Palle Bekker Jeppesen, MD, PhD
LifelineLetter, January/February 2013

	Cross section of mouse intestine in an animal treated for 10 days with placebo (left) compared with an animal treated with native GLP-2 (right). (Photo: Steen Seier Poulsen, Panum Institute)

Note: because this topic is so complex, some terms are defined in a glossary at the end of the article.

Recently, the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved the glucagon-like peptide 2 (GLP 2) analog teduglutide for the treatment of adults with short bowel syndrome (SBS). In the U.S., teduglutide is marketed as Gattex® (NPS Pharmaceuticals, Bedminster, N.J.).

SBS results from surgical resection, congenital defects, or disease-associated loss of intestinal absorption. The symptoms of SBS vary based on the amount of remaining small bowel, the health of the remaining bowel, and the specific part of the small bowel that has been removed. Many SBS patients with intestinal insufficiency are able to compensate for their malabsorption by changing their diet and increasing oral intake. SBS patients with intestinal failure (SBS-IF), however, need parenteral nutrition (PN) and/or fluids (IV) to maintain nutrient, fluid, electrolyte, trace element, and/or vitamin balances. 1

Although typically life-saving in SBS-IF patients, PN/IV has been associated with potentially life-threatening complications, including catheter-related bloodstream infection, central venous thrombosis, and embolism.2 In addition, some components of PN and chronic dehydration may contribute to progressive IF-associated liver and renal disease. These burdens, combined with the symptoms of malabsorption (e.g., diarrhea, large stomal output, stomal problems, fear of fecal incontinence, flatulence, and abdominal pain), may cause restrictions in the lifestyle of SBS-IF patients and may lead to significant impairment of their quality of life.3 Therefore, treatments of SBS-IF aim to maximize the absorptive capacity of the remaining intestine; minimize symptoms of malabsorption; and avoid, eliminate, or minimize the need for PN.

Current Approaches to Managing SBS 

The fundamental principle of SBS management is to decrease fluid secretion in the upper bowel and to maximize the contact time between the digested nutrients and the intestinal mucosa, thereby increasing absorption of the nutrients. In general, SBS patients are encouraged to compensate for malabsorption by adjusting their diet and by increasing oral intake. Frequent meals and snacks are encouraged.

Historically, treatment strategies have included changes in dietary composition, for example high-carbohydrate, low-fat diets,4 the use of preferred luminal substrates (e.g., glutamine or medium-chain triglycerides); and even the addition of bile acids in relation to meals. However, the effects of these interventions have not been evaluated in long-term, placebo-controlled studies. Continuous tube feeding has been suggested to improve the absorption of macronutrients, but it may be accompanied by increased fecal fluid and electrolyte losses, which can aggravate abdominal discomfort and diarrhea, and further increase the need for IV fluids and electrolytes. 5

The extremely salty taste of oral rehydration solutions with a high sodium concentration may keep people from using them over the long term, and their effects on intestinal fluid and adequate electrolyte absorption have yet to be established in studies in SBS patients with more severe IF.6 Agents such as codeine, loperamide, and tincture of opium slow intestinal motility, but, again, their effect in SBS patients with severe malabsorption has yet to be established. Antisecretory drugs such as H2-receptor antagonists, proton pump inhibitors, or somatostatin analogs have been shown to reduce gastric acid secretions, jejunostomy fluid output, and diarrhea, but no effect on macronutrient absorption has been established. Therefore, there is a high unmet need for medical treatments in SBS-IF patients.

The Role of Hormones 

In the last two decades, a hormonal treatment plan that focuses on intestinal rehabilitation by promoting intestinal hyperadaptation has been suggested to minimize the medical consequences of SBS. It has become apparent that, in SBS patients with distal bowel resections, the malabsorption is not only caused by a diminished absorptive area, but also by the disruption of the ileal brake feedback mechanism regulated by hormones such as glucagon-like peptide (GLP) 1 and 2 and PYY. The lack of this meal-stimulated hormonal feedback leads to gastric hypersecretion, rapid gastric and intestinal transit, and poor intestinal adaptation.

