alx-0600 and Short-Bowel-Syndrome

Background: teduglutide is an agonist of glucagon-related peptide (aGLP2) effective as a treatment for patients with short bowel syndrome (SBS), an entity that affects quality of life, usually requires home parenteral nutrition (HPN) and generates significant health costs. The objective of the present narrative review was to assess the real-life experience reported with teduglutide. Methods and results: in real life, one meta-analysis and studies published with 440 patients indicate that Teduglutide is effective after the period of intestinal adaptation after surgery, reducing the need for HPN and in some cases even allowing it to be suspended. The response is heterogeneous, increasing progressively up to 2 years after the start of treatment and reaching 82 % in some series. The presence of colon in continuity is a negative predictor of early response, but a positive predictive factor for the withdrawal of HPN. The most common side effects are gastrointestinal in the early stages of treatment. There are late complications related to the stoma or the occurrence of colon polyps, although the frequency of the latter is very low. In adults, data on improved quality of life and cost-effectiveness are scarce. Conclusions: teduglutide is effective and safe and data from pivotal trials for the treatment of patients with SBS are confirmed in real life and can reduce or even stop HPN in some cases. Although it seems cost-effective, more studies are needed to identify those patients with the greatest benefit.. Introducción: la teduglutida es un agonista del péptido relacionado con glucagón (aGLP2) eficaz como tratamiento de pacientes con síndrome de intestino corto (SIC) una entidad que afecta a la calidad de vida, suele precisar de nutrición parenteral domiciliaria (NPD) y genera importantes costes sanitarios. El objetivo de la presente revisión narrativa fue evaluar la experiencia en vida real reportada con teduglutida. Métodos y resultados: en vida real un metaanálisis y estudios publicados con 440 pacientes, indican que teduglutida es efectivo pasado el periodo de adaptación intestinal posterior a la cirugía, reduciendo las necesidades de NPD y en algunos casos permite incluso suspenderla. La respuesta es heterogénea, aumenta progresivamente hasta 2 años después del inicio del tratamiento y alcanza el 82 % en algunas series. La presencia de colon en continuidad es factor predictivo negativo de respuesta precoz, pero un factor predictivo positivo para la retirada de NPD. Los efectos adversos más frecuentes son de origen gastrointestinal en las primeras etapas del tratamiento. Hay complicaciones tardías relacionadas con el estoma o con la aparición de pólipos de colon, aunque la frecuencia de estas últimas es muy baja. En adultos son escasos los datos en mejoría de calidad de vida y en coste eficacia. Conclusiones: teduglutida es efectivo y seguro confirmándose en vida real los datos de los ensayos pivotales para tratamiento de pacientes con SIC y permite reducir o incluso suspender en algunos casos la NPD. Aunque parece coste efectivo son necesarios más estudios para identificar aquellos pacientes con mayor beneficio.

Topics: Adult; Gastrointestinal Agents; Humans; Intestines; Peptides; Quality of Life; Short Bowel Syndrome

Teduglutide has been described as an effective treatment for parenteral support (PS) reduction in patients with short bowel syndrome (SBS). However, a quantitative summary of the available evidence is still lacking. PubMed/Medline, EMBASE, Cochrane library, OVID, and CINAHL databases were systematically searched up to July 2021 for studies reporting the rate of response (defined as a ≥20% reduction in PS) to teduglutide among PS-dependent adult patients. The rate of weaning (defined as the achievement of PS independence) was also evaluated as a secondary end-point. Ten studies were finally considered in the meta-analysis. Pooled data show a response rate of 64% at 6 months, 77% at 1 year and, 82% at ≥2 years; on the other hand, the weaning rate could be estimated as 11% at 6 months, 17% at 1 year, and 21% at ≥2 years. The presence of colon in continuity reduced the response rate (-17%, 95%CI: (-31%, -3%)), but was associated with a higher weaning rate (+16%, 95%CI: (+6%, +25%)). SBS etiology, on the contrary, was not found to be a significant predictor of these outcomes, although a nonsignificant trend towards both higher response rates (+9%, 95%CI: (-8%, +27%)) and higher weaning rates (+7%, 95%CI: (-14%, +28%)) could be observed in patients with Crohn's disease. This was the first meta-analysis that specifically assessed the efficacy of teduglutide in adult patients with SBS. Our results provide pooled estimates of response and weaning rates over time and identify intestinal anatomy as a significant predictor of these outcomes.

Topics: Adult; Gastrointestinal Agents; Humans; Parenteral Nutrition; Peptides; Short Bowel Syndrome

In recent years, the spectrum of possible treatments for Intestinal Failure (IF)-Short Bowel Syndrome (SBS) has been enriched by the implementation of GLP-2 analogues. In Italy, teduglutide (Ted), an analogue of GLP-2, was approved in January 2021 by the Italian Regulatory Agency for Drugs (AIFA) for IF-SBS patients ≥1 year old. According to the Agency indications, Ted can now be prescribed by regional reference centers, with costs fully charged to the National Health Service. Following pediatric-use approval in our country and in light of scarce evidence in childhood, the pediatric network for IF of the Italian Society for Pediatric Gastroenterology, Hepatology and Nutrition (SIGENP) planned to share management methods of Ted in pediatric IF. The main purpose was to identify the best candidates from a cost-effective perspective. Thus, focusing on available literature and on expert opinions, the present position statement provides consensus-based recommendations on the use of Ted for pediatric gastroenterologists and nutritionists treating children with SBS.

Topics: Child; Gastroenterology; Gastrointestinal Agents; Glucagon-Like Peptide 2; Humans; Infant; Intestinal Failure; Peptides; Short Bowel Syndrome; State Medicine

Topics: Adaptation, Physiological; Adolescent; Adult; Child; Child, Preschool; Gastrointestinal Agents; Glucagon-Like Peptide 2; Humans; Infant; Intestines; Peptides; Short Bowel Syndrome; Treatment Outcome

Short bowel syndrome (SBS) is a rare, highly disabling, life-threatening condition due to extensive intestinal resections, characterized by diarrhea, malabsorption, and malnutrition. SBS is the main cause of intestinal failure (SBS-IF). The primary therapy for SBS-IF is intravenous supplementation (IVS) of nutrients. The pharmacological therapy aims to improve the remnant bowel function, leading to the decrease of IVS requirement.. This review provides a safety perspective and discusses unmet clinical needs on pharmacotherapy for SBS, ranging from symptomatic agents traditionally used off-label to manage hypersecretion and diarrhea, to curative drugs with selective intestinotrophic properties. Real-world evidence on symptomatic drugs is lacking. Data on teduglutide - the first-in-class glucagon-like peptide-2 (GLP-2) receptor agonist approved in SBS - are mainly derived from clinical trials, with several unsettled safety issues, including the risk of malignancies.. Defining the long-term safety of drugs used for SBS is a priority; a unified list of commonly used drugs with consolidated proof of effectiveness is needed to harmonize the symptomatic pharmacological approach to SBS. GLP-2 receptor agonists are a promising curative pharmaco-therapeutic approach, although long-term safety and effectiveness deserve further real-world assessment. Pharmacovigilance and global data sharing are crucial to support safe prescribing in SBS.

Topics: Animals; Gastrointestinal Agents; Glucagon-Like Peptide-2 Receptor; Humans; Off-Label Use; Parenteral Nutrition; Peptides; Short Bowel Syndrome

Chronic intestinal failure (CIF) due to short-bowel syndrome (SBS) is characterized by failure to achieve optimal intestinal adaptation required to maintain oral/enteral autonomy. The conventional management strategy relies heavily on home parenteral support (PS; parenteral nutrition and/or intravenous fluids). Teduglutide, an analog of the hormone glucagon-like peptide-2, facilitates intestinal adaptation, as evidenced by reductions in PS volume in patients with SBS-associated CIF. In 2016, the European Society for Clinical Nutrition and Metabolism (ESPEN) developed guidelines for the management of adult patients with CIF, consisting of a comprehensive list of recommendations. Owing to the limited number of studies at the time of the finalization of the GRADE-method review of the available literature, teduglutide received a moderate grade of evidence (GOE) as the first choice for growth-factor treatment in patients with SBS-CIF. The GOE was also low for 7 points of recommended information to be discussed with the candidate patients. This review summarizes findings from recent studies that fill some gaps identified in the 2016 ESPEN guidelines regarding the use of teduglutide in the management of SBS-CIF. Collectively, these studies provide useful information about the probability and timing of clinical response in the individual patient. Also, recent studies report longer-term safety findings with teduglutide. These results can help physicians better manage patients with SBS-CIF by aligning clinical decision making with specific disease characteristics, setting the right expectations, and encouraging treatment adherence.

Topics: Adult; Glucagon-Like Peptide 2; Humans; Intestines; Peptides; Short Bowel Syndrome

Short bowel syndrome (SBS) is a rare malabsorptive disorder as a result of the loss of bowel mass mostly secondary to surgical resection of the small intestine. Other causes are vascular diseases, neoplasms or inflammatory bowel disease. The spectrum of the disease is widely variable from single micronutrient malabsorption to complete intestinal failure, depending on the remaining length of the small intestine, the anatomical portion of intestine and the function of the remnant bowel. Over the last years, the management of affected patients has remarkably improved with the increase in patients' quality of life and survival, mainly thanks to advances in home-based parenteral nutrition (PN). In the last ten years new treatment strategies have become available together with increasing experience and the encouraging results with new drugs, such as teduglutide, have added a new dimension to the management of SBS. This review aims to summarize the knowledge available in the current literature on SBS epidemiology, pathophysiology, and its surgical (including intestinal lengthening procedures and intestinal transplantation) and medical management with emphasis on the recent advances. Moreover, this review attempts to provide the new understanding and recent approaches to SBS complications such as sepsis, catheter thrombosis, and intestinal failure-associated liver disease.

Topics: Disease Management; Gastrointestinal Agents; Humans; Intestines; Parenteral Nutrition, Home; Peptides; Quality of Life; Short Bowel Syndrome

Since the approval of teduglutide, a glucagon-like peptide-2 (GLP-2) analog, for the treatment of patients with short bowel syndrome (SBS) associated with intestinal failure, enterohormone therapy has received significant interest and is becoming the first choice of treatment in selected patients. As such, it is paramount to assess and understand the new place of hormonal therapy in the algorithm of treatments in SBS-intestinal failure.. Specialized intestinal failure units have recently reported their outcomes with teduglutide to evaluate if they are consistent with the phase III trials results. SBS-intestinal failure patients are very heterogenous including their response to this treatment, hence the importance of real-life studies beyond the context of clinical trials. Moreover, it is essential to find a consensus on criteria identifying candidate patients for teduglutide. In addition, the impact of teduglutide on quality of life and its cost-effectiveness are emerging as well as new enterohormone treatments are being studied whether it is long action GLP-2 analog or other ileocolonic break hormones like glucagon-like peptide-1 analog.. Hormonotherapy is currently modifying the natural history of patients with SBS-intestinal failure by decreasing their need for parenteral support and possibly even complications associated with long-term parenteral support. Enterohormone treatment is now the cornerstone in SBS-intestinal failure and should be offered as a first-line therapy to selected patients.

Topics: Gastrointestinal Agents; Gastrointestinal Hormones; Humans; Intestinal Diseases; Intestines; Peptides; Short Bowel Syndrome

In children, short-bowel syndrome (SBS) accounts for two-thirds of the cases of intestinal failure, and motility disorders and congenital mucosal diarrheal disorders account for the remaining one-third. Children with SBS are supported primarily by parenteral nutrition, which is the single-most important therapy contributing to their improved prognosis. More than 90% of children with SBS who are cared for at experienced intestinal rehabilitation programs survive, and roughly 60% to 70% undergo intestinal adaptation and achieve full enteral autonomy. This article focuses on the predictors of pediatric intestinal adaptation and discusses the pathophysiology and clinical management of children with SBS.

Topics: Adaptation, Physiological; Bacteremia; Biomarkers; Catheterization, Central Venous; Child; Citrulline; Enteral Nutrition; Gastrointestinal Agents; Humans; Liver Diseases; Parenteral Nutrition; Peptides; Prognosis; Short Bowel Syndrome

The ultimate goal of treatment of short bowel syndrome/intestinal failure patients is to achieve enteral autonomy by eliminating parenteral nutrition (PN)/intravenous fluids (IV). After optimization of diet, oral hydration and anti-diarrheal medications, attempt should be made to eliminate PN/IV. Weaning from PN/IV should be individualized for each patient. Although teduglutide is the preferred agent for PN/IV volume reduction or successful weaning, optimal patient selection and long-term safety need further evaluation. Following PN/IV elimination, patients need long-term monitoring for nutritional deficiencies. This article will address clinical considerations before, during, and after PN/IV weaning to facilitate safe and successful PN/IV weaning process.

Topics: Adaptation, Physiological; Algorithms; Antidiarrheals; Diet; Enteral Nutrition; Fluid Therapy; Gastrointestinal Agents; Growth Hormone; Humans; Parenteral Nutrition; Patient Participation; Peptides; Short Bowel Syndrome; Trace Elements; Vitamins

Topics: Adenomatous Polyposis Coli; Adult; Colorectal Neoplasms; Gastrointestinal Agents; Humans; Immunocompromised Host; Intestine, Small; Male; Peptides; Prognosis; Short Bowel Syndrome

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.

Topics: Animals; Carcinogenesis; Glucagon-Like Peptide 2; Humans; Intercellular Signaling Peptides and Proteins; Intestinal Neoplasms; Peptides; Short Bowel Syndrome; Tumor Burden

Teduglutide is an analog of glucagon-like peptide 2 (GLP-2) which is approved for the treatment of patients with short bowel syndrome (SBS) who are dependent on parenteral support. Areas covered: Short bowel syndrome is a rare condition that can result from extensive resection of small bowel, congenital abnormalities, or inflammatory conditions that leads to poor nutrient processing capacity of the intestine. In this review, the safety reported in controlled clinical trials and real-world experience with teduglutide are presented in depth. Expert opinion: Trials and limited real-world experience demonstrated that teduglutide could decrease parenteral support requirements with the potential of achieving independence from parenteral support in some patients. This is an important treatment option for SBS patients given the well-established risks associated with parenteral support. The available data, albeit limited due to the small number of patients in the so-far performed studies, suggest that teduglutide appears to be safe to use in patients with intestinal failure who are dependent on parenteral support. However, additional long-term safety data are needed.

Topics: Animals; Gastrointestinal Agents; Humans; Parenteral Nutrition; Peptides; Short Bowel Syndrome

Dumping syndrome is a common and debilitating complication of upper gastrointestinal surgery. Accelerated gastric emptying and dysregulated secretion of gastrointestinal (GI) hormones are involved in its pathophysiology. Pasireotide, a novel somatostatin analogue, improved dumping in a phase-2 study. Preliminary data suggest that the glucagon-like peptide-1 (GLP-1) analogue liraglutide can also improve dumping. Short bowel syndrome is the most common cause of intestinal failure and involves not only a loss of mucosal absorptive area but also hypersecretion and accelerated transit. GLP-2 is the best studied hormone involved in intestinal adaptation. An increasing body of evidence demonstrates that the GLP-2 analogue teduglutide reduces parenteral support needs. New GLP-2 analogues and analogues of other GI hormones such as liraglutide are being investigated as promising treatments in short bowel syndrome.

Topics: Animals; Dumping Syndrome; Gastrointestinal Agents; Gastrointestinal Motility; Gastrointestinal Tract; Humans; Intestinal Absorption; Ligands; Liraglutide; Peptides; Receptors, Gastrointestinal Hormone; Short Bowel Syndrome; Signal Transduction; Somatostatin; Treatment Outcome

Topics: Humans; Peptides; Short Bowel Syndrome

To examine the most recent literature on the clinical trials associated with the relevant growth factors that have been of interest in the treatment of short bowel.. Short bowel is a rare but devastating condition that condemns patients to lifelong parenteral support. Historically, treatment options negating the need for parenteral support were limited. Therapeutic growth factor use is of interest, but the clinical trial data are inconclusive. The STEPS-2 trial was the first trial that showed a sustained positive effect of the growth factor glucagon-like peptide-2 (GLP-2). This led to a phase shift in the management of short bowel, with the US Food and Drug Administration approval of the GLP-2 analogue teduglutide in 2012. This review summarizes all the relevant clinical trials of growth factors in the treatment of short bowel.. GLP-2 has shown that growth factors can revolutionize the treatment of short bowel. Data however are lacking with regards to the solitary use of other factors. This review highlights the need for further work using the factors in combination as well as considering their use in novel methods for example in the field of regenerative medicine.

Topics: Gastrointestinal Agents; Glucagon-Like Peptides; Humans; Intercellular Signaling Peptides and Proteins; Peptides; Randomized Controlled Trials as Topic; Short Bowel Syndrome

The European Society for Clinical Nutrition has published recommendations on the 'definition and classification of intestinal failure (IF)'. Two criteria must be present: a 'decreased absorption of macronutrients and/or water and electrolytes due to a loss of gut function' and the 'need for parenteral support'. Home parenteral support (HPS) is the primary treatment for chronic IF but is associated with complications. Areas covered: The principal cause of chronic IF is short bowel syndrome (SBS). The aim of treatment is to maximize intestinal absorption and reduce or eliminate the need for HPS to achieve the best possible quality of life. Teduglutide, an analog of glucagon-like peptide 2, improves intestinal rehabilitation by promoting mucosal growth, reducing intestinal loss and promoting intestinal absorption. This article provides an overview and opinion on teduglutide for SBS. Expert opinion: Teduglutide may provide a new treatment strategy for SBS patients with chronic IF. When prescribed, patients should be informed of the benefits and risks of the drug and must be closely monitored in an expert center. Furthermore, as this treatment is costly, cost-effectiveness analysis as well as the risk-benefit ratio needs to be better evaluated.

Topics: Adult; Clinical Trials as Topic; Cost-Benefit Analysis; Glucagon-Like Peptide 2; Humans; Intestinal Absorption; Parenteral Nutrition; Peptides; Quality of Life; Risk Assessment; Short Bowel Syndrome; Treatment Outcome

Teduglutide (Gattex; NPS Pharma, Bedminster, NJ), a recombinant analogue of human glucagon-like peptide 2 (GLP-2), is the first long-term medical therapy approved for the treatment of adults dependent on parenteral nutrition (PN).. To assess the efficacy and safety of teduglutide in reducing PN (parenteral nutrient and/or fluid) requirements in PN-dependent adults.. Studies were identified using predefined search criteria and multiple databases, including Medline and Embase. The search was completed to November 30, 2014, in the absence of date or study design restrictions. Citation inclusion criteria and methodological quality were assessed by 2 independent reviewers. Outcomes of interest were changes in parenteral nutrient or fluid requirements and adverse event incidence. From 2693 unique citations, 76 abstracts were reviewed. Fourteen reports met the inclusion criteria, including data from 2 phase III, double-blind, placebo-controlled clinical trials and their respective extension studies. Data extraction was performed by 2 reviewers using a standardized form.. Teduglutide reduced PN requirements compared with placebo, whereas adverse event incidence was similar.. Number of subjects studied and length of follow-up.. Teduglutide appears to be a safe and well-tolerated means to reduce PN dependence in adults, regardless of PN dependence duration.

Topics: Databases, Factual; Glucagon-Like Peptide 2; Humans; Intestinal Absorption; Parenteral Nutrition, Total; Peptides; Randomized Controlled Trials as Topic; Recombinant Proteins; Short Bowel Syndrome

Intestinal failure because of more or less extensive resection of parts of the small and large intestine (short bowel syndrome) results from the reduction of absorptive surface of the remaining intestine and frequently results in dependence on parenteral nutrition. Parenteral nutrition, although lifesaving, is associated with short and long-term complications as well as with reduced quality of life and overall survival.. Pharmacological enhancement of the physiological intestinal adaptive response by subcutaneous application of the glucagon-like peptide 2 analogue teduglutide results in an improved, hyperadaptive response. This is reflected by decreased parenteral calorie and fluid requirements, decreased parenteral nutrition infusion days per week including complete weaning off parenteral nutrition with complete oral autonomy, improved quality of life, and metabolic and nutritional stability.. The advent of teduglutide as an authority-approved specific medication for intestinal failure in parenteral nutrition-dependent short bowel syndrome offers an effective and beneficial treatment for these patients. As a result, patients are more stable whether for medical or further surgical management including intestinal transplantation. Long-term efficacy and safety still have to be proven.

