Are GLP-1 Agonists More Than Just Anti-obesity Drugs?

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A recently published article in the journal, Nature Medicine, discusses a significant study on the effects of blockbuster obesity drugs like Ozempic, which are known as glucagon-like peptide 1 (GLP-1) receptor agonists. These drugs, originally developed for diabetes management, have gained widespread attention and popularity for their ability to promote weight loss and potentially treat a variety of other conditions, including heart disease and neurodegenerative diseases like Parkinson’s and Alzheimer’s.
A new comprehensive study involving nearly two million people in the Veterans’ Health System has provided deeper insights into both the benefits and risks associated with these drugs. The research, led by Ziyad Al-Aly of the Veterans Affairs St. Louis Health Care System, tracked over 200,000 diabetes patients on GLP-1 medications and compared them with about 1.7 million patients on other diabetes medications over a period of roughly 3.5 years.
“The [study] highlighted several potential advantages of GLP-1 drugs, including reduced risks of heart disease, stroke, kidney disease, psychotic disorders, Alzheimer’s disease, and substance use disorders.”
The findings highlighted several potential advantages of GLP-1 drugs, including reduced risks of heart disease, stroke, kidney disease, psychotic disorders, Alzheimer’s disease and substance use disorders. For instance, the risk of substance use disorders was lowered by an average of 13%, which could be attributed to the drugs’ effects on brain regions involved in reward and impulse control, potentially helping to reduce cravings for substances like tobacco and alcohol. Such a mechanism could also play a role in the success of these drugs as anti-obesity drugs in patients with uncontrollable food cravings (“food addiction”).
“…the effective treatment and reversal of systemic immune activation associated with weight loss may remove this risk factor for a variety of disorders.”
The mechanism(s) underlying these drug benefits outside the original indications type 2 diabetes and obesity are unknown. A simple explanation could be that the reduction of obesity and associated metabolic disturbances results in a reduction in systemic immune activation (metabolic endotoxemia).
As discussed in detail in my book The Mind Gut Immune Connection, metabolic endotoxemia has been identified as a risk factor for many disorders making up the current chronic noncontagious disease epidemic, including neurodevelopmental (Autism Spectrum Disorders), neurodegenerative, (Parkinson’s, Alzheimer’s) cardiovascular disorders, inflammatory bowel disorders and colon cancer.
According to this theory, the effective treatment and reversal of systemic immune activation associated with weight loss would remove this risk factor for a variety of disorders. Another hypothesis states that the chronic exposure to unphysiological doses of the GLP-1 stimulant has unknown effects on targets other than the gut brain axis, such as the dopaminergic system in the brain which is involved in substance use disorders. Intense ongoing research efforts by the makers of the anti-obesity drugs are aimed at identifying such mechanisms.
“…patients on GLP-1 drugs showed an 11% increased risk of developing arthritis and a 146% higher risk of pancreatitis…”
However, the VA study also identified new risks. Notably, patients on GLP-1 drugs showed an 11% increased risk of developing arthritis and a 146% higher risk of pancreatitis—a serious condition that can lead to life-threatening complications. These risks were previously unrecognized and highlight the need for careful consideration when prescribing these medications.
Critics of the study, argue that while the data is useful, the study lacked detail in certain areas, such as matching participants on factors like age and lifestyle, which could affect the results. Furthermore, it was pointed out that the study mainly compared the likelihood of developing conditions over time without detailing the absolute number of events, which can limit the practical application of the findings in clinical settings.
“As GLP-1 drugs continue to be prescribed, understanding their full range of effects on health, including the potential serious side effects during long term use is crucial.”
The study’s results are particularly relevant given the widespread use of these medications beyond diabetes treatment, primarily for weight loss. As GLP-1 drugs continue to be prescribed, understanding their full range of effects on health, including the potential serious side effects during long term use is crucial. Also, hypothesis-driven preclinical studies and prospective clinical trials in patients with chronic disorders other than obesity and diabetes are required to determine if the observed effects are real, and could open up new indications for the anti-obesity drugs.

Emeran Mayer, MD is a Distinguished Research Professor in the Departments of Medicine, Physiology and Psychiatry at the David Geffen School of Medicine at UCLA, the Executive Director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience and the Founding Director of the Goodman-Luskin Microbiome Center at UCLA.