A new study suggests that the long-term administration of GLP-1 receptor agonists—the class of anti-obesity medications surging in popularity globally—may trigger systemic metabolic instability.
A joint research team involving Seoul National University Hospital, CHA Bundang Medical Center, and Logsynk announced their findings on the 29th. The conclusion followed an extensive meta-analysis of approximately 120 clinical papers and an in-depth review of the biological mechanisms underlying GLP-1 therapies.
GLP-1 is a naturally occurring hormone that regulates appetite by acting on the hypothalamus, the brain region responsible for the autonomic nervous and endocrine systems. By mimicking this hormone, medications like Novo Nordisk’s Wegovy (semaglutide) increase satiety and suppress hunger to induce weight loss.
However, the research team looked beyond weight reduction to analyze the physiological shifts occurring during treatment. The study found that when carbohydrate intake is chronically restricted due to medication-induced appetite suppression, the body aggressively burns stored fat for energy. While this leads to weight loss, the process also causes a sharp rise in reactive oxygen species, leading to increased oxidative stress.
To neutralize this surge, the body’s antioxidant defense system must work overtime. Because patients eat significantly less while on these drugs, they often fail to consume the nutrients necessary to regenerate these defense mechanisms, creating a metabolic "vicious cycle."
"If the body’s detoxification capacity cannot keep pace with the increased demand, a 'metabolic bottleneck' occurs," the team explained.
According to the study, if this state persists, proteins that should be utilized for muscle maintenance and antioxidant defense are instead depleted, resulting in severe muscle loss. Furthermore, a deficiency in essential micronutrients can cause enzyme functions to decline significantly. The researchers also noted that changes in gastrointestinal and bile acid functions could impair the body’s ability to absorb nutrients even when food is consumed.
To mitigate these metabolic risks, the research team urged clinicians to adopt a more comprehensive monitoring strategy during GLP-1 treatment. They recommended:
Tracking changes in muscle mass rather than focusing solely on total body weight.
Ensuring patients consume adequate protein to preserve muscle tissue.
Monitoring levels of essential micronutrients, such as iron and magnesium, which support enzyme function.
Regularly checking antioxidant enzyme levels to assess overall metabolic stability.
"GLP-1 therapies drive effective weight loss, but they simultaneously place the body in a state of chronic energy restriction," said Baek Seon-ha, a professor of neurosurgery at Seoul National University Hospital. "We need a paradigm shift in obesity treatment—one that prioritizes whole-body metabolic stability over simple numbers on a scale."
The study was recently published in the international academic journal Current Obesity Reports.
