Beyond intestinal failure: Expanding therapeutic frontiers of glucagon-like peptide-2 in gastrointestinal disease

Abstract

Short bowel syndrome represents a severe form of intestinal failure characterized by malabsorption and dependence on parenteral nutrition (PN). Advances in gut hormone research have positioned glucagon-like peptide-2 (GLP-2) and its analogues as key pharmacologic agents promoting intestinal adaptation and reducing PN dependence. This minireview summarizes current evidence on the mechanisms, clinical efficacy, and expanding therapeutic applications of GLP-2 analogues, with emphasis on emerging agents such as glepaglutide and their safety profiles. GLP-2, a 33-amino acid peptide secreted by enteroendocrine L cells, enhances mucosal growth, nutrient absorption, and intestinal barrier integrity through activation of cyclic adenosine monophosphate-dependent and insulin-like growth factor-1-mediated pathways. Clinical trials have demonstrated that teduglutide and newer long-acting analogues such as glepaglutide significantly increase plasma citrulline levels, reduce fecal output, and decrease PN requirements while improving hepatic function and quality of life. Additionally, preclinical and clinical data support GLP-2’s anti-inflammatory effects in inflammatory bowel disease and its potential to mitigate intestinal failure-associated liver disease. Although current evidence indicates low neoplastic risk, long-term safety monitoring remains essential. GLP-2 analogues represent a paradigm shift in short bowel syndrome management, transforming care from supportive nutrition to regenerative therapy. Ongoing studies exploring novel formulations, broader indications, and precision medicine approaches will further refine their clinical integration and maximize therapeutic benefit.

Key Words: Glucagon-like peptide-2; Short bowel syndrome; Intestinal failure; Teduglutide; Intestinal rehabilitation; Inflammatory bowel disease; Crohn’s disease

Core Tip: Short bowel syndrome is a life-threatening cause of intestinal failure traditionally managed with long-term parenteral nutrition. Recent advances highlight glucagon-like peptide-2 analogues as disease-modifying therapies that enhance intestinal adaptation rather than merely providing nutritional support. By stimulating mucosal growth, improving absorptive capacity, and strengthening the intestinal barrier, agents such as teduglutide and emerging long-acting analogues like glepaglutide significantly reduce parenteral nutrition dependence and improve quality of life. Beyond short bowel syndrome, accumulating evidence suggests anti-inflammatory and hepatoprotective benefits, supporting broader therapeutic potential. Ongoing research and long-term safety surveillance will be crucial to optimizing their clinical application.

INTRODUCTION

Short bowel syndrome (SBS) is a rare yet serious malabsorptive disease due to the significant loss of segments from the small intestine, decreasing not only nutrient but also water, and electrolyte intake[1,2]. The average bowel length in healthy adults ranges around 3-8 m, however, individuals with SBS generally have a bowl length of not more than 2 m[1-3]. This condition can be congenital, because of developmental abnormalities (genetic mutation, intestinal atresia, gastroschisis) or acquired, usually secondary to reduction in functional bowel length due to inflammatory bowel diseases (IBDs) such as Crohn’s disease (CD), along with mesenteric ischemia, radiation enteritis, or any surgical complications[1,3-5]. Functionally, intestinal failure (IF), which might follow SBS, according to the European Society for Clinical Nutrition and Metabolism is categorized into: Type I (acute and self-limiting), type II (prolonged acute in metabolically unstable patients requiring multidisciplinary care and intravenous supplementation for a specific period of time), and type III [chronic, stable IF requiring long term parenteral support (PS)][1,3,6].

Nowadays, research helped achieve a tremendous transition in the management of SBS from solely depending on parenteral nutrition (PN) towards intestinal rejuvenation and pharmacologic intestinal trophic therapy[3,4,7]. One of the most impactful hormonal agents studied was glucagon-like peptide-2 (GLP-2) which played a pivotal role in regulation of intestinal adaptation[1,3,8,9]. This hormone is composed of a 33-amino acid peptide secreted by enteroendocrine L cells present in the distal small intestine and colon after nutrient ingestion[4]. The following article highlights the intestinotrophic effect of GLP-2 on enterocytes and its advantages on nutrient absorption, crypt cell hyperplasia in SBS. The aim of this paper is to provide an updated and comprehensive overview of the physiological mechanisms, clinical efficacy, and safety of GLP-2 and its analogues in the management of SBS and IF, with additional emphasis on their emerging therapeutic roles in IBD and other intestinal disorders. By synthesizing current experimental and clinical evidence, this minireview seeks to highlight how GLP-2-based therapies are reshaping intestinal rehabilitation strategies and to identify key gaps and future directions for research and clinical practice.

