With the release of a compounded version, the market for glucagon-like peptide 1 receptor agonists (GLP-1RAs), such as semaglutide, has exploded. While GLP-1RAs are widely used to treat diabetes and obesity, their overall health effects have remained underexplored.
When comparing GLP-1RA users to those taking other diabetes medications, researchers using data from the U.S. Department of Veterans Affairs (VA) databases discovered that GLP-1RAs were associated with higher risks of pancreatitis, kidney problems, and gastrointestinal problems but lower risks of infections, mental health problems, neurocognitive disorders, and cardiometabolic problems.
In this Nature Medicine study, a team of three researchers—Yan Xie, PhD, Taeyoung Choi, and Ziyad Al-Aly, MD—from the VA St. Louis Health Care System used a discovery approach to systematically evaluate the effectiveness and risks of incident GLP-1RA use on a comprehensive set of 175 health outcomes. Xie, Choi, and Al-Aly examined the relationship between GLP-1RA use and incident use of three common antihyperglycemic medications: sodium-glucose cotransporter-2 (SGLT2) inhibitors, dipeptidyl peptidase 4 (DPP4) inhibitors, and sulfonylureas. They also examined a composite control group that comprised an equal percentage of people who had incident use of these three antihyperglycemics, as well as a control group of people who continued their previous non-GLP-1RA antihyperglycemic regimen without undergoing any new treatment (usual care).
This study followed nearly two million individuals over a median of 3.68 years, mapping the associations between GLP-1RA use and 175 health outcomes. GLP-1RAs showed broad effects beyond current understanding, reducing risks for substance use disorders, neurocognitive conditions (like Alzheimer’s and dementia), seizures, cardiovascular and renal issues, and respiratory illnesses. They also demonstrated potential neuroprotective, anti-inflammatory, and antithrombotic properties.
Notable neuropsychiatric findings included reduced risks of substance use disorders, psychotic disorders, and suicidal ideation, aligning with experimental and clinical data suggesting antidepressive and antipsychotic effects. GLP-1RAs also lowered risks of dementia and Alzheimer’s, with ongoing trials expected to provide further evidence. Additionally, reduced seizure risks suggest potential anticonvulsant benefits. Cardiovascular and renal benefits were consistent with prior studies, showing lower risks of heart failure, stroke, kidney disease, and thromboembolic conditions.
Adverse effects included gastrointestinal issues, hypotension, syncopal episodes, joint pain, kidney stones, interstitial nephritis, and drug-induced pancreatitis, warranting careful monitoring. Overall, the findings highlight the multifaceted effects of GLP-1RAs, suggesting potential roles in managing diverse conditions while emphasizing the need for ongoing research and vigilant clinical use.
Although this study used extensive data from the U.S. Department of Veterans Affairs and examined 175 health outcomes in a diverse cohort of almost two million people, its generalizability is limited by its population, primarily older white males. However, it did include significant representation of women, younger people, and people from various racial backgrounds. Xie, Choi, and Al-Aly write that potential confounding or misclassification biases cannot be entirely ruled out, and the focus on drug classes rather than individual GLP-1RAs may overlook within-class differences.
Importantly, this observational study does not demonstrate the causality of GLP-1RA benefits or risks. Despite these limitations, the study confirms prior findings and uncovers new benefits and risks of GLP-1RAs. These results provide valuable insights for clinical care, pharmacovigilance, and further research to investigate the broad effects of GLP-1RAs, including their potential to address specific outcomes and mechanistic pathways.
Xie, Choi, and Al-Aly suggest that future research should explore the broad effects of GLP-1RAs on treating multiple coexisting conditions, especially those involving obesity or related pathways. Given the overlap between biological pathways affected by SARS-CoV-2 and GLP-1RAs, the authors propose that studies should also assess their potential in preventing and treating COVID-19-related complications, such as cardiovascular and neurological issues.
