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.