Long-Term Effects of Teduglutide for Short-Bowel Syndrome

The glucagon-like peptide (GLP) teduglutide is effective for long-term treatment of patients with short-bowel syndrome intestinal failure, according to the July issue of Clinical Gastroenterology and Hepatology.

Short-bowel syndrome is a relatively rare condition that results from massive small bowel resection or bypass. Patients used to die from nutrient malabsorption and malnutrition, but the development of parenteral nutrition (intravenous feeding) has allowed them to survive for many years. Although parenteral nutrition is life saving, it is labor intensive, expensive, and leads to complications such as infection, loss of venous access, and liver failure.

Glucagon and related peptides can induce intestinal villous hyperplasia, increasing the absorptive surface area of the intestinal epithelium. GLP-2, which is secreted by enteroendocrine L-cells in the distal bowel, produces villous hypertrophy, retards gastric secretion and emptying, and increases mucosal blood flow and absorption. Teduglutide, a dipeptidyl peptidase IV resistant GLP-2 anologue, is a longer-acting form of GLP-2.

To determine the long-term effects of teduglutide, Stephen J.D. O’Keefe et al. analyzed data from  52 patients with short-bowel syndrome who received teduglutide (0.05 or 0.10 mg/kg/day) in an initial 6-month trial and then a 6-month extension study.

After 52 weeks on teduglutide, 68% of those receiving 0.05-mg/kg/day and 52% of those receiving 0.10-mg/kg/day had a ≥20% reduction in parenteral nutrition. Dependence on parenteral nutrition was reduced by 1 day or more for 68% and 37% of patients, respectively (see below figure).

Mean reduction in parenteral support over 52 weeks for 2 dose levels of teduglutide.

Mean reduction in parenteral support over 52 weeks for 2 dose levels of teduglutide.

Four patients achieved complete independence from parenteral nutrition. Eleven of the 19 patients who had not responded to teduglutide at 24 weeks became responders by the end of the study.

The most common adverse events included headache (35%), nausea (31%), and abdominal pain (25%). Seven patients withdrew because of adverse events (gastrointestinal disorders in 4).

Although the study focused primarily on reducing volume of parenteral nutrition, patients also had reduced need for intravenous nutrients. Among the 43 patients who received the entire 52 weeks of teduglutide therapy, those receiving 0.05 mg/kg/day teduglutide were able to reduce the intravenous energy intake by 3511.09 kcal/wk, and those receiving 0.10 mg/kg/day reduced their intravenous energy intake by 1556.32 kcal/wk.

Four weeks after stopping the drug, patients who received 0.05-mg/kg/day teduglutide, but not those who received 0.10-mg/kg/day, needed to increase their parenteral nutrition volumes.

Why would there be a linear decrease in the need for parenteral nutrition over a 12-month period, when experiments have shown that the hormone has maximal effects on intestinal morphology within 4 weeks? O’Keefe et al. propose that, with tight fluid balance control, the adaptation process continues as exogenous GLP-2 is administered.

The authors remind readers that potent drugs have potent adverse effects, and although the adverse effect profile observed during 52 weeks of observation is acceptable, there is concern that the proliferative properties of the peptide could cause subacute obstructions or even cancer in epithelial tissues. Although no new neoplastic lesions were detected in any of the patients over the 12-month study period, careful colonoscopic surveillance is mandatory for future, longer-term studies.

Another important factor to consider is that teduglutide is likely to increase the absorption of drugs, which could lead to toxicities. The symptoms of most patients with severe short-bowel syndrome  are managed with high doses of anti-diarrheal drugs, such as loperamide and codeine. Increased absorption could cause constipation and symptoms of intestinal obstruction. Drugs with a narrow therapeutic index, such as benzodiazepine and digoxin, should be monitored carefully.

In an editorial that accompanies the article, Carol E. Semrad says that the true safety and side effect profile of teduglutide and its broader applications will be determined with its ongoing use and careful patient monitoring. She reminds us that even 1 day off parenteral nutrition, and decreased stool or ostomy output, provides a better day in the life of a patient with short bowel syndrome.

More Information on Short Bowel Syndrome

Read the article online.
O’Keefe SJD, Jeppesen PB, Gilroy R, et al. Safety and efficacy of teduglutide after 52 weeks of treatment in patients with short bowel intestinal failure. Clin Gastroenterol Hepatol 2013;11:815-823.e3.

Read the accompanying editorial.
Semrad CE. The long road to a new short bowel therapy: teduglutide for clinical use. Clin Gastroenterol Hepatol 2013;11:824-825.

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About Kristine Novak, PhD, Science Editor

Dr. Kristine Novak is the science editor for Gastroenterology and Clinical Gastroenterology and Hepatology, both published by the American Gastroenterological Association. She has worked as an editor at biomedical research journals and as a science writer for more than 12 years, covering advances in gastroenterology, hepatology, cancer, immunology, biotechnology, molecular genetics, and clinical trials. She has a PhD in cell biology and an interest in all areas of medical research.
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