The first of these “ileal brake hormones” to be tested in clinical experiments was GLP-2. When food is eaten, GLP-2 is secreted from specialized cells in the distal bowel. Drucker, et al. discovered that GLP-2 induces growth of the absorptive cells (aka the enterocytes) in the intestinal mucosa.7 Furthermore, GLP-2 inhibits gastric acid secretion and gastric emptying,8,9 stimulates intestinal blood flow,10 and increases intestinal barrier function.11 It was encouraging to find that GLP-2 indeed decreased diarrhea and increased intestinal wet weight absorption in the first study performed by Jeppesen, et al. in 2001.12

The Studies 

GLP-2 as produced naturally in the intestinal cells is rapidly degraded by a human enzyme and has a short half-life of only seven minutes. Teduglutide is a GLP-2 analog that has just one single amino acid substitution which extends the half-life to approximately three hours.13,14 In a metabolic balance study, seventeen adult patients with SBS were split into five treatment groups using doses of 0.03, 0.10, or 0.15 mg/kg (of patient’s body weight) teduglutide injected under the skin once daily, or 0.05 or 0.75 mg/kg twice daily.15 Treatment resulted in structural adaptation as evidenced by increased cell numbers in the intestinal mucosa, and functional adaptation as evidenced by enhanced gastrointestinal fluid absorption of approximately 750 mL/day, with improvements in the absorption of macronutrients and electrolytes. The finding of increased urine production as a consequence of enhanced fluid absorption set the basis for the design of a randomized controlled trial.

In two double-blind placebo-controlled, multicenter, multinational studies, the ability to wean patients from PN/IV, based on increases in urine production, was evaluated. In the first teduglutide study, adult patients with SBS were randomly assigned to a dose of 0.05 mg/kg/day (35 patients), 0.10 mg/kg/day (32 patients), or placebo (16 patients) for up to 24 weeks.16 No statistically significant difference between the group on teduglutide 0.10 mg/kg/day and the placebo group was shown. However, in the group that received the recommended dose of 0.05 mg/kg/day, 46 percent achieved at least a 20 percent reduction of PN/IV at week 20 and 24, while only 6 percent of those receiving the placebo achieved the 20 percent reduction of PN/IV. At week 24, teduglutide treatment resulted in a 2.5 L/week reduction in PN/IV requirements from 9.6 L/week at baseline. In this study, teduglutide also induced growth of the intestinal mucosa.

Sixty-five of the patients who participated in this study opted to enter an open-label, 28-week extension study. In these patients, who received one year of continuous teduglutide treatment (the course of the original study plus the extension study), the average reduction of weekly PN/IV volume was 4.9 L/week, equivalent to a 52 percent reduction from baseline levels.

After the study protocol was modified to allow for earlier (at week 2 vs. week 4) and more aggressive PN/IV weaning (10–30% vs. 10%) a second double-blind placebo-controlled study was performed.17 Forty-three SBS patients were randomized to a 0.05 mg/kg/day dose of teduglutide and forty-three patients received placebo for up to 24 weeks. Findings were significant. Twenty-seven of the patients who received teduglutide achieved a 20 percent to 100 percent reduction of PN/IV at weeks 20 and 24, compared to thirteen of the patients who received a placebo (62.8% versus 30.2%). At week 24, teduglutide treatment resulted in a 4.4 L/week reduction in PN/IV volume from a pre-treatment baseline of 12.9 L/week. Those on placebo had a 2.3 L/week reduction from a pre-treatment baseline of 13.2 L/week. In patients completing the study, twenty-one patients treated with teduglutide (54%) were able to reduce their PN/IV by at least one day, compared to nine of those given a placebo (23%).

The Risks

When using new treatment strategies, it is necessary to evaluate and balance the benefit of the treatment versus the inconveniences, adverse effects, and risks it presents. The studies have revealed that teduglutide treatment may be associated with adverse events, mainly of gastrointestinal origin (abdominal distension, abdominal pain, nausea, and stoma enlargement). However, it was reassuring that only two patients in the teduglutide group and three in the placebo group terminated the final study because of emergent adverse events encountered during treatment. A carefully monitored reduction of the daily dose may be considered for some patients with adverse events.  

