Short Bowel Syndrome-associated Intestinal Failure Research Articles

Teduglutide improves liver chemistries in short bowel syndrome-associated intestinal failure: Post hoc analysis.

Chronic hepatic complications are common in patients with short bowel syndrome-associated intestinal failure (SBS-IF). Teduglutide, a glucagon-like peptide-2 analogue, demonstrated efficacy in reducing parenteral nutrition and/or intravenous fluid dependence among patients with SBS-IF in phase 3 clinical studies. This was a post hoc analysis of pooled data from two separate randomized, double-blind, placebo-controlled, multinational phase 3 clinical studies. Adult patients with SBS-IF with parenteral nutrition and/or intravenous fluid dependence without liver disease at baseline were randomized to treatment with the glucagon-like peptide-2 analogue teduglutide (0.05 or 0.10 mg/kg/day) or placebo subcutaneously once daily for 24 weeks. Mixed-effects models assessed the baseline predictors of change in liver chemistries. Between baseline and week 24, teduglutide treatment (n = 109) was associated with least squares mean reductions in aspartate aminotransferase (-7.51 IU/L; P = 0.014), alanine aminotransferase (-12.15 IU/L; P = 0.002), and bilirubin (-5.03 µmol/L [-0.057 mg/dl]; P < 0.001) compared with that of the placebo (n = 59). These values were independent of reductions in parenteral nutrition and/or intravenous fluid dependence. Teduglutide treatment was associated with reductions in liver chemistries by week 24, which is beneficial for patients with SBS-IF beyond improvements in parenteral nutrition and/or intravenous fluid dependence. Future studies should examine how long-term teduglutide might mitigate the risk of liver disease in patients with SBS-IF.

Effects of Teduglutide on Diarrhea in Pediatric Patients with Short Bowel Syndrome-Associated Intestinal Failure.

This post-hoc analysis evaluated the effect of teduglutide treatment on diarrhea in patients with short bowel syndrome-associated intestinal failure (SBS-IF). Data from 2 open-label, multicenter, phase 3 pediatric SBS-IF clinical trials of teduglutide (NCT01952080 and NCT02682381) were pooled where possible. The primary objective was to evaluate the change in stool consistency, frequency, and volume from baseline to weeks 12 and 24 of treatment in patients who received any teduglutide dose from both studies ("total teduglutide"). Safety assessments included gastrointestinal adverse event reporting. Overall, 101 patients were analyzed. Among the total teduglutide group (n = 87), there were significant changes from baseline to weeks 12 and 24 in mean (standard error) Bristol Stool Form Scale (BSFS) score [-1.8 (0.26; P < 0.0001) and -2.2 (0.27; P < 0.0001), respectively], parenteral nutrition and/or intravenous fluid (PN/IV) volume [-16.9 (1.7; P < 0.0001) and -20.1 (2.3; P < 0.0001) mL/kg/day, respectively], and enteral nutrition volume [9.2 (1.7; P < 0.0001) and 9.6 (2.3; P = 0.0002) mL/kg/day, respectively]. Among patients in the standard of care group (n = 14) there were numerical changes in BSFS score, and enteral nutrition volume at weeks 12 and 24; significant changes in PN/IV volume [-6.9 (1.5) mL/kg/day; P = 0.0041] were observed at 24 weeks, but not at 12 weeks. In this post-hoc analysis, short-term treatment with teduglutide was associated with improved stool consistency, as well as trends towards reductions in PN/IV requirements and advancements in enteral nutrition volume in children with SBS-IF. Further research assessing the impact of patient-level factors on stool characteristics when using teduglutide is warranted.

Use of teduglutide in adults with short bowel syndrome-associated intestinal failure.