GLP-2: DEFINITION AND MECHANISM OF ACTION

GLP-2 is a hormone made up of 33-amino-acid peptides derived from the proglucagon geneon chromosome 2[10,11]. It is known to be excreted with GLP-1 by enteroendocrine L cells in the small intestine distally and in the colon[4] (Figure 1). GLP-2 has essential intestinotrophic effect, for example it is effective in stimulating crypt-cell proliferation as well as increasing villus height and enhancing nutrient absorption[3,4,7,11-13]. It also slows gastrointestinal motility and gastric acid secretion while increasing mesenteric blood flow which in turn promotes mucosal repair and creates a stronger intestinal barrier[4,11,14,15]. GLP-2 acts through a specific G-protein-coupled GLP-2 receptor found on enteroendocrine cells, enteric neurons and myofibroblasts throughout the gut[10,11]. Binding to the receptor activates adenylyl cyclase and raises intracellular cyclic adenosine monophosphate and activates other kinase cascades such as protein kinase A, mitogen-activated protein kinase A and epidermal growth factor receptor[10,11,16,17]. Notably, GLP-2 stimulates intestinal epithelial proliferation indirectly through the release of insulin-like growth factor-1 (IGF-1), which essential for enterocyte growth, inhibition of intestinal epithelium apoptosis and thus an increase in total gut weight[10,11,18-20]. These trophic actions translate into functional effects when it comes to SBS and IF by playing a major role in reducing gastrointestinal losses and augmenting absorption through the increase of absorptive surface area[1,3].

Figure 1  Glucagon-like peptide-2 mechanism of action.

ADVANCES IN GLP-2 ANALOGUE THERAPY FOR SBS

GLP-2 analogues including teduglutide, glepaglutide, and apraglutiderepresent a major therapeutic advancement in the management of SBS, a condition characterized by IF due to reduced absorptive surface area. These agents exert potent intestinotrophic effects, stimulating mucosal growth, enhancing nutrient and fluid absorption, and reducing intestinal secretion and motility[1,4,10,21]. Their primary mechanism of action lies in promoting intestinal adaptation, leading to improved absorption and a reduced need for PN or PS.

Clinical trials have demonstrated that GLP-2 therapy significantly increases plasma citrulline levels, a reliable biomarker of enterocyte mass and intestinal mucosal growth[21]. This increase reflects a direct expansion of the functional absorptive surface, confirming a true disease-modifying effect. In parallel, reductions in serum alkaline phosphatase and gamma-glutamyl transferase have been observed, suggesting a beneficial impact on liver function likely due to reduced PN dependence and improved enteral tolerance, which mitigate PN-associated liver complications[21].

Teduglutide remains the most extensively studied and clinically established GLP-2 analogue, validated by the pivotal STEPS trials, which confirmed significant reductions in PN requirements and enabled some patients to achieve complete PN independence[4]. Long-term follow-up studies, including STEPS-2 and STEPS-3, demonstrated sustained efficacy and safety, though discontinuation often led to the reversal of benefits. Newer, long-acting analogues such as glepaglutide and apraglutide have been engineered to provide once- or twice-weekly dosing with comparable efficacy and improved adherence[1,4].

Mechanistically, GLP-2 analogues act indirectly via subepithelial cells and enteric neurons, inducing growth factors such as IGF-1 and epidermal growth factor that promote epithelial expansion and prevent enterocyte apoptosis[10]. They also enhance intestinal blood flow, strengthen mucosal barrier integrity, and improve absorptive efficiency. While generally well tolerated, potential risks include gastrointestinal side effects and the theoretical concern of neoplastic stimulation, necessitating periodic colonoscopic surveillance during long-term therapy[10].

