Authors Urge Regular Monitoring for Gastrointestinal, Kidney Adverse Effects
The study’s senior author, Ziyad Al-Aly, MD, is a clinical epidemiologist and nephrologist at the St. Louis VA Healthcare System and WashU Medicine. Photo from Matt Miller of WashU Medicine.
ST. Louis — While glucagon-like peptide-1 receptor agonists (GLP-1RA) are known to successfully treat diabetes and aid weight loss, they also have other widespread benefits, including for cognitive and behavioral health, as well as other conditions, according to review of a large cohort of U.S. veterans using the drugs.
But the medications also increase the risk for kidney conditions, pancreatitis and other gastrointestinal conditions, according to researchers from the VA St. Louis Healthcare System and the Washington University School of Medicine.
“GLP-1RA drugs can have broad health benefits,” said senior author Ziyad Al-Aly, MD, a clinical epidemiologist and nephrologist who treats patients at WashU Medicine and the VA. “However, they are not without risks. Our findings underscore the possibility for wider applications for these medications but also highlight important risks that should be carefully monitored in people taking these drugs.”
The article in Nature Medicine noted that GLP-1RAs are increasingly being used to treat diabetes and obesity, even though their effectiveness and risks have not yet been systematically evaluated in a comprehensive set of possible health outcomes. The researchers used VA databases to build a cohort of 215,970 diabetes patients who initiated GLP-1RA and compared them to 159,465 who initiated sulfonylureas; 117,989 who initiated dipeptidyl peptidase 4 (DPP4) inhibitors or 258,614 who initiated sodium−glucose cotransporter-2 (SGLT2) inhibitors. In addition, the study team created a 536,068-member control group with an equal proportion of individuals initiating sulfonylureas, DPP4 inhibitors and SGLT2 inhibitors and a 1.2 million person control group of individuals who continued use of non-GLP-1RA antihyperglycemics, defined as usual care. The records were from Oct. 1, 2017, to Dec. 31, 2023.
“We used a discovery approach to systematically map an atlas of the associations of GLP-1RA use versus each comparator with 175 health outcomes,” the authors explained. “Compared to usual care, GLP-1RA use was associated with a reduced risk of substance use and psychotic disorders, seizures, neurocognitive disorders (including Alzheimer’s disease and dementia), coagulation disorders, cardiometabolic disorders, infectious illnesses and several respiratory conditions. There was an increased risk of gastrointestinal disorders, hypotension, syncope, arthritic disorders, nephrolithiasis, interstitial nephritis and drug-induced pancreatitis associated with GLP-1RA use compared to usual care. The results provide insights into the benefits and risks of GLP-1RAs and may be useful for informing clinical care and guiding research agendas.”
Demand for the weight-loss medications, which are sold under brand names such as Ozempic and Wegovy, continues to surge, with a recent study reporting 1 in 8 Americans has taken or is currently using the drugs to treat diabetes, heart disease or obesity, according to a Washington University press release.
“Given the drugs’ newness and skyrocketing popularity, it is important to systematically examine their effects on all body systems—leaving no stone unturned—to understand what they do and what they don’t do,” Al-Aly pointed out. “Our approach has allowed us to build a comprehensive atlas mapping the associations of GLP-1RA spanning all organ systems,” he said. “The study’s results provide insights into some known and unrecognized benefits and risks of GLP-1RA that may be useful to inform clinical care and guide research agendas.”
Impulse Control
The study team emphasized that the GLP-1RA drugs were associated with significant benefits to neurological and behavioral health, with reduced risks of seizures and addiction to substances such as alcohol, cannabis, stimulants and opioids. It noted that users of the weight-loss drugs also experienced decreased risks of suicidal ideation, self-harm, bulimia and psychotic disorders such as schizophrenia. “Interestingly, GLP-1RA drugs act on receptors that are expressed in brain areas involved in impulse control, reward and addiction—potentially explaining their effectiveness in curbing appetite and addiction disorders,” Al-Aly advised. “These drugs also reduce inflammation in the brain and result in weight loss; both these factors may improve brain health and explain the reduced risk of conditions like Alzheimer’s disease and dementia.”
While GLP-1RA drugs demonstrated effectiveness against a wide array of health issues, the magnitude of associated benefits was found to be modest—about a 10% to 20% reduction for most outcomes. “However, the modest effect does not negate the potential value of these drugs, especially for conditions where few effective treatment options exist, for example, dementia,” Al-Aly said. “This may also imply that these drugs are most beneficial when used in conjunction with other interventions, such as lifestyle changes or other medications.”
The study also confirmed previous findings about the drugs’ potential to lower the risk of heart attack, stroke and other cardiovascular concerns, likely related to weight loss, according to the authors.
Al-Aly cautioned, however, that the study put a spotlight on potential downsides to the medications, including an increased risk of gastrointestinal problems such as nausea, vomiting, diarrhea and, in rare cases, paralysis of the stomach. “These have been well documented in the research and anecdotally,” he noted. “Our study confirmed such findings.”
The study also had novel findings on how GLP-1RA drugs can negatively affect the pancreas and kidneys. While these adverse effects are uncommon, the researchers warned that they can be very serious and urged regular monitoring.
“GLP-1RA drugs can have broad health benefits,” Al-Aly said. “However, they are not without risks. Our findings underscore the possibility for wider applications for these medications but also highlight important risks that should be carefully monitored in people taking these drugs.”
- Xie, Y., Choi, T. & Al-Aly, Z. Mapping the effectiveness and risks of GLP-1 receptor agonists. Nat Med (2025). https://doi.org/10.1038/s41591-024-03412-w
