Retatrutide Phase 2 Trial Breakdown: What the 2023 NEJM Data Actually Showed

Retatrutide Phase 2 results in brief

In the Phase 2 trial published in the New England Journal of Medicine in 2023, once-weekly retatrutide produced dose-dependent weight reduction in 338 adults with obesity or overweight. At 48 weeks the least-squares mean change in body weight was -8.7% (1 mg), -17.1% (4 mg), -22.8% (8 mg) and -24.2% (12 mg), against -2.1% with placebo.

Retatrutide (LY3437943) is Eli Lilly's agonist of the GIP, GLP-1 and glucagon receptors. It is investigational and not FDA-approved. Every figure in this article comes from the published paper (PMID 37366315) or the results posted to the trial's registry record (NCT04881760), and each table names which one it uses.

How was the trial designed?

The study was a double-blind, randomized, placebo-controlled trial run for 48 weeks. Adults were eligible with a body-mass index of 30 or higher, or 27 to under 30 plus at least one weight-related condition. Participants were randomized in a 2:1:1:1:1:2:2 ratio to placebo or one of six retatrutide arms given subcutaneously once weekly:

• 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

The primary endpoint was the percentage change in body weight from baseline to 24 weeks. The 48-week change and the share of participants reaching 5%, 10% and 15% weight reduction were secondary endpoints. Of the 338 adults enrolled, 51.8% were men. The paper reports the two 4 mg arms and the two 8 mg arms combined; the registry reports all seven arms separately.

Dose-by-dose results at 24 and 48 weeks

The published results, with the 4 mg and 8 mg arms combined, were:

Source: Jastreboff et al., N Engl J Med 2023 (PMID 37366315), least-squares mean percentage change from baseline.

The registry record splits the escalation arms by starting dose. The participant counts below are the safety population for each arm.

Source: ClinicalTrials.gov NCT04881760 posted results, least-squares mean percentage change from baseline.

Two patterns stand out. At 24 weeks the 8 mg and 12 mg groups were close (-17.3% and -17.5% combined), and the gap opened by 48 weeks (-22.8% and -24.2%). And within each dose, the arms that started at 4 mg showed slightly larger reductions than the arms that started at 2 mg.

How many participants reached 5%, 10% and 15% weight reduction?

Source: PMID 37366315, share of participants at 48 weeks.

What adverse events were reported?

The paper reports that the most common adverse events in the retatrutide groups were gastrointestinal, that they were dose-related and mostly mild to moderate, and that a lower starting dose (2 mg rather than 4 mg) partially reduced them. It also reports dose-dependent increases in heart rate that peaked at 24 weeks and declined afterwards.

The registry lists participant counts for each event:

Source: ClinicalTrials.gov NCT04881760 posted adverse event data (non-serious events reported at a 5% frequency threshold; MedDRA terms).

The starting-dose effect is visible in these counts. Nausea was reported by 36.4% of the 4 mg arm that started at 4 mg against 18.2% of the 4 mg arm that started at 2 mg, and by 60.0% against 17.1% in the two 8 mg arms. In the registry's participant flow, study withdrawals attributed to an adverse event were 0 to 2 per arm.

What does the triple-agonist mechanism add?

Earlier incretin compounds target one receptor (semaglutide, GLP-1) or two (tirzepatide, GIP and GLP-1). Retatrutide adds the glucagon receptor:

• GLP-1 receptor: glucose-dependent insulin secretion, slower gastric emptying, reduced appetite
• GIP receptor: insulin secretion and effects on lipid handling that complement GLP-1 signaling
• Glucagon receptor: raises hepatic glucose output, but also increases energy expenditure and mobilizes liver fat

Glucagon on its own raises blood glucose. The design hypothesis was that simultaneous GLP-1 receptor activity would offset that while the energy-expenditure effect added to weight reduction. The Phase 2 data tested the combination on body weight; it was not designed to isolate how much each receptor contributed.

How does this compare with tirzepatide's SURMOUNT-1?

In SURMOUNT-1, tirzepatide 15 mg produced a mean -20.9% change in body weight at 72 weeks against -3.1% with placebo (PMID 35658024). Retatrutide 12 mg reported -24.2% at 48 weeks. The trials differ in size (2,539 versus 338 participants), duration, and population, so the comparison is approximate. The retatrutide vs tirzepatide vs semaglutide comparison covers the cross-trial data in more detail.

Where does Phase 3 (TRIUMPH) stand?

As of October 2026, ClinicalTrials.gov lists four TRIUMPH Phase 3 trials as completed: TRIUMPH-1 (NCT05929066) in obesity or overweight, 2,335 enrolled; TRIUMPH-2 (NCT05929079) with type 2 diabetes, 1,152 enrolled; TRIUMPH-3 (NCT05882045) with cardiovascular disease, 1,946 enrolled; and TRIUMPH-4 (NCT05931367) with knee osteoarthritis, 445 enrolled. None has posted results on the registry yet. Topline figures so far come from company announcements, summarized in the TRIUMPH program overview. Retatrutide remains an investigational compound.

What the Phase 2 data does not answer

• Durability. The trial ran 48 weeks. It does not show what happens with longer administration or after stopping.
• Cardiovascular outcomes. The study was not powered for cardiovascular events.
• Broader populations. Participants with type 2 diabetes, established cardiovascular disease or other comorbidities were studied separately in the Phase 3 program.
• Rare or delayed adverse events. A 338-person, 48-week trial is too small and too short to detect them.

Sources

• Jastreboff AM, et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity: A Phase 2 Trial. N Engl J Med. 2023;389(6):514-526. PMID 37366315
• ClinicalTrials.gov NCT04881760, A Study of LY3437943 in Participants Who Have Obesity or Are Overweight (posted results)
• Jastreboff AM, et al. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2022. PMID 35658024
• ClinicalTrials.gov registry records for TRIUMPH-1 to TRIUMPH-4, accessed October 2026

Note

This article reports published clinical trial data for informational and educational purposes only. It does not describe or endorse any use of retatrutide and is not medical advice.