BACKGROUND AND AIMS:Glepaglutide is a long-acting glucagon-like peptide 2 (GLP-2) analog under development for the treatment of short bowel syndrome (SBS). Glepaglutide enhances intestinal absorption, which may hypothetically lead to changes in the intestinal microbiota, mainly by slowing gastrointestinal transit time. This study evaluated whether glepaglutide affects bacterial load and composition of the intestinal microbiota in SBS patients enrolled in a phase 3b trial assessing its 24-week efficacy on intestinal wet weight and energy absorption. METHODS:In this single-center, open-label, EASE SBS-4 phase 3b study, 10 patients with SBS (8 of the 10 with intestinal failure and 8 of the 10 without colon-in-continuity) were treated with glepaglutide 10 mg by subcutaneous injection once weekly for 24 weeks. While the primary trial findings demonstrated increased intestinal wet weight and energy absorption assessed by metabolic balance studies, this study investigated whether these adaptations were associated with changes in bacterial load and composition of the intestinal microbiota. Samples were obtained from either stool or ostomy effluent at baseline and after 24 weeks of treatment with glepaglutide. Bacterial load was quantified using a spike-in approach, and microbiota composition was assessed by V3V4 16S rRNA gene sequencing. RESULTS:No major changes in bacterial load or microbiota composition were observed following glepaglutide treatment. Bacterial load showed distinct differences between patients with and without a colon-in-continuity; in patients without a colon, most samples had values below 109 cells per gram, whereas those with a colon-in-continuity had bacterial loads within the physiological range observed in healthy individuals, ranging from 1010 to 1011 cells per gram feces. Microbiota composition also differed markedly by intestinal anatomy: patients without a colon-in-continuity had higher abundances of genera mainly associated with the upper gastrointestinal tract, such as Streptococcus, while those with a colon-in-continuity exhibited greater abundance of genera more commonly found in the lower gastrointestinal tract, including Bifidobacterium. CONCLUSIONS:Treatment with the GLP-2 analog glepaglutide increased intestinal wet weight and energy absorption without altering the intestinal bacterial microbiota in the majority of the SBS patients participating in this study. Differences in bacterial load and composition were influenced by intestinal anatomy. CLINICALTRIALS:gov no: NCT04991311; ClincalTrialsRegister.eu EudraCT no: 2020-005194-27.

BACKGROUND:A randomized, double-blind, placebo-controlled trial was conducted to evaluate efficacy and safety of glepaglutide in patients who have short bowel syndrome with intestinal failure (SBS-IF). At the end of the trial, exit interviews were conducted to explore participants' experiences and to assess the impact of the disease and treatment during the trial. METHODS:Thirty patients from four countries were interviewed over the phone. Data were collected using a semistructured interview manual, and interviews were recorded and transcribed for analysis. RESULTS:Patients reported that SBS-IF negatively impacted their lives before the trial, causing loss of freedom, disrupted sleep, limited physical activity, and pain. During the interviews, patients reported that the treatment improved their well-being across multiple domains. Seventy-three percent of the patients receiving glepaglutide (n = 16/22) reported positive changes in health-related quality of life compared with 25% receiving placebo (n = 2/8). Twenty-six patients reported experiencing a reduction in parenteral support (PS) volume. Of these, 21 patients (18 glepaglutide, three placebo) reported a change in overall status, with 94% receiving glepaglutide (n = 17/18) and 67% (n = 2/3) receiving the placebo finding this change meaningful. Although descriptive, these findings should be interpreted cautiously given the small number of patients. CONCLUSION:During exit interviews, patients receiving glepaglutide reported improvements in well-being across multiple domains, noting meaningful reductions in PS volume and a reduced impact of SBS-IF on daily life, which was proportionally greater than in those receiving placebo. These findings underscore the patient-reported positive experiences of glepaglutide and its beneficial effects.