Topics: Adaptation, Physiological; Animals; Clinical Trials as Topic; Glucagon-Like Peptide 2; Humans; Peptides; Quality of Life; Short Bowel Syndrome

Introducción:la nutrición parenteral (NP) a largo plazo puede asociarse a complicaciones graves, con un deterioro importante de la calidad de vida de los pacientes con síndrome de intestino corto (SIC). Teduglutida, un análogo del péptido-2 similar al glucagón, pertenece a una nueva familia terapéutica y representa el primer abordaje no sintomático del SIC. Objetivos: revisar los datos preclínicos y clínicos en cuanto a eficacia y seguridad de teduglutida. Resultados: la aprobación de teduglutida se basó en los resultados de un estudio en fase III de 24 semanas, doble ciego, controlado con placebo (STEPS). Pacientes con fallo intestinal por SIC dependientes de NP ≥ 3 veces/semana durante ≥ 12 meses recibieron 0,05 mg/kg de teduglutida (n = 43) o placebo (n = 43) 1 vez/día. En la semana 24 hubo significativamente más respondedores en el grupo de teduglutida que en el de placebo (63 vs.30%; p = 0,002). La reducción absoluta media del volumen de NP frente al valor basal en la semana 24 fue significativamente mayor con teduglutida (4,4 vs.2,3 l/semana; p < 0,001). La necesidad de NP se redujo ≥ 1 día en la semana 24 en el 54% de pacientes tratados con teduglutida vs.23% con placebo. Del total de pacientes que recibieron teduglutida en los ensayos en fase III (n = 134), el 12% consiguió una autonomía completa de la NP. Por lo general, la administración subcutánea de teduglutida se toleró bien. Conclusiones: se ha demostrado que teduglutida recupera la absorción intestinal y reduce significativamente la dependencia de la NP, consiguiendo incluso la independencia en algunos pacientes.

Topics: Animals; Gastrointestinal Agents; Humans; Peptides; Short Bowel Syndrome

Teduglutide (Gattex(®)) is a recombinant analogue of human glucagon-like peptide-2 and is indicated for the treatment of adults with short bowel syndrome (SBS) dependent on parenteral support (PS). In a pivotal, 24-week clinical trial in SBS patients, subcutaneous teduglutide 0.05 mg/kg once daily increased absorption from the remnant intestine as evidenced by significant reductions in PS volume requirements versus placebo. Improvements attained in absorption in the first 6 months of therapy were maintained during the extension trial (total teduglutide treatment periods of up to 30 months), with evidence indicating that benefits accrue over time. Among patients who received teduglutide treatment for up to 30 months, 11 of 30 were able to achieve at least one additional day off PS and another ten achieved complete independence from PS. Subcutaneous teduglutide was generally well tolerated in clinical trials, including over the long term, with most adverse events that led to study discontinuation being gastrointestinal in origin.

Topics: Clinical Trials, Phase III as Topic; Humans; Intestinal Absorption; Parenteral Nutrition; Peptides; Short Bowel Syndrome

The approval of teduglutide, a recombinant analog of human glucagon-like peptide (GLP) 2, by the US Food and Drug Administration (Gattex) and the European Medicines Agency (Revestive) has illustrated the potential of selected gut hormones as treatments in patients with short-bowel syndrome and intestinal failure. Gut hormones may improve the structural and functional intestinal adaptation following intestinal resection by decreasing a rapid gastric emptying and hypersecretion, by increasing the intestinal blood flow, and by promoting intestinal growth. This review summarizes the findings from phase 2 and 3 teduglutide studies, and pilot studies employing GLP-1 and agonists for this orphan condition.. In a 3-week, phase 2, metabolic balance study, teduglutide increased the 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. Adverse events were mainly of gastrointestinal origin and consistent with the known mechanism of action of teduglutide. Pilot studies suggest that GLP-1 may be less potent. Synergistic effects may be seen by co-treatment with GLP-2.. Gut hormones promote intestinal adaptation and absorption, decreasing fecal losses, thereby decreasing or even eliminating the need for parenteral support. This will aid the intestinal rehabilitation in these severely disabled short-bowel syndrome patients.

Topics: Clinical Trials, Phase II as Topic; Gastrointestinal Agents; Glucagon-Like Peptide 1; Humans; Intestinal Absorption; Intestine, Small; Parenteral Nutrition; Peptides; Pilot Projects; Quality of Life; Short Bowel Syndrome; United States

Intestinal failure is characterized by intestinal water and electrolyte losses as well as malabsorption of macronutrients. It often requires individually composed parenteral support (so call compounding). Teduglutide, a DPP-IV resistant GLP2 analogue, is available a pharmacologic treatment, which stimulates intestinal absorption and can facilitate infusion free days. Catheter infections are the most common complication of home parenteral support. The incidence can be minimized using Taurolidin as a catheter block solution.

Topics: Catheter-Related Infections; Evidence-Based Medicine; Humans; Intestinal Diseases; Malabsorption Syndromes; Parenteral Nutrition, Total; Peptides; Short Bowel Syndrome; Water-Electrolyte Imbalance

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.

Topics: Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Gastrointestinal Agents; Glucagon-Like Peptide 2; Humans; Intestinal Absorption; Parenteral Nutrition; Peptides; Short Bowel Syndrome

The purpose of this review is to provide an update of recent advances in the areas of short bowel syndrome (SBS) and small bowel transplantation (SBT).. Recent reports from two of the largest multicenter randomized, controlled trials in patients with SBS support the safety and efficacy of teduglutide as an aid to parenteral nutrition weaning. In well selected SBS patients, outcomes as diverse as survival, macronutrient absorption and parenteral nutrition weaning are improved after autologous gastrointestinal reconstructive surgery. SBT is no longer considered investigational and given improved outcomes noted in recent reports, indications for transplantation are expanding. Although SBT early survival rates are approaching those of other organ allografts, long-term graft survival remains suboptimal.. Recently available trophic factors hold promise as aids in restoring freedom from parenteral nutrition support; however, their long-term benefits, preferred timing of administration in relation to the onset of SBS, optimal patient selection for use, duration of treatment and cost effectiveness require further study. Despite recent evidence of improved early survival after SBT, more dedicated research is needed to design more effective strategies to better tolerize small bowel grafts, prevent rejection and, ultimately, improve long-term outcomes. Reserved for well selected patients, autologous gastrointestinal reconstruction should be considered complementary and not antagonistic to SBT.

Topics: Adaptation, Physiological; Gastrointestinal Agents; Graft Rejection; Humans; Intestine, Small; Peptides; Short Bowel Syndrome

Intestinal adaptation is a natural compensatory process that occurs following extensive intestinal resection, whereby structural and functional changes in the intestine improve nutrient and fluid absorption in the remnant bowel. In animal studies, postresection structural adaptations include bowel lengthening and thickening and increases in villus height and crypt depth. Functional changes include increased nutrient transporter expression, accelerated crypt cell differentiation, and slowed transit time. In adult humans, data regarding adaptive changes are sparse, and the mechanisms underlying intestinal adaptation remain to be fully elucidated. Several factors influence the degree of intestinal adaptation that occurs post resection, including site and extent of resection, luminal stimulation with enteral nutrients, and intestinotrophic factors. Two intestinotrophic growth factors, the glucagon-like peptide 2 analog teduglutide and recombinant growth hormone (somatropin), are now approved for clinical use in patients with short bowel syndrome (SBS). Both agents enhance fluid absorption and decrease requirements for parenteral nutrition (PN) and/or intravenous fluid. Intestinal adaptation has been thought to be limited to the first 1-2 years following resection in humans. However, recent data suggest that a significant proportion of adult patients with SBS can achieve enteral autonomy, even after many years of PN dependence, particularly with trophic stimulation.

Topics: Adaptation, Physiological; Animals; Disease Models, Animal; Glucagon-Like Peptide 2; Humans; Intestinal Mucosa; Intestine, Small; Parenteral Nutrition; Peptides; Randomized Controlled Trials as Topic; Short Bowel Syndrome

A primary goal of intestinal rehabilitation programs is to facilitate intestinal adaptation. Adult patients with short bowel syndrome (SBS) who are dependent on parenteral nutrition and/or intravenous fluid (PN/IV) support have 2 hormonal pharmacologic treatment options available that may promote intestinal growth: a glucagon-like peptide 2 analog (teduglutide) and recombinant human growth hormone (somatropin). In two phase III clinical trials (N=169), 24 weeks of teduglutide administered to outpatients with SBS resulted in significant decreases in PN/IV volume requirements of 2.5-4.4 L/wk. In an extension study of one of these trials, patients with SBS who completed 30 months of teduglutide experienced a mean PN/IV reduction of 7.6 L/wk from baseline. Furthermore, some patients achieved independence from PN/IV support. The most common adverse events associated with teduglutide treatment in clinical trials were gastrointestinal symptoms, including abdominal distension, abdominal pain, and nausea. This safety profile is consistent with the associated underlying diseases leading to SBS or the known mechanism of action of teduglutide. A single phase III study (N=41) evaluated the safety and efficacy of a 4-week inpatient course of somatropin in combination with a glutamine-supplemented diet for adults with SBS. Somatropin treatment significantly reduced parenteral support requirements by 1.1 L/d in these patients. The most common adverse events were peripheral edema and musculoskeletal events. Large-scale, long-term follow-up studies of somatropin for SBS have not been conducted. Although treatment for patients with SBS must be individualized, teduglutide and somatropin are positive extensions to existing fluid and nutrient management strategies.

Topics: Adaptation, Physiological; Clinical Trials, Phase III as Topic; Glucagon-Like Peptide 2; Human Growth Hormone; Humans; Intestinal Absorption; Intestines; Parenteral Nutrition; Peptides; Short Bowel Syndrome

The recombinant analogue of human glucagon-like peptide-2 (GLP-2) teduglutide (Gattex(®), Revestive(®)) is a novel therapy for short bowel syndrome (SBS). GLP-2 is a naturally occurring hormone that regulates the growth, proliferation and maintenance of cells lining the gastrointestinal tract. Subcutaneous teduglutide is the first long-term medical therapy approved for the treatment of adult patients with SBS who are dependent on parenteral support (parenteral nutrition and/or intravenous fluids). In a pivotal, double-blind, multicentre, phase III study in adult patients with SBS who were dependent on parenteral support, a significantly higher proportion of teduglutide 0.05 mg/kg/day recipients than placebo recipients achieved at least a 20% reduction from baseline in weekly parenteral support volume at week 20 and maintained at week 24 (primary endpoint). The overall mean reduction in weekly parenteral support volume from baseline was greater in patients who received teduglutide compared with those who received placebo. Additionally, more teduglutide-treated patients achieved at least a one-day reduction in parenteral support than those receiving placebo. Subcutaneous teduglutide had an acceptable tolerability profile; the most frequently reported adverse events were of gastrointestinal origin, consistent with the underlying disease condition and the known mechanism of action of teduglutide.

Topics: Animals; Clinical Trials, Phase III as Topic; Double-Blind Method; Humans; Peptides; Short Bowel Syndrome

Recently, the US Food and Drug Administration and the European Medicines Agency approved the glucagon-like peptide 2 analogue, teduglutide, for the treatment of short bowel syndrome (SBS), and this review describes the physiological basis for its clinical use.. By affecting the intestinal neuroendocrine system, hormones may promote the growth of the intestinal mucosa, restore a more normal gastric emptying and secretion, stimulate intestinal blood flow, increase intestinal barrier function, immunity and absorption, and thereby promote structural and functional adaptation following intestinal resection. In a 3-week, phase 2, metabolic balance study, teduglutide increased intestinal wet weight absorption by ∼700 g/day and reduced faecal energy losses by ∼0.8 MJ/day. In two subsequent 24-week, phase 3 studies in SBS patients with intestinal failure (SBS-IF), teduglutide reduced the need for parenteral support in the same magnitude.. Teduglutide adds incremental benefit to the limited medical treatment armamentarium in SBS patients. Modern treatments should aim to maximize remnant intestinal absorption, decrease malabsorption and accompanying symptoms, reduce the need, burdens and complications related to parenteral support, and ultimately improve the health-related quality of life in SBS-IF patients. Future research should target and implement other key hormones with similar effects, thereby promoting intestinal adaptation and rehabilitation in SBS patients.

Topics: Glucagon-Like Peptide 2; Humans; Intestinal Absorption; Parenteral Nutrition; Peptides; Quality of Life; Risk Assessment; Short Bowel Syndrome

Loss of intestinal absorptive capacity from congenital defect, surgical resection or mucosal disease results in short bowel syndrome (SBS)-associated intestinal failure. In the past, few medical management options were available besides dietary modification, controlling diarrhea or high stomal output, and providing parenteral fluid, electrolyte and nutrient support (parenteral support). Recent research on strategies to enhance the intestinal absorptive capacity focused on glucagon-like peptide-2, an intestinotrophic hormone that has been shown to increase the villus height and crypt depth, and decrease gastric motility and intestinal secretory losses. STEPS is a Phase III randomized double-blinded controlled trial in which teduglutide, a recombinant analog of glucagon-like peptide-2, or placebo was given subcutaneously to SBS patients for 24 weeks. A clinically meaningful response, defined as a 20-100% reduction in parenteral support volume, was achieved in 63% of the treatment group compared with 30% in the placebo group (p = 0.002) without an increase in serious side effects. Teduglutide offers a new targeted approach to SBS-associated intestinal failure management. Its specific role in clinical practice remains to be evaluated.

Topics: Clinical Trials, Phase III as Topic; Combined Modality Therapy; Gastrointestinal Agents; Humans; Intestinal Absorption; Intestine, Small; Parenteral Nutrition; Peptides; Randomized Controlled Trials as Topic; Short Bowel Syndrome; Time Factors; Treatment Outcome

Glucagon-like peptide 2 (GLP-2) decreases gastric and intestinal motility, reduces gastric secretions, promotes intestinal growth and improves post-resection structural and functional adaptation in short bowel syndrome (SBS). Teduglutide, an analogue of GLP-2, has a prolonged half-life and provides intestinotrophic effects with once-daily subcutaneous injection in patients with SBS. This monograph reviews the preclinical and clinical data that provide the scientific rationale for the use of teduglutide in this orphan condition. Teduglutide increases intestinal absorption and diminishes the need for parenteral support in patients with SBS. The adverse event profile is consistent with the underlying disease and the known mechanism of action of teduglutide. Following its positive regulatory review and approval by the European Medicines Agency and the U.S. Food and Drug Administration in 2012, teduglutide has moved from the research setting to clinical practice, offering a new treatment paradigm for this burdensome and potentially life-threatening condition.

Topics: Amino Acid Sequence; Animals; Humans; Molecular Sequence Data; Peptides; Short Bowel Syndrome

Topics: Biomarkers; Child; Citrulline; Humans; Intestines; Lipids; Parenteral Nutrition; Peptides; Randomized Controlled Trials as Topic; Short Bowel Syndrome; Treatment Outcome

Parenteral support is lifesaving in short bowel syndrome patients with intestinal failure (SBS-IF), who are unable to compensate for their malabsorption by metabolic or pharmacologic adaptation. Mutually, the symptoms of SBS-IF and the inconveniences and complications in relation to parenteral support may cause impairment of the quality of life of SBS-IF patients. Conventional treatments include dietary manipulations, oral rehydration solutions, antidiarrheal and antisecretory treatments. However, the evidence base for these interventions is limited, and treatments improving structural and functional integrity of the remaining intestine are desired. Teduglutide , an analog of glucagon-like peptide 2, improves intestinal rehabilitation by promoting mucosal growth and possibly by inhibiting gastric emptying and secretion, which in turn reduces intestinal losses and promotes intestinal absorption.. This paper reviews the following findings: in a 3-week, Phase II balance study, teduglutide reduced diarrhea by ∼ 700 g/day and fecal energy losses by ∼ 0.8 MJ/day, and in a randomized, placebo-controlled, 24-week, Phase III study, corresponding reductions in the need for parenteral support were obtained.. Teduglutide seems to be safe and well-tolerated and demonstrates restoration of structural and functional integrity of the remaining intestine with significant intestinotrophic and proabsorptive effects, facilitating a reduction in diarrhea and an equivalent reduction in the need for parenteral support in SBS-IF patients.

Topics: Gastrointestinal Agents; Glucagon-Like Peptide 2; Humans; Peptides; Short Bowel Syndrome

Short bowel syndrome (SBS) reflects a state of malabsorption that occurs due to loss of a significant portion of the small bowel. The pathophysiology of SBS is determined largely by the process of adaptation, which is the innate attempt by the remnant portions of the intestine to increase fluid and nutrient reabsorption. In recent years, emphasis has been placed on intestinal rehabilitation with multidisciplinary teams as a comprehensive approach to the management of patients with SBS. In our institution, the multidisciplinary team members include pediatric gastroenterologists, pediatric surgeons, pediatric dieticians, physical therapists, occupational therapists, neonatologists (especially for patients still under their care), transplant surgeons, transplant coordinators and social workers. Parenteral nutrition plays a significant role in the management of SBS, but its use is associated with many potential complications, including cholestatic liver disease. Fish oil-based lipid emulsions have shown promise in their ability to reverse and also prevent the development of cholestasis in these patients. Clinical trials have shown that growth factors and other trophic hormones facilitate the process of adaptation. The most significant impact has been shown with the use of glucagon-like peptide-2 and its analog (teduglutide). Surgical interventions remain an important part of the management of SBS to facilitate adaptation and treat complications. Intestinal transplantation is a last resort option when the process of adaptation is unsuccessful. This review article is intended to provide an overview of the conventional and emerging therapies for pediatric SBS.

Topics: Adaptation, Physiological; Gastrointestinal Agents; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Humans; Intestine, Small; Intestines; Malabsorption Syndromes; Nutritional Status; Parenteral Nutrition; Parenteral Nutrition, Total; Peptides; Short Bowel Syndrome

Short bowel syndrome (SBS) and intestinal failure are chronic malabsorption disorders with considerable nutritional and growth consequences in children. Intestinal failure occurs when the functional gastrointestinal mass is reduced even if there is normal anatomical gastrointestinal length. A number of management strategies are often utilized to achieve successful intestinal rehabilitation and maintain adequate nutrition to avoid intestinal transplant. These strategies include minimizing the effect of parenteral associated liver disease, limiting catheter complications, and treating bacterial overgrowth in the remaining small intestine. In addition, there continues to be significant research interest in enhancing intestinal adaptation with targeted therapies. The purpose of this review is to discuss current perspectives and to highlight recent medical advances in novel investigational therapies.

Topics: Biomarkers; Blind Loop Syndrome; Catheter-Related Infections; Child; Enteral Nutrition; Gastrointestinal Agents; Humans; Malabsorption Syndromes; Nutrition Disorders; Peptides; Short Bowel Syndrome

Teduglutide is a GLP-2 analog currently evaluated for the treatment of short bowel syndrome, Crohn's disease, and other gastrointestinal disorders. The population pharmacokinetics (PK) of teduglutide were assessed following daily subcutaneous (SC) administrations of 2.5 to 80 mg doses in a total of 256 patients. A 1-compartment model with a site-specific rate constant of absorption in the abdomen, arm, and thigh was used to assess the PK of teduglutide. Apparent clearance (CL/F) of teduglutide in male participants was approximately 18% higher than that observed in female participants (12.4 vs 10.5 L/h, respectively). Body weight was detected as a significant covariate explaining the volume of distribution of teduglutide. The elimination half-life (t((1/2))) of teduglutide was also influenced by the body weight of participants. For a male patient weighing 50 and 90 kg, t((1/2)) of teduglutide was 0.897 and 2.99 hours, respectively. Renal and hepatic function of patients did not affect the PK of teduglutide. As a result, no dose adjustment was deemed necessary in patients with altered renal or liver function. The population PK model will help to support adequate drug labeling following SC administrations in patients and determine whether an individualized dosage is required.

