Efficacy and safety of endoscopic sleeve gastroplasty for patients with metabolic dysfunction-associated steatohepatitis: protocol for a systematic review and trial sequential meta-analysis

Abstract

Background

Metabolic dysfunction-associated steatohepatitis (MASH) represents a progressive form of liver disease with rising global prevalence, where sustained weight loss is essential for histological improvement. Current therapies—lifestyle modification, pharmacotherapy, and bariatric surgery—face limitations including variable efficacy, cost, invasiveness, or accessibility. Endoscopic sleeve gastroplasty (ESG) emerges as a minimally invasive alternative for moderate obesity, demonstrating promising weight loss and preliminary metabolic benefits. However, robust evidence regarding its impact on core histological outcomes remains limited and heterogeneous, necessitating a systematic evaluation to establish its therapeutic role in MASH management.

Methods and analysis

Randomized controlled trials (RCTs) and cohort studies that compare endoscopic sleeve gastroplasty and usual care in patients with metabolic dysfunction-associated steatohepatitis will be included. Literature searches will be conducted in PubMed, Web of Science, Embase, and Cochrane Library. Two reviewers will independently perform the processes of literature retrieval, screening, data extraction, and assessment of risk of bias. The primary outcome is total body weight loss (TBWL). Secondary outcomes include resolution of MASH without worsening of fibrosis, improvement in fibrosis without worsening of steatohepatitis, and incidence of adverse events. Risk of bias in included RCTs will be evaluated using Revised Cochrane risk-of-bias tool (ROB 2) for RCTs. Review Manager (RevMan) will be used for data pooling. Effect estimates will be expressed as risk ratios (RR) for dichotomous outcomes and mean differences (MD) for continuous outcomes, with 95% confidence intervals (CI). Subgroup analysis, trial sequential analysis (TSA), and sensitivity analysis will be conducted.

Ethics and dissemination

Ethical approval is not required because this study is a secondary analysis of existing data. We will disseminate the findings through peer- reviewed publications.

Systematic review registration

PROSPERO CRD420251121461.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13643-026-03071-7.

Introduction

Metabolic dysfunction-associated steatohepatitis (MASH) constitutes a progressive and clinically critical subtype of metabolic dysfunction-associated steatotic liver disease (MASLD), pathologically defined by the triad of hepatocellular steatosis, lobular inflammation, and hepatocellular ballooning [1, 2]. This pathogenic process drives sequential hepatic damage, initiating fibrosis through excessive extracellular matrix deposition, which may advance to cirrhosis with irreversible architectural distortion and functional compromise, significantly elevating the risk of hepatocellular carcinoma [3, 4]. Fueled by the global rise in obesity, diabetes, and metabolic syndrome, MASH has emerged as a leading cause of chronic liver disease worldwide. Notably, it represents the fastest-growing indication for liver transplantation due to its propensity for progression to end-stage complications [5–7]. This accelerating clinical burden poses a formidable multi-faceted challenge to global healthcare systems, demanding urgent strategies for early intervention and resource allocation.

Currently, comprehensive lifestyle interventions—including calorie restriction, nutritional restructuring, and regular exercise—remain the cornerstone of MASH treatment [8, 9]. Research data indicates that achieving histological remission of MASH typically requires a total body weight loss (TBWL) of at least 7–10%. However, in clinical practice, the proportion of patients who can achieve this goal within a year through lifestyle adjustments alone is very low, highlighting the significant challenges faced in the management of metabolic liver disease. Traditionally, for patients with severe obesity and MASH, weight-loss surgeries such as Roux-en-Y gastric bypass or sleeve gastrectomy have been proven to achieve significant and sustained weight loss, while also improving liver inflammation and fibrosis [10–12]. However, due to factors such as surgical risks and costs, only a small proportion of eligible patients ultimately undergo such procedures. For patients with mild to moderate obesity and MASH who do not meet the criteria for weight-loss surgery, treatment options are more limited. Lifestyle interventions yield inconsistent results, while pharmacological treatments face challenges such as long-term safety concerns, weight regain after discontinuation, and limited efficacy in improving fibrosis [13–15]. In this context, endoscopic bariatric and metabolic therapies have emerged as an important option to address the treatment gap for patients with mild to moderate obesity, thanks to their minimally invasive nature, reversibility, and lower risk of complications [16–19].

