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Summary Background This practical guideline is based on the ESPEN Guidelines on Chronic Intestinal Failure in Adults. Methodology ESPEN guidelines have been shortened and transformed into flow charts for easier use in clinical practice. The practical guideline is dedicated to all professionals including physicians, dieticians, nutritionists, and nurses working with patients with chronic intestinal failure. Results This practical guideline consists of 112 recommendations with short commentaries for the management and treatment of benign chronic intestinal failure, including home parenteral nutrition and its complications, intestinal rehabilitation, and intestinal transplantation. Conclusion This practical guideline gives guidance to health care providers involved in the management of patients with chronic intestinal failure.

BACKGROUND & AIMS: Disease-associated factors influence parenteral support (PS) reduction in response to teduglutide in patients with intestinal failure associated-short bowel syndrome (SBS-IF). We sought to determine correlative relationships between plasma citrulline levels, small bowel length, and PS volume.METHODS: A post hoc analysis of plasma citrulline levels from patients in the STEPS 24-week study of teduglutide in patients with SBS-IF. Plasma citrulline was assessed in all patients; patients were stratified 3 times into subgroups based on bowel anatomy, cause of SBS-IF, and baseline PS volumes. Correlation analyses used simple linear regression models. Statistical comparisons between study groups were conducted using 2-sided t tests for 2 independent mean differences.RESULTS: Baseline plasma citrulline correlated with remnant small bowel length (r = 0.355, P = 0.002), but not with baseline PS volume (r = -0.167, P = 0.14), in the overall population. There was a robust correlation between the baseline and Week 24 citrulline (r = 0.705, P < 0.0001), and an inverse correlation between change from baseline in citrulline and PS volume from baseline to Week 24 (r = -0.359, P = 0.001). In all subgroups, patients treated with teduglutide showed numerically greater increases in plasma citrulline at Week 24 compared with placebo.CONCLUSION: Baseline plasma citrulline showed significant correlations with small bowel length in patients with ≥50% colon remaining/no stoma/colon-in-continuity, and patients with SBS-IF causes other than IBD/vascular disease. Citrulline levels may correlate with PS changes in response to teduglutide and more research may reveal a relationship between citrulline levels within the heterogeneous population of patients with SBS-IF. ClinicalTrials.gov NCT00798967, ClinicalTrialsRegister.eu 2008-006193-15.

IntroductionPregnancy in patients with chronic intestinal failure (CIF) is a relatively rare occurrence but is an important contemporary topic given both the increasing use of home parenteral nutrition (HPN) and the demographics of patients with CIF.MethodAn opinion-based survey was produced in a multidisciplinary manner, which was then distributed internationally, via the European Society for Clinical Nutrition and Metabolism network, using a web-based survey tool for healthcare professionals with a specialist interest in the management of CIF.ResultsSeventy specialists from 11 countries completed the survey. Fifty-four per cent of the respondents reported some experience of managing pregnancy in patients with CIF. However, 60% stated that they did not feel that it was their role to discuss the topic of pregnancy with their patients, with fewer than 10% stating that they routinely did so. Respondents felt that an individualised approach was required when considering alterations to parenteral support prior to conception, during pregnancy and in the postnatal period. Most respondents also felt there was no increased risk of catheter-related blood stream infections, while catheter-related thrombosis was deemed to be the most significant HPN-related complication for pregnant women.ConclusionThis study reports a variable experience, knowledge and confidence of healthcare professionals when considering pregnancy in patients with CIF. The risk of HPN-related complication was felt to be greater during pregnancy, with an individualised approach being the preferred route for most aspects of care. The findings support the need for an international registry and subsequent consensus guidelines for the management of pregnancy in CIF.

Background: Patients with short-bowel syndrome and intestinal failure (SBS-IF) require parenteral support (PS) and may need long-term home-care support. This survey assessed the impact of care provision on adult caregivers of adult patients receiving PS for SBS-IF. Methods: An online, cross-sectional survey of caregivers of adults with a self-reported physician diagnosis of SBS-IF was conducted in France, Germany, Italy, the UK, and USA. Impact on caregivers was evaluated using the 18-item Caregiver Strain Index (CSI), the Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI:SHP), and self-reporting impact questionnaires. Results: Caregivers (N = 121; aged 51 ± 13.7 years; 59% women) provided assistance for a mean of 9.9 ± 12.53 years; 77% were providing care 7 days per week. Patients (51 ± 16.4 years; 56% women) of caregivers were typically family members: spouse/partner (61%), adult son/daughter (19%), or parent (10%). Caregivers reported experiencing some strain (CSI score 4 ± 3.4). Among 71 of 73 employed caregivers, the WPAI:SHP assessment showed that caregivers missed 7% ± 12.7% of work hours in the preceding week and were present but not productive at work 37% ± 23.1% of the time; 28% of caregivers reported a reduced number of working hours because of caregiving. Many caregivers reported limitations in recreational activities (53%), and ≥30% had difficulty spending time with family and friends. Caregivers (87%) also reported worrying about the patient's health. Conclusions: Caregivers of adult patients with SBS-IF experience negative daily personal impacts and loss of productivity arising from their caregiving responsibilities.