CLINICAL EVIDENCE ON GLEPAGLUTIDE IN SBS

Glepaglutide, a next-generation long-acting GLP-2 analogue, has emerged as a promising therapeutic agent in the management of SBS. Its pharmacological profile is designed to promote intestinal adaptation, enhance nutrient absorption, and reduce PS dependence by prolonging the trophic effects of native GLP-2. A growing body of clinical research supports its efficacy, safety, and potential disease-modifying properties across different stages of SBS management (Table 1).

Table 1 Summary of clinical and experimental studies on glepaglutide in short bowel syndrome.

Ref.	Design/population	Intervention and dose	Duration	Key findings	Main outcomes/notes
Hvistendahl et al[22]	Randomized, double-blind, phase 2 crossover trial (n = 18 SBS patients with distal resections)	Daily glepaglutide 0.1 mg, 1 mg, or 10 mg	3 weeks per dose (with washout)	Dose-dependent delay in gastric emptying and small-bowel transit (scintigraphy)	Prolonged nutrient exposure; improved absorption potential; scintigraphy most sensitive to gastrointestinal transit changes
Agersnap et al[23]	Phase 1 study in healthy volunteers	SC 5 or 10 mg weekly × 6 weeks; single IV 1 mg dose	6 weeks	Sustained plasma exposure via active metabolites (M1, M2); half-life 88-124 hours	Supports once- or twice-weekly dosing; increased plasma citrulline (increased enterocyte mass); mild injection-site reactions only
Naimi et al[24]	Randomized, cross-over phase 2 trial (n = 18 SBS patients)	Daily glepaglutide 0.1 mg, 1 mg, or 10 mg	3 weeks	10 mg improved hepatic excretory function (increased ICG clearance, decreased retention)	Suggests benefit in IFALD; mild macrophage activation (increased soluble CD163); no major safety issues
Vanuytsel et al[25]	International real-world survey (19 intestinal failure centers)	Clinical use of GLP-2 analogues (mainly teduglutide, some glepaglutide)	Cross-sectional	Approximately 30% eligible; approximately 10% treated due to cost barriers; early initiation common	Mean PS reduction ≥ 20%; improved urine output; mild AEs (abdominal pain, stoma hypertrophy)
Naimi et al[26]	Randomized, phase 2 crossover study (n = 18 SBS patients)	Daily glepaglutide 0.1-10 mg	3 weeks	Increased plasma citrulline (1 and 10 mg); increased crypt depth and epithelial height	Reduced fecal output; structural mucosal adaptation without perfusion changes
Pinar et al[27]	Open-label phase 3b study (n = 10 SBS patients; SBS-IF and SBS-II)	Glepaglutide (dose not specified, long-term use)	52 weeks	Increased intestinal energy absorption (+1038 kJ/day, +23%); decreased PS volume by 800 mL/day (-30%)	Improved carbohydrate absorption and electrolyte balance; well tolerated long term

SC: Subcutaneous; IV: Intravenous; SBS: Short bowel syndrome; IFALD: Intestinal failure-associated liver disease; GLP-2: Glucagon-like peptide-2; PS: Parenteral support; AEs: Adverse events; SBS-IF: Short bowel syndrome-intestinal failure; SBS-II: Short bowel syndrome-intestinal inflammation.

In a randomized, double-blind, phase 2 crossover trial, glepaglutide demonstrated a dose-dependent effect on gastrointestinal motility and transit time in patients with SBS and distal-bowel resections[22]. Eighteen patients received 3-week treatment periods of glepaglutide at 0.1, 1, or 10 mg daily, separated by washout intervals. Gastrointestinal transit was evaluated using scintigraphy, wireless motility capsule, and the paracetamol absorption test. The highest dose (10 mg) significantly prolonged both gastric emptying and small-bowel transit times for solids and fluids on scintigraphy, whereas lower doses showed minimal effects. This delay in transit time suggests prolonged mucosal exposure to luminal nutrients, promoting improved absorption, an effect clinically relevant in SBS where accelerated transit contributes to malabsorption. Interestingly, the wireless motility capsule and paracetamol tests yielded limited concordant results, underscoring scintigraphy as the most sensitive tool for evaluating gastrointestinal transit changes in this population. These findings align with glepaglutide’s mechanism of enhancing absorptive capacity by slowing transit, complementing previously observed reductions in fecal output and improvements in intestinal fluid retention[22].

