ABSTRACT
Background and Objective
Short bowel syndrome (SBS) is a malabsorptive condition often requiring long‐term parenteral support (PS), which is associated with significant complications. Glucagon‐like peptide‐2 (GLP‐2) analogues are shown to enhance intestinal adaptation and reduce PS dependency. This systematic review and meta‐analysis aimed to evaluate the efficacy and safety of GLP‐2 analogues in adult patients with SBS dependent on PS.
Methods
A systematic search of CENTRAL, PubMed, Embase, ClinicalTrials.gov, and Google Scholar was conducted from inception till May 2025. We included randomized controlled trials (RCTs) comparing GLP‐2 analogues with placebo in adult SBS patients on stable PS. We analyzed the outcomes using RevMan 5.4, with risk ratio (RR) and mean differences (MD) as the effect measures.
Results
Six RCTs comprising 454 patients were included. GLP‐2 analogues significantly reduced PS volume (MD: −251.51 mL/day; 95% CI: −363.93 to −139.08; I 2 = 2.5%). The proportion of responders was significantly higher in the treatment group (RR: 1.97; 95% CI: 1.47–2.64), with no significant difference in adverse or serious adverse events between the two groups.
Conclusion
Our meta‐analysis found that GLP‐2 analogues are effective in reducing PS volume in patients with SBS who are dependent on PS, without an increase in adverse events. However, the current evidence is limited by a small number of early clinical trials, heterogeneity in dosing regimens, and a paucity of data on newer agents like glepaglutide. Further large‐scale phase 3 RCTs are needed to validate the safety and efficacy of GLP‐2 analogues before they can be adopted for routine clinical practice.
1. Introduction
Short bowel syndrome (SBS) in adults is defined as having less than 180–200 cm of remaining functional small intestine (typically ranging from 275 to 850 cm), leading to decreased nutrient absorption [1]. This condition can result from extensive surgical removal of the bowel, congenital disorders, or diseases that lead to impaired absorption [1]. This leads to diarrhea, dehydration, malnutrition, electrolyte imbalance, and eventually, chronic intestinal failure (CIF) [1, 2]. The initial management of SBS focuses on maintaining adequate nutrition and enhancing the absorptive capacity of the remnant intestine [2]. Patients with SBS often require long‐term parenteral support (PS) to maintain adequate nutrition during the intestinal adaptation phase, and some may require lifelong PS if they develop CIF [3, 4, 5].
PS carries risks, including catheter‐related infections and resultant sepsis, metabolic imbalances, liver dysfunction, thrombosis, and kidney dysfunction [5, 6, 7]. Long‐term use may also cause micronutrient deficiencies, bone disease, and reduced quality of life due to psychosocial burdens, such as social isolation and disturbed sleep patterns [8, 9]. Other conventional pharmacologic treatments for patients with SBS include antisecretory agents and gastrointestinal motility‐modulating drugs [10]. These medications help reduce water and electrolyte losses, particularly in patients with high fecal outputs, thereby minimizing the symptoms and consequences of diarrhea. The limited efficacy of conventional treatments, coupled with the risks and complications associated with PS, underscores the necessity for the development of novel therapeutic strategies [5, 10].
In recent years, therapies that target and enhance intestinal adaptation have garnered increasing attention as a means to improve nutrient absorption and maintain fluid‐electrolyte balance in patients who have undergone bowel resection. Intestinal adaptation involves both structural changes, such as an increase in surface area, and functional changes, including slower transit time [11, 12]. Most adaptations occur within the first 12–24 months [2, 3]. Strategies aimed at enhancing intestinal adaptation could enable patients with CIN to discontinue PS [13]. These approaches encompass the use of growth stimulators such as growth hormone, epidermal growth factor (EGF), insulin‐like growth factor 1 (IGF‐1), and glucagon‐like peptide‐2 (GLP‐2), as well as somatostatin analogues like octreotide, and luminal nutrients including glutamine, soluble dietary fibers, short‐chain fatty acids, and pancreaticobiliary secretions [3, 10, 11]. GLP‐2 is a gut hormone that is closely associated with intestinal growth and adaptation after resection. It activates the G protein‐coupled receptor (GLP‐2R) and mediates its intestinotrophic effects through downstream effectors [4]. GLP‐2 analogues, such as Teduglutide, Apraglutide, and Glepaglutide, have hence emerged as a promising treatment option for managing SBS [12, 13].