Background/Objectives: New guidelines for management of metabolic-dysfunction-associated steatotic liver disease (MASLD) patients recommend an individualized medicine approach mainly targeting patients with fibrotic metabolic-dysfunction-associated steatohepatitis (MASH) and metabolic risk factors for progression of disease. This cohort study reports real-world experience for the individual evaluation and final diagnosis of patients on suspicion of fibrotic MASH according to standardized international criteria. We aimed to identify patients with significant fibrosis (F2-F4). Methods: Adult patients with metabolic syndrome and/or elevated alanine aminotransferases (ALT > 50) referred in a 5-year period (2018-2022) on suspicion of fibrotic MASH were included. Medical history, anthropometric measurements, and routine (blood tests, ultrasound) and specific examinations were applied. Liver biopsy was offered for definite diagnosis and to evaluate MASLD characteristics. Patient demographics and characteristics as well as the absolute number and proportion of patients with definite MASLD and fibrotic MASH are reported. Results: A total of 137 adult patients were included. Ten percent of patients were evaluated without liver biopsy and diagnosed with chronic liver diseases other than MASLD. Liver-biopsied patients (n = 123) had a mean age (SD) of 49 (14) years, and 50% were males. Overweight or obesity was present in 94%, dyslipidemia in 74%, hypertension in 40%, and type 2 diabetes mellitus in 34%. Of all 137 patients, 104 (76%) were diagnosed with definite MASLD and 80 (58%) with definite MASH. A total of 74 (54%) patients had definite fibrotic MASH, while 41 (30%) had significant (F2-4) fibrotic MASH. Eight patients (6%) had cirrhotic (F4) MASH. A multivariate logistic regression analysis indicated that patients with type 2 diabetes, older age, and higher BMI were associated with an apparent increased risk of F2-F4 fibrosis. Conclusions: The majority of referred patients had cardiometabolic-hepatic metabolic risk factors and were diagnosed with definite MASLD. More than half of these were diagnosed with fibrotic MASH. Older age, type 2 diabetes, and higher BMI were apparent risk factors for MASH F2-F4 fibrosis. We conclude that the individual cardiovascular-hepatic risk profile applied supports the new guidelines and may be useful for referral and further evaluation at expert care centers in a real-world setting.

OBJECTIVES:M2 macrophage activation contributes to pancreatitis pathophysiology and may drive progression from recurrent acute pancreatitis (RAP) to chronic disease. Evidence is mainly preclinical or cross-sectional, highlighting a need for prospective studies. METHODS:This was an exploratory analysis of a multicenter, randomized, placebo-controlled trial, which included patients with RAP randomized to naldemedine (tablet 0.2 mg daily), a peripherally acting µ-opioid receptor agonist hypothesized to reduce RAP frequency, or placebo for 12 months. Biomarkers of M2 macrophage activation (plasma levels of sCD163 and sCD206) were measured at baseline and trial end. Linear mixed-effects models assessed biomarker changes within and between treatment groups. Spearman correlation assessed associations between biomarker changes and disease activity, defined by RAP attacks and pain flares. RESULTS:Fifty-six patients with paired plasma samples were included (32 naldemedine, 24 placebo) in this exploratory analysis. Despite a numerical reduction in RAP frequency with naldemedine (hazard ratio 0.49; 95% confidence interval: 0.23 to 1.08; p = 0.076), no differences in mean change of sCD163 (-0.07 mg/L, p = 0.652) or sCD206 (0.01 mg/L, p = 0.299) were observed compared to placebo. Change in plasma levels of sCD163 correlated with the frequency of RAP attacks (rho = 0.348, p = 0.009) and pain flares (rho = 0.318, p = 0.017). No associations between disease activity and plasma levels of sCD206 were observed. CONCLUSIONS:Naldemedine did not significantly affect M2 macrophage activation, suggesting limited immunomodulatory effects. However, changes in sCD163 plasma levels correlated with clinical disease activity, highlighting macrophage activation in RAP.

