — then it settled into a steady 1.2 lbs a week for about nine months, and now it's crawling along at 0.4.

Chop that chart at 48 weeks, fine number. Let it run to 68, better number.

Nothing changed except the timeline.

So I'd want to know whether the phase 3 folks were still descending at their endpoint or had flattened out, because flat at 28% and still-falling at 28% are completely different claims, and the press release isn't going to tell us which one it was.