| Parameter | Retatrutide (LY3437943) | Tirzepatide (LY3298176) |
|---|---|---|
| Receptor targets | GLP-1R + GIPR + GCGR (triple) | GLP-1R + GIPR (dual) |
| Development stage (mid-2026) | Phase 3 ongoing (TRIUMPH program) | Phase 3 complete; FDA approved |
| FDA status | Not approved | Mounjaro (T2D, 2022); Zepbound (obesity, 2023) |
| Best available weight loss data | 24.2% at 48 weeks (12 mg, Phase 2) | 22.5% at 72 weeks (15 mg, Phase 3) |
| Source trial | Jastreboff et al., NEJM 2023 | Jastreboff et al., NEJM 2022 (SURMOUNT-1) |
| Head-to-head data | TRIUMPH-5 (NCT06662383), Phase 3 ongoing, estimated December 2026 | |
Receptor profiles: dual agonist vs triple agonist
Tirzepatide (LY3298176) binds two receptors: the GLP-1 receptor (GLP-1R) and the glucose-dependent insulinotropic polypeptide receptor (GIPR). GLP-1R agonism reduces appetite through hypothalamic satiety signaling and slows gastric emptying. GIPR agonism improves insulin sensitivity and amplifies GLP-1R-driven weight loss beyond what single-receptor agents achieve. Eli Lilly received FDA approval for tirzepatide for type 2 diabetes in May 2022 (Mounjaro) and for obesity in November 2023 (Zepbound).
Retatrutide (LY3437943) adds a third target: the glucagon receptor (GCGR). Glucagon is normally a hyperglycemic counterpart to insulin, but at the receptor-binding profile and dose ranges used in retatrutide, GCGR co-agonism drives increased energy expenditure through thermogenic pathways and stimulates hepatic fatty acid oxidation. Beta-hydroxybutyrate, a reliable ketogenesis marker reflecting that oxidation, rose two to threefold in participants given retatrutide at 4 mg and above in the Phase 2 trial.
Retatrutide Phase 2: the NEJM 2023 dataset
The primary evidence base for retatrutide comes from a 48-week, double-blind, randomized, placebo-controlled Phase 2 trial published in the New England Journal of Medicine in August 2023 by Jastreboff et al. (PMID 37366315, n=338). Participants had a BMI of 30 or higher, or 27 to 29.9 with at least one weight-related comorbidity, and received once-weekly subcutaneous injections across four dose arms.
Mean percent weight loss at week 48 by dose arm: the 1 mg arm lost 8.7%, the 4 mg arm 17.3%, the 8 mg arm 22.8%, and the 12 mg arm 24.2%. In the 12 mg group, 100% of participants achieved at least 5% body weight reduction, 93% achieved at least 10%, and 83% at least 15%.
Gastrointestinal adverse events were the principal safety signal. Nausea occurred in approximately 33% of participants and vomiting in 12%, predominantly at dose-escalation steps and graded as mild to moderate in severity. Fasting glucose showed no clinically significant increase; the theoretical concern about GCGR-driven hyperglycemia did not materialize in this dataset.
Tirzepatide Phase 3: SURMOUNT-1 and the broader trial program
Tirzepatide's obesity evidence is anchored by SURMOUNT-1, a Phase 3 trial published in NEJM in July 2022 by Jastreboff et al. (PMID 35658024, n=2,539). Participants were adults without type 2 diabetes; the trial ran 72 weeks across 119 sites in nine countries.
Mean weight loss at week 72: the 5 mg arm achieved 16.0%, the 10 mg arm 21.4%, and the 15 mg arm 22.5%. In the 15 mg group, 88% of participants achieved at least 5% body weight reduction, 69% at least 10%, and 43% at least 15%.
The broader SURMOUNT program covers post-lifestyle-intervention settings (SURMOUNT-3), weight maintenance after initial loss (SURMOUNT-4), and obstructive sleep apnea (SURMOUNT-OSA). As of mid-2026, tirzepatide has the most complete Phase 3 dataset of any next-generation incretin therapy for obesity.
Why retatrutide vs tirzepatide weight loss data needs context
The numbers from the two compounds appear comparable on paper, but the datasets are structurally different. Retatrutide's 24.2% figure comes from a 48-week Phase 2 trial in 338 participants. Tirzepatide's 22.5% comes from a 72-week Phase 3 trial in 2,539 participants. Phase 2 trials are smaller, shorter, and designed for dose-finding rather than definitive efficacy estimation; Phase 3 trials enroll broader populations and are powered for regulatory endpoints.
Duration also matters. Weight loss with GLP-1-class drugs continues to accumulate beyond 48 weeks for most patients. Tirzepatide's own Phase 2 data at 40 weeks showed 20.9% mean weight loss at the top dose; the Phase 3 data surpassed that at 72 weeks. Extrapolating retatrutide's trajectory past 48 weeks is speculative until Phase 3 data is available.
No randomized head-to-head trial has reported results. Statements claiming retatrutide "outperforms" tirzepatide in weight reduction are cross-trial comparisons, not observed findings from a controlled study.
What the glucagon receptor component adds beyond weight loss
The GCGR component of retatrutide appears most consequential for liver fat. In a 48-week Phase 2a MASLD substudy nested within the obesity trial, 98 participants with baseline liver fat of 10% or more by MRI-PDFF were enrolled. Retatrutide produced up to 82% relative reduction in liver fat, as published in Nature Medicine in 2024 by Harrison et al. (n=98). No comparable dedicated MASLD substudy with MRI-PDFF endpoints has been published for tirzepatide.
The glycemic balance under combined GLP-1R and GCGR agonism is a relevant variable for any research protocol. GLP-1R activity lowers postprandial glucose; GCGR activity works in the opposite direction on fasting glucose. In Phase 2, these effects offset each other without clinically significant hyperglycemia at the doses studied. The TRANSCEND-T2D trials will test whether that balance holds across larger populations with varying glycemic baselines.
The direct comparison trial: TRIUMPH-5
Eli Lilly registered a randomized direct comparison in November 2024. TRIUMPH-5 (NCT06662383) is a Phase 3, double-blind trial comparing retatrutide to tirzepatide in adults with obesity. Estimated primary completion is December 2026. Results from this trial will provide the first controlled evidence on whether the added GCGR agonism in retatrutide translates to a measurable difference in primary weight loss endpoints versus tirzepatide.
Two additional Phase 3 studies provide broader context. TRIUMPH-1 (NCT05929066) is the foundational retatrutide-versus-placebo obesity trial. TRIUMPH-Outcomes (NCT06383390) is a cardiovascular and kidney outcomes trial with an estimated enrollment of 10,000 participants, which started in April 2024 with primary completion estimated for February 2029. Researchers modeling protocol doses can use the dosing calculator alongside the published Phase 2 dose-response data while Phase 3 results mature.
For a deeper look at retatrutide's mechanism and Phase 2 data in isolation, see the retatrutide research overview. For the comparison with semaglutide, see retatrutide vs semaglutide.