Previously, there have been meta‐analyses on GLP‐2 analogues in SBS, but some of them included observational studies, while others included non‐randomized trials [14, 15]. Numerous new randomized controlled trials (RCTs) on GLP‐2 analogues for SBS have been published, including larger studies with robust data [16, 17]. Hence, there is a need to conduct a meta‐analysis to take all these factors into account. We performed this systematic review and meta‐analysis to investigate the safety and efficacy of GLP2 analogues in patients with SBS who are dependent on PS.
2. Methods
We conducted this systematic review and meta‐analysis adhering to the Cochrane Handbook for Systematic Reviews of Interventions guidelines and reported according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analysis (PRISMA) statement (Table S1) [18, 19]. The study protocol was prospectively registered in the International Prospective Register of Systematic Reviews (PROSPERO) under the registration number (CRD420251071898).
2.1. Data Sources and Searches
A comprehensive search was conducted in PubMed, Scopus, the Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science, without language restrictions, from inception to May 2025. All the randomized controlled trials (RCTs) assessing the safety and efficacy of GLP‐2 analogues for short bowel syndrome were included [20]. Reference lists of included trials and relevant reviews were manually screened to identify additional eligible studies. The detailed search strategy is included in the Table S2.
2.2. Eligibility Criteria
Randomized controlled trials were eligible if they included adult patients (aged 18 years or more) with SBS stable on PS taking any GLP‐2 analogues (teduglutide, glepaglutide, and apraglutide), regardless of the dosing regimen or route of administration. The comparator should be a placebo. Studies were required to report at least one predefined primary or secondary outcome. Trials enrolling animal populations, or not reporting parenteral support volume as an outcome, were excluded. The primary outcomes were changes in parenteral support volume and all‐cause mortality. Our secondary outcomes were the number of responders (defined as the proportion of patients achieving a ≥ 20% reduction in PS volume) and the incidence of serious adverse events.
2.3. Study Selection and Data Extraction
The studies yielded by our search strategy were imported into the Rayyan tool, where duplicate articles were removed. Two authors independently reviewed the full texts of the remaining articles and finalized studies that met the pre‐specified eligibility criteria. Any disagreements between the reviewers were resolved by reaching a consensus or discussion with a third independent reviewer.
Data regarding study characteristics (including authors and study location), patient population (including mean age, BMI, parenteral support volume, time since the start of parenteral support, remnant small bowel length with jejunostomy/ileostomy, remnant small bowel length with colon in continuity, and follow‐up duration), GLP2 analogues (including type and dosage), and primary and secondary outcomes were extracted into a prepared Excel sheet.
2.4. Risk of Bias Assessment
Risk of bias was assessed using the Cochrane Risk of Bias 2 (ROB‐2) [21] tool across five domains: (D1) bias arising from the randomization process, (D2) bias due to deviations from intended interventions, (D3) bias due to missing outcome data, (D4) bias in measurement of the outcome, and (D5) bias in selection of the reported result. Based on the domain‐level judgments, two independent authors evaluated the overall risk of bias for each study, categorized as “low risk,” “some concerns,” or “high risk.” Any discrepancy in the evaluation of bias risk was resolved by a senior author.
2.5. Data Synthesis
Review Manager (RevMan, Version 5.4; The Cochrane Collaboration, Copenhagen, Denmark) was used to conduct the meta‐analyses. Rest plots were generated using risk ratio (RR) for dichotomous outcomes and standardized mean difference (SMD) for continuous outcomes, each of which was presented with its respective 95% confidence intervals (CI). A random‐effects model was applied to all outcomes. Statistical heterogeneity was evaluated using Higgins' I 2 statistics. An I 2 < 30% indicated low heterogeneity, while 30%–70% was considered as moderate, and > 70% indicated high heterogeneity. Subgroup analysis based on the type of agonist used was conducted for the primary outcome. Additionally, pre‐specified subgroup analyses were conducted based on the type of GLP‐2 analogues used to examine the primary outcomes. The publication bias was assessed using a funnel plot and Egger's test for funnel plot asymmetry in Stata 17.0 (StataCorp LLC, College Station, TX, USA).
