Applications of peptide hormone ligands for the treatment of dumping and short bowel syndrome
Introduction
Dumping syndrome is a common and debilitating complication of esophageal and gastric surgery which is characterized by accelerated gastric emptying (GE) following a meal with early and late symptoms [1]. The rapid delivery of undigested nutrients in the small bowel causes a fluid shift from the intravascular to the luminal compartment and secretion of gastrointestinal (GI) peptide hormones with GI and vasomotor symptoms (early dumping) and/or reactive hypoglycemia (late dumping). Although the majority of patients with mild symptoms respond to dietary measures, a significant subset will require medical therapy, mainly somatostatin analogues. The increasing incidence of dumping syndrome, especially after bariatric surgery, has fueled the evaluation of both analogues and antagonists of other GI peptide hormones.
Intestinal failure (IF) has been defined by the European society of clinical nutrition and metabolism (ESPEN) as a reduced absorptive capacity of the GI tract, below the minimum necessary to sustain life and/or growth, necessitating parenteral nutrition and/or intravenous fluids and electrolytes [2]. IF is associated with a reduced quality of life and a 5-year survival of 64% [3]. Short bowel syndrome (SBS) is the most common cause of IF worldwide [4•]. Until recently, medical therapy was limited to supportive treatment, including anti-secretory and anti-motility treatment, to increase absorption and limit fecal losses. However, the advent of GLP-2 analogues has drastically changed the management of SBS.
A schematic overview of the disease mechanisms and the effects of treatments targeting GI peptide receptors is represented in Figure 1. Rapid transit and dysregulated release of GI peptide hormones play a role in both conditions.
In the current narrative review, we report on the recent advances in the treatment of dumping and short bowel syndrome using agonists and blockers of GI peptide hormone receptors. An electronic literature search was conducted using Pubmed up to 1st of July 2018. The following keywords were used in various combinations: ‘dumping syndrome’, ‘short bowel syndrome’, ‘peptide hormones’, ‘somatostatin analogues’, ‘octreotide’, ‘lanreotide’, ‘pasireotide’, ‘glucagon-like peptide 1’, ‘GLP-1’, ‘glucagon-like peptide 2’, ‘GLP-2’, ‘teduglutide’, ‘glepaglutide’. A manual search was performed of the reference list of the initially selected articles, and the abstract lists of the two major yearly gastroenterology conferences Digestive Disease Week and United European Gastroenterology Week. Only articles in English were reviewed.
Section snippets
Dumping syndrome
Somatostatin analogues (SSA) slow down GE and decrease the meal-induced release of insulin, glucagon and several gastrointestinal peptide hormones implicated in the pathogenesis of dumping, including glucagon-like peptide 1 (GLP-1), gastric inhibitory polypeptide (GIP), neurotensin, vasoactive intestinal peptide (VIP) and pancreatic polypeptide (PP) via activation of the somatostatin receptor [5•]. Both short-acting and long-acting release (LAR) formulations of octreotide, a first-generation
Short bowel syndrome
Intestinal failure in SBS involves not only a reduction in intestinal surface area but also an impaired ileo-colonic brake or feedback loop causing accelerated gastro-intestinal motility after food intake, shorter duration of the migrating motor complex cycle in the fasted state and gastric and intestinal hypersecretion [2,24]. Mainly in the first years of SBS, intestinal adaptation occurs as a compensatory process to stimulate nutrient and fluid absorption in the remaining part of the bowel,
Conclusion
Dumping and short bowel syndrome have an important negative impact on quality of life and in both conditions, there is an unmet medical need for innovative and effective treatments.
Preliminary data suggest pasireotide may be superior to the older generation somatostatin analogues in dumping syndrome for the treatment of hypoglycemia, but controlled trials are warranted. The position of GLP-1 analogues and potentially also antagonists needs to be further established in future studies. Novel
Conflicts of interest statement
TV has served as a consultant for Shire.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
LW and TV are supported by the Flanders Research Foundation (FWO Vlaanderen) through a doctoral fellowship and a senior clinical research mandate respectively.
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