Comprehensive evaluation of GLP-1 receptor agonists: an umbrella review of clinical outcomes across multiple diseases

Domain: neuroscience
Published: 2026-01-07
Editorial outcome: major_revision

Abstract
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) were initially approved for type 2 diabetes mellitus. Recent evidence suggests their therapeutic potential in various diseases, though their efficacy and safety remain incompletely understood. Here, we conduct an umbrella review including 123 meta-analyses covering 464 outcomes from 5617 articles to comprehensively assess the effectiveness and adverse events (AEs) of GLP-1 RAs across diverse outcomes. GLP-1 RAs showed trends toward improvements in endocrine and metabolic, cardiovascular, renal, and respiratory outcomes, cognitive function, with a potential reduction in fracture risk and all-cause mortality in certain populations. However, increased risks of certain AEs, including diabetic retinopathy, ketoacidosis, gastrointestinal events, and treatment discontinuation, were also observed. AMSTAR 2 assessments indicate that the existing evidence is limited by methodological shortcomings, including incomplete reporting of excluded studies, suboptimal literature search strategies, and insufficient evaluation of how bias in primary studies may influence meta-analytic estimates. Some outcomes did not reach statistical significance in all populations, highlighting the need for further high-quality clinical research. Careful consideration of potential benefits and risks is essential for optimizing treatment outcomes and ensuring patient safety when using GLP-1 RAs in clinical practice.

Introduction
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a class of drugs that mimic the effects of endogenous gut-derived incretin hormone GLP-11. These agents primarily exert their effects through specific binding to GLP-1 receptors, thereby stimulating G protein Gs-mediated signaling pathways2. The currently approved GLP-1 RAs include exenatide, liraglutide, lixisenatide, dulaglutide, and semaglutide3. Additionally, several novel GLP-1 RAs, including efpeglenatide, ecnoglutide, and orforglipron, are under development and have entered preclinical and clinical trials. GLP-1 RAs were initially approved for the treatment of type 2 diabetes mellitus (T2DM). However, further research has revealed their therapeutic potential across various diseases and health conditions. Exenatide, the first FDA-approved GLP-1 RA in 2005, was derived from Gila monster venom4. In 2010, liraglutide—97% homologous to human GLP-1—was approved first for diabetes and later for obesity in 2014, while semaglutide, also a modified GLP-1 analogue, now treats both conditions5. Multiple clinical studies have demonstrated that semaglutide effectively induces weight loss, establishing it as an effective anti-obesity treatment for individuals with overweight or obesity6,7. The weight reduction effect of GLP-1 RAs has gained global attention, prompting researchers to explore their potential in managing other diseases.

In 2023, a pooled analysis of two clinical trials investigated the impact of semaglutide on individuals with obesity and heart failure (HF) with preserved ejection fraction. The results showed that semaglutide significantly improved both weight and HF-related clinical symptoms8. Moreover, a large-scale randomized controlled trial (RCTs) involving more than 17,000 individuals with obesity and cardiovascular disease demonstrated that semaglutide reduced the risk of cardiovascular death, myocardial infarction (MI), and stroke compared to the placebo9. In addition to cardiovascular outcomes, GLP-1 RAs have been studied in various fields, including endocrine disorders, renal diseases, and neurological conditions, generating encouraging findings in these areas. Consequently, GLP-1 RAs were recognized by Science as the top scientific breakthrough in 2023, highlighting their current and future significance as a research hotspot10.

Despite significant progress in GLP-1 RA research, their adverse events (AEs) should not be ignored. Gastrointestinal side effects, such as nausea and vomiting, have been reported, along with concerns about an increased risk of intestinal obstruction and pancreatitis11,12. However, some clinical evidences have presented conflicting evidence, suggesting that the AEs of GLP-1 RAs may not be as severe or widespread as initially thought. A growing body of meta-analyses examines the overall or specific therapeutic efficacy of GLP-1 RAs across various diseases. Yet overlapping analyses of variable quality complicate drawing definitive, comprehensive conclusions.

In this work, we systematically evaluate the therapeutic efficacy and AEs of GLP-1 RAs across multiple disease areas through an umbrella review of meta-analyses. We show that GLP-1 RAs improve endocrine and metabolic, cardiovascular, renal, respiratory, and cognitive outcomes, and reduce all-cause mortality in certain populations. However, their use is associated with increased risks of specific AEs, and some outcomes do not reach statistical significance across all populations, although the direction of effects remains largely consistent. Overall, GLP-1 RAs demonstrate promising clinical benefits across multiple domains, while further large-scale and high-quality studies are warranted to confirm these findings and elucidate the underlying mechanisms.

Results
Characteristics of included meta-analyses
A total of 5617 articles were retrieved from five databases. After deduplication and screening based on inclusion and exclusion criteria, 123 meta-analyses (115 based on RCTs and 8 based on observational studies) with 464 outcomes were included in this umbrella review (Fig. 1, Supplementary data 1). These outcomes were categorized into endocrine and metabolic outcomes, cardiovascular outcomes, cancer outcomes, renal outcomes, respiratory outcomes, mortality and AEs, and other outcomes. Only statistically significant results are presented in the main text, while non-significant findings are reported in Supplementary information.

Detailed AMSTAR 2 and GRADE assessments are provided in supplementary data 2 and 3. The median AMSTAR 2 score for the included meta-analyses was 23 (range: 7–32; interquartile range: 19–26). Several critical domains showed consistently low ratings. Item 7 (whether a list of excluded primary studies with justification was provided) received the lowest scores, with only eight reviews explicitly presenting such a list. While most reviews reported the total number of excluded primary studies and general exclusion criteria, few provided detailed justifications for individual exclusions. This omission, possibly due to space limitations, compromises the transparency and reproducibility of the evidence synthesis process. Item 4 (whether a comprehensive literature search strategy was used) was also frequently rated as partially met, as most meta-analyses did not clarify whether grey literature was searched when appropriate or whether experts in the field were consulted. These omissions may have led to incomplete retrieval of relevant primary studies and introduced selection bias. Additionally, Item 12 (whether the impact of risk of bias in individual primary studies on the meta-analysis results was assessed) also received relatively low scores. Many meta-analyses failed to adequately explore how bias in the primary studies may have influenced the overall findings, thereby undermining the robustness and credibility of the synthesized results. To further evaluate the reliability of the evidence, we assessed the degree of overlap among systematic reviews using the CCA method (Supplementary data 4). Although some primary studies were included in multiple meta-analyses, the overall level of overlap was low, indicating a limited impact of duplicate data. However, overlapping primary studies were predominantly concentrated in a limited number of large-scale, frequently cited RCTs in the field of GLP-1 RAs - such as LEADER, SUSTAIN, EXSCEL, HARMONY Outcomes, REWIND, ELIXA, SELECT, PIONEER, AWARD, AMPLITUDE, LEAD, SCALE, and STEP.

Endocrine and metabolic outcomes
A total of 41 meta-analyses (118 outcomes) evaluated GLP-1 RAs for endocrine and metabolic outcomes (Fig. 2, supplementary table 1, supplementary data 5). Evidence classification showed that one outcome was Class I (0.8%), one outcome was Class III (0.8%), 86 were Class IV (73%), and the rest were NS. The GRADE assessment rated 24 outcomes (20%) as High, 17 (14%) as Moderate, 25 (21%) as Low, and 52 (44%) as Very Low. Among 41 meta-analyses, 6 did not report primary studies. The CCA for the remaining meta-analyses was 1.32%, indicating a slight level of overlap.

Liver enzyme profiles: For clarity, we synthesize legacy labels (NAFLD/NASH and MAFLD) under the current steatotic liver disease (SLD) framework—MASLD (formerly NAFLD) and MASH (formerly NASH). Across the SLD spectrum, GLP-1 RAs demonstrated modest but directionally consistent improvements in liver enzyme profiles (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]), with 4 of the 7 ALT outcome estimates showing significant reductions, and 4 of the 9 AST outcome estimates showing significant reductions. For transparency, the following results are presented according to the original terminology used in the included meta-analyses. In drug-specific analyses, exenatide was associated with reductions in ALT (Class IV; High) and AST (Class IV; Low) among persons labeled NAFLD/NASH. At the drug-class level, ALT decreased in NAFLD, NAFLD or NASH, and T2DM with NAFLD (all Class IV; Very Low), while AST decreased in MAFLD, NAFLD, and T2DM with NAFLD (all Class IV; Very Low).

BMI and Body Weight: GLP-1 RAs were associated with notable reductions in both body mass index (BMI) and body weight across a wide range of populations. Of the 24 reported BMI outcomes, 18 showed significant reductions, and 30 of the 33 reported body-weight outcomes were significant. At the class level, GLP-1 RAs reduced BMI in individuals with Alzheimer’s disease (AD) or mild cognitive impairment (MCI) (Class IV; High), those overweight/obesity and psychotic disorders (Class IV; High), individuals with polycystic ovary syndrome (PCOS) (Class IV; High), PCOS with overweight (Class IV; High), T2DM with NAFLD (Class IV; Moderate), adolescents with overweight/obesity (Class IV; Low), MAFLD (Class IV; Very Low), and T2DM (Class IV; Very Low). For body weight, significant reductions were observed in individuals with overweight/obesity (Class I; Low), youth with T2DM (Class IV; High), premenopausal women with PCOS and overweight/obesity (Class IV; Moderate), adolescents with overweight/obesity (Class IV; Low), individuals with psychotic disorders receiving antipsychotic medications and having overweight/obesity (Class IV; Low), T1DM (Class IV; Low), NAFLD or NASH (Class IV; Very Low), NAFLD (Class IV; Very Low), T2DM with NAFLD (Class IV; Very Low), and T2DM with obesity (Class IV; Very Low). Detailed single-drug findings are provided in Supplementary Materials 2.

Hemoglobin A1c (HbA1c): Among 27 outcome estimates, 24 showed significant reductions in HbA1c. At the class level, GLP-1 RAs significantly reduced HbA1c in individuals with T2DM and severe chronic kidney disease (CKD) (Class IV; High), youth with T2DM (Class IV; High and Moderate), individuals with T1DM (Class IV; Low), individuals with T2DM and NAFLD (Class IV; Low), individuals with NAFLD or NASH (Class IV; Very Low), and individuals with T2DM and obesity (Class IV; Very Low). Detailed single-drug findings are provided in Supplementary Materials 2.

Hepatic Fat Accumulation: GLP-1 RAs were associated with reductions in hepatic steatosis, as reflected by decreases in intrahepatic fat accumulation (IHA) and liver fat content (LFC), both of which are measures of hepatic lipid deposition. Among 1 IHA outcome estimate, 1 showed a significant reduction; among 6 LFC outcome estimates, 5 showed significant reductions. GLP-1 RAs significantly reduced IHA in individuals with T2DM and NAFLD (Class IV; Very Low). For LFC, significant reductions were observed in individuals with MAFLD (Class IV; High), NAFLD (Class IV; Moderate), T2DM (Class IV; Very Low), and NAFLD or NASH (Class IV; Very Low). In analyses of semaglutide as a single agent, LFC was significantly reduced in individuals with NAFLD (Class IV; Very Low).

Diabetic Ketoacidosis and Ketosis: In individuals with T1DM, GLP-1 RAs were associated with an increased risk of ketosis, including diabetic ketoacidosis (DKA) (Class IV; Low). However, analyses of single-drug agent interventions found that neither exenatide nor liraglutide significantly affected the risk of DKA in individuals with T1DM, indicating insufficient evidence to support a definitive protective or harmful effect at the individual drug level.

Diabetic Retinopathy: Evidence from eight outcomes assessing diabetic retinopathy risk yielded predominantly non-significant findings. One meta-analysis reported a statistically significant increase in risk, whereas the remaining seven showed no significant associations. Across drug-specific analyses, liraglutide, lixisenatide, semaglutide, and albiglutide generally showed no significant associations. In one RCT, albiglutide 30 mg was associated with an increased risk of retinopathy (Class IV; High), while albiglutide 50 mg showed no significant effect.

Cardiovascular outcomes
A total of 52 meta-analyses (covering 141 outcomes) evaluated GLP-1 RAs for cardiovascular outcomes (Fig. 3, supplementary table 2, supplementary data 6). Evidence classification indicated that ten outcomes were Class III (7%), 50 were Class IV (35%), and the rest were NS. The GRADE assessment rated 36 outcomes (26%) as High, 34 (24%) as Moderate, 31 (22%) as Low, and 40 (28%) as Very Low. Among 52 meta-analyses, 7 did not report primary studies. The CCA for the remaining meta-analyses was 2%, indicating a slight level of overlap.