Background: Treatment with glucagon-like peptide-2 (GLP-2) analogs improve intestinal adaptation in patients with short bowel syndrome–associated intestinal failure (SBS-IF) and may reduce parenteral support requirements. Apraglutide is a novel, long-acting GLP-2 analog designed for once-weekly dosing. This trial investigated the safety and efficacy of apraglutide in patients with SBS-IF. Methods: In this placebo-controlled, double-blind, randomized, crossover phase 2 trial, eight adults with SBS-IF were treated with once-weekly 5-mg apraglutide doses and placebo for 4 weeks, followed by once-weekly 10-mg apraglutide doses for 4 weeks, with a washout period of 6–10 weeks between treatments. Safety was the primary end point. Secondary end points included changes from baseline in urine volume output compared with placebo, collected for 48 h before and after each treatment period. Results: Common treatment-related adverse events (AEs) were mild to moderate and included polyuria, decreased stoma output, stoma complications, decreased thirst, and edema. No serious AEs were considered to be related to apraglutide treatment. The safety profile was comparable for the lower and higher doses. Treatment with once-weekly 5- and 10-mg apraglutide doses significantly increased urine volume output by an adjusted mean of 714 ml/day (95% CI, 490–939; P

Background The objective of this retrospective cohort study was to assess the frequency, duration, and causes of hospitalizations in patients receiving home parenteral support (HPS) due to short-bowel syndrome (SBS) of nonmalignant causes. Furthermore, we aimed to investigate potential risk factors and hypothesized that patients with the shortest remnant, functional, small bowel-hence, the highest need for HPS-would have the highest incidence of hospitalizations. Methods Patients with nonmalignant SBS who initiated HPS in the period from 1970 to 2016 from the Department of Gastroenterology, Rigshospitalet, Copenhagen, Denmark, were included. Information about demography, hospitalizations at the department, and duration of HPS was obtained from the Copenhagen intestinal failure database. Results Patients (n = 331) received HPS for a total of 1409.9 years in the period. Hospitalizations accounted for 6.6% of the time registered as HPS-dependent. The average patient was hospitalized for 5.7% (range 0%-82%) of the registered HPS days. The incidence of admissions was 2.5 per HPS year. The median length of stay was 7 days (range; 0-387). Catheter-related complications were the most frequently registered causes of admissions (35.2%), subsequently accounting for 31.3% of the total admission time. A Cox regression of admissions showed no significant influence of the remnant-bowel anatomy but identified the ability to administer HPS unaided as associated with a significantly reduced hazard. Conclusions This retrospective study illustrated that 6.6% of the provided HPS days were, in fact, spent hospitalized. Since admissions elsewhere were not accounted for, this may be an underestimation.

Background In patients with intestinal failure (IF), who are receiving home parenteral support (HPS), variations between centers in estimates of survival and HPS dependency often reflect differences in population characteristics. However, variations in methodology and adherence to model assumptions may further contribute. Objectives We investigated how differences in methodology affect estimates of outcomes in IF patients. Methods We applied different model assumptions and statistical methods to real-life outcome data from a well-characterized cohort of nonmalignant short bowel syndrome (SBS) patients. This retrospective study was based on extracts from the Copenhagen IF database and from the Danish death registry. Results Estimates of mortality varied substantially, depending on the study design and statistical method. The 5-y mortality rate obtained with the Kaplan-Meier (KM) method was estimated to be 10.1% higher if patients were only followed during HPS treatment, compared with follow-up regardless of HPS treatment. The 5-y cumulative incidence of weaning off HPS was overestimated by 4.4% when inappropriately using the KM method, instead of the cumulative incidence function. The 5-y survival rates in nonmalignant SBS-IF patients who initiated HPS were 89.1% for those aged younger than 40 y, 74.8% for patients aged 40-60 y, and 52.1% for those older than 60 y. A Cox regression analysis identified age and diagnoses other than inflammatory bowel disease as significant risk factors for mortality. For HPS dependency, bowel anatomy was significantly associated with the ability to wean off, and no patients without a colon and less than 100 cm remnant of the small bowel remained continuously weaned off and alive for one year. Conclusions The large variations in outcomes illustrated in this study emphasize the importance of the appropriate selection of statistical methods. A comparison between studies is problematic, due to differences in the methods employed.

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.

BACKGROUND: Teduglutide response, in terms of parenteral support (PS) volume reduction, is associated with specific disease characteristics among adults with short bowel syndrome-associated intestinal failure (SBS-IF). Whether these associations apply to PS weaning with teduglutide is unknown.METHODS: Adults with SBS-IF treated with teduglutide in the phase III STEPS study and open-label extensions STEPS-2 and STEPS-3 were included in the analysis. Patients required PS ≥ 3 times weekly for ≥ 12 months at enrollment. The study population was stratified 3 times to create 3 distinct analysis populations based on bowel anatomy, etiology, and baseline PS volume. Outcomes included characteristics of patients who achieved PS independence and total and percentage of patients who had ≥ 1, ≥ 2, and ≥ 3 d/wk off PS at the end of STEPS, STEPS-2, and STEPS-3.RESULTS: Eight of 39 patients who received teduglutide in STEPS obtained PS independence during the STEPS study series. Patients required > 6 months of teduglutide treatment before enteral autonomy was achieved, regardless of underlying disease characteristics. Patients who attained PS independence and greater numbers of days per week off PS tended to have lower baseline PS volumes and noninflammatory bowel disease (non-IBD) etiology. Patients with ≥ 50% colon-in-continuity showed a trend for achieving greater numbers of days per week off PS.CONCLUSION: Although this analysis was limited by low patient numbers, results suggest that SBS-IF characteristics of lower baseline PS volume and non-IBD etiology were associated with PS reduction benefits with teduglutide in terms of days off per week and enteral autonomy.

