¹ Department of Surgery, University of Bisha, Bishah, Aseer Province, Saudi Arabia
² Department of Surgery, King Saud University Medical City, Riyadh, Riyadh Province, Saudi Arabia
³ University of Bisha, Bishah, Aseer Province, Saudi Arabia
⁴ King Khalid University College of Medicine, Abha, Aseer Province, Saudi Arabia
⁵ Sana'a University Faculty of Medicine, Sana'a, Capital Municipality, Yemen

Saad Dhafer Alshahrani
Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Software, Validation, Visualization, Writing – Review & Editing

Riyadh Farraj S. Al Areef
Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Software, Validation, Visualization, Writing – Review & Editing

Romoz Ali S. Aloqaybi
Roles: Investigation, Methodology, Resources, Validation, Visualization, Writing – Original Draft Preparation

Fatimah Ghaidan A. Almuawi
Roles: Data Curation, Formal Analysis, Investigation, Methodology, Validation, Visualization, Writing – Original Draft Preparation

Azzah Mesfer Almaeawi
Roles: Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Resources, Software, Validation, Visualization, Writing – Original Draft Preparation

Rimas Safar S. Alshahrani
Roles: Data Curation, Investigation, Methodology, Software, Validation, Visualization, Writing – Original Draft Preparation

Aws Abdullah S. Abuliat
Roles: Data Curation, Investigation, Methodology, Project Administration, Software, Validation, Writing – Original Draft Preparation

Mohammed Abdulrahman Alharthi
Roles: Data Curation, Formal Analysis, Investigation, Methodology, Software, Validation, Visualization, Writing – Original Draft Preparation

Abdulaziz Obaid G. Alharthi
Roles: Data Curation, Formal Analysis, Investigation, Methodology, Validation, Visualization, Writing – Original Draft Preparation

Sarah Saeed A. Alghamdi
Roles: Data Curation, Formal Analysis, Investigation, Methodology, Software, Validation, Visualization, Writing – Original Draft Preparation

Nourah Ali M. Alshahrani
Roles: Data Curation, Investigation, Methodology, Resources, Validation, Visualization, Writing – Original Draft Preparation

Rawabi Shaalan Alqarni
Roles: Data Curation, Formal Analysis, Investigation, Methodology, Resources, Software, Supervision, Validation, Writing – Original Draft Preparation

Ehab Sharyan
Roles: Data Curation, Investigation, Methodology, Resources, Validation, Visualization, Writing – Original Draft Preparation

Bushra Saeed S. Alshehri
Roles: Data Curation, Investigation, Methodology, Software, Supervision, Validation, Visualization, Writing – Original Draft Preparation

Amal Fayez Hamuman
Roles: Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Supervision, Validation, Visualization, Writing – Review & Editing

This work was conducted as a systematic review and meta-analysis evaluating the comparative effectiveness of metabolic bariatric surgery (including sleeve gastrectomy and Roux-en-Y gastric bypass) versus medical and incretin-based therapies for weight loss and metabolic outcomes. The study was designed and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement and methodological guidance from the Cochrane Handbook for Systematic Reviews of Interventions.^10,11 A predefined protocol guided the search strategy, eligibility assessment, data extraction, risk-of-bias evaluation, and statistical analysis; however, the protocol was not registered in PROSPERO. All analyses were conducted after completion of the final literature search.

A comprehensive electronic search was performed in PubMed, Scopus, and Web of Science from database inception until January 2026. Additional manual searching was conducted using Google Scholar and by screening the reference lists of relevant publications to identify further eligible studies. The search strategy incorporated both controlled vocabulary and free-text keywords related to metabolic bariatric surgery and medical or incretin-based therapies, including terms such as “sleeve gastrectomy,” “Roux-en-Y gastric bypass,” “metabolic surgery,” “bariatric surgery,” “GLP-1 receptor agonist,” “semaglutide,” “liraglutide,” “exenatide,” “tirzepatide,” and “medical therapy,” combined with comparative terms. Searches were limited to studies conducted in humans and published in English, with no restriction on publication year. The complete database-specific search strings are provided in Supplementary File 1.

Eligible studies were comparative clinical investigations evaluating adults with obesity and/or type 2 diabetes who underwent metabolic bariatric surgery and were directly compared with medical or incretin-based therapies. Both randomized and non-randomized comparative designs were eligible provided that at least one clinically relevant outcome, including weight loss, glycemic control, or metabolic parameters, was reported with extractable quantitative data. Studies were excluded if they were non-clinical or experimental animal studies, mechanistic laboratory investigations, narrative reviews, editorials, case reports, conference abstracts lacking full data, or studies without a direct comparison between surgical and pharmacologic approaches. Articles that included mixed surgical populations without separable outcomes for eligible interventions, studies with insufficient outcome data, or those involving pediatric populations were excluded after full-text review. When multiple publications reported overlapping cohorts, the most comprehensive dataset with the longest follow-up was retained.