Stroke-related outcomes: GLP-1 RAs were associated with a reduced risk of stroke, including non-fatal and fatal subtypes. Among 17 outcome estimates, 6 reported significant reductions. Significant reductions were observed in individuals with cardiovascular disease or at high cardiovascular risk (Class IV; Low), and in individuals with T2DM (Class IV; Low-Very Low). Specifically, non-fatal stroke risk was reduced in individuals with cardiovascular disease/high-risk populations (Class IV; Low), and in individuals with T2DM and established atherosclerotic cardiovascular disease (ASCVD) or high cardiovascular risk (Class IV; Moderate). GLP-1 RAs also significantly lowered fatal stroke risk in individuals with T2DM (Class IV; High).

MI: GLP-1 RAs showed a trend toward a reduced risk of myocardial infarction (MI), including acute subtypes. Among 18 outcome estimates, 4 reported significant reductions. Significant reductions in MI risk were observed in individuals with T2DM (Class IV; High), individuals with overweight or obesity without diabetes (Class III; High), and those without cardiovascular disease or at high cardiovascular risk (Class IV; Very Low). Additionally, liraglutide significantly reduced the risk of acute myocardial infarction (AMI) in individuals with T2DM (Class IV; High).

HF-related outcomes: GLP-1 RAs showed a trend toward a reduced risk of hospitalization for heart failure (HF). Among 20 outcome estimates, 4 reported significant reductions. Significant effects were observed in individuals with diabetes excluding T1DM/GDM (Class IV; High), individuals with T2DM (Class IV; High), and individuals without a history of HF (Class IV; Moderate). In meta-analyses of observational studies, GLP-1 RAs also reduced the risk of HF hospitalization individuals with T2DM without serious cardiovascular events (Class IV; Very Low).

Atherosclerotic/Ischemic outcomes: GLP-1 RAs were associated with a reduced risk of revascularization in individuals with overweight or obesity without diabetes (Class III; High), and a reduced risk of peripheral artery disease in individuals with T2DM (Class IV; Low).

Composite cardiovascular outcomes: GLP-1 RAs were associated with overall cardiovascular benefits across multiple populations. Among the outcome estimates, significant reductions were reported in 13 of 17 for major adverse cardiovascular events (MACE), 5 of 8 for cardiovascular mortality, 3 of 4 for cardiovascular disease (CVD) events, 1 of 3 for cardiovascular death, and 1 of 1 for composite cardiovascular outcomes. These benefits were observed in individuals with T2DM, those with established cardiovascular disease or at high cardiovascular risk, and in individuals with or without a history of HF. Collectively, GLP-1 RAs reduced the risks of MACE, composite cardiovascular outcomes, CVD events, and cardiovascular mortality (Class III–IV; Very Low to High). Full stratified findings are provided in Supplementary Materials 2.

Myocardial injury and function: Among the outcome estimates, significant benefits were reported in 4 of 8 for left ventricular ejection fraction (LVEF), 10 of 17 for systolic blood pressure (SBP), 5 of 12 for LDL cholesterol, and 1 of 1 for final infarct size. GLP-1 RAs improved LVEF in individuals with acute myocardial infarction (AMI) (Class IV; Very Low). Liraglutide, as an individual agent, significantly improved LVEF in individuals with AMI (Class IV; Moderate), MI (Class IV; Moderate), and T2DM with coronary artery disease (CAD) (Class IV; High). SBP reductions were observed in individuals with overweight/obesity, T2DM, and T1DM. Exenatide, liraglutide, and semaglutide were effective in individuals with overweight or obesity (Class IV–III; Moderate to High), while dulaglutide, liraglutide, and semaglutide were effective in those with T2DM (Class IV; Low to High), including those with concomitant obesity (Class IV; Low). Liraglutide also lowered SBP in individuals with T1DM (Class IV; High). GLP-1 RAs reduced LDL cholesterol in multiple populations with metabolic disorders, including individuals with overweight or obesity and antipsychotic-treated psychotic disorders (Class IV; High), non-diabetic individuals treated with semaglutide (Class IV–III; High to Moderate), and individuals with NASH receiving liraglutide (Class IV; Low). In individuals with T2DM and CAD, liraglutide also showed LDL-lowering effects, though with very low evidence certainty (Class IV; Very Low).

Cancer outcomes
Eight meta-analyses (covering 31 outcomes) evaluated GLP-1 RAs for cancer outcomes (Fig. 4A, supplementary data 7). Evidence classification indicated that one outcome was Class IV (3%), and the rest were NS. The GRADE assessment rated three outcomes (10%) as High, 15 (48%) as Moderate, seven (23%) as Low, and six (19%) as Very Low. Among 8 meta-analyses, 4 did not report primary studies. The CCA for the remaining meta-analyses was 8.93%, indicating a moderate level of overlap. Most outcomes were classified as NS, indicating that GLP-1 RAs have no overall effect on cancer risk. However, compared to placebo or active drugs, GLP-1 RAs were associated with a reduced risk of prostate neoplasm in individuals with T2DM (Class IV, High).

Renal outcomes
Eleven meta-analyses (17 outcomes) evaluated GLP-1 RAs for renal outcomes (Fig. 4B, supplementary data 8). Evidence classification indicated that one outcome was Class II (6%), three outcome was Class III (18%), five were Class IV (29%), and the rest were NS. The GRADE assessment rated seven outcomes (41%) as High, three (18%) as Moderate, five (29%) as Low, and two (12%) as Very Low. Among 11 meta-analyses, 3 did not report primary studies. The CCA for the remaining meta-analyses was 10.58%, indicating a high level of overlap. GLP-1 RAs showed a trend toward improvements in renal damage markers and albuminuria indicators, and toward reduced risks of renal failure and composite renal outcomes across various populations. Detailed outcome-specific results, including effect estimates and stratification by population, are provided in Supplementary Materials 2.

Respiratory outcomes
11 meta-analyses (covering 24 outcomes) evaluated GLP-1 RAs for respiratory outcomes (Fig. 4C, supplementary data 9). Evidence classification indicated that five were Class IV (21%), and the rest were NS. The GRADE assessment rated five outcomes (21%) as High, four (17%) as Moderate, 13 (54%) as Low, and two (8%) as Very Low. Among 11 meta-analyses, 4 did not report primary studies. The CCA for the remaining meta-analyses was 20.83%, indicating a very high level of overlap. In individuals with T2DM and high cardiovascular risk, GLP-1 RAs reduced the risk of pneumonia (Class IV; Low). In individuals with COVID-19 and T2DM, use of GLP-1 RAs was linked to a lower risk of hospitalization (Class IV; High), risk of severe manifestations (Class IV; High), and mortality (Class IV; Very Low). Similarly, in individuals with diabetes and SARS-CoV-2 infection, GLP-1 RAs were associated with decreased mortality risk (Class IV; Moderate).

Mortality and AEs
In all, 48 meta-analyses (covering 101 outcomes) evaluated GLP-1 RAs for mortality and AEs (Fig. 5, supplementary Table 3, supplementary data 10). Evidence classification indicated that three outcomes were Class I (3%), one outcome was Class II (1%), 13 outcomes were Class III (13%), 23 outcomes were Class IV (23%), and the rest were NS. The GRADE assessment rated 29 outcomes (29%) as High, 14 (14%) as Moderate, 18 (18%) as Low, and 40 (40%) as Very Low. Non-significant results were primarily observed for pancreatitis, severe hypoglycemia, and serious adverse events (SAEs). Among 48 meta-analyses, 2 did not report primary studies. The CCA for the remaining meta-analyses was 1.39%, indicating a slight level of overlap.

AEs: GLP-1 RAs showed a trend toward an increased risk of AEs across multiple populations. Among 16 outcome estimates, 9 reported significant associations. Significant associations were observed in individuals with T1DM (Class III; Very Low), individuals with T2DM (Class III; Low), and women with PCOS and overweight (Class IV; High). Individual agent analyses showed a consistent increase in AE risk with liraglutide, semaglutide, lixisenatide and dulaglutide across individuals with diabetes and obesity.

All-Cause Mortality: GLP-1 RAs showed a trend toward reduced all-cause mortality across diverse populations. Among 15 outcome estimates, 8 reported significant reductions. Significant associations were observed in individuals with T2DM (Class III–IV; High), including those with ASCVD or high cardiovascular risk (Class III; Moderate), and those without a history of HF (Class IV; Low). Similar reductions were reported in individuals with cardiovascular disease (Class IV; Moderate) or at high cardiovascular risk (Class IV; Low). Among individual agents, liraglutide demonstrated a consistent mortality benefit in individuals with T2DM (Class IV; Very Low), consistent with the class effect.

Discontinuation Due to AEs: GLP-1 RAs were associated with an increased risk of treatment discontinuation due to AEs. Among 17 outcome estimates, 13 reported significant associations. Significant increases were observed in individuals with overweight/obesity (Class IV; High), those with obesity and obesity-related comorbidities without diabetes (Class III; Very Low), and individuals with T1DM (Class III; Very Low). Among individual agents, semaglutide, liraglutide, dulaglutide, exenatide, efpeglenatide, and lixisenatide all demonstrated similar trends of increased discontinuation risk in various diabetic and non-diabetic individuals with overweight.

Gastrointestinal AEs: GLP-1 RAs were associated with an increased risk of gastrointestinal AEs in both diabetic and non-diabetic populations. Among 10 outcome estimates, 6 reported significant associations. Elevated risks were observed in individuals with overweight or obesity (Class I–IV; Low to High), individuals with T1DM (Class I; High), and individuals with T2DM (Class II–III; Very Low to High). Among individual agents, semaglutide showed consistently high risk of gastrointestinal AEs in individuals with T2DM (Class II; High), non-diabetic individuals with overweight or obesity (Class I; High), and individuals with overweight/obesity without T2DM (Class III; High). Liraglutide also increased gastrointestinal AEs in individuals with overweight or obesity (Class IV; Low).

Hypoglycemia: GLP-1 RAs showed a trend toward an increased risk of hypoglycemia across several populations. Among 12 outcome estimates, 4 reported significant associations. Elevated risks were observed in individuals with T1DM (Class IV; Low to High), and in youths with T2DM aged 10–18 years (Class IV; High). Among individual agents, liraglutide significantly increased the risk of hypoglycemia in individuals with T1DM (Class IV; High), while semaglutide was associated with a higher risk of hypoglycemia in individuals with overweight/obesity (Class III; High).

Other outcomes
Twenty meta-analysis (covering 32 outcomes) evaluated GLP-1 RAs for other outcomes (Fig. 4D, supplementary table 4, supplementary data 11). Evidence classification indicated that one outcome was Class I (3%), eight were Class IV (25%), and the rest were NS. The GRADE assessment rated 15 outcomes (47%) as High, six (19%) as Moderate, three (9%) as Low, and eight (25%) as Very Low. GLP-1 RAs showed a trend toward favorable neurological outcomes, including improved cognitive function in individuals with AD/MCI, reduced dementia risk in individuals with T2DM, and improvements in Parkinson’s disease scores. However, they were linked to an increased risk of headache in women with PCOS. Additionally, GLP-1 RAs reduced the risks of genital infections and bone fractures in individuals with T2DM. Detailed outcome-specific results across individual groups and agents are presented in Supplementary Materials 2.

Methods
Umbrella review methods
This umbrella review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and is prospectively registered with PROSPERO (CRD42024585231).

Literature search
Data were systematically searched across five databases: PubMed, Embase, Web of Science, the Cochrane Database of Systematic Reviews, and Epistemonikos, with the search conducted up to August 26, 2024. The search strategy combined subject headings and free-text terms related to GLP-1 RAs. Representative terms included: (“GLP-1 RAs” OR “liraglutide” OR “semaglutide” OR “exenatide” OR “dulaglutide” OR “albiglutide”) AND (“systematic review” OR “meta-analys*”). The complete search strategies tailored for each database are provided in Supplementary Materials 1. All retrieved articles were imported into EndNote X9 for deduplication and subsequent screening. F.K. and Y.Z. independently reviewed the titles, abstracts, and full texts of the articles according to the inclusion criteria, and any disagreements were resolved through discussion with W.Z. and X.W. Additionally, the reference lists of all included meta-analyses were manually searched to ensure that no relevant meta-analyses were overlooked.

Eligibility criteria
Inclusion criteria were summarized according to the PICOS principle: (1) P (Participants): No restriction on diseases; but participants in each meta-analysis must have the same condition; (2) I (Intervention): GLP-1 RAs as a whole or as a single drug; (3) C (Comparison): Comparators included placebo alone, active non-GLP-1 RA drugs alone, or both placebo and active comparators; (4) O (Outcomes): Dichotomous and/or continuous variables; (5) S (Study Design): Meta-analyses of RCTs or observational studies. Network meta-analyses were also eligible if they provided direct pairwise comparisons between GLP-1 RAs and relevant control groups.