BACKGROUND: Teduglutide reduces or eliminates parenteral support (PS) dependency in patients with short bowel syndrome (SBS). Recent post hoc analyses demonstrated that effects are correlated with baseline PS volume. We assessed the SBS-related quality-of-life (QoL) impact of teduglutide, particularly whether improvements are greater among subgroups achieving more PS volume reduction.METHODS: Using phase 3 trial data of teduglutide in patients with SBS (NCT00798967), change in Short Bowel Syndrome-Quality of Life (SBS-QoL) scores from baseline were compared between teduglutide vs placebo in the overall population and subgroups classified by baseline PS volume requirement, disease etiology, and bowel anatomy. Generalized estimating equation models were fitted to assess impact of teduglutide on SBS-related QoL using data from all visits, adjusted for baseline characteristics.RESULTS: Of 86 patients, 43 each were randomized to teduglutide or placebo (mean age: 51 vs 50 years, respectively). In adjusted analyses, teduglutide had a nonsignificant reduction (improvement) of -8.6 points (95% CI: 2.6 to -19.8) in SBS-QoL sum score from baseline to Week-24 vs placebo. The impact of teduglutide varied by subgroup. Patients treated with teduglutide experienced significantly greater reductions in SBS-QoL sum score at Week-24 vs placebo in 2 subgroups, ie, the third (highest) tertile baseline PS volume (-27.3, 95% CI: -50.8 to -3.7) and inflammatory bowel disease (IBD; -29.6, 95% CI: -46.3 to -12.9). Results were similar for SBS-QoL subscale and item scores.CONCLUSIONS: The impact of teduglutide treatment on SBS-related QoL vs placebo varied among subgroups and was significant and most pronounced among patients with highest baseline PS volume requirement or IBD.

Background: The gut-liver axis and enterohepatic circulation have gained increasing attention lately. Patients with short bowel syndrome (SBS) are, in fact, human knock-out models that may assist in the understanding of bile acid synthesis and regulation. We evaluated effect of glepaglutide (a long-acting glucagon-like peptide-2 analog) on bile acid synthesis (the enterohepatic circulation of bile acids and liver biochemistry in patients with SBS.Method: In a single-center, double-blinded, dose-finding, crossover phase 2 trial, 18 patients with SBS were randomly assigned to 2 of 3 treatment arms (0.1, 1 and 10 mg) with daily subcutaneous injections of glepaglutide for 3 weeks. The washout period between the 2 treatment periods was 4-8 weeks. Measurements were performed at baseline and at the end of each treatment period and included postprandial plasma samples for fibroblast growth factor 19 (FGF19), 7α-hydroxy-4-cholesten-3-one (C4), total excretion of fecal bile acids, gene expression of farnesoid X receptor (FXR) in intestinal mucosal biopsies, total plasma bile acids, and liver biochemistry.Results: Compared to baseline, the median (interquartile range) postprandial response (area under the curve 0-2h) of FGF19 increased by 150 h × ng/L (41, 195; P = 0.001) and C4 decreased by 82 h × μg/L (-169, -28; P = 0.010) in the 10-mg dose. FXR gene expression did not change in any of the groups. Alkaline phosphatase significantly decreased.Conclusions: Glepaglutide may stimulate the bile acid/FXR/FGF19 axis, leading to increased plasma concentrations of FGF19. Thereby, glepaglutide may ameliorate the accelerated de novo bile acid synthesis and play a role in the prevention and/or treatment of intestinal failure-associated liver disease.

BACKGROUND Progressive renal impairment, given by an annual decline in estimated glomerular filtration rate (eGFR), has been described in patients with intestinal failure (IF) receiving home parenteral support (HPS). The objective of this study was to examine changes in eGFR over 5 years following initiation of HPS treatment and to identify potential risk factors for loss of renal function. METHOD This retrospective database study investigates eGFR changes in nonmalignant IF patients discharged with HPS from Rigshospitalet, Copenhagen, in an 8-year period. RESULTS One year after HPS initiation, mean eGFR decreased by 15.3 ml/min/1.73 m2 . Paired t-test showed a decline of 15.0 ml/min/1.73 m2 (95% CI, -18.3 to -11.6; P < .0001). Over the following years, eGFR continued to decrease but at insignificant lower rates. Decreased eGFR was associated with increasing age, female sex, increasing body weight, diabetes at HPS initiation, and a high requirement of HPS volume. CONCLUSION In nonmalignant IF patients, the decrease of eGFR was mainly seen during the first year of HPS. This may be due to a higher risk of dehydration and possibly secondary hyperaldosteronism leading to renal damage following the onset of IF. However, the decrease in eGFR may also represent a higher production of creatinine due to a beneficial increase of muscle mass in the initial recovery phase. In general, once the patients were stabilized, the eGFR decline followed a physiological course resembling the background population. Patients with diabetes or high HPS volume needs seem to be more vulnerable and may require special attention.

