Gastroenterology

Gastroenterology

Volume 155, Issue 6, December 2018, Pages 1753-1763
Gastroenterology

Original Research
Full Report: Clinical—Alimentary Tract
Efficacy of Secretagogues in Patients With Irritable Bowel Syndrome With Constipation: Systematic Review and Network Meta-analysis

https://doi.org/10.1053/j.gastro.2018.08.021Get rights and content

Background & Aims

Several secretagogues have been approved for the treatment of irritable bowel syndrome with constipation (IBS-C). However, their relative efficacy is unclear because there have been no head-to-head randomized controlled trials. We conducted a network meta-analysis to compare their efficacies in patients with IBS-C.

Methods

We searched MEDLINE, EMBASE, EMBASE Classic, and the Cochrane Central Register of Controlled Trials through June 2018 to identify randomized controlled trials assessing the efficacy of secretagogues in adults with IBS-C. Trials included in the analysis reported a dichotomous assessment of overall response to therapy, and data were pooled using a random-effects model. Efficacy and safety of secretagogues were reported as a pooled relative risk with 95% confidence interval to summarize the effect of each comparison tested, and treatments were ranked according to their P score.

Results

We identified 15 eligible randomized controlled trials of secretagogues that included 8462 patients. Linaclotide, lubiprostone, plecanatide, and tenapanor were superior to placebo for the treatment of IBS-C. Linaclotide (290 μg once daily) was ranked first in efficacy based on the end point recommended by the Food and Drug Administration for trials in IBS-C, the primary end point used in each trial, abdominal pain, and complete spontaneous bowel movements. Tenapanor (50 mg twice daily) was ranked first for decreasing bloating. Total numbers of adverse events were significantly larger with linaclotide (290 and 500 μg once daily) and plecanatide (3 mg once daily) compared with placebo. However, plecanatide 6 mg once daily ranked first for safety. Diarrhea was significantly more common with all drugs, except lubiprostone (8 μg twice daily). Nausea was significantly more common in patients who received lubiprostone.

Conclusions

In a network analysis of randomized controlled trials of secretagogues for IBS-C, we found all drugs to be superior to placebo. Efficacy was similar among individual drugs and dosages for most end points. However, data were extracted at the 12-week time point, so the long-term relative efficacy of these drugs is unknown.

Section snippets

Search Strategy and Study Selection

A search of the medical literature was conducted using MEDLINE (1947 to June 2018), EMBASE, EMBASE Classic (1947 to June 2018), and the Cochrane Central Register of Controlled Trials. We also searched clinicaltrials.gov for unpublished trials or supplementary data for potentially eligible studies. RCTs examining the effect of secretagogues (lubiprostone, linaclotide, plecanatide, and tenapanor) in adult patients (>16 years) with IBS-C were eligible for inclusion (Supplementary Table 1).

Results

The search strategy generated 1163 citations, 75 of which appeared to be relevant to the systematic review and were retrieved for further assessment (Figure 1). Of these, 62 were excluded for various reasons, leaving 13 eligible articles reporting on 15 trials that included a total of 8462 patients. There were 3 RCTs reported in 2 articles20, 21 of lubiprostone in IBS-C, 6 trials of linaclotide (4 of which used linaclotide 290 μg once daily [od], the licensed dose in the United States,22, 23, 24

Discussion

This systematic review and network meta-analysis demonstrated that all secretagogues tested in IBS-C to date were more effective than placebo for global symptoms. Although all drugs performed similarly, linaclotide 290 μg od was ranked first for efficacy for global symptoms. This was irrespective of the outcome measure used, whether the FDA-recommended end point to define relief of global symptoms in IBS-C or the primary end point used to define global symptom improvement in each trial. For the

Acknowledgments

We are grateful to Dr Takeshi Kanno for translation of one of the eligible articles.

Author contributions: Christopher J. Black, Nicholas E. Burr, Eamonn M.M. Quigley, Paul Moayyedi, Lesley A. Houghton, and Alexander C. Ford conceived and drafted the study. Alexander C. Ford and Christopher J. Black collected all data. Christopher J. Black, Alexander C. Ford, and Nicholas E. Burr analyzed and interpreted the data. Christopher J. Black, Alexander C. Ford, and Nicholas E. Burr drafted the

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    Conflicts of interest Christopher J. Black and Nicholas E. Burr report no conflicts of interest. Eamonn M.M. Quigley has acted as a consultant for Allergan, Ironwood, Salix, Synergy, and Vibrant and received research funding from Vibrant and 4D Pharma. Paul Moayyedi has acted as a consultant for Allergan, Lupin, Shire, and Takeda and received research funding from Allergan and Takeda. Lesley A. Houghton has acted as a consultant for Pfizer USA and received research funding from Takeda USA. Alexander C. Ford has acted as a consultant for and received researching funding from Almirall.

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    Authors share co-senior authorship.

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