For meta-analyses reporting multiple drugs or outcomes, data were extracted separately. If meta-analyses were identical in type, intervention, participants, and outcomes, selection was based on: (1) publication year (most recent if >24 months apart); (2) number of included trials (highest if ≤24 months apart); (3) AMSTAR 2 score (highest if trials were identical); (4) evidence quality and population size if AMSTAR 2 scores were identical58.

Exclusion criteria were: (1) non-English publications; (2) non-clinical research; (3) meta-analyses with heterogeneous participant conditions or GLP-1 RAs in the control group; (4) systematic reviews without meta-analyses; (5) network meta-analyses reporting only indirect comparisons.

Data extraction
F.K., Y.Z., and W.Z. independently extracted the following information from the included meta-analyses: first author, publication year, intervention type, study population, study design, number of included trials, number of participants, outcomes, effect model, effect size, heterogeneity, and publication bias. Any discrepancies were resolved by discussion between X.W. and T.W.

Evaluation of primary study overlap
To assess the potential risk of bias due to overlapping primary studies across the included meta-analyses, outcome indicators were first categorized by clinical system, and each outcome was assigned to a single system category.

For each system, a citation matrix was constructed, with rows representing unique primary studies and columns representing the included meta-analyses. Based on these matrices, the Corrected Covered Area (CCA) was calculated using the following formula:

CCA = N - r / r(c - 1)

Where N is the total number of primary study occurrences across all meta-analyses, r is the number of unique primary studies, and c is the number of meta-analyses. The degree of overlap was interpreted as slight (≤5%), moderate (6-10%), high (11-15%), or very high (>15%). All calculations were performed using Microsoft Excel 2019.

Quality assessment of methods and evidence
The methodological quality of the included meta-analyses was assessed using the AMSTAR 2 tool59. The GRADE approach was employed to systematically assess the certainty of evidence for each outcome. GRADE categorizes evidence quality into four levels: high, moderate, low, and very low60. Finally, the certainty of the outcomes was categorized into four classes based on evidence classification criteria: Class I (convincing evidence), Class II (highly suggestive evidence), Class III (suggestive evidence), Class IV (weak evidence), and NS (non-significant)58,61.

Data analysis
Given the broad range of conditions and outcomes assessed, all outcome indicators were categorized a priori by clinical system to facilitate a structured synthesis and interpretation. To further account for heterogeneity in the populations, interventions, and outcome definitions reported in the included meta-analyses, we performed a stratified synthesis. Specifically, outcomes were grouped and presented by clinical domain, individual population, and intervention type, as reported in the original meta-analyses.

Where meta-analysis-level data were available, we extracted effect sizes and 95% confidence intervals (CIs) and recalculated pooled estimates using a random-effects model. If unavailable, original pooled results were retained. Statistical significance was set at p < 0.05. Heterogeneity was assessed using I² and Cochran’s Q test and interpreted as low (I² ≤ 40%), moderate (30% < I² ≤ 60%), or high (I² ≥ 50%). All analyses and visualizations were conducted using R (v4.4.1) and RevMan (v5.3).

Ethics statement
Not needed.