Accumulating evidence implicates glucagon-like peptide-1 (GLP-1) to have, beyond glucose maintenance, a beneficial role in the gastrointestinal tract. Here, we review emerging data investigating GLP-1 as a novel treatment for intestinal diseases, including inflammatory bowel diseases, short-bowel syndrome, intestinal toxicities and coeliac disease. Possible beneficial mechanisms for these diseases include GLP-1′s influence on gastric emptying, its anti-inflammatory properties and its intestinotrophic effect. The current knowledge basis derives from the available GLP-1 agonist treatments in experimental animals and small clinical trials. However, new novel strategies including dual GLP-1/GLP-2 agonists are also in development for the treatment of intestinal diseases.

ObjectivePatients with short bowel syndrome (SBS) and colon in continuity have better adaptation potential compared with patients with jejunostomy. Adaptation may involve enhanced postprandial secretion of the enteroendocrine hormones glucagon-like peptide (GLP)-1 and GLP-2 which are normally degraded by dipeptidyl peptidase (DPP)-4. Nevertheless, some patients with SBS with colon in continuity suffer from high-volume faecal excretions and have been shown to benefit from treatment with GLP-2. Therefore, we aimed to evaluate efficacy of sitagliptin, a DPP-4 inhibitor, on reducing faecal excretions in this patient group.DesignIn an open-label, case series, proof-of-concept pilot study, 100 mg oral sitagliptin was given two times per day for 8 weeks to patients with SBS with ≥50% colon in continuity with or without the need for parenteral support (PS). To assess intestinal function, metabolic balance studies were done at baseline and following 8 weeks of treatment.ResultsOf the 10 patients planned for enrolment, 8 patients were included; 7 patients completed the study. Although postprandial endogenous GLP-2 concentrations increased by 49 hours×pmol/L (39, 105; p=0.018) (median (min, max)), sitagliptin did not significantly reduce median faecal wet weight (−174 g/day (−1510, 675; p=0.176)) or increase intestinal wet weight absorption. However, heterogeneity in the treatment effect was observed: intestinal wet weight absorption increased in all four patients with intestinal failure. One patient achieved a reduction in PS by 500 mL per administration day.ConclusionFollowing this negative, small pilot study, larger, placebo-controlled, studies are needed to establish the therapeutic potential of DPP-4 inhibition in patients with SBS.

Aim was to investigate the association between quality of life (QoL), bowel anatomy, and the need for home parenteral support (HPS) volume in patients with nonmalignant short-bowel syndrome (SBS) and intestinal failure (IF).The SBS-QoL scale was used in a cross-sectional study of 95 nonmalignant SBS-IF patients. Sum QoL scores (0: best, 170: worst) were calculated. Patients were defined as having a small bowel (≤200 cm), and patients with jejunostomy or ileostomy were subclassified based on functional small-bowel length (cm) into 4 anatomy subgroups: 1a-1d (0-49, 50-99, 100-149, 150-200 cm, respectively). Multiple linear regression analyses explored associations between QoL, patient groups, and HPS volume, adjusting for age, sex, body mass index, and education.Complete data were obtained from 60 patients. HPS volume was associated with a worse SBS-QoL score (L/d, β = 7.91; SE = 3.90; P = .048), but male sex associated with improvement (β = -26.28; SE = 11.06; P = .021). No differences in sum QoL were seen between the benign SBS-IF subgroups 1a-d (P = .210). Multivariate regression analyses showed that patients with a small-bowel stoma, a small-bowel length50 cm was associated with a significantly worse/higher SBS-QoL score compared with a length50 cm.In patients with benign SBS-IF, high HPS volume was associated with poor QoL. Also, jejunostomy or ileostomy with small-bowel length50 cm was associated with impaired QoL. These findings support rehabilitation strategies that reduce fecal losses and decrease HPS needs.

BACKGROUND & AIMS: Teduglutide promotes intestinal growth and is approved for the treatment of short bowel syndrome and intestinal failure (SBS-IF). Based on the pharmacologic activity and preclinical findings, teduglutide can potentially induce proliferative colonic mucosal changes. The aim of this study is to report the occurrence of colorectal polyps in adult patients with SBS-IF who received teduglutide in clinical studies conducted to date.METHODS: A post hoc analysis of the completed Study of Teduglutide Effectiveness in Parenteral Nutrition-Dependent Short Bowel Syndrome Subjects (STEPS) clinical study series (NCT00798967, EudraCT 2008-006193-15; NCT00930644, EudraCT 2009-011679-65; NCT01560403) evaluated electronic case report form data for baseline colonoscopies (performed before treatment) and for surveillance or end-of-study (performed after treatment with teduglutide 0.05 mg/kg/day for 24 and 36 months) post-exposure procedures.RESULTS: In the STEPS studies, 73 patients treated with teduglutide had a baseline colonoscopy. No post-exposure colonoscopy was scheduled in STEPS. In STEPS-2/3, 50 of 65 patients with remnant colon (77%) underwent a protocol-mandated post-exposure colonoscopy. Colon polyps were reported at baseline in 12% (9/73) of patients and post-exposure in 18% (9/50) of patients. Two had polyps both at baseline and post-exposure. On histology, available for 7 patients, 5 had adenomas (1 serrated, 4 tubular) and none had malignancy or high-grade dysplasia.CONCLUSION: These data support recommendations for colonoscopic screening before teduglutide therapy and subsequent on-therapy colonoscopic surveillance for patients with SBS-IF. Further studies are required to assess the risk of polyp formation in patients with SBS-IF and the most appropriate colon polyp surveillance strategies.

