Published on:  28 Aug 2025

Introduction

Bariatric surgery is a well-established intervention for severe obesity, leading to substantial weight loss (WL) and improvements in comorbid conditions such as diabetes mellitus (DM), hypertension (HTN), and hyperlipidemia (HLP). However, 20–25% of patients experience weight regain (WR) or insufficient weight loss (IWL) after surgery. These challenges stem from a complex interplay of factors including anatomical changes, genetic predispositions, hormonal imbalances, dietary noncompliance, and insufficient physical activity.

Despite the benefits of surgery, WR and IWL significantly impair long-term success. The variability of weight outcomes is influenced by baseline weight, surgical technique, and patient adherence, with typical weight reductions ranging between 20–30% of pre-surgical weight. Understanding and managing WR is critical for maintaining health improvements and preventing relapse into obesity-related complications.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as promising pharmacologic agents for weight management, showing efficacy in non-surgical populations including those with obesity and type 2 diabetes. Beyond weight loss, GLP-1RAs improve glycemic control and reduce cardiovascular risks. However, their specific role in patients post-bariatric surgery remains under-investigated, with limited and varied evidence. Furthermore, clinical challenges such as determining optimal timing, duration, managing side effects, and cost-effectiveness have complicated their integration into post-surgical care.

Objectives and Methods

This systematic review and meta-analysis aimed to synthesize current evidence on the efficacy and safety of GLP-1RAs in treating and preventing WR after bariatric surgery. The authors conducted a comprehensive search of PubMed, Scopus, and Web of Science databases up to March 2024, without language restrictions, following PRISMA guidelines and with protocol registration in PROSPERO (CRD42023466256).

Inclusion criteria encompassed original studies initiating GLP-1RA therapy in post-bariatric patients with reported weight outcomes. Risk of bias was evaluated using Cochrane RoB2 for randomized controlled trials (RCTs) and ROBINS-I for observational studies. Data extraction included demographic characteristics, surgery type, GLP-1RA type and dosage, timing and duration of therapy, weight changes, and adverse events.

Meta-analyses employed standardized mean difference (SMD) for continuous outcomes (WL and WR) and odds ratios (OR) for adverse events, with subgroup analyses based on treatment duration (≤6 months vs. >6 months). Sensitivity analyses assessed robustness by excluding outlier studies, and publication bias was evaluated via funnel plots.

Results

Study Characteristics

• 27 original studies met inclusion criteria, with 10 studies (5 RCTs and 5 cohort studies) included in the meta-analysis.
• Total participants numbered 769, with 392 receiving GLP-1RAs and the remainder placebo or standard care.
• Mean participant age was 05 years, with approximately 30.47% male.
• Types of bariatric surgeries included laparoscopic sleeve gastrectomy (LSG), Roux-en-Y gastric bypass (RYGB), gastric banding, and one anastomosis gastric bypass.
• GLP-1RAs administered were primarily liraglutide (up to 3 mg daily) and semaglutide (up to 2.4 mg weekly).
• Time from surgery to GLP-1RA initiation varied widely (1.5 to 87.6 months), with treatment durations ranging from 4 to 12 months.

Weight Loss Outcomes

• Initial meta-analysis of nine studies showed no significant difference in WL between GLP-1RA and placebo groups (SMD = 0.56; 95% CI -0.19 to 1.30), with high heterogeneity.
• Sensitivity analysis excluding an outlier study revealed a significant WL benefit for GLP-1RAs (SMD = 0.82; 95% CI 0.23 to 1.42).
• Subgroup analysis by treatment duration:
  • For ≤6 months treatment, GLP-1RAs showed significantly greater WL (SMD = 0.79; 95% CI 0.25 to 1.34).
  • For >6 months treatment, differences were non-significant (SMD = 0.74; 95% CI -0.32 to 1.79).
• Absolute weight loss favored GLP-1RAs by approximately 17 kg overall, with a significant difference for ≤6 months treatment (5.07 kg) but not for longer durations.
• No significant differences were found in WL or WR before therapy initiation between groups, though sensitivity analysis suggested a possible effect on WR after excluding an outlier.

Adverse Events

• Gastrointestinal side effects were most common.
• Nausea incidence was significantly higher in the GLP-1RA group (OR = 2.01; 95% CI 1.24 to 3.27).
• No significant differences were observed for vomiting or diarrhea.
• These side effects were generally manageable and did not preclude treatment.

Meta-Regression and Observational Data

• Meta-regression suggested no significant influence of demographic factors (age, sex, baseline weight) on WL or WR.
• Observational studies (17 studies, 1592 participants) reported substantial variability in WL (3.6% to 66.7%) and WR (8% to 80%) after surgery.
• After GLP-1RA initiation, weight loss ranged from 3.6% to 17.6%, reinforcing the potential role of GLP-1RAs in managing post-surgical WR.

Discussion

This comprehensive analysis supports the efficacy of GLP-1RAs in promoting weight loss among patients experiencing WR or IWL after bariatric surgery. The most marked effects occur within the first six months of treatment, consistent with patterns observed in non-surgical populations. Longer-term use may maintain or incrementally increase WL, though weight loss rates typically slow over time due to physiological adaptation and adherence issues.

Among GLP-1RAs, liraglutide was the most commonly studied agent and demonstrated significant improvements in BMI and weight reduction. However, the relative efficacy of liraglutide versus semaglutide remains to be conclusively established, highlighting a need for direct comparative trials.

Gastrointestinal adverse events, primarily nausea, were more frequent in treated patients but generally tolerable and manageable. These findings align with known side effect profiles and should not discourage clinicians from considering GLP-1RAs, given their overall safety and benefit profile.

The optimal timing for GLP-1RA initiation remains an open question. Postoperative metabolic adaptations, including increased endogenous GLP-1 secretion, may affect drug responsiveness. Early initiation might prevent WR, especially as WR typically increases after the first postoperative year, but premature use may not maximize benefit.

Sex differences also emerged as a point for further research, with women predominating in study populations and some evidence suggesting better responses to GLP-1RAs in females. Understanding these nuances could inform personalized treatment approaches.

Limitations

• Reliance on published studies introduces potential publication bias.
• Variability in GLP-1RA types, dosages, surgery types, and timing resulted in heterogeneity.
• Insufficient data limited detailed subgroup analyses.
• Observational studies often initiated treatment long after surgery, challenging conclusions about early intervention effects.
• Higher diabetes prevalence in some cohorts might influence outcomes.
• Lack of long-term follow-up restricts understanding of sustained efficacy and adverse events after treatment cessation.

Conclusion

GLP-1 receptor agonists represent a promising therapeutic strategy to address weight regain and insufficient weight loss following bariatric surgery. They provide significant weight loss benefits, especially within the first six months of treatment, and have a favorable safety profile with manageable adverse effects.

Their use may also confer additional metabolic and cardiovascular benefits, particularly in patients with diabetes or cardiovascular risk factors, though this meta-analysis focused on weight outcomes alone.

Future research must aim to:

• Define the optimal timing and duration of GLP-1RA therapy post-surgery.
• Compare the effectiveness of different GLP-1RA agents.
• Explore sex-specific responses and predictors of treatment success.
• Provide long-term real-world data on sustained weight management and safety.

Overall, GLP-1RAs offer a valuable adjunct to surgical intervention, potentially improving long-term weight management and enhancing patients’ quality of life after bariatric surgery.

SOURCE/READ FULL ARTICLE: https://pubmed.ncbi.nlm.nih.gov/40691334/

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