Retatrutide clinical trials: what we know, what we don't

Eli Lilly has positioned retatrutide as a successor program to tirzepatide. Phase 1 studies established that the once-weekly triple agonist was tolerable across a range of doses, and that its plasma half-life supported weekly dosing. Phase 2 data, in NEJM and The Lancet, established proof-of-concept for industry-leading weight-loss and HbA1c outcomes. [1][2]

Phase 3 — the TRIUMPH program — is now generating the safety and efficacy data Lilly will use to seek US and EU approval. Topline readouts are expected starting in 2026. [3]

The Phase 2 type 2 diabetes trial (Rosenstock et al., Lancet 2023) demonstrated robust glycemic effects: participants on the highest dose achieved an HbA1c reduction of approximately 2.0 percentage points at 36 weeks, alongside an average weight loss near 17%. Active comparator dulaglutide produced HbA1c reductions of around 1.4 percentage points and weight loss in the low single digits. [2]

The TRIUMPH studies share a common design template: randomized, double-blind, placebo-controlled, with multiple maintenance-dose arms and primary endpoints reported at 60 to 76 weeks. The four indications collectively cover most of the patient populations for whom obesity treatment is most clinically valuable.

In addition to the four TRIUMPH studies, Lilly has additional long-term cardiovascular outcomes trials underway and registered on ClinicalTrials.gov. [3]

For obesity trials, two endpoint types matter most:

1. Mean % change in body weight from baseline at the primary timepoint. This is the headline figure that gets quoted in press releases.
2. Proportion of participants achieving ≥5%, ≥10%, ≥15%, ≥20%, or ≥25% weight loss. This shows how the response is distributed — i.e., whether everyone loses some weight or whether most of the headline number comes from a subset of strong responders.

In the Phase 2 obesity trial, the proportion of participants achieving ≥15% weight loss reached approximately 75% on the 12 mg dose, and ≥25% weight loss was achieved by about 26%. [1]

The most common adverse events in Phase 2 were gastrointestinal: nausea (39–55% on top doses), diarrhea, vomiting, and constipation. As with other GLP-1-class drugs, these were concentrated in dose-escalation periods and largely abated at maintenance dose.

A small dose-dependent increase in resting heart rate was observed, with mean increases generally a few beats per minute at the highest doses. Whether this signal has long-term clinical relevance is one of the questions Phase 3 — particularly TRIUMPH-3 in patients with established cardiovascular disease — is designed to answer. [1]

• No head-to-head trial against tirzepatide. Cross-trial comparison is the only available comparison today.
• Limited long-term safety data. Phase 2 follow-up was 48 weeks. Multi-year tolerability and cardiovascular outcomes will only be characterized as the TRIUMPH program reads out.
• Unknown durability after discontinuation. As with other GLP-1-class drugs, weight regain after stopping is expected, but the magnitude has not been formally reported for retatrutide specifically.
• Population breadth. Phase 2 trials enrolled relatively healthy adults. Generalizability to older adults, patients with multiple comorbidities, and underrepresented populations will depend on Phase 3 readouts.