Teduglutide

Mechanism

A GLP-2 analog that promotes growth of the intestinal lining. It is used for people with short bowel syndrome — a condition where much of the small intestine has been surgically removed and the remaining gut can't absorb enough nutrients. Teduglutide makes the remaining intestine grow taller villi (finger-like absorptive projections), improving nutrient and fluid absorption and reducing dependence on IV nutrition.

Effects

## Gastrointestinal System [Tier 1 - FDA-Approved, Phase III Human Data] - Recombinant analog of GLP-2 (glucagon-like peptide 2) with Gly2→Ala substitution for DPP-IV resistance - Half-life ~3-5 hours (vs. 7 minutes for native GLP-2) - Profound intestinotrophic effects: stimulates crypt cell proliferation, inhibits apoptosis, and increases villous height in the small and large intestine - Increases intestinal surface area, blood flow, and absorptive capacity - FDA-approved for short bowel syndrome (SBS) in patients dependent on parenteral nutrition (PN) - Phase III trials showed 50-60% of patients achieved ≥20% reduction in parenteral nutrition volume ## Absorptive/Nutritional System [Tier 1 - Human Data] - Enhanced absorption of macronutrients, micronutrients, and fluids through increased mucosal surface area - Patients on parenteral nutrition can reduce PN volume by 20-100%, with some achieving complete PN independence - Improved wet weight absorption and reduced fecal output - Effects are dependent on remaining intestinal length — patients with >10cm of residual small bowel are most likely to respond ## Mucosal Barrier [Tier 2 - Human/Preclinical Data] - Strengthens tight junctions between enterocytes, reducing intestinal permeability - Promotes goblet cell differentiation and mucus production - Enhanced mucosal immune defense through improved barrier function - May have applications beyond SBS for conditions involving mucosal damage (IBD, radiation enteritis) ## Systemic Effects [Tier 1 - Human Data] - Minimal systemic effects beyond GI tract - Does NOT affect glycemic control significantly (unlike GLP-1, GLP-2 has no incretin effect) - Fluid and electrolyte balance improves as intestinal absorption improves - Rare: polyp formation — GLP-2's trophic effects include stimulating intestinal epithelial proliferation, raising theoretical concern about neoplasia ## Hepatobiliary [Tier 2 - Clinical Observation] - Reduced parenteral nutrition dependence decreases risk of PN-associated liver disease (intestinal failure-associated liver disease, IFALD) - Improved enterohepatic circulation of bile acids as intestinal absorption recovers - Reduced gallstone formation risk with improved GI motility and bile acid recycling

Practitioner Guide

## Clinical Positioning Teduglutide (Gattex) is a highly specialized orphan drug for short bowel syndrome. It is NOT used in general peptide therapy or optimization clinics. It is relevant to practitioners managing patients with SBS, intestinal failure, or extensive bowel resections. ## FDA-Approved Indication - Short bowel syndrome in adult and pediatric patients (≥1 year) dependent on parenteral support ## Dosing - Adults: 0.05mg/kg SC once daily - Pediatric (≥1 year): 0.05mg/kg SC once daily - Administered in the abdomen, alternating injection sites - Treatment is indefinite; discontinuation leads to loss of intestinal adaptive changes within weeks ## Requirements Before Prescribing - Colonoscopy within 6 months before starting (to rule out polyps/neoplasia) - Colonoscopy at the end of year 1, then every 5 years minimum - Small bowel imaging if feasible - This is required due to the trophic (growth-promoting) nature of GLP-2 on intestinal epithelium ## Monitoring - PN volume adjustments: work with nutrition team to reduce PN as intestinal absorption improves - Fluid status: as PN is weaned, oral/enteral fluid needs increase - Electrolytes: particularly sodium, potassium, magnesium during PN weaning - Stoma output (if applicable): should decrease as teduglutide takes effect - Colonoscopy surveillance per schedule ## Timeline of Response - Week 1-4: initial intestinal adaptation begins; stoma output may start decreasing - Month 1-3: PN volume reductions become possible (10-20% reduction) - Month 3-6: further PN optimization; some patients achieve >50% reduction - Month 6-12: maximum adaptation; some patients achieve PN independence - Beyond 12 months: maintained benefit with continued treatment ## Side Effects - Abdominal pain, nausea, injection site reactions (most common, usually mild) - Intestinal obstruction/stenosis: rare but serious — patients with strictures are at higher risk - Polyp formation: colonoscopic surveillance required - Fluid overload: as intestinal absorption improves while PN volume is maintained, patients can develop fluid overload if PN is not reduced promptly ## NOT for General Peptide Therapy Use - This is a high-cost specialty medication ($300,000+/year) - Risk of intestinal polyp/neoplasia promotion makes it inappropriate for gut optimization in healthy individuals - BPC-157 and larazotide serve the gut-healing niche in peptide therapy; teduglutide is for severe intestinal failure only

Evidence

• Teduglutide reduces need for parenteral support among patients with short bowel syndrome with intestinal failure

  Jeppesen PB et al. (2012) — Gastroenterology — PMID: 22982184

  Over 24 weeks in SBS-IF, teduglutide 0.05 mg/kg/day produced significantly more responders with >20% reduction in parenteral support than placebo (63% vs 30%, P=.002) and reduced parenteral support volume by 4.4 vs 2.3 L/week.

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Research Summary

## Tier 1 — Phase III/FDA-Approved Human Data - STEPS trial (Phase III): teduglutide 0.05mg/kg daily vs. placebo in SBS patients on PN. 63% of teduglutide patients achieved ≥20% PN reduction at 24 weeks vs. 30% placebo. - STEPS-2 (extension): sustained PN reduction over 2 years; 21% achieved complete PN independence - Pediatric trials: similar efficacy in children ≥1 year with SBS - Safety: well-tolerated over 2+ years; colonoscopic polyp detection rate slightly elevated but no malignant transformations reported in trials - Post-marketing surveillance: confirmed safety profile consistent with trials; rare cases of intestinal obstruction in patients with pre-existing strictures ## Tier 2 — Mechanistic Human Data - Intestinal biopsies confirm increased villous height (30-50% increase) and crypt depth in treated patients - Increased GLP-2 receptor expression in remaining bowel segments (upregulation) - Improved citrulline levels (biomarker of functional enterocyte mass) correlate with clinical response - Fecal wet weight reduction of 500-1000g/day in responders ## Tier 3 — Preclinical - GLP-2 receptor signaling through cAMP/PKA/CREB pathway in subepithelial myofibroblasts - Trophic effects mediated indirectly through IGF-1, ErbB, and KGF released from subepithelial cells - Rodent SBS models show complete mucosal regeneration with sustained GLP-2 agonism - Concern: GLP-2 promotes intestinal tumor growth in APC-min mice (colorectal cancer model) — basis for colonoscopy surveillance requirement ## Evidence Gaps - Very long-term (>5 year) neoplasia risk not fully characterized - Predictive biomarkers for response not validated - Use in IBD, radiation enteritis, or other mucosal injury conditions not studied in Phase III - Combination with other gut-healing peptides (BPC-157, larazotide) never studied