3. Results
We included six RCTs reporting data from 454 patients in our meta‐analysis [16, 17, 22, 23, 24, 25]. The detailed study selection process is illustrated in the PRISMA flowchart (Figure 1). All RCTs were multinational, except two, which were conducted in the United States and Denmark [17, 23]. Two of the included studies were crossover trials [17, 23] All studies used one of the three GLP‐2 analogues (Apraglutide, Glepaglutide, or Teduglutide). Glepaglutide was administered at 10 mg once or twice weekly, and teduglutide was administered at 0.05 mg/kg/day in three trials [16, 23, 24, 25]. Apraglutide was used in two trials and administered at a dose of 2 mg, 5 mg, or 5 mg/day [17, 22]. The detailed characteristics of each study are presented in Table 1.
FIGURE 1.
PRISMA flowchart for the screening process.
TABLE 1.
Characteristics of included studies.
| Study ID | Jeppesen 2025 | Iturrino 2015 | Eliasson 2022 | Jeppesen 2011 | Jeppesen 2012 | STARS trial |
|---|---|---|---|---|---|---|
| Study type | Randomized, placebo‐controlled, double‐blind, phase 3 trial | Double‐blinded, randomized, crossover study | Double‐blind, crossover, randomized, placebo‐controlled, phase 2 trial | Randomized Placebo Controlled Trial | Randomized, placebo‐controlled, double‐blind, phase 3 trial | Phase 3, double‐blind, randomized, placebo‐controlled trial |
| NCT number | NCT03690206 | NCT02099084 | NCT03415594 | NCT00172185 | NCT00798967 | NCT04627025 |
| Location | United States, the United Kingdom, Belgium, Canada, Denmark, France, Germany, the Netherlands, and Poland. | USA | Denmark | USA, Canada, Denmark, France, Poland, Germany, Netherlands, the UK, and Belgium | Europe and North America | 18 countries across Europe, the UK, and Japan |
| Study arms | Glepaglutide versus Placebo | Teduglutide versus Placebo | Apraglutide versus Placebo | Teduglutide versus Placebo | Teduglutide versus Placebo | Apraglutide versus Placebo |
| No. of patients | 106 (35 vs. 35 vs. 36) | 8 versus 8 | 8 versus 8 | 83 (35 vs. 32 vs. 16) | 86 (43 vs. 43) | 163 (110 vs. 53) |
| Study population | Adult patients > 18 years with SBS; intestinal resection at least 6 months before screening; requirement for PS at least 3 days/week; presence of a stoma or a colon‐in‐continuity (CiC) | Adult patients > 18 years with SBS who were dependent on HPN. | Adult patients > 18 years with SBS‐IF secondary to surgical resection of the small bowel with a jejuno‐ or ileostomy, ≥ 6 months since the last bowel resection, dependent on PS ≥ 3 times per week for ≥ 12 months | Adult patients > 18 years with SBS‐IF secondary to surgical resection of the small bowel with a jejuno‐ or ileostomy, ≥ 6 months since the last bowel resection, dependent on PS ≥ 3 times per week for ≥ 12 months | Adult patients > 18 years with SBS resulting from intestinal failure caused by a major intestinal resection (e.g., injury, cancer, Crohn's disease, vascular disease, volvulus) who were dependent on PS for at least 12 months | Adult patients aged ≥ 18 with SBS‐IF, considered stable and receiving PS, secondary to surgical resection of the small intestine with either stoma or colon‐in‐continuity (CIC). |