All identified records were imported into Rayyan software for organization and duplicate removal.¹² Screening was conducted in two sequential stages consisting of title and abstract review followed by full-text evaluation. Six reviewers independently assessed eligibility according to predefined inclusion and exclusion criteria. Any disagreements during the screening process were resolved through discussion and consensus within the research team. The overall study selection process is presented in the PRISMA flow diagram.

Data extraction was performed independently by four reviewers using a standardized data extraction template, while two additional reviewers verified the accuracy and completeness of the extracted data. Extracted variables included study characteristics such as author, year, country, and study design, along with participant demographics, surgical procedures, pharmacologic interventions, and duration of follow-up. Outcome data focused on measures of weight loss, HbA1c reduction, lipid parameters, medication use, and adverse events when reported. When multiple follow-up time points were reported, the time point corresponding to the primary outcome assessment used in the quantitative synthesis was extracted. Follow-up duration was recorded and subsequently explored in subgroup analyses. Any discrepancies identified during extraction or verification were resolved through consensus among the reviewers.

Because outcome reporting varied across studies, a prespecified harmonization strategy was applied before quantitative synthesis. Weight-loss outcomes (%EWL, %TWL, or kg change) were pooled using standardized mean differences (SMDs), with effect directions aligned so that negative values favored surgery. For glycemic outcomes, only continuous measures reported as mean change from baseline (HbA1c or FPG) were included in meta-analyses, while categorical outcomes such as diabetes remission and glycemic target achievement were summarized narratively. Detailed harmonization procedures are provided in Supplementary Tables S1 and S2.

The methodological quality of included studies was evaluated using validated risk-of-bias tools according to study design. Four reviewers independently conducted the risk-of-bias assessment. Randomized controlled trials were assessed using the Cochrane Risk of Bias 2 (RoB 2) tool,¹³ which evaluates bias arising from the randomization process, deviations from intended interventions, missing outcome data, outcome measurement, and selection of reported results. Non-randomized comparative studies were evaluated using the Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) framework,¹⁴ which assesses potential bias across seven domains including confounding, participant selection, intervention classification, deviations from intended interventions, missing data, outcome measurement, and selective reporting. Any disagreements in domain-level judgments were resolved through discussion until consensus was achieved.

All statistical analyses were conducted using R software version 4.3.3. Meta-analyses were performed using the meta and metafor packages. Continuous outcomes were pooled using inverse-variance random-effects models to account for anticipated clinical and methodological heterogeneity across studies, including differences in study design, patient populations, surgical procedures, pharmacologic regimens, and follow-up duration. Because outcome reporting varied in scale and units between studies, standardized mean differences (SMDs) were calculated with corresponding 95% confidence intervals as the primary effect measure for weight loss and HbA1c reduction. When necessary, standard deviations were derived or estimated from available summary statistics according to established meta-analytic methods.

Statistical heterogeneity was evaluated using Cochran’s Q test and quantified with the I² statistic, with higher values indicating greater between-study variability. Forest plots were generated to present individual study effects alongside pooled estimates. Prespecified subgroup analyses were conducted according to treatment era, follow-up duration, and study design to explore potential sources of heterogeneity. Sensitivity analyses excluding studies classified as having serious overall risk of bias according to ROBINS-I were prespecified to assess the robustness of the pooled estimates. Outcomes that could not be quantitatively synthesized because of inconsistent reporting were described narratively. Assessment of publication bias was not performed because the number of included studies was below the commonly recommended minimum threshold of ten studies required for reliable funnel plot interpretation and statistical tests of asymmetry.¹⁵ Methods such as Egger’s regression or Begg’s test have limited statistical power when applied to small meta-analyses and may lead to misleading conclusions; therefore, no formal evaluation of publication bias was undertaken.^15,16

A total of 648 records were initially identified through database searching, including PubMed, Scopus, Web of Science, and Google Scholar. After removal of 282 duplicate records, 366 articles underwent title and abstract screening. Of these, 351 records were excluded primarily due to lack of a direct comparison between bariatric surgery and GLP-1 receptor agonist or medical therapy, non-comparative study design, irrelevant populations, or non-original research formats. Fifteen reports were retrieved for full-text assessment, all of which were available for evaluation. Following eligibility assessment, eight studies were excluded because they lacked extractable quantitative outcomes, did not include a GLP-1 comparator, involved non-eligible populations, or represented overlapping datasets. Ultimately, seven studies met the predefined inclusion criteria and were included in the qualitative synthesis and quantitative analyses. Figure 1 illustrates the study selection process according to PRISMA guidelines.

