Efficacy and safety of glucagon-like peptide 1 receptor agonists across all health outcomes in type 2 diabetes: An umbrella review and evidence map of randomised controlled trials

Abstract

Aim: Glucagon-like peptide 1 receptor agonists (GLP-1RAs) have been established as effective treatments for type 2 diabetes, offering benefits beyond glycaemic control; however, their associations across multiple health outcomes remain insufficiently assessed. Thus, we conducted an umbrella review of meta-analyses of randomised controlled trials (RCTs) to comprehensively evaluate the broad spectrum of their effects. Materials and Methods: We conducted a systematic search of PubMed/MEDLINE, Embase, CINAHL, and Google Scholar through June 13, 2025, to identify meta-analyses of RCTs assessing the effects of GLP-1RAs on various health outcomes, including cardiovascular, renal, metabolic, oncologic, gastrointestinal and other domains. Effect sizes were recalculated using random-effects models and converted to equivalent odds ratios (eORs) with 95% confidence intervals (CIs) for consistency. The methodological quality of each review was assessed using the AMSTAR 2, and the certainty of evidence for each association was evaluated according to the Grading of Recommendations, Assessment, Development and Evaluation framework (high, moderate, low or very low certainty). We preregistered our study protocol with PROSPERO (CRD420251112823). Results: After applying predefined inclusion and exclusion criteria, 17 studies comprising 432 RCTs were included, covering 65 unique outcomes across 6 clinical domains. GLP-1RAs use was associated with reduced risks of heart failure (eOR, 0.71 [95% CI, 0.64–0.79]; low certainty) and peripheral artery disease (0.75 [0.67–0.84]; low certainty). Drug-specific analyses exhibited protective effects of liraglutide (eOR, 0.86 [95% CI, 0.80–0.91]), albiglutide (0.65 [0.47–0.89]), and dulaglutide (0.78 [0.68–0.90]) for major cardiovascular events, myocardial infarction and stroke, respectively. Renal outcomes indicated that GLP-1RAs use was associated with reducing the risk of kidney-specific composite outcomes (eOR, 0.76 [95% CI, 0.66–0.87]; low certainty), including nephropathy (0.74 [0.61–0.92]; low certainty) and albuminuria (0.73 [0.55–0.97]; very low certainty). GLP-1RAs were also associated with reductions in body weight (eOR, 0.46 [95% CI, 0.36–0.60]; moderate certainty) and glycated haemoglobin A1c (0.83 [0.71–0.97]; high certainty), but no substantial association with cancer risk was found. Gastrointestinal adverse events, including nausea (9.62 [4.60–20.10]; high certainty), dyspepsia (4.85 [1.52–15.45]; moderate certainty), and constipation (3.39 [1.54–7.47]; high certainty), were consistently reported. GLP-1RAs use was associated with higher lumbar spine (eOR, 1.99 [95% CI, 1.38–2.85]; low certainty) and hip-neck bone mineral density (1.79 [1.08–2.98]; low certainty). Conclusions: In this study, GLP-1RAs were associated with cardiovascular, renal, and metabolic benefits in type 2 diabetes without increasing cancer risk, though gastrointestinal adverse events were common. Our findings support the clinical use of GLP-1RAs, with attention to individual risk profiles and treatment tolerability.