| Dose of GLP‐2 agonist | Glepaglutide 10 mg once weekly, or Glepaglutide 10 mg twice weekly. | Teduglutide; once daily, subcutaneously, 0.05 mg/kg | Apraglutide (5 mg) | Teduglutide (0.05 mg/kg/day) and Teduglutide (0.05 mg/kg/day) once daily | Teduglutide (0.05 mg/kg/day) for 24 weeks | Apraglutide 5 mg if wt > 50 kg, 2.5 mg if wt < 50 kg |
| Mean age (Mean ± SD) | 56.9 ± 13.4 versus 54.0 ± 11.8 (years) | 54 ± 13 | 57.25 (37.53) | 47.1 (14.2) versus 50.3 (14.0) versus 49.4 (15.1) | 49.7 (15.6) versus 50.9 (12.6) | — |
| BMI (Mean ± SD) | 23.6 ± 3.4 versus 23.5 ± 3.6 (kg/m2) | 25 ± 4 | 25.32 (9.65) | 21.2 (3.0) versus 21.7 (2.6) versus 22.0 (2.9) | 22.3 (3.1) versus 22.5 (3.2) | — |
| PS volume (Mean ± SD) | 13.8 ± 8.1 versus 14.8 ± 7.9 (L/week) | N/A | 3468.87 (5531.71) | 1374 mL/day (639) versus 1816 mL/day (1008) versus 1531 mL/day (874) | 1929 mL/day (1026) versus 1844 mL/day (1057) | — |
| Time since start of PS (Mean ± SD) | 7.6 ± 8.3 versus 5.0 ± 5.2 (years) | 11.86 ± 22.24 | N/A | 6.6 years (6.5) versus 7.3 years (5.9) versus 7.9 years (7.5) | 5.9 years (5.7) versus 6.8 years (6.3) | — |
| Remnant small bowel length with jejunostomy/ileostomy (Mean ± SD) | N/A | 63 ± 12 | 8 | 105 (54) versus 77 (60) versus 144 (52) | 122.8 cm (81.6) versus 137.7 cm (70.9) | — |
| Remnant small bowel length with colon in continuity (Mean ± SD) | 59.0 ± 28.6 versus 64.3 ± 21.5 (%) | 0 | 45 (29) versus 62 (27) versus 53 (26) | 45 (29) versus 62 (27) versus 53 (26) | 43.3 cm (31.5) versus 52.4 cm (31.8) | — |
| Follow‐up duration | 24 weeks | 21 days | 34–38 weeks | 24 weeks | 24 weeks | 48 weeks |
Abbreviations: BMI, body mass index; CiC, colon‐in‐continuity; cm, centimeter; GLP‐2, glucagon‐like peptide‐2; HPN, home parenteral nutrition; kg, kilogram; mg, milligram; mL/ml, milliliter; NCT, National Clinical Trial (registry number); PS, parenteral support; SBS, short bowel syndrome; SBS‐IF, short bowel syndrome with intestinal failure; SD, standard deviation; vs, versus; wt, weight; yrs, years.
3.1. Risk of Bias of Included Studies
Three of the six included studies had a low risk of bias [17, 23, 24]. The other three studies had some concerns of bias, primarily due to issues in the domain of bias due to missing outcome data [16, 22, 25]. The risk of bias assessment is summarized in Figure 2.
FIGURE 2.
Risk of bias assessment of included studies.
3.2. Synthesis of Results
3.2.1. Primary Outcomes
3.2.1.1. Change in PS Volume From Baseline
The pooled analysis showed that GLP‐2 analogue administration was associated with a significant mean reduction in parenteral support volume from baseline in patients with SBS (MD −251.51 mL/day; 95% CI: −363.93 to −139.08 mL/day, Figure 3). Statistical heterogeneity was minimal (I 2 = 2.5%).
FIGURE 3.
Effect of GLP‐2 analogues versus placebo on mean change in parenteral support volume from baseline.
