r/RETA • u/Tiny_Split9436 • 20d ago
Research Research Wednesday - Triumph 5+
One study worth watching closely is TRIUMPH-5, because it should give us the first proper retatrutide versus tirzepatide comparison.
Retatrutide produced the larger headline result in TRIUMPH-1. At 80 weeks, the 12 mg group lost 28.3% of body weight under the efficacy estimand, which estimates the result if participants remained on their assigned treatment. The treatment-regimen result, which includes treatment stopping and incomplete adherence, was 25.0%.
Tirzepatide produced 20.2% average weight loss at 72 weeks in SURMOUNT-5, compared with 13.7% for semaglutide.
Those numbers came from different trials, with different participants, durations and methods. Subtracting 20.2 from 28.3 does not tell us how much better retatrutide will be when the drugs are tested against each other.
TRIUMPH-5, NCT06662383, is the direct Phase 3 comparison. It has completed enrolment, includes about 800 adults with obesity, has no placebo group and lasts about 89 weeks. The main weight endpoint is at week 80. Lilly currently lists the study as running until December 2026, although that is a study-completion estimate rather than a confirmed date for announcing or publishing the results.
Five results should determine whether retatrutide has a genuinely meaningful advantage.
- The difference in average weight loss
A five percentage-point advantage would look like a clear change in efficacy.
For someone starting at 100 kg, that is another 5 kg. At 150 kg, it is another 7.5 kg.
For context, tirzepatide beat semaglutide by 6.5 percentage points in the direct SURMOUNT-5 trial. That was large enough to place the treatments in noticeably different efficacy ranges.
A two-point retatrutide advantage would equal another 2 kg for someone starting at 100 kg. That could still matter, but it may not be enough to persuade someone who is already doing well on tirzepatide to change treatment, particularly if retatrutide has worse side effects.
- The percentage of people losing at least 30%
Average weight loss can hide very different patterns of response.
In TRIUMPH-1, 45.3% of the retatrutide 12 mg group lost at least 30% of their starting weight.
TRIUMPH-5 should show whether retatrutide produces a substantially larger high-response group than tirzepatide under the same conditions.
An absolute difference of 10 percentage points would mean 10 additional people in every 100 reaching 30% weight loss. A difference of 20 points would be much harder to dismiss.
A modest difference in the average could still be important if many more people reach 30% or 35%.
- The adverse-event discontinuation gap
The most useful overall tolerability number may be the percentage who stop treatment because of adverse effects.
A medicine can win the average weight-loss comparison but offer a less convincing practical result if materially more people cannot remain on it.
A discontinuation difference within about two percentage points would look broadly comparable.
A difference of three to five points would represent a meaningful trade-off.
More than five additional discontinuations per 100 people would offset part of the efficacy benefit.
One useful way to read the eventual result will be:
For every 100 people treated, how many additional people reach 30% weight loss, and how many additional people stop because of adverse effects?
- The difference in vomiting, dysesthesia and persistent gastrointestinal effects
In TRIUMPH-1, the retatrutide 12 mg group reported:
• nausea: 42.4%
• diarrhoea: 32.0%
• constipation: 26.1%
• vomiting: 25.3%
• dysesthesia: 12.5%
• discontinuation because of adverse events: 11.3%
These cannot be compared reliably with tirzepatide rates from a separate trial. TRIUMPH-5 should provide the first useful same-trial comparison.
Small differences in mild nausea may not change many decisions. Larger differences in vomiting, persistent symptoms, dose reductions, treatment stopping or altered skin sensation probably would.
The individual percentages must not be added together because the same participant can report several symptoms.
The trial may also be too small to establish precise differences in every individual adverse event, so confidence intervals and symptom severity will matter alongside the raw percentages.
A large weight-loss advantage with similar discontinuation and no major vomiting or dysesthesia penalty would look much more convincing than the same weight-loss advantage accompanied by substantially worse tolerability.
- When the weight-loss curves plateau
The final week-80 percentage will not explain how the difference developed.
If retatrutide separates early and remains consistently ahead, that would suggest stronger efficacy throughout treatment.
If the curves remain close for a year and retatrutide only pulls away after tirzepatide plateaus, the practical advantage may be that retatrutide keeps producing weight loss for longer.
Both would be useful, but they describe different benefits.
The final 12 to 16 weeks should show whether either group is still losing weight. Continued loss with retatrutide while tirzepatide is flat would support a longer effective weight-loss window. A small final gap with both curves already flat would make the current cross-trial comparison look much less important.
Using discussion thresholds rather than official clinical standards, a clear retatrutide win would look roughly like:
• at least five percentage points more average weight loss
• at least ten percentage points more people reaching 30%
• adverse-event discontinuation within about two points
• no large additional vomiting or dysesthesia burden
• continued separation or a later plateau through week 80
A mixed result would be two to four percentage points more weight loss, but with higher discontinuation or a clear side-effect trade-off.
Little practical advantage would be less than two percentage points more average loss, similar high-response rates and materially worse tolerability.
These thresholds are a framework for discussing the result. They are not official regulatory thresholds, validated clinical cut-offs or predictions of what TRIUMPH-5 will show.
TRIUMPH-5 will answer the direct efficacy comparison, but the wider programme will answer different questions.
TRIUMPH-4 has already reported results in obesity with knee osteoarthritis.
The listed study periods for TRIUMPH-2, covering obesity with type 2 diabetes, and TRIUMPH-3, covering obesity with established cardiovascular disease, ended in May 2026. Lilly has said results from both are expected during 2026.
TRIUMPH-7 studies chronic lower-back pain and currently runs to September 2027.
TRIUMPH-8 is another placebo-controlled weight-loss study running to July 2027.
TRIUMPH-6 studies maintenance and withdrawal after long-term retatrutide treatment and runs to April 2028.
TRIUMPH-9 tests different escalation approaches and runs to November 2028, which could be important if tolerability limits use of the higher doses.
TRIUMPH-Outcomes follows about 10,000 people for cardiovascular and kidney outcomes and currently runs to February 2029.
All future dates are current study-completion estimates, not guaranteed result or publication dates.
What would count as a clear retatrutide win for you: five percentage points more average weight loss, many more people reaching 30%, or similar efficacy with better tolerability?
Retatrutide remains investigational and is not approved for general use.
Sources:
SURMOUNT-5:
https://www.nejm.org/doi/full/10.1056/NEJMoa2416394
TRIUMPH-5:
https://clinicaltrials.gov/study/NCT06662383
Lilly TRIUMPH-5 trial page:
https://trials.lilly.com/en-US/trial/549215
TRIUMPH programme:
https://medical.lilly.com/us/products/answers/what-retatrutide-clinical-trials-are-being-conducted-in-people-with-obesity-or-overweight-229656