GLP-1 Receptor Agonists and Noncardiometabolic Outcomes: An Umbrella Review of Meta-Analyses.

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are foundational therapies for type 2 diabetes and obesity. Beyond established cardiometabolic benefits, GLP-1 RAs' associations with noncardiometabolic outcomes remain uncertain. To evaluate the associations between GLP-1 RAs and noncardiometabolic outcomes, and to appraise the certainty and credibility of the supporting evidence. A systematic search of PubMed, Web of Science, Embase, Scopus, and the Cochrane Database of Systematic Reviews was conducted from database inception to January 15, 2026. Eligible studies were systematic reviews with meta-analyses of randomized clinical trials evaluating GLP-1 RAs and outcomes beyond glycemic control, weight management, and major cardiorenal end points. This umbrella review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guideline. For each eligible meta-analysis, relevant data were extracted by 2 independent reviewers at both the meta-analysis level and individual study level. Data were reanalyzed using random-effects models to estimate odds ratios (ORs) and 95% CIs. The primary outcomes were noncardiometabolic outcomes across gastrointestinal, adverse event (AE), cancer, fracture, respiratory, neurologic, psychiatric, hepatic, and endocrine domains. Methodological quality was appraised via AMSTAR 2 (A Measurement Tool to Assess Systematic Reviews). Evidence certainty was categorized using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) framework and prespecified credibility criteria. A total of 60 meta-analyses representing 116 unique adverse health outcomes were included, comprising 1751 randomized clinical trials and 3 580 616 participants. The study populations primarily involved people with type 2 diabetes (43 [71.7%]) and obesity (20 [33.3%]), with follow-up durations ranging from 3 months to 5.4 years or longer. The most consistent signals were for gastrointestinal AEs, with higher odds of nausea (OR, 2.47 [95% CI, 1.84-3.34]; GRADE: high quality of evidence), vomiting (OR, 2.78 [95% CI, 1.91-4.06]; GRADE: moderate quality of evidence), and diarrhea (OR, 1.94 [95% CI, 1.52-2.49]; GRADE: high quality of evidence), although between-study heterogeneity and 95% prediction intervals suggested residual uncertainty. Infection-related outcomes suggested possible protective associations, particularly for serious infections (OR, 0.89 [95% CI, 0.87-0.92]; GRADE: high quality of evidence), and a suggestive association was observed for incident respiratory disease (OR, 0.85 [95% CI, 0.80-0.92]). Other outcomes, including gastrointestinal disease and biliary events (eg, gallbladder or biliary disease: OR, 1.34 [95% CI, 1.16-1.55]), did not meet stringent credibility thresholds and should be considered exploratory. In this umbrella review of meta-analyses, evidence for most noncardiometabolic outcomes associated with GLP-1 RAs was of lower certainty. Potential safety signals were observed for gastrointestinal AEs, while suggested protective associations with respiratory diseases and serious infections require further confirmation.