A complementary phase I study further elucidated the pharmacokinetic and pharmacodynamic characteristics of glepaglutide in healthy volunteers[23]. Participants received subcutaneous doses of 5 mg or 10 mg weekly for six weeks or a single intravenous dose of 1 mg. The study revealed that glepaglutide undergoes slow release from a subcutaneous depot, resulting in sustained plasma exposure primarily through its active metabolites (M1 and M2), which accounted for over 98% of total exposure at steady state. The effective half-life ranged from 88 hours to 124 hours after subcutaneous administration, markedly longer than the approximately 12-hour half-life observed following intravenous infusion, supporting the feasibility of once- or twice-weekly dosing. Additionally, plasma citrulline, a biomarker of enterocyte mass, increased during treatment, reflecting stimulation of intestinal mucosal growth. The drug was well tolerated, with only mild injection-site reactions reported, confirming a favorable safety and pharmacological profile conducive to long-term SBS therapy[23].

Beyond its intestinal effects, glepaglutide may also influence hepatic function and the gut-liver axis. In a randomized, cross-over phase 2 trial, researchers explored its potential role in mitigating IF-associated liver disease[24]. Eighteen SBS patients received daily glepaglutide at 0.1, 1, or 10 mg for three weeks. The 10 mg dose significantly improved hepatic excretory function, evidenced by an increased indocyanine green plasma disappearance rate and decreased retention after 15 minutes, suggesting enhanced hepatic clearance. However, this dose also led to increased levels of soluble CD163, a marker of hepatic macrophage activation, and a non-significant rise in liver stiffness on transient elastography. These mixed effects may reflect glepaglutide-induced splanchnic vasodilation and altered hepatic perfusion, warranting further evaluation in larger, longer-term trials[24].

Real-world data provide additional insight into the clinical implementation of GLP-2 analogues. An international survey across 19 experts IF centers revealed that although approximately 30% of SBS-IF patients met eligibility criteria for GLP-2 therapy, only around 10% were receiving it[25]. The principal barriers were financial constraints and limited reimbursement, especially in the United States. Most centers initiated therapy between 6 and 12 months post-resection, earlier than recommended in formal guidelines, emphasizing the perceived benefits of timely intervention. Treatment success was predominantly defined by reductions in PS volume (> 20%) or frequency (≥ 1 day/week off PS), alongside increased urinary output. Reported adverse events were generally mild, with abdominal discomfort and stoma hypertrophy being the most frequent[25].

In a phase 2 crossover study in 18 SBS patients evaluated glepaglutide’s dose-dependent intestinotrophic effects. After three weeks of daily treatment (0.1-10 mg), plasma citrulline levels increased significantly at 1 mg and 10 mg, indicating greater enterocyte mass. Intestinal biopsies confirmed increased crypt depth and epithelial height at 10 mg, correlating with reduced fecal output and enhanced absorption. No sustained changes in intestinal perfusion were observed, suggesting structural mucosal adaptation, rather than persistent blood flow alterations, underlies glepaglutide’s clinical benefits[26].

Finally, long-term benefits were confirmed in a 52-week, open-label phase 3b study evaluating the sustained efficacy and safety of glepaglutide in ten patients with SBS, including both SBS-IF and SBS-intestinal inflammation subtypes[27]. After 24 weeks, intestinal energy absorption increased by an average of 1038 kJ/day (a 23% improvement), and after 52 weeks, mean PS volume was reduced by 800 mL/day, a 30% relative reduction. Improvements in intestinal carbohydrate absorption and electrolyte balance further supported glepaglutide’s capacity to enhance absorptive function. Treatment was well tolerated throughout the study period[27].

Collectively, these findings position glepaglutide as a potent, long-acting GLP-2 analogue capable of addressing key pathophysiologic aspects of SBS accelerated transit, impaired absorption, and hepatic dysfunction while offering practical dosing flexibility and sustained therapeutic benefits. Larger phase 3 trials will be essential to confirm its long-term efficacy, safety, and potential role as a cornerstone therapy for intestinal rehabilitation in SBS.