Peer review rounds
[{"round": 1, "reviewer_comments": {"reviewer_1": "GLP-1 receptor agonists are important medications for obesity, type 2 diabetes, heart failure and chronic kidney disease.\nAssessing the benefits and harms of GLP-1 receptor agonists are interesting but this umbrella review including systematic\nreviews did not add novel information to a single systematic review including randomised trials. To be noted, although the\nstudy included many systematic reviews, it missed some important ones and thus the outcomes are far from comprehensive.\nThe stats methods are very crude and need assistance by stats experts.", "reviewer_2": "The authors did an umbrella review to comprehensively assess the effectiveness and adverse events (AEs) of GLP-1 RAs\nacross diverse outcomes. They found that GLP-1 RAs significantly improve outcomes across various diseases and health\nconditions, although several AEs warrant caution. Differences in study populations and drug types may contribute to\ninconsistencies in some outcome assessments.\nThe authors should be applauded for being able to piece together such a large amount of data. There are, however, some\npoints that could be improved and streamlined to allow the reader to have a clear message.\nABSTRACT\nAlthough it is clear to me that an umbrella review put together previous meta-analyses, this may not so evident for the mean\nreader, especially when the authors state:\n“After de-duplication and screening based on inclusion and exclusion criteria, 143 articles (134 RCTs and 9 observational\nstudies) with outcomes were included in this study.”\nThis may be misleading, suggesting that the authors have meta-analysed 134 randomised controlled trials (RCTs) and 9\nobservational studies.\nThe results section within the abstract is not well balanced. Only one line to summarize improvements of disease outcomes\nby GLP-1RAs and 5 lines to describe in detail all the negative effects (AEs). The reader might be led to imagine that the\nadverse effects far outweigh the benefits. This is also in contrast to the worldwide spread of this class of drugs.\n“The findings indicate that GLP-1 RAs generally improve most disease outcomes, independent on disease or drug types.\nHowever, it’s worth noting the negative effects, including increased risks of ketoacidosis, retinopathy, deep vein thrombosis,\nhematoma, aortic aneurysm, total arrhythmias, gallstone, acute cholecystitis, gastric ulcer bleeding, headache,\ngastrointestinal adverse events, pancreatitis, and drug discontinuation due to AEs.”\nMoreover, they should refer to the very recent published article on Nature Medicine by Xie et al. (Mapping the effectiveness\nand risks of GLP-1 receptor agonists. Nat Med 2025. https://doi.org/10.1038/s41591-024-03412-w) whose results provide\ninsights into the benefits and risks of GLP-1RAs and may be useful for informing clinical care and guiding research agendas.\nFIGURES\nFigures from the second one to onward are really hard to read.\nI realize the difficulty to translate in visual practice the huge quantity of information the authors had in their hands. However,\nmy feeling is that the way chosen by the authors to accomplish the task is not the best one to leave a message. For example,\nFigure 2 could be ameliorated by increasing the size of letters and numbers, reducing the width by putting in the legend\nEffect measure, evidence class, and GRADE.\nAlthough the exhaustive supplements offer a detailed view of all the meta-analyses evaluated, my fear is that the non-\nspecialist reader will get lost within the myriads of data that could distance him from clarity.\nDISCUSSION\nIt is very long and dispersive.\nAlthough I am clear about the authors' desire to describe all the outcomes and side effects, this inevitably translates into the\nfragmentation of the discussion that loses its logical thread. The authors must find the way to make clear the message they\nwish to give. This could be accomplished, for example, by putting into the Supplements some part of discussion that are not\nstrictly linked to its general assembly, in order to fluidify the narrative. In this way, the average reader will not give up before\nthe end.", "reviewer_3": "Thank you for giving me the opportunity to review this manuscript. My comments are below.\n• Summary: This umbrella review compares GLP-1 RAs to placebo/other drugs across a range of patient populations and\noutcomes. It found that GLP-1 RAs are effective in reducing mortality, improving neurological disorders, renal outcomes,\nrespiratory outcomes, and metabolic and endocrine outcomes, as well as demonstrating cardioprotective effects across a\nrange of patient populations. However, it was also noted that adverse events were often observed but often with only some\ntherapies in certain populations. Common adverse events included some cardiovascular risks, events related to the\ndigestive system and an increased risk of hypoglycaemia in those with diabetes.\n• Abstract: this is quite broad and somewhat vague, though this reflects the complexity of the evidence base included in the\nreview.\nMethods:\n• In my opinion, more information is needed to clarify if methodological approaches were appropriate in places. I also note\nwhere methodology could potentially be improved below.\n• Minor comment on use of terminology: be clear throughout if you are referring to systematic reviews/meta-analyses as the\nterm “studies” can be misleading.\n• Searches:\no You could have considered searching Epistemonikos, as one of the largest repositories of systematic reviews and meta-\nanalyses.\no There is no detailed search strategy given in the supplementary information. The terms listed in the text indicate quite a\nsimple search which could possibly have been improved with the use of further terms and/or truncation. Whilst the key meta-\nanalyses were likely found, there are concerns that some could potentially have been missed.\no Minor: be clear that you are referring to the Cochrane Database of Systematic Reviews.\n• Eligibility criteria:\no Population included any disease, but stated participants in each review must be the same population. However, there is\nsome ambiguity with this as some of the meta-analyses included had unspecified populations, which upon investigation,\noften included primary studies from a range of diseases (e.g. diabetes, overweight without diabetes etc.).\no Were just meta-analyses included? Or could systematic reviews without meta-analyses be included too? I wasn’t initially\nclear on this.\no It’s not entirely clear what “GLP-1 RAs as a whole or as a single drug” meant. Was this in combination with other drugs?\nPlease disregard this comment if there are clinical connotations that I am not aware of.\no Comparator is stated as those without GLP-1 RA but be clear that this also included placebo or an alternative drug.\no The statement about including network meta-analyses containing pairwise comparisons was somewhat unclear and\nfurther clarification is ideally needed.\n• It’s important to have an approach to handling the potential overlap of patient data within an umbrella review and this is\nclearly described in the methods.\n• Data analysis:\no Major: In my opinion, this section is very vague, and more detail is required to understand how the analyses were\nundertaken. This analysis could not be reproduced with this information. Further useful guidance can be found in the\nCochrane Handbook on undertaking an analysis in umbrella reviews (or overviews of reviews), as well as reporting these\nfindings (https://training.cochrane.org/handbook/current/chapter-v)\no It’s unclear how the data were reanalysed and more detail is needed. E.g. were the original systematic review data taken\nand presented, or were data extracted and reanalysed, if so, how was this done? In what instances were random effects or\nfixed effects models used? Were data from multiple reviews combined? Was clinical/methodological heterogeneity\nconsidered?\no It’s not entirely clear if any network meta-analyses were included, but if so, how were these handled?\no There is little information on how the broadness of the data were to be handled. E.g. there are many conditions and\noutcomes explored, but no discussion of how this was handled in subgroup analysis by condition or type of outcome. Did\nyou consider any sensitivity analyses based on the risk of bias findings? All of this should be clearly described in the\nmethods.\n• Results\no It’s slightly unclear what 143 articles (134 RCTs and 9 observational studies) refers to. What was the number of systematic\nreviews? Try and be consistent with wording throughout.\no Major: A large concern is the lack of description of the included systematic review characteristics, making it difficult to\nunderstand the evidence base and put the findings into context. How were the searches undertaken in the included reviews,\nhow many studies were included, what were the populations, outcomes, interventions (dose, delivery, duration etc.). Usually\nthis would be reported in some sort of table as per the Cochrane Handbook guidance. This further helps with interpretation\nof findings for the reader. I also noted that I couldn’t find a reference for all of the included systematic reviews/meta-analyses,\nwhich is something that should be done as standard and could easily be incorporated into a table of characteristics.\no In the results the categorisation of data by outcome is discussed, but this could have been described in the methods.\no Risk of bias: relying mostly on scores is not always sufficient to convey the risk of bias of the systematic reviews. A more\ndetailed narrative discussion could have been implemented. Furthermore, generalisability based on the included primary\nstudies could have been discussed.\no Major: Presentation of results: I think it might be useful to have some sort of table which conveys information on the number\nof systematic reviews/meta-analyses relating to each condition and outcome for each intervention type, as this is difficult to\ncomprehend from the text alone and would aid in understanding a very broad range of evidence.\no I think grouping the results by outcome type is an appropriate approach to try and handle the broad range of findings.\no It could be made clearer what GLP-1 RAs vs placebo/active control meant – did this indicate data from meta-analyses\nwhere they included studies which compared to both placebo or some sort of active control? If so make sure this is detailed\nin the methods.\no The unspecified populations could have been explored or detailed further to aid in understanding. Having looked at one of\nthe systematic reviews which was detailed as “unspecified population” (Rivera, 2024), the population of each individual\nstudy is listed and included mostly those with T2DM or those wanting to lose weight for example.\no Minor: ensure all abbreviations are defined at first use.\no The supplementary tables are generally useful and aid in understanding of the main text.\nDiscussion and conclusions:\n• This section is quite long, though this is reflective of the complexity and breadth of the evidence included.\n• It's acknowledged that some recent primary studies with important findings are not included in any meta-analyses meaning\nthey have not been included in this review and these are explored in the discussion. The evident heterogeneity of the\nincluded evidence, and therefore the limitations of the findings, are acknowledged somewhat.\n• The conclusions generally appear to align with the findings, though the broad evidence base sometimes makes it difficult\nto follow and better summaries could be implemented in places.\n• The risk of bias of the systematic reviews and also the studies within these could have been considered more in the\ndiscussion and interpretation of the findings."}, "author_response": "Point-by-Point Response\nDear Editors and Reviewers,\nWe appreciate the time and effort spent in reviewing our manuscript titled\n“Comprehensive Evaluation of GLP-1 Receptor Agonists: An Umbrella Review of\nClinical Outcomes Across Multiple Diseases” (Manuscript ID: NCOMMS-25-\n01334A-Z). We are grateful for the constructive comments, which have greatly helped\nus improve the quality of our umbrella review. We also sincerely thank the editors and\nreviewers for recognizing the innovation and extensive effort involved in our work,\nand for providing invaluable constructive feedback that has been instrumental in\nenhancing our manuscript. As the first and most comprehensive umbrella review\nsystematically evaluating both the efficacy and safety of GLP-1 receptor agonists\n(GLP-1 RAs) across a wide range of diseases, this study provides an extensive\nsynthesis of the current evidence and aims to inform future clinical practice and\nresearch. Guided by your valuable feedback, we have thoroughly revised the\nmanuscript, greatly improving its clarity, scientific rigor, and overall quality. Below,\nwe provide a detailed point-by-point response to each comment. All the revisions in\nthe manuscript have been highlighted in yellow in the “Revised Manuscript”.\nThe specific modifications are outlined below:\nReviewer #1\n1) Comment 01\n“Assessing the benefits and harms of GLP-1 receptor agonists are interesting but\nthis umbrella review including systematic reviews did not add novel information to a\nsingle systematic review including randomised trials.”\nReply:\nWe respectfully disagree with the reviewer’s statement, which we believe reflects\na misunderstanding of the purpose and value of an umbrella review. The aim of an\numbrella review is not to produce new effect estimates for individual outcomes—as\nsingle systematic reviews do—but rather to synthesize, reappraise, and grade the\nstrength and consistency of existing meta-analyses across a wide spectrum of diseases\nand outcomes. This higher-level evidence synthesis provides a cross-condition,\ncomparative perspective that cannot be achieved by any single systematic review1,2.\nThe core objectives of an umbrella review include: systematically comparing the\neffects of a given intervention across different disease contexts; evaluating the\nconsistency, robustness, and credibility of the available evidence; identifying research\ngaps; and providing high-level evidence to inform clinical decision-making and policy\nformulation.\nThis methodological framework has been extensively applied in high-impact\numbrella reviews3–10, and is now widely recognized as a valuable tool in evidence-\nbased medicine. It has been adopted across diverse domains including drug efficacy,\nnutritional epidemiology, lifestyle interventions, and environmental health research.\n1. Ioannidis, J. Next-generation systematic reviews: prospective meta-analysis, individual-level data,\nnetworks and umbrella reviews. Br J Sports Med 51, 1456–1458 (2017).\n2. Ioannidis, J. P. A. Integration of evidence from multiple meta-analyses: a primer on umbrella\nreviews, treatment networks and multiple treatments meta-analyses. CMAJ 181, 488–493 (2009).\n3. Huang, Y. et al. Dietary sugar consumption and health: umbrella review. BMJ 381, e071609\n(2023).\n4. Zhu, J. et al. Association of glucose-lowering medications with cardiovascular outcomes: an\numbrella review and evidence map. Lancet Diabetes Endocrinol 8, 192–205 (2020).\n5. Solmi, M. et al. Balancing risks and benefits of cannabis use: umbrella review of meta-analyses of\nrandomised controlled trials and observational studies. BMJ 382, e072348 (2023).\n6. Leichsenring, F., Steinert, C., Rabung, S. & Ioannidis, J. P. A. The efficacy of psychotherapies and\npharmacotherapies for mental disorders in adults: an umbrella review and meta-analytic\nevaluation of recent meta-analyses. World Psychiatry 21, 133–145 (2022).\n7. Sanders, T. et al. An umbrella review of the benefits and risks associated with youths’ interactions\nwith electronic screens. Nat Hum Behav 8, 82–99 (2024).\n8. Singh, B. et al. A systematic umbrella review and meta-meta-analysis of eHealth and mHealth\ninterventions for improving lifestyle behaviours. NPJ Digit Med 7, 179 (2024).\n9. Rouyard, T. et al. Effects of workplace interventions on sedentary behaviour and physical activity:\nan umbrella review with meta-analyses and narrative synthesis. Lancet Public Health 10, e295–\ne308 (2025).\n10. Sun, S., Simonsson, O., McGarvey, S., Torous, J. & Goldberg, S. B. Mobile phone interventions to\nimprove health outcomes among patients with chronic diseases: an umbrella review and evidence\nsynthesis from 34 meta-analyses. Lancet Digit Health 6, e857–e870 (2024).\n2) Comment 02\n“To be noted, although the study included many systematic reviews, it missed\nsome important ones and thus the outcomes are far from comprehensive.”\nReply:\nWe respectfully disagree with the reviewer’s comment, as it provides no specific\nexamples or citations to support the claim that “important” studies were omitted. In\nthe absence of such clarification, it is not possible to objectively assess which studies\nare being referred to, nor to evaluate the validity of the assertion that “the outcomes\nare far from comprehensive”.