Short bowel syndrome (SBS) is a rare gastrointestinal disorder associated with intestinal failure (SBS-IF) and poor health-related outcomes. Patients with SBS-IF are unable to absorb sufficient nutrients or fluids to maintain significantly metabolic homeostasis via oral or enteral intake alone and require long-term intravenous supplementation (IVS), consisting of partial or total parenteral nutrition, fluids, electrolytes, or a combination of these. The goal of medical and surgical treatment for patients with SBS-IF is to maximize intestinal remnant absorptive capacity so that the need for IVS support may eventually be reduced or eliminated. Daily subcutaneous administration of the glucagon-like peptide 2 analog, teduglutide, has been shown to be clinically effective in reducing IVS dependence and potentially improving the health-related quality of life of patients with SBS-IF. The management of patients with SBS-IF is complex and requires close monitoring. This narrative review discusses the use of teduglutide for patients with SBS-IF in clinical practice. The screening of patient eligibility for teduglutide treatment, initiation, monitoring of efficacy and safety of treatment, adapting or weaning off IVS, and the healthcare setting needed for SBS-IF management are described, taking into consideration data from clinical trials, observational studies, and clinical experience.

Clinical Recommendations of the Northwest Society for Enteral and Parenteral Nutrition, Interregional Association for Emergency Surgery, Russian Gastroenterological Association, Union of Rehabilitation Therapists of Russia and Russian Transplantation Society on Diagnosis and Treatment of Short Bowel Syndrome-Associated Intestinal Failure in Adults

Aim. Current clinical recommendations address the epidemiology, causes, clinical manifestations and pathogenesis of possible immediate and long-term complications, as well as the problematic issues related to treatment and rehabilitation of adult short bowel syndrome patients.Key points. Short bowel syndrome (SBS) is a symptom complex of impaired digestion caused by the reduction of small intestine absorptive surface and manifested by intestinal failure (IF) of various severity (maldigestion and malabsorption) developing into malnutrition and systemic somatogenic disorders. The vital strategic aspects of its treatment are the personalisation of liquid, macro- and micronutrients consumption as well as avoidance of intestinal failure- and parenteral nutrition-associated complications. Various nutritional support regimes and the indications for infusion therapy and maintenance parenteral nutrition are considered in this patient category, also in outpatient settings. To mitigate the dependence on intravenous fluid- and nutrient administration and attain enteral autonomy in SBS-IF patients, the use of recombinant glucagon-like peptide-2 (GLP-2) is justified as exerting a pronounced trophic effect on the epithelial regenerative potential as well as structural and functional adaptation of intestinal mucosa. The SBS-IF patients prescribed with home parenteral nutrition and/or their caregivers should be trained in a special programme that covers the catheter care, preparation of infusion solutions and nutrient mixture container, infusion pump operation as well as the prevention, recognition and management of complications. The main referral indications for small bowel transplantation (SBT) are: fast-progressing cholestatic liver disease-complicated irreversible intestinal failure; thrombosis of two or more central venous conduits used for parenteral nutrition; recurrent catheter-associated bloodstream infection.Conclusion. Current recommendations on diagnosis and treatment as well as the developed criteria of medical aid quality assessment are applicable at different levels of healthcare.

Changes in Parenteral Nutrition Requirements and BMI in Patients with Parenteral Nutrition-Dependent Short Bowel Syndrome after Stopping Teduglutide-9 Years of Follow-Up.