Topics: Adolescent; Adult; Aged; Clinical Trials as Topic; Crohn Disease; Dose-Response Relationship, Drug; Female; Gastrointestinal Agents; Humans; Injections, Subcutaneous; Kidney Diseases; Liver Diseases; Male; Middle Aged; Models, Statistical; Peptides; Sex Characteristics; Short Bowel Syndrome

Inflammatory bowel disease (IBD) is a chronic, debilitating disease associated with severe damage to the intestinal mucosa. Glucagon-like peptide-2 (GLP-2) is a potent and specific gastrointestinal growth factor that is demonstrating therapeutic potential for the prevention or treatment of an expanding number of intestinal diseases, including short bowel syndrome (SBS), small bowel enteritis and IBD. The biological activity of GLP-2 is limited due to proteolytic inactivation by the protease dipeptidyl peptidase (DP)IV. Inhibitors of DPIV activity may represent a novel strategy to prolong the growth promoting actions of GLP-2. This review outlines evidence for the clinical application of GLP-2, its degradation resistant analogue, Teduglutide, and novel DPIV inhibitors in efficacy studies utilizing pre-clinical models of intestinal damage, in particular IBD.

Topics: Animals; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 2; Humans; Inflammatory Bowel Diseases; Intestinal Diseases; Neoplasms; Peptides; Short Bowel Syndrome

The medical management of short bowel syndrome frequently requires lifelong parenteral nutrition. Methods of increasing intestinal absorption and reducing parenteral nutrition dependence, by improving postresection intestinal adaptation, are increasingly being explored. Glucagon-like peptide-2 (GLP-2) is an important intestinotrophic growth factor and mediator of intestinal adaptation. This review summarizes our current understanding of GLP-2 physiology and provides an update on clinical trials in short bowel syndrome and related conditions.. There is growing understanding how the effects of GLP-2 are mediated by downstream effectors such as insulin-like growth factor-1. In the treatment of short bowel syndrome, GLP-2 and the long-acting GLP-2 analogue teduglutide (Gattex) are effective in improving fluid absorption. A recent multicentre, placebo-controlled study demonstrates that this can translate into meaningful reductions in parenteral nutrition requirements. Treatment dose and timing of treatment initiation might influence the mucosal growth response. Most of the small intestine has to be preserved to facilitate the previously documented benefits of GLP-2 on bone metabolism. Therapeutic uses of GLP-2 in other gastrointestinal conditions are being explored. GLP-2 treatment appears well tolerated, although concerns about the long-term use of this growth-promoting agent remain.. GLP-2 therapy holds promise as an adjuvant treatment modality for short bowel syndrome and other gastrointestinal disorders.

Topics: Adaptation, Physiological; Glucagon-Like Peptide 2; Humans; Intestinal Absorption; Intestinal Mucosa; Nutritional Requirements; Parenteral Nutrition; Peptides; Short Bowel Syndrome; Treatment Outcome

Malabsorption of nutrients, fluids and electrolytes is a key finding in patients with short bowel syndrome. If not compensated for by increased intake, it leads to diminished body stores and subclinical, and eventually clinical, deficiencies. Until recently, management options were limited to interventions aimed at provision of adequate macro- and micronutrients and fluids to prevent malnutrition, nutrient deficiencies and dehydration, treatment of associated infections and correction and prevention of acid-base disturbances. Identification of novel gut hormones, combined with the growing understanding of their pivotal role in intestinal adaptation, has provoked interest in developing more specific therapies.. To provide an update on the recent advances on the use of teduglutide in patients with short bowel syndrome.. A comprehensive Medline search using the terms teduglutide, ALX-0600, dipeptidyl peptidase IV (DPP-IV) and glucagon like peptide-2 (GLP-2).. Teduglutide (GATTEX, ALX-0600; NPS Allelix Corp) is a synthetic DPP-IV-resistant recombinant human GLP-2 analog that differs from GLP-2 only by an N-terminus substitution of glycine for alanine in position 2 of the peptide that renders the component resistant to enzymatic degradation. Based on the results of the few Phase II studies and the preliminary results of a Phase III trial, teduglutide at doses of 0.05 or 0.10 mg/kg/day may improve many clinical, laboratory and histologic abnormalities in short bowel syndrome patients. It appears to be safe and well tolerated.. Teduglutide is a first-in-class therapy with the potential to create a new standard of care for patients suffering from short bowel syndrome. Future studies to address the appropriate initial and maintenance dosage and optimal duration of treatment are needed.

Topics: Adaptation, Physiological; Adult; Amino Acid Substitution; Body Weight; Child; Clinical Trials, Phase III as Topic; Crohn Disease; Dipeptidyl Peptidase 4; Gastrointestinal Hormones; Glucagon-Like Peptide 2; Half-Life; Human Growth Hormone; Humans; Inactivation, Metabolic; Intestinal Absorption; Peptides; Recombinant Proteins; Short Bowel Syndrome

Although long-term parenteral nutrition is lifesaving in patients with intestinal failure, it is expensive and associated with serious complications such as catheter sepsis, venous occlusions, and liver failure and severely impairs the quality of life in the short bowel patients. Therefore, treatments that increase the absolute intestinal absorption, thereby eliminating or minimizing the need for parenteral support, are needed. In this respect, glucagon-like peptide 2 (GLP-2) has received attention. In this review, the nature of the short bowel syndrome is described, and the antisecretory, transit-modulating, but also intestinotrophic effects of GLP-2 are presented. As illustrated in 2 pilot studies, one using native GLP-2 and the other a degradation-resistant analogue, teduglutide, these new agents may prove important in optimizing remnant intestinal function, thereby eliminating the need for parenteral support and improving quality of life in short bowel patients with intestinal failure.

Topics: Adaptation, Physiological; Clinical Trials as Topic; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Humans; Jejunostomy; Nutritional Support; Peptides; Short Bowel Syndrome

To date, the hormonal factors used in the treatment of patients with short-bowel syndrome have been growth hormone and glucagon-like peptide (GLP)-2. In high-dose growth hormone studies, the effects on wet-weight absorption of approximately 0.7 kg/day have mainly been described in short-bowel syndrome patients with a preserved colon who also received oral rehydration solutions. Treatment with high doses of growth hormone is associated with severe adverse effects in the majority of patients. Low-dose growth hormone increased energy absorption by approximately 1.8 MJ/day in a group of 12 short-bowel syndrome patients (9 with a preserved colon), but it did not affect wet-weight absorption. Growth hormone does not seem to affect either wet-weight or energy absorption in patients with a jejunostomy. GLP-2 and the analogue teduglutide mainly affect wet-weight absorption, resulting in a mean increase in wet-weight absorption of 0.4-0.7 kg/day. The effects on energy absorption are minor at 0.4-0.8 MJ/day. However, these effects are seen in all short-bowel syndrome patients, regardless of anatomy, and the adverse effects are minor. In all studies employing growth hormone or GLP-2, the effects are transient, disappearing when treatments are discontinued. With the need for long-term treatment, adverse effects and safety issues become important. Therefore, it is recommended that treatment is initiated in research settings only and that close monitoring of the long-term effects is a part of the protocol.

Topics: Body Composition; Body Weight; Creatinine; Drug Monitoring; Energy Intake; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Glutamine; Growth Hormone; Humans; Hyperplasia; Intestinal Absorption; Intestinal Mucosa; Intestines; Peptides; Randomized Controlled Trials as Topic; Short Bowel Syndrome; Time Factors

To summarize the pharmacology, development, and clinical application of teduglutide (ALX-0600), a glucagon-like peptide-2 (GLP-2) analog for the treatment of short bowel syndrome (SBS).. Clinical literature, including both primary sources and review articles, was accessed through a search of the MEDLINE databases (1980-March 2006). Key search terms included teduglutide, ALX-0600, glucagon-like peptide-2, short bowel syndrome, short gut, and intestinal adaptation. Clinical trial and drug data were supplied by the manufacturer, NPS Pharmaceuticals.. Review articles, abstracts, and clinical studies related to GLP-2 and its analog, teduglutide, were analyzed. An evaluation of the research exploring teduglutide for the management of SBS was conducted. Relevant information was then selected.. Research has revealed that administration of GLP-2 to patients following major small bowel resection improves intestinal adaptation and nutrient absorption. Teduglutide is an enzyme-resistant GLP-2 analog that shows promise in preventing intestinal injury, restoring mucosal integrity, and enhancing intestinal absorptive function.. Data from ongoing clinical trials indicate that teduglutide may have the ability to enhance intestinal absorptive capacity in patients with SBS. Further studies and the completion of Phase III trials are necessary to determine the appropriate dosage and length of treatment for patients with SBS to gain optimal therapeutic benefit from this drug.

Topics: Animals; Clinical Trials as Topic; Humans; Peptides; Short Bowel Syndrome

NPS Allelix (formerly Allelix Biopharmaceuticals) is developing the glucagon-like peptide 2 (GLP-2) analog ALX-0600 for the potential treatment of gastrointestinal diseases, including short bowel disease. GLP stimulates the growth of the lining of the small intestine, thus increasing the absorptive area of the intestine [214370], [315107]. ALX-0600 also has potential for mucositis associated with cancer chemotherapy and inflammatory bowel disease [331459]. During the third quarter of 1999, a pilot phase II trial began for short bowel syndrome (SBS) [331459]. ALX-0600 began pivotal phase II trials in 2000 following the completion of the pilot trial which was designed to measure the safety, tolerability, and any other drug-related improvements in nutrient absorption and physical changes in the gut of a small number of patients with SBS. Allelix hopes to bring this drug to the market by 2001 [341519]. Allelix filed an application to the FDA for Orphan Drug designation in the third quarter of 1999 [331459]; in August, the designation was approved [377524]. As of November 1998, Allelix was in discussions with a potential marketing partner for worldwide development and marketing [305000]. In August 1998, the USPTO issued a notice of allowance to Allelix for its basic patent containing claims covering the composition and medical uses of ALX-0600 and related GI drug candidate compounds [2946571.

Topics: Amino Acid Sequence; Animals; Clinical Trials as Topic; Gastrointestinal Agents; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Humans; Molecular Sequence Data; Peptides; Short Bowel Syndrome; Structure-Activity Relationship

The short- and long-term efficacy, safety, and pharmacokinetics of teduglutide were analyzed in adult Japanese patients with short bowel syndrome and intestinal failure (SBS-IF).. Patients received teduglutide 0.05 mg/kg/day in clinical trials (TED-C14-004, SHP633-306, and extension SHP633-307). Data were analyzed at 24 weeks and an interim data cut-off of 4.5 years.. The parenteral support (PS) volume decreased by ≥ 20% for 9/18 patients at 24 weeks and in all 11 patients by data cut-off in SHP633-307. The mean (standard deviation) PS volume decreased from baseline at 24 weeks in TED-C14-004 (-30.1 ± 25.9%) and SHP633-306 (-25.6 ± 25.5%), and at data cut-off in SHP633-307 (-57.08 ± 28.49%). Teduglutide was absorbed quickly. The adverse events were consistent with the underlying disease and known adverse drug reactions. Anti-teduglutide antibody titers declined with long-term treatment.. In Japanese adults with SBS-IF, teduglutide treatment was associated with clinically meaningful reductions in PS requirements, similar to findings in prior international studies. No new safety concerns specific to the Japanese SBS-IF patient population were identified with short- or long-term teduglutide treatment. Anti-teduglutide antibody titers disappeared in most Japanese adults with long-term treatment. These results constitute the longest evaluation of teduglutide treatment within clinical trials reported to date.

Topics: Adult; East Asian People; Gastrointestinal Agents; Humans; Intestinal Failure; Parenteral Nutrition; Short Bowel Syndrome

Our objective was to evaluate the short- and long-term safety and efficacy of teduglutide treatment in infants and children with short bowel syndrome with intestinal failure (SBS-IF).. Two open-label phase 3 studies and 1 extension study investigated the short- and long-term safety and efficacy of teduglutide (0.05 mg/kg/day) in infants and children with SBS-IF: NCT03571516, 24-week study of infants who were randomized to receive teduglutide or standard of care (SoC); NCT02980666, 24-week study of infants and children who all received teduglutide; and NCT03268811, 24-week extension study of patients who completed NCT02980666 (patients could receive up to 48 weeks of total treatment).. Twelve infants and 8 children enrolled in the core studies, and 2 infants and 7 children in the extension study. After 24 weeks of treatment, parenteral support (PS) requirements reduced by ≥20% from baseline for 4 infants (57.1%) and 4 children (66.7%) receiving teduglutide and for 2 infants receiving SoC (50.0%). One infant (50.0%) and 4 children (80.0%) receiving teduglutide maintained the ≥20% reduction in PS at 48 weeks of treatment. Two children receiving teduglutide achieved enteral autonomy, after 12 weeks and 28 weeks of treatment, respectively. All adverse events (AEs) were in line with known impacts of SBS-IF and adverse reactions to teduglutide. Only one serious AE (abdominal pain) was considered related to teduglutide.. Short- and long-term treatment with teduglutide resulted in clinically meaningful reductions in PS requirements for infants and children with SBS-IF. Teduglutide was well tolerated, and efficacy improved with longer-term treatment.

Topics: Child; Gastrointestinal Agents; Humans; Infant; Intestine, Small; Parenteral Nutrition; Peptides; Short Bowel Syndrome

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.

Topics: Child; Diarrhea; Gastrointestinal Agents; Humans; Intestinal Failure; Short Bowel Syndrome

This study aimed to identify predictors and estimate time to teduglutide response among adult patients with short bowel syndrome with intestinal failure (SBS-IF) dependent on parenteral support (PS).. Post-hoc analysis was performed on individual patient data from teduglutide-treated patients in the phase III teduglutide trial STEPS and the STEPS-2 extension. Response was defined as ≥20% PS volume reduction from baseline for two consecutive visits. Early responders experienced the reduction at 20 and 24 weeks during STEPS while late responders experienced the reduction during STEPS-2. Timing and predictors for response were assessed among the treated population using Cox proportional hazard model. Time to response was compared in aetiological subgroups using Kaplan-Meier analysis. Patient characteristics and time to response were compared between early vs. late responders.. A total of 34 patients were included in this analysis; overall median time to response was 4.3 months. The presence of stoma predicted a positive response to teduglutide (hazard ratio [HR]: 5.6; 95% confidence interval [CI]: 1.4-21.9; p = 0.013). Vascular disease (vs. inflammatory bowel disease [IBD]) as cause of major intestinal resection (HR: 0.2; 95% CI: 0.0-0.8; p = 0.015), presence of ileocecal valve (HR: 0.1; 95% CI: 0.0-0.8; p = 0.047), and female sex (HR: 0.3; 95% CI: 0.1-1.0; p = 0.026) are negatively associated with response. In subgroup analyses, patients with IBD (vs. vascular disease), with (vs. without) a stoma, and without (vs. with) colon-in-continuity had a shorter time to response (all p < 0.05). The mean times to response were 3.6 (standard deviation (SD): 1.1) months for early responders (n = 27) and 10.0 (SD: 6.1) months for late responders (n = 7). Fewer early responders had colon-in-continuity (51.9%) and ileocecal valve (0.0%) compared to late responders (100% and 28.6%, respectively; both p < 0.05). Early responders had a lower mean percentage of colon remaining compared to late responders (24.6% vs. 57.1%, respectively; p = 0.016).. Time to response to teduglutide depends on bowel anatomy and SBS-IF aetiology. IBD, presence of a stoma, and absence of ileocecal valve were associated with earlier response to teduglutide. These findings may enhance management of patients with SBS-IF; however, due to sample size limitations, additional studies are needed to confirm these findings.

Topics: Adult; Female; Gastrointestinal Agents; Humans; Male; Parenteral Nutrition; Peptides; Short Bowel Syndrome

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.. 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.. 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.. 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.

Topics: Adult; Citrulline; Colectomy; Colon; Drug Monitoring; Female; Gastrointestinal Agents; Humans; Intestine, Small; Linear Models; Male; Middle Aged; Parenteral Nutrition; Peptides; Postoperative Complications; Short Bowel Syndrome; Treatment Outcome

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.. 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.. 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.. 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.

Topics: Adult; Female; Gastrointestinal Agents; Humans; Intestines; Male; Middle Aged; Peptides; Quality of Life; Short Bowel Syndrome

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.. 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 r. In a post hoc analysis of data from a phase III study of the effects of teduglutide on patients with SBS, we associated reduced parenteral support volume with baseline parenteral support volume, bowel anatomy, and SBS features. These findings may inform initial parenteral support volume adjustments and management of these severely disabled patients. ClinicalTrials.gov no: NCT00798967; ClinicalTrialsRegister.eu no: 2008-006193-15.

Topics: Adult; Female; Gastrointestinal Agents; Humans; Intention to Treat Analysis; Intestines; Linear Models; Male; Middle Aged; Parenteral Nutrition; Peptides; Recovery of Function; Short Bowel Syndrome; Time Factors; Treatment Outcome

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 (0.05 mg/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 ≤42 months, 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.

Topics: Adult; Aged; Female; Fluid Therapy; Gastrointestinal Agents; Humans; Intestinal Diseases; Intestines; Male; Middle Aged; Parenteral Nutrition; Peptides; Short Bowel Syndrome; Time Factors; Treatment Outcome

Narcotic agents are frequently administered to manage increased intestinal motility in patients with short bowel syndrome, but long-term use is associated with gastrointestinal (GI) complaints. This analysis evaluated the incidence of narcotic use and abdominal adverse events among patients with short bowel syndrome receiving teduglutide.. Pooled data from patients who received ≥1 dose of teduglutide 0.05 mg/kg/d (n = 77) or placebo (n = 59) in either of 2 randomized, double-blind, phase III studies were analyzed.. Of 136 patients, 52 (38%) received narcotics. GI adverse events occurred more often among patients who received narcotics than among those who did not (abdominal pain, 51% vs 21%; nausea, 42% vs 11%; abdominal distension, 17% vs 8%; vomiting, 19% vs 6%). Logistic regression analysis indicated that the probability of GI adverse events was significantly increased in patients with narcotic use ( P = .0009). In contrast, teduglutide treatment, as well as the interaction between teduglutide and narcotic use, did not affect the probability of GI adverse events.. These results suggest that patients with short bowel syndrome receiving narcotics have chronic GI complaints independent of teduglutide treatment. Data included in this analysis were derived from ClinicalTrials.gov NCT00081458 and NCT00798967 (EudraCT 2004-000438-35 and 2008-006193-15).

Topics: Abdominal Pain; Administration, Oral; Adult; Dose-Response Relationship, Drug; Double-Blind Method; Gastrointestinal Agents; Humans; Logistic Models; Narcotics; Nausea; Peptides; Short Bowel Syndrome; Vomiting

To determine safety and pharmacodynamics/efficacy of teduglutide in children with intestinal failure associated with short bowel syndrome (SBS-IF).. This 12-week, open-label study enrolled patients aged 1-17 years with SBS-IF who required parenteral nutrition (PN) and showed minimal or no advance in enteral nutrition (EN) feeds. Patients enrolled sequentially into 3 teduglutide cohorts (0.0125 mg/kg/d [n = 8], 0.025 mg/kg/d [n = 14], 0.05 mg/kg/d [n = 15]) or received standard of care (SOC, n = 5). Descriptive summary statistics were used.. All patients experienced ≥1 treatment-emergent adverse event; most were mild or moderate. No serious teduglutide-related treatment-emergent adverse events occurred. Between baseline and week 12, prescribed PN volume and calories (kcal/kg/d) changed by a median of -41% and -45%, respectively, with 0.025 mg/kg/d teduglutide and by -25% and -52% with 0.05 mg/kg/d teduglutide. In contrast, PN volume and calories changed by 0% and -6%, respectively, with 0.0125 mg/kg/d teduglutide and by 0% and -1% with SOC. Per patient diary data, EN volume increased by a median of 22%, 32%, and 40% in the 0.0125, 0.025, and 0.05 mg/kg/d cohorts, respectively, and by 11% with SOC. Four patients achieved independence from PN, 3 in the 0.05 mg/kg/d cohort and 1 in the 0.025 mg/kg/d cohort. Study limitations included its short-term, open-label design, and small sample size.. Teduglutide was well tolerated in pediatric patients with SBS-IF. Teduglutide 0.025 or 0.05 mg/kg/d was associated with trends toward reductions in PN requirements and advancements in EN feeding in children with SBS-IF.. ClinicalTrials.gov:NCT01952080; EudraCT: 2013-004588-30.

