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

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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).


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.


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.


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.

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This material is the result of work supported in part by resources from the Veterans Health Administration. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs. Dr Schoenfeld is supported by K24-DK1K24DK084208.

Author information


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

    • Eric D Shah
    •  & Philip Schoenfeld
  2. Center for Statistical Consultation and Research, University of Michigan, Ann Arbor, MI, USA

    • Hyungjin Myra Kim
  3. John D. Dingell VA Medical Center, Detroit, MI, USA

    • Philip Schoenfeld


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Competing interests

Guarantor of the article: Philip Schoenfeld.

Specific author contributions: Eric Shah and Philip Schoenfeld conducted the study and collected and interpreted data. Eric Shah drafted the manuscript and both authors edited the manuscript. Eric Shah and Hyung-Jin Myra Kim conducted statistical analysis. All authors approve the final draft submitted.

Financial support: There was no financial support for this study.

Potential competing interests: Dr Shah and Dr Kim have no conflicts of interest to declare. Dr Schoenfeld has served as a consultant and advisory board member for Ironwood Pharmaceuticals, Allergan Pharmaceuticals, Synergy Pharmaceuticals, and Salix Pharmaceuticals. He has served on the speakers bureau for Ironwood Pharmaceuticals, Allergan Pharmaceuticals, and Salix Pharmaceuticals. He is on the Board of Trustees for the GI Health Foundation. He was formerly a partner in MD-Evidence, LLC, a medical education and consulting firm.

Corresponding author

Correspondence to Philip Schoenfeld.

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