\nAs clearly outlined in our Methods section (Section 2.3), this umbrella review\nfollowed a rigorous and transparent selection process. Specifically, when multiple\nmeta-analyses were available for the same PICO framework, we included only the\nhighest-quality and most comprehensive one to represent that outcome. This is a well-\nestablished and widely endorsed methodological standard in umbrella reviews3,\ndesigned to prevent data duplication, overlapping populations, and inconsistent effect\nestimates.\nNotably, our umbrella review included 124 meta-analyses, covering 464 distinct\nclinical outcomes—making it, to our knowledge, the most comprehensive umbrella\nreview of GLP-1 RAs to date across a wide range of disease areas. Thus, the claim\nthat the outcomes are “far from comprehensive” does not accurately reflect the\nbreadth and depth of the current evidence base. That said, we acknowledge—as\ndiscussed in the manuscript (page 33-34)—that in certain emerging areas, some\nrecent primary studies have not yet been incorporated into meta-analyses. We have\nalready cited several such studies and expanded this section in the revised version to\nhighlight ongoing developments and evidence gaps in the field (pages 33-34, lines\n550-575).\n3) Comment 03\n“The stats methods are very crude and need assistance by stats experts.”\nReply:\nWe respectfully but firmly disagree with the reviewer’s characterization of our\nstatistical methods as “very crude.” The statistical approach adopted in this umbrella\nreview adheres to internationally recognized standards for evidence synthesis and has\nbeen widely applied in high-impact umbrella reviews. Specifically, our analysis\nincluded: Where study-level data were available, we extracted effect sizes and 95%\nconfidence intervals (CIs) and recalculated pooled estimates using a random-effects\nmodel. If unavailable, original pooled results were retained. Heterogeneity was\nassessed using I² and Cochran’s Q test. Study overlap was calculated using the\ncorrected covered area (CCA). We also assessed methodological quality and evidence\nstrength using AMSTAR 2, GRADE, and evidence class.\nThese methods fully comply with internationally accepted methodological\nguidelines (e.g., the Cochrane Handbook) and have been widely employed in\numbrella reviews published in high-impact journals.\nWe also noted that the reviewer’s comment was overly broad and lacked\nspecificity, making it challenging to identify any concrete methodological issues that\ncould be addressed effectively.\nNevertheless, we acknowledge that the description of certain statistical\nprocedures in the original manuscript may have been insufficiently detailed,\npotentially contributing to the reviewer’s impression. Therefore, we have revised and\nexpanded the “Methods” section to ensure greater clarity and transparency, aligning\nwith best practices in umbrella review methodology (pages 7-8, lines 128-161). We\nhope these revisions will dispel any concerns about the scientific rigor of our methods.\nReviewer #2\n1) Comment 01\n“Although it is clear to me that an umbrella review put together previous meta-\nanalyses, this may not so evident for the mean reader, especially when the authors\nstate: “After de-duplication and screening based on inclusion and exclusion criteria,\n143 articles (134 RCTs and 9 observational studies) with outcomes were included in\nthis study.” This may be misleading, suggesting that the authors have meta-analysed\n134 randomised controlled trials (RCTs) and 9 observational studies.”\nReply:\nWe thank the reviewer for the insightful comment. The sentence has been revised\nto clarify that only meta-analyses were included, not individual trials or observational\nstudies. The updated text reads: “After de-duplication and screening based on\ninclusion and exclusion criteria, 124 meta-analyses (116 based on RCTs and 8 based\non observational studies) with 464 outcomes were included in this umbrella review.”\nThe corresponding part has been revised in the manuscript (lines 164–167), as\nreflected in the updated version.\n2) Comment 02\n“The results section within the abstract is not well balanced. Only one line to\nsummarize improvements of disease outcomes by GLP-1RAs and 5 lines to describe\nin detail all the negative effects (AEs). The reader might be led to imagine that the\nadverse effects far outweigh the benefits. This is also in contrast to the worldwide\nspread of this class of drugs.”\nReply:\nWe thank the reviewer for this valuable comment and suggestion. The abstract\nresults section has been thoroughly revised to provide a more balanced and\ncomprehensive summary of both positive and negative findings. The revised abstract\nnow includes a clearer and more proportional summary of the efficacy of GLP-1 RAs\nacross various disease outcomes, ensuring that the positive therapeutic benefits are\nappropriately emphasized alongside adverse events. The corresponding part has been\nrevised in the manuscript (lines 31–39), as reflected in the updated version.\n3) Comment 03\n“Moreover, they should refer to the very recent published article on Nature\nMedicine by Xie et al. (Mapping the effectiveness and risks of GLP-1 receptor\nagonists. Nat Med 2025. https://doi.org/10.1038/s41591-024-03412-w) whose results\nprovide insights into the benefits and risks of GLP-1RAs and may be useful for\ninforming clinical care and guiding research agendas.”\nReply:\nWe thank the reviewer for recommending this recently published high-quality\nstudy. We have carefully reviewed the article by Xie et al. in Nature Medicine and\nhave incorporated relevant citations and comparisons in the Discussion section of the\nrevised manuscript. By contrasting their findings with ours, we have further refined\nour comprehensive interpretation of the efficacy and risks of GLP-1 RAs, enhancing\nthe clinical relevance and practical guidance of our study. The corresponding part has\nbeen supplied and refined in the revised manuscript (lines 567-575), as reflected in\nthe updated version.\n4) Comment 04\n“Figures from the second one to onward are really hard to read. I realize the\ndifficulty to translate in visual practice the huge quantity of information the authors\nhad in their hands. However, my feeling is that the way chosen by the authors to\naccomplish the task is not the best one to leave a message. For example, Figure 2\ncould be ameliorated by increasing the size of letters and numbers, reducing the width\nby putting in the legend Effect measure, evidence class, and GRADE.”\nReply:\nWe thank the reviewer for the valuable feedback on figure readability. Following\nthe suggestion, we have redesigned Figure 2 and the subsequent figures by\nappropriately increasing the size of letters and numbers, optimizing the aspect ratio,\nand replacing some textual explanations with symbols and legends. These adjustments\nimprove the overall clarity and efficiency of information delivery, making the figures\nmore intuitive and easier to understand.\n5) Comment 05\n“Although the exhaustive supplements offer a detailed view of all the meta-\nanalyses evaluated, my fear is that the non-specialist reader will get lost within the\nmyriads of data that could distance him from clarity. ”\nReply:\nWe thank the reviewer for the valuable suggestion regarding the readability of\nthe supplementary materials. We have reorganized the tables in the supplementary\nfiles by adding an overview table summarizing the basic characteristics of all included\nstudies, with unique numbering assigned to each study to facilitate quick navigation\nfor readers. Additionally, the comprehensive results tables in the supplements have\nbeen reordered according to outcome indicators, patient types, and intervention drugs\nto enhance logical flow and ease of reference.\nMeanwhile, we have optimized the Results section in the main manuscript by\nsummarizing outcome indicators by system, avoiding repetitive listing of every\nindividual effect size and confidence interval, which are already presented in detail in\nthe figures for intuitive understanding. In the Discussion section, we have also\ncondensed key findings for each system, making it easier for readers to grasp overall\ntrends and main conclusions. We believe these revisions significantly improve the\nstructural clarity and readability of the content, addressing the needs of both specialist\nand non-specialist readers.\nThe corresponding parts have been revised in the manuscript (lines 184–424;\n434-473; 482-513) and in the supplementary files Supplementary Material 1 and\nSupplementary Tables 3–9, as reflected in the updated materials.\n6) Comment 06\n“It is very long and dispersive. Although I am clear about the authors' desire to\ndescribe all the outcomes and side effects, this inevitably translates into the\nfragmentation of the discussion that loses its logical thread. The authors must find the\nway to make clear the message they wish to give. This could be accomplished, for\nexample, by putting into the Supplements some part of discussion that are not strictly\nlinked to its general assembly, in order to fluidify the narrative. In this way, the\naverage reader will not give up before the end.”\nReply:\nWe thank the reviewer for acknowledging the comprehensiveness of our study\nand for the constructive suggestion to improve the narrative flow. Following your\nadvice, we have structurally optimized the Discussion section by retaining only the\ncontent directly related to our primary findings in the main text, while moving\ndetailed analyses of secondary outcomes to the supplementary materials, where they\nare briefly summarized in the main discussion. Additionally, background information\nand extended discussions not essential to the central narrative have also been\nrelocated to the supplements. We believe these adjustments enhance the coherence\nand logical progression of the main text, enabling readers to better follow the core\nmessage and improving the overall fluency of the manuscript. The corresponding\nparts have been revised in the manuscript (lines 434-473; 482-513) and in the\nsupplementary files Supplementary Material 3-5, as reflected in the updated\nmaterials.\nReviewer #3\n1) Comment 01\n“Abstract: this is quite broad and somewhat vague, though this reflects the\ncomplexity of the evidence base included in the review.”\nReply:\nWe thank the reviewer for this valuable comment. The abstract has been\nsubstantially revised to improve specificity and clarity while maintaining conciseness.\nThe revised abstract now provides detailed information on the therapeutic benefits of\nGLP-1 RAs across endocrine/metabolic, cardiovascular, renal, respiratory, cognitive,\nand fracture outcomes, as well as all-cause mortality, along with a balanced\ndescription of key adverse events. This updated version more precisely reflects the\nscope and findings of the umbrella review and aims to enhance clarity for readers. The\ncorresponding part has been revised in the manuscript (lines 31–39), as reflected in\nthe updated version.\n2) Comment 02\n“Methods: Minor comment on use of terminology: be clear throughout if you are\nreferring to systematic reviews/meta-analyses as the term “studies” can be misleading.”\nReply:\nWe thank the reviewer for this valuable suggestion. The terminology has been\ncarefully revised throughout the manuscript to clearly distinguish between the\numbrella review itself and the included meta-analyses. Specifically, the term “studies”\nhas been replaced with “meta-analyses” or “umbrella review” where appropriate, to\navoid any potential confusion.\n3) Comment 03\n“Methods: You could have considered searching Epistemonikos, as one of the\nlargest repositories of systematic reviews and meta-analyses.”\nReply:\nWe thank the reviewer for this important suggestion regarding the\ncomprehensiveness of our literature search. We fully acknowledge the significant\nvalue of the Epistemonikos database in aggregating systematic reviews and meta-\nanalyses from multiple major sources, including the Cochrane Database of Systematic\nReviews, PubMed, EMBASE, CINAHL, and PsycINFO, which ensures broad\ncoverage.\nIn response to the reviewer’s recommendation, we have included Epistemonikos\ndatabase in our search. The search was conducted following our original strategy to\nensure comprehensive and systematic coverage of relevant literature. Details of the\nupdated search strategy and results have been added to the Methods section of the\nrevised manuscript (lines 92-97), and the complete revised search strategy is provided\nin Supplementary material 1.\n4) Comment 04\n“Methods: There is no detailed search strategy given in the supplementary\ninformation. The terms listed in the text indicate quite a simple search which could\npossibly have been improved with the use of further terms and/or truncation. Whilst\nthe key meta-analyses were likely found, there are concerns that some could\npotentially have been missed.”\nReply:\nWe thank the reviewer for this valuable comment and fully understand the\nimportance of providing a detailed and transparent search process to ensure\ncomprehensive literature coverage and research reproducibility. In the original\nsubmission, we were unable to include the complete search strategies for all databases\ndue to manuscript length limitations. However, during the study, we systematically\nsaved and documented the detailed search strategies for each database.\nIn the revised manuscript, we have now provided the complete search strategies\nfor the five databases—PubMed, Embase, Web of Science, Cochrane Database of\nSystematic Reviews, and Epistemonikos—in Supplementary material 1. We hope\nthis addition will enhance the transparency and systematic nature of our methodology.\n5) Comment 05\n“Methods: be clear that you are referring to the Cochrane Database of Systematic\nReviews.”\nReply:\nWe thank the reviewer for this helpful comment. We confirm that our literature\nsearch indeed included the Cochrane Database of Systematic Reviews. In the revised\nmanuscript, we have explicitly specified the full name of this database in the Methods\nsection (line 92) to improve the accuracy and clarity of our expression, ensuring\nclearer understanding of the search sources for readers.\n6) Comment 06\n“Methods: Eligibility criteria: Population included any disease, but stated\nparticipants in each review must be the same population. However, there is some\nambiguity with this as some of the meta-analyses included had unspecified\npopulations, which upon investigation, often included primary studies from a range of\ndiseases (e.g. diabetes, overweight without diabetes etc.).”\nReply:\nWe thank the reviewer for raising this important issue. To comprehensively cover\nthe existing evidence, we initially included some meta-analyses labeled as having\n“unspecified populations” and provided a preliminary discussion of their potential\nstrengths and limitations: on one hand, they can broaden the scope of the analysis;\non the other hand, since these meta-analyses often include primary studies with\nheterogeneous patient populations (e.g., combining diabetes and overweight without\ndiabetes), they may introduce substantial confounding, affecting the accuracy and\ninterpretability of the results.\nIn response to the reviewer’s valuable comment, we re-examined all included\nmeta-analyses and their primary studies individually. Meta-analyses involving\npopulations with inconsistent disease types were excluded. For those with\nhomogeneous populations but lacking clear specification in the original articles, we\nrevised their descriptions from “unspecified population” to the actual disease type\nwherever possible, ensuring a more consistent and homogeneous analytical basis.\nAs a result of these revisions, 19 meta-analyses (covering 241 outcomes) were\nexcluded, leading to a final inclusion of 124 meta-analyses with 464 outcomes.\nAlthough the exclusion of meta-analyses involving heterogeneous populations led to\nsome changes in the pooled conclusions for certain outcomes, the main findings for\nthe majority of outcomes remained consistent. We believe these adjustments\nsubstantially improve the methodological rigor and clarity of our analysis, and we\nhave updated the relevant sections of the Methods, Results, and Discussion.\n7) Comment 07\n“Methods: Were just meta-analyses included? Or could systematic reviews\nwithout meta-analyses be included too? I wasn’t initially clear on this.”\nReply:\nWe thank the reviewer for raising this important point regarding our inclusion\ncriteria. As stated in the Eligibility criteria section of the Methods (“Meta-analyses of\nrandomized controlled trials (RCTs) or observational studies, including network\nmeta-analyses containing direct comparisons”), our study included only systematic\nreviews that contained quantitative pooled analyses (i.e., meta-analyses).