GLP-2 AND ITS ANALOGUES IN IBD: EXPERIMENTAL AND CLINICAL EVIDENCE

The dual role of GLP-2 as an intestinotrophic and anti-inflammatory mediator has generated interest in its potential application in IBD[11]. Preclinical studies consistently demonstrate that GLP-2 modulates intestinal inflammation and mucosal repair. In animal models of colitis, GLP-2 exerts its effects partly through activation of vasoactive intestinal polypeptide neurons in the submucosal plexus, leading to reductions in pro-inflammatory cytokines such as interferon-γ and tumor necrosis factor-α. These effects are accompanied by increased crypt cell proliferation, attenuation of epithelial apoptosis, upregulation of suppressor of cytokine signaling 3, and modulation of signal transducer and activator of transcription 3 signaling, collectively promoting mucosal integrity and repair[28,29].

A systematic review published between 2010 and 2023 evaluated anti-inflammatory peptides in IBD, including GLP-2, and included 17 studies (12 animal studies, four clinical trials, and one case-control study). Among the peptides assessed, GLP-2, particularly its dimeric form [GLP-2(2)], demonstrated inhibition of tumor necrosis factor-α-mediated cytotoxicity, reduction of inflammatory markers, and preservation of mucosal architecture. However, the minireview also highlighted important translational limitations, including peptide instability, susceptibility to proteolytic degradation, and suboptimal bioavailability, which constrain clinical applicability and emphasize the need for optimized formulations and delivery strategies[30].

The anti-inflammatory and regenerative potential of long-acting GLP-2 analogues has also been explored. In a rat model of indomethacin-induced small intestinal inflammation, glepaglutide administered as both co-treatment and post-treatment significantly attenuated inflammation. Treatment reversed intestinal shortening, reduced α-1-acid glycoprotein and myeloperoxidase levels, and increased intestinal mass, supporting a regenerative effect beyond disease prevention. While these findings suggest therapeutic potential, they remain confined to preclinical settings and require validation in human disease models[31].

Additional experimental work evaluated a recombinant, stabilized GLP-2(2) in both lipopolysaccharide-induced in vitro systems and dextran sodium sulfate (DSS)-induced colitis models. Compared with the Gly2, GLP-2 monomer, GLP-2(2) resulted in greater reductions in inflammatory cytokine secretion, improved body weight recovery, lower disease activity scores, and decreased mucosal injury. These effects were associated with downregulation of nucleotide-binding and leucine-rich repeat receptor family pyrin domain containing 3, inflammasome components and cyclooxygenase-2, as well as reduced epithelial apoptosis, suggesting enhanced anti-inflammatory and cytoprotective efficacy relative to native GLP-2[32].

In DSS-induced ulcerative colitis models, GLP-2 administration reduced disease activity index scores, histopathologic damage, and inflammatory cytokine expression. Mechanistically, these effects were linked to suppression of nuclear factor kappa-B and Janus kinase/signal transducer and activator of transcription signaling pathways, alongside modulation of glucose metabolism. Notably, GLP-2 also altered gut microbiota composition, increasing microbial diversity and dominant bacterial species, which may contribute to its anti-inflammatory effects. While these findings broaden the mechanistic rationale for GLP-2 therapy, their relevance to human IBD remains speculative[33].

Innovative delivery approaches have been explored to overcome pharmacokinetic limitations. A rectal foam formulation of glepaglutide demonstrated enhanced mucosal healing and reduced disease severity in DSS-induced colitis, with improvements in crypt architecture, colonoscopic appearance, and systemic healing biomarkers. Transient increases in colonic permeability facilitated local drug absorption without sustained barrier disruption. Although promising, such approaches remain experimental and require clinical validation[34].

Clinical evidence for GLP-2 analogues in IBD is limited and largely indirect. A retrospective cohort study evaluated teduglutide in CD patients with SBS and PS dependence. Most patients experienced substantial reductions in PN and intravenous fluid requirements, with acceptable safety profiles. However, outcomes primarily reflected improvements in IF rather than direct modulation of inflammatory disease activity[35]. Similarly, a single case report described sustained remission and nutritional recovery in refractory microscopic colitis following teduglutide therapy, though conclusions are inherently limited by anecdotal design[36].

Additional supportive evidence derives from animal models outside traditional IBD paradigms. In a feed-restriction model in Holstein cows, GLP-2 administration preserved villus architecture, mucosal surface area, and goblet cell morphology while reducing inflammatory protein expression, reinforcing its role in maintaining intestinal barrier integrity under stress conditions[37].

