Applications of peptide hormone ligands for the treatment of dumping and short bowel syndrome

Highlights

• Pasireotide, a novel somatostatin analogue, is effective in early and late dumping syndrome.

• GLP-1 analogues alleviate signs and symptoms of dumping syndrome.

• Teduglutide decreases the needs for parenteral support in short bowel syndrome.

• The effects of GLP-1 analogues in short bowel syndrome are promising.

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.

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.