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Linaclotide: a new option for the treatment of irritable bowel syndrome with constipation and chronic idiopathic constipation in adults.

ABSTRACT: Chronic idiopathic constipation (CC) and irritable bowel syndrome with predominant constipation (IBS-C) are the 2 most common conditions among functional gastrointestinal disorders. Despite current multiple therapeutic options, treatment remains challenging and dissatisfactory to many patients. Linaclotide is a novel therapeutic agent, which is a guanylate cyclase receptor agonist that stimulates water secretion from the intestinal epithelium by promoting chloride and bicarbonate efflux into the lumen through activation of the cystic fibrosis transmembrane conductance regulator. Clinical trials have demonstrated that linaclotide is effective, safe and well tolerated in patients with CC and IBS-C. This review article highlights the mechanism of action of linaclotide, reviews published literature based on a search of databases, including MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL), up to February 2013, and compares its utility with other currently available agents.

SUBMITTER: Parker CH

PROVIDER: S-EPMC4020405 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Linaclotide: a new option for the treatment of irritable bowel syndrome with constipation and chronic idiopathic constipation in adults.

Parker Colleen H CH Yuan Yuhong Y Liu Louis Wing Cheong LW

Clinical medicine insights. Gastroenterology 20130731

Chronic idiopathic constipation (CC) and irritable bowel syndrome with predominant constipation (IBS-C) are the 2 most common conditions among functional gastrointestinal disorders. Despite current multiple therapeutic options, treatment remains challenging and dissatisfactory to many patients. Linaclotide is a novel therapeutic agent, which is a guanylate cyclase receptor agonist that stimulates water secretion from the intestinal epithelium by promoting chloride and bicarbonate efflux into the ...[more]

PMID: 24833940

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Project description:IntroductionTo inform the patient-centered discussion regarding comparative outcomes with irritable bowel syndrome/chronic idiopathic constipation pharmacotherapy, we evaluated reasons and timing of discontinuation of FDA-approved pharmacotherapy for irritable bowel syndrome and chronic idiopathic constipation in a large observational real-world cohort.MethodsWe identified patients initiating lubiprostone or linaclotide within the University of Michigan Electronic Medical Record (2012-2016). Medication start and stop dates were determined in manual chart review including detailed review of all documentation including office notes and telephone encounters. A Cox model was constructed to predict the hazard of discontinuation.ResultsOn multivariate analysis of 1,612 patients, linaclotide users had a lower risk of discontinuing therapy than lubiprostone users for any reason (hazard ratio [HR] = 0.6, 95% confidence interval [CI] 0.5-0.8). At 3 and 12 months, the overall discontinuation rates were 23% and 43% for lubiprostone compared with 14% and 24% for linaclotide. Over the first year of therapy, more than half of discontinuations due to intolerance occurred in the first 3 months for both drugs. Linaclotide users were more likely to discontinue due to intolerance (HR = 1.6 [95% CI, 1.2-2.3]) but less likely to discontinue due to insufficient efficacy of therapy (HR = 0.5 [95% CI, 0.4-0.8]). IBS diagnosis increased the hazard of discontinuation of lubiprostone relative to linactolide (HR = 1.4, 95% CI, 1.1-1.6). Loss of prescription drug coverage remained a common reason for discontinuation over the first year of therapy.DiscussionIndividuals appear more likely to discontinue lubiprostone than linaclotide overall, but more likely to discontinue linaclotide compared with lubiprostone due to intolerance (mostly diarrhea). Most discontinuations due to intolerance occur in the first 3 months. These results may be useful in individualized treatment selection and enhancing patient knowledge regarding long-term outcomes.