Teduglutide (TED) is widely used in patients with short-bowel-syndrome-associated intestinal failure (SBS-IF) to enhance intestinal adaptation and reduce the need for parenteral support (PS). There are limited data on the effects of discontinuing TED. In this study, we describe the changes in parenteral nutrition (PN) requirements and body mass index (BMI) in a 9-year follow-up of patients receiving home parenteral nutrition after discontinuation of the TED treatment. We performed a retrospective analysis of changes in weekly PN orders and BMI in all patients with PN-dependent SBS from two Polish home parenteral nutrition (HPN) centers who received teduglutide between 2009 and 2013 and still required HPN 9 years after discontinuation of the TED treatment. Data included in the analysis were collected prospectively at mandatory visits to the HPN centers at 12, 24, 60, 84, and 108 months after drug discontinuation and compared with values before and after TED treatment. Weekly PN volume values varied significantly between all of the above time points from baseline to 9 years after TED discontinuation (χ2 = 34.860, p < 0.001). After an initial increase within the first year after treatment discontinuation (not statistically significant), the PN volume requirements remained stable for 4 years and increased 5–9 years after treatment discontinuation. The rate of patients requiring an increase in PN volume was 84.62% at 60 and 84 months and 92.30% at 108 months. At 9 years after cessation of the TED treatment, 53.85% of the study group required a 21.21% increase in PN volume compared with values before treatment. The need for PN volume in patients with PN-dependent SBS who discontinued the TED treatment increased within the first year and 4–5 years after treatment cessation, and in some cases might even exceed pretreatment values after 9 years.

Results of an International Survey on Feeding Management in Infants With Short Bowel Syndrome-Associated Intestinal Failure.

Short bowel syndrome (SBS) is a complex and rare condition (incidence 1200/100,000 live births) that requires a multidisciplinary team approach to management. In January 2019, the first European Reference Network on Rare and Inherited Congenital Anomalies (ERNICA) Intestinal Failure (IF) workshop was held. Several questions about the strategies used in managing IF associated with SBS were devised. The aim of our study was to collect data on the enteral feeding strategies adopted by the ERNICA centres. A questionnaire (36 questions) about strategies used to introduce enteral nutrition post-operatively and start complementary food/solids in infants with SBS associated IF was developed and sent to 24 centres in 15 countries that participated in the ERNICA-IF workshop. The answers were collated and compared with the literature. There was a 100% response rate. In infants, enteral nutrition was introduced as soon as possible, ideally within 24-48 hours post-small intestinal surgical resection. In 10 of 24 centres, bolus feeding was used, in nine continuous, and in five a combination of both. Twenty-three centres used mothers' own milk as the first choice of feed with extensively hydrolysed feed, amino acid-based feed, donor human milk or standard preterm/term formula as the second choice. Although 22 centres introduced complementary/solid food by 6 months of age, food choice varied greatly between centres and appeared to be culturally based. There is diversity in post-surgical enteral feeding strategies among centres in Europe. Further multi-centre studies could help to increase evidence-based medicine and management on this topic.

Safety Findings in Pediatric Patients During Long-Term Treatment With Teduglutide for Short-Bowel Syndrome-Associated Intestinal Failure: Pooled Analysis of 4 Clinical Studies.

BackgroundThis analysis assessed combined safety data from 4 clinical studies of teduglutide in pediatric patients with short‐bowel syndrome–associated intestinal failure (SBS–IF).MethodsSafety data from teduglutide‐treated patients in 4 clinical trials were pooled. The completed 12‐week and 24‐week phase 3 core studies (NCT01952080/EudraCT 2013‐004588‐30 and NCT02682381/EudraCT 2015‐002252‐27) enrolled children aged 1–17 years with SBS–IF. Patients could elect to enroll in ongoing open‐label extensions (NCT02949362/EudraCT 2016‐000863‐17 and NCT02954458/EudraCT 2016‐000849‐30). Interim data from ongoing studies were included.ResultsSafety data are reported for 89 pediatric patients treated with teduglutide for a median (range) of 51.7 (5.0–94.7) weeks. Adverse events (AEs) were reported in all patients; the most common were vomiting (51.7%), pyrexia (43.8%), upper respiratory tract infection (41.6%), and cough (33.7%). Thirty‐five patients (39.3%) had AEs considered related to teduglutide treatment; abdominal pain and vomiting were most frequent (5.6% each). Three serious AEs in 3 patients (3.4%) were considered related to teduglutide treatment: ileus, d‐lactic acidosis, and gastrointestinal obstruction due to hard stools. All 3 events resolved. One cecal polyp was detected, which was not biopsied or found on repeat colonoscopy. No cases of neoplasia occurred.ConclusionBased on integrated data from 4 clinical studies, including long‐term follow‐up for ≤161 weeks, teduglutide had a safety profile consistent with the individual core pediatric studies and as expected for pediatric patients with SBS–IF who never received teduglutide. The most frequent AEs reflected treatment with teduglutide, complications of the underlying disease, and typical childhood illnesses.

