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Efficacy and Tolerability of Guanylate Cyclase-C Agonists for Irritable Bowel Syndrome with Constipation and Chronic Idiopathic Constipation: A Systematic Review and Meta-Analysis

Shah, Eric D MD, MBA1; Kim, Hyungjin Myra ScD2; Schoenfeld, Philip MD, MS1,3

American Journal of Gastroenterology: March 2018 - Volume 113 - Issue 3 - p 329–338
doi: 10.1038/ajg.2017.495

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,, 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 μg (Odds ratio (OR)=3.11, 95% CI 1.81–5.34); linaclotide 145 μg (OR=3.25, 2.15–4.91); plecanatide 3 mg (OR=1.99, 1.57–2.51)) and IBS-C (linaclotide 290 μg (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 μg (OR=3.07, 1.97–4.77); linaclotide 145 μg (OR=3.70, 2.69–5.10); plecanatide 3 mg (OR=3.86, 1.83–8.12)) and IBS-C (linaclotide 290 μg (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.

1Division of Gastroenterology, University of Michigan, Ann Arbor, MI, USA

2Center for Statistical Consultation and Research, University of Michigan, Ann Arbor, MI, USA

3John D. Dingell VA Medical Center, Detroit, MI, USA

Correspondence: P Schoenfeld, MD, MS, Division of Gastroenterology, University of Michigan 111M-GAS, 4646 John R Street, John D. Dingell VA Medical Center, Detroit, MI 48201, USA. E-mail:

published online 30 January 2018

SUPPLEMENTARY MATERIAL accompanies this paper at

Received 1 April 2017; accepted 28 November 2017

© The American College of Gastroenterology 2018. All Rights Reserved.
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