Topics: Adolescent; Age Factors; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Administration Schedule; Enteral Nutrition; Female; Follow-Up Studies; Humans; Male; Patient Safety; Peptides; Prospective Studies; Risk Assessment; Severity of Illness Index; Sex Factors; Short Bowel Syndrome; Treatment Outcome

In phase III clinical studies, treatment with teduglutide was associated with clinically meaningful reductions (≥20% from baseline) in parenteral support (PS; parenteral nutrition and/or intravenous fluids) requirements in adult patients with intestinal failure associated with short bowel syndrome (SBS-IF). This analysis reports clinical characteristics of patients who achieved complete independence from PS during teduglutide treatment.. Post hoc analysis of adult patients who achieved complete PS independence during treatment with teduglutide 0.05 mg/kg/d. Data were pooled from 5 teduglutide clinical trials (2 phase III placebo-controlled trials [NCT00081458 and NCT00798967] and their respective extension studies [NCT00172185, NCT00930644, NCT01560403]). Descriptive statistics were used; no between-group comparisons were performed because of the small sample size and lack of comparator.. Of 134 patients, 16 gained oral or enteral autonomy after a median of 5 years of PS dependence and 89 weeks of teduglutide treatment. Demographic and baseline disease characteristics varied among patients (median age, 55 years; 50% men; median baseline PS volume, 5.1 L/wk; median residual small intestine length, 52.5 cm). Most patients who achieved PS independence had colon-in-continuity; however, there was no significant difference in the frequency of PS independence among patients who maintained colon-in-continuity vs those who did not.. Findings from this post hoc analysis suggest that oral or enteral autonomy is possible for some patients with SBS-IF who are treated with teduglutide, regardless of baseline characteristics and despite long-term PS dependence.

Topics: Adult; Endpoint Determination; Female; Gastrointestinal Agents; Humans; Intestinal Diseases; Intestines; Male; Middle Aged; Parenteral Nutrition; Parenteral Nutrition Solutions; Peptides; Short Bowel Syndrome

Glucagon-like peptide 2 (GLP-2) agonists decrease the need for parenteral nutrition (PN) in short bowel syndrome (SBS); mechanisms evaluated to date have focused on the intestinotrophic effect of GLP-2 agonists such as increased absorptive capacity of the remnant intestine and increased citrulline levels. Other mechanisms may also play a role in effects of GLP-2 agonists.. To measure effects of a GLP-2 agonist, teduglutide (TED), compared with placebo (PLA) on gastric emptying (GE), overall gut transit, fluid balance, intestinal monosaccharide absorption, and permeability in patients with SBS on home PN (HPN).. In 8 adults with SBS on HPN, we compared daily subcutaneous TED (0.05 mg/kg) and PLA (crossover design, each treatment 7 days with a 14-day washout) on gut transit, intestinal absorption, and permeability after oral mannitol (200 mg) and lactulose (1 g), as well as stool weight and urine volume over 8 hours. Analysis used the paired t test.. Seven-day TED treatment in 8 participants suggests beneficial effects on fluid balance and monosaccharide absorption, and it retarded overall gut transit with no effects on GE or mucosal permeability. Larger, longer, mechanistic studies of TED in SBS are warranted. This trial was registered at clinicaltrials.gov as NCT02099084.

Topics: Adult; Aged; Citrulline; Cross-Over Studies; Double-Blind Method; Female; Gastric Emptying; Gastrointestinal Tract; Glucagon-Like Peptide 2; Humans; Intestinal Absorption; Lactulose; Male; Mannitol; Middle Aged; Parenteral Nutrition, Home; Peptides; Permeability; Pilot Projects; Recombinant Proteins; Short Bowel Syndrome; Treatment Outcome

Intestinotrophic therapies, such as glucagon-like peptide-2 (GLP-2) analogs, may enhance intestinal adaptation and reduce dependence on parenteral nutrition (PN) in patients with intestinal failure associated with short bowel syndrome (SBS-IF). However, because GLP-2 enhances cellular growth, there is concern that GLP-2 analogs may also encourage growth of malignant cells.. To histologically examine the effects of teduglutide, a recombinant human GLP-2 analog, on the mucosa of the small and large intestine for indications of dysplastic transformation.. In a multicenter, prospective, randomized, placebo-controlled study, 83 PN-dependent patients with SBS-IF were monitored for several weeks to ensure optimal and stable PN. Patients were then randomized to receive 24 weeks of placebo (n=16), teduglutide (0.5 mg/kg/d; n=35), or teduglutide (0.10 mg/kg/d; n=32).. Biopsies were obtained from 77 patients to yield 390 individual histologic interpretations. After 6 months of treatment, no features of dysplasia were found in any biopsy from the large or small intestine of patients receiving placebo or either dose of teduglutide. New secondary diagnoses, such as eosinophilic colitis or Crohn's disease, were found at a low frequency overall: teduglutide (0.05 mg/kg/d; range, 3.1% to 6.3%); teduglutide (0.10 mg/kg/d, 3.3%); placebo (range, 6.7% to 13.3%).. Although this histologic substudy of biopsy samples was not powered to detect differences in occurrence of dysplasia between teduglutide-treated patients and those randomized to placebo, it demonstrated that no dysplasia or other pathologic processes were evident within the intestinal mucosa in the placebo group or the 2 teduglutide groups after 6 months of treatment.

Topics: Adaptation, Physiological; Biopsy; Cohort Studies; Gastrointestinal Agents; Humans; Intestinal Mucosa; Intestine, Large; Intestine, Small; Parenteral Nutrition; Peptides; Prospective Studies; Short Bowel Syndrome

Short bowel syndrome (SBS)-intestinal failure (IF) patients have impaired quality of life (QoL) and suffer from the burden of malabsorption and parenteral support (PS). A phase III study demonstrated that treatment with teduglutide, a glucagon-like peptide 2 analogue, reduces PS volumes by 32% while maintaining oral fluid intake constant; placebo-treated patients had reduced PS by 21%, but oral fluid intake increased accordingly. As effects of teduglutide on QoL are unknown, they were investigated here.. QoL analyses from a double-blind, randomised Phase III study in 86 SBS-IF patients receiving teduglutide (0.05 mg/kg/day s.c.) or placebo over 24 weeks. At baseline and every 4 weeks, QoL was assessed using the validated SBS-QoL™ scale.. PS reductions were associated with QoL improvements (ANCOVA, p = 0.0194, SBS-QoL per-protocol). Compared to baseline, teduglutide significantly improved the SBS-QoL™ total score and the score of 9 of 17 items at week 24. These changes were not significant compared to placebo. Teduglutide-treated patients with remaining small intestine >100 cm experienced more gastrointestinal adverse events (GI-AE), unfavourably affecting QoL.. Overall, PS volume reductions were associated with improvements in SBS-QoL™ scores. The short observation period, imbalances in oral fluid intake in relation to PS reductions, large patient and effect heterogeneity and occurrence of GI-AE in a subgroup of teduglutide-treated patients may account for the inability to show statistically significant effects of teduglutide on SBS-QoL™ scores compared to placebo.

Topics: Adult; Aged; Cost of Illness; Double-Blind Method; Drinking; Drug Resistance; Gastrointestinal Agents; Glucagon-Like Peptide 2; Glucagon-Like Peptide-2 Receptor; Humans; Injections, Subcutaneous; Intestinal Diseases; Intestine, Small; Middle Aged; Organ Dysfunction Scores; Organ Size; Parenteral Nutrition, Home; Peptides; Quality of Life; Receptors, Glucagon; Short Bowel Syndrome

Subjects with short bowel syndrome (SBS) have impaired quality of life (QoL). No disease-specific instrument has been available to measure treatment-induced changes in QoL over time. Therefore, the aim was to develop and validate an SBS-specific QoL scale.. Classical test theory and Food and Drug Administration (FDA) guidance were applied for development and validation of the SBS-QoL™. Procedures included item generation and raw scale construction. Factor analysis, construct validity and internal consistency were assessed in a non-interventional observation, test re-test reliability and responsiveness in a randomised clinical study.. The SBS-QoL™ comprises 17 items including two subscales. Subjects assessed the scale as easy to handle and comprehensible. Good construct validity was shown by comparison with the Home Parenteral Nutrition-Quality Of Life questionnaire as an external scale, which yielded moderately high correlation (r ≥ 0.7). High internal consistency was demonstrated (Cronbach's alpha: 0.94). Also the test re-test reliability was high (r ≥ 0.95), indicating reliable reproducibility of results. The Responsiveness Index (1.84) indicated the ability of the scale to detect changes in QoL over time.. The SBS-QoL™ is an easy to handle and comprehensible SBS-specific subject-reported QoL scale. It is valid, reliable and sensitive with excellent psychometric characteristics to measure treatment-induced changes in QoL over time in subjects with SBS.

Topics: Activities of Daily Living; Adult; Aged; Cost of Illness; Diarrhea; Double-Blind Method; Drug Resistance; Female; Gastrointestinal Agents; Gastrointestinal Tract; Glucagon-Like Peptide-2 Receptor; Humans; Male; Middle Aged; Peptides; Psychometrics; Quality of Life; Receptors, Glucagon; Recombinant Proteins; Reproducibility of Results; Severity of Illness Index; Short Bowel Syndrome; Surveys and Questionnaires

Although home parenteral nutrition (PN) can save the lives of patients with massive bowel loss that results in short-bowel syndrome and intestinal failure, quality of life is impaired by PN and its complications. We examined the 12-month tolerability and efficacy of teduglutide to reduce PN dependency.. Patients who received teduglutide (0.05 or 0.10 mg/kg/d) for 24 weeks in a randomized controlled trial were eligible for a 28-week double-blind extension study; 52 patients were given 52 weeks of the same doses of teduglutide. We investigated the safety, tolerability, and clinical efficacy (defined as a clinically meaningful ≥20% reduction in weekly PN volume from baseline) at week 52.. The most common adverse events reported included headache (35%), nausea (31%), and abdominal pain (25%); 7 patients withdrew because of adverse events (gastrointestinal disorders in 4). Both groups had progressive reduction in PN. At week 52, 68% of the 0.05-mg/kg/d and 52% of the 0.10-mg/kg/d dose group had a ≥20% reduction in PN, with a reduction of 1 or more days of PN dependency in 68% and 37%, respectively. Four patients achieved complete independence from PN.. For patients with short-bowel syndrome intestinal failure, the efficacy of teduglutide was maintained over 52 weeks and the safety profile was sufficient for it to be considered for long-term use. Further studies are needed to determine whether these effects will translate into improved quality of life and reduced PN complications. ClinicalTrials.gov number, NCT00172185.

Topics: Adult; Aged; Aged, 80 and over; Double-Blind Method; Female; Gastrointestinal Agents; Humans; Male; Middle Aged; Parenteral Nutrition; Peptides; Short Bowel Syndrome; Treatment Outcome; Young Adult

Teduglutide, a glucagon-like peptide 2 analogue, might restore intestinal structural and functional integrity by promoting growth of the mucosa and reducing gastric emptying and secretion. These factors could increase fluid and nutrient absorption in patients with short bowel syndrome with intestinal failure (SBS-IF). We performed a prospective study to determine whether teduglutide reduces parenteral support in patients with SBS-IF.. We performed a 24-week study of patients with SBS-IF who were given subcutaneous teduglutide (0.05 mg/kg/d; n = 43) or placebo (n = 43) once daily. Parenteral support was reduced if 48-hour urine volumes exceeded baseline values by ≥ 10%. The primary efficacy end point was number of responders (patients with >20% reduction in parenteral support volume from baseline at weeks 20 and 24).. There were significantly more responders in the teduglutide group (27/43 [63%]) than the placebo group (13/43 [30%]; P = .002). At week 24, the mean reduction in parenteral support volume in the teduglutide group was 4.4 ± 3.8 L/wk (baseline 12.9 ± 7.8 L/wk) compared with 2.3 ± 2.7 L/wk (baseline 13.2 ± 7.4 L/wk) in the placebo group (P < .001). The percentage of patients with a 1-day or more reduction in the weekly need for parenteral support was greater in the teduglutide group (21/39 [54%]) than in the placebo group (9/39 [23%]; P = .005). Teduglutide increased plasma concentrations of citrulline, a biomarker of mucosal mass. The distribution of treatment-emergent adverse events that led to study discontinuation was similar between patients given teduglutide (n = 2) and placebo (n = 3).. Twenty-four weeks of teduglutide treatment was generally well tolerated in patients with SBS-IF. Treatment with teduglutide reduced volumes and numbers of days of parenteral support for patients with SBS-IF; ClinicalTrials.gov Number, NCT00798967.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers; Citrulline; Dose-Response Relationship, Drug; Double-Blind Method; Endpoint Determination; Female; Humans; Injections, Subcutaneous; Intestinal Absorption; Intestinal Diseases; Intestines; Male; Middle Aged; Parenteral Nutrition; Peptides; Prospective Studies; Short Bowel Syndrome; Treatment Outcome; Video Recording; Young Adult

Teduglutide, a GLP-2 analogue, may restore intestinal structural and functional integrity by promoting repair and growth of the mucosa and reducing gastric emptying and secretion, thereby increasing fluid and nutrient absorption in patients with short bowel syndrome (SBS). This 24-week placebo-controlled study evaluated the ability of teduglutide to reduce parenteral support in patients with SBS with intestinal failure.. In 83 patients randomised to receive subcutaneous teduglutide 0.10 mg/kg/day (n = 32), 0.05 mg/kg/day (n = 35) or placebo (n = 16) once daily, parenteral fluids were reduced at 4-week intervals if intestinal fluid absorption (48 h urine volumes) increased ≥ 10%. Responders were subjects who demonstrated reductions of ≥ 20% in parenteral volumes from baseline at weeks 20 and 24. The primary efficacy end point, a graded response score (GRS), took into account higher levels and earlier onset of response, leading to longer duration of response. The intensity of the response was defined as a reduction from baseline in parenteral volume (from 20% to 100%), and the duration of the response was considered the response at weeks 16, 20 and 24. The results were tested according to a step-down procedure starting with the 0.10 mg/kg/day dose.. Using the GRS criteria, teduglutide in a dose of 0.10 mg/kg/day did not have a statistically significant effect compared with placebo (8/32 vs 1/16, p=0.16), while teduglutide in a dose of 0.05 mg/kg/day had a significant effect (16/35, p = 0.007). Since parenteral volume reductions were equal (353 ± 475 and 354 ± 334 ml/day), the trend towards higher baseline parenteral volume (1816 ± 1008 vs 1374 ± 639 ml/day, p=0.11) in the 0.10 mg/kg/day group compared with the 0.05 mg/kg/day group may have accounted for this discrepancy. Three teduglutide-treated patients were completely weaned off parenteral support. Serious adverse events were distributed similarly between active treatment groups and placebo. Villus height, plasma citrulline concentration and lean body mass were significantly increased with teduglutide compared with placebo.. Teduglutide was safe, well tolerated, intestinotrophic and suggested pro-absorptive effects facilitating reductions in parenteral support in patients with SBS with intestinal failure. ClinicalTrials.gov number NCT00172185.

Topics: Adult; Aged; Algorithms; Body Composition; Body Weight; Combined Modality Therapy; Dose-Response Relationship, Drug; Female; Fluid Therapy; Gastrointestinal Agents; Humans; Male; Middle Aged; Parenteral Nutrition; Peptides; Short Bowel Syndrome; Treatment Outcome; Young Adult

Glucagon-like peptide 2 (GLP-2) may improve intestinal absorption in short bowel syndrome (SBS) patients with an end jejunostomy. Teduglutide (ALX-0600), a dipeptidyl peptidase IV resistant GLP-2 analogue, prolongs the intestinotrophic properties of GLP-2 in animal models. The safety and effect of teduglutide were investigated in SBS patients with and without a colon in continuity.. Teduglutide was given subcutaneously for 21 days once or twice daily to 16 SBS patients in the per protocol investigational group, 10 with end jejunostomy (doses of 0.03 (n = 2), 0.10 (n = 5), or 0.15 (n = 3) mg/kg/day), one with <50% colon in continuity (dose 0.03 mg/kg/day), and five with > or = 50% colon in continuity (dose 0.10 mg/kg/day). Nutrient balance studies, D-xylose tests, and intestinal mucosa biopsies were performed at baseline, on the last three days of treatment, and after three weeks of follow up. Pre-study fasting native GLP-2 levels were determined for the five patients with > or = 50% colon in continuity.. Pooled across groups and compared with baseline, teduglutide increased absolute (+743 (477) g/day; p<0.001) and relative (+22 (16)%; p<0.001) wet weight absorption, urine weight (+555 (485) g/day; p<0.001), and urine sodium excretion (+53 (40) mmol/day; p<0.001). Teduglutide decreased faecal wet weight (-711 (734) g/day; p = 0.001) and faecal energy excretion (-808 (1453) kJ/day (-193 (347) kcal/day); p = 0.040). In SBS patients with end jejunostomy, teduglutide significantly increased villus height (+38 (45)%; p = 0.030), crypt depth (+22 (18)%; p = 0.010), and mitotic index (+115 (108)%; p = 0.010). Crypt depth and mitotic index did not change in colonic biopsies from SBS patients with colon in continuity. The most common side effects were enlargement of the stoma nipple and mild lower leg oedema. The improvements in intestinal absorption and decreases in faecal excretion noted after treatment had reversed after the drug free follow up period. A controlled study with a more robust design is ongoing in order to determine the optimal dosage of teduglutide for SBS patients to achieve the maximal effect and utility of this drug in clinical practice.. Teduglutide, at three dose levels for 21 days, was safe and well tolerated, intestinotrophic, and significantly increased intestinal wet weight absorption in SBS patients with an end jejunostomy or a colon in continuity.

Topics: Adult; Aged; Colon; Drug Administration Schedule; Female; Gastrointestinal Agents; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Humans; Intestinal Absorption; Jejunostomy; Jejunum; Male; Middle Aged; Mitotic Index; Pilot Projects; Short Bowel Syndrome

Surgery in Crohn's disease may be the cause of short bowel syndrome that may lead to kidney dysfunction. Dual biologic therapy is rarely needed to control activity. We present a case of a 61-year-old steroid dependent (A2L1B3p) female who had undergone surgery on three occasions: ileocecal resection (resection of 15 cm of terminal ileum); resection of right and left colon up to sigmoid; proctectomy with intersphincteric resection along with ileostomy due to a rectovaginal fistula. She had been previously treated with prednisone, azathioprine, methotrexate, infliximab and adalimumab but the treatment was discontinued owing to adverse effects. Vedolizumab was started, showing good control of the luminal activity but the rectovaginal fistula recurred. Treatment changed to ustekinumab, the fistula activity was controlled but the mucosa activity recurred. 11 months after commencing with ustekinumab, vedolizumab was added to the treatment and complete remission was achieved for three years. Simultaneously, the patient developed renal dysfunction derived from the short bowel syndrome that led to chronic kidney failure. In the face of potential renal replacement therapy, a new therapy with 2.5 mg/sc/d teduglutide was started achieving stable figures of creatinine and normalization of the glomerular filtration rate.