Six-month outcomes of teduglutide treatment in adult patients with short bowel syndrome with chronic intestinal failure: A real-world French observational cohort study.

Teduglutide, a GLP-2-analog, has proven effective in two placebo-controlled studies in reducing parenteral support (PS) in patients with short bowel syndrome-associated intestinal failure (SBS-IF) after 24 weeks. The aim of this study was to describe in a real-life situation the effects of teduglutide treatment and their predictive factors. We included 54 consecutive SBS-IF patients treated with teduglutide in France for at least 6 months from 10 expert centers. Small bowel length was 62±6cm and 65% had colon in continuity. PS was 4.4±0.2 infusions per week, started 9.8±1.2 years before. Response (PS reduction≥20%) and PS discontinuation rates were assessed at week 24. Adjusted p values of factors associated with response and weaning were calculated using a multivariate logistic regression model. At week 24, 85% of patients were responders and 24% had been weaned off PS, with a 51% reduction of PS needs and 1.5±0.2 days off PS per week. Response to teduglutide was influenced by a higher baseline oral intake (p=0.02). Weaning off PS was influenced by the presence of colon (p=0.04), a lower PS volume (p=0.03) and a higher oral intake (p=0.01). There were no differences based on age, bowel length or SBS-IF causes. Our study confirms the effectiveness of teduglutide in reducing PS needs in SBS-IF patients. We associated reduced parenteral support volume with baseline parenteral volume support, bowel anatomy, and oral intake. These findings underline the role of nutritional optimization when starting the treatment.

Safety and Efficacy of Teduglutide in Pediatric Patients With Intestinal Failure due to Short Bowel Syndrome: A 24-Week, Phase III Study.

BackgroundThis study evaluated the safety and efficacy of teduglutide in pediatric patients with short bowel syndrome–associated intestinal failure (SBS‐IF).MethodsA 24‐week, phase III trial with 2 randomized, double‐blind teduglutide dose groups and a nonblinded standard of care (SOC) arm was used; patients received 0.025 mg/kg or 0.05 mg/kg teduglutide once daily. Safety end points included treatment‐emergent adverse events (TEAEs) and growth parameters. The primary efficacy/pharmacodynamic end point was the number of patients who achieved a ≥20% reduction in parenteral support (PS) from baseline at week 24.ResultsAll 59 enrolled patients completed the study (0.025 mg/kg, n = 24; 0.05 mg/kg, n = 26; SOC, n = 9). Baseline demographics and disease characteristics were comparable among groups. TEAEs were reported by 98% and 100% of patients in the teduglutide and SOC groups, respectively. The most common TEAEs in the teduglutide‐treated groups were pyrexia and vomiting. The primary end point was achieved by 13 (54.2%), 18 (69.2%), and 1 (11.1%) patients who received 0.025 mg/kg teduglutide, 0.05 mg/kg teduglutide, and SOC, respectively (P < 0.05 vs SOC). Both 0.025‐mg/kg and 0.05‐mg/kg teduglutide groups showed clinically significant reductions in PS volume (P < 0.05 vs SOC), PS calories, days per week and hours per day of PS infusions, and increases in enteral nutrition and plasma citrulline at week 24 compared with baseline. Two (8.3%, 0.025 mg/kg teduglutide) and 3 patients (11.5%, 0.05 mg/kg teduglutide) achieved enteral autonomy.ConclusionThe safety profile of teduglutide was similar to that reported previously in children and adults. Treatment with teduglutide was associated with significant reductions in PS for pediatric patients with SBS‐IF over 24 weeks.