BACKGROUND AND AIMS:No medications are currently approved for the prevention of recurrent acute pancreatitis. This trial evaluated whether naldemedine, a peripherally acting μ-opioid receptor antagonist, reduces the risk of acute pancreatitis in patients with recurrent acute pancreatitis. METHODS:This was a multicentre, double-blinded, placebo-controlled randomised trial conducted at four Danish pancreatitis referral centres. Participants aged 18-75 years with recurrent acute pancreatitis, both with and without a diagnosis of chronic pancreatitis, were randomised to receive naldemedine 0.2 mg or a matching placebo daily for up to 12 months. The primary outcome was acute pancreatitis recurrence, defined by the revised Atlanta Criteria. Secondary outcomes included pain flares, gastrointestinal symptoms, and quality of life. At the end of follow-up, the participant's global impression of change, safety and tolerability outcomes, new-onset diabetes and pancreatic exocrine insufficiency were assessed. RESULTS:74 participants (mean age: 46 years; 41% female) were randomised to naldemedine (n = 36) or placebo (n = 38). During a median follow-up time of 365 days (IQR, 352-370), participants in the naldemedine group had a numerically lower risk of acute pancreatitis compared to placebo (HR 0.54; 95% CI, 0.29-1.01; p = 0.05). No differences were observed between the groups for secondary efficacy, safety, and tolerability outcomes. Participants treated with naldemedine for at least 1 year had a lower risk of acute pancreatitis (HR 0.49; 95% CI, 0.24-0.97; p = 0.04). CONCLUSIONS:Treatment with naldemedine was safe and well-tolerated and may reduce the risk of recurrent acute pancreatitis. A larger confirmatory trial is needed to verify these findings. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: PAMORA-RAP: NCT04966559.

BACKGROUND & AIMS:Glepaglutide, a long-acting glucagon-like peptide 2 (GLP-2) analog, is under development for the treatment of patients with short bowel syndrome (SBS). GLP-2 enhances intestinal adaptation and absorption. This study assessed glepaglutide in terms of its 24-week efficacy on intestinal wet weight and energy absorption, as well as its impact on reducing parenteral support (PS) and maintaining body composition at week 52 in patients with SBS. METHODS:In this single-center, open-label, phase 3b study, 10 patients with SBS - 8 with intestinal failure (SBS-IF) and 2 with intestinal insufficiency - received glepaglutide 10 mg once weekly via subcutaneous injection. Intestinal absorption was assessed by the gold-standard metabolic balance studies. The primary endpoint was absolute change in intestinal wet weight absorption, while secondary endpoints assessed changes in energy, electrolyte, and macronutrient absorption after 24 weeks of treatment. Additional endpoints included changes in PS use, body composition and safety after 52 weeks of treatment. RESULTS:At week 24, mean numerical increase in intestinal wet weight absorption was 398 g/day (P = 0.0585) and mean energy absorption 1038 kJ/day (P = 0.0215). Improvements occurred in electrolyte and macronutrient absorption. At week 52, mean PS volume was reduced by 800 mL/day (P = 0.0106) with a reduction in mean PS energy content of 866 kJ/day (P = 0.0103). Body composition and weight remained stable, and glepaglutide demonstrated a manageable safety profile. CONCLUSION:Patients with SBS treated with glepaglutide demonstrated increased intestinal wet weight and energy absorption, allowing corresponding reductions in PS requirements in those with SBS-IF. Glepaglutide demonstrated a favorable safety profile, positioning it as a promising treatment for patients with SBS. CLINICALTRIALS:gov no: NCT04991311; ClinicalTrialsRegister.eu EudraCT no: 2020-005194-27.

