Teduglutide
A DPP-4-resistant glucagon-like peptide-2 (GLP-2) analog that promotes intestinal mucosal growth and absorption in short bowel syndrome.
Overview
GLP-2 is an intestinotrophic hormone secreted by enteroendocrine L-cells that stimulates growth of the intestinal mucosa. Native GLP-2 is rapidly inactivated by dipeptidyl peptidase-4 (DPP-4); teduglutide's Ala-to-Gly substitution at position 2 confers DPP-4 resistance, extending its half-life enough for once-daily subcutaneous dosing.
In the pivotal 24-week STEPS trial, teduglutide 0.05 mg/kg/day produced a clinically meaningful (20–100%) reduction in weekly parenteral support in 63% of patients versus 30% on placebo, and earlier work in Gut established its ability to reduce parenteral nutrition and IV fluid requirements. Some patients achieve enteral autonomy (independence from parenteral support) over long-term treatment.
Because it stimulates cell proliferation, teduglutide carries warnings around colorectal polyps/neoplasia, and patients require colonoscopic surveillance. Other adverse effects include abdominal pain, injection-site reactions, fluid overload, and stoma complications.
Mechanism of Action
GLP-2 receptors are expressed on intestinal subepithelial cells rather than directly on enterocytes; receptor activation drives paracrine signaling (including IGF-1 and keratinocyte growth factor) that promotes epithelial proliferation and reduces apoptosis. The net effect is a larger, more absorptive intestinal surface plus slowed gastric emptying and reduced secretion, which together lessen dependence on parenteral support in short bowel syndrome. DPP-4 resistance from the Ala2→Gly substitution is what makes sustained once-daily dosing possible.
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References (2)
- [1]Jeppesen PB, Pertkiewicz M, Messing B, et al. Teduglutide reduces need for parenteral support among patients with short bowel syndrome with intestinal failure Gastroenterology (2012)
→ In the pivotal 24-week STEPS trial, teduglutide 0.05 mg/kg/day reduced parenteral support in 63% of patients versus 30% on placebo.
- [2]Jeppesen PB, Gilroy R, Pertkiewicz M, et al. Randomised placebo-controlled trial of teduglutide in reducing parenteral nutrition and/or intravenous fluid requirements in patients with short bowel syndrome Gut (2011)
→ Teduglutide reduced parenteral nutrition/IV fluid requirements in short bowel syndrome, supporting its intestinotrophic effect.
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