Teduglutide
[Gly2]GLP-2, ALX-0600, recombinant human GLP-2 analogue
Teduglutide is a 33-amino-acid analogue of human glucagon-like peptide-2 (GLP-2) in which the alanine at position 2 is replaced by glycine, making it resistant to breakdown by dipeptidyl peptidase-4. It is a licensed medicine that promotes growth and absorptive capacity of the remaining intestinal mucosa in short bowel syndrome. Its purpose is to let patients dependent on intravenous parenteral nutrition reduce or stop that support.
Mechanism
Teduglutide binds the GLP-2 receptor, a class B G-protein-coupled receptor. Critically, GLP-2 receptors are not expressed on enterocytes themselves but on subepithelial myofibroblasts, enteric neurons and a subset of enteroendocrine cells. The trophic effect on the epithelium is therefore indirect and paracrine: receptor activation raises cyclic AMP and triggers release of downstream mediators, principally insulin-like growth factor-1 from myofibroblasts, together with keratinocyte growth factor, vasoactive intestinal peptide and nitric oxide from enteric neurons. IGF-1 signalling through beta-catenin in crypt cells is the best-characterised route to increased crypt-cell proliferation and reduced enterocyte apoptosis.
The net structural result is taller villi, deeper crypts and greater mucosal surface area in the residual bowel, which increases fluid, electrolyte and nutrient absorption. Teduglutide additionally slows gastric emptying, reduces gastric acid secretion and increases mesenteric blood flow, all of which reduce ostomy or stool output. Native GLP-2 is cleaved at the Ala2-Asp3 bond by DPP-4 within minutes; substituting glycine for alanine at position 2 blocks that cleavage and extends the plasma half-life from roughly 7 minutes to about 2 hours, which is what makes once-daily subcutaneous dosing viable.
What the research shows
The registration programme comprised two phase 3 trials. In the first (Jeppesen 2011, Gut), 83 patients were randomised to teduglutide 0.05 mg/kg/day (n=35), 0.10 mg/kg/day (n=32) or placebo (n=16) for 24 weeks; the higher dose failed the pre-specified primary analysis while the 0.05 mg/kg/day arm achieved a significant reduction in parenteral support. The pivotal STEPS trial (Jeppesen 2012, Gastroenterology; NCT00798967) randomised 86 patients 1:1 to 0.05 mg/kg/day or placebo for 24 weeks and found 27 of 43 (63 per cent) of teduglutide-treated patients achieved a 20-100 per cent reduction in weekly parenteral support volume versus 13 of 43 (30 per cent) on placebo, with mean weekly reductions of 4.4 versus 2.3 litres. A 52-week extension of the first trial (O'Keefe 2013) reported continued response in 68 per cent of the 0.05 mg/kg/day group. STEPS-2, the 2-year open-label extension (Schwartz 2016), enrolled 88 patients of whom 65 completed; thirteen achieved full enteral autonomy.
Honest caveats matter here. The effect is real but partial for most patients: the typical response is a reduction of one to three infusion days per week rather than cure, and benefit is lost when treatment stops, implying indefinite therapy. Response is more likely in patients with a longer remnant small bowel and retained colon in continuity. Because GLP-2 is a growth factor, the label requires colonoscopy before starting and periodically thereafter; colorectal polyps have been detected, and although no causal increase in colorectal cancer has been demonstrated, the theoretical concern is taken seriously by both regulators. Pooled safety data across four trials (Pape 2020) confirmed the adverse event profile is dominated by gastrointestinal and stoma-related events rather than by neoplasia, with no new safety concerns identified.
Evidence assessment
High-quality evidence
Two independent randomised, double-blind, placebo-controlled phase 3 trials met their primary endpoints (Jeppesen 2011, n=83; Jeppesen 2012 STEPS, n=86), supported by a 52-week extension, the 2-year STEPS-2 open-label extension, and pooled safety data across four trials. Teduglutide holds full marketing authorisation from both the FDA and the EMA and is recommended by NICE within its licensed indication. Every citation in this record was individually verified against PubMed. This is a genuinely strong evidence base by the standards of a rare disease.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
Randomised placebo-controlled trial of teduglutide in reducing parenteral nutrition and/or intravenous fluid requirements in patients with short bowel syndrome Preclinical only
Teduglutide 0.05 mg/kg/day produced a significant graded reduction in parenteral support compared with placebo; the higher 0.10 mg/kg/day dose did not meet the pre-specified primary endpoint, an inconsistency that shaped the dose selected for licensing.