Topics: Biological Therapy; Crohn Disease; Female; Humans; Middle Aged; Rectovaginal Fistula; Short Bowel Syndrome; Treatment Outcome; Ustekinumab

Teduglutide (Revestive®) is a glucagon-like peptide-2 analogue used for the treatment of short bowel syndrome, a rare life-threatening condition in which the amount of functional gut is too short to enable proper absorption of nutrients and fluids. During handling prior to administration to the patient in hospital, it is possible that peptide-based medicines may be exposed to environmental stress conditions that could affect their quality. It is therefore essential to carry out stress testing studies to evaluate how such medicines respond to these stresses. For this reason, in this paper we present a strategy for a comprehensive analytical characterization of a peptide and a stress testing study in which it was subjected to various stress conditions: heating at 40 °C and 60 °C, light exposure and shaking. Several complementary analytical techniques were used throughout this study: Far UV circular dichroism, intrinsic protein fluorescence spectroscopy, dynamic light scattering, size-exclusion chromatography and intact and peptide mapping reverse-phase chromatography coupled to mass spectrometry. To the best of our knowledge, this is the first study to offer an in-depth description of the chemical structure of teduglutide peptide and its physicochemical characteristics after stress stimuli were applied to the reconstituted medicine Revestive®.

Topics: Gastrointestinal Agents; Glucagon-Like Peptide 2; Humans; Mass Spectrometry; Peptides; Short Bowel Syndrome

Short bowel syndrome is a low-incidence disorder among pediatric patients, but it is associated with high morbidity and mortality rates. Management of these patients by an interdisciplinary team of experts focused on intestinal rehabilitation improves short- and long-term outcomes. Available resources for treatment include teduglutide, a glucagon-like peptide type 2 (GLP-2) analog made by recombinant techniques. Considering the available evidence and the authors' experience, Delphi-based recommendations for the use of teduglutide are suggested for healthcare professionals who treat pediatric patients with short bowel syndrome, as well as for health authorities.. El síndrome de intestino corto es una entidad de baja incidencia en los pacientes pediátricos, pero se asocia con elevadas tasas de morbimortalidad. El abordaje de estos pacientes por un equipo interdisciplinario de expertos enfocados en la rehabilitación intestinal mejora los resultados a corto y a largo plazo. Entre los recursos disponibles para el tratamiento se incluye el teduglutide, un análogo del péptido similar al glucagón tipo 2 (GLP-2) elaborado mediante técnicas recombinantes. Por medio de la aplicación del método Delphi, a partir de la evidencia disponible y de la experiencia de los autores, se proponen recomendaciones para el uso de teduglutide, dirigidas a los profesionales de la salud que tratan a los pacientes pediátricos con síndrome de intestino corto, así como a las autoridades sanitarias.

Topics: Child; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Humans; Peptides; Short Bowel Syndrome

The short-term effects of teduglutide (TED) for short bowel syndrome with chronic intestinal failure (SBS-IF) in patients with Crohn's disease (CD) remain unknown. The aim of this study was to investigate the effects of TED in patients with CD on home parenteral support (PS) for SBS-IF.. We retrospectively investigated the medical records of patients with CD associated with SBS-IF who initiated TED between 2020 and 2021. The primary outcomes were the change in PS volume and proportion of patients with a reduction of PS volume by ≥ 20% at week 8. Secondary outcomes were the change in PS volume in patients with CD without/with colon in continuity and adverse events during the observation period.. Eighteen patients with CD who underwent home PS for SBS-IF were included in this study. Two patients were excluded owing to intolerable abdominal pain or vomiting within 8 weeks (11%). Sixteen patients continued TED throughout the observation period. The median PS duration was 10.5 years. The median observation period was 22 weeks after starting TED. TED significantly reduced the PS volume from 15,825.0 mL/week to 10,700.0 mL/week (p = 0.0038), and the PS volume decreased by ≥ 20% in 7 patients (43.8%) at week 8. The PS volume was significantly reduced at week 4 (p = 0.0078) in 11 patients without colon in continuity but not in 5 patients with colon in continuity. Two patients successfully stopped home PS. No serious adverse events occurred.. TED administration significantly reduced PS volume at week 8 in patients with CD associated with SBS-IF, and at week 4 in patients without colon in continuity.

Topics: Crohn Disease; Gastrointestinal Agents; Humans; Intestinal Failure; Retrospective Studies; Short Bowel Syndrome

Topics: Gastrointestinal Agents; Humans; Peptides; Short Bowel Syndrome

Teduglutide is a GLP-2 analog indicated for the treatment of short bowel syndrome (SBS) since 2015. Its efficacy in reducing parenteral nutrition (PN) has been shown in patients with SBS.. Because teduglutide is a trophic factor, the aim of this study was to assess risk of developing polypoid intestinal lesions during treatment.. A retrospective study was conducted in 35 patients with SBS treated with teduglutide for ≥1 y in a home PN expert center. All patients underwent ≥1 follow-up intestinal endoscopy during treatment.. In the 35 patients, the small bowel length was 74 cm (IQR: 25-100), and 23 patients (66%) had a colon in continuity. Upper and lower gastrointestinal endoscopy was performed after a mean treatment duration of 23 mo (IQR: 13-27), and polypoid lesions were found in 10 patients (6 with a colon in continuity, 4 with an end jejunostomy) and no lesion in 25 patients. In 8 out of the 10 patients, the lesion was found in the small bowel. Five of these lesions presented an aspect of hyperplastic polyp without dysplasia, and 3 of a traditional adenoma with low-grade dysplasia.. Our study highlights the importance of performing follow-up upper and lower gastrointestinal endoscopy in SBS patients treated with teduglutide and the potential need to make changes to the recommendations with respect to treatment initiation and follow-up.

Topics: Gastrointestinal Agents; Humans; Parenteral Nutrition, Home; Retrospective Studies; Short Bowel Syndrome

Short bowel syndrome (SBS) is the main cause of intestinal failure in children.. This single-center study evaluated the safety and efficacy of teduglutide in pediatric patients with SBS-associated intestinal failure (SBS-IF).. Children with SBS followed at our center with ≥2 y on parenteral nutrition (PN) and with small bowel length <80 cm who had reached a plateau were consecutively included in the study. At baseline, participants underwent a clinical assessment including a 3-d stool balance analysis, which was repeated at the end of the study. Teduglutide was administered subcutaneously 0.05 mg/kg/d for 48 wk. PN dependence was expressed as the PN dependency index (PNDI), which is the ratio PN non-protein energy intake/REE. Safety endpoints included treatment-emergent adverse events and growth parameters.. Median age at inclusion was 9.4 y (range: 5-16). The median residual SB length was 26 cm (IQR: 12-40). At baseline, the median PNDI was 94% (IQR: 74-119), (median PN intake: 38.9 calories/kg/d, IQR: 26.1-48.6). At week 24, 24 (96%) children experienced a reduction of >20% of PN requirements with a median PNDI = 50% (IQR: 38-81), (PN intake: 23.5 calories/kg/d IQR: 14.6-26.2), P < 0.01. At week 48, 8 children (32%) were weaned completely off PN. Plasma citrulline increased from 14 μmol/L (IQR: 8-21) at baseline to 29 μmol/L (IQR: 17-54) at week 48 (P < 0.001). Weight, height, and BMI z-scores remained stable. The median total energy absorption rate increased from 59% (IQR: 46-76) at baseline to 73% (IQR: 58-81) at week 48 (P = 0.0222). Fasting and postprandial endogenous GLP-2 concentrations increased at weeks 24 and 48 compared with baseline. Mild abdominal pain at the early phase of treatment, stoma changes, and redness at the injection site were commonly reported.. Increased intestinal absorption and PN dependency reduction were observed with teduglutide treatment in children with SBS-IF.. ClinicalTrials.gov NCT03562130. https://clinicaltrials.gov/ct2/show/NCT03562130?term=NCT03562130&draw=2&rank=1.

Topics: Child; Gastrointestinal Agents; Humans; Intestinal Failure; Intestine, Small; Peptides; Short Bowel Syndrome

Teduglutide, a GLP-2 analogue, has been available in France since 2015 to treat short-bowel-syndrome (SBS)-associated chronic intestinal failure (CIF) but it remains very expensive. No real-life data on the number of potential candidates are available. The aim of this real-life study was to assess teduglutide initiation and outcomes in SBS-CIF patients. All SBS-CIF patients cared for in an expert home parenteral support (PS) center between 2015 and 2020 were retrospectively included. Patients were divided into two subpopulations: prevalent patients, already cared for in the center before 2015, and incident patients, whose follow-up started between 2015 and 2020. A total of 331 SBS-CIF patients were included in the study (156 prevalent and 175 incident patients). Teduglutide was initiated in 56 patients (16.9% of the cohort); in 27.9% of prevalent patients and in 8.0% of incident patients, with a mean annual rate of 4.3% and 2.5%, respectively. Teduglutide allowed a reduction in the PS volume by 60% (IQR: 40-100), with a significantly higher reduction in incident versus prevalent patients (

Topics: Adult; Chronic Disease; Gastrointestinal Agents; Humans; Intestinal Diseases; Intestinal Failure; Retrospective Studies; Short Bowel Syndrome

Teduglutide is a synthetic glucagon-like peptide-2 analogue approved for the treatment of short bowel syndrome associated with chronic intestinal failure (SBS-IF) in adult patients. Clinical trials have demonstrated its ability to reduce parenteral support (PS) requirement. This study aimed to describe the effect of 18-month treatment with teduglutide, evaluating PS and factors associated with PS volume reduction of ≥20% from baseline and weaning. Two-year clinical outcomes were also assessed.. This descriptive cohort study collected data prospectively from adult patients with SBS-IF treated with teduglutide and enrolled in a national registry. Data were collected every 6 months and included demographics, clinical, biochemical, PS regimen, and hospitalizations.. Thirty-four patients were included. After 2 years, 74% (n = 25) had a PS volume reduction of ≥20% from baseline, and 26% (n = 9) achieved PS independency. PS volume reduction was significantly associated with longer PS duration, significantly lower basal PS energy intake, and absence of narcotics. PS weaning was significantly associated with fewer infusion days, lower PS volume, longer PS duration, and lower narcotics use at baseline. Alkaline phosphatase was significantly lower in weaned patients after 6 and 18 months of treatment. During the 2-year study duration, patients who had PS volume reduction of ≥20% had significantly fewer yearly hospitalizations and hospital-days.. Teduglutide reduces PS volume and promotes weaning in adults with SBS-IF. Lack of narcotics and longer PS duration were associated with PS volume reduction and weaning, and lower baseline PS volume and fewer infusion days were favorable in obtaining enteral autonomy.

Topics: Adult; Cohort Studies; Gastrointestinal Agents; Humans; Intestine, Small; Short Bowel Syndrome

Short bowel syndrome (SBS) is a rare condition defined as a reduced residual functional small intestinal length to less than 200 cm often resulting from extensive intestinal resection, and can lead to chronic intestinal failure (CIF). Patients with SBS-CIF are unable to absorb sufficient nutrients or fluids to maintain metabolic homeostasis through oral or enteral intake and require long-term parenteral nutrition and/or fluids and electrolytes. However, complications may arise from both SBS-IF and life-sustaining intravenous support, such as intestinal failure-associated liver disease (IFALD), chronic renal failure, metabolic bone disease and catheter-related complications. An interdisciplinary approach is required to optimize intestinal adaptation and decrease complications. In the last two decades, glucagon-like peptide 2 (GLP-2) analogs have sparked pharmacological interest as a potential disease-modifying therapy for SBS-IF. Teduglutide (TED) is the first developed and marketed GLP-2 analog for SBS-IF. It is approved in the United States, Europe, and Japan for use in adults and children with SBS-IF who are intravenous supplementation dependent. This article discusses the indications, candidacy criteria and results of the use of TED in patients with SBS.

Topics: Adult; Child; Chronic Disease; Gastrointestinal Agents; Glucagon-Like Peptide 2; Humans; Intestinal Diseases; Intestinal Failure; Intestine, Small; Intestines; Short Bowel Syndrome

We present the case of a 35-y-old woman with short bowel syndrome secondary to extensive intestinal resection with associated chronic kidney disease who was undergoing hemodialysis. This patient required permanent supplementation with intradialytic parenteral nutrition because of a high-output end-jejunostomy. The patient was a candidate for treatment with teduglutide, a glucagon-like peptide 2 analog, intending to increase intestinal absorption. A complete nutritional assessment was performed using bioelectrical impedance vector analysis. Teduglutide treatment was successful, and after a 1-y follow-up, the patient had considerably reduced end-jejunostomy output (reduction of 6 L/d) and an improved nutritional status (9.1 kg weight gain, 1.4 kg fat-free mass gain, and a 2.2-degree increase in bioimpedance phase angle). However, we have been unable to reduce intradialytic parenteral nutrition, which the patient requires thrice weekly. No significant secondary effects have occurred because of teduglutide administration. This may be the first reported use of teduglutide in a patient with short bowel syndrome undergoing hemodialysis who was monitored using bioelectrical impedance data during follow-up.

Topics: Chronic Disease; Female; Gastrointestinal Agents; Humans; Intestinal Diseases; Intestinal Failure; Short Bowel Syndrome

The human intestinal tract reacts to extensive resection with spontaneous intestinal adaptation. We analyzed whether gene expression analyses or intestinal permeability (IP) testing could provide biomarkers to describe regulation mechanisms in the intestinal barrier in short bowel syndrome (SBS) patients during adaptive response or treatment with the glucagon-like peptide-2 analog teduglutide.. Relevant regions of the GLP-2 receptor gene were sequenced. Gene expression analyses and immunohistochemistry were performed from mucosal biopsies. IP was assessed using a carbohydrate oral ingestion test.. The study includes 59 SBS patients and 19 controls. Increases in gene expression with teduglutide were received for sucrase-isomaltase, sodium/glucose cotransporter 1, and calcium/calmodulin serine protein kinase. Mannitol recovery was decreased in SBS but elevated with teduglutide (Δ 40%), showed a positive correlation with remnant small bowel and an inverse correlation with parenteral support.. Biomarkers predicting clinical and functional features in human SBS are very limited. Altered specific gene expression was shown for genes involved in nutrient transport but not for genes controlling tight junctions. However, mannitol recovery proved useful in describing the absorptive capacity of the gut during adaptation and treatment with teduglutide.

Topics: Biomarkers; Gastrointestinal Agents; Glucagon-Like Peptide 2; Humans; Intestine, Small; Mannitol; Short Bowel Syndrome

A growing proportion of children with short bowel syndrome (SBS) remain dependent on long-term parenteral nutrition (PN). Teduglutide offers the potential for more children to decrease PN support and achieve enteral autonomy (EA), but at a significant expense. This study aims to assess the incremental costs of teduglutide plus standard of care compared to standard of care alone in weaning PN support per quality-adjusted life year (QALY) gained in children with SBS.. This is a cost-utility analysis comparing teduglutide with standard of care alone in children with SBS. A microsimulation model of children with SBS on PN aged 1-17 years was constructed over a time horizon of six years, with a cycle length of one month. The study adopted the healthcare system and societal payer perspectives in Ontario, Canada. The health outcome measure was QALYs, with results expressed in terms of incremental costs and QALYs. Scenario analyses were performed to examine the effects of different time horizons, timing of teduglutide initiation, and modeling cost of teduglutide based on pediatric weight-dosing.. Incremental healthcare system costs for teduglutide compared to standard of care were CAD$441,314 (95% CI, 414,006 to 441,314) and incremental QALYs were 1.80 (95% CI, 1.70 to 1.89) resulting in an incremental cost-effectiveness ratio (ICER) of CAD$285,334 (95% CI, 178,209 to 392,459) per QALY gained. Incremental societal costs were CAD$418,504 (95% CI, 409,487 to 427,522) and incremental societal QALYs were 1.91 (95% CI, 1.85 to 1.98) resulting in an ICER of CAD$261,880 (95% CI, 136,887 to 386,874) per QALY gained. Scenario analysis showed that teduglutide was cost-effective when it was started two years after intestinal resection (ICER CAD$48,741, 95% CI, 17,317 to 80,165) and when its monthly cost was adjusted using weight-based dosing, avoiding wastage of the remaining 5 mg dose vial (Teduglutide dominated over SOC as the less costly and most effective strategy).. Although teduglutide was not cost-effective in weaning PN support in children with SBS, starting teduglutide once natural intestinal adaptation is reduced and adjusting its monthly cost to reflect cost by volume as dictated by weight-based dosing rendered the intervention cost-effective relative to standard of care. These results indicate the potential for clinicians to re-assess optimal time for initiation of teduglutide after intestinal resection, drug manufacturers to consider the use of multi-dose or paediatric-dose vials, and the opportunity for decision-makers to re-evaluate teduglutide funding.

Topics: Child; Cost-Benefit Analysis; Gastrointestinal Agents; Humans; Ontario; Parenteral Nutrition; Short Bowel Syndrome; Weaning

The glucagon-like peptide 2 analogue teduglutide is an effective drug for the treatment of short bowel syndrome patients with intestinal failure (SBS-IF). This intestinotrophic peptide improves intestinal capacity for fluid and nutrient absorption through induction of mucosal growth and reduction of gastrointestinal motility. Clinical trials demonstrated the efficacy of teduglutide in reducing the need for parenteral support (PS). This study describes an SBS-IF patient population receiving teduglutide therapy in a specialized medical care setting.. A retrospective analysis was performed using data of patients experiencing nonmalignant SBS-IF. They were treated with teduglutide in a multidisciplinary SBS-IF program at a single university medical center between June 2016 and June 2020.. Thirteen patients under teduglutide treatment were included in the final analysis. Mean small bowel length was 82 ± 31 cm, with 77% of patients having their colon in continuity. Over a median follow-up of 107 weeks, all patients (13 of 13, 100%) responded to the therapy with a clinically significant reduction of PS volume. Mean PS reduction increased with therapy duration and ranged from -82.5% at week 24 (n = 13) to -100% in patients (n = 5) who were treated for 144 weeks. Enteral autonomy was achieved in 12 of 13 (92%) patients. Teduglutide therapy improved stool frequency and consistency, changed dietary habits, and reduced disease-associated sleep disruptions.. Integrating SBS-IF patients treated with teduglutide in a proactive and tight-meshed patient care program significantly improves the clinical outcome, leading to an increased proportion of patients reaching enteral autonomy.

Topics: Gastrointestinal Agents; Humans; Peptides; Retrospective Studies; Short Bowel Syndrome; Treatment Outcome

Introduction: teduglutide (TED) is indicated for the treatment of patients with short-bowel syndrome (SBS) who are dependent on parenteral support. Case report: we report the case of a 60-year-old woman with SBS treated with TED. She had previously undergone multiple surgical resections due to Crohn's disease. Her remnant bowel included only the duodenum and 50-60 centimeters of jejunum. The patient was dependent on intravenous fluids (2,320 mL/48 h) and had a high stoma output (3,000 mL/day). After four months of TED the jejunostomy output had decreased to 2,200 mL/day with a thicker consistency, and intravenous fluid therapy was reduced to 2,010 mL/48 h. TED was withdrawn due to acute pancreatitis and enlargement of two supraumbilical hernias with high strangulation risk. Discussion: pancreatitis has been reported in clinical studies, and determination of amylase and lipase is recommended in all patients receiving TED. In contrast, there are no recommendations for the surveillance of hernia enlargement in patients on TED therapy, but we suggest the need for surveillance based on this case report.. Introducción: la teduglutida (TED) está indicada para el tratamiento de pacientes con síndrome de intestino corto (SBS) que precisen soporte parenteral. Caso clínico: mujer de 60 años con SBS tratada con TED. Previamente se había sometido a múltiples resecciones quirúrgicas por su enfermedad de Crohn. Su intestino remanente incluía el duodeno y 50-60 centímetros de yeyuno. La paciente era dependiente de líquidos por vía intravenosa (2320 ml/48 h) y tenía una ostomía de alto débito (3000 ml/día). Después de cuatro meses de TED, el débito de la yeyunostomía disminuyó a 2200 ml/día, con una consistencia más espesa, y la fluidoterapia intravenosa se redujo a 2010 ml/48 h. Se retiró la TED por pancreatitis aguda y agrandamiento de dos hernias supraumbilicales con alto riesgo de estrangulamiento. Discusión: se han descrito casos de pancreatitis en estudios previos, por lo que se recomienda la determinación de la amilasa y la lipasa en los pacientes tratados con TED. Sin embargo, no hay recomendaciones específicas sobre la vigilancia del agrandamiento de hernias, pero sugerimos su idoneidad basada en este caso clínico.

Topics: Acute Disease; Female; Gastrointestinal Agents; Hernia; Humans; Middle Aged; Pancreatitis; Peptides; Short Bowel Syndrome

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.

