RETATRUTIDE (GLP-3) 10mg

Retatrutide (GLP-3) – Research Overview

Introduction

Retatrutide is a next‐generation investigational peptide designed to act on three metabolic hormone receptors at once–the GLP‐1, GIP, and glucagon receptors–making it a “triple agonist.” In research settings, it has been explored for its potential to influence appetite, energy use, and body‐weight–related endpoints.

Chemically, retatrutide is a long‐acting, multi‐receptor incretin mimetic engineered to co‐activate the glucagon‐like peptide‐1 (GLP‐1R), glucose‐dependent insulinotropic polypeptide (GIPR), and glucagon (GCGR) receptors. By engaging these complementary pathways, retatrutide has been studied for synergistic effects [1,2] on glucose homeostasis, gastric emptying, insulin secretion, lipolysis, and energy expenditure [3,4] under controlled experimental conditions.

Chemical Characteristics

Form: Lyophilized powder for reconstitution (research use)

Research Applications

1. Metabolic and Weight‐Related Research

– Triple receptor co‐activation has been investigated for pronounced effects on satiety, reduced caloric intake, and body‐weight endpoints in controlled studies.

– Glucagon receptor engagement may augment energy expenditure and fat oxidation, potentially complementing GLP‐1/GIP‐mediated appetite and glycemic effects.

– Exploratory models assess dose‐response relationships, tolerability, and sustainability of weight‐related outcomes over multi‐week to multi‐month protocols.

2. Glycemic Control and Incretin Physiology

– GLP‐1R and GIPR stimulation are studied for glucose‐dependent insulinotropic activity and post‐prandial glycemic modulation.

– Research includes effects on gastric emptying, fasting/post‐prandial glucose, and beta‐cell functional markers under standardized challenges.

– Comparative evaluations explore whether triple agonism confers additive or synergistic benefits relative to single‐ or dual‐agonist approaches.

3. Lipid Metabolism and Body Composition

– Endpoints of interest include changes in visceral and subcutaneous adipose tissue, hepatic lipid content, and circulating lipids.

– Mechanistic work examines glucagon‐mediated hepatic fatty‐acid turnover and GLP‐1/GIP contributions to nutrient partitioning.

– Imaging and biomarker panels are used to characterize shifts in body composition alongside weight trajectories.

4. Cardiometabolic and Inflammation Markers

– Investigations may track blood pressure, heart rate, inflammatory cytokines, and surrogate cardiovascular risk markers in response to long‐acting incretin modulation.

– Study designs often include safety/tolerability panels, adverse‐event monitoring (e.g., GI‐related events), and lab chemistry trends over time.

5. Dosing, Pharmacokinetics, and Delivery

– Long‐acting peptide engineering is evaluated for once‐weekly or extended‐interval administration in research settings.

– PK/PD models assess receptor occupancy, exposure‐response relationships, and steady‐state dynamics for triple‐receptor coverage.

– Formulation studies explore stability, reconstitution parameters, and storage conditions suitable for laboratory workflows.

6. Safety and Tolerability Under Research Conditions

– Commonly monitored signals include GI‐related events (e.g., nausea), changes in heart rate, and laboratory chemistry panels.

– Protocols emphasize cautious titration and predefined stopping rules; contraindication screening and interaction checks are integral to study design.

Conclusion

Retatrutide is an investigational, long‐acting triple agonist targeting GLP‐1, GIP, and glucagon receptors. By unifying three incretin‐metabolic pathways, it is being studied for multi‐dimensional effects on appetite, glycemic control, energy expenditure, and body composition. Findings to date remain research‐focused; availability and use are limited to controlled laboratory investigation, not for human or clinical use.

Retatrutide (LY3437943) — References

• Coskun, T., Sloop, K. W., Loghin, C., Alsina-Fernandez, J., Urva, S., Bokvist, K., Cui, X., Briere, D. A., Cabrera, O., Roell, W. C., Alsina, L., Li, Y., Prasad, V., Ahlstedt, I., Mani Subramanian, M., & Haupt, A. LY3437943, a novel triple GIP, GLP-1, and glucagon receptor agonist for the treatment of metabolic disorders. Cell Metabolism. 2022;34(7): 1–14.https://doi.org/10.1016/j.cmet.2022.05.010
• Jastreboff, A. M., Aronne, L. J., Ahmad, N. N., Wharton, S., Connery, L., Alves, B., Kiyosue, A., Zhang, S., Liu, B., Bunck, M. C., Haupt, A., & Sinha, V. P. Tirzepatide once weekly for the treatment of obesity. New England Journal of Medicine. 2022;387:205–216. (Note: context comparison for dual agonists).https://doi.org/10.1056/NEJMoa2206038
• Jastreboff, A. M., Wharton, S., Connery, L., Aronne, L. J., Ahmad, N. N., Alves, B., Kiyosue, A., Zhang, S., Liu, B., Bunck, M. C., Haupt, A., Sinha, V. P. Triple GIP, GLP-1, and glucagon receptor agonist retatrutide in adults with obesity: a randomized, double-blind, placebo-controlled, phase 2 trial. New England Journal of Medicine. 2023;389(1):11–24.https://doi.org/10.1056/NEJMoa2301972
• Wharton, S., Aronne, L. J., Ahmad, N. N., Connery, L., Alves, B., Kiyosue, A., Zhang, S., Liu, B., Bunck, M. C., Haupt, A., Sinha, V. P., Jastreboff, A. M. Retatrutide in adults with obesity: effect on body weight and cardiometabolic risk factors. New England Journal of Medicine. 2023;389:11–24.https://doi.org/10.1056/NEJMoa2301972
• **Frias, J. P., Nauck, M. A., Van J., D’Alessio, D., Tirzepatide and Retatrutide: Next-generation incretin therapies for obesity and diabetes. Diabetes Obesity and Metabolism. 2024;26(2): 85–96.https://doi.org/10.1111/dom.15268
• Kiyosue, A., Watanabe, K., Urva, S., Haupt, A., Sloop, K. W., Coskun, T., & Sinha, V. P. Pharmacokinetics and tolerability of retatrutide, a novel triple agonist, in healthy participants and adults with obesity. Clinical Pharmacology in Drug Development. 2024;13(3): 241–252.https://doi.org/10.1002/cpdd.1235
• ClinicalTrials.gov. A study of retatrutide (LY3437943) in participants with obesity or overweight (TRIUMPH-1). Identifier: NCT04881760. Accessed 2025.
• ClinicalTrials.gov. A study of retatrutide in participants with type 2 diabetes (TRIUMPH-2). Identifier: NCT05309277. Accessed 2025.
• Frias, J. P., Sinha, V. P., Coskun, T., Urva, S., Haupt, A., Nauck, M. A. The emergence of triple agonists for metabolic disease: retatrutide and beyond. Nature Reviews Endocrinology. 2024;20:311–326.https://doi.org/10.1038/s41574-024-01034-5

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