Cited by 300Diabetes Treatment and ManagementDiabetes Management and ResearchPharmacology and Obesity Treatment

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Mapping the effectiveness and risks of GLP-1 receptor agonists

Xie, Yan, Choi, Taeyoung, Al-Aly, Ziyad·2025·Nature Medicine

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Abstract

Glucagon-like peptide 1 receptor agonists (GLP-1RAs) are increasingly being used to treat diabetes and obesity. However, their effectiveness and risks have not yet been systematically evaluated in a comprehensive set of possible health outcomes. Here, we used the US Department of Veterans Affairs databases to build a cohort of people with diabetes who initiated GLP-1RA (n = 215,970) and compared them to those who initiated sulfonylureas (n = 159,465), dipeptidyl peptidase 4 (DPP4) inhibitors (n = 117,989) or sodium-glucose cotransporter-2 (SGLT2) inhibitors (n = 258,614), a control group composed of an equal proportion of individuals initiating sulfonylureas, DPP4 inhibitors and SGLT2 inhibitors (n = 536,068), and a control group of 1,203,097 individuals who continued use of non-GLP-1RA antihyperglycemics (usual care). We used a discovery approach to systematically map an atlas of the associations of GLP-1RA use versus each comparator with 175 health outcomes. 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.

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Authors: Xie, Y., Choi, T., & Al-Aly, Z.
Affiliations: Washington University in St. Louis (US)
VA St. Louis Health Care System (US)
ORCID: Xie, Yan
Choi, Taeyoung
Al-Aly, Ziyad
Venue: Nature Medicine
Publisher: Springer Science and Business Media LLC
Published: 2025-01-20
Volume: 31
Issue: 3
Pages: 951-962
ISSN: 1078-8956 (ISSN-L)
1546-170X
DOI: 10.1038/s41591-024-03412-w
OpenAlex: W4406602151
Cited by: 300
References: 110
Citations by year: 2026: 137 · 2025: 161
FWCI: 203.24
Type: journal article
Language: en
Update notices: correction (2025-01-31)
Open access: closed
Licence: www.springernature.com/gp/researchers/text-and-data-mining (tdm)
www.springernature.com/gp/researchers/text-and-data-mining (vor)
Locations: Nature Medicine (publishedVersion)
PubMed (publishedVersion)
Funders: U.S. Department of Veterans Affairs
Topics: Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
Health Sciences › Medicine › Pharmacology (medical) › Pharmacology and Obesity Treatment
Keywords: GLP-1 receptor agonists, diabetes mellitus, obesity, drug safety, adverse drug reactions, sulfonylureas, DPP-4 inhibitors, SGLT2 inhibitors, substance use, psychosis, seizures, neurocognitive disorders, Alzheimer's disease, dementia, gastrointestinal diseases, drug-induced pancreatitis, kidney stones, interstitial nephritis, veterans
MeSH terms: Glucagon-Like Peptide-1 Receptor, Sodium-Glucose Transporter 2 Inhibitors, Glucagon-Like Peptide-1 Receptor Agonists, Aged, Diabetes Mellitus, Type 2, Female, Humans, Hypoglycemic Agents, Male, Middle Aged, Sulfonylurea Compounds, United States, United States Department of Veterans Affairs, Treatment Outcome, Dipeptidyl-Peptidase IV Inhibitors

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