The characteristics of the included studies are summarized in Table 1. Seven studies met the eligibility criteria, comprising two randomized controlled trials, two prospective non-randomized studies, two retrospective comparative cohorts, and one non-randomized pilot study. Studies were conducted in China, Italy, and the United States and enrolled adults with obesity and/or type 2 diabetes. Sample sizes varied substantially, ranging from small clinical cohorts in Yong et al.¹⁷ and Capristo et al.²⁷ to a large real-world comparative cohort reported by Barrett et al.¹⁹ Surgical interventions included gastric bypass, sleeve gastrectomy, Roux-en-Y gastric bypass, or mixed metabolic bariatric surgery cohorts, while comparators consisted of GLP-1 receptor agonist therapy, intensive medical therapy, lifestyle-supported pharmacotherapy, or conventional medical management. Follow-up durations ranged from 6 months to 10 years, reflecting both short-term comparative effectiveness and long-term durability of treatment outcomes.

Key clinical outcomes are summarized in Table 2. Weight-loss outcomes consistently favored metabolic bariatric surgery across all included studies, although the reported metrics varied and included percentage excess weight loss (%EWL), percentage total weight loss (%TWL), and absolute weight change in kilograms. Yong et al.¹⁷ reported greater excess weight loss following gastric bypass compared with exenatide therapy (−57.3% vs −23.8%), while Cotugno et al.¹⁸ observed a larger reduction in body weight with surgery than liraglutide (−38.0 kg vs −5.0 kg). Similarly, Schauer et al.,²³ Mingrone et al.,²⁴ Barrett et al.,¹⁹ and Yen et al.²⁰ all demonstrated substantially greater weight reduction in the surgical groups.

Glycemic outcomes were reported using a mixture of continuous measures and categorical endpoints. Continuous reductions in HbA1c generally favored surgery, with larger improvements observed in Cotugno et al.,¹⁸ Schauer et al.,²³ Mingrone et al.,²⁴ and Yen et al.²⁰ Improvements in fasting plasma glucose were also reported across several studies, although the magnitude of benefit varied. Diabetes remission and glycemic target achievement were reported in selected studies, with higher remission rates consistently observed following surgical intervention.

Lipid outcomes were reported less consistently across studies. Cotugno et al.¹⁸ and Schauer et al.²³ demonstrated favorable reductions in triglycerides and increases in HDL cholesterol following surgery, whereas other studies reported more modest differences between treatment groups. Additional findings included higher rates of medication discontinuation after surgery, durable long-term metabolic improvement, reduced comorbidity burden in large observational cohorts, and weight regain following discontinuation of semaglutide therapy in contemporary pharmacologic cohorts.

Studies were categorized according to treatment era and therapeutic context as shown in Table 3. The Early Era included Yong et al.¹⁷ and Cotugno et al.,¹⁸ which compared bariatric surgery with first-generation incretin therapies such as exenatide and liraglutide. The Transitional Era included Schauer et al.,²³ Capristo et al.,²⁷ and Mingrone et al.,²⁴ reflecting the expansion of high-quality surgical evidence alongside intensified medical and pharmacologic treatment strategies. The Modern Era included Barrett et al.¹⁹ and Yen et al.,²⁰ incorporating contemporary GLP-1–based therapies, including semaglutide and mixed high-potency incretin regimens. This classification was used as an interpretive framework to evaluate how comparative effectiveness may have evolved alongside advances in obesity pharmacotherapy.

The pooled analysis of weight loss outcomes, strictly harmonized to reflect negative standardized mean differences (SMD), is presented in Figure 2. Overall, metabolic bariatric surgery was associated with significantly greater weight loss compared to medical and GLP-1 based therapies (SMD = −2.02; 95% CI, −2.59 to −1.45). While overall statistical heterogeneity remained substantial (I² = 74.7%), stratification by treatment era markedly reduced heterogeneity within the Transitional Era (I² = 0%) and Modern Era (I² = 0%) subgroups. Residual heterogeneity persisted within the Early Era subgroup. The magnitude of the pooled effect favoring surgery decreased from the Early Era (SMD = −3.92) to the Modern Era (SMD = −1.74), although formal subgroup differences were not statistically significant.

Figure 3 presents the pooled analysis of HbA1c reduction following harmonization of glycemic outcome reporting. Metabolic bariatric surgery demonstrated significantly greater HbA1c reduction compared with medical and incretin-based therapies (SMD = −0.63; 95% CI, −0.88 to −0.37). No statistical heterogeneity was observed across the included studies (I² = 0%).

