Teduglutide (ALX-0600), a dipeptidyl peptidase IV resistant glucagon-like peptide 2 analogue, improves intestinal function in short bowel syndrome patients

Abstract

Background and aims: 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. Methods: 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 >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 >50% colon in continuity.Results: 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 (2711 (734) g/day; p = 0.001) and faecal energy excretion (2808 (1453) kJ/day (2193 (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. Conclusion: 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.

Randomised controlled trial of colostrum to improve intestinal function in patients with short bowel syndrome

“…However, in a similar setting, it has been possible to demonstrate significant improvements in intestinal function employing other treatment modalities, and therefore, the effects of colostrum seem to be so modest that the clinical relevance is negligible. 20,21,43 In fact, two of the eight patients showed a negative value for relative improvement of intestinal absorption; the other six had improvements, though mainly minor, in the magnitude of 2-3%, and one patient improved his relative absorption with 11% from 47 to 58%.…”

“…Anti-diarrhoeals 13,14 reduce intestinal motility, whereas antisecretory agents [15][16][17] reduce upper GI secretions, but their effect on macronutrient absorption remains to be established. 18 Stimulation of remnant bowel adaptation with growth hormone 19 or glucagon-like peptide 2 (GLP-2) 20 has improved energy and wet weight absorption in patients with intestinal insufficiency or failure that were already well adapted, 21 probably mediated by local release of growth factors such as insulin-like growth factor 1. 22 In this context, colostrum, the first milk produced after birth in mammals, has interesting properties in addition to its normal role to stimulate growth and maturation of the newborn gut.…”

New growth factor therapies aimed at improving intestinal adaptation in short bowel syndrome

“…111 However, in a more recent open-label, multicenter, dose-ranging pilot study of 18 SBS patients Jeppesen et al reported significant effects of teduglutide on reducing intestinal wet weight excretion and improving wet weight absorption, but only minor effects on macronutrient and energy absorption and no effect on urinary sodium excretion or bodyweight. 96 Morphologically, patients treated with teduglutide exhibited significantly increased small bowel villus heights, crypt depth, and mitotic index. 96 The variability in effect of teduglutide on weight gain and energy absorption between the two studies …”

“…93,94 The biological actions of GLP-2 are modulated by a single GLP-2 receptor (GLP-2R), which is expressed in enteroendocrine cells. 95 Glucagon-like peptide-2 raises considerable interest for SBS patients 96 because it has been shown to slow gastric emptying, 97 reduce gastric secretions, 98 increase intestinal blood flow, 99 and stimulate growth of the small and large intestine. 93 In addition, increased basal plasma GLP-2 levels have been reported following small bowel resection in rats, pigs, and humans, and circulating GLP-2 levels have been suggested as an indicator of the early phase of the adaptive response.…”

“…Teduglutide differs from GLP-2 by only one amino acid (alanine is replaced by glycine in position 2 of the peptide), but this change increases the plasma half-life of the drug from 7 min (GLP-2) to 0.9-2.3 h (teduglutide). 96 In an initial open-label pilot study of 16 SBS patients, s.c. administration of teduglutide for 21 days resulted in a significant improvement in intestinal wet weight absorption and a more modest improvement in energy absorption that led to an increase in bodyweight, lean body mass, and a rise in urinary creatinine secretion. 111 However, in a more recent open-label, multicenter, dose-ranging pilot study of 18 SBS patients Jeppesen et al reported significant effects of teduglutide on reducing intestinal wet weight excretion and improving wet weight absorption, but only minor effects on macronutrient and energy absorption and no effect on urinary sodium excretion or bodyweight.…”