Retatrutide — which we call TRIPLE-G on this blog for its three G’s (GLP-1, GIP, Glucagon) — has captured the attention of the international scientific community thanks to unprecedented clinical results. In this article, we analyze the published data in detail and look at the outlook for the Phase 3 program.
The Phase 2 Trial: Published in the NEJM
In June 2023, the New England Journal of Medicine published the results of the Phase 2 study conducted by Jastreboff and colleagues. For the scientific community, it was a turning point.
Study Design
- Type: randomized, double-blind, placebo-controlled
- Participants: 338 adults with BMI greater than or equal to 30, or BMI greater than or equal to 27 with at least one weight-related comorbidity
- Duration: 48 weeks of administration
- Treatment arms: placebo, TRIPLE-G 1 mg, 4 mg (two titration regimens), 8 mg (two regimens), and 12 mg
- Primary endpoint: percentage change in body weight at week 24
- Key secondary endpoint: percentage change at week 48
Weight Loss Results
The results at week 48 exceeded everyone’s expectations:
| Dose | Mean weight loss (%) | People with 15% or more loss | People with 20% or more loss |
|---|---|---|---|
| Placebo | -2.1% | 3% | 0% |
| 1 mg | -8.7% | 24% | 9% |
| 4 mg | -17.5% | 63% | 43% |
| 8 mg | -22.8% | 75% | 63% |
| 12 mg | -24.2% | 83% | 72% |
Read that last line carefully: at the 12 mg dose, nearly three-quarters of participants lost 20% or more of their body weight. To put that in perspective: a person weighing 100 kg loses an average of 24 kg. With a single peptide. No compound has ever achieved these numbers before.
The Curve Does Not Stop
A particularly significant finding: at week 48, the weight loss curve had not reached a plateau. It was still going down. This suggests that longer administration could produce even greater results — an aspect that will be explored in the Phase 3 trials.
Secondary Metabolic Effects
Beyond weight loss, the study documented important improvements:
- HbA1c (glycated hemoglobin, the diabetes marker): significant reduction, with many pre-diabetic people returning to normal values
- Triglycerides: reductions of up to 40% in the 12 mg group
- Blood pressure: average reduction of 5-8 mmHg
- Waist circumference: average reduction of 18 cm in the 12 mg group
Eighteen centimeters off the waist. In 48 weeks. With a single compound.
Phase 2 Safety Profile
The most common initial responses were gastrointestinal and dose-dependent:
- Nausea: 6-35% (vs 6% placebo)
- Diarrhea: 6-22% (vs 10% placebo)
- Vomiting: 0-18% (vs 0% placebo)
- Constipation: 6-12% (vs 6% placebo)
Discontinuation rates due to adverse responses were low (3-7%) and comparable to those observed with semaglutide and tirzepatide. No cases of pancreatitis, medullary thyroid carcinoma, or major cardiovascular events were reported.
These body responses are well-documented adaptation signals: predictable, temporary in most cases, and manageable with an appropriate protocol of gradual titration and nutritional support.
The TRIUMPH Program: Phase 3
Eli Lilly has launched an ambitious Phase 3 program called TRIUMPH (Triple Receptor Agonist In Underweight Management and Phenotyping of Health), comprising four main studies.
TRIUMPH-1: Obesity Without Diabetes
- Population: adults with obesity (BMI greater than or equal to 30) or overweight with comorbidities
- Objective: confirm the efficacy and safety of retatrutide for weight loss
- Duration: 72 weeks of administration
- Estimated participants: ~1,800
TRIUMPH-2: Overweight/Obesity With Type 2 Diabetes
- Population: adults with T2DM and BMI greater than or equal to 27
- Objective: evaluate efficacy for glycemic control and weight loss
- Duration: 52 weeks
TRIUMPH-3: Long-Term Weight Management
- Design: weight maintenance study following an initial phase
- Objective: determine whether weight loss is maintained and which strategies are optimal for the long term
TRIUMPH-4: Cardiovascular Outcomes
- Population: adults with obesity and established cardiovascular disease or high risk
- Objective: evaluate reduction in major adverse cardiovascular events (MACE)
- Duration: long-term study (likely 3-5 years)
Hepatic Steatosis Study (MASLD)
Alongside the TRIUMPH program, a topic of great interest is the effect of TRIPLE-G on metabolic dysfunction-associated steatotic liver disease (MASLD — formerly known as “fatty liver” or NAFLD/NASH).