Enteral Autonomy and Days Off Parenteral Support With Teduglutide Treatment for Short Bowel Syndrome in the STEPS Trials.

BackgroundTeduglutide 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.MethodsAdults 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.ResultsEight 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.ConclusionAlthough 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.

Teduglutide reduced parenteral support in children with short bowel syndrome associated-intestinal failure: a phase 3 study

Teduglutide reduced parenteral support in children with short bowel syndrome associated-intestinal failure: a phase 3 study

Teduglutide reduced parenteral support in children with short bowel syndrome associated-intestinal failure (SBS–IF): A phase 3 study

Rationale: A 12-wk, open-label study demonstrated the safety and efficacy of teduglutide (TED) treatment in children with SBS‒IF.1 This 24 wk, phase 3 study (NCT02682381; EudraCT 2015-002252-27) assessed the safety and efficacy of 0.025 and 0.05 mg/kg TED in children with SBS‒IF.

Reduction of Parenteral Nutrition and Hydration Support and Safety With Long-Term Teduglutide Treatment in Patients With Short Bowel Syndrome-Associated Intestinal Failure: STEPS-3 Study.

Patients with intestinal failure associated with short bowel syndrome (SBS-IF) require parenteral support (PS) to maintain fluid balance or nutrition. Teduglutide (TED) reduced PS requirements in patients with SBS-IF in the randomized, placebo (PBO)-controlled STEPS study (NCT00798967) and its 2-year, open-label extension, STEPS-2 (NCT00930644). STEPS-3 (NCT01560403), a 1-year, open-label extension study in patients with SBS-IF who completed STEPS-2, further monitored the safety and efficacy of TED (0.05mg/kg/day). Baseline was the start of TED treatment, in either STEPS or STEPS-2. At the end of STEPS-3, patients treated with TED in both STEPS and STEPS-2 (TED-TED) received TED for≤42months, and patients treated with TED only in STEPS-2 (no TED treatment [NT]/PBO-TED) received TED for≤36 months. Fourteen patients enrolled (TED-TED, n=5; NT/PBO-TED, n=9) and 13 completed STEPS-3. At the last dosing visit, mean (SD) PS was reduced from baseline by 9.8 (14.4 [50%]) and 3.9 (2.8 [48%]) L/week in TED-TED and NT/PBO-TED, respectively. Mean (SD) PS infusions decreased by 3.0 (4.6) and 2.1 (2.2) days per week from baseline in TED-TED and NT/PBO-TED, respectively. Two patients achieved PS independence; 2 additional patients who achieved independence in STEPS-2 maintained enteral autonomy throughout STEPS-3. All patients reported≥1 treatment-emergent adverse event (TEAE); 3 patients had TEAEs that were reported as treatment related. No patient had a treatment-related treatment-emergent serious AE. Long-term TED treatment yielded a safety profile consistent with previous studies, sustained efficacy, and a further decline in PS requirements.

Targeted therapy of short-bowel syndrome with teduglutide: the new kid on the block.

Extensive intestinal resection impairs the absorptive capacity and results in short-bowel syndrome-associated intestinal failure (SBS-IF), when fluid, electrolyte, acid-base, micro-, and macronutrient homeostasis cannot be maintained on a conventional oral diet. Several factors, including the length and site of the resected intestine, anatomical conformation of the remnant bowel, and the degree of postresection intestinal adaptation determine the disease severity. While mild SBS patients achieve nutritional autonomy with dietary modification (eg, hyperphagia, small frequent meals, and oral rehydration fluids), those with moderate-to-severe disease may develop SBS-IF and become dependent on parenteral support (PS) in the form of intravenous fluids and/or nutrition for sustenance of life. SBS-IF is a chronic debilitating disease associated with a poor quality of life, and carries significant morbidity and health care costs. Medical management of SBS-IF is primarily focused on individually tailored symptomatic treatment strategies, such as antisecretory and antidiarrheal agents to mitigate fluid losses, and PS. However, PS administration is associated with potentially life-threatening complications, such as central venous thromboses, bloodstream infections, and liver disease. In pursuit of a targeted therapy to augment intestinal adaptation, research over the past 2 decades has identified glucagon-like peptide, an intestinotrophic gut peptide that has been shown to enhance intestinal absorptive capacity by causing an increase in the villus length, crypt depth, and mesenteric blood flow and by decreasing gastrointestinal motility and secretions. Teduglutide, a recombinant analog of glucagon-like peptide-2, is the first targeted therapeutic agent to gain approval for use in adult SBS-IF. Teduglutide was shown to result in significant (20%–100%) reduction in PS-volume requirement and have a satisfactory safety profile in three randomized control trials. Further research is warranted to see if reduction in PS dependency translates to improved quality of life and reduced PS-associated complications.