Subgroup analyses based on the type of GLP‐2 analogue used showed that the results were consistent in the teduglutide (MD −274.79 mL/day; 95% CI: −428.00 to −121.59 mL/day) and glepaglutide (MD −326.00 mL/day; 95% CI: −546.79 to −105.21 mL/day) groups, and inconsistent in the apraglutide (MD −94.00 mL/day; 95% CI: −344.00 to 156.00 mL/day) group. There was evidence of publication bias on the inspection of funnel plot asymmetry (Egger's p‐value = 0.99), but the number of studies was small (Figure S1).
3.2.2. Adverse Events
The meta‐analysis of five studies showed that the rate of any adverse events (RR 1.01; 95% CI: 0.94–1.09, Figure 4) did not differ between the two groups. Heterogeneity was minimal (I 2 = 0%). Subgroup analysis based on the type of GLP‐2 analogue showed consistent results (P heterogeneity = 0.83). There was no evidence of publication bias on the inspection of funnel plot asymmetry (Egger's p‐value = 0.45), but the number of studies was small (Figure S2).
FIGURE 4.
Effect of GLP‐2 analogues versus placebo on incidence of adverse events.
3.2.3. Secondary Outcomes
3.2.3.1. Number of Responders
A meta‐analysis of four studies comprising 371 patients showed that patients with SBS responded significantly to GLP‐2 analogues (RR 1.97; 95% CI: 1.47–2.64; Figure 5) compared to the placebo group. The heterogeneity was found to be minimal (I 2 = 0%). There was no evidence of publication bias on the inspection of funnel plot asymmetry (Egger's p‐value = 0.20), but the number of studies was small (Figure S3).
FIGURE 5.
Effect of GLP‐2 analogues versus placebo on the number of responders.
3.2.3.2. Incidence of Serious Adverse Events
The analysis revealed that the incidence of serious adverse events was comparable between the two groups. (RR 1.19, 95% CI: 0.86–1.63; Figure 6). The heterogeneity was minimal (I 2 = 0%). The inspection of the funnel plot showed slight asymmetry but not statistically significant (Egger's p‐value = 0.21) (Figure S4).
FIGURE 6.
Effect of GLP‐2 analogues versus placebo on the incidence of serious adverse events.
4. Discussion
This systematic review and meta‐analysis included six RCTs that evaluated the efficacy and safety of GLP‐2 analogues in patients with SBS. Our analysis shows the superiority of GLP‐2 analogues in reducing PS volume in patients with SBS. Notably, a greater proportion of patients treated with GLP‐2 receptor analogues achieved a clinical response than those who received a placebo. These findings align with those of a previous meta‐analysis by Biolleto et al., who reported comparable benefits of teduglutide in reducing PS volume and increasing the number of responders [15]. However, our research offers an extensive contribution to the current body of literature, as it encompasses multiple GLP‐2 analogues, including teduglutide, glepaglutide, and apraglutide, with a larger sample size. This enables a more comprehensive evaluation of the entire GLP‐2 analogues class. Notably, the quality of evidence was superior for the teduglutide and glepaglutide subgroups compared with apraglutide. However, these findings primarily stem from a limited number of small RCTs [16, 17, 22], highlighting the need for large‐scale RCTs in this specific population.
Furthermore, the incidence of adverse events and serious adverse events did not differ significantly between the GLP‐2 analogues and placebo groups, indicating a favorable safety profile of the drug. Importantly, no mortality was reported in either group during the study period. Although the precise mechanism remains unclear, GLP‐2 analogues specifically target intestinal L‐cells and enteric neurons, thereby improving nutrient absorption while minimizing unintended effects on other areas [12]. This localized action may explain the low incidence of systemic adverse events such as abdominal pain, nausea, bloating/distension, vomiting, diarrhea, or constipation [11]. This finding is consistent with two previous meta‐analyses, both of which demonstrated an overall safe profile of GLP‐2 analogues [12, 13].