Sensitivity analyses excluding studies judged to have serious risk of bias were performed to evaluate the robustness of the primary findings (Supplementary figures S1–S2). Following exclusion of the serious-risk studies, the pooled effect for weight loss remained strongly in favor of metabolic bariatric surgery (SMD = −1.70; 95% CI, −1.84 to −1.57), with complete resolution of statistical heterogeneity (I² = 0%). Similarly, the pooled effect for HbA1c reduction continued to favor surgery (SMD = −0.81; 95% CI, −1.18 to −0.43), with no observed heterogeneity (I² = 0%). In contrast, the pooled analysis of triglyceride reduction remained non-significant (SMD = −0.21; 95% CI, −0.97 to 0.55) and continued to demonstrate substantial heterogeneity (I² = 82.7%).

To address the high statistical heterogeneity observed in the primary weight loss analysis, pre-specified subgroup analyses were conducted based on follow-up duration and study design. When stratified by follow-up duration (supplementary figure 3), the superiority of surgical intervention remained consistent across both subgroups. Notably, long-term studies (≥ 2 years) demonstrated a precise pooled effect favoring surgery with a complete resolution of heterogeneity (SMD = −1.71; 95% CI, −1.85 to −1.57; I² = 0%), whereas short-term studies (≤ 1 year) retained high variability (SMD = −2.68; 95% CI, −4.08 to −1.28; I² = 83.1%). Similarly, stratification by study design (supplementary figure 4) revealed that while both Randomized Controlled Trials (RCTs) and observational cohorts favored surgery, the pooled effect of the RCTs entirely eliminated statistical heterogeneity (SMD = −1.52; 95% CI, −1.93 to −1.11; I² = 0%).

Beyond weight reduction and HbA1c, the comparative effects on secondary metabolic parameters, specifically triglycerides, high-density lipoprotein (HDL), and fasting plasma glucose (FPG), were evaluated to assess broader cardiovascular risk reduction. While individual studies frequently reported metabolic benefits favoring surgical intervention, the pooled analyses for these parameters demonstrated substantial heterogeneity and no statistically significant overall differences between surgery and medical therapy. The pooled standardized mean difference for triglyceride reduction (supplementary figure 5) numerically favored surgery but crossed the threshold of non-significance (SMD = −0.56; 95% CI, −1.19 to 0.07; I² = 83.0%). Likewise, overall effect sizes for HDL increase (supplementary figure 6) (SMD = 0.38; 95% CI, −0.45 to 1.22; I² = 90.4%) and FPG reduction (supplementary figure 7) (SMD = −0.27; 95% CI, −0.88 to 0.34; I² = 79.8%) did not demonstrate definitive superiority for either intervention.

Risk of bias for non-randomized studies assessed using ROBINS-I is presented in Figure 4. Yong et al.,¹⁷ Cotugno et al.,¹⁸ and Yen et al.²⁰ were judged to have serious overall risk of bias. Capristo et al.²⁷ and Barrett et al.¹⁹ were assessed as having moderate overall risk of bias. Across studies, bias due to confounding and participant selection represented the most frequent domains with elevated risk, while classification of interventions and outcome measurement were generally assessed as low risk.

Risk of bias for randomized controlled trials assessed using the Cochrane RoB 2 tool is shown in Figure 5. Schauer et al.²³ and Mingrone et al.²⁴ demonstrated low risk of bias across most domains, including randomization process, missing outcome data, outcome measurement, and reporting. Both trials were rated as having some concerns overall due to potential deviations from intended interventions.

Several limitations should be considered when interpreting the findings of this review. First, the number of eligible comparative studies remained relatively small and included both randomized and non-randomized designs, introducing potential methodological heterogeneity and residual confounding. Second, substantial clinical variation existed across studies with respect to patient populations, surgical procedures, comparator therapies, and follow-up duration. Although treatment-era stratification, subgroup analyses, and sensitivity analyses substantially reduced or eliminated heterogeneity for the primary outcomes, residual variability remained for several secondary metabolic endpoints. Third, outcome harmonization was necessary because studies reported weight-loss and glycemic outcomes using different metrics and scales. While standardized meta-analytic methods were applied to improve comparability, pooling heterogeneous measures may reduce clinical interpretability. Fourth, several non-randomized studies were judged to have moderate or serious risk of bias; however, sensitivity analyses excluding serious-risk studies produced findings consistent with the primary analyses, supporting the robustness of the main conclusions. Finally, the limited number of included studies precluded formal assessment of publication bias and highlights the need for additional high-quality head-to-head trials comparing contemporary incretin-based therapies with metabolic bariatric surgery.

We would like to express our gratitude to Shohob Research Services Center for their efforts in training the research team and supervising the research process until the completion of this study.

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AWAITING PEER REVIEW

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