Teduglutide reduces need for parenteral support among patients with short bowel syndrome with intestinal failure Preclinical only
27 of 43 (63 per cent) teduglutide recipients achieved a 20-100 per cent reduction in weekly parenteral support volume versus 13 of 43 (30 per cent) on placebo; mean weekly reduction 4.4 versus 2.3 litres. This was the pivotal registration trial.
Safety and efficacy of teduglutide after 52 weeks of treatment in patients with short bowel intestinal failure Preclinical only
Response was maintained over one year, with 68 per cent of the 0.05 mg/kg/day and 52 per cent of the 0.10 mg/kg/day group achieving clinically meaningful reductions in parenteral support. Being open-label, it cannot separate drug effect from continued intestinal adaptation.
Long-term teduglutide for the treatment of patients with intestinal failure associated with short bowel syndrome Preclinical only
Sustained and continued reductions in parenteral support (mean reductions 28-66 per cent by group), with thirteen patients achieving full enteral autonomy. Overall health and nutritional status was maintained. No control arm, so drug effect cannot be separated from ongoing adaptation.
Teduglutide for the treatment of adults with intestinal failure associated with short bowel syndrome: pooled safety data from four clinical trials Preclinical only
Teduglutide had a safety profile consistent with prior adult data and no new safety concerns were identified. Adverse events were predominantly gastrointestinal, mostly mild to moderate, and declined in frequency over time. No malignancy signal emerged, though follow-up duration limits conclusions about a growth factor's long-term neoplastic risk.
Safety
The commonest adverse effects are abdominal pain, abdominal distension, nausea, vomiting, headache, upper respiratory tract infection and injection-site reactions. In STEPS-2 the commonest events were abdominal pain (34 per cent), catheter sepsis (28 per cent) and weight loss (25 per cent). Patients with a stoma frequently report stomal swelling or increased output requiring stoma appliance adjustment. Label warnings cover neoplastic growth (colonoscopy required before treatment and at intervals during it, with polyps removed), intestinal obstruction, biliary and pancreatic disease (baseline and periodic bilirubin, alkaline phosphatase, lipase and amylase testing), and fluid overload with resulting cardiac failure. Because absorption improves, parenteral fluid must be reduced in step or the patient becomes volume overloaded. Contraindicated in active or suspected malignancy and in patients with a history of gastrointestinal malignancy within the past five years. This is a specialist hospital medicine that requires structured monitoring; it is not a compound suitable for use outside intestinal failure services.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | Holds a UK marketing authorisation for short bowel syndrome in patients aged 1 year and above who are stable following a period of intestinal adaptation after surgery. Originally authorised centrally by the EMA in 2012 with orphan designation, with the UK authorisation continuing after EU exit. NICE technology appraisal TA804 (June 2022) recommends it within its marketing authorisation, following an earlier terminated appraisal. |
| United States | FDA-approved December 2012 for adults with short bowel syndrome who are dependent on parenteral support; paediatric indication extended to patients aged 1 year and above in 2019. Prescription-only, supplied as a subcutaneous injection. |
| WADA (sport) | Not listed on the WADA Prohibited List. GLP-2 receptor agonists are not covered by section S2 and there is no plausible performance rationale. |
Questions
Not quite. It is a near-copy of human GLP-2 with a single amino acid change: glycine replaces alanine at position 2. That one substitution blocks the enzyme DPP-4 from chopping the peptide up, extending its half-life from roughly 7 minutes to about 2 hours. Native GLP-2 is far too short-lived to be a practical medicine.
No. In the pivotal STEPS trial the typical result was a 20-100 per cent reduction in the volume of parenteral support needed, which for many patients translates to one to three fewer infusion days per week. In the 2-year STEPS-2 extension, thirteen of 88 enrolled patients achieved full enteral autonomy, a real but minority outcome. Benefit is lost if treatment stops.
Because GLP-2 is a growth factor for intestinal mucosa, and anything that stimulates crypt-cell proliferation raises a theoretical concern about neoplasia. Colorectal polyps were detected in the trial programme. Regulators require a colonoscopy before starting, with polyps removed, and periodic surveillance afterwards. No causal increase in colorectal cancer has been shown, but the monitoring requirement stands.
Yes, within its licensed indication. NICE technology appraisal TA804, published in June 2022, recommends teduglutide for short bowel syndrome in people aged 1 year and above whose condition is stable following intestinal adaptation after surgery. It is prescribed through specialist intestinal failure centres.