Glucagon-like peptide-1 receptor agonists may be associated with a reduced risk of neurocognitive disorders, including Alzheimer's disease and dementia, alongside an increased risk of gastrointestinal side effects, according to a recent study.
In a study, published published in Nature Medicine, investigators evaluated the benefits and risks of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) using a cohort of 1,955,135 participants with diabetes. The cohort was derived from the U.S. Department of Veterans Affairs health care system and included 215,970 participants who initiated GLP-1 RA therapy. Comparators included sulfonylureas (n = 159,465), dipeptidyl peptidase 4 (DPP4) inhibitors (n = 117,989), sodium-glucose cotransporter-2 (SGLT2) inhibitors (n = 258,614), a composite control group (n = 536,068), and a usual care group of 1.2 million participants continuing non-GLP-1 RA antihyperglycemic therapy. The participants were followed-up for a median of 3.68 years, corresponding to 7.2 million person-years.
For their study, the investigators employed a discovery approach to evaluate associations between GLP-1 RA use and 175 health outcomes. After applying inverse probability weighting to balance baseline characteristics, they identified significant reductions in the risk of several conditions among GLP-1 RA users compared with usual care. These conditions included neurocognitive disorders such as dementia (hazard ratio [HR] = 0.92, 95% confidence interval [CI] = 0.88–0.97) and Alzheimer’s disease (HR = 0.88, 95% CI = 0.78–0.99), as well as substance use disorders, including alcohol (HR = 0.89, 95% CI = 0.86–0.92) and opioid use disorders (HR = 0.87, 95% CI = 0.82–0.92). Cardiovascular and renal benefits included reduced risks of myocardial infarction (HR = 0.91, 95% CI = 0.87–0.94), ischemic stroke (HR = 0.93, 95% CI = 0.90–0.96), and chronic kidney disease (HR = 0.97, 95% CI = 0.96–0.99). Reduced risks of respiratory conditions, such as pneumonia (HR = 0.84, 95% CI = 0.82–0.86) and chronic obstructive pulmonary disease (HR = 0.90, 95% CI = 0.87–0.92), were also noted.
However, GLP-1 RA use was associated with an increased risk of gastrointestinal disorders, including nausea and vomiting (HR = 1.30, 95% CI = 1.26–1.33) and gastroesophageal reflux disease (HR = 1.14, 95% CI = 1.12–1.16). Risks for nephrolithiasis (HR = 1.15, 95% CI = 1.12–1.19) and drug-induced acute pancreatitis (HR = 2.46, 95% CI = 2.05–2.96) were also elevated.
The findings demonstrated the diverse effects of GLP-1 RAs. They showed significant benefits for neurocognitive, cardiometabolic, and respiratory conditions and indicated potential risks for gastrointestinal and renal events. These investigators suggested further research to refine therapeutic approaches and explore broader clinical applications.
Full disclosures can be found in the published study.
