Effects of glepaglutide, a long-acting glucagon-like peptide-2 analog, on intestinal morphology and perfusion in patients with short bowel syndrome: Findings from a randomized phase 2 trial.

BACKGROUND: The proadaptive effects of glucagon-like peptide-2 (GLP-2) include stimulation of intestinal mucosal growth as well as intestinal blood flow and angiogenesis. We have recently reported that daily subcutaneous injections of glepaglutide, a long-acting GLP-2 analog, improved intestinal absorptive function in patients with short bowel syndrome (SBS). As secondary and exploratory end points, the effects of glepaglutide on intestinal morphology and perfusion are reported. METHODS: The following assessments were done in 18 patients with SBS in a randomized, crossover, dose-finding, phase 2 trial before and after three weeks of treatment with glepaglutide: plasma citrulline and mucosa biopsies to assess changes in (1) intestinal morphology by immunohistochemistry and (2) gene expressions associated with absorption, proliferation, and markers of tight-junction integrity by quantitative polymerase chain reaction. Intestinal perfusion was assessed in stoma nipples by laser speckle contrast imaging and quantitative fluorescence angiography with indocyanine green. RESULTS: In the 1- and 10-mg dose groups, glepaglutide significantly increased plasma citrulline by 15.3 µmol/L (P = 0.001) and 15.6 µmol/L (P = 0.001), respectively. Trends toward an increase in villus height, crypt depth, and epithelium height were seen in the same groups. No significant changes were seen in gene expressions or intestinal perfusion. CONCLUSION: The increase in plasma citrulline and the morphological improvements may partly account for improvement in the intestinal absorptive function. However, the finding of a stability in perfusion after three weeks of treatment with glepaglutide may have been preceded by a more profound acute-phase increase in intestinal perfusion at treatment initiation.

Repeated Metabolic Balance Studies in Patients With Short Bowel Syndrome.

BACKGROUND: Weaning from parenteral support is considered indirect evidence of intestinal adaptation in patients with short bowel syndrome (SBS), but direct evidence is lacking. The objective of this study was to examine if intestinal adaptation could be demonstrated as increase in intestinal absorption of energy and wet weight over time measured by repeated metabolic balance studies (MBSs) and to examine whether adaptation was determined by the anatomy of the remnant bowel. METHODS: We retrospectively analyzed data from 48 repeated MBSs performed in 13 adult patients with SBS. Results were presented graphically and interpreted. The interpatient and intrapatient heterogeneity was compared based on anatomy of the remnant bowel. RESULTS: The number of repeated MBSs ranged from 2 to 7, and time between last intestinal resection and MBS from 5 months to 18.1 years. In 6 patients, the first MBS was performed within 2 years after last resection, but only 1 patient had repeated MBSs within this period. Nine patients had an end jejunoileostomy, and 4 patients had a jejuno-colonic or ileo-colonic anastomosis. None of the patients had jejunoileal anastomosis with a preserved ileocecal valve. Interpatient and intrapatient heterogeneity of wet weight and energy absorption was larger in patients without colon in continuity. The wet weight and energy absorption data showed no tendency toward intestinal adaptation in any anatomical group. CONCLUSION: We observed no signs of late-phase intestinal adaptation in this selected group of patients with SBS. Future prospective MBSs are needed to understand the time course and magnitude of intestinal adaptation.

Glepaglutide, a novel long-acting glucagon-like peptide-2 analogue, for patients with short bowel syndrome: a randomised phase 2 trial.

