Retatrutide phase 2: a triple GIP, GLP-1 and glucagon receptor agonist for obesity

Retatrutide adds glucagon receptor agonism to the GIP and GLP-1 activity of tirzepatide. This phase 2 trial is where the "24 percent" figure comes from. It is a dose-finding study, and it should be read as one.

What the trial asked

How retatrutide's side effects, safety and weight-loss efficacy vary with dose in adults with obesity, and whether a lower starting dose reduces gastrointestinal effects.

Design

Phase 2, double-blind, randomised, placebo-controlled, 48 weeks. Randomised 2:1:1:1:1:2:2 to once-weekly retatrutide 1 mg; 4 mg (starting at 2 mg); 4 mg (starting at 4 mg); 8 mg (starting at 2 mg); 8 mg (starting at 4 mg); 12 mg (starting at 2 mg); or placebo. Primary endpoint: percent change in body weight from baseline to week 24. Secondary endpoints included the change at 48 weeks and responder thresholds of 5, 10 and 15 percent.

Who was enrolled

338 adults with a BMI of 30 or higher, or 27 to under 30 with at least one weight-related condition. 51.8 percent were men, which is unusual for a weight-loss trial (most enrol 70 to 80 percent women). Baseline weight is not stated in the abstract.

Primary endpoint and result

Least-squares mean percent change in body weight at 24 weeks (arms with two starting doses combined):

The abstract gives no confidence intervals and no P values for these comparisons. That is normal for a phase 2 abstract and it is why this page shows none.

Key secondary results

Responder rates at 48 weeks (5, 10 and 15 percent or more): 92, 75 and 60 percent on 4 mg; 100, 91 and 75 percent on 8 mg; 100, 93 and 83 percent on 12 mg; 27, 9 and 2 percent on placebo.

Adverse events and discontinuation

The most common adverse events were gastrointestinal, dose-related, mostly mild to moderate, and partially mitigated by starting at 2 mg rather than 4 mg. Dose-dependent increases in heart rate peaked at 24 weeks and declined afterwards. The abstract gives no discontinuation percentages.

Funding and registration

Eli Lilly. ClinicalTrials.gov NCT04881760.

What this trial does not show

• It is phase 2. The 12 mg arm is a fraction of 338 people. Phase 3 programmes routinely produce smaller effects than the phase 2 that preceded them.
• Weight was still falling at week 48 in the higher-dose arms, so the trial does not define a plateau.
• The heart-rate increase is reported as a finding, not explained. Longer trials are needed to know whether it matters.
• The obesity phase 3 programme, TRIUMPH, had a published design paper (PubMed 41090431) but, as of our 4 September 2026 PubMed search, no primary results paper indexed. When one appears we will digest it. Until then, any "phase 3 retatrutide" weight number you see online is not from a peer-reviewed publication we can verify. The phase 3 diabetes trial TRANSCEND-T2D-1 is published and is digested separately.
• Retatrutide is not approved anywhere and is not available as a legitimate prescription product. Anything sold under that name outside a trial is unregulated.

Where the numbers come from

PubMed abstract of the primary paper (PubMed 37366315), fetched 4 September 2026, and a PubMed search for TRIUMPH results on the same date. The sibling site GLP-1s Explained tracks the regulatory status of investigational agents.