INTRODUCTION:Dysmotility is common in acute pancreatitis (AP) and may be evaluated using radiopaque markers and imaging. We present a simple CT-based approach, which was employed in hospitalized patients with AP. METHODS:This was a secondary analysis of a randomized, controlled trial conducted at four Danish centers. Patients admitted with AP and systemic inflammatory response syndrome were randomized to receive 5 days of intravenous methylnaltrexone or placebo (lactated ringer) added to standard management. Self-reported stool frequency was documented daily. Patients ingested a capsule containing 10 radiopaque markers on Day 3. A subsequent CT scan on Day 5 was used to identify the location of retained markers for the calculation of gastrointestinal transit, and colonic dimensions (diameters and cross-sectional areas) were measured. RESULTS:In total, 47 patients were included. Patients receiving methylnaltrexone less often had laxative treatment (57% vs. 88%, p = 0.01) compared with placebo. Transit times were similar between the methylnaltrexone and the placebo groups (difference, -4 h (95% CI, -16 to 8), p = 0.53). Marker retention scores, colon diameters, and colon cross-sectional areas did not differ between treatment groups (all p > 0.05). Transit times (ρ = -0.53; p < 0.001), marker retention scores (ρ = -0.42; p = 0.004), diameter (ρ = -0.43; p = 0.003), and cross-sectional areas (ρ = -0.36; p = 0.01) of the descending colon were negatively correlated with self-reported stool frequency. CONCLUSION:Our CT-based method was feasible in hospitalized patients with AP. Methylnaltrexone did not change gastrointestinal transit compared with placebo. However, laxative therapy was more frequent with the placebo.

Colorectal cancer (CRC) is a major cause of cancer-related mortality, especially in the Western world, and its incidence is expected to increase in the years to come. Prevention and early detection are key strategies to improve CRC morbidity and mortality. Although pathogenesis is still not fully understood, several signaling pathways have been studied and some are associated with the development of colorectal neoplasia (CRN) and CRC. Further identification of individuals with an increased risk of developing CRN would allow optimization of surveillance programs and help guide pharmacological preventive strategies. This perspective review outlines signaling pathways, biomarkers, and related pharmacological targets potentially implicated in the pathogenesis of CRN. We present our research based on studies carried out in normal appearing colonic mucosa from patients with and without CRN. With a focus on arachidonic acid signaling pathways, and in contrast to many other studies on cell culture and CRN tissue samples, our research is based on fresh colonic biopsies from normal tissue and presents and documents alterations in the function, expression, and location of enzymes, receptors, and transporters potentially involved in CRN pathogenesis. Based on these findings, we suggest areas of focus for future research and drug development for prevention and maybe even treatment of CRN and CRC. Furthermore, based on our observations of the COX-1 enzyme, we also discuss the implications of this enzyme in the development of CRN.

BACKGROUND & AIMS:Glepaglutide is a long-acting glucagon-like peptide (GLP)-2 analogue developed to improve intestinal absorption in patients with short bowel syndrome (SBS). The authors conducted a trial to establish the efficacy and safety of glepaglutide in reducing parenteral support (PS) needs in patients with SBS with intestinal failure. METHODS:In an international, placebo-controlled, randomized, parallel-group, double-blind, phase 3 trial, patients with SBS with intestinal failure requiring PS ≥3 d/wk were randomized 1:1:1 to 24 weeks of glepaglutide 10 mg twice weekly or once weekly or placebo. PS volume was equivalently reduced if mean urine volume of a 48-hour balance period exceeded baseline values by >10%. RESULTS:One hundred six patients were randomized and dosed. Glepaglutide twice weekly significantly reduced weekly PS volumes from baseline to week 24 vs placebo (mean change, -5.13 vs -2.85 L/wk; P = .0039; primary end point). Results were similar across major anatomic subgroups. Glepaglutide twice weekly was also superior to placebo for key secondary end points of proportion of patients achieving clinical response, defined as ≥20% PS volume reduction from baseline to weeks 20 and 24 (65.7% vs 38.9%; P = .0243) and patients achieving a reduction in days on PS ≥1 d/wk from baseline to week 24 (51.4% vs 19.4%; P = .0043). Complete PS weaning ("enteral autonomy") was achieved for 5 patients (14%) receiving glepaglutide twice weekly vs 0 for patients receiving placebo. No statistically significant differences were found for glepaglutide once weekly vs placebo for primary or key secondary end points. Significant glepaglutide benefits on patient-reported outcome (Patient Global Impression of Change) were found. Glepaglutide was assessed to be safe and well tolerated. CONCLUSIONS:Glepaglutide treatment in patients with SBS with intestinal failure resulted in clinically relevant reductions in PS requirements and was well tolerated. (ClinicalTrials.gov, Number: NCT03690206; ClinicalTrialsRegister.eu, Number: 2017-004394-14.).