\nWe did not include systematic reviews that were purely qualitative without\nconducting meta-analyses. This criterion is based on current methodological\nconsensus for umbrella reviews, which emphasizes the necessity of including studies\nwith extractable effect sizes and confidence intervals to enable subsequent evidence\ngrading, heterogeneity analysis, and bias assessment. In the revised manuscript, we\nhave further clarified this point in the Methods section (lines 109-111; 120-121) to\nenhance the precision of our description and avoid potential misunderstandings\namong readers.\n8) Comment 08\n“Methods: It’s not entirely clear what “GLP-1 RAs as a whole or as a single drug”\nmeant. Was this in combination with other drugs? Please disregard this comment if\nthere are clinical connotations that I am not aware of.”\nReply:\nWe thank the reviewer for raising this question. GLP-1 RAs refer to a class of\ndrugs that includes several individual agents, such as liraglutide, semaglutide, and\nothers. In our study, we included both meta-analyses that assessed GLP-1 RAs as a\nwhole class and those focusing on a single specific drug (e.g., meta-analyses\nanalyzing only liraglutide or only semaglutide).\nThis approach was intended to capture the overall therapeutic trends of the entire\nGLP-1 RA class while also preserving potential differences and heterogeneity among\nindividual agents, thereby enhancing the interpretability of the results and providing a\nmore comprehensive understanding of the effects of GLP-1 RAs.\n9) Comment 09\n“Methods: Comparator is stated as those without GLP-1 RA but be clear that this\nalso included placebo or an alternative drug.”\nReply:\nWe thank the reviewer for this valuable comment. In our study, the “non–GLP-1\nRA comparator group” included placebo alone, active non–GLP-1 RA drugs alone, or\na combination of placebo and active comparators. To improve accuracy and\nconsistency, we have clarified in the revised Methods section that comparator groups\nmay consist of placebo, active drugs, or both, and we have separately presented\nresults comparing GLP-1 RAs against these different types of comparators. This\nclarification ensures that readers fully understand the composition of the comparator\ngroups and helps avoid potential misunderstandings. The corresponding part has been\nrevised in the manuscript (lines 107–108), as reflected in the updated version.\n10) Comment 10\n“Methods: The statement about including network meta-analyses containing\npairwise comparisons was somewhat unclear and further clarification is ideally\nneeded.”\nReply:\nWe thank the reviewer for this valuable comment. In the manuscript, we\nmentioned the inclusion of “network meta-analyses containing pairwise comparisons”,\nwhich may have been unclear to readers. We would like to clarify that our study did\ninclude some network meta-analyses; however, we only extracted data on direct\ncomparisons between GLP-1 RAs and comparator groups, and did not use any results\nderived solely from indirect comparison pathways.\nIn the revised Methods section, we have further specified that network meta-\nanalyses were included only if they provided extractable direct comparison data\nmeeting our predefined inclusion criteria. We also explicitly stated that we excluded\nall results based solely on indirect comparisons, ensuring that the effect estimates\nincluded in our analysis were supported by direct evidence, thereby enhancing the\ninterpretability and methodological robustness of our findings. The corresponding part\nhas been revised in the manuscript (lines 109-111; 120-121), as reflected in the\nupdated version.\n11) Comment 11\n“Methods: It’s important to have an approach to handling the potential overlap of\npatient data within an umbrella review and this is clearly described in the methods.”\nReply:\nWe thank the reviewer for this valuable comment and great suggestion. We fully\nagree on the importance of addressing potential overlap of primary study data in\numbrella reviews and greatly appreciate the reviewer’s emphasis on enhancing\nmethodological transparency and reproducibility. In our study, we explicitly defined\nthe PICO framework for populations, interventions, comparators, and outcomes, and\napplied predefined inclusion and exclusion criteria. When multiple systematic reviews\nwere available for the same outcome, we included only the meta-analysis with the\nhighest methodological quality. Therefore, each included outcome corresponds to a\nrelatively independent PICO question, forming distinct analytical units and\nminimizing the risk of duplicate data inclusion at the individual outcome level.\nHowever, we acknowledge that the same primary studies may still contribute to\nmultiple meta-analyses across different outcomes, potentially leading to overlapping\ndata across outcomes. To more comprehensively control for this potential source of\nbias, we identified and coded all primary studies included in the selected meta-\nanalyses and calculated the Corrected Covered Area (CCA) at the disease-system\nlevel to assess the degree of overlap of primary studies across different outcomes. The\ncorresponding parts have been revised in the manuscript (lines 128–140; 176-178;\n187–188; 254-256; 320-322; 337-338; 348-350; 364-366) and the Supplementary\nCCA file, as reflected in the updated version.\n12) Comment 12\n“Methods: Data analysis: In my opinion, this section is very vague, and more\ndetail is required to understand how the analyses were undertaken. This analysis could\nnot be reproduced with this information. Further useful guidance can be found in the\nCochrane Handbook on undertaking an analysis in umbrella reviews (or overviews of\nreviews), as well as reporting these findings\n(https://training.cochrane.org/handbook/current/chapter-v)”\nReply:\nWe thank the reviewer for this valuable comment and helpful recommendation\nregarding the need for greater detail in the Data Analysis section. This concern is\nclosely related to Comment 13, and we have addressed both comments together by\nthoroughly revising and expanding the Data Analysis section in the Methods. We have\nensured that the updated description aligns with the guidance provided in the\nCochrane Handbook to enhance the transparency and reproducibility of our analyses.\n13) Comment 13\n“Methods: It’s unclear how the data were reanalysed and more detail is needed.\nE.g. were the original systematic review data taken and presented, or were data\nextracted and reanalysed, if so, how was this done? In what instances were random\neffects or fixed effects models used? Were data from multiple reviews combined? Was\nclinical/methodological heterogeneity considered?”\nReply:\nWe thank the reviewer for this valuable comment and great suggestion. In\nresponse, we provide a unified explanation below and have included corresponding\nclarifications in the revised Methods section of the manuscript.\nOur analysis followed the Cochrane Handbook (Chapter V) and methodologies\napplied in several high-quality published umbrella reviews. Where original study-\nstudy level data were available within the included systematic reviews, we extracted these\ndata and reanalyzed them. Specifically, for outcomes with accessible primary study\ndata, we extracted all relevant data and recalculated pooled effect estimates,\n95% confidence intervals, heterogeneity (I²), and overall p-values using the DerSimonian–\nLaird random-effects model. If primary data were not available, we retained the\npooled estimates reported in the original meta-analyses. All reanalyses employed\nrandom-effects models to account for potential variability between studies.\nImportantly, we did not combine results from multiple systematic reviews into\nnew pooled estimates; instead, each outcome indicator from each meta-analysis was\ntreated as an independent analytical unit to avoid double counting. All data analyses\nand visualizations were performed using R (version 4.4.1) and Review Manager\n(version 5.3).\nRegarding control of clinical and methodological heterogeneity, we strictly\nadhered to the PICO framework (uniform populations, interventions, comparators,\nand outcomes) during study selection and data extraction to minimize heterogeneity\nrisk at the outset. The use of random-effects models in our reanalysis further\naccounted for potential between-study variability.\nTo enhance transparency and robustness, we also conducted three key\nassessments: Methodological quality assessment of systematic reviews (AMSTAR 2)\nto identify any design flaws or bias in included reviews; Statistical evidence\nclassification (Evidence Class) based on criteria such as sample size, p-values,\nprediction intervals, heterogeneity, and small-study effects; Confidence in evidence\nassessment (GRADE), evaluating risk of bias, inconsistency, indirectness, imprecision,\nand publication bias for each outcome. These complementary assessments provided a\nmultidimensional grading of the results in terms of review quality, statistical support,\nand evidence credibility, thereby strengthening the systematic nature, clinical\ninterpretability, and scientific rigor of our study.\nIn summary, our analytical approach ensured independence of outcomes,\nmethodological robustness, and reproducibility of conclusions. This information has\nbeen comprehensively updated and clarified in the revised Methods section.\n14) Comment 14\n“Methods: It’s not entirely clear if any network meta-analyses were included, but\nif so, how were these handled?”\nReply:\nWe thank the reviewer for this valuable comment and great suggestion. Our\nstudy did include some network meta-analyses; however, we extracted only the data\non direct comparisons between GLP-1 RAs and comparator groups. Effect estimates\nbased on indirect comparisons or network-derived estimates were excluded from our\nanalysis.\nDuring the data extraction process, we carefully examined each outcome in each\nincluded network meta-analysis to determine the type of comparison. We extracted\nand reanalyzed data only when the comparison was explicitly identified as a direct\ncomparison with clearly distinguishable intervention and comparator groups. If it was\nunclear whether an estimate represented a direct comparison or if the result was\nderived from network modeling of indirect comparisons, we excluded those outcomes\nto avoid incorporating data with high uncertainty or increased methodological\nheterogeneity. This approach has been further clarified in the revised Methods section.\nThe corresponding part has been revised in the manuscript (lines 109–111; 120–121),\nas reflected in the updated version.\n15) Comment 15\n“There is little information on how the broadness of the data were to be handled.\nE.g. there are many conditions and outcomes explored, but no discussion of how this\nwas handled in subgroup analysis by condition or type of outcome. Did you consider\nany sensitivity analyses based on the risk of bias findings? All of this should be\nclearly described in the methods.”\nReply:\nThank you for this insightful comment. We have revised the Methods section to\nclarify our approach to handling the broad range of conditions and outcomes: “Given\nthe wide range of conditions and outcomes included, outcomes were categorized a\npriori by clinical system (e.g., cardiovascular, endocrine/metabolic, renal, cancer, and\nadverse events) to facilitate structured synthesis and interpretation. To further\naccount for heterogeneity in study populations, interventions, and outcome definitions\nacross the included meta-analyses, we conducted a stratified synthesis. Specifically,\noutcomes were grouped and presented by clinical domain, patient population, and\nintervention type, as reported in the original meta-analyses.” Although we did not\nperform formal subgroup analyses, this stratified synthesis provided a transparent\napproach to managing heterogeneity.\nRegarding sensitivity analyses, we applied a stringent PICO-based selection\nprocess, including only the most comprehensive and methodologically robust meta-\nanalysis per question to minimize bias. Across similar outcomes, the direction and\nsignificance of effects were largely consistent, supporting the robustness of our\nfindings. Additionally, we conducted a comprehensive methodological quality\nassessment using AMSTAR 2 and, as per your suggestion, we now include an\nevaluation of study overlap to assess the independence and breadth of the evidence.\nThese revisions have been incorporated into the updated Methods and Discussion\nsections.\n16) Comment 16\n“It’s slightly unclear what 143 articles (134 RCTs and 9 observational studies)\nrefers to. What was the number of systematic reviews? Try and be consistent with\nwording throughout.”\nReply:\nWe thank the reviewer for highlighting this ambiguity. We have revised the\nwording throughout the manuscript to clearly state that our umbrella review included\n124 meta-analyses (116 based on RCTs and 8 based on observational studies)\ncomprising 464 outcomes. The revised sentence now reads (lines 164-167): “After de-\nduplication and screening based on inclusion and exclusion criteria, 124 meta-\nanalyses (116 based on RCTs and 8 based on observational studies) with 464\noutcomes were included in this umbrella review.”\n17) Comment 17\n“A large concern is the lack of description of the included systematic review\ncharacteristics, making it difficult to understand the evidence base and put the\nfindings into context. How were the searches undertaken in the included reviews, how\nmany studies were included, what were the populations, outcomes, interventions\n(dose, delivery, duration etc.). Usually this would be reported in some sort of table as\nper the Cochrane Handbook guidance. This further helps with interpretation of\nfindings for the reader. I also noted that I couldn’t find a reference for all of the\nincluded systematic reviews/meta-analyses, which is something that should be done\nas standard and could easily be incorporated into a table of characteristics.”\nReply:\nWe thank the reviewer for highlighting the lack of a consolidated description of\nthe included meta-analyses characteristics. Although we previously provided relevant\ninformation in the supplementary materials, including the number of primary studies,\nstudy populations, interventions, and outcomes covered by each systematic review,\nwe recognize that this information was dispersed across multiple supplementary tables,\nwhich may have hindered readers’ ability to gain a comprehensive understanding of\nthe evidence base.\nIn response to the reviewer’s valuable suggestion, we have added a unified table\nsummarizing the key characteristics of all included meta-analyses in the revised\nmanuscript (see Supplementary table 1). This consolidated table presents essential\ninformation for each included meta-analyses, including article ID, first author,\npublication year, number of included studies, characteristics of the study populations,\nintervention details, comparator type, and primary outcomes. This addition will help\nreaders better understand the context and heterogeneity of the included evidence,\nthereby enhancing the interpretability of our findings.\nFurthermore, we have included complete references for all included meta-\nanalyses within this summary table to ensure clear citation of sources, in line with\nstandard reporting practices for systematic reviews and umbrella reviews, and to\nfurther improve the transparency and completeness of our study.\n18) Comment 18\n“In the results the categorisation of data by outcome is discussed, but this could\nhave been described in the methods.”\nReply:\nWe thank the reviewer for this constructive suggestion. In the revised manuscript,\nwe have clarified in the Methods section that outcomes were categorized by system\n(e.g., endocrine/metabolic, cardiovascular, renal, cancer, etc.) to improve the structure\nand clarity of the results presentation. The corresponding part has been revised in the\nmanuscript (lines 129-131; 150-155), as reflected in the updated version.\n19) Comment 19\n“Risk of bias: relying mostly on scores is not always sufficient to convey the risk\nof bias of the systematic reviews. A more detailed narrative discussion could have\nbeen implemented. Furthermore, generalisability based on the included primary\nstudies could have been discussed.”\nReply:\nWe thank the reviewer for this professional and insightful suggestion. In the\nrevised manuscript, we have added a more detailed narrative discussion based on the\nAMSTAR 2 ratings, highlighting common methodological biases identified in the\nincluded meta-analyses and discussing their potential impact on the reliability of our\nconclusions. Additionally, in line with your recommendation, we conducted an\nanalysis of study overlap. Our findings revealed that several large randomized\ncontrolled trials on GLP-1 RAs (e.g., LEADER, SUSTAIN-6, EXSCEL) were\nincluded multiple times across different meta-analyses, resulting in some overlap\namong primary studies. Although we applied strict PICO-based criteria to retain only\none representative meta-analysis per outcome, this overlap could still introduce some\nrisk of bias. Our analysis and discussion of these issues have been incorporated into\nthe revised Discussion section (lines 518-543).