Background Glucagon-like peptide-2 (GLP-2) is an intestinotrophic factor released from L-cells in the ileum, a segment commonly resected or atretic in neonatal short bowel syndrome (SBS). In piglets, ileal resection decreases intestinal adaptation and endogenous GLP-2 production, whereas exogenous replacement promotes adaptation. In this study, we determined the effect of a novel long-acting GLP-2 analogue, FE 203799 (FE; apraglutide), upon intestinal growth, adaptation, and function in neonatal SBS piglets without ileum. Methods Neonatal piglets were randomized to saline (n = 10) vs FE treatment (n = 8). All piglets underwent 75% intestinal resection with jejunocolic anastomosis and were pair-fed parenteral and enteral nutrition. Saline and FE (5 mg/kg) treatments were administered subcutaneously on days 0 and 4. On day 6, 24-hour fecal samples were collected for subsequent nutrient analysis. On day 7, small-intestinal length and weight were measured and tissue collected for analyses. Results On day 7, saline and FE-treated piglets were healthy and gained equivalent weight (P = 0.12). Compared with saline piglets, FE-treated piglets had lower fecal fat (P = 0.043) and energy (P = 0.043) losses and exhibited intestinal lengthening (P = 0.001), greater small-intestinal weight (P = 0.004), longer villus height (P = 0.027), and greater crypt depth (P = 0.054). Conclusions The subcutaneous GLP-2 analogue, FE, enhanced intestinal adaptation in a neonatal model of SBS without ileum. The observed intestinal lengthening with FE treatment was unique compared with our prior experience with native GLP-2 in this same model and has important clinical implications for treating neonatal SBS. At this developmental stage, growth in the intestine, if augmented, could accelerate weaning from parenteral nutrition.

Aim Analogues of several gastrointestinal peptide hormones have been developed into effective medicines for treatment of diseases such as type 2 diabetes mellitus (T2DM), obesity and short bowel syndrome (SBS). In this study, we aimed to explore whether the combination of glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) into a potent co-agonist could provide additional benefits compared to existing monotherapies. Methods A short-acting (GUB09-123) and a half-life extended (GUB09-145) GLP-1/GLP-2 co-agonist were generated using solid-phase peptide synthesis and tested for effects on food intake, body weight, glucose homeostasis, and gut proliferation in lean mice and in diabetic db/db mice. Results Sub-chronic administration of GUB09-123 to lean mice significantly reduced food intake, improved glucose tolerance, and increased gut volume, superior to monotherapy with the GLP-2 analogue teduglutide. Chronic administration of GUB09-123 to diabetic mice significantly improved glycemic control and showed persistent effects on gastric emptying, superior to monotherapy with the GLP-1 analogue liraglutide. Due to the short-acting nature of the molecule, no effects on body weight were observed, whereas a marked and robust intestinotrophic effect on mainly the small intestine volume and surface area was obtained. In contrast to GUB09–123, sub-chronic administration of a half-life extended GUB09-145 to lean mice caused marked dose-dependent effects on body weight while maintaining its potent intestinotrophic effect. Conclusion Our data demonstrate that the GLP-1/GLP-2 co-agonists have effects on gut morphometry, showing a marked increase in intestinal volume and mucosal surface area. Furthermore, effects on glucose tolerance and long-term glycemic control are evident. Effects on body weight and gastric emptying are also observed depending on the pharmacokinetic properties of the molecule. We suggest that this novel co-agonistic approach could exemplify a novel concept for treatment of T2DM or SBS.

Background: In patients with intestinal failure who are receiving home parenteral support (HPS), catheter-related bloodstream infections (CRBSIs) inflict health impairment and high costs.Objective: This study investigates the efficacy and safety of the antimicrobial catheter lock solution, taurolidine-citrate-heparin, compared with heparin 100 IE/mL on CRBSI occurrence.Design: Forty-one high-risk patients receiving HPS followed in a tertiary HPS unit were randomly assigned in a double-blinded, placebo-controlled trial. External, stratified randomization was performed according to age, sex, and prior CRBSI incidence. The prior CRBSI incidence in the study population was 2.4 episodes/1000 central venous catheter (CVC) days [95% Poisson confidence limits (CLs): 2.12, 2.71 episodes/1000 CVC days]. The maximum treatment period was 2 y or until occurrence of a CRBSI or right-censoring because of CVC removal. The exact permutation tests were used to calculate P values for the log-rank tests.Results: Twenty patients received the taurolidine-citrate-heparin lock and 21 received the heparin lock, with 9622 and 6956 treatment days, respectively. In the taurolidine-citrate-heparin arm, no CRBSIs occurred, whereas 7 CRBSIs occurred in the heparin arm, with an incidence of 1.0/1000 CVC days (95% Poisson CLs: 0.4, 2.07/1000 CVC days; P = 0.005). The CVC removal rates were 0.52/1000 CVC days (95% Poisson CLs: 0.17, 1.21/1000 CVC days) and 1.72/1000 CVC days (95% Poisson CLs: 0.89, 3.0/1000 CVC days) in the taurolidine-citrate-heparin and heparin arm, respectively, tending to prolong CVC survival in the taurolidine arm (P = 0.06). Costs per treatment year were lower in the taurolidine arm (€2348) than in the heparin arm (€6744) owing to fewer admission days related to treating CVC-related complications (P = 0.02).Conclusions: In patients with intestinal failure who are life dependent on HPS, the taurolidine-citrate-heparin catheter lock demonstrates a clinically substantial and cost-beneficial reduction of CRBSI occurrence in a high-risk population compared with heparin. This trial was registered at clinicaltrials.gov as NCT01948245.

