Retatrutide — Tri-agonista GLP-1 / GIP / Glucagone
What is Retatrutide? Retatrutide (LY3437943) is a next-generation peptide belonging to the class of incretin mimetics. It acts simultaneously on three key hormonal receptors — GLP-1, GIP, and glucagon — aiming to synergistically modulate appetite, glucose metabolism, and energy expenditure. This triple mechanism positions it as the potential successor to tirzepatide, expanding the “dual agonist” concept into a new class of tri-agonists. All Pepticore Aminos products are strictly intended for research and laboratory use (Research Use Only).
How it works (GLP-1, GIP, Glucagon)
GLP-1 (glucagon-like peptide-1) sends satiety signals to the brain, slows gastric emptying, and stimulates insulin secretion in a glucose-dependent manner. It also helps reduce endogenous glucagon release, improving postprandial glucose control.
GIP (glucose-dependent insulinotropic polypeptide) enhances the insulin response after carbohydrate and fat intake, promoting glucose utilization for energy and reducing hepatic glucose production. Acting synergistically with GLP-1, it supports insulin sensitivity and lipid metabolism.
Glucagon in this context does not act as an insulin antagonist but as a regulator of energy metabolism. Its controlled activation increases lipolysis and fatty acid oxidation, promoting a higher resting energy expenditure and reduction of visceral fat. This triad of mechanisms makes retatrutide a unique research platform for studying complex metabolic balance.
🔬 Research Highlights
- −24.2% mean body weight reduction after 48 weeks in adults with obesity (Phase 2, NEJM 2023)
- −2.16 HbA1c points and ~17% weight loss in T2D after 36 weeks (Phase 2, Lancet 2023)
- −81–82% liver fat reduction with normalization <5% in the MASLD substudy (Nature Medicine 2024)
Clinical Evidence (Phase 2)
Obesity without diabetes: In the New England Journal of Medicine study, retatrutide produced mean weight reductions of −22.8% (8 mg) and −24.2% (12 mg) after 48 weeks, along with improvements in BMI, waist circumference, and blood pressure. See NEJM 2023 / PubMed.
Type 2 Diabetes: In the Lancet Phase 2 trial, retatrutide reduced HbA1c by up to −2.16 percentage points at the highest doses, accompanied by a robust weight reduction (~17% at 36 weeks). The most frequent adverse events were gastrointestinal (nausea, reduced appetite), generally mild to moderate. See Lancet 2023 / PubMed.
Liver (MASLD): The Nature Medicine substudy reported a relative liver fat reduction of −81–82% at 8–12 mg doses, with normalization (<5%) in most participants and improvement in inflammation and liver function biomarkers. See Nature Medicine 2024 / PubMed.
Comparison with Semaglutide and Tirzepatide
Semaglutide (GLP-1 agonist) achieved ~15% mean weight loss over ~68 weeks; tirzepatide (GLP-1+GIP agonist) reached ~22.5% over ~72 weeks. Retatrutide, through additional glucagon receptor activation, achieved ~24% in 48 weeks. Although not head-to-head comparisons, these results show a progressive enhancement of efficacy across incretin-agonist generations, positioning retatrutide as a likely pharmacological evolution of tirzepatide.
| Drug | Activated Receptors | Main Effects | Riduzione peso (durata) |
|---|---|---|---|
| Semaglutide | GLP-1 | Satiety↑, delayed gastric emptying↓, improved glycemic control | ~15% (≈68 weeks)* |
| Tirzepatide | GLP-1 + GIP | > Appetite↓, glucose↓, enhanced insulin response↑ | ~22,5% (≈72 weeks)* |
| Retatrutide | GLP-1 + GIP + glucagon | All of the above + increased energy expenditure↑; marked reduction in liver fat | ~24% (48 weeks) |
Values derived from different clinical studies (not head-to-head). Retatrutide data from NEJM 2023; tirzepatide and semaglutide from SURMOUNT and STEP trials.
Clinical status and registries
Retatrutide remains under clinical investigation. Multiple Phase 3 trials are ongoing in various populations (obesity, type 2 diabetes, weight maintenance, comorbid conditions). For official protocols, see:
References
- NEJM 2023 — Retatrutide per l’obesità (fase 2) · PubMed 37366315
- Lancet 2023 — Retatrutide in T2D (fase 2) · PubMed 37385280
- Nature Medicine 2024 — Sottostudio MASLD · PubMed 38858523
- ClinicalTrials.gov — Studi di fase 3
Pepticore Aminos products are intended exclusively for research and laboratory use (Research Use Only). Not for human or animal consumption, nor for clinical or therapeutic use.
