Sitagliptin, a dipeptidyl peptidase-4 inhibitor, in patients with short bowel syndrome and colon in continuity: an open-label pilot study

Abstract

ObjectivePatients with short bowel syndrome (SBS) and colon in continuity have better adaptation potential compared with patients with jejunostomy. Adaptation may involve enhanced postprandial secretion of the enteroendocrine hormones glucagon-like peptide (GLP)-1 and GLP-2 which are normally degraded by dipeptidyl peptidase (DPP)-4. Nevertheless, some patients with SBS with colon in continuity suffer from high-volume faecal excretions and have been shown to benefit from treatment with GLP-2. Therefore, we aimed to evaluate efficacy of sitagliptin, a DPP-4 inhibitor, on reducing faecal excretions in this patient group.DesignIn an open-label, case series, proof-of-concept pilot study, 100 mg oral sitagliptin was given two times per day for 8 weeks to patients with SBS with ≥50% colon in continuity with or without the need for parenteral support (PS). To assess intestinal function, metabolic balance studies were done at baseline and following 8 weeks of treatment.ResultsOf the 10 patients planned for enrolment, 8 patients were included; 7 patients completed the study. Although postprandial endogenous GLP-2 concentrations increased by 49 hours×pmol/L (39, 105; p=0.018) (median (min, max)), sitagliptin did not significantly reduce median faecal wet weight (−174 g/day (−1510, 675; p=0.176)) or increase intestinal wet weight absorption. However, heterogeneity in the treatment effect was observed: intestinal wet weight absorption increased in all four patients with intestinal failure. One patient achieved a reduction in PS by 500 mL per administration day.ConclusionFollowing this negative, small pilot study, larger, placebo-controlled, studies are needed to establish the therapeutic potential of DPP-4 inhibition in patients with SBS.

Treatment of short bowel syndrome: Breaking the therapeutic ceiling?

“…Larger randomized and placebo‐controlled studies are needed to confirm these results. Finally, treatment with the DPP‐4 inhibitor sitagliptin, which increases postprandial concentrations of endogenous GLP‐1, GLP‐2, and PYY, did not reduce fecal output in eight patients with SBS‐JC after 8 weeks 35 . However, responses were variable with increased wet weight absorption in those with high‐volume fecal output and need for parenteral support.…”

Enterohormone therapy for short bowel syndrome

“…Naimi et al hypothesized that by inhibiting DPP IV, endogenous postprandial plasma concentrations of GLP-1, GLP-2, and PYY would increase resulting in a decreased fecal wet weight output and increased intestinal absorption of wet weight, energy and electrolytes, and urine production. However, despite the significant increase in intact GLP-2 plasma concentrations, the overall outcomes of this 8-week study with sitagliptin treatment in SBS patients with !50% of colon-in-continuity were negative [73].…”

Definition, classification, and causes of short bowel syndrome

“…They exert transit and trophic effects on the gut by enhancing small and large intestinal cell growth and slowing gastric emptying and small bowel transit (ie, ileo‐colonic brake), thereby facilitating nutrient absorption 29,30 . The secretion of these hormones has been shown to be enhanced in SBS type 3 31 and in SBS type 2 with part of the ascending colon remaining 32 and to be reduced or absent in SBS type 1 33 . In SBS type 1, this translates clinically into reduced or absent structural and functional post‐resection adaptation and in more rapid gastric emptying, especially for liquids 31–36 .…”

“…The secretion of these hormones has been shown to be enhanced in SBS type 3 31 and in SBS type 2 with part of the ascending colon remaining 32 and to be reduced or absent in SBS type 1 33 . In SBS type 1, this translates clinically into reduced or absent structural and functional post‐resection adaptation and in more rapid gastric emptying, especially for liquids 31–36 . The colon contributes to the energy balance though the absorption of SCFAs produced by bacteria fermentation of nonabsorbed carbohydrate, particularly soluble fibers.…”

“…33 In SBS type 1, this translates clinically into reduced or absent structural and functional post-resection adaptation and in more rapid gastric emptying, especially for liquids. [31][32][33][34][35][36] The colon contributes to the energy balance though the absorption of SCFAs produced by bacteria fermentation of nonabsorbed carbohydrate, particularly soluble fibers. Whereas in healthy humans this mechanism allows for absorption of about 150 kcal/day (0.62 MJ), in patients with SBS with a remnant colon in continuity, energy absorption from SCFAs can increase up to 1000 kcal/day (4 MJ).…”