Retatrutide: Research Applications

Research Applications

Retatrutide is under active preclinical and clinical investigation across 7+ major research domains, leveraging its unique triple-receptor agonist mechanism:

1. Obesity and Weight Management — The primary investigational focus. Phase 2 trials (Jastreboff et al., 2023) demonstrated dose-dependent weight loss up to 24.2% at 48 weeks with the 12 mg dose, and weight loss had not plateaued at study conclusion.[1] Phase 3 TRIUMPH program data confirmed up to 28.7% mean weight loss at 68 weeks (approximately 71.2 lbs average), with the 12 mg dose group showing the greatest reductions.[5] Preclinical studies in diet-induced obese mice demonstrated 36.9% body weight loss (vs. 21.2% for tirzepatide) with 86.8% fat mass reduction.[4]
2. Type 2 Diabetes Mellitus (T2D) — Rosenstock et al. (2023) demonstrated significant glycemic improvements in Phase 2, with HbA1c reductions of up to -2.02% at the 12 mg dose over 36 weeks, along with improvements in fasting glucose, insulin sensitivity, and beta-cell function.[2] Body composition substudies confirmed that weight loss was primarily driven by fat mass reduction.[6]
3. Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD/NAFLD) — A Phase 2a substudy by Sanyal et al. (2024) published in Nature Medicine demonstrated that the 8 mg and 12 mg doses normalized liver fat (<5%) in over 85% of participants, with relative liver fat reductions of up to 86% from baseline. This effect is linked to glucagon receptor-mediated increases in hepatic fatty acid oxidation and elevated beta-hydroxybutyrate biomarkers.[3]
4. Cardiovascular Disease (CVD) — The TRIUMPH-OUTCOMES Phase 3 trial is assessing whether retatrutide reduces the incidence of major adverse cardiovascular events (MACE) in adults with obesity and established atherosclerotic cardiovascular disease. Pre-trial data show dose-dependent heart rate increases that peak at 24 weeks before declining.[5][10]
5. Chronic Kidney Disease (CKD) — The TRANSCEND-CKD trial is investigating retatrutide's effects on kidney structure and function, including measured glomerular filtration rate (mGFR). Post-hoc analyses from Phase 2 data suggested potential renoprotective effects, including reduced albuminuria and improved renal hemodynamics over time.[7][9]
6. Knee Osteoarthritis (OA) — The TRIUMPH-4 Phase 3 trial evaluates retatrutide in patients with obesity and knee osteoarthritis. Results showed a significant reduction in WOMAC pain scores (up to 75.8% improvement) and improved physical function, alongside substantial weight loss.[5]
7. Obstructive Sleep Apnea (OSA) — Included within the TRIUMPH-1 and TRIUMPH-2 basket trials, research aims to determine retatrutide's efficacy in reducing the apnea-hypopnea index in patients with obesity.[5]
8. Obesity-Associated Cancer — Preclinical research by Marathe et al. (2025) demonstrated that retatrutide-induced weight loss reduced tumor engraftment, delayed tumor onset, and significantly attenuated tumor growth in pancreatic and lung cancer models, outperforming semaglutide. Antitumor effects persisted despite partial weight regain, suggesting durable systemic and tumor immune reprogramming.[14]
9. Diabetic Kidney Disease (DKD) — In preclinical studies, Ma et al. (2025) showed retatrutide demonstrated superior efficacy over liraglutide and tirzepatide in controlling risk factors associated with diabetic kidney disease in db/db mice, effectively mitigating inflammatory and fibrotic processes.[15]

Clinical Efficacy Summary by Dose (Phase 2)

Dose	Weight Loss (48 wks, Obesity)	HbA1c Reduction (36 wks, T2D)	Evidence
1 mg	-8.7%	—	Jastreboff et al. (2023)[1]
0.5 mg	—	-0.43%	Rosenstock et al. (2023)[2]
4 mg	-17.1%	~-1.3%	[1][2]
8 mg	-22.8%	~-1.9%	[1][2]
12 mg	-24.2%	-2.02%	[1][2]