WeightControl.com Interview with
Thomas Leung, MD, PhD
Herman Beerman Professor of Dermatology
Associate Professor, and
Founding Director of the Penn 4D Center for Human Biology
University of Pennsylvania, and Physician at the
Michael Crescenz VA at Philadelphia.
WeightControl.com: What is the background for this study? What are the main findings?
Response: While GLP-1 medications have transformed how we manage obesity, real-world data shows that more than half of patients stop taking them within two years, and many eventually try to restart the treatment. This study was designed to understand the metabolic consequences of this stopping-and-starting pattern.
We found that when mice cycled on and off semaglutide, they developed therapeutic resistance. The drug lost its “punch” each time it was restarted, leading to much less weight loss in later rounds compared to mice that stayed on the drug without breaks.
The physical makeup of the mice between the two groups also changed. While weight loss naturally involves losing some muscle, the rapid regain during the “off” cycles was almost entirely fat. This created a “biological yo-yo” effect where the body ended up with more fat mass and less lean muscle percentage than before, which also led to poor blood sugar control. Cycling GLP-1 RA drugs made them lose their efficacy and caused mice to be 20% fatter than mice who took the medication continuously.
WeightControl.com: Does this include patients who may skip doses or who stay off the medication for months or more?
Response: We didn’t test different patterns of stopping or starting the drugs. In our study, mice went through two-week cycles of taking the drug and not taking the drug. After being off the drug for two weeks, all mice rapidly regained their lost weight, even gaining more than their original weight. We don’t think this situation applies for someone who misses one dose, but we cannot make firm predictions for people who stay off the drug for months or more.
WeightControl.com: What should readers take away from your report?
Response: The most important takeaway is that consistency is the secret sauce for these medications to work effectively over the long term. Our data suggests that every time a person stops the treatment, it might trigger a survival instinct in the body that makes it harder to lose weight the next time around. This isn’t just a quirk of one specific drug — we believe it is a “class effect” that likely applies to other similar GLP-1 RA drugs as well.
Other drugs work in a similar fashion. Rogaine to prevent hair loss also needs to be taken consistently or else its effects don’t work either.
WeightControl.com: What recommendations do you have for future research as a result of this work?
Response: While these results are striking, it is important to remember that this study was performed in male obese mice. We still need to confirm if these same patterns occur in humans and if the results are the same for women. Future research will focus on the exact molecular reasons why the body “resists” the drug after a break.
Disclosures: The researchers have no financial conflicts of interest to disclose. The work was supported by public and private funding, including the National Institutes of Health, the Department of Veterans Affairs, and several academic foundations.
Citation
Cycling GLP-1 receptor agonist treatment induces therapeutic resistance and increased adiposity. March 2026; JCI Insight. DOI:10.1172/jci
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Last Updated on April 30, 2026 by weightcontrol