\n20) Comment 20\n“Presentation of results: I think it might be useful to have some sort of table\nwhich conveys information on the number of systematic reviews/meta-analyses\nrelating to each condition and outcome for each intervention type, as this is difficult to\ncomprehend from the text alone and would aid in understanding a very broad range of\nevidence.”\nReply:\nWe thank the reviewer for this valuable suggestion. As this study is an umbrella\nreview, we rigorously screened systematic reviews addressing the same PICO\nquestions and retained only the highest-quality meta-analysis for each, ensuring that\neach result corresponds to a distinct disease–intervention–comparator–outcome\ncombination.\nTo enhance clarity regarding the relationships among intervention types,\noutcome indicators, and study populations, we have reorganized the results tables in\nthe supplementary materials. Specifically, outcomes are now grouped by clinical\nsystem, and within each system, results are systematically ordered by outcome\nindicator, study population, and intervention type. This structured layout facilitates a\nclearer understanding of the distribution and characteristics of the included evidence.\nThe full set of results is available in the revised Supplementary Tables 3–9.\nIn the main text, we present only statistically significant results for clarity and\nconciseness. Class-level effects of GLP-1 RAs are shown in Figures 2–5, while drug-\nspecific effects are summarized in Tables 1–4. This presentation strategy allows for a\nmore intuitive comparison of therapeutic effects across both drug classes and\nindividual agents.\n21) Comment 21\n“I think grouping the results by outcome type is an appropriate approach to try\nand handle the broad range of findings.”\nReply:\nWe sincerely thank the reviewer for this positive comment. We are pleased that\nour approach of grouping the results by outcome type was considered appropriate.\n22) Comment 22\n“It could be made clearer what GLP-1 RAs vs placebo/active control meant – did\nthis indicate data from meta-analyses where they included studies which compared to\nboth placebo or some sort of active control? If so make sure this is detailed in the\nmethods.”\nReply:\nWe thank the reviewer for this valuable comment. We recognize that our original\nmanuscript did not clearly define the term “GLP-1 RAs vs placebo/active control”,\nwhich could lead to misunderstanding among readers. In the revised Methods section,\nwe have added clarification under the “Comparators (C)” subsection, explicitly\nstating: “Comparators included placebo alone, active non–GLP-1 RA drugs alone, or\nboth placebo and active comparators.” In our data extraction and analysis, we\nretained and analyzed data from all three comparator types to provide a\ncomprehensive assessment of the efficacy and safety evidence for GLP-1 RAs.\nAdditionally, to improve the logical flow and integration of the results, we\noptimized the structure of the Results section. While the original manuscript primarily\norganized results by clinical system, it further stratified within each system by\ncomparator type, which led to fragmented presentation of the same outcome\nindicators. In the revised manuscript, we maintained the system-based categorization\nbut reorganized the content within each system to summarize outcomes by specific\noutcome indicators rather than splitting them by comparator type. This adjustment\nenhances the coherence of results for each indicator across different study conditions,\nthereby improving interpretability and reader comprehension. The corresponding part\nhas been revised in the manuscript (lines 107-108; 194-424), as reflected in the\nupdated version.\n23) Comment 23\n“The unspecified populations could have been explored or detailed further to aid\nin understanding. Having looked at one of the systematic reviews which was detailed\nas “unspecified population” (Rivera, 2024), the population of each individual study is\nlisted and included mostly those with T2DM or those wanting to lose weight for\nexample.”\nReply:\nThank you for this important comment. This issue is closely related to Comment\n6, which we have addressed in detail above, including clarifying our approach to\nreviewing and updating the descriptions of unspecified populations to ensure\nconsistency and accuracy.\n24) Comment 24\n“Ensure all abbreviations are defined at first use.”\nReply:\nWe thank the reviewer for this important suggestion. All abbreviations have been\nchecked throughout the manuscript and have been defined upon their first appearance\nto ensure clarity and consistency.\n25) Comment 25\n“The supplementary tables are generally useful and aid in understanding of the\nmain text.”\nReply:\nWe appreciate the reviewer’s positive feedback regarding the supplementary\ntables. We are pleased that they were found helpful in enhancing the understanding of\nthe main text.\n26) Comment 26\n“This section is quite long, though this is reflective of the complexity and\nbreadth of the evidence included.”\nReply:\nWe thank the reviewer for this valuable comment. We recognize that the length\nof the Discussion section reflects the complexity and breadth of the included evidence.\nTo improve the logic and readability of the manuscript, we have reorganized the\nDiscussion section by retaining the analysis of core findings in the main text while\nmoving the analysis of secondary results and extended discussions to the\nsupplementary materials. This adjustment makes the main text more focused and the\nstructure clearer. The corresponding part has been revised in the manuscript (lines\n433-513), as reflected in the updated version.\n27) Comment 27\n“It’s acknowledged that some recent primary studies with important findings are\nnot included in any meta-analyses meaning they have not been included in this review\nand these are explored in the discussion. The evident heterogeneity of the included\nevidence, and therefore the limitations of the findings, are acknowledged somewhat.”\nReply:\nWe thank the reviewer for this valuable comment. We acknowledge that in\ncertain research areas, no systematic reviews or meta-analyses have yet been\nconducted, which has resulted in some recent primary studies with important findings\nnot being included in this umbrella review. In the original manuscript, we discussed\nsome of these developments (e.g., increased risk of endoscopy interruption and\nsuicide). Based on your suggestion, we have now expanded this section to further\nexplore the potential evidence value of these primary studies and highlight the current\ngaps in systematic evidence, providing a more comprehensive overview of research\nprogress and areas of uncertainty in the field.\nMoreover, although subgroup analyses were not feasible due to the nature of\numbrella reviews, we addressed heterogeneity by reporting the I² for each meta-\nanalysis and conducting stratified synthesis according to PICO components. We have\nalso supplemented the Discussion section with a detailed consideration of the\npotential limitations of our study. The corresponding part has been revised in the\nmanuscript (lines 518-543; 550-575; 586-592), as reflected in the updated version.\n28) Comment 28\n“The conclusions generally appear to align with the findings, though the broad\nevidence base sometimes makes it difficult to follow and better summaries could be\nimplemented in places.”\nReply:\nWe thank the reviewer for this helpful suggestion. To improve clarity, we revised\nthe conclusion section by adding concise summaries of the direction and consistency\nof findings across outcome indicators within each clinical system. This enables\nreaders to more easily grasp the overarching patterns. As the observed trends were\nconsistent across different patient subgroups and types of GLP-1 RAs, summarizing\nby clinical system does not compromise the accuracy of our conclusions.\nAdditionally, we reorganized the supplementary results tables by categorizing\nand ordering outcomes within each system, providing a more intuitive presentation of\nthe evidence distribution and enhancing the overall readability and logical flow of the\nmanuscript. The corresponding part has been revised in the manuscript (lines 595-\n600), as reflected in the updated version.\n29) Comment 29\n“The risk of bias of the systematic reviews and also the studies within these\ncould have been considered more in the discussion and interpretation of the findings.”\nReply:\nWe thank the reviewer for this important suggestion. This comment closely\nrelates to Comment 19, and as detailed there, we have expanded the Discussion\nsection to include an analysis and interpretation of the risk of bias both within the\nincluded systematic reviews and the primary studies they encompassed."}, {"round": 2, "reviewer_comments": {"reviewer_1": "Thanks for letting me re-review this manuscript. I have no further comments.", "reviewer_3": "Thank you for addressing the comments raised. It's clear that substantial revisions have been made to the manuscript and I\nbelieve these generally improve the rigour, clarity and readability of the review. The tables in the supplementary are\nimproved and informative. I have a few further minor comments that could be considered.\n1. You mention ensuring that the use of the phrase \"study or studies\" is not used ambiguously without but there are still a few\ninstances where this is used. I would consider being explicit throughout the manuscript.\n2. There is a statement to confirm that only significant results are described in the results of the main text, and other findings\nare reported in the supplementary material. I was just a little unsure on the use of \"generally significant\" in the results and\nwhat this implied.\n3. You don't really address the potential clinical significance of any of the findings, which is something you could raise in the\ndiscussion. Statistical significance doesn't always result in a real clinical impact.\n4. The extra text added on the risk of bias in the discussion section may be more suited to the results section as it appears to\nbe mostly descriptive. The discussion should ideally focus mainly on the impact of these risk of bias results on the overall\nfindings.", "reviewer_4": "Thank you for your revision and response which largely addresses the comments of reviewer 2. I appreciate your response\nto comments 5 and 6 to improve readability and clarity, and have the following two remaining comments in relation to these\npoints.\n1. There remains abundant material that may not add strong value and may be better omitted for the sake of clarity or\nrelevance e.g\n- Supplementary material 5 p15-16; discussion line 507-510 it doesn’t seem necessary to discuss possible mechanisms of\npancreatitis when the evidence [including from your review] does not support an increased risk with GLP-1RAs;\n- supplementary material 4 p12 – the renal benefits of these drugs are well-established – do the authors really propose that\nmore studies are required to evaluate their renal safety and value?;\n- discussion p31 lines 512-515 – it appears that the increased risk of hypoglycemia is derived from studies in which people\neither had diabetes and were on other glucose-lowering agents that are likely to have been contributing, or in people without\ndiabetes in whom there were no severe hypoglycemic events. Do the authors really propose that close monitoring of blood\nglucose levels is warranted in all patients to prevent hypoglycemia?\n- supplementary material 4 p13 re MASLD, the discussion refers to historical guidelines which predate the current data and\nregulatory approval of semaglutide as a treatment for MASH). This and the following paragraph on cardiac guidelines would\nbenefit from synthesis into the key points the authors wish to convey to the reader.\nAdditionally, there are many different terms used for the same/very similar concepts (e.g. p13-14 MASLD and NAFLD; IHA\nand LFC, MASH and NASH) for which results are mentioned and discussed separately - it would be clearer for the reader\nif findings were synthesised\nFinally, there are also areas where the discussion risks over-interpreting the significance of the findings. E.g. supplemental\nmaterial 3 re bone fractures. While meta-analyses indicate a lower risk of fractures, there are as yet no dedicated trials\nexamining this question, and no data to indicate improvement in bone density, therefore I suggest modifying the wording in\nthe discussion (which relates to effects on bone cells in animal models but not bone density or fractures);\n2. some of the information in the introduction could be reworded to improve accuracy (e.g. line 60 semaglutide is no longer\n\"promising\" because it is an established treatment; line 63 it is two studies (not one - the cited reference pools data from both\noriginal studies); line 66 it was >17,000 patients (not 10k)\nAdditionally, I have some minor comments:\n3. throughout - please use \"person first\" language; e.g. person with...obesity, diabetes etc (rather than obese, diabetic, T2DM\npatients)\n4. please define acronyms in the figure legends and tables. Some of them are non-standard (e.g. NRFLD, NRSH) so will not\nbe understood unless explained.\n5. Fig 5 - please check. It does not seem that the risk estimates correspond with the stated effect sizes?\n6. p31 line 503, nausea is not mainly due to peripheral effects of GLP-1RA but likely centrally mediated (reviewed\nhttps://doi.org/10.1210/endocr/bqae167)"}, "author_response": "Point-by-Point Response\nDear Editors and Reviewers,\nWe sincerely appreciate the editors and reviewers for their continued time and\neffort in re-reviewing our manuscript titled “Comprehensive Evaluation of GLP-1\nReceptor Agonists: An Umbrella Review of Clinical Outcomes Across Multiple\nDiseases” (Manuscript ID: NCOMMS-25-01334A-Z). We are grateful for the valuable\ncomments and recognition of the substantial revisions made in the previous round,\nwhich have significantly improved the rigor, clarity, and readability of our umbrella\nreview. We particularly thank Reviewer #3 and Reviewer #4 for their insightful and\nconstructive follow-up comments, which have guided us in making further refinements\nto enhance the manuscript’s precision, coherence, and clinical relevance. We also thank\nReviewer #1 for their prior feedback and final positive assessment. In this\ncomprehensive revision, we have carefully addressed all remaining comments. All the\nrevisions in the manuscript have been highlighted in yellow in the “Revised Manuscript”\nand “Supplementary materials”.\nReviewer #1\nFinal Comment\n“Thanks for letting me re-review this manuscript. I have no further comments.”\nResponse:\nWe sincerely thank the reviewer for taking the valuable time to re-review our\nmanuscript and for their positive and supportive feedback. We greatly appreciate their\ngreat efforts and encouragement throughout the revision process.\nReviewer #3\n1) Comment 01\n“You mention ensuring that the use of the phrase “study or studies” is not used\nambiguously without but there are still a few instances where this is used. I would\nconsider being explicit throughout the manuscript.”\nResponse:\nThanks to the reviewer’s valuable comment and great suggestion. In the revised\nmanuscript, all instances of the terms “study” and “studies” have been thoroughly\nreviewed. To eliminate ambiguity, they have been replaced with more precise\nexpressions depending on the context. Specifically, the terms “meta-analysis/meta-\nanalyses” are now used when referring to the included research, “primary studies” when\nreferring to the original RCTs or observational studies within meta-analyses, and\n“clinical evidence,” “observational studies,” or “randomized controlled trials” where\nappropriate. Corresponding corrections have been made in the figure legends, section\nheadings, and methodological descriptions to ensure consistency. Through these\nrevisions, all ambiguous usages have been removed, and the terminology has been\nmade explicit throughout the manuscript.\nThe corresponding part has been added and refined in the revised manuscript (lines\n40, 60, 67-68, 79, 104, 108, 115-116, 121-122, 127, 131, 145, 160, 167, 177, 262-263,\n606, 609, 620, 639-645, 653, 656, 664, 871-873, 880, 890, 897) with the reviewer’s\nvaluable guidance.\n2) Comment 02\n“There is a statement to confirm that only significant results are described in the\nresults of the main text, and other findings are reported in the supplementary material.\nI was just a little unsure on the use of “generally significant” in the results and what this\nimplied.”\nResponse:\nThanks to the reviewer’s valuable comment and great suggestion. In the original\nsubmission, most non-significant results were presented in the supplementary material\ndue to space constraints and the large number of outcomes. In this revision, we have\nmaintained that structure. However, we realized that excluding all non-significant\nresults from the main text might limit readers’ understanding of the overall evidence\ndistribution and consistency. To address this issue, annotations have been added under\neach system or outcome category to indicate both the total number of outcomes and the\nnumber of statistically significant results. This addition helps readers better grasp the\noverall trends and proportion of significant findings.