What is the recommended approach for using oral Glucagon-like peptide-2 (GLP-2) therapy in patients with short bowel syndrome or severe malabsorption?

Oral GLP-2 Therapy

Critical Point: There Is No Oral GLP-2 Formulation Available

GLP-2 therapy (teduglutide/Gattex) is administered exclusively via subcutaneous injection, not orally—no oral formulation exists or has been studied in clinical practice. 1

The native GLP-2 peptide has an extremely short half-life and would be rapidly degraded in the gastrointestinal tract if taken orally, making oral administration pharmacologically impossible. 2 Teduglutide was specifically engineered as a protease-resistant analog to extend the half-life to approximately 1.3-2 hours, allowing once-daily subcutaneous dosing. 1, 3

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Proper Administration of GLP-2 Therapy (Teduglutide)

Route and Dosing

• Teduglutide is administered subcutaneously at 0.05 mg/kg once daily in both adults and pediatric patients ≥1 year old with short bowel syndrome dependent on parenteral nutrition. 1
• Injection sites should be rotated between the four quadrants of the abdomen, alternating thighs, or alternating arms. 1
• Self-administration is appropriate for adults; pediatric self-administration has not been tested and requires caregiver administration. 1

Renal Dose Adjustment

• Reduce dose by 50% (to 0.025 mg/kg once daily) in patients with eGFR <60 mL/min/1.73 m², including moderate/severe renal impairment and end-stage renal disease. 1
• Teduglutide exposure increases 1.5-2 fold with declining renal function, as the kidney is the primary clearance route. 1

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Patient Selection and Pre-Treatment Requirements

Mandatory Pre-Treatment Screening (Within 6 Months)

Adults:

• Perform colonoscopy AND upper GI endoscopy with removal of any polyps found. 2, 1
• Obtain baseline labs: bilirubin, alkaline phosphatase, lipase, and amylase. 2, 1

Pediatric patients:

• Perform fecal occult blood testing. 1
• If new or unexplained blood in stool is detected, proceed to colonoscopy/sigmoidoscopy and upper GI endoscopy. 1
• Obtain same baseline labs as adults. 1

Absolute Contraindications

• Active gastrointestinal malignancy (teduglutide accelerates growth of GI polyps and cancers). 2, 1
• Recent malignancy of any location within 5 years (based on Phase 3 STEPS trial data showing liver and lung cancers in treated patients). 2

When to Consider Teduglutide

Teduglutide should only be used after optimizing dietary management and conventional SBS treatments have failed to achieve enteral independence. 2 This is not simply another antidiarrheal agent—it is a growth factor with significant risks and costs that mandate careful patient selection. 2

Appropriate candidates include:

• SBS patients with intestinal failure requiring parenteral nutrition despite completed intestinal adaptation (typically >2 years post-resection). 2
• Patients who have maximized dietary optimization (high complex carbohydrate, normal fat, added sodium chloride to 90-120 mmol/L). 2, 4
• Patients already on optimal antimotility therapy (loperamide ± codeine) and acid suppression. 2, 4
• Patients without contraindications who can commit to intensive monitoring. 2

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Clinical Efficacy

Absorption Improvements

• Teduglutide increases wet weight (fluid) absorption by approximately 750 g/day, which is clinically meaningful for reducing parenteral fluid requirements. 2
• Energy absorption increases are modest at <250 kcal/day. 2
• Sodium absorption increases by approximately 38 mmol/day and potassium by 18 mmol/day. 5
• These effects occur in patients both with and without colon in continuity. 2

Structural Changes

• Teduglutide increases villus height by 38-45% and crypt depth by 18-22% in jejunostomy patients. 2
• It is the only growth factor that has demonstrated histologic intestinal growth in SBS patients. 2

Parenteral Nutrition Weaning

• Teduglutide can enable PN weaning and allow some patients to achieve enteral autonomy. 2
• Effects are not sustained after treatment discontinuation—ongoing therapy is required to maintain benefits. 2

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Monitoring Requirements During Treatment

Surveillance for Malignancy

Adults:

• Perform colonoscopy and upper GI endoscopy (or alternate imaging) after 1 year of treatment. 1
• Repeat colonoscopy and upper GI studies at least every 5 years thereafter while on therapy. 1

Pediatric patients:

• Perform annual fecal occult blood testing. 1
• Colonoscopy/sigmoidoscopy after 1 year of treatment, then every 5 years. 1
• Consider upper GI endoscopy or alternate imaging during treatment. 1

Laboratory Monitoring

• Check bilirubin, alkaline phosphatase, lipase, and amylase every 6 months. 1
• If clinically meaningful changes occur, obtain imaging and reassess whether to continue teduglutide. 1

Parenteral Nutrition Adjustment

• Systematically taper PN in a planned manner as intestinal absorption improves. 6, 4
• Monitor for fluid overload, including congestive heart failure, and adjust parenteral support accordingly. 1

Upon Discontinuation

• Monitor closely for fluid and electrolyte imbalances when stopping teduglutide, as absorptive capacity will decline. 1

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Critical Safety Concerns

Growth Factor Risks

• Teduglutide enhances growth of colonic polyps and can accelerate gastrointestinal cancer progression. 2, 1
• GLP-2 receptors are primarily expressed in the GI tract and brain, but the Phase 3 STEPS trial documented 1 liver cancer and 2 lung cancers among treated subjects. 2
• Long-term tumor promotion risk remains a theoretical concern requiring ongoing surveillance. 2, 6

Intestinal Obstruction

• Temporarily discontinue teduglutide if intestinal or stomal obstruction develops pending clinical evaluation. 1

Fluid Overload

• Teduglutide increases fluid absorption, which can precipitate or worsen congestive heart failure. 1
• Adjust parenteral support proactively and reassess continued treatment if fluid overload occurs. 1

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Prescriber Requirements

Teduglutide should only be prescribed by physicians experienced in diagnosing and managing SBS who have the facilities to objectively evaluate benefits versus risks. 2 This includes:

• Ability to perform standardized metabolic balance studies measuring fluid, electrolyte, and energy absorption. 2
• Access to multidisciplinary SBS care including nutrition support, gastroenterology, and surgery. 2
• Capability for intensive monitoring and surveillance protocols. 2

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Patient Counseling Essentials

Patients must be fully informed about:

• Probability of PN weaning (not guaranteed—individual response varies). 2, 6
• Expected quality of life improvements (reduced PN dependency, potentially fewer catheter complications). 2
• Duration of treatment (indefinite—effects cease upon discontinuation). 2
• Malignancy risks (polyp growth, potential cancer acceleration requiring lifelong surveillance). 2, 6
• Cost considerations (extremely expensive therapy). 2
• Monitoring burden (frequent endoscopies, labs, clinical assessments). 2, 6