GLP-1 Receptor Agonists and Noncardiometabolic Outcomes

Importance: 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. Objective: To evaluate the associations between GLP-1 RAs and noncardiometabolic outcomes, and to appraise the certainty and credibility of the supporting evidence. Data Sources: 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. Study Selection: 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. Data Extraction and Synthesis: 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. Main Outcomes and Measures: 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. Results: 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. Conclusions and Relevance: 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.