GLP‐2 is an enteroendocrine hormone that plays a key role in regulating the growth and function of the intestinal mucosa [12, 13]. It has been extensively studied for its potential therapeutic benefits in patients with SBS, particularly those with intestinal failure. Although Teduglutide is currently approved for SBS, its half‐life is less than two hours [26]. Therefore, it is administered as a subcutaneous injection once daily, which is inconvenient for patients. Glepaglutide, on the other hand, is a novel GLP‐2 analogue, with a half‐life of 88.3 h, and can be given once or twice weekly in the form of subcutaneous depot, hence improving compliance and quality of life [11, 16, 27]. Our results, incorporating the promising findings of a recent trial by Jeppesen et al., found that GLP‐2 analogues, especially glepaglutide and teduglutide, are well‐tolerated and effective in patients with SBS dependent on PS.
The strength of our review stems from the fact that, unlike previous meta‐analyses, it is strictly limited to RCTs with both parallel‐group and crossover designs, thereby maximizing internal validity and minimizing the risk of bias. Additionally, the inclusion of the recent, large‐scale multicenter trial by Jeppesen et al. expanded our sample size, thereby improving the precision and robustness of our pooled estimates compared to previous analyses [16]. We detected no statistical heterogeneity, indicating robust consistency across the trials. Several limitations must be considered when interpreting the results of this study. There were variations among studies regarding the dosages of regimens, follow‐up durations, and etiology of SBS (e.g., jejunostomy vs. colon‐in‐continuity), which limits the generalizability. However, the small number of trials and limited data constrain further subgroup analyses based on the etiology of SBS or the presence or absence of concurrent CIF.
There was evidence of publication bias in some of the outcomes, but the number of studies was < 10; hence, it is unreliable. The study population is limited, and external generalizability should be interpreted cautiously. These results should be interpreted as exploratory and hypothesis‐generating rather than confirmatory. Currently, our analysis includes the only available RCT on Glepaglutide. However, two ongoing trials are anticipated to further strengthen the evidence base in the future [28, 29]. Future research should focus on large‐scale, head‐to‐head RCTs with standardized dosing regimens, long‐term follow‐up, and relevant subgroups to better define the optimal indications and dosing of GLP‐2 analogues based on the etiology and progression of SBS. The inclusion of patient‐centric outcomes such as quality of life, nutritional autonomy, and long‐term survival can enhance clinical relevance in future studies.
Our meta‐analysis found that GLP‐2 analogues are effective in reducing PS volume in patients with SBS who are dependent on PS, without an increase in adverse events. However, the current evidence is limited by a small number of early clinical trials, heterogeneity in dosing regimens, and a paucity of data on newer agents like glepaglutide. Further large‐scale phase 3 RCTs are needed to validate the safety and efficacy of GLP‐2 analogues before they can be adopted for routine clinical practice.
Funding
The authors have nothing to report.
Conflicts of Interest
The authors declare no conflicts of interest.
Supporting information
Table S1: PRISMA checklist.
Table S2: Search strategy for electronic databases.
Figure S1: Funnel Plot for the effect of GLP‐2 analogues versus placebo on mean change in parenteral support volume from baseline.
Figure S2: Funnel Plot for the effect of GLP‐2 analogues versus placebo on incidence of adverse events.
Figure S3: Funnel Plot for the effect of GLP‐2 analogues versus placebo on the number of responders.
Figure S4: Funnel Plot for the effect of GLP‐2 analogues versus placebo on the incidence of serious adverse events.
Acknowledgments
The authors have nothing to report.
Hyder A., Alria A., Rafiq A., et al., “Glucagon‐Like Peptide‐2 (GLP‐2) Analogues in Patients With Short Bowel Syndrome Dependent on Parenteral Support: A Systematic Review and Meta‐Analysis of Randomized Controlled Trials,” JGH Open 9, no. 12 (2025): e70327, 10.1002/jgh3.70327.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1: PRISMA checklist.
Table S2: Search strategy for electronic databases.
Figure S1: Funnel Plot for the effect of GLP‐2 analogues versus placebo on mean change in parenteral support volume from baseline.
Figure S2: Funnel Plot for the effect of GLP‐2 analogues versus placebo on incidence of adverse events.
Figure S3: Funnel Plot for the effect of GLP‐2 analogues versus placebo on the number of responders.
Figure S4: Funnel Plot for the effect of GLP‐2 analogues versus placebo on the incidence of serious adverse events.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.