INTRODUCTION: Opioids used to manage severe pain in acute pancreatitis (AP) might exacerbate the disease through effects on gastrointestinal and immune functions. Methylnaltrexone, a peripherally acting µ-opioid receptor antagonist, may counteract these effects without changing analgesia. METHODS: This double-blind, randomized, placebo-controlled trial included adult patients with AP and systemic inflammatory response syndrome at 4 Danish centers. Patients were randomized to receive 5 days of continuous intravenous methylnaltrexone (0.15 mg/kg/d) or placebo added to the standard of care. The primary end point was the Pancreatitis Activity Scoring System score after 48 hours of treatment. Main secondary outcomes included pain scores, opioid use, disease severity, and mortality. RESULTS: In total, 105 patients (54% men) were randomized to methylnaltrexone (n = 51) or placebo (n = 54). After 48 hours, the Pancreatitis Activity Scoring System score was 134.3 points in the methylnaltrexone group and 130.5 points in the placebo group (difference 3.8, 95% confidence interval [CI] −40.1 to 47.6; P = 0.87). At 48 hours, we found no differences between the groups in pain severity (0.0, 95% CI −0.8 to 0.9; P = 0.94), pain interference (−0.3, 95% CI −1.4 to 0.8; P = 0.55), and morphine equivalent doses (6.5 mg, 95% CI −2.1 to 15.2; P = 0.14). Methylnaltrexone also did not affect the risk of severe disease (8%, 95% CI −11 to 28; P = 0.38) and mortality (6%, 95% CI −1 to 12; P = 0.11). The medication was well tolerated. DISCUSSION: Methylnaltrexone treatment did not achieve superiority over placebo for reducing the severity of AP.

Background and aims: Glucagon-like peptide 2 (GLP-2) analogues are the first available disease-modifying treatments for patients with intestinal failure (IF) due to short bowel syndrome (SBS). Efficacy in terms of reduction of parenteral support (PS) has been demonstrated in multiple studies and real-world reports. However, it remains unclear how many patients are eligible to receive the treatment, when treatment is started after intestinal resection, how treatment efficacy is assessed outside of clinical trials, and how the treatment is modified in case of non-response or adverse events. The aim of this study was to investigate the real-world management of patients treated with GLP-2 analogues in expert centers around the world. Methods: A survey questionnaire was developed by a multidisciplinary working group consisting of 52 questions related to various aspects of multidisciplinary care of SBS-IF patients. The 17 questions related to the use of GLP-2 analogues in clinical practice were analyzed for this study. The online survey was sent to 33 participating centers in a phase 3 study of a long-acting GLP-2 analogue. Only responses from countries with access to commercially available GLP-2 analogues were included in the study. A descriptive analysis was performed for each question. Results are presented as median (interquartile range). Results: The responses from the 19 expert IF centers with access to GLP-2 analogues indicated that 10 (10-20) % of patients with SBS-IF were treated with a GLP-2 analogue, which was less than the number of eligible patients (30 (25-40) %). In most centers (10 centers, 53 %), GLP-2 therapy was started 6-12 months after the last intestinal resection, with 5 centers (26 %) starting later (12-24 months). Multiple parameters were used in combination to determine the response to GLP-2 analogues of which the three most common were >20 % decrease in PS (95 %), at least 1 day of PS reduction per week (84 %) and increased urinary output (68 %). In non-responders GLP-2 therapy was stopped within the first year by 67 % of the centers. Finally, strategies in case of significant adverse events include stopping the GLP-2 analogue (used by 79 % of experts), dose reduction (67 %) and temporary treatment interruption (62 %). Conclusion: The results of this survey completed by expert IF centers show the real-life use of GLP-2 analogues in clinical practice. Key learning points identified include the accounting for a period of intestinal adaptation before starting GLP-2 analogues and not stopping the treatment too early in case of non-response. The best strategy in case of adverse effects should be studied further.

