Also known as: LY3437943, ELI-002
Investigational triple agonist (GIP/GLP-1/glucagon) for obesity and type 2 diabetes
Amount
0.5 mg starting dose, escalating to target of 8-12 mg
Frequency
Once weekly
Duration
48 weeks in Phase 2 trials (ongoing therapy anticipated)
Step-wise Titration (12 weeks)
Route
SCSchedule
Once weekly
Timing
Same day each week, any time of day
✓ Rotate injection sites
Duration
48 weeks in Phase 2 trials (ongoing therapy anticipated)
Repeatable
Yes
✓ Ready-to-use — no reconstitution required
Storage: Investigational product; storage per clinical trial protocol
HbA1c and fasting glucose
When: Baseline
Why: Baseline glycemic status
Lipid panel
When: Baseline
Why: Baseline cardiovascular risk markers
CMP with liver enzymes
When: Baseline
Why: Liver function (glucagon component affects hepatic metabolism)
Thyroid panel (TSH, free T4)
When: Baseline
Why: GLP-1 agonist class has MTC black box warning
Amylase and lipase
When: Baseline
Why: Baseline pancreatic function
HbA1c
When: 12 weeks
Why: Monitor glycemic improvement
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Retatrutide (LY3437943) is an investigational triple-hormone receptor agonist developed by Eli Lilly. It is a synthetic peptide that simultaneously activates three metabolically important receptors: the glucose-dependent insulinotropic polypeptide receptor (GIPR), the glucagon-like peptide-1 receptor (GLP-1R), and the glucagon receptor (GCGR). This triple agonism distinguishes it from tirzepatide (dual GIP/GLP-1 agonist) and semaglutide (GLP-1 agonist alone).
Retatrutide is currently in Phase 3 clinical development under the TRIUMPH program. In December 2025, the first Phase 3 results from TRIUMPH-4 showed 28.7% mean body weight loss at 68 weeks with the 12 mg dose -- the highest weight loss ever reported in a Phase 3 obesity trial. Seven additional TRIUMPH readouts are expected throughout 2026.
Retatrutide's triple receptor agonism leverages complementary metabolic pathways to produce weight loss that exceeds any single or dual agonist therapy tested to date.
The inclusion of glucagon receptor agonism is retatrutide's primary differentiator. Glucagon increases energy expenditure by activating thermogenesis and promotes hepatic glycogenolysis and gluconeogenesis. While glucagon alone would raise blood glucose, the combined GLP-1R/GIPR activity counterbalances potential hyperglycemia, allowing net metabolic benefit. This three-receptor approach appears to explain the substantially greater weight loss observed with retatrutide compared to dual agonists.
The glucagon component is also hypothesized to drive hepatic fat reduction, which is being evaluated in a dedicated TRIUMPH trial for metabolic dysfunction-associated steatohepatitis (MASH).
The TRIUMPH program, described by Giblin et al. (2026) in Diabetes, Obesity and Metabolism (PMID: 41090431), consists of four primary Phase 3 trials enrolling over 5,800 participants. All trials test retatrutide 9 mg and 12 mg versus placebo with dose escalation starting at 2 mg weekly.
TRIUMPH-4 (NCT05931367) was the first Phase 3 trial to report results, enrolling 445 adults with obesity and knee osteoarthritis. Key findings:
| Trial | Population | Duration | Key Question |
|---|---|---|---|
| TRIUMPH-1 | Obesity (general) | 80 weeks | Will weight loss exceed 30%? |
| TRIUMPH-2 | Obesity + type 2 diabetes | ~68-80 weeks | Glycemic control advantages? |
| TRIUMPH-3 | Obesity + CV disease | ~68-80 weeks | Cardiovascular outcomes? |
| Additional | MASLD/MASH, chronic low back pain, OSA | Varies | Liver histology, comorbidities? |
TRIUMPH-1 is particularly anticipated because its 80-week duration (vs 68 weeks in TRIUMPH-4) may demonstrate even greater weight loss. Analysts have projected that retatrutide could exceed 30% mean weight loss in this trial.
GI adverse events in TRIUMPH-4 were the most common, consistent with all incretin-based therapies but at higher rates than seen with semaglutide or tirzepatide:
The most notable finding was dose-dependent dysesthesia (abnormal touch sensations):
This signal was not observed in Phase 2 and has not been reported with GLP-1 or dual agonists. Events were generally mild per Eli Lilly, though the 20.9% rate at 12 mg requires further characterization in remaining TRIUMPH readouts.
Treatment discontinuation due to adverse events was 18.2% at 12 mg and 12.2% at 9 mg, compared to 4.0% with placebo. These rates are higher than semaglutide (~7%) and tirzepatide (~6.2%) in their respective Phase 3 trials. Notably, patients with BMI 35+ had lower discontinuation rates (12.1% at 12 mg).