\nFurthermore, to avoid ambiguity, the term “generally significant” has been\nremoved throughout the manuscript and replaced with more precise expressions.\nThe corresponding part has been added and refined in the revised manuscript (lines\n214-215, 224-226, 242, 252-254, 268-270, 284, 294, 301-302, 314-317, 324-326, 362-\n364, 392-394, 400-401, 410, 419-420, 429-430, 453-454, 457-458, 486, 508-509, 512-\n518) with the reviewer’s valuable guidance.\n3) Comment 03\n“You don't really address the potential clinical significance of any of the findings,\nwhich is something you could raise in the discussion. Statistical significance doesn't\nalways result in a real clinical impact.”\nResponse:\nThanks to the reviewer’s valuable comment and great suggestion. In response, a\nnew paragraph has been incorporated into the Discussion section to summarize and\nelaborate on the potential clinical significance of our findings. This addition synthesizes\nthe quantitative evidence from our umbrella review and provides a contextual\ninterpretation of its practical implications. Specifically, our analyses showed that the\nmean reduction in HbA1c with GLP-1 RAs in most T2DM populations approaches or\nreaches the widely recognized threshold for clinical relevance of approximately 0.5%,\nwhich represents the minimal change typically associated with perceptible\nimprovement in glycemic control. In target populations with concomitant obesity, the\nmean HbA1c reduction can reach approximately 0.8–1.0%. The average weight\nreduction observed was about 2–5 kg, with some studies reporting a weight loss\nexceeding 5%, meeting the generally accepted criterion for clinically meaningful\nweight reduction. These results indicate that the benefits of GLP-1 RAs are not only\nstatistically significant but also clinically meaningful to patients.\nFurthermore, the paragraph emphasizes that the clinical value of GLP-1 RAs lies\nin their ability to achieve integrated improvements across multiple organs and risk\nfactors in complex metabolic diseases, rather than effects limited to isolated endpoints.\nCompared with conventional glucose-lowering therapies, GLP-1 RAs can improve\nglycemic control and promote weight loss without increasing the risk of severe\nhypoglycemia or cardiovascular adverse events, thereby demonstrating tangible clinical\nvalue in the holistic management of metabolic diseases.\nThe corresponding part has been added and refined in the revised manuscript (lines\n547-586) with the reviewer’s valuable guidance.\n4) Comment 04\n“The extra text added on the risk of bias in the discussion section may be more\nsuited to the results section as it appears to be mostly descriptive. The discussion should\nideally focus mainly on the impact of these risk of bias results on the overall findings.”\nResponse:\nThanks to the reviewer’s valuable comment and great suggestion. In accordance\nwith your valuable advice, the previously descriptive AMSTAR 2 and CCA results have\nbeen moved to the Results section (Section 3.1, Characteristics of included meta-\nanalyses) to more clearly present the findings on methodological quality and overlap\nanalysis. Meanwhile, additional discussion has been added to address how these\nsources of bias and structural issues in the evidence base—such as data overlap and\ndominance by large trials—may have potentially influenced the overall conclusions.\nThe corresponding part has been added and refined in the revised manuscript (lines\n178-200, 587-605) with the reviewer’s valuable guidance.\nReviewer #4\nComment 01\nThe reviewer raised several detailed subpoints within this comment. For clarity,\nthese subpoints have been separated and are addressed individually below.\n1) Comment 01(a)\n“There remains abundant material that may not add strong value and may be better\nomitted for the sake of clarity or relevance e.g Supplementary material 5 p15-16;\ndiscussion line 507-510 it doesn’t seem necessary to discuss possible mechanisms of\npancreatitis when the evidence [including from your review] does not support an\nincreased risk with GLP-1RAs;”\nResponse:\nThanks to the reviewer’s valuable comment and great suggestion. In accordance\nwith the suggestion, we have revised the manuscript by deleting the discussion of the\npossible mechanisms of pancreatitis in Supplementary Material 5 (pages 15-16) and in\nthe Discussion section (lines 507-510) to improve clarity and relevance. The reference\nin the main text that referred to this supplementary content has also been removed\naccordingly. In addition, the entire manuscript was carefully reviewed to identify and\nremove other unnecessary or less relevant discussions to further enhance focus and\ncoherence.\nComment 01(b)\n“supplementary material 4 p12 – the renal benefits of these drugs are well-\nestablished – do the authors really propose that more studies are required to evaluate\ntheir renal safety and value?;”\nResponse:\nThanks to the reviewer’s valuable comment and great suggestion. We agree that\nthe renal benefits of GLP-1 RAs have been well established. Accordingly, the relevant\nstatements have been revised, and the previous wording that suggested “further studies\nare required to evaluate their renal safety and clinical value” has been removed. The\nrevised sentence now reads as follows:\n“However, our findings indicate that GLP-1 RAs are associated with a reduced\nrisk of adverse renal outcomes, suggesting that although vigilance remains warranted\nin persons with impaired renal function or those at risk of dehydration, their overall\nrenal effects appear to be beneficial.”\nThe corresponding part has been added and refined in the revised manuscript\n(supplementary material 4 p11) with the reviewer’s valuable guidance.\nComment 01(c)\n“discussion p31 lines 512-515 – it appears that the increased risk of hypoglycemia\nis derived from studies in which people either had diabetes and were on other glucose-\nlowering agents that are likely to have been contributing, or in people without diabetes\nin whom there were no severe hypoglycemic events. Do the authors really propose that\nclose monitoring of blood glucose levels is warranted in all patients to prevent\nhypoglycemia?”\nResponse:\nThanks to the reviewer’s valuable comment and great suggestion. We agree with\nthe reviewer’s view that the observed risk of hypoglycemia associated with GLP-1 RAs\nis likely attributable to the background use of antidiabetic medications in diabetic\npopulations, rather than an intrinsic effect of the drugs themselves. To avoid\novergeneralization, the relevant text has revised to make the statement more cautious\nand accurate. The revised version is presented as follows:\n“However, our findings indicated a potential increase in hypoglycemic events.\nGiven that some included studies involved populations with diabetes, this increased risk\nmay be related to prior or concomitant use of other glucose-lowering medications rather\nthan an intrinsic effect of GLP-1 RAs. Therefore, in clinical practice, close monitoring\nof blood glucose levels is recommended for individuals with diabetes, particularly those\nreceiving combination antidiabetic therapy or during the early phase of dose\nadjustment.”\nThe corresponding part has been added and refined in the revised manuscript (lines\n538-544) with the reviewer’s valuable guidance.\nComment 01(d)\n“supplementary material 4 p13 re MASLD, the discussion refers to historical\nguidelines which predate the current data and regulatory approval of semaglutide as a\ntreatment for MASH). This and the following paragraph on cardiac guidelines would\nbenefit from synthesis into the key points the authors wish to convey to the reader.”\nResponse:\nThanks to the reviewer’s valuable comment and great suggestion. In accordance\nwith your comments, we have comprehensively revised the guideline-related content.\nFor the hepatic section, lengthy descriptions of outdated guidelines have been removed,\nand the text has been updated to reflect the latest evidence, including the 2025 U.S.\nFDA approval of semaglutide (Wegovy, 2.4 mg) for the treatment of adults with MASH\nand moderate-to-severe liver fibrosis. This update highlights the transition of GLP-1\nRAs from “potential therapy” to “formally approved treatment.” In the cardiovascular\nsection, the main consensus statements from U.S., European, and Chinese guidelines\nhave been synthesized, and the related paragraphs have been streamlined and\nrestructured to more clearly present the key points based on the reviewer’s insightful\ncomment.\nThe corresponding part has been added and refined in the revised manuscript\n(supplementary material 4 p11-12) with the reviewer’s valuable guidance.\nComment 01(e)\n“Additionally, there are many different terms used for the same/very similar\nconcepts (e.g. p13-14 MASLD and NAFLD; IHA and LFC, MASH and NASH) for\nwhich results are mentioned and discussed separately - it would be clearer for the reader\nif findings were synthesized.”\nResponse:\nThanks to the reviewer’s valuable comment and great suggestion. We noted that\nthe latest international guidelines have unified the terminology of NAFLD and NASH\nunder the MASLD/MASH framework. Accordingly, in the revised manuscript,\nclarification has been added at the beginning of the liver-related section to indicate that\nlegacy terms such as NAFLD/NASH and MAFLD are placed under the current steatotic\nliver disease (SLD) framework—MASLD (formerly NAFLD) and MASH (formerly\nNASH)—to align with the latest international terminology. However, as the meta-\nanalyses included in this review were conducted using the earlier nomenclature (e.g.,\nNAFLD, NASH, MAFLD), the original terminology used in those publications has\nbeen retained to ensure traceability and methodological rigor. It has also been clearly\nindicated in the text that these labels were analyzed within the unified SLD framework.\nTo avoid confusion, clarification has been added to the main text indicating that\nIHA and LFC are both measures of hepatic steatosis. This clarification is now included\nin the opening sentence of the subsection.\nThe corresponding part has been added and refined in the revised manuscript\n(lines 210-221, 250-259) with the reviewer’s valuable guidance.\nComment 01(f)\n“Finally, there are also areas where the discussion risks over-interpreting the\nsignificance of the findings. E.g. supplemental material 3 re bone fractures. While meta-\nanalyses indicate a lower risk of fractures, there are as yet no dedicated trials examining\nthis question, and no data to indicate improvement in bone density, therefore I suggest\nmodifying the wording in the discussion (which relates to effects on bone cells in animal\nmodels but not bone density or fractures);”\nResponse:\nThanks to the reviewer’s valuable comment and great suggestion. To address this,\nthe corresponding section in Supplementary Material 3 has been revised to present the\nevidence more cautiously. The updated text is as follows:\n“Although these findings indicate a potential protective association, the\nmechanisms underlying this reduced fracture risk remain at the preclinical stage, and\nno clinical studies have yet elucidated how GLP-1 RAs influence fracture outcomes.\nEvidence from animal studies indicates that GLP-1 RAs could influence bone\nhomeostasis—the dynamic balance between bone resorption and formation—by\nsuppressing osteoclast activity while promoting osteoblast differentiation. This\npotential shift toward a net anabolic state may partly explain the observed reduction in\nfracture risk.”\nThe corresponding part has been added and refined in the revised manuscript\n(supplementary material 3 p11) with the reviewer’s valuable guidance.\n2) Comment 02\n“2. some of the information in the introduction could be reworded to improve\naccuracy (e.g. line 60 semaglutide is no longer \"promising\" because it is an established\ntreatment; line 63 it is two studies (not one - the cited reference pools data from both\noriginal studies); line 66 it was >17,000 patients (not 10k)”\nResponse:\nWe thank the reviewer for the careful correction. The Introduction section has been\nrevised according to the suggestions: at line 60 (current line 61), “a promising anti-\nobesity drug” has been modified to “an effective anti-obesity treatment” to reflect the\nestablished efficacy of the therapy; at line 63 (current line 64), “a clinical trial” has been\ncorrected to “a pooled analysis of two clinical trials” to accurately represent the\nreferenced source; and at line 66 (current line 68), “over 10,000 patients” has been\nupdated to “more than 17,000 individuals” to ensure data accuracy and alignment with\nperson-first language.\n3) Comment 03\n“Additionally, I have some minor comments: 3. throughout - please use \"person\nfirst\" language; e.g. person with...obesity, diabetes etc (rather than obese, diabetic,\nT2DM patients)”\nResponse:\nThanks to the reviewer’s valuable comment and great suggestion. The entire\nmanuscript, including the supplementary materials, has been thoroughly checked and\nrevised to ensure the consistent use of person-first language (e.g., “individuals with\nobesity,” “individuals with diabetes,” “individuals with T2DM”).\nThe corresponding part has been added and refined in the revised manuscript (lines\n61-62, 65-66, 68, 226-231, 235-237, 243-247, 261-264, 285-291, 295-296, 299, 303-\n307, 309-311, 318, 328, 331-333, 336, 353, 375-376, 379, 394-395, 397-398, 402, 407,\n411, 413, 416, 421-422, 424-427, 433, 435, 443, 445-446, 474, 479, 481, 497-498, 506,\n511-512, 519-520, Supplementary material p5-12) with the reviewer’s valuable\nguidance.\n4) Comment 04\n“4. please define acronyms in the figure legends and tables. Some of them are non-\nstandard (e.g. NRFLD, NRSH) so will not be understood unless explained.”\nResponse:\nWe sincerely thank the reviewer for the careful review and corrections. Regarding\nthe abbreviations in the figure legends and tables, all instances have been carefully\nchecked and corrected. The original abbreviations “NRFLD” and “NRSH” were\nidentified as typographical errors and have been corrected to “NAFLD (Nonalcoholic\nfatty liver disease)” and “NASH (Nonalcoholic steatohepatitis),” respectively. The error\nwas unintentionally introduced during the batch replacement of “NR” (not reported).\nAll such errors have been fully corrected, and all abbreviations in the figures and tables\nhave been standardized and clearly defined to avoid any ambiguity.\nThe corresponding part has been added and refined in the revised manuscript (lines\n874-879, 883-888, 893-896, 901-904, table 1, 907-913, table 2, 916-922, table 3, 925-\n928, 931-933) with the reviewer’s valuable guidance.\n5) Comment 5\n“5. Fig 5 - please check. It does not seem that the risk estimates correspond with\nthe stated effect sizes?”\nResponse:\nWe sincerely thank the reviewer for the careful review and valuable comments.\nUpon re-examination of Figure 5, an inconsistency was identified between the\ndisplayed risk estimates in the forest plot and the corresponding effect sizes. The figure\nhas been redrawn and corrected. The inconsistency was due to a minor technical error\nduring figure preparation, which has now been fully resolved. In addition, all other\nfigures and tables throughout the manuscript have been thoroughly checked to ensure\nfull consistency between the reported risk estimates and effect sizes. We once again\nthank the reviewer for the helpful feedback and kind assistance in improving our work.\n6) Comment 6\n“6. p31 line 503, nausea is not mainly due to peripheral effects of GLP-1RA but\nlikely centrally mediated (reviewed https://doi.org/10.1210/endocr/bqae167)”\nResponse:\nWe thank the reviewer for the careful review and professional suggestion. In\naccordance with the comment, the relevant statements have been revised to more\naccurately reflect the current scientific consensus. The revised text now clarifies that\nnausea is not primarily caused by delayed gastric emptying through peripheral\nmechanisms, but is instead predominantly mediated by central pathways, particularly\ninvolving the activation of GLP-1R neurons in the area postrema of the medulla. The\ncorresponding sentence in the revised manuscript has been updated as follows:\n“While delayed gastric emptying increases satiety and reduces caloric intake,\nexcessive delay can result in gastric content retention, leading to upper abdominal\ndiscomfort. In addition, nausea is believed to result mainly from central mechanisms,\nin which activation of GLP-1R neurons in the area postrema plays a predominant role\nrather than from delayed gastric emptying alone.”\nThe corresponding part has been added and refined in the revised manuscript (lines\n530-536) with the reviewer’s valuable guidance."}, {"round": 3, "reviewer_comments": {"reviewer_4": "Thank you for the revision. I have no further comments."}, "author_response": ""}]

Decision letter