Real-world effectiveness and safety of teduglutide in patients with short bowel syndrome

Abstract

This Latin American research supported the use of teduglutide following the early identification of advantageous anatomy (partial colon in continuity) and reduced reliance on parenteral nutrition at baseline. The therapy was maintained for 24 weeks, with the evaluation commencing after 12 weeks of treatment, leading to total parenteral nutrition independence in 26.6% of patients. The reported adverse effects related to the treatment were minimal and aligned with those found in existing literature. Limitations of the study included limited patient recruitment, a lack of discussion regarding the actual treatment duration, no data on routine endoscopies/colonoscopies performed to detect tumor or polyp recurrence during treatment, and the cost implications of such treatment. In a recent article, the median time for adverse events to occur was 393 days (56 weeks). At the same time, the current study lasted 24 weeks, suggesting that theoretically, numerous adverse events may have gone unnoticed.

Key Words: Short bowel syndrome; Parenteral nutrition; Teduglutide; Diarrhea; Malabsorption syndromes

Core Tip: Teduglutide (rDNA) is a Food and Drug Administration sanctioned medication for individuals with short bowel syndrome. The majority of short bowel syndrome patients receive parenteral support, and this medication enhances their chances of achieving parenteral independence to different extents. Daily subcutaneous injections are routinely prescribed, along with regular gastrointestinal colonoscopies/endoscopies to observe the enterocyte dysplasia present in certain individuals. The expensive nature of the treatment significantly discourages its regular use, leading the prescribing physician to adjust its dosage. Nonetheless, only a limited number of treatment-related side effects are seen, making it the sole pharmacological choice for these patients.

TO THE EDITOR

We have thoroughly examined a recent article in the World Journal of Gastrointestinal Pharmacology and Therapeutics by Solar Muñiz et al[1]. This article effectively addresses the safety and efficacy of teduglutide therapy in adult and pediatric patients with short bowel syndrome (SBS) in Argentina, a Latin American nation.

FUNCTION OF TEDUGLUTIDE IN THE TREATMENT OF SBS

The article emphasizes the effectiveness and care of patients with SBS experiencing various levels of intestinal failure on parenteral support (PS). The definition of intestinal failure was updated by the European Society for Clinical Nutrition and Metabolism in 2015 as a decrease in gut function below the essential level for absorbing macronutrients and/or water and electrolytes, necessitating intravenous supplementation to sustain health and/or growth[2]. Most treatment strategies for SBS patients rely on the available intestinal functions, typically beginning with small portions of an oral high-protein, calorie-rich diet, antidiarrheal medications, antisecretory agents, rehydration fluids, and any additional nutritional requirements are fulfilled through PS. The range of intestinal transplantation is constrained because of the risk of morbidity and mortality involved. The delivery of parenteral nutrition in impacted patients involves a collaborative approach, with documented higher morbidity resulting from issues like malabsorption and infections of ports and stomas, which diminishes the quality of life for those affected, showing a 5%-10% mortality rate over a 5-year period[3,4].

Solar Muñiz et al[1] have reported the prevalence of SBS to be 4-20 per 1000000 inhabitants, derived from secondary data from the United States and Europe, emphasizing the importance of the study in such individuals. They evaluated the efficacy of subcutaneous 0.05 mg/kg teduglutide in 21 adults and 24 pediatric patients who had been on PS for the last 7-7.5 years and had already taken one dose of teduglutide prior to and after the authorization of the drug in Argentina. This drug was authorized for use in Argentina in November 2020, and the local health authority mandated the study. To include some patients who were already using this drug before authorization, the study design was quasi-legacy retrospective and partly de novo prospective. They reported a clinical response of ≥ 20% reduction in PS, which was better in adult patients than in pediatric patients, at 90.4% and 83.3%, respectively, with complete PS independence observed in 26.6% of the patients (6 adults and 6 children).

STRENGTHS AND LIMITATIONS OF THE STUDY

The major strength of the study is the inclusion of both adults and children in the study cohort, with the duration of the study extending up to 24 weeks. The treatment-emergent adverse effects such as abdominal distension and pain were reported in 9.5%-16.6% of patients and were similar to those reported at around 10% in other studies[5].

The major limitations of the study are that the included patients had different diseases, ages, and were on different doses and regimens of the drug, creating significant bias. Studies on diseases with low incidence generally have few recruited patients; hence, this heterogeneity among the included patients may be acceptable. Wang et al[6] scrutinized data from 10114 reported events suspected primarily due to teduglutide use in the Food and Drug Administration adverse events reporting system. There was substantial variability in the occurrence of these events, so the median value for such events was reported to be 393 days (with an interquartile range of 97-996 days). They concluded that, apart from abdominal pain, bloating, stomal and catheter infections, nephrolithiasis is a new risk factor to be monitored in such patients. Since our reported study had a duration of only 24 weeks, this event could have been missed. In the reported study[1], baseline PS volume requirement was inversely associated with weaning from PS, implying that if the baseline requirement of PS was small, there was an increased likelihood of that patient becoming a complete responder (P = 0.025). In routine also the gut absorption also improves over time in type 3 patients, so the exact role of teduglutide is questionable in this subset of patients. The characteristics of one type 1 patient (end jejunostomy with no colon in continuation) who was successfully weaned from PS are not elaborated upon. The exact duration of the therapy in the included patients is not clearly defined in the article. The responder incidence in patients with short therapy, if any, is not elaborated in the results.

The Food and Drug Administration recommends a yearly colonoscopy and regular gastrointestinal endoscopies to detect the occurrence of new polyps or malignancies in patients on teduglutide due to the drug’s ability to accelerate neoplastic growth in patients[4]. The reported study period was of six months ' duration, so this important data is not available. de Dreuille et al[7] observed dysplasia in 8 out of 35 patients on teduglutide therapy. Five patients had hyperplastic polyps without dysplasia, while 3 patients had adenomas with low-grade dysplasia. They recommend upper and lower gastrointestinal endoscopies in SBS patients on teduglutide. The authors of a recent article in the American Journal of Gastroenterology refuted earlier claims of increased malignancies in patients on teduglutide compared to the control group. Their findings support the long-term use of this drug in patients. They included 514 patients who had received teduglutide and compared them with 12120 control patients, following up on the patients for over 950 days[8].

The high cost of treatment is another factor to consider when using teduglutide over parenteral nutrition, and this data is not provided in the present study. Raghu et al[9] analyzed the cost-effectiveness criteria of teduglutide and concluded that a cost reduction of teduglutide by over 65% would relate to an improvement in the quality of life of SBS patients. In another study, the cost of teduglutide treatment was compared with the usual parenteral treatment these patients receive. The reported annual cost of daily treatment with teduglutide in adults was higher than that of weekly parenteral treatment (99002 dollars for one day/week treatment for parenteral nutrition compared to 321755 dollars for seven days/week treatment with teduglutide)[10]. The high cost could be the reason for different treatment regimens and durations followed by clinicians.

FUTURE DIRECTIONS

The major limitation to the use of teduglutide is its fast renal clearance with a short half-life, requiring daily dosing via the subcutaneous route[11]. This shortcoming has persuaded researchers to develop new molecules with low clearance, high protein binding, and a long half-life. Currently, phase 2 trials are underway for approval of other glucagon-like peptide molecules like glepaglutide and apraglutide, aiming for a long half-life of around 100 hours, presumably requiring less frequent dosing in patients, which could increase acceptability and decrease the cost of treatment in SBS patients[12]. Thus, with the expected approval of newer drugs, the role of teduglutide treatment may decrease over time.