New approaches to the treatments of short bowel syndrome-associated intestinal failure

Teduglutide, a recombinant analog of human glucagon-like peptide 2, has recently been approved in the US and Europe (Gattex and Revestive, respectively) as the first targeted treatment of short bowel syndrome-associated intestinal failure (SBS-IF). Glucagon-like peptide 2 improves structural and functional intestinal adaptation following intestinal resection by decelerating a rapid gastric emptying, by decreasing gastric hypersecretion, by increasing intestinal blood flow and by promoting intestinal growth. This review summarizes the findings from phase 2 and 3 studies preceding the US Food and Drug Administration and the European Medicines Agency approval of subcutaneous teduglutide for this orphan condition. In a 3-week, phase 2, metabolic balance study, teduglutide increased intestinal wet weight absorption by approximately 700 g/day and reduced fecal energy losses by approximately 0.8 MJ/day (∼200 kcal/day). In two subsequent 24-week, phase 3 studies, teduglutide reduced the need for parenteral support in the same magnitude. Teduglutide had an acceptable tolerability profile, where adverse events generally were of gastrointestinal origin consistent with the known mechanism of action. Teduglutide will add incremental benefit to the limited medical treatment armamentarium in SBS patients by maximizing intestinal absorption, decreasing fecal losses, thereby decreasing or even eliminating the need for parenteral support. Future research should target and implement other key hormones with similar and possible additive or synergistic effects, thereby further promoting structural and functional adaptation and intestinal rehabilitation in these severely disabled SBS patients.

Increased Intestinal Absorption in the Era of Teduglutide and Its Impact on Management Strategies in Patients With Short Bowel Syndrome–Associated Intestinal Failure

Short bowel syndrome-associated intestinal failure (SBS-IF) as a consequence of extensive surgical resection of the gastrointestinal (GI) tract results in a chronic reduction in intestinal absorption. The ensuing malabsorption of a conventional diet with associated diarrhea and weight loss results in a dependency on parenteral nutrition and/or intravenous fluids (PN/IV). A natural compensatory process of intestinal adaptation occurs in the years after bowel resection as the body responds to a lack of sufficient functional nutrient-processing intestinal surface area. The adaptive process improves bowel function but is a highly variable process, yielding different levels of symptom control and PN/IV independence among patients. Intestinal rehabilitation is the strategy of maximizing the absorptive capacity of the remnant GI tract. The approaches for achieving this goal have been limited to dietary intervention, antidiarrheal and antisecretory medications, and surgical bowel reconstruction. A targeted pharmacotherapy has now been developed that improves intestinal absorption. Teduglutide is a human recombinant analogue of glucagon-like peptide 2 that promotes the expansion of the intestinal surface area and increases the intestinal absorptive capacity. Enhanced absorption has been shown in clinical trials by a reduction in PN/IV requirements in patients with SBS-IF. This article details the clinical considerations and best-practice recommendations for intestinal rehabilitation, including optimization of fluids, electrolytes, and nutrients; the integration of teduglutide therapy; and approaches to PN/IV weaning.