Topics: Body Mass Index; Follow-Up Studies; Gastrointestinal Agents; Humans; Nutritional Requirements; Parenteral Nutrition, Home; Peptides; Retrospective Studies; Short Bowel Syndrome

The glucagon-like peptide-2 analog Teduglutide has been shown to enhance intestinal absorption and decrease parenteral nutrition (PN) requirements in short bowel syndrome (SBS). As data in children is limited, we evaluated nationwide real-life experience and treatment outcome in children with SBS.. Longitudinal data of children treated with Teduglutide for ≥3 months was collected. Data included demographic and medical background, anthropometrics, laboratory assessments and PN requirements. Treatment response was defined as >20% reduction in PN requirement.. The study included 13 patients [54% males, median (interquartile range {IQR}) age of 6 (4.7-7) years]. The most common SBS etiology was necrotizing enterocolitis (38%), and median (IQR) small bowel length was 20 (15-40) cm. Teduglutide treatment ranged between 3 and 51 months [median (IQR) of 18 (12-30) months], with 10 patients (77%) treated >1 year. Response to treatment was observed in 8 patients (62%), with a mean [±standard deviation (SD)] treatment duration of 5.9 (±3.2) months. Among responders, 2 patients were weaned off PN and additional 4 decreased PN needs by >40%. There was a median (IQR) reduction in PN volume/kg of 36% (15%-55%) and in PN energy/kg of 27% (6%-58%). Response was not associated with patients' background, and no correlation was found with bowel length or PN dependency at baseline.. Real-life response to Teduglutide is highly variable among children with SBS. While most patients did reach 20% reduction in PN, less achieved further significant reduction or enteral autonomy. No predictive factors of response to treatment were identified, and large multicenter studies are needed to elucidate predictive factors and long-term outcome.

Topics: Child; Female; Gastrointestinal Agents; Humans; Infant, Newborn; Male; Parenteral Nutrition; Peptides; Short Bowel Syndrome

Teduglutide, the active ingredient of the medicine Revestive® (5 mg), is a recombinant therapeutic peptide that mimics the effects of the endogenous glucagon-like peptide 2 (GLP-2). It stimulates intestinal growth, adaptation and function in patients with Short Bowel Syndrome who are dependent on parenteral nutrition. The Summary of Product Characteristics recommends immediate use of the reconstituted solutions and the discarding of any subsequent surplus. This study aims to carry out a long-term stability study that reproduces hospital conditions of use which provide sound evidence regarding the use of teduglutide surplus beyond the Summary Product Characteristics recommendations. We conducted a stability study of teduglutide solutions prepared from a 5 mg vial of Revestive®. Some of the solutions were stored in their original vial after reconstitution, while others were repackaged in plastic syringes to evaluate their physicochemical stability over time. For this purpose, we applied a set of previously validated analytical methodologies to evaluate the main critical quality attributes of teduglutide, i.e., primary (including post-tralational modifications), secondary and tertiary structures, aggregates, particulate, concentration and pH. The results indicate that the solutions maintain high physicochemical stability over time, regardless of the storage temperature (4ºC or -20ºC) or the storage container (vials or syringes). This research provides new data on the stability of Revestive® that will be of great value to hospital pharmacists. This comprehensive assessment of the physicochemical long-term stability of TGT has demonstrated that under the storage conditions and over the period studied here, the medicine maintains its quality, efficacy and safety profiles.

Topics: Gastrointestinal Agents; Glucagon-Like Peptide 2; Humans; Peptides; Plastics; Short Bowel Syndrome

Teduglutide is a Glucagon-like peptide-2 (GLP-2) agonist indicated for the treatment of patients with parenteral support (PS) dependent short bowel syndrome (SBS) with chronic intestinal failure (cIF). Its application is accompanied by a structured nation-wide home-care service program in Germany. We investigated care characteristics and outcome parameters in a clinical real-world observational setting.. Data generated within a therapy-accompanying home-care service program for adult SBS-cIF patients were analyzed retrospectively for patients treated up to 1 year (data cut: April 2020).. In total, 52 teduglutide-treated patients were included by 6 German cIF centers. At teduglutide administration start, 49/52 patients were on PS, 3 of them without macronutrients. The majority of patients received individualized parenteral nutrition (PN) (n = 32/46), while 13/46 were on commercial premixed bags. PS application was done by patients themselves (37%), home-care nurses (19%), relatives (8%) or by a combination of those (16%). In patients with PS dependency at baseline and available follow-up data (n = 40-44), teduglutide treatment resulted in significantly reduced PN days, caloric needs, infusion time, and infusion volume after 6 and 12 months. After 1 year, reduction of infusion time was positively correlated with a reduction of PN calories and volume; 30 patients (68%) were responders (PS-volume reduction ≥20%), and 6 patients (14%) were completely weaned off PS. Sleep disturbances per night were significantly reduced after 3 months of treatment and stool characteristics improved in consistency and significantly in frequency, while meal frequency remained stable.. Teduglutide treatment associated reduction in PS volume and calories was accompanied by reduced infusion days, infusion times, sleep disturbances, stable oral intake surrogates, and improved stool characteristics, all of these potential parameters for improving quality of life. Furthermore, analyzed care characteristics reflect SBS-cIF treatment as a complex, resource-intensive and demanding task for both, healthcare system and patients.

Topics: Adult; Chronic Disease; Gastrointestinal Agents; Glucagon-Like Peptides; Humans; Intestinal Diseases; Intestinal Failure; Peptides; Quality of Life; Retrospective Studies; Short Bowel Syndrome

Teduglutide, a glucagon-like peptide-2 analog, is a novel therapy for intestinal failure that reduces need for parenteral support, especially in patients without a functional terminal ileum or colon. It can also predispose patients to accelerated progression of gastrointestinal (GI) malignancy and fluid overload. We demographically and clinically characterized American patients prescribed teduglutide.. The Explorys database is an aggregate of deidentified patient data from dozens of US healthcare systems. We used SNOMED classification to identify patients prescribed teduglutide from 2015 to 2019. Through the browse cohort feature we determined the demographics, postsurgical anatomy, comorbidities, and indication for teduglutide use among these patients.. Of approximately 72 million patients, 170 were prescribed teduglutide. A large majority were female (70.6%). Most common etiologies of short-bowel syndrome were intestinal obstruction (52.9%) and Crohn's disease (41.2%). Common postsurgical anatomy included total colectomy (41.2%) and ileostomy. Common incident symptoms included abdominal pain (41.2%) and nausea (23.5%). Thirty (17.6%) patients were prescribed teduglutide despite comorbid heart failure, and 5.9% despite prior GI malignancy. A total of 11.8% of patients had a history of benign GI neoplasms before starting teduglutide. A total of 5.9% of patients had posttreatment formation of colon polyps.. In a large American database, the teduglutide prescription is rare. Only a minority have postsurgical anatomy associated with the most robust response to teduglutide. Serious adverse events appear rare, but a substantial number of patients are at risk for adverse effects because of the presence of comorbid heart failure or GI neoplasm.

Topics: Female; Gastrointestinal Agents; Humans; Male; Parenteral Nutrition; Peptides; Short Bowel Syndrome

The aim of this study was to quantify the long-term clinical outcomes for individuals receiving teduglutide for short-bowel syndrome (SBS).. A single-center, retrospective study was performed for individuals commencing use of teduglutide between March 2013 and May 2019.. Eighteen patients were included in the final analysis, among which the median duration of teduglutide administration was 3.2 (range, 0.6-6.2) years. Twelve of 16 (75%) patients at 12 months, 10 of 13 (76.9%) at 24 months, 7 of 10 (70%) at 36 months, and 3 of 3 (100%) at 60 months had a response to teduglutide therapy, defined as a >20% reduction in parenteral support (PS) requirement. Among responders at 12, 24, and 36 months, the presence of a colon-in-continuity, an ileocecal valve, a response at 3 months, the length of small bowel, nor the baseline volume affected response to therapy (P > .05 for all comparisons). Five (28%) patients were able to achieve freedom from PS, among which all had a history of Crohn's disease with loss of the ileocecal valve and among which 3 had a colon-in-continuity. Four of the 5 patients discontinued PS by 6 months of teduglutide therapy.. In a real-world experience, teduglutide therapy results in rapid and sustained reductions in PS. Larger postmarketing studies will be required to reliably predict response to treatment and the factors associated with enteral autonomy.

Topics: Gastrointestinal Agents; Humans; Peptides; Retrospective Studies; Short Bowel Syndrome

The glucagon-like peptide-2 (GLP-2) analogue teduglutide is a medical treatment option for patients with short-bowel syndrome-associated chronic intestinal failure. Because studies in mice have shown that GLP-2 analogues may promote the growth of colonic neoplasms, surveillance colonoscopies before and during teduglutide therapy were recommended. The occurrence of small-intestinal neoplasms has not been reported so far, except for a recent report about de novo development of hamartomatous duodenal polyps. We report a case of de novo development of small-intestinal premalignant adenomatous polyps in both bulbar duodenum and distal jejunum in a patient treated with teduglutide for 41 months. Therefore, additional endoscopic surveillance of the upper gastrointestinal tract may be advised during teduglutide therapy for early detection and removal of potential small-bowel adenomas.

Topics: Adenoma; Gastrointestinal Agents; Humans; Jejunum; Peptides; Short Bowel Syndrome

Topics: Adenomatous Polyposis Coli; Gastrointestinal Agents; Humans; Peptides; Short Bowel Syndrome

This analysis assessed combined safety data from 4 clinical studies of teduglutide in pediatric patients with short-bowel syndrome-associated intestinal failure (SBS-IF).. Safety 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.. Safety 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.. Based 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.

Topics: Child; Gastrointestinal Agents; Humans; Parenteral Nutrition; Peptides; Short Bowel Syndrome

The glucagon-like peptide-2 (GLP-2) analogue, teduglutide, allows to reduce the intravenous supplementation (IVS) dependency of patients with short bowel syndrome and intestinal failure (SBS-IF). The rate of candidacy of SBS-IF patients for the treatment is unknown. The candidacy for teduglutide treatment of our patient cohort was investigated by a systematic analysis.. The indications, contraindications, special warnings and precautions for use of teduglutide, listed in the drug monographs and in the phase-III trial protocol were adopted to categorize the patients as non-candidates (NC), potential candidates (PC) or straight candidates (SC) for the treatment. All the SBS-IF adult patients who were cured at our centre were assessed according to their clinical status on January 1st, 2020.. Seventy-nine patients were evaluated: 34.2% were NC due to risk of digestive malignancy, recent history of any other cancer, or listing for intestinal transplantation; 30.4% were PC, because of other premalignant conditions, risk of intestinal obstruction, entero-cutaneous fistulas, or severe co-morbidities; 35.4% were SC. The SC group showed the lowest requirement of IVS: the lowest number of days of infusion per week (p = 0.0054), the lowest amount of energy (p = 0.0110) and volume (p = 0.0136).. This systematic analysis allowed a pragmatic categorization of the candidacy of patients with SBS-IF for GLP-2 analogue treatment. The SC group appeared to have the highest probability of a successful response to the treatment. A systematic analysis of SBS-IF patient candidate for GLP-2 analogue therapy would allow a homogeneous patient selection and facilitate the worldwide comparison of the results of clinical practice and research.

Topics: Aged; Clinical Trials, Phase III as Topic; Cross-Sectional Studies; Female; Gastrointestinal Agents; Humans; Intestinal Failure; Italy; Male; Middle Aged; Patient Selection; Peptides; Prospective Studies; Short Bowel Syndrome

Teduglutide (TED) is a glucagon-like peptide 2 analogue approved in patients with short bowel syndrome with chronic intestinal failure. Bowel epithelial hyperplasia has been reported after TED treatment.. The aim of this study was to describe small bowel modifications at imaging in patients with SBS-CIF receiving TED and to assess their predictive value for clinical response.. Monocentric retrospective study including patients with SBS-CIF treated with TED from 2009 to 2018 with available computed tomography (CT) scans at baseline and during follow-up (≥12 mo). Small bowel (SB) wall thickness was measured as the average of 3 measurements on different SB segments. Clinical response to TED was defined as a ≥20% reduction of weekly parenteral support (PS) volume at 12 mo.. Thirty-one patients [20 male (65%), median age 51 y (IQR: 37-59)] were included. Baseline weekly PS volume was a median 7500 mL (IQR: 3500-15,000). After a median (IQR) follow-up of 16 mo (14-27), 26 of 31 patients (84%) had a clinical response. During follow-up, patients underwent 1 (n = 18/31, 58%), 2 (10/31, 32%), or 3 (3/31 10%) CT scans. Median SB wall thickness was 4.0 mm (IQR: 2.8-4.7) and 8.5 mm (IQR: 6.1-9.8) at baseline and after treatment, respectively [paired P < 0.001, median +122% increase (IQR: +65% to +172%)]. Patients with a clinical response had a trend toward a higher SB wall thickness increase [median +133% (IQR: +70% to +176%) compared with +90% (IQR: +52% to +93%), P = 0.061]. All patients with a ≥95% SB wall thickness increase (n = 18) had a clinical response, whereas only 8 of 13 (62%) patients with a <95% SB thickness increase did (P = 0.008).. Teduglutide induces a significant SB wall thickness increase that can be depicted by imaging <6 mo after treatment initiation, and the degree of such increase may be associated with clinical response. Bowel imaging in response to pharmacologic treatments may represent an important outcome to follow.

Topics: Adult; Chronic Disease; Female; Gastrointestinal Agents; Humans; Intestine, Small; Male; Middle Aged; Peptides; Retrospective Studies; Short Bowel Syndrome

Topics: Crohn Disease; Gastrointestinal Agents; Humans; Intestinal Mucosa; Peptides; Short Bowel Syndrome

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.. 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.. 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.. 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.

Topics: Adult; Female; Humans; Intestine, Small; Male; Parenteral Nutrition; Peptides; Short Bowel Syndrome

This study evaluated the safety and efficacy of teduglutide in pediatric patients with short bowel syndrome-associated intestinal failure (SBS-IF).. A 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.. All 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.. The 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.

Topics: Adult; Aged; Child; Child, Preschool; Double-Blind Method; Female; Gastrointestinal Agents; Humans; Male; Parenteral Nutrition; Peptides; Short Bowel Syndrome

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.. 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.. 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.. 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.

Topics: Adenomatous Polyps; Adult; Aged; Colonic Polyps; Colonoscopy; Female; Gastrointestinal Agents; Humans; Incidence; Male; Middle Aged; Peptides; Predictive Value of Tests; Prevalence; Risk Assessment; Risk Factors; Short Bowel Syndrome; Time Factors; Treatment Outcome

Adults with short bowel syndrome have a high mortality and significant morbidity due to unsuccessful attempts at rehabilitation that necessitate chronic use of parenteral nutrition (PN). Teduglutide is a novel therapy that promotes intestinal adaptation to improve rehabilitation but with a price >$400,000/y.. The current study evaluated the cost-effectiveness of using teduglutide in US adult patients with short bowel syndrome.. A Markov model evaluated the costs (in US dollars) and effectiveness (in quality-adjusted life years, or QALYs) of treatment compared with no teduglutide use, with a presumed starting age of 40 y. Parameters were obtained from published data or estimation. The primary effect modeled was the increased likelihood of reduced PN days per week when using teduglutide, leading to greater quality of life and lower PN costs. Sensitivity analyses were performed on all model parameters.. In the base scenario, teduglutide cost $949,910/QALY gained. In 1-way sensitivity analyses, only reducing teduglutide cost decreased the cost/QALY gained to below the typical threshold of $100,000/QALY gained. Specifically, teduglutide cost would need to be reduced by >65% for it to reach the threshold value. Probabilistic sensitivity analysis favored no teduglutide use in 80% of iterations at a $100,000/QALY threshold. However, teduglutide therapy was cost-saving in 13% of model iterations.. Teduglutide does not meet a traditional cost-effectiveness threshold as treatment for PN reduction in adult patients with short bowel syndrome compared with standard intestinal rehabilitation. Subpopulations that demonstrate maximum benefit could be cost-saving, and complete nonuse could lead to financial loss. Teduglutide becomes economically reasonable only if its cost is substantially reduced.

Topics: Adult; Cost-Benefit Analysis; Female; Gastrointestinal Agents; Humans; Male; Markov Chains; Peptides; Quality-Adjusted Life Years; Short Bowel Syndrome; Young Adult

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 ± 6 cm 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.

Topics: Chronic Disease; Cohort Studies; Female; France; Gastrointestinal Agents; Humans; Intestinal Diseases; Male; Middle Aged; Parenteral Nutrition; Peptides; Short Bowel Syndrome; Treatment Outcome

In short bowel syndrome, epithelial surface loss results in impaired nutrient absorption and may lead to intestinal insufficiency or intestinal failure. Nucleotide oligomerization domain 2 (Nod2) dysfunction predisposes to the development of intestinal failure after intestinal resection and is associated with intestinal barrier defects. Epithelial barrier function is crucial for intestinal absorption and for intestinal adaptation in the short bowel situation.. The aim of the study was to characterize the effects of the GLP-2 analogue Teduglutide in the small intestine in the presence and absence of Nod2 in a mouse model of short bowel syndrome.. Mice underwent 40% ICR and were thereafter treated with Teduglutide versus vehicle injections. Survival, body weight, stool water, and sodium content and plasma aldosterone concentrations were determined. Intestinal and kidney tissue was examined with light and fluorescence microscopy, Ussing chamber studies and quantitative PCR in wild type and transgenic mice.. Teduglutide reduced intestinal failure incidence in Nod2 k.o. mice. In wt mice, Teduglutide attenuated intestinal insufficiency as indicated by reduced body weight loss and lower plasma aldosterone concentrations, lower stool water content, and lower stool sodium losses. Teduglutide treatment was associated with enhanced epithelial paracellular pore function and enhanced claudin-10 expression in tight junctions in the villus tips, where it colocalized with sodium-glucose cotransporter 1 (SGLT-1), which mediates Na-coupled glucose transport.. In the SBS situation, Teduglutide not only maximizes small intestinal mucosal hypertrophy but also partially restores small intestinal epithelial function through an altered distribution of claudin-10, facilitating sodium recirculation for Na-coupled glucose transport and water absorption.

Topics: Animals; Disease Models, Animal; Gastrointestinal Agents; Glucagon-Like Peptide 2; Intestinal Absorption; Intestinal Mucosa; Mice; Mice, Inbred ICR; Nod2 Signaling Adaptor Protein; Peptides; Short Bowel Syndrome; Tight Junctions

Glucagon-like peptide-2 (GLP-2) agonists have therapeutic potential in clinical indications in which the integrity or absorptive function of the intestinal mucosa is compromised, such as in short bowel syndrome (SBS). Native hGLP-2, a 33-amino acid peptide secreted from the small intestine, contributes to nutritional absorption but has a very short half-life because of enzymatic cleavage and renal clearance and thus is of limited therapeutic value. The GLP-2 analog teduglutide (Revestive/Gattex; Shire Inc.) has been approved for use in SBS since 2012 but has a once-daily injection regimen. Pharmacokinetic (PK) and pharmacodynamic studies confirm that apraglutide, a novel GLP-2 analog, has very low clearance, long elimination half-life, and high plasma protein binding compared with GLP-2 analogs teduglutide and glepaglutide. Apraglutide and teduglutide retain potency and selectivity at the GLP-2 receptor comparable to native hGLP-2, whereas glepaglutide was less potent and less selective. In rat intravenous PK studies, hGLP-2, teduglutide, glepaglutide, and apraglutide had clearances of 25, 9.9, 2.8, and 0.27 ml/kg per minute, respectively, and elimination half-lives of 6.4, 19, 16, and 159 minutes, respectively. The unique PK profile of apraglutide administered via intravenous and subcutaneous routes was confirmed in monkey and minipig and translated into significantly greater in vivo pharmacodynamic activity, measured as small intestinal growth in rats. Apraglutide showed greater intestinotrophic activity than the other peptides when administered at less-frequent dosing intervals because of its prolonged half-life. We postulate that apraglutide offers several advantages over existing GLP-2 analogs and is an excellent candidate for the treatment of gastrointestinal diseases, such as SBS. SIGNIFICANCE STATEMENT: Apraglutide is a potent and selective GLP-2 agonist with an extremely low clearance and prolonged elimination half-life, which differentiates it from teduglutide (the only approved GLP-2 agonist). The enhanced pharmacokinetics of apraglutide will benefit patients by enabling a reduced dosing frequency and removing the need for daily injections.