Endoscopic sleeve gastroplasty (ESG) is a representative technique among endoscopic bariatric procedures. It involves reshaping the gastric cavity into a tubular structure via endoscopic manipulation, thereby limiting gastric capacity and delaying gastric emptying, which enhances satiety and reduces food intake [20, 21]. Compared to traditional weight-loss surgery, ESG preserves the integrity of the gastrointestinal anatomical structure, significantly reducing the risk of surgery-related complications, while also lowering treatment costs compared to traditional surgery [22, 23]. However, current research still has several limitations: first, existing literature primarily focuses on the short-term effects of ESG on liver enzymes and liver fat content, but lacks a systematic assessment of its ability to alter the core histological endpoints of MASH. Additionally, the limited number of patients included in individual studies may affect the stability of the results [24, 25]. Therefore, it is necessary to integrate existing clinical trial evidence through rigorously designed systematic reviews and sequential meta-analyses to assess the long-term clinical outcomes of ESG in MASH patients, thereby providing comprehensive evidence for clinicians and researchers.

Methods

Protocol and registration

This systematic review will be conducted according to the Cochrane Handbook for Systematic Reviews of Interventions. The protocol is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P) statement. Prior to initiation, the study protocol was prospectively registered with the PROSPERO international database (Registration ID: CRD420251121461) [26].

Inclusion criteria

Participants

Adult patients (≥ 18 years) diagnosed with metabolic dysfunction-associated steatohepatitis.

Intervention

Patients in the experimental group received endoscopic sleeve gastroplasty as intervention.

Comparison

Patients in the control group only received usual care.

Primary outcome

The primary outcome is total body weight loss.

Secondary outcomes

Resolution of MASH without worsening of fibrosis; improvement in fibrosis without worsening of steatohepatitis; incidence of adverse events.

Study design

We will include randomized controlled trials (RCTs) and prospective or retrospective comparative cohort studies with at least two parallel groups (ESG vs. usual care).

Exclusion criteria

The exclusion criteria are as follows: non-human studies (animal experiments), crossover studies, and published in languages other than English will be excluded from this systematic review and meta-analysis.

Literature sources and retrieval strategy

To ensure methodological rigor and minimize bias, two reviewers will independently search four major electronic databases: PubMed, Web of Science, Embase, and the Cochrane Library. In addition to the electronic databases, we will search clinical trial registries (ClinicalTrials.gov, WHO ICTRP), conference abstracts, and reference lists of included studies and relevant reviews to identify additional eligible studies. Only English-language studies will be included. The search strategy will combine terms related to MASH, endoscopic sleeve gastroplasty, and study design. An example of the PubMed search strategy is provided in Additional file 1. The search will cover from inception to the date of final search (planned for December 2025). Discrepancies in study identification or selection will be resolved through discussion.

Literature screening and data extraction

Two reviewers will independently conduct literature screening and data extraction following standard systematic review methodology. Screening involves: (1) title/abstract review, (2) full-text assessment, with discrepancies resolved through consensus or third-reviewer adjudication." The screening process will be reported using a PRISMA flow diagram [27]. A standardized, piloted form will extract: study design, participant characteristics, intervention details, and outcomes. Two reviewers will independently extract data, with disagreements resolved by a third reviewer.

Assessment of risk of bias

To ensure standardized and unbiased quality appraisal, two independent reviewers will assess the risk of bias of included randomized controlled trials using the Revised Cochrane risk-of-bias tool (ROB 2). This tool will evaluate five critical domains: bias arising from the randomization process, deviations from intended interventions, missing outcome data, outcome measurements, and selection of the reported result. To assess the risk of bias in non-randomised studies, the Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-1) tool will be used. The assessments of observational studies will cover seven dimensions: confounding adjustment, selection of patients, classification of interventions, deviation from intended interventions, missing data, outcome measurement and selection of reported results. Controversies will be discussed and solved in the research team.

Statistical analysis

Data synthesis and statistical analyses will be performed using Review Manager software (version 5.4). For dichotomous variables, risk ratios (RR) with 95% confidence intervals (CI) will be derived using the Mantel–Haenszel method. Continuous variables will be pooled and analyzed as mean difference (MD) with 95% CIs, employing the inverse variance method. The statistical significance level (α) is set at 0.05. Statistical differences are deemed significant if the P value is less than 0.05. Random-effects models will be used for all meta-analyses due to anticipated clinical/methodological heterogeneity. Heterogeneity will be quantified using I², with values of 0–30% considered low, 30–60% moderate, and > 60% substantial [28]. Publication bias will be assessed using funnel plots and Egger's regression test if ≥ 10 studies are included.

Subgroup analysis and sensitivity analysis

Subgroup analyses will be conducted based on age (< 60 vs. ≥ 60 years) and sex, provided sufficient data are available from included studies. Sensitivity analyses will be performed by (1) excluding studies with a high risk of bias, and (2) including only RCTs (excluding cohort studies).

Trial sequential analysis

Random errors can lead to spurious conclusions when a meta-analysis involves a limited number of trials and a small patient population. TSA will be employed to assess the risks associated with random errors due to insufficient sample size or repeated testing, and to estimate the required information size (RIS) for the meta-analysis. TSA will be conducted only if heterogeneity (I²) is < 50% using the TSA version 0.9.5.10 beta software. The type 1 error rate and power are set at 5% and 80%, respectively.