The Phase 2 trial (Jastreboff et al., NEJM 2023; PMID: 37366315) enrolled 338 adults with obesity over 48 weeks:
A separate Phase 2 trial in type 2 diabetes (Rosenstock et al., The Lancet 2023; PMID: 37385280) showed HbA1c reductions of up to 2.0% from baseline, with significant weight loss and superiority over dulaglutide 1.5 mg comparator.
| Parameter | Retatrutide | Tirzepatide | Semaglutide |
|---|---|---|---|
| Mechanism | Triple (GIP/GLP-1/GCG) | Dual (GIP/GLP-1) | Single (GLP-1) |
| Max Phase 3 Weight Loss | -28.7% (68 wk) | -20.9% (72 wk) | -14.9% (68 wk) |
| Approval Status | Phase 3 | FDA-approved (2023) | FDA-approved (2021) |
| Nausea Rate | 43% | ~31% | ~44% |
| Discontinuation (AEs) | 18.2% | ~6.2% | ~7.0% |
For a detailed analysis of these comparisons, see Retatrutide Phase 3 Results: TRIUMPH Trial Weight Loss Data.
TRIUMPH registrational clinical trials design paper, published in Diabetes, Obesity and Metabolism (Giblin K et al., 2026; PMID: 41090431):
Triple-hormone-receptor agonist retatrutide for obesity -- a Phase 2 trial, published in New England Journal of Medicine (Jastreboff AM et al., 2023; PMID: 37366315):
Retatrutide Phase 2 in type 2 diabetes, published in The Lancet (Rosenstock J et al., 2023; PMID: 37385280):
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Amycretin: Novo Nordisk unimolecular GLP-1/amylin receptor agonist. Phase 1b/2a showed up to 24.3% weight loss at 36 weeks. SC and oral formulations. Phase 3 planned.
CT-388: Roche/Carmot signal-biased dual GLP-1/GIP receptor agonist for obesity. Phase 2 showed 22.5% weight loss at 48 weeks. Phase 3 planned for 2026.
Mazdutide: Dual GLP-1/glucagon agonist approved in China for obesity. Covers up to 20% weight loss in trials, mechanism, dosing, and side effects.
Ribupatide (HRS9531): dual GLP-1/GIP agonist by Hengrui/Kailera. Injectable showed 21.1% weight loss at 36 weeks. Oral 12.1% at 26 weeks. Phase 3 underway.
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CagriSema and retatrutide represent two fundamentally different approaches to next-generation obesity treatment. CagriSema combines two proven mechanisms (amylin + GLP-1) in a fixed-dose injection, achieving 20.4% weight loss in Phase 3, with an NDA already filed and the advantage of building on the well-characterized semaglutide platform. Retatrutide's novel triple-agonist approach produced 28.7% weight loss in Phase 3 TRIUMPH-4 (confirming 24.2% in Phase 2) by adding glucagon and GIP receptor activation. CagriSema is likely to reach market sooner, but retatrutide offers the greatest peak efficacy of any single anti-obesity agent.
Retatrutide holds a clear advantage in both efficacy and development timeline. Its triple-receptor mechanism produced 28.7% weight loss in Phase 3 -- substantially greater than CT-388's 22.5% in Phase 2 -- and it is approximately 2-3 years ahead in the regulatory pathway. However, this superior efficacy comes at a cost: higher GI side effect rates and a novel dysesthesia safety signal. CT-388's signaling-biased approach offers a potentially better-tolerated dual agonist with impressive Phase 2 results and no plateau at 48 weeks. For patients who cannot tolerate triple agonist side effects, CT-388 may eventually represent a compelling alternative. Both remain investigational and are not available outside clinical trials.
Retatrutide achieved greater peak weight loss (28.7% at 68 weeks in Phase 3 TRIUMPH-4; 24.2% at 48 weeks in Phase 2) compared to mazdutide's Phase 3 results (20.1% at 60 weeks), likely due to its additional GIP receptor agonism. However, mazdutide is significantly further along in clinical development, with multiple completed Phase 3 trials, regulatory approval in China for T2D, and a head-to-head Phase 3 win over semaglutide. Mazdutide's development is primarily focused on Chinese populations, while retatrutide targets global markets. Both represent meaningful advances over single-target GLP-1 agonists.
Semaglutide is the established gold standard with FDA approval, proven cardiovascular benefit, extensive clinical data, and multiple formulation options. Retatrutide's triple agonism shows promise for greater weight loss and liver fat reduction, but remains investigational with Phase 2 data only. Phase 3 results will determine whether retatrutide's early advantages translate into meaningful clinical superiority.
Retatrutide demonstrated greater weight loss than survodutide in their respective Phase 2 trials (24.2% vs 18.7%), likely driven by its unique triple-agonist mechanism that adds GIP receptor activation. However, survodutide is further along in clinical development with Phase 3 trials fully enrolled and FDA Breakthrough Therapy Designation for MASH, where it has shown strong efficacy. Both represent significant advances beyond single-target GLP-1 agonists. The choice between them may ultimately depend on clinical indication: retatrutide for maximum weight loss and metabolic improvement, survodutide for MASH-focused treatment where it has the most advanced regulatory pathway.
Tirzepatide is the proven choice with FDA approval and extensive clinical data; Retatrutide shows potential for greater efficacy through triple-agonism but awaits Phase 3 results
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