Background Acute and chronic pancreatitis constitute a continuum of inflammatory disease of the pancreas with an increasing incidence in most high-income countries. A subset of patients with a history of pancreatitis suffer from recurrence of acute pancreatitis attacks, which accelerate disease progression towards end-stage chronic pancreatitis with loss of exocrine and endocrine function. There is currently no available prophylactic treatment for recurrent acute pancreatitis apart from removing risk factors, which is not always possible. Pain is the primary symptom of acute pancreatitis, which induces the endogenous release of opioids. This may further be potentiated by opioid administration for pain management. Increased exposure to opioids leads to potentially harmful effects on the gastrointestinal tract, including, e.g. increased sphincter tones and decreased fluid secretion, which may impair pancreatic ductal clearance and elevate the risk for new pancreatitis attacks and accelerate disease progression. Peripherally acting µ-opioid receptor antagonists (PAMORAs) have been developed to counteract the adverse effects of opioids on the gastrointestinal tract. We hypothesize that the PAMORA naldemedine will reduce the risk of new pancreatitis attacks in patients with recurrent acute pancreatitis and hence decelerate disease progression. Methods The study is a double-blind, randomized controlled trial with allocation of patients to either 0.2 mg naldemedine daily or matching placebo for 12 months. A total of 120 outpatients will be enrolled from five specialist centres in Denmark and Sweden. The main inclusion criteria is a history of recurrent acute pancreatitis (minimum of two confirmed pancreatitis attacks). The primary endpoint is time to acute pancreatitis recurrence after randomization. Secondary outcomes include changes in quality of life, gastrointestinal symptom scores, new-onset diabetes, exocrine pancreatic insufficiency, disease severity, health care utilization, adherence to treatment, and frequency of adverse events. Exploratory outcomes are included for mechanistic linkage and include the progression of chronic pancreatitis-related findings on magnetic resonance imaging (MRI) and changes in circulating blood markers of inflammation and fibrosis. Discussion This study investigates if naldemedine can change the natural course of pancreatitis in patients with recurrent acute pancreatitis and improve patient outcomes. Trial registration EudraCT no. 2021–000069-34. ClinicalTrials.gov NCT04966559. Registered on July 8, 2021.

Background & aims: An international, multidisciplinary management working group (MWG) convened to review clinically useful short bowel syndrome (SBS) literature and identify gaps and inconsistencies in the management of adults with SBS.Methods: Using nominal group technique for literature review, key publications were identified, dis-cussed, and ranked by importance related to management of SBS. Gaps in management recommenda-tions for SBS were identified upon critical review of the selected publications.Results: Five guidelines, seven review articles, one series of six articles, and one single center series were selected and prioritized for their importance to SBS management. Evaluation of the articles by the MWG identified ten gaps and opportunities to standardize and improve SBS management.Conclusion: The main practice areas in need of more definitive guidelines are the management of high stool output and strategies to improve absorption of medications, nutrients, and fluids. An understanding of current real-world clinical practices related to these gaps could allow for development of best practice standards and improve patient-focused care.(c) 2023 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.