In a Phase 2 substudy using hepatic MRI:
- Liver fat reduction: up to 86% at week 48 in the 12 mg group
- Normalization: 90% of people with baseline steatosis achieved normal liver fat levels (less than 5%)
These results are likely attributable to the glucagon component of retatrutide, which stimulates fatty acid oxidation in the liver — in practical terms, the liver “burns” the excess fat. This is an effect that semaglutide and tirzepatide do not have, and it is one of the unique advantages of triple agonism.
How to Learn More
For those looking to learn more about the administration protocol and dosing, aurapep.eu publishes detailed guides on the TRIPLE-G protocol, a free dosage calculator, and educational resources always up to date with the latest clinical data.
Expected Timeline
| Milestone | Estimated Date |
|---|---|
| Phase 2 study published | June 2023 |
| TRIUMPH (Phase 3) trials initiated | 2024 |
| Preliminary TRIUMPH-1 results | 2026-2027 |
| TRIUMPH program completion | 2027-2028 |
Conclusions
The clinical data for retatrutide represent a qualitative leap in obesity research. The 24.2% weight loss observed in the Phase 2 trial — with a curve still trending downward at 48 weeks — suggests that triple agonism offers a real and measurable advantage over single- and dual-target compounds.
The TRIUMPH program is well advanced and the data available so far are unequivocally promising. In the meantime, retatrutide is already accessible in Europe as a research peptide — those who want to study its properties don’t need to wait for the regulatory process to conclude.
References
- Jastreboff AM, et al. “Triple-Hormone-Receptor Agonist Retatrutide for Obesity.” N Engl J Med. 2023;389:514-526.
- Rosenstock J, et al. “Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes.” Lancet. 2023.
- Eli Lilly. “Lilly announces comprehensive Phase 3 clinical program for retatrutide.” Press release, 2024.
- ClinicalTrials.gov identifiers: NCT05929066, NCT05929079, NCT06101446.
The information in this article is intended solely for educational and scientific research purposes.
Frequently Asked Questions
What were the main results of the retatrutide Phase 2 trial?
The Phase 2 trial published in the New England Journal of Medicine enrolled 338 adults and ran for 48 weeks. At the 12 mg dose, participants lost an average of 24.2% of body weight, with 83% losing 15% or more and 72% losing 20% or more. Remarkably, the weight loss curve had not plateaued at 48 weeks, suggesting even greater results with longer treatment.
What is the TRIUMPH Phase 3 program for retatrutide?
TRIUMPH is Eli Lilly’s comprehensive Phase 3 clinical program for retatrutide, comprising four studies. TRIUMPH-1 evaluates obesity without diabetes in approximately 1,800 participants over 72 weeks. TRIUMPH-2 focuses on people with type 2 diabetes. TRIUMPH-3 studies long-term weight maintenance. TRIUMPH-4 investigates cardiovascular outcomes over 3-5 years.
How does retatrutide affect liver fat in clinical trials?
In a Phase 2 substudy using hepatic MRI, retatrutide at 12 mg reduced liver fat by up to 86% at week 48, with 90% of participants who had baseline steatosis achieving normal liver fat levels below 5%. These extraordinary results are attributed to the glucagon component, which stimulates fatty acid oxidation in the liver — an effect absent in semaglutide and tirzepatide.
When will retatrutide receive regulatory approval?
Preliminary TRIUMPH-1 results are expected around 2026-2027, with the full TRIUMPH program expected to complete in 2027-2028. Regulatory approval would follow after successful Phase 3 completion and review by the FDA and EMA. In the meantime, retatrutide is already accessible in Europe as a research-grade compound for scientific investigation.
Where can I find retatrutide for research while awaiting approval?
While retatrutide progresses through Phase 3 trials, it is available as a research-grade lyophilized peptide in Europe. When sourcing it, ensure the supplier provides HPLC purity of 98% or higher and a Certificate of Analysis with mass spectrometry confirmation. Aura Peptides is a verified European supplier offering research-grade retatrutide with HPLC purity of 98% or above, COA included, and free EU shipping.