Among human studies, the most direct evidence comes from a pilot randomized, placebo-controlled trial evaluating teduglutide in moderate-to-severe CD. Teduglutide-treated patients demonstrated higher response and remission rates than placebo, particularly at higher doses, with early clinical improvement and increased plasma citrulline levels indicating mucosal growth. However, the short treatment duration and exploratory nature of the study limit definitive conclusions[38]. Further evidence from real-world data reinforces these findings: In a multicenter retrospective cohort of 54 SBS patients, 52 responded to teduglutide, including 15 with CD[39]. Similarly, in another series of 18 patients with SBS-IF treated with teduglutide, 10 had CD, and notably, all five who successfully discontinued PN belonged to this subgroup[40].

GLP-2 THERAPY AND INTESTINAL NEOPLASIA RISK

A systematic review investigated the potential risk of intestinal neoplasia in patients treated with GLP-2, a trophic peptide that enhances mucosal healing and is used in managing SBS. Findings indicated that GLP-2 administration for up to 30 months in humans without pre-existing malignancy did not increase the incidence of intestinal neoplasia. Conversely, in animal models with experimentally induced tumors, GLP-2 exposure was associated with enhanced tumor growth. Although current evidence suggests no clear oncogenic risk in clinical settings, the limited number of patients and relatively short follow-up durations necessitate further long-term studies to establish safety profiles with greater certainty[41].

A post hoc analysis from the STEPS clinical trial series further examined the occurrence of colorectal polyps in adults with SBS-IF treated with teduglutide at a standard dose of 0.05 mg/kg/day. Among 73 patients who underwent baseline colonoscopy, polyps were identified in 12%. During follow-up, 50 participants received post-exposure colonoscopic evaluation, and polyps were detected in 18%, including two cases of recurrence. Histopathological analysis revealed adenomatous changes in five patients, though none showed malignancy or high-grade dysplasia. These data underscore the importance of colonoscopic screening prior to teduglutide initiation and continued surveillance during treatment. While findings do not indicate a significant risk of neoplasia, ongoing monitoring remains prudent until long-term data further clarify the safety of GLP-2–based therapies[42].

Similarly, a retrospective study involving 35 SBS patients treated with teduglutide for one year at a specialized home PN center evaluated the development of polypoid intestinal lesions. After a median of 23 months, endoscopic reassessment identified polyps in 10 patients (29%), predominantly in the small intestine (8 cases). Histology revealed five hyperplastic polyps without dysplasia and three adenomas with low-grade dysplasia, with no evidence of high-grade dysplasia or malignancy. These findings reinforce the need for regular upper and lower endoscopic surveillance in patients receiving long-term teduglutide, enabling early detection and informed management of potential mucosal changes[43].

FUTURE PERSPECTIVES

The expanding therapeutic landscape of GLP-2 analogues marks a pivotal transition in the management of SBS and related intestinal disorders. Despite the significant progress achieved with agents such as teduglutide and the newer long-acting analogues glepaglutide and apraglutide, several clinical and translational challenges remain. Future research should focus on refining patient selection, optimizing treatment timing, and evaluating long-term safety and cost-effectiveness to fully integrate GLP-2-based therapy into intestinal rehabilitation programs[1,3,7,10,21].

A major future direction involves personalized treatment approaches guided by biomarkers such as plasma citrulline and fecal output reduction, which correlate with enterocyte mass and treatment response[21,22,26]. Individual variability in GLP-2 receptor expression, downstream signaling through IGF-1 and epidermal growth factor pathways, and gut microbiota composition may explain differential therapeutic outcomes and warrants deeper molecular investigation[10,18,33]. Stratifying patients according to these biological parameters could enhance therapeutic precision and minimize unnecessary exposure.

Another critical area of ongoing inquiry is long-term safety surveillance. While existing data suggest no clear increase in intestinal neoplasia risk, particularly in humans without pre-existing malignancy, the mitogenic nature of GLP-2 continues to justify regular colonoscopic monitoring and postmarketing registries with extended follow-up durations[41-43]. Furthermore, continuous assessment of hepatic and cardiovascular parameters is recommended, given the interplay between GLP-2, mesenteric perfusion, and the gut-liver axis[15,24].

