Introduction
Irritable bowel syndrome (IBS) is a chronic functional disorder characterized by chronic or recurrent abdominal pain due to bloating/distention and associated with defecation or a change in bowel habits (i.e., constipation, diarrhea, or a mix of constipation and diarrhea) [
1]. This is a relatively common gastrointestinal disorder detected worldwide, and its prevalence in the general population ranges from 3% to 21% depending on the criteria used to define IBS. Accordingly, the prevalence of IBS is around 11% according to the Rome Criteria III [
1,
2] and approximately 5% according to the Rome Criteria IV [
3]. In Spain, the prevalence of IBS-based on the former (Rome Criteria III) is 8.3% [
4]. In addition, the health-related quality of life (HR-QoL) of IBS patients is relatively low, comparable to that of patients with diabetes and heart failure/defect who have a high rate of mortality [
5].
Although the pathophysiology of IBS is not yet fully understood, various events may be responsible for the motility and hypersensitivity disorders associated with the IBS, such as micro-inflammatory phenomena, changes in intestinal permeability and in the gut-brain axis, and alterations to the gut microbiota [
6]. IBS is classified into three main subtypes according to the predominant alteration in bowel habits: constipation-predominant IBS (IBS-C), diarrhea-predominant IBS (IBS-D) and IBS alternating between constipation and diarrhea (IBS-M) [
1]. Patients who meet the diagnostic criteria for IBS but whose bowel habits cannot be accurately categorized into one of these three groups should be categorized as having unclassified IBS (IBS-U).
In clinical practice, IBS-C represents a challenge in terms of both diagnosis and therapeutic management [
7], which makes it necessary to establish specific clinical guidelines [
8]. Currently, the management of this disorder is based on a combination of lifestyle changes and the administration of certain non-specific symptomatic treatments. Linaclotide is a selective agonist of guanylate cyclase C (GC-C). The GC-C receptor is expressed on the luminal surface of intestinal epithelial cells, and its activation leads to a significant increase in the intra- and extracellular concentrations of cyclic guanosine monophosphate (cGMP). This cGMP is involved in a wide range of physiological processes, including the regulation of intestinal fluid homeostasis [
9,
10] and the modulation of afferent gut nerve activity, which may be related to its analgesic effects [
11‐
13]. The efficacy and safety of linaclotide in patients with IBS-C have been demonstrated in two randomized, double-blind, placebo-controlled phase III multicenter clinical trials [
14,
15]. An analysis of both these trials was published in 2013 [
16], presenting the pre-specified analysis of primary efficacy end points required by the European Medicines Agency (EMA). According to the results of these studies, linaclotide treatment significantly improved abdominal pain/discomfort and the overall relief of IBS-C symptoms compared with a placebo over 12 and 26 weeks (53.6% linaclotide vs. 36.0% placebo at week 26, [
16]). Regarding efficacy, the odds ratio of a response to linaclotide relative to the placebo was 1.95 (95% confidence interval, CI 1.3–2.9:
p < 0.0001 [
16]).
On the basis of a meta-analysis, linaclotide was shown to improve bowel function and to reduce abdominal pain and overall IBS-C severity relative to a placebo [
17]. Regarding safety, the most common treatment-emergent adverse event (AE) was diarrhea, which was experienced by approximately 20% of patients who received linaclotide. In 90% of these patients diarrhea was considered to be mild or moderate, and it was only considered to be severe in 2% of patients, in all of whom it was resolved within a few days of drug withdrawal [
18]. Thus, the data from clinical trials and the low bioavailability of the compound make linaclotide a drug with a favorable safety profile.
Based on the above, in November 2012 linaclotide received European marketing authorization for the symptomatic treatment of moderate to severe IBS-C in adults. Indeed, it is currently the only drug specifically indicated for the treatment of IBS-C [
19]. Linaclotide has also been approved in the USA by the Food and Drug Administration (FDA) for the treatment of IBS-C and functional constipation at a dose of 290 and 145 µg, respectively [
20]. Although therapeutic management with linaclotide is relatively simple, some doubts may arise as it is a first-in-class medication for the treatment of IBS-C with a novel mechanism of action. Hence, the purpose of this review is to evaluate the evidence currently available, as well as the experiences of a group of clinical experts with linaclotide, to facilitate and optimize its use in clinical practice, establishing common guidelines for patient monitoring.
Methods
This article is based on previous studies and does not involve any new studies carried out on human or animal subjects by any of the authors. In May 2016, a group of experts in gastroenterology was convened to review the efficacy and safety of linaclotide and to develop an updated expert consensus report for the treatment of patients with IBS-C. At this meeting, the Coordinating Committee for this project was defined (made up of the first and second authors of this manuscript), and all the authors deliberated on the main questions that need to be addressed regarding the management of IBS-C patients treated with linaclotide in daily clinical practice.
Similarly, a literature search was carried out in May 2016 for English, French and Spanish language articles indexed in PubMed or EMBASE and for abstracts at DDW or UEGW. The search terms used were “irritable bowel syndrome” OR “constipation-predominant irritable bowel syndrome” AND “linaclotide”. Additionally, relevant national and international guidelines were also scrutinized. All papers fulfilling these criteria were studied before drafting the consensus. An initial version of the guidelines was produced by the Coordinating Committee, and it was reviewed by the expert panel who recommended modifications. The Coordinating Committee evaluated the panel’s comments and drafted a document that included the necessary modifications. Subsequent revisions were performed based on feedback from all the authors until a consensus was reached on the final validated text at a meeting held in October 2016.
Conclusions
Irritable bowel syndrome is a highly prevalent chronic functional gastrointestinal disorder with a complex underlying pathophysiology. It is characterized by abdominal pain and/or discomfort, altered bowel function and a recurrence of symptoms over an extended period of time. Altered bowel function, a hallmark of IBS, may present as constipation (irritable bowel syndrome with constipation), diarrhea or alternating periods of constipation and diarrhea (mixed irritable bowel syndrome).
Despite their widespread use, traditional treatments for IBS-C are of limited effectiveness in improving IBS symptoms, such as bulking agents, stool softeners, laxatives and antispasmodics. Linaclotide is a selective agonist of GC-C, which is selectively expressed in the brush border membranes of the intestinal mucosa from the duodenum to the rectum. The results of clinical trials have demonstrated that linaclotide can improve a wide spectrum of IBS symptoms in patients with IBS-C, including abdominal pain, bloating and constipation.
The panel agrees to recommend taking the drug 30 min before a meal, preferably breakfast. Additionally, it is advisable to warn the patient about the incidence of diarrhea and make adequate recommendations to avoid this side effect. This consensus highlights key elements that will help clinicians standardize linaclotide use in clinical practice, establishing common guidelines to monitor patients.
Acknowledgements
The authors wish to thank Allergan Laboratories for their collaboration with the logistics of the meetings and the assistance with the medical writing. It should be noted that Allergan S.A. was not involved in the preparation of the recommendations nor did the company in any way influence the scientific consensus reached. The authors were not employed by Allergan S.A. Article processing charges and the open access fee were funded by Allergan S.A. All authors had full access to all of the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis.
Editorial assistance in the preparation of this manuscript was provided by Dr. Antonio Martinez of Ciencia y Deporte S.L. and Mark Sefton of Biomedred S.L. Support for this assistance was funded by Allergan S.A.
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole and have given final approval to the version to be published.