As a precaution for the development of neoplasia (or tumors), a colonoscopy with removal of polyps should be performed at the start of treatment with teduglutide. Adherence to follow-up guidelines is recommended. In the case of neoplasia of the liver, gall bladder, pancreas, or the gastrointestinal tract, teduglutide treatment should be discontinued. In general, teduglutide should not be prescribed to patients who have had malignancies within the last five years. Cases of cholecystitis, cholangitis, cholelithiasis, and pancreatitis have been reported in the clinical studies; in such cases continued teduglutide treatment should be reassessed. Cases of intestinal obstruction have been described in clinical studies. The cause of obstruction should be evaluated; if it is felt to be attributable to teduglutide, continued treatment should be reassessed. Due to the increased fluid absorption in relation to teduglutide, patients with cardiovascular disease should be monitored for cardiac insufficiency or hypertension, especially during initiation of treatment. Because teduglutide may also alter absorption of medications, it is important that the primary physician monitors the blood level and the effect of medicines, especially those with a narrow therapeutic index. One example is that warfarin (Coumadin) absorption may be increased, causing its effect to be accentuated.

The Benefits 

Because SBS patients vary considerably, it is relevant to ask: Which SBS patients will benefit from teduglutide and how? The only SBS patients who will be able to discontinue PN/IV completely are probably those who are on the borderline between intestinal insufficiency and intestinal failure. It is estimated that these patients may account for 10 to 15 percent of the SBS-IF patients. With teduglutide treatment, these patients may regain intestinal nutritional autonomy. However, in SBS patients with intestinal insufficiency who are “on the edge”—those who are challenged by IF and the potential need for PN/IV—teduglutide may prevent the need for PN/IV.

At the other end of the spectrum, the most severe IF patients may not be able to reduce their PN/IV by a full day. Due to their net-secretory condition and very large fecal fluid and electrolyte losses, these patients would become dehydrated within a day, even with teduglutide treatment, if PN/IV was not provided. The benefits of teduglutide in these patients will relate to the reduction in the burden and inconveniences related to the daily PN/IV infusions and in a reduction in the symptoms of malabsorption. In these patients, who are the most disabled by the condition, a 33 percent reduction of their need for PN/IV (from 6 L/day to 4 L/day) would mean significant time off PN/IV. Patients who require additional daytime IV infusions could avoid these additional infusions. Furthermore, a reduction of stool losses of 2 kg/day could dramatically decrease the symptoms and inconveniences of malabsorption.

In patients with intermediary degrees of IF, the consequences of improved intestinal absorption resulting from teduglutide treatment may vary according to the individual patient. Some may prefer days off PN/IV, even at the risk of becoming slightly dehydrated, whereas others will prefer a larger day-to-day stability, requiring smaller PN/IV volumes and possibly shorter daily infusion times.

Conclusion 

The recent approval of teduglutide by the FDA and the EMA bodes well for the clinical use of teduglutide as an adjunct to the limited treatment options for adult SBS patients. However, it should be emphasized that this potent drug should be used only under the guidance and monitoring of skilled caretakers with a substantial knowledge of the pathophysiology of SBS and the management of SBS patients.

Teduglutide treatment has the potential to optimize intestinal absorption, decrease malabsorption and accompanying symptoms, reduce the need, burdens and complications related to PN and IV fluids, and ultimately improve the health-related quality of life in these severely disabled patients. In individual patients with adverse events, adjusted doses may be required depending on tolerability.

Glossary 

analog—a manmade compound that is chemically related to the normally synthesized product 

double-blind study—neither patient nor researcher know whether the drug or a placebo is being given
half-life—the length of time required for half of an absorbed substance to leave the body
hyperadaptation—increased changes of intestinal structure in the setting of SBS
ileal brake feedback mechanism—the ability of the small intestine to slow the movement of unabsorbed nutrients into the colon
intestinal barrier function—the ability of the intestine to control absorption of certain nutrients
intestinal mucosa—lining of the intestine that contains, among others, specialized cells for absorption also known as enterocytes
metabolic balance study—in a balance study, all of the patient’s intake and output are measure
narrow therapeutic index—medicines that have a small range between effective and toxic doses
open-label—patient and clinician know that the patient is receiving the drug being studied
placebo—an inactive substance that looks similar to another active substance
placebo-controlled—results of subjects receiving the drug are compared to the results of subjects who receive a placebo instead
preferred luminal substrates—nutrients that are preferred for fuel (energy) by the intestinal cells
randomized—chosen at random, usually with the researcher being unaware of which subjects are allocated to specific groups

For more information on Gattex®(Teduglide [rDNA origin]) for Injection, visit www.gattex.com.

References

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