From a pharmacologic perspective, next-generation analogues and delivery systems hold promise for improving adherence and broadening access. Long-acting formulations such as glepaglutide and apraglutide, offering once- or twice-weekly administration, have demonstrated comparable efficacy and tolerability with enhanced convenience[1,4,23,27]. Advances in peptide engineering and sustained-release or transmucosal delivery such as the recently developed glepaglutide-loaded rectal foam may further expand clinical utility, especially for IBD where local mucosal repair is desired[34].

Beyond SBS, the therapeutic spectrum of GLP-2 analogues is expanding. Preclinical and early clinical studies have shown GLP-2’s potential to ameliorate mucosal injury and inflammation in IBD by suppressing pro-inflammatory cytokines, modulating nuclear factor kappa-B and Janus kinase/signal transducer and activator of transcription signaling, and promoting epithelial regeneration[28,33]. Similarly, their beneficial effects on IF-associated liver disease through improved hepatic excretory function and splanchnic circulation suggest broader applications across gastrointestinal pathologies.

Finally, real-world data and health-economic evaluations will be indispensable for guiding implementation. International surveys indicate that despite approximately 30% of SBS-IF patients being eligible for GLP-2 therapy, only around 10% currently receive it, primarily due to financial constraints and limited reimbursement[25]. Systematic cost-effectiveness analyses and updated reimbursement frameworks are therefore essential to ensure equitable access and sustainable adoption in clinical practice.

In summary, while GLP-2 analogues have already revolutionized the therapeutic paradigm of SBS, their full potential lies ahead. Precision medicine strategies, long-term safety monitoring, innovative delivery technologies, and expanded disease indications supported by multidisciplinary and international collaboration will define the next era of GLP-2-based intestinal rehabilitation.

LIMITATIONS AND TRANSLATIONAL CONSIDERATIONS

Interpretation of GLP-2 and GLP-2 analogue studies across indications is challenged by substantial heterogeneity in study design, endpoints, and populations. In SBS, randomized controlled trials with clearly defined clinical endpoints provide high-quality evidence supporting therapeutic efficacy. In contrast, studies evaluating glepaglutide and other GLP-2 analogues in IBD are characterized by small sample sizes, short follow-up durations, and reliance on preclinical or exploratory clinical endpoints.

Moreover, variability in disease severity, anatomical involvement, and concomitant therapies limits cross-study comparability. Animal models of colitis, while informative mechanistically, do not fully recapitulate the complexity of human IBD, raising concerns regarding overestimation of translational potential. These limitations underscore the need for adequately powered, well-designed clinical trials with standardized endpoints before GLP-2-based therapies can be considered for routine use beyond SBS and IF.

CONCLUSION

GLP-2 and its analogues have redefined the therapeutic landscape of SBS and IF by shifting management from exclusive parenteral dependence toward pharmacologic intestinal rehabilitation. Through stimulation of mucosal growth, enhancement of nutrient absorption, and modulation of intestinal motility and perfusion, GLP-2-based therapies such as teduglutide, glepaglutide, and apraglutide have demonstrated robust efficacy in improving absorptive function and reducing PS requirements. Beyond their intestinotrophic effects, accumulating evidence highlights GLP-2’s broader physiological roles, including anti-inflammatory, cytoprotective, and hepatotropic properties that may extend therapeutic benefits to conditions such as IBD and IF-associated liver disease. Importantly, current data indicate a favorable safety profile, though ongoing vigilance is warranted regarding potential mucosal proliferation and neoplasia risk during long-term use. As newer long-acting analogues and innovative delivery systems continue to emerge, GLP-2 therapy is poised to become an integral component of multidisciplinary intestinal rehabilitation. Future directions should emphasize individualized treatment algorithms, biomarker-guided monitoring, and real-world cost-effectiveness analyses to optimize outcomes and accessibility.

In conclusion, GLP-2 analogues represent a major advancement in the treatment of SBS and related disorders. By harnessing the hormone’s regenerative and anti-inflammatory capacities, these agents not only improve patient independence and quality of life but also pave the way for a new era of targeted intestinal medicine bridging the gap between supportive care and true functional restoration.