Background:In multiple clinical studies, teduglutide reduced parenteral support (PS) with a consistent safety profile in adults with short bowel syndrome–associated intestinal failure (SBS–IF). The objective of this study was to assess adverse events (AEs) from a pooled data set.Methods:Safety data from four prospective clinical trials of teduglutide in patients with SBS–IF were assimilated. AEs were evaluated in patient groups based on treatment received in each study and in populations stratified to create distinct subgroups based on aetiology, bowel anatomy and baseline PS volume requirements.Results:Safety data are reported for up to 2.5 years, totalling 222 person-years exposure to teduglutide. In most patients, AEs were reported as mild or moderate in severity in all patient groups and occurred at comparable rates between patients who received teduglutide or placebo. Several common gastrointestinal AEs, including abdominal pain, nausea and abdominal distension, were reported more frequently earlier in the course of treatment, with their frequency declining over time. Fewer gastrointestinal AEs were reported in patients with vascular causes of SBS–IF and patients with most of their colon-in-continuity than in other patient subgroups. Across the patient stratification subgroups, the predominant treatment-emergent AEs for which patients receiving teduglutide had a significantly increased relative risk were abdominal distension and gastrointestinal stoma complication compared with patients receiving placebo.Conclusions:Teduglutide had a safety profile consistent with prior adult data and no new safety concerns were identified. The most frequently reported AEs were gastrointestinal in origin, consistent with the underlying disease condition and intestinotrophic actions of teduglutide.Clinical Trial Registry information:NCT00081458/EudraCT, 2004-000438-35; NCT00798967/EudraCT, 2008-006193-15; NCT00172185/EudraCT, 2004-000439-27; NCT00930644/EudraCT, 2009-011679-65

Background Patients with short bowel syndrome (SBS) and distal-bowel resections lack neuroendocrine feedback regulations, potentially resulting in rapid gastrointestinal (GI) transit. The objective was to assess the efficacy of glepaglutide, a long-acting glucagon-like peptide-2 analog, on GI transit in patients with SBS. Methods In this single-center, double-blind, dose-finding, phase 2 trial, patients with SBS were randomly assigned to 3 treatments (0.1, 1, and 10 mg) in a 2-period crossover design. Each treatment period included 3 weeks of daily, subcutaneous glepaglutide injections separated by a washout period of 4-8 weeks. Endpoints were changes from baseline and included scintigraphy, wireless motility capsule (WMC, SmartPill Given Imaging, Ltd, Yokneam, Israel), and paracetamol absorption test. Results A total of 18 patients were randomized. In the 10-mg dose group (n = 9), glepaglutide significantly increased time to 10% gastric emptying (GE) of solids by 27 (4-50) minutes (adjusted mean [95% CI]), time to 50%GE of fluids by 40 (1-80) minutes, and time to 10% small bowel-emptying of solids by 21 (1-41) minutes. The WMC transit did not significantly change in any of the dose groups. The maximum paracetamol concentration significantly increased in the 10-mg dose group; however, the area under the curve remained the same. Conclusion The prolonged GI transit after glepaglutide treatment, along with demonstrated positive effects on intestinal mucosal growth and potential effects on GI hypersecretions, is believed to contribute to the observed beneficial effects on fecal output (primary endpoint) and associated improvement in intestinal absorption.

The ability to provide parenteral support represents a revolutionary change in medical therapy for patients with temporary and inadequate intestinal absorptive capacity or for patients with chronic intestinal failure due to digestive diseases. Nevertheless, due to the rarity of intestinal failure, a de facto policy of "discrimination by organ failure treatment" exists in many countries whereby this problem is under-recognized and under-treated. With the increasing recognition of the pathophysiological consequences of intestinal resection and the occurrence of new pro-adaptive treatments for patients suffering from short bowel syndrome, this review reflects on the history of developments in this area and discusses current practice and future directions of the field.

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.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.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.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.

