DDW 2011: STEPS Study Shows Promising Results for Patients with Short Bowel Syndrome

GLP-2 analog teduglutide reduces the need for parenteral support in patients with short bowel syndrome-intestinal failure.

In patients with short bowel syndrome-intestinal failure (SBS/IF), teduglutide (TDG), a dipeptidyl peptidase-IV degradation-resistant, recombinant analog of human GLP-2, reduces the need for parenteral support, according to findings from STEPS (Study of Teduglutide Effectiveness in Parenteral Support-dependent Short Bowel Syndrome) in an oral session and press conference at Digestive Disease Week 2011.

STEPS investigator Palle B. Jeppesen, MD, associate professor of gastroenterology at Rigshospitalet, University Hospital of Denmark, said GLP-2 repairs and restores functional integrity of the intestinal mucosa, improving fluid and nutrient balance by enhancing absorption. Enhanced absorption ensues from GLP-2-induced increases in villus height/diameter and crypt depth, dilatation and thickening of mucosa and increases in RNA/DNA content. It has been shown also in some SBS/IF patients to promote rapid gastric emptying and gastric acid hypersecretion, intestinal blood flow, and adaptation. TDG has been show further to increase wet weight absorption (equivalent to 750 ml/d) and urine sodium excretion, and to reduce fecal weight and energy excretion in SBS patients.

SBS/IF, Jeppesen noted, is generally the result of surgical resection, congenital defect, or disease-related loss of absorption. SBS/IF patients are characterized by an inability to maintain protein, energy, fluid and electrolyte levels and micronutrient balance. Compensatory fluid or nutritional support for this malabsorption is accomplished through hyperphagia (additional oral intake) and intravenous parenteral support (PN/IV). Intestinal rehabilitation may be addressed through intestinal growth factors, anti-secretory agents, anti-diarrheals, rehydration solutions and dietary modifications.

Among the medical needs of SBS/IF patients, Dr. Jeppesen listed decreasing dependence on PN/IV, and reducing the morbidity and life-threatening complications associated with parenteral support, which include catheter-related blood stream infections, venous thrombosis and intestinal failure-associated liver disease. There is further need, he added, to improve quality of life and to seek novel treatment options.

In order to evaluate TDG’s ability to reduce the volume of parenteral support (intravenous fluids, nutrients, or both), 86 SBS-IF subjects, dependent on parenteral support for ≥1 year were enrolled in a randomized, double-blind, placebo-controlled, parallel-group, multinational, multicenter study. After an initial optimization/stabilization period of parenteral support volume (ensuring stable urine output), subjects were randomized to subcutaneous TDG (0.05 mg/kg/d) or placebo, once daily, for 24 weeks. Parenteral support volumes were reduced at scheduled visits if urine volumes exceeded baseline by ≥10%. Response was defined as a 20% to 100% reduction from baseline in weekly parenteral support volume at weeks 20 and 24. The primary efficacy endpoint was a comparison of the percentage of responders in the teduglutide and placebo groups.

Among 78 study completers, 39 received TDG and 39 received placebo. In the intention-to-treat (ITT) population, responses were reported in 63% (27/43) of SBS-IF subjects receiving TDG and in 30% (13/43) receiving placebo (p=0.002). At week 24, TDG reduced mean weekly parenteral support volume by 4.4 L/wk (12.9 L/wk at baseline), as compared with 2.3 L/wk (13.2 L/wk at baseline; p≤0.001) volume reduction with placebo. Significantly more TDG-treated subjects than placebo treated were able to reduce the number of infusion days by 1 or more days (54% versus 23%; p=0.0047). Despite the significant parenteral support volume reduction, however, body weight remained constant.

TDG was well tolerated. Of the eight dropouts, three of four in the placebo group and two of four in the teduglutide group were due to adverse events (AEs). AEs were found in 83% (35/42) treated with teduglutide versus 79% (34/43) for placebo. The most common AEs were abdominal pain, nausea, gastrointestinal stoma complications, and abdominal distension.

Jeppesen pointed out that more than 97% of the subjects who completed this study elected to enroll in an open-label 24-month continuation study.

At the DDW press conference, Jeppesen emphasized the debilitating nature of SBS/IF, saying that while the normal absorptive surface area of the gut is like that of a tennis court, in these patients it is closer to that of a table tennis surface. “Their treatment is isolating; with their nightly infusions they alternate between dehydration and fluid overload and have quality of life comparable to those on dialysis,” he said. Jeppesen added that in actual practice, the 30% reduction in parenteral support volume with TGD treatment might allow an additional two days off from parenteral support. “They cherish days off so they can lead a more normal life.”