Stopping and Restarting a GLP-1 Drug Repeatedly May Worsen Metabolic Health in Aging Obese Mice

What the researchers found

Aged obese UM-HET3 mice subjected to three cycles of liraglutide treatment followed by withdrawal (ON/OFF group) developed hyperleptinemia and visceral fat expansion, resulting in impaired metabolic health compared to both untreated controls and continuously treated mice.

Importantly, while the ON/OFF mice regained fat mass after each treatment cycle, they consistently failed to restore lean mass. This unfavorable shift in body composition — losing muscle but regaining fat — suggests that intermittent GLP-1 therapy may increase vulnerability to sarcopenia, the age-related loss of muscle mass and function.

Why it matters

GLP-1 receptor agonists like liraglutide and semaglutide are among the most prescribed weight-loss drugs today. Many patients stop and restart these medications due to cost, side effects, or supply issues. This study provides the first evidence in aged animals that this yo-yo pattern may not simply return you to baseline — it could actively worsen metabolic health by driving up leptin, expanding visceral fat, and eroding muscle mass, which is especially dangerous in older adults already at risk for sarcopenia.

How the study worked

Aged obese UM-HET3 mice (a genetically diverse mouse strain) were divided into three groups: one receiving no liraglutide (OFF), one undergoing three cycles of treatment followed by withdrawal (ON/OFF), and one on continuous liraglutide treatment (ON). Researchers tracked body weight, food intake, body composition (fat vs. lean mass), leptin levels, and metabolic health markers across the treatment cycles.

What this study cannot tell us

This was conducted in mice, not humans, so the findings may not directly translate to human patients. The UM-HET3 strain, while genetically diverse, does not fully replicate human metabolic complexity. The study did not report specific numerical values for leptin levels, body weight changes, or lean mass loss in the abstract. Long-term survival outcomes were not assessed.

How to read the evidence

This is a preclinical animal study using a genetically diverse mouse model. While the study design included appropriate control groups and the findings are biologically significant, results from mice cannot be directly extrapolated to humans without clinical trials.

When this study was published

Published in 2025, this study addresses a very current clinical question as GLP-1 agonist use has surged globally. The findings are timely and highly relevant to ongoing debates about treatment adherence.

The bigger picture

As millions of people worldwide use GLP-1 agonists for obesity and diabetes, questions about what happens when treatment is interrupted are increasingly urgent. This study adds to growing evidence that these drugs may need to be taken continuously to maintain benefits, and that cycling on and off could create a worse metabolic profile than never starting treatment — particularly for aging populations where muscle preservation is critical.

Questions still open

• Would these same metabolic consequences occur in humans who cycle on and off GLP-1 receptor agonists?
• Could resistance training or protein supplementation during drug withdrawal periods help preserve lean mass?
• Is there a minimum continuous treatment duration that avoids the negative rebound effects seen with intermittent use?

Common questions

Read the original research

Repeated Withdrawal of a GLPR Agonist Induces Hyperleptinemia and Deteriorates Metabolic Health in Obese Aging UM-HET3 Mice.

Aging cell, 24(10), e70210

Citation

Jiang, Nisi; Yin, Jiyuan; Lawrence, Noah; Meng, Jieyi; Maeyens, Laurence T; Xu, Ziying; Li, Xin; Ekane, Mbolle; Chaudhary, Ariana; Cao, Pengju; Li, Guannan; Solis-Herrera, Carolina; Zhu, Yi; Zhao, Shangang. (2025). Repeated Withdrawal of a GLPR Agonist Induces Hyperleptinemia and Deteriorates Metabolic Health in Obese Aging UM-HET3 Mice.. Aging cell, 24(10), e70210. https://doi.org/10.1111/acel.70210