BACKGROUND: Patients with short bowel syndrome might have impaired postprandial endogenous glucagon-like peptide-2 (GLP-2) secretion, which is required for optimal intestinal adaptation. We aimed to assess the therapeutic potential of glepaglutide, a novel long-acting GLP-2 analogue, for reducing faecal output and increasing intestinal absorption in patients with short bowel syndrome. METHODS: In this single-centre, double-blind, crossover, randomised phase 2 trial, adults (aged ≥18 to ≤90 years) with short bowel syndrome and with a faecal wet weight output of 1500 g/day or more were randomly assigned to receive one of six dose sequences of glepaglutide (10 mg, 1 mg; 10 mg, 0·1 mg; 1 mg, 10 mg; 1 mg, 0·1 mg; 0·1 mg, 10 mg; or 0·1 mg, 1 mg). Patients received daily subcutaneous injections of the first assigned dose of glepaglutide for 3 weeks, followed by a washout period of 4-8 weeks, and then the second dose of glepaglutide for 3 weeks. An unmasked statistician generated the randomisation list, and the trial investigator enrolled patients and assigned them their patient numbers. Trial investigators, patients, and other care providers were masked throughout the trial. The primary endpoint was the absolute change from baseline in faecal wet weight output, measured separately over the two treatment periods. Metabolic balance studies were done before and after each treatment period to assess the primary endpoint. Per-protocol analysis was used to assess the efficacy. Safety analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT02690025, and has completed. FINDINGS: Of the 22 patients screened between Feb 5, 2016, and Jan 25, 2017, 18 patients were randomly assigned and treated with glepaglutide; 16 patients completed the trial. Treatment with 1 mg and 10 mg glepaglutide changed the adjusted mean faecal output by -592 g/day (95% CI -913 to -272; p=0·002) and -833 g/day (-1152 to -515; p=0·0002) from baseline, respectively. No changes were observed with 0·1 mg glepaglutide. Of the 18 patients who were randomly assigned to treatment, common treatment-related adverse events were stoma complications (13 [72%] patients), injection site reactions (11 [61%]), peripheral oedema (ten [56%]), nausea and abdominal pain (eight [44%] each), polyuria and fatigue (six [33%] each), abdominal distention, vomiting, and dizziness (five [28%] each); and cough and decreased appetite (four [22%] each). Related or possibly related serious adverse events were reported in two patients in the 0·1 mg dose group and two patients in the 10 mg dose group. These events included abdominal pain, stoma obstruction, catheter-related sepsis, and infection of unknown origin. No patients died during the trial. INTERPRETATION: Glepaglutide was well tolerated, and was associated with improved intestinal absorption in patients with short bowel syndrome with 1 mg and 10 mg glepaglutide, but not with 0·1 mg glepaglutide. Larger phase 3 clinical trials of longer durations have been initiated to fully assess the safety and efficacy of glepaglutide. FUNDING: Zealand Pharma.

Home Parenteral Nutrition in Adult Patients With Chronic Intestinal Failure: Catheter-Related Complications Over 4 Decades at the Main Danish Tertiary Referral Center.

BACKGROUND/AIMS: Catheter-related complications (CRCs) cause mortality and morbidity in patients dependent on parenteral support at home (HPN) due to intestinal failure (IF). This study describes the incidences of CRCs in an adult IF cohort over 40 years. It illustrates the evolution and consequences of CRCs, their association to demographic characteristics, and potential risk factors in an effort to provide the rationale for preventive precautions to the relevant patients with IF at risk. METHODS: All patients with IF discharged with HPN from 1970-2010 were included. Patient and treatment characteristics were extracted from the Copenhagen IF database. The incidences were given per 1000 central venous catheter (CVC) days. RESULTS: The 1715 CRCs occurred in 70% of the 508 patients with IF (56% of the 2191 CVCs). The incidence of catheter-related bloodstream infections (CRBSIs) was 1.43. Higher age, HPN administration by community home nurses, and prior CRBSIs significantly raised the hazard for CRBSIs. In the 1970s, catheters were generally replaced following CRBSIs, whereas catheter salvage was the norm in the 2000s. The incidences of mechanical complications, tunnel infections, and catheter-related venous thromboses were 0.80, 0.25, and 0.11, respectively. The overall CRC incidence was 2.58, decreasing the first 3 decades but peaking in the last (2.84). The deaths related to CRCs were low (0.018). CONCLUSION: Even in an experienced IF center of excellence, the incidence of CRCs increased over the 4 decades. This increase could be explained by the expansion of the indication of HPN to a more elderly and frail patient population.

Home Parenteral Nutrition in Adult Patients With Chronic Intestinal Failure: The Evolution Over 4 Decades in a Tertiary Referral Center.

BACKGROUND/AIMS: In Denmark, the public healthcare system ensures patients with intestinal failure (IF) the same rights for a life-saving treatment as patients with other organ failures. This study reports the epidemiological data from the largest Danish IF center. As one of the pioneering centers in treating IF with home parenteral nutrition (HPN), this study documents the HPN evolution and describes the demographics and outcome in one of the world's largest single-center cohorts. METHODS: We included patients with IF discharged with HPN from 1970-2010. Data were extracted according to European Society for Clinical Nutrition and Metabolism classifications from the Copenhagen IF database. RESULTS: Over the decades, we observed an exponential increase in the number of HPN patients. The 508 patients with IF collectively received HPN for 1751 years. While receiving HPN, 211 patients with IF (42%) died. Only 24 deaths were HPN related: sepsis (n = 10), liver disease (n = 12), central venous thrombosis (n = 1), and a complicated catheter placement (n = 1). The HPN-related mortality was as low as 0.014 deaths/HPN year. In the first decade, HPN was mainly provided to younger, intestinally resected adult patients with IF with inflammatory bowel disease (IBD), but numerically, they were subsequently outnumbered by elderly patients with IF with cancer or complications from non-IBD, noncancer abdominal surgery. Despite these demographic changes, the HPN-related mortality has decreased in the past decade. CONCLUSION: Evolving from being a rare, experimental treatment in the 1970s, HPN at present is safe with a low treatment-related mortality in the experienced center, despite HPN being more widely used in a more elderly population.