What does this research mean for the field?

Combining the novel oral mitochondrial uncoupler RV-202 with a sub-efficacious dose of semaglutide produces synergistic, fat-selective weight loss, preserves lean mass, and prevents post-treatment weight rebound in diet-induced obese mice. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

The study aimed to identify the minimum effective dose of RV-202 to enhance weight loss from semaglutide and prevent weight rebound.

June 7, 2026

2553-P: Low Dose of Oral Mitochondrial Uncoupler Converts a Subefficacious Semaglutide Dose into a Durable, Fat-Selective Weight Loss Treatment in Obesity Model

Puntos clave

The study aimed to identify the minimum effective dose of RV-202 to enhance weight loss from semaglutide and prevent weight rebound.
Male diet-induced obese mice were administered low-dose semaglutide with RV-202 at three different doses.
Body composition and energy expenditure were measured using EchoMRI and indirect calorimetry, respectively.
A 7-day off-drug period followed the discontinuation of semaglutide to evaluate weight loss durability.
High-dose RV-202 led to a significant 16% weight loss by increasing energy expenditure.
Co-administration of mid-dose RV-202 with low-dose semaglutide achieved weight loss of 16%, and high-dose RV-202 reached 30%.
Weight loss was durable for at least 7 days post-semaglutide, with significant fat mass reductions (24% at mid-dose, 48% at high-dose).

Resumen

Introduction and Objective: RV-202 is a novel oral mitochondrial uncoupler (MU) that increases energy expenditure (EE) and induces weight loss (WL) as a monotherapy. The objective of this study was to determine the minimum dose of RV-202 required to convert a sub-efficacious dose of semaglutide (SEMA) into an effective WL regimen and to prevent weight rebound after SEMA discontinuation. Methods: Male diet-induced obese (DIO) mice were treated with low-dose SEMA plus RV-202 at 3 doses. SEMA was stopped on day 21, followed by a 7-day off-drug period to assess WL durability and rebound. Body composition was measured by EchoMRI and EE by indirect calorimetry. Results: High-dose RV-202 produced significant WL (-16%) by increasing EE. In combination studies, low-dose SEMA had a modest effect on WL (-6%). Co-administration of RV-202 with low-dose SEMA enhanced WL (-16% at mid-dose, -30% at high-dose) and further reduced food intake, suggesting a synergy between the mechanisms. A mid-dose of RV-202, which yields a 10% increase in EE, was sufficient to render low-dose SEMA effective when combined, achieving WL comparable to high-dose SEMA alone. WL in the combination groups was sustained for at least 7 days after SEMA discontinuation. Relative to SEMA alone, addition of RV-202 led to greater, dose-dependent fat mass reduction (-24% at mid-dose, -48% at high-dose) while preserving lean mass after 21 days. Conclusion: RV-202, an oral MU, promotes fat-selective WL in DIO mice by increasing EE and fat oxidation. RV-202, combined with a sub-efficacious SEMA dose, amplified the effect on food intake, resulting in greater and more durable WL and fat loss than high-dose SEMA monotherapy, while preserving lean mass. All RV-202 doses were sufficient to prevent post-SEMA weight rebound. Combining low-dose MU with low-dose incretins may provide durable, fat-selective WL with an improved tolerability profile relative to high-dose incretin therapy. Disclosure M. Luse: None. A. Scott: None. H. Chobanian: None. T.E. Richardson: None. B. Dalesandro: None. C.A. Hamilton: None. S. Eaton: None. A. Cole: None. O.M. Khan: None. J. Dennis: Employee; Current; Rivus Pharmaceuticals. Stock/Shareholder; Current; Viking Therapeutics. S.M. Khan: Employee; Current; Rivus Pharmaceuticals. S. Collado: Employee; Current; Rivus Pharmaceuticals.

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Cite This Study

LUSE et al. (Fri,) studied this question.

synapsesocial.com/papers/6a250c507def13d035e1c64d https://doi.org/https://doi.org/10.2337/db26-2553-p

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