Intestinal failure (IF) is a debilitating condition of inadequate nutrition due to an anatomical and/or physiological deficit of the intestine. Surgical management of patients with acute and chronic IF requires expertise to deal with technical challenges and make correct decisions. Dedicated IF units have expertise in patient selection, operative risk assessment and multidisciplinary support such as nutritional input and interventional radiology, which dramatically improve the morbidity and mortality of this complex condition and can beneficially affect the continuing dependence on parenteral nutritional support. Currently there is little guidance to bridge the gap between general surgeons and specialist IF surgeons. Fifteen European experts took part in a consensus process to develop guidance to support surgeons in the management of patients with IF. Based on a systematic literature review, statements were prepared for a modified Delphi process. The evidence for each statement was graded using Oxford Centre for Evidence-Based Medicine Levels of Evidence. The current paper contains the statements reflecting the position and practice of leading European experts in IF encompassing the general definition of IF surgery and organization of an IF unit, strategies to prevent IF, management of acute IF, management of wound, fistula and stoma, rehabilitation, intestinal and abdominal reconstruction, criteria for referral to a specialist unit and intestinal transplantation.

Background: With the introduction of glucagon-like peptide-2 (GLP-2) in the treatment of short bowel syndrome (SBS), there is emerging evidence that GLP-2 may play a role in the restoration of the disturbed homeostatic feedback in the gut-liver axis and may ameliorate SBS-associated liver damage.We have previously presented that daily subcutaneous injections with 1 and 10 mg of glepaglutide improved intestinal function in patients with SBS. As exploratory endpoints, we here assessed the effect of glepaglutide on liver function. Methods: Liver tests, transient elastography (TE) with controlled attenuation parameter (CAP), indocyanine green (ICG) kinetics, soluble CD163 (sCD163), soluble mannose receptor (sMR), and lipopolysaccharide binding protein (LBP) were assessed in 18 patients with SBS in a randomised, cross-over, dose-finding phase 2 trial before and after three weeks of treatment with glepaglutide. This trial is completed and registered at ClinicalTrials.gov: NCT02690025. Findings: Between Feb 2016 and Jan 2017, 22 patients with SBS were screened. Of these, 18 patients were randomised and treated with glepaglutide; 16 patients completed the trial. Treatment with glepaglutide was associated with increase in TE and ICG-elimination. In the 10 mg dose group, glepaglutide increased sCD163 by 0·44 mg/mL (P = 0·0498), and alkaline phosphatase (ALP) decreased in the 1 mg dose group by 33 U/L (P = 0·032). CAP, sMR, LBP, liver transaminases, and INR were not affected. Interpretation: Glepaglutide may improve hepatic excretory function, but at the same time activate resident liver macrophages and increase liver stiffness. The excretory and the stiffness findings may to some extent relate to increased splanchnic blood flow which would not influence the marker of macrophage activation. Thus, glepaglutide exerted diverse effects on liver status that call for attention in future studies. Funding: Zealand Pharma. Keywords: Short bowel syndrome, Transient elastography, Indocyanine green, Soluble CD163, Soluble mannose receptor

Summary 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.

Kristina S Chen,1 Jipan Xie,2 Wenxi Tang,3 Jing Zhao,4 Palle B Jeppesen,5 James E Signorovitch4 1Outcomes Research and Epidemiology, Shire Human Genetic Therapies, Inc., Cambridge, MA, USA; 2Analysis Group, Inc., Los Angeles, CA, USA; 3Analysis Group, Inc., New York, NY, USA; 4Analysis Group, Inc., Boston, MA, USA; 5Department of Medical Gastroenterology, Rigshospitalet, Copenhagen, Denmark Purpose: Teduglutide, a glucagon-like peptide-2 analog, has demonstrated efficacy in reducing parenteral support (PS) among patients with short bowel syndrome with intestinal failure (SBS–IF). This study aims to identify a subpopulation of SBS–IF patients for whom teduglutide has an especially pronounced effect. Patients and methods: Data were from a 24-week, Phase III trial (Study of Teduglutide Effectiveness in Parenteral Nutrition-Dependent SBS Subjects; NCT00798967) that randomized SBS–IF patients with PS dependency to receive teduglutide (n=43) or placebo (n=43). Two prediction models (1 for each arm) were developed for response, defined as 20% reduction in weekly PS at Weeks 20 and 24. Potential predictors included demographics, disease characteristics, and concomitant medications. Patients were then ranked based on the effect score, an individualized predicted response rate difference with teduglutide versus placebo. A subpopulation of patients with a pronounced benefit from teduglutide versus placebo was identified. Baseline characteristics and clinical outcomes were compared between patients included versus those not included in the subpopulation. Results: Six predictors of response to teduglutide were selected: older age, volvulus as the cause of major intestinal resection, baseline PS volume >6 L per week, longer time since start of PS dependency, absence of ileocecal valve, and lower percentage of colon remaining. Higher percentage of colon remaining and volvulus were the selected predictors for response to placebo. A subpopulation of patients more likely to respond to teduglutide was identified as those with the top 60% effect scores. The difference in response rate between teduglutide and placebo was 62% in the subpopulation, which was substantially higher than the difference of 33% in the overall population. Mean PS day reduction was also significantly higher for teduglutide compared to placebo in the subpopulation. Conclusion: Pretreatment characteristics as predictors of response to teduglutide versus placebo within 24 weeks were identifiable in the clinical trial population of SBS–IF patients. Keywords: SBS, intestinal failure, teduglutide, subpopulation

Intestinal failure (IF) is the reduction of gut function below the minimum necessary for the absorption of macronutrients and/or water and electrolytes, such that parenteral support (PS) is required to maintain health and/or growth. This article critically revises the gaps in and evidence for providing general nutritional therapy recommendations in the Short Bowel Syndrome-IF population. It addresses the need for an individualized approach, aiming to reduce or even eliminate the need for PS, and emphasizes a need to focus on effects of dietary interventions on the quality of life of these patients.