Topics: Animals; Glucagon-Like Peptide 2; Glucagon-Like Peptide-2 Receptor; Half-Life; HEK293 Cells; Humans; Macaca fascicularis; Male; Peptides; Rats; Rats, Sprague-Dawley; Short Bowel Syndrome; Swine; Swine, Miniature

We report the case of a 62-y-old woman with short bowel syndrome (SBS) and chronic renal failure, successfully treated with teduglutide, who underwent comprehensive systematic nutritional assessment including bioelectrical impedance vectorial analysis (BIVA). The patient did not tolerate the attempt of gradual suspension of parenteral nutrition (PN), bumping into the worsening of nutritional status and renal function. She was declared eligible for teduglutide, a glucagonlike peptide 2 analog that stimulates structural and functional intestinal adaptation and increases nutrient and fluid absorption. To date, there is no standardized nutritional management protocol for PN-dependent SBS patients treated with teduglutide. We here report our first 1-y follow-up data. The patient underwent comprehensive systematic nutritional assessment initially every 2 wk, then monthly. It included handgrip strength (HGS), blood tests (particularly serum creatinine, estimated glomerular filtration rate, urea, electrolytes, micronutrients, serum albumin), fluid intake, urine output, quality-of-life (QoL) evaluation, and BIVA, which estimates fat-free mass (FFM) and measures phase angle (PhA) and hydration status. At treatment initiation, the patient was on PN 3 d/wk. After 3 mo, she was weaned off PN. At 1 y, weight and serum albumin were reduced (-7.5 kg and -0.6 g/dL, respectively); FFM, PhA, and HGS slightly decreased; hydration status and renal function were preserved; and QoL subtly improved. No relevant clinical complications or metabolic imbalances occurred. The inclusion of BIVA in the comprehensive systematic nutritional assessment of SBS patients treated with teduglutide could be proposed for appropriate and safe management, particularly in the presence of renal impairment.

Topics: Female; Gastrointestinal Agents; Hand Strength; Humans; Kidney Failure, Chronic; Nutrition Assessment; Peptides; Quality of Life; Short Bowel Syndrome

Historically, adults with ultra short bowel syndrome (USBS) have been considered candidates for lifetime parenteral nutrition (PN) or are referred for visceral transplantation. We examined the surgical and nutritional outcomes of adult patients with USBS managed at a single intestinal rehabilitation center.. We retrospectively reviewed data on 588 adult patients referred to our center between January 2013 and December 2018. USBS was defined as residual small bowel (SB) length ≤ 50 cm.. Forty-five patients (7.6%) with a mean age of 46.7 years (range 17-78) were identified. Indications for enterectomy included mesenteric ischemia (n=17) and internal hernias (n=6), followed by large intraabdominal fibroids, trauma, and allograft enterectomies, with five cases each. Median SB length was 18.0 cm; 20 patients (44.4%) had their entire SB resected. Thirteen patients had an intact colon, of which nine had preservation of the ileocecal valve. Patients who underwent autologous reconstruction of their gastrointestinal (GI) tract required a lower total PN volume (29.0 ± 7.6 vs. 40.8 ± 13.2 ml/Kg/day, p=0.002) and presented better short- and long- term survival (p=0.005). Patients with no gut had higher mortality (p=0.036). Hormonal therapy with the glucagon-like peptide-2 analog teduglutide was used in nine patients (20%) five of whom were weaned off TPN. Excluding patients with no gut (n=20), discontinuation of total PN rate for patients with an end ostomy or tube decompression (n= 6), jejunocolostomy (n= 10), and jejunoileostomy (n=9) were 0%, 40%, and 77.7%, respectively. Eleven patients (44%) with some residual small intestine achieved nutritional autonomy in an average of 20 months after GI reconstruction. Fifteen patients were listed for transplantation (33.3%). Seven patients underwent isolated SB transplantation and achieved nutritional autonomy in an average of three months after transplantation. One-year patient and graft survival were 100%. After a 37-month median follow-up period, 36 of 42 patients followed by our center were still alive (85.7%).. Nutritional autonomy can be achieved in a significant number of patients with USBS in specialized centers with surgical and/or hormonal therapy. The presence of an intact colon and ileocecal valve can significantly increase the adaptation rate. Moreover, restoration of GI tract continuity has a positive impact on medical management and survival.

Topics: Adolescent; Adult; Aged; Algorithms; Digestive System Surgical Procedures; Female; Gastrointestinal Agents; Humans; Intestine, Small; Male; Middle Aged; Nutritional Status; Parenteral Nutrition, Total; Peptides; Retrospective Studies; Short Bowel Syndrome; Transplant Recipients; Young Adult

Teduglutide (TED) reduces the need for parenteral support (PS) in patients with short-bowel syndrome with intestinal failure (SBS-IF). It is a glucagon-like peptide-2 analog that improves absorption, induces the expansion of the absorptive epithelium in the small intestine, and may be used in patients with SBS-IF after a 6- to 12-month adaptation period, if PS is always necessary. We described the functional and morphological effect of TED in a 40-year-old female patient with SBS-IF due to Crohn's disease who underwent terminal jejunostomy after 12 months of drug exposition. Marked hypertrophy of the villi was detected by endoscopic capsule and confirmed by histological measurements. This is the first publication demonstrating an increase in intestinal absorption in an SBS-IF patient treated with TED because of a morphological adaptation of the small bowel, with hyperplasia confirmed by capsule endoscopy and histology. The capsule endoscopy, a noninvasive exploration of the gut, could be evaluated to monitor the real efficacy of treatments with growth factors in SBS patients.

Topics: Adult; Female; Gastrointestinal Agents; Glucagon-Like Peptide 2; Humans; Intestine, Small; Peptides; Short Bowel Syndrome

Topics: Anti-Inflammatory Agents; Crohn Disease; Female; Glucagon-Like Peptide 2; Humans; Middle Aged; Peptides; Short Bowel Syndrome; Treatment Outcome

Topics: Animals; Glucagon-Like Peptide 2; Humans; Mice; Peptides; Short Bowel Syndrome; Sodium; Tight Junctions

Intestinal failure (IF) is defined as a reduction in intestinal function below the minimum necessary for the absorption of nutrients, requiring intravenous supplementation to maintain health and/or growth. The most common cause is short bowel syndrome (SBS). Approximately 50% of patients with SBS have IF and require parenteral support. Teduglutide is a human glucagon-like peptide-2 analogue (GLP-2) approved for the treatment of patients with SBS. Clinical trial results have proven its efficacy by reducing volume and days of administration of parenteral nutrition and fluid therapy. Few publications evaluate the effects on long-term bowel function in respondent patients after teduglutide suspension. A patient with type I SBS (terminal jejunostomy) due to multiple surgeries for Crohn's disease, who was treated with liraglutide for one year and sequential teduglutide for 21 months, is described. With the former, a reduction in the need for contribution and debit by jejunostomy was observed. The GLP-2 analogue achieved a greater reduction in the hydric disbalance that allowed the suspension of the nocturnal suerotherapy, with weight gain and maintenance of nutritional parameters; situation maintained two years after its suspension.. El fallo intestinal se define como una reducción de la función intestinal por debajo del mínimo necesario para la absorción de nutrientes y que precisa suplementación intravenosa para mantener la salud y/o el crecimiento. La causa más frecuente es el síndrome de intestino corto. Aproximadamente el 50% de pacientes con SIC presenta FI y requiere soporte parenteral. Teduglutida es un análogo del péptido-2 similar al glucagón (GLP-2) humano aprobado para el tratamiento de pacientes con SIC. Los resultados de ensayos clínicos han probado su eficacia: se reducen el volumen y los días de administración de nutrición parenteral y fluidoterapia. Pocas publicaciones evalúan los efectos sobre la función intestinal a largo plazo en pacientes respondedores tras la suspensión de teduglutida. Se describe un paciente con SIC tipo I (yeyunostomía terminal) debido a múltiples intervenciones quirúrgicas por enfermedad de Crohn, que recibió tratamiento con liraglutida un año y teduglutida secuencial durante 21 meses. Con el primero, se objetivó una reducción en la necesidad de aporte y débito por yeyunostomía. El análogo del GLP-2 consiguió una mayor reducción del desequilibrio hídrico que permitió suspender sueroterapia nocturna, con ganancia ponderal y mantenimiento de parámetros nutricionales, situación mantenida dos años después de su suspensión.

Topics: Crohn Disease; Fluid Therapy; Gastrointestinal Agents; Humans; Intestinal Diseases; Jejunostomy; Liraglutide; Male; Middle Aged; Parenteral Nutrition; Peptides; Product Recalls and Withdrawals; Short Bowel Syndrome

The aim of the study was to describe the experience with teduglutide of several Spanish hospitals in pediatric patients with SBS (SBS).. Seventeen pediatric patients with intestinal failure associated with SBS were treated with teduglutide. Patients received 0.05 mg · kg · day of subcutaneous teduglutide. Patients' demographics and changes in parenteral nutrition (PN) needs, fecal losses, and citrulline level initially and at 3, 6, and 12 months were collected, as well as any adverse events.. Patients were receiving 55 ml · kg · day and 33 kcal · kg · day of parenteral supplementation on average at baseline (2 patients received only hydroelectrolytic solution). A total of 12/17 patients achieved parenteral independence: 3 patients after 3 months of treatment, 4 patients at 6 months, and 5 after 12 months. One patient discontinued treatment 1 year after the beginning as no changes in parenteral support or fecal losses were obtained. All others decreased their intravenous requirements by 50%. One patient suffered an episode of cholecystitis, and another one with a pre-existing cardiac disease, developed a cardiac decompensation.. Teduglutide seems to be a safe and effective treatment in the pediatric SBS population with better results than in the pivotal study as well as in the adult population.

Topics: Adult; Child; Gastrointestinal Agents; Humans; Parenteral Nutrition; Peptides; Short Bowel Syndrome

Topics: Child; Glucagon-Like Peptide 2; Humans; Intestines; Peptides; Short Bowel Syndrome

Teduglutide, a glucagon-like peptide 2 (GLP-2) analog, is an approved medication specific for short bowel syndrome patients with chronic intestinal failure (SBS-IF). Due to its intestinotrophic properties, it improves intestinal absorption of fluids and nutrients, which was shown to reduce the need for parenteral support in clinical trials. The present report aims to describe the experience of teduglutide's effects in routine medical care with focus on clinical and nutritional effects.. Data of adult SBS-IF patients, treated with teduglutide between Sept. 2014 and May 2017 within a structured multidisciplinary program to enhance intestinal rehabilitation, were analyzed retrospectively from a single university medical center.. In total, 27 patients were treated with teduglutide. Parenteral nutrition independency was achieved in 4/19 (21%) patients analyzed, with two remaining on intravenous fluids. A clinically significant reduction of parenteral volume was observed in 15/19 patients (79%) with onset between 1 and 45 weeks. Significant parenteral support reductions were observed, ranging from about -20% in patients treated for 3 months to about -45% in patients treated for 2 years. This was accompanied by an increase in parenteral nutrition-free days. We also report on a clinically relevant and significant effect of teduglutide-mediated improvement of stool frequency and consistency. Furthermore, nutritional status subgroup analysis revealed long-term stability in body weight, albumin levels and body composition albeit parenteral support reduction. Structural effects of teduglutide treatment were observed on small intestinal mucosa with significantly increased villus height, crypt depth and plasma citrulline levels.. Teduglutide can be applied to anatomically and clinically heterogeneous SBS-IF patients and results in an adaptive response with variable time and effect range in routine medical care. Teduglutide-induced functional and structural changes bring on a gradual reduction of parenteral support at no cost to body composition and suggest an improved intestinal function with compensatory effect on nutritional status.

Topics: Adult; Aged; Aged, 80 and over; Chronic Disease; Female; Gastrointestinal Agents; Glucagon-Like Peptide 2; Humans; Intestines; Male; Middle Aged; Nutritional Status; Parenteral Nutrition; Peptides; Retrospective Studies; Short Bowel Syndrome; Young Adult

Topics: Adult; Biological Therapy; Crohn Disease; Drug Combinations; Gastrointestinal Agents; Humans; Male; Peptides; Prognosis; Short Bowel Syndrome

It is not known whether Teduglutide can allow patients with Short bowel syndrome, previously dependent on continuous or periodic intravenous (IV) magnesium, to attain oral autonomy with or without supplementation. Here, we report on two patients previously dependent on continuous or intermittently administered IV magnesium to achieve autonomy from IV, one with and one without oral supplementation that was previously ineffective in both patients.

Topics: Aged; Dietary Supplements; Female; Gastrointestinal Agents; Humans; Intestinal Absorption; Magnesium; Magnesium Deficiency; Middle Aged; Nutritional Status; Peptides; Short Bowel Syndrome; Treatment Outcome

Teduglutide (TG) is approved for the treatment of parenteral nutrition (PN)-dependent adult patients with short bowel syndrome (SBS). Its well-known adverse effect is expedited growth of colon polyps and potential formation of new polyps. Apart from animal studies, de novo development of duodenal polyps in a patient during TG therapy has not been reported in the literature. We report a case of a 71-year-old man with SBS on TG who developed multiple new duodenal polyps that were found incidentally during a diagnostic endoscopy. Furthermore, an accelerated growth of duodenal polyps was noted while on TG therapy, suggesting a potential trophic effect of TG on these polyps. There are no current recommendations for the surveillance of intestinal polyps in patients on TG therapy, but we recommend exercising caution and possible need for surveillance based on this case report.

Topics: Aged; Duodenal Diseases; Duodenoscopy; Duodenum; Gastrointestinal Agents; Humans; Intestinal Polyps; Male; Parenteral Nutrition; Peptides; Short Bowel Syndrome

Teduglutide is a glucagon-like peptide 2 (GLP-2) analog that has been approved for the treatment of adult short bowel syndrome (SBS)-associated intestinal failure (IF; SBS-IF). Teduglutide increases villus height and crypt depth in the small bowel mucosa, promoting nutrition absorption and enteral independence from parenteral nutrition (PN). We aim to report our single-center experience with teduglutide in adult patients with SBS to provide real-world context to its use.. We conducted a retrospective analysis on patients managed within our tertiary-level intestinal rehabilitation program to identify patients with SBS-IF treated with teduglutide from 2009-2015. The current report includes all patients at our center who had any exposure to teduglutide, including those who received commercial drug after approval by the Food and Drug Administration (FDA) and outside the scope of clinical trials.. A total of 18 patients were treated with teduglutide. Eleven patients (61%) achieved complete enteral independence from PN and/or intravenous fluids (IV) at a median time of 10 months (range: 3-36 months). PN/IV volume requirement was reduced in all patients except two. Ten of the 11 patients (91%) who achieved enteral autonomy had colon. All patients off PN/IV required additional oral vitamins and electrolyte supplementations.. Our preliminary experience is consistent with prior reports of successful partial or complete weaning from PN/IV with teduglutide treatment in adult patients with SBS. The presence of colon appears to be favorable in obtaining enteral independence from PN/IV, regardless of residual small bowel length. Patients on teduglutide may remain at high risk of micronutrient deficiencies.

Topics: Adult; Aged; Aged, 80 and over; Female; Gastrointestinal Agents; Humans; Male; Middle Aged; Peptides; Retrospective Studies; Short Bowel Syndrome; Young Adult

Teduglutide is an enterotrophic analogue of glucagon-like peptide-2, with an indirect and poorly understood mechanism of action, approved for the rehabilitation of short-bowel syndrome. This study aims to analyze the response of tissue growth factors to surgical injury and teduglutide administration on an animal model of intestinal anastomosis.. Wistar rats (n = 59) were distributed into four groups: "ileal resection" or "laparotomy", each one subdivided into "postoperative teduglutide administration" or "no treatment"; and sacrificed at the third or the seventh day, with ileal sample harvesting. Gene expression of insulin-like growth factor 1 (Igf1), vascular endothelial growth factor a (Vegfa), transforming growth factor β1 (Tgfβ1), connective tissue growth factor (Ctgf), fibroblast growth factor 2 (Fgf2), fibroblast growth factor 7 (Fgf7), epidermal growth factor (Egf), heparin-binding epidermal-like growth factor (Hbegf), platelet-derived growth factor b (Pdgfb) and glucagon-like peptide 2 receptor (Glp2r)was studied by real-time polymerase chain reaction.. Upregulation of Fgf7, Fgf2, Egf, Vegfaand Glp2rat the third day and of Pdgfat the seventh day was verified in the perianastomotic segment. Teduglutide administration was associated with higher fold-change of relative gene expression of Vegfa(3.6 ± 1.3 vs.1.9 ± 2.0, p = 0.0001), Hbegf(2.2 ± 2.3 vs. 1.1 ± 0.9, p = 0.001), Igf1(1.6 ± 7.6 vs. 0.9 ± 0.7, p = 0.002) and Ctgf(1.1 ± 2.1 vs. 0.6 ± 2.0, p = 0.013); and lower fold-change of Tgfβ1, Fgf7and Glp2r.. Those results underscore the recognized role of Igf1and Hbegfas molecular mediators of the effects of teduglutide and suggest that other humoral factors, like Vegfand Ctgf, may also be relevant in the perioperative context. Induction of Vegfa, Igf1and Ctgfgene expressions might indicate a favorable influence of teduglutide on the intestinal anastomotic healing.

Topics: Anastomosis, Surgical; Animals; Gastrointestinal Agents; Gene Expression Regulation; Ileum; Intercellular Signaling Peptides and Proteins; Intestines; Male; Peptides; Rats; Rats, Wistar; Short Bowel Syndrome

To review all cases of parenteral support (PS)-dependent patients with short bowel syndrome (SBS) treated with teduglutide (Gattex, Shire) and to evaluate its efficacy and adverse effects.. This is a retrospective descriptive cohort of SBS patients treated with teduglutide. Demographics, bowel length, primary diagnosis, PS volume/duration, teduglutide dose, and side effects were collected prospectively.. Six SBS patients (4 females, 2 males) received teduglutide. Mean age was 46.3 years (range 26-71). SBS etiology was vascular (n = 3), multiple resections (n = 2), and strangulation (n = 1). Length of residual small bowel was between 30-120 cm. The bowel anatomy was colon present (n = 3) and stoma n = 3 (ileostomy, 2; colostomy, 1). PS duration was 1.5-14 years. Weekly PS volume was mean 7.7 liters/week (1-14). Number of PS days per week ranged 1-7 days. Mean duration of teduglutide therapy was 31 months (24-36). All patients achieved ≥20% reduction in PS weekly volume within 6 months. PS was weaned in all patients. Adverse effects included abdominal bloat/discomfort (n = 3), stoma enlargement (n = 3), bowel obstruction (n = 1), and congestive heart failure (n = 1).. All PS-dependent SBS patients treated with teduglutide were weaned off PS. Patients with colon in continuity and lower PS weekly volume requirements were weaned off PS sooner than those with end-stomas and higher PS volume requirements. Teduglutide was well tolerated. Additional clinical studies of teduglutide in SBS patients with marginal PS requirements are needed.