Project description:Irritable bowel syndrome (IBS) is a functional bowel disorder characterized by chronic or recurrent abdominal pain in association with defecation or a change in bowel habits. A predominant disorder of bowel habits, IBS is classified into three main subtypes: constipation-predominant IBS (IBS-C), diarrhea-predominant IBS (IBS-D) and IBS alternating between constipation and diarrhea (IBS-M). Linaclotide is a first-in-class, oral, once-daily guanylate cyclase-C receptor agonist (GC-CA) that is licensed for the symptomatic treatment of moderate-to-severe IBS-C in adults. This review aims to facilitate and optimize clinical practices, establishing common guidelines to monitor patients with IBS-C that are treated with linaclotide.A group of experts in functional digestive disorders was convened to review the efficacy and safety of linaclotide and to develop an updated consensus report for the treatment of patients with IBS-C. A search was performed for English, French and Spanish language articles in PubMed. On the basis of the articles identified, an initial document was drafted addressing different issues frequently raised by general practitioners and GI specialists that are related to the prescription, efficacy and safety of linaclotide. This document was then reviewed and modified by the expert panel until a final text was agreed upon and validated.Based on the evidence, the panel addressed the following recommendations: (1) Linaclotide is indicated for the treatment of moderate to severe IBS-C in adults; (2) it is recommended that patients take linaclotide continuously and not sporadically; (3) patients should be warned about the risk of diarrhea and given choices concerning how to deal with this possible side effect; (4) the absence of tachyphylaxis or potential risks implies that linaclotide treatment can be maintained for long periods of time.This document seeks to lay down a set of recommendations and to identify key issues that may be useful for the clinical management of IBS-C patients treated with linaclotide.

Project description:OBJECTIVES:Linaclotide and plecanatide are guanylate cyclase-C (GCC) agonists for the treatment of chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C). Our objective is to evaluate the efficacy and tolerability of GCC agonists based on data from multiple randomized controlled trials (RCTs). METHODS:We searched PubMED, EMBASE, Cochrane databases, clinicaltrials.gov, major conference abstracts, Food and Drug Administration (FDA) websites, and United States Securities and Exchange Commission filings of drug sponsors to identify RCTs of CIC or IBS-C patients. We assessed efficacy based on FDA-approved composite responder endpoints, diarrhea as an adverse event, and study withdrawal owing to diarrhea for each therapy. Trial results were pooled using DerSimonian and Laird random effects model of meta-analysis and exact logistic regression when appropriate with 95% confidence intervals. Meta-regression was performed to compare outcomes between therapies adjusting for placebo event rate. RESULTS:Eight linaclotide trials (five CIC; three IBS-C) and seven plecanatide trials (four CIC; three IBS-C) evaluating 10,369 patients met inclusion criteria. FDA publications documented that different definitions for diarrhea were used in linaclotide vs. plecanatide trials. Both drugs were efficacious in treating CIC (linaclotide 72??g (Odds ratio (OR)=3.11, 95% CI 1.81-5.34); linaclotide 145??g (OR=3.25, 2.15-4.91); plecanatide 3?mg (OR=1.99, 1.57-2.51)) and IBS-C (linaclotide 290??g (OR=2.43, 1.48-3.98); plecanatide 3?mg (OR=1.87, 1.47-2.38); plecanatide 6?mg (OR=1.92, 1.48-2.48)). Diarrhea occurred in excess of placebo in treating CIC (linaclotide 72??g (OR=3.07, 1.97-4.77); linaclotide 145??g (OR=3.70, 2.69-5.10); plecanatide 3?mg (OR=3.86, 1.83-8.12)) and IBS-C (linaclotide 290??g (OR=8.02, 5.20-12.37); plecanatide 3?mg (OR=5.55, 1.62-19.00); plecanatide 6?mg (OR=4.13, 1.57-10.83)). Based on meta-regression, there were no statistically significant differences between therapies in odds ratios for efficacy, diarrhea, or diarrhea-related study withdrawals. CONCLUSIONS:Both linaclotide and plecanatide demonstrate similar efficacy and tolerability in treating IBS-C and CIC. No differences in odds of diarrhea were seen between linaclotide and plecanatide.

Dataset Information

Linaclotide: a new option for the treatment of irritable bowel syndrome with constipation and chronic idiopathic constipation in adults.

Publications

Linaclotide: a new option for the treatment of irritable bowel syndrome with constipation and chronic idiopathic constipation in adults.

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