We propose a new OLT transmitter for WDM-PON based on optical Fourier transformation of a single-source TDM-PON signal to WDM-PON signals. We demonstrate flexible bit rates (10×1-to-64×2Gb/s) and 40×1Gb/s WDM-PON record unamplified downstream transmission reach of 150 km.

BACKGROUND: The catheter lock solutions 2% taurolidine and 0.9% saline are both used to prevent catheter-related bloodstream infections (CRBSIs) in home parenteral nutrition patients.AIMS: To compare the effectiveness and safety of taurolidine and saline.METHODS: This multicentre double-blinded trial randomly assigned home parenteral nutrition patients to use either 2% taurolidine or 0.9% saline for 1 year. Patients were stratified in a new catheter group and a pre-existing catheter group. Primary outcome was the rate of CRBSIs/1000 catheter days in the new catheter group and pre-existing catheter group, separately.RESULTS: We randomised 105 patients, of which 102 were analysed as modified intention-to-treat population. In the new catheter group, rates of CRBSIs/1000 catheter days were 0.29 and 1.49 in the taurolidine and saline arm respectively (relative risk, 0.20; 95% CI, 0.04-0.71; P = 0.009). In the pre-existing catheter group, rates of CRBSIs/1000 catheter days were 0.39 and 1.32 in the taurolidine and saline arm respectively (relative risk, 0.30; 95% CI, 0.03-1.82; P = 0.25). Excluding one outlier patient in the taurolidine arm, mean costs per patient were $1865 for taurolidine and $4454 for saline (P = 0.03). Drug-related adverse events were rare and generally mild.CONCLUSIONS: In the new catheter group, taurolidine showed a clear decrease in CRBSI rate. In the pre-existing catheter group, no superiority of taurolidine could be demonstrated, most likely due to underpowering. Overall, taurolidine reduced the risk for CRBSIs by more than four times. Given its favourable safety and cost profile, taurolidine locking should be considered as an additional strategy to prevent CRBSIs.TRIAL REGISTRATION: Clinicaltrials.gov, identifier: NCT01826526.

Glucagon like peptide-2 is synthesized from enteroendocrine L cells primarily located in the ileum and large intestine. GLP-2 stimulates crypt cell proliferation, increases intestinal blood flow, enhances gut barrier function, induces mucosal healing, and exerts an anti-apoptotic effect. Due to these effects GLP-2 is used in the treatment of short bowel syndrome (SBS). Areas covered: The aim of this systematic review was to provide information on the potential risk of intestinal neoplasia in patients receiving treatment with GLP-2. The literature search was performed independently by two authors in the following databases; Pubmed, Embase, Scopus, Web of Science and Cochrane. Expert commentary: This systematic review indicated that treatment with GLP-2(1-33) up to 30 months in humans without any known pre-existing cancer did not confer an increased risk of intestinal neoplasia in patients or animals. However, due to the small amount of patients studied it is premature to reach any final conclusions about GLP-2 - induced neoplasia. GLP-2(1-33) treatment in animals with a pre-induced cancer showed that GLP-2(1-33) may promote growth of existing neoplasia.

Background In intestinal failure (IF) patients receiving home parenteral support (HPS), catheter-related bloodstream infections (CRBSIs) frequently result in replacement of their tunneled central venous catheters (CVCs), which may lead to future loss of central venous access. Objective This observational study investigated the consequences of a catheter-salvage strategy related to CRBSIs. Design All CRBSIs from 2002 to 2016 in the Copenhagen IF and microbiological databases were retrospectively analyzed. Catheter salvage was defined by successful antimicrobial therapy with a retained CVC at discharge. Re-occurrences of CRBSIs with the same microbial species and identical antibiogram were defined as a relapse (

Background & Aims: Clinical studies showed teduglutide to increase urine production and reduce need for parenteral support volume in patients with short bowel syndrome (SBS) with intestinal failure, increasing intestinal wet weight absorption and reducing diarrhea. However, the effects of teduglutide on parenteral support vary among patients. We performed a post hoc analysis of a phase III placebo-controlled study to identify characteristics of patients in whom teduglutide has the largest effects on parenteral support volume response. Methods: We collected data from 85 patients with SBS with intestinal failure, according to the European Society for Clinical Nutrition and Metabolism classification system, who received teduglutide or placebo between November 25, 2008, and January 4, 2011, at 27 sites in 10 countries. Changes in parenteral support volume were evaluated according to baseline parenteral support volume, bowel anatomy (group 1, jejunostomy/ileostomy; group 2, ≥50% colon-in-continuity without stoma; and group 3, other colon anatomies), and disease features (with inflammatory bowel disease, mesenteric vascular diseases, or other conditions). Correlation analyses were conducted using simple linear regression models, with unadjusted r2 values reported. Two-sided t tests were used for comparisons between treatment groups. Results: We correlated parenteral support volume reduction with teduglutide treatment and baseline parenteral support volume (y = –0.3870x + 90.0279, r2 = 0.61; P