Certainty for evidence

Two reviewers will independently assess the certainty of the evidence using GRADEpro, a tool developed by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group [29]. The assessment criteria for certainty included, but are not limited to the initial study design, risk of bias, imprecision, indirectness, and inconsistency. Following the guidelines, the certainty of the evidence will be categorized as “high, moderate, low, or very low” with the assistance of GRADEpro. Disagreements will be resolved by consensus or by a third reviewer.

Patient and public involvement

No patient involved.

Ethics and dissemination

No ethical approval is required for this review. Our findings will be submitted to peer- reviewed journals.

Discussion

This systematic review and trial-sequential meta-analysis protocol aims to address the critical evidence gap regarding ESG in MASH. If our findings demonstrate significant histological improvement and acceptable safety, they may support ESG as a viable minimally invasive option for patients with moderate obesity and MASH, potentially influencing clinical guidelines and access policies. The results will also highlight evidence gaps and inform the design of future trials.

This study will introduce the sequential analysis method, which uses cumulative Z-curve monitoring boundaries and desired information volume to pre-determine the sample size threshold required to avoid random errors. Specifically, we will conduct the analysis under conditions of 80% test power and a 5% Type I error probability. When the cumulative Z-curve crosses the traditional significance boundary but does not reach the TSA boundary, it indicates that the current evidence is insufficient; while crossing the TSA boundary confirms the conclusion’s sufficient reliability. This methodological design is particularly important in the field of ESG research, as existing studies often have small sample sizes and conflicting results, and traditional meta-analyses may lead to misjudgments due to random error. The evidence landscape generated by trial sequential analysis not only objectively assesses the sufficiency of current evidence but also provides precise sample size calculation criteria for future research, effectively avoiding resource waste.

In terms of clinical outcomes, this protocol marks the first systematic focus on the integration and assessment of histological endpoints. Our primary endpoint is uniformly defined as MASH remission and fibrosis improvement. By consolidating and analyzing the evidence from included studies, this strategy aims to overcome the limitations of existing literature—most studies have focused on surrogate endpoints such as liver enzyme markers or imaging parameters, while a few studies incorporating histological assessments have been unable to draw reliable conclusions due to sample size constraints. Of particular note, we will explore the dose–response relationship between weight loss and histological improvement through pre-specified subgroup analyses, with a focus on the extent of histological benefits in patients achieving weight loss beyond a specific threshold. Additionally, we will prioritise monitoring long-term safety events in patients.

Despite the rigorous design of the study, several potential limitations must be acknowledged. Technical heterogeneity is the primary challenge, as differences among centers in suturing patterns, suturing density, and operational procedures may directly impact treatment outcomes. The lack of long-term data is another significant limitation, as current studies typically have follow-up periods of less than 12 months, making it difficult to assess the sustainability of histological improvements and the long-term stability of the technique. The diversity of the control group may also introduce bias, as the sham surgery control group may achieve unintended weight loss effects due to the placebo effect or intensive follow-up.

Abbreviations

MASH

Metabolic dysfunction-associated steatohepatitis

MASLD

Metabolic dysfunction-associated steatotic liver disease

TBWL

Total body weight loss

ESG

Endoscopic sleeve gastroplasty

RCTs

Randomized controlled trials

TSA

Trial sequential analysis

ROB 2

Revised Cochrane risk-of-bias tool

RevMan

Review manager

RIS

Required information size

RR

Risk ratio

CI

Confidence interval

MD

Mean difference

PRISMA-P

Referred Reporting Items for Systematic Reviews and Meta-Analysis Protocols

GRADE

Grading of Recommendations Assessment, Development, and Evaluation

Authors’ contributions

Shi-ping Sun and Han Min conceptual and designed the study. Shi-ping Sun drafted the manuscript. Shi-ping Sun and Chen Chen will retrieve relevant databases. Shi-ping Sun and Chen Chen will conduct literature screening and data extraction. Shi-ping Sun and Chen Chen will assess the risk of bias. Shi-ping Sun and Han Min proofread the manuscript and improved the English writing. Shi-ping Sun is responsible for the overall content as guarantor. All authors read and approved the manuscript.

Funding

This work was supported by Youth Project for Promoting Science and Education to Strengthen Health Care in Suzhou [Grant ID: KJXW2022035 to Chen Chen], Suzhou Municipal Key Laboratory Project of Multimodal Data Fusion and Intelligent Gerontechnology [Grant ID: 25SZZD09 to Han Min], and Suzhou Major Disease Multicenter Clinical Research Project [Grant ID: DZXYJ202508 to Han Min].

Data availability

All data and materials related to this systematic review and meta-analysis are available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.