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

Nov 19, 2025Diabetes, obesity & metabolism

Effectiveness and safety of glucagon-like peptide 1 drugs for all health outcomes in type 2 diabetes

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Abstract

GLP-1 receptor agonists (GLP-1RAs) were linked to a 46% reduction in body weight among type 2 diabetes patients.

Use of GLP-1RAs was associated with a lower risk of heart failure (odds ratio 0.71) and peripheral artery disease (0.75), both with low certainty.
Specific GLP-1RAs, such as liraglutide, albiglutide, and dulaglutide, showed protective effects against major cardiovascular events, myocardial infarction, and stroke.
Reduced risk of kidney-related outcomes was observed, including a composite kidney-specific outcome (odds ratio 0.76) and nephropathy (0.74), with low certainty.
No significant association between GLP-1RAs and cancer risk was found.
Common gastrointestinal adverse events included nausea, dyspepsia, and constipation, with varying levels of certainty regarding their occurrence.
GLP-1RAs were also linked to increases in bone mineral density at the lumbar spine (odds ratio 1.99) and hip-neck (1.79), both with low certainty.

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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 () 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.

Key numbers

0.71

Reduced Risk of Heart Failure

for heart failure with GLP-1RAs

0.74

Reduced Risk of Nephropathy

for nephropathy with GLP-1RAs

9.62

Increased Risk of Nausea

for nausea with GLP-1RAs

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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

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