Topics: Adult; Aged; Female; Gastrointestinal Agents; Humans; Intestine, Small; Male; Middle Aged; Parenteral Nutrition; Parenteral Nutrition, Total; Peptides; Retrospective Studies; Short Bowel Syndrome; Time Factors; Treatment Outcome

Topics: Adult; Crohn Disease; Drug Administration Schedule; Female; Gastrointestinal Agents; Humans; Peptides; Short Bowel Syndrome; Time Factors; Treatment Outcome

Teduglutide is an active, glucagon-like peptide (GLP)-2 analog with proven clinical efficacy regarding intestinal adaptation in patients with short bowel syndrome (SBS). There are two factors that preclude its reimbursement, and thereby, its availability: its cost (reaching ∼$300,000/y)-which significantly exceeds the cost of home parenteral nutrition (HPN) in most countries-and the lack of clear guidelines. The aim of this study was to create evidence-based working criteria for the use of teduglutide that could be used in clinical settings.. Experts from the Polish Network of Intestinal Failure Centers analyzed available research and considered experience on the topic of HPN and intestinal failure to create guidelines.. Experts agreed that there are two groups of HPN patients who can benefit from therapy with a GLP-2 analog: those with a good prognosis (in whom complete weaning from HPN may be possible) and those with a poor prognosis (the therapy would be lifesaving). Patient criteria comprise the following: inclusion and exclusion criteria, parameters that can be used for monitoring, outcome measures, and the rationale for the termination of the treatment.. It was possible to describe inclusion criteria for both patient groups that justify the use of teduglutide from medical and economic perspectives.

Topics: Gastrointestinal Agents; Humans; Peptides; Poland; Short Bowel Syndrome; Treatment Outcome

Topics: Digestive System Surgical Procedures; Enteral Nutrition; Female; Humans; Intestinal Atresia; Parenteral Nutrition; Peptides; Pneumatosis Cystoides Intestinalis; Postoperative Complications; Short Bowel Syndrome; Young Adult

Teduglutide, a glucagon-like peptide-2 (GLP-2) analogue, is available for long-term use by parenteral nutrition (PN)-dependent adults to promote intestinal adaptation but is not approved for use in pediatric patients. The objective of this study was to assess teduglutide-stimulated induced intestinal adaptation, potential synergies with partial enteral nutrition (PEN), and distinct temporal markers of adaptation in a neonatal piglet model of short bowel syndrome (SBS).. Neonatal piglets (48 hours old; n = 72) underwent an 80% jejunoileal resection and were randomized to 1 of 4 treatment groups, in a 2 × 2 factorial design, with PN or PEN (80% standard PN/20% standard enteral nutrition) and teduglutide (0.1 mg/kg/d) or control. Piglets received nutrient infusions for 4 hours, 48 hours, or 7 days.. Teduglutide improved ( P < .05) mucosal surface area (villus height: duodenum, jejunum, ileum; crypt depth: ileum, colon; proliferation: duodenum, jejunum, ileum; colon; apoptosis: jejunum, ileum, colon) and acute nutrient processing capacity (glucose: duodenum, jejunum, ileum; glutamine: duodenum, jejunum). These effects were complemented and synergistically enhanced by PEN in both site and timing of action. Structural adaptations preceded functional adaptations, but crypt depth remained a strong indicator of adaptation, regardless of time.. The combination of teduglutide and PEN enhances intestinal adaptation beyond that of either therapy alone.

Topics: Adaptation, Physiological; Animals; Animals, Newborn; Apoptosis; Cell Differentiation; Cell Proliferation; Disease Models, Animal; Enteral Nutrition; Epithelial Cells; Gastrointestinal Agents; Ileum; Intestine, Small; Parenteral Nutrition; Peptides; Short Bowel Syndrome; Swine

Teduglutide is a GLP-2 analogue indicated for treatment of adults with short bowel syndrome (SBS). Because of the rarity of SBS, real-world safety or efficacy data are not available in patients with Crohn's disease (CD) and SBS treated with teduglutide.. To evaluate teduglutide's safety and efficacy in CD patients with SBS.. We conducted a retrospective cohort study at 3 tertiary centers in the United States between 2012 and 2014. Demographic, clinical, and therapeutic data were retrieved from medical record systems.. Thirteen CD patients were included, 8 (62%) of whom were on concomitant immunosuppression. Median duration of teduglutide therapy was 365 days [interquartile range (IQR), 122 to 482 d] and 9/13 patients (69%) remain on therapy. At teduglutide initiation, 69% were on parenteral nutrition. At conclusion of follow-up, 1 patient was on parenteral nutrition. All patients were on intravenous fluids (IVF) before teduglutide; median IVF were 9000 mL/wk (IQR, 7000 to 14,000 mL/wk). IVF requirements decreased by a median of 3100 mL/wk (IQR, 2400 to 8400 mL/wk). Six patients (46%) ceased IVF. Adverse events attributed to teduglutide were obstructive symptoms (n=1), pancreatitis (n=1), asymptomatic lipase and amylase elevation (n=1), nausea (n=1), and abdominal pain (n=1). Catheter-related sepsis occurred in 4 patients.. This is the first report evaluating the safety and efficacy of teduglutide in a cohort of CD patients with SBS requiring parenteral support. More of half the cohort was on concomitant immunosuppression. Teduglutide seemed to be safe and the majority of patients were weaned off parenteral support.

Topics: Adult; Aged; Cohort Studies; Crohn Disease; Female; Follow-Up Studies; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Male; Middle Aged; Parenteral Nutrition; Peptides; Retrospective Studies; Short Bowel Syndrome; Tertiary Care Centers

Topics: Adult; Crohn Disease; Female; Gastrointestinal Agents; Humans; Peptides; Short Bowel Syndrome

The evolution of managing short gut syndrome optimizes management and decision making of intestinal failure by way of a multidisciplinary team utilizing the latest advances in therapeutic options. Only the minority of patients referred for small bowel transplantation will actually need a transplant. Many of these patients can be rehabilitated without the need for transplant, by way of early referral, and thus the likelihood of medical therapy increases. On the other hand, in those patients with little likelihood of success with medical therapy, early referral decreases the morbidity and mortality associated with long-term total parenteral nutrition and associated complications and will improve their overall survival outcomes.

Topics: Digestive System Surgical Procedures; Human Growth Hormone; Humans; Immunosuppressive Agents; Intestines; Parenteral Nutrition, Total; Peptides; Short Bowel Syndrome

Clinical trials of the glucagon-like peptide 2 analogue teduglutide resulted in approval of the drug by the Food and Drug Administration in 2012 as a treatment for parenteral nutrition-dependent short bowel syndrome in adults. This report presents the case study of a man with short bowel syndrome caused by portal vein thrombosis who had 4 years exposure to the drug at the time of his death due to cardiovascular disease.

Topics: Cardiovascular Diseases; Fatal Outcome; Gastrointestinal Agents; Heart Failure; Humans; Male; Middle Aged; Parenteral Nutrition; Peptides; Portal Vein; Randomized Controlled Trials as Topic; Short Bowel Syndrome; Thrombosis

Patients with intestinal failure, who are dependent on parenteral nutrition (PN) to supplement their limited absorption of dietary nutrients, are subject to complications associated with long-term PN therapy. Medication therapy that results in improved dietary nutrient absorption may enable these patients to reduce or even become independent from PN therapy and its related complications. The glucagon-like peptide 2 (GLP-2) analogue teduglutide was approved for use in such patients by the U.S. Food and Drug Administration in 2012.. The purpose of this article is to describe the experience of 7 patients with PN-dependent intestinal failure who were treated with teduglutide by a single center that had been involved in the teduglutide clinical trials.. Two patients who were treated during the clinical trials and 5 others who were treated since teduglutide came to market in the United States are described. Protocols used to prepare and monitor patients with this drug and PN weaning and adverse event outcomes are presented.. While some patients had uncomplicated PN reduction, others experienced various complications. Careful monitoring of patients' clinical course is needed during drug therapy.

Topics: Adult; Aged; Clinical Trials as Topic; Disease Management; Dose-Response Relationship, Drug; Female; Gastrointestinal Agents; Humans; Intestines; Male; Middle Aged; Parenteral Nutrition; Peptides; Short Bowel Syndrome

Topics: Humans; Intestines; Peptides; Permeability; Short Bowel Syndrome

Topics: Glucagon-Like Peptide 2; Humans; Intestines; Peptides; Permeability; Short Bowel Syndrome

Topics: Gastroenterology; Germany; Humans; Peptides; Practice Guidelines as Topic; Risk Assessment; Short Bowel Syndrome

Neonatal short bowel syndrome following massive gut resection is associated with malabsorption of nutrients. The intestinotrophic factor glucagon-like peptide 2 (GLP-2) improves gut function in adult patients with short bowel syndrome, but its effect in pediatric patients remains unknown. Our objective was to test the efficacy of the long-acting synthetic human GLP-2 analogue, teduglutide (ALX-0600), in a neonatal piglet jejunostomy model. Two-day-old pigs were subjected to resection of 50% of the small intestine (distal part), and the remnant intestine was exteriorized on the abdominal wall as a jejunostomy. All pigs were given total parenteral nutrition for 7 days and a single daily injection of the following doses of teduglutide: 0.01 (n = 6), 0.02 (n = 6), 0.1 (n = 5), or 0.2 mg · kg · day (n = 6), and compared with placebo (n = 9). Body weight increment was similar for all 4 teduglutide groups but higher than placebo (P < 0.05). There was a dose-dependent increase in weight per length of the remnant intestine (P < 0.01) and fractional protein synthesis rate in the intestine was increased in the 0.2 mg · kg · day group versus placebo (P < 0.001); however, functional and structural endpoints including activity of digestive enzymes, absorption of enteral nutrients, and immunohistochemistry (Ki67, villin, FABP2, ChgA, and GLP-2R) were not affected by the treatment. Teduglutide induces trophicity on the remnant intestine but has limited acute effects on functional endpoints. Significant effects of teduglutide on gut function may require a longer adaptation period and/or a more frequent administration of the peptide. In perspective, GLP-2 or its analogues may be relevant to improve intestinal adaptation in pediatric patients with short bowel syndrome.

Topics: Adaptation, Physiological; Animals; Body Weight; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Gastrointestinal Agents; Glucagon-Like Peptide 2; Glucagon-Like Peptide-2 Receptor; Growth; Intestine, Small; Jejunostomy; Organ Size; Parenteral Nutrition, Total; Peptides; Protein Biosynthesis; Receptors, Glucagon; Short Bowel Syndrome; Swine

Teduglutide is a recombinant analogue of human glucagonlike peptide-2 (GLP-2) that was recently approved by the US and European regulatory agencies FDA and EMA for the treatment of short bowel syndrome (SBS). The objectives of this work were, firstly, to develop a population pharmacokinetic (popPK) model based on the available PK data of the entire clinical development program and, secondly, to utilize the model for the justification of the proposed dosing regimen. The exploratory analysis was based on a previously established structural PK model and focused primarily on the investigation of covariate effects.. The plasma concentrationtime profiles of teduglutide after subcutaneous application were adequately described by a 1-compartment model with first order absorption and elimination. The area under the curve (AUC) was lower for male subjects, for subjects with higher creatinine clearance, for overweight subjects, and for SBS patients. However, except for subjects with severe renal impairment no clinically relevant effects on AUC were identified.. Our model-based analysis supports the approved dose adjustment for SBS patients with and without renal impairments maintaining the exposure in a value range with acceptable variance for the target population.

Topics: Adolescent; Adult; Aged; Drug Approval; Drug Interactions; Female; Humans; Male; Meta-Analysis as Topic; Middle Aged; Models, Biological; Peptides; Renal Insufficiency; Short Bowel Syndrome

Topics: Glucagon-Like Peptide 2; Humans; Intestinal Absorption; Parenteral Nutrition; Peptides; Quality of Life; Short Bowel Syndrome

Topics: Abdominal Pain; Glucagon-Like Peptide 2; Humans; Injections; Peptides; Randomized Controlled Trials as Topic; Short Bowel Syndrome

Topics: Female; Gastrointestinal Agents; Humans; Male; Parenteral Nutrition; Peptides; Short Bowel Syndrome

Short bowel syndrome (SBS) is an increasingly common condition encountered across neonatal intensive care units. Improvements in parenteral nutrition (PN), neonatal intensive care and surgical techniques, in addition to an improved understanding of SBS pathophysiology, have contributed in equal parts to the survival of this fragile subset of infants. Prevention of intestinal failure associated liver disease (IFALD) and promotion of intestinal adaptation are primary goals of all involved in the care of these patients. While enteral nutritional and pharmacological strategies are necessary to achieve these goals, there remains great variability in the application of therapeutic strategies in units that are not necessarily evidence-based.. A search of major English language medical databases (SCOPUS, Index Medicus, Medline, and the Cochrane database) was conducted for the key words short bowel syndrome, medical management, nutritional management and intestinal adaptation. All pharmacological and nutritional agents encountered in the literature search were classified based on their effects on absorptive capacity, intestinal adaptation and bowel motility that are the three major strategies employed in the management of SBS. The Oxford Center for Evidence-Based Medicine (CEBM) classification for levels of evidence was used to develop grades of clinical recommendation for each variable studied.. We reviewed various medications used and nutritional strategies included soluble fiber, enteral fat, glutamine, probiotics and sodium supplementation. Most interventions have scientific rationale but little evidence to support their role in the management of infant SBS. While some of these agents symptomatically improve diarrhea, they can adversely influence pancreatico-biliary function or actually impair intestinal adaptation. Surgical anatomy and liver function are two important variables that should determine the selection of pharmacological and nutritional interventions.. There is a paucity of research investigating optimal clinical practice in infant SBS and the little evidence available is consistently of lower quality, resulting in a wide variation of clinical practices among NICUs. Prospective trials should be encouraged to bridge the evidence gap between research and clinical practice to promote further progress in the field.

Topics: Atrophy; Case-Control Studies; Cohort Studies; Combined Modality Therapy; Critical Care; Diarrhea, Infantile; Dietary Fats; Dietary Fiber; Enteral Nutrition; Evidence-Based Medicine; Exocrine Pancreatic Insufficiency; Food, Formulated; Gastrointestinal Agents; Gastrointestinal Hormones; Gastrointestinal Motility; Glutamine; Humans; Infant; Infant Food; Infant, Newborn; Intensive Care Units, Neonatal; Liver Diseases; Pancreas, Exocrine; Pancreatic Extracts; Parenteral Nutrition; Peptides; Probiotics; Randomized Controlled Trials as Topic; Short Bowel Syndrome

Topics: Adaptation, Physiological; Adult; Combined Modality Therapy; Dose-Response Relationship, Drug; Fluid Therapy; Germany; Glucagon-Like Peptide 2; Humans; Injections, Subcutaneous; Intestinal Mucosa; Multicenter Studies as Topic; Parenteral Nutrition; Peptides; Randomized Controlled Trials as Topic; Short Bowel Syndrome

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.

Topics: Adaptation, Physiological; Digestive System Surgical Procedures; Gastrointestinal Agents; Humans; Intestinal Absorption; Intestinal Diseases; Intestinal Mucosa; Malnutrition; Nutritional Support; Peptides; Postoperative Complications; Short Bowel Syndrome

Topics: Female; Humans; Intestinal Absorption; Intestinal Diseases; Intestines; Male; Parenteral Nutrition; Peptides; Short Bowel Syndrome

Teduglutide was discontinued after being tested for ≥ 24 weeks in patients with parenteral nutrition (PN) -dependent short bowel syndrome in a clinical trial for efficacy to reduce PN volume. This study was describes change in body mass index (BMI) and PN volume over 12 months in patients who stopped drug after the clinical trial.. Prescribed PN volume, weight, and complications were reported. Patients with stable (NEUT, n = 15) or decreased (DEC, n = 7) PN volume by 12 months after stopping drug (NEUT/DEC, n = 22) were compared to those who had increased PN volume (INC, n = 15). With drug response defined by ≥ 20% reduction from pre-drug PN volume to end of drug therapy, 12 INC and 13 NEUT/DEC patients were drug responders.. Eleven of 20 eligible sites reported data for 39 of 53 eligible study participants, with follow-up data for 37. INC patients had shorter colon and less frequently had colon in continuity than NEUT/DEC. BMI was decreased at 3, 6, and 12 months relative to the first off-drug visit in INC patients (P = .001), but not in NEUT/DEC patients. Change in BMI off-drug was predicted by colon and small bowel length, baseline BMI, and on-drug change in PN volume (adjusted R2 = 0.708).. Gastrointestinal anatomy, baseline BMI, and PN volume reduction on-drug predicted change in BMI off-drug. Whether this response would be maintained for a longer time or in the context of a challenging clinical situation has not been evaluated.

Topics: Adult; Aged; Body Mass Index; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Intestine, Small; Linear Models; Male; Middle Aged; Parenteral Nutrition; Peptides; Randomized Controlled Trials as Topic; Short Bowel Syndrome; Treatment Outcome; Weight Loss; Young Adult

Extensive resection of the intestine impairs its absorptive capacity and results in short bowel syndrome when the nutritional equilibrium is compromised. The remnant intestine adapts structurally to compensate, but nutritional autonomy cannot be achieved in patients with intestinal failure, requiring intravenous fluids and parenteral nutrition (PN) for sustenance of life. PN is expensive and associated with serious complications. Efforts to minimize or eliminate the need for PN heralded research focusing on the therapeutic utility of intrinsic gut factors involved in the postresection adaptation process. With the breakthrough recognition of the intestinotrophic properties of glucagon-like peptide-2, teduglutide, a recombinant analogue of glucagon-like peptide-2, is being investigated as a promising hope to mitigate the requirement of PN. Clinical studies to date have demonstrated a desirable benefit-to-risk profile in regards to its safety and efficacy. If approved for marketing, it will be the first of its class in short bowel syndrome management, offering an innovative therapeutic modality for this debilitating condition.

Topics: Amino Acid Sequence; Glucagon-Like Peptide 2; Humans; Molecular Sequence Data; Parenteral Nutrition; Peptides; Short Bowel Syndrome; Treatment Outcome

Glucagon-like peptide-2 (GLP-2) is a potent intestinotrophic growth factor with therapeutic potential for the prevention or treatment of an expanding number of gastrointestinal diseases, including short bowel syndrome (SBS). Teduglutide, being developed by NPS Allelix and licensee Nycomed, is a protease-resistant analog of GLP-2 for the potential treatment of gastrointestinal disease. Teduglutide has prolonged biological activity compared with native GLP-2, and preclinical studies demonstrated significant intestinotrophic activity in models of SBS, experimental colitis and chemotherapy-induced intestinal mucositis. Patients with SBS rely on parenteral nutrition (PN) following bowel resection, and in a phase III clinical trial with teduglutide, > 20% reduction in PN was observed in patients with SBS receiving teduglutide. A phase II clinical trial for teduglutide in Crohn's disease observed remission rates of 55.6% in patients. At the time of publication, phase III clinical trials for SBS were ongoing, as were preclinical studies for chemotherapy-induced mucositis and pediatric indications. Teduglutide represents a novel, efficacious drug capable of increasing intestinal growth and improving intestinal function, and may change clinical management of intestinal disease and damage.

Topics: Clinical Trials as Topic; Crohn Disease; Gastrointestinal Agents; Gastrointestinal Diseases; Glucagon-Like Peptide 2; Humans; Nausea; Peptides; Short Bowel Syndrome; Treatment Outcome; Vomiting

Teduglutide, a synthetic glucagon-like peptide-2 (GLP-2) analog with activity relating to the regeneration, maintenance, and repair of the intestinal epithelium, is currently being evaluated for the treatment of short-bowel syndrome (SBS), Crohn's disease, and other gastrointestinal disorders. On the basis of promising results from teduglutide studies in adults with SBS and from studies in neonatal and juvenile animal models, a pediatric multiple-dose phase I clinical study was designed to determine the safety, efficacy, and pharmacokinetics of teduglutide in pediatric patients with SBS who have undergone resection for necrotizing enterocolitis, malrotation, or intestinal atresia. This report details the application of clinical trial simulations coupled with a novel approach using generalized additive modeling for location, scale, and shape (GAMLSS) that facilitates the simulation of demographic covariates specific to the targeted patient populations. The goal was to optimize phase I dosing strategies and the likelihood of achieving target exposure and therapeutic effect.

Topics: Adult; Age Factors; Body Weight; Clinical Trials, Phase I as Topic; Computer Simulation; Drug Dosage Calculations; Gastrointestinal Agents; Glucagon-Like Peptide 2; Humans; Infant; Infant, Newborn; Models, Biological; Peptides; Short Bowel Syndrome; Treatment Outcome

Topics: Animals; Humans; Jejunum; Mice; Peptides; Short Bowel Syndrome