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Cited by 119Gastrointestinal motility and disordersPelvic floor disorders treatmentsCongenital gastrointestinal and neural anomalies

Efficacy and tolerability of guanylate cyclase-C agonists for irritable bowel syndrome with constipation and chronic idiopathic constipation: A systematic review and meta-analysis

Open access
Shah, Eric D, Kim, Hyungjin Myra, Schoenfeld, Philip·2018·American Journal of Gastroenterology
DOI 10.1038/ajg.2017.495PMC PMC7213047
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Abstract

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 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.

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  • Use of linaclotide might be associated with diarrhea leading to discontinuation or dose reduction, but this was not very common (in one study, 4.7% discontinued because of diarrhea).

    “The use of linaclotide might be associated with diarrhea leading to discontinuation or dose reduction; however, this was not very common (in one study, 4.7% discontinued the medication because of diarrhea). 68,69”

    From American Gastroenterological Association-American College of Gastroenterology Clinical Practice Guideline: Pharmacological Management of Chronic Idiopathic Constipation (2023) · cites this paper as [68]

    The Results sections on diarrhea-related outcomes in IBS-C and CIC trials report that linaclotide was associated with study withdrawal due to diarrhea. The Discussion suggests dose reduction as a possible way to manage diarrhea, but does not report it as an observed outcome. The passages do not substantiate the claimed 4.7% discontinuation rate; page numbers are unavailable in our copy. (LLM, conf=0.86)

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  • Participants treated with plecanatide might have higher rates of reported diarrhea leading to treatment discontinuation compared with placebo (RR 5.39, 95% CI 2.40-12.11; 27 more per 1,000, 95% CI 9 to 69 more).

    “Participants treated with plecanatide might have higher rates of reported diarrhea leading to treatment discontinuation (RR 5.39, 95% CI 2.40-12.11), 27 more per 1,000 (from 9 to 69 more).”

    From American Gastroenterological Association-American College of Gastroenterology Clinical Practice Guideline: Pharmacological Management of Chronic Idiopathic Constipation (2023) · cites this paper as [68]

    The Results sections on CIC and IBS-C trials report that plecanatide was associated with more study withdrawals due to diarrhea than placebo. They report dose- and condition-specific odds ratios, however, not the claimed RR of 5.39 (95% CI 2.40–12.11) or 27 additional withdrawals per 1,000 (95% CI 9–69). (LLM, conf=0.88)

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  • Secretory mechanisms are common therapeutic targets of medications used to treat FGIDs.

    “Secretory mechanisms are common therapeutic targets94, 95 of medications used to treat FGIDs.”

    From The gut Microbiome in adult and pediatric functional gastrointestinal disorders (2019) · cites this paper as [95]

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Research works printed but not linked: 2

  1. [15]Hanes LS. Clinical review (Application Number 208745Orig1s000). US Food Drug Adm 2016; 140: 140.
  2. [16]Wynn EL. Clinical review (Application Number 202811Orig1s000). US Food Drug Adm 2012; 169: 169.

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Authors
Shah, E. D., Kim, H. M., & Schoenfeld, P.
Affiliations
University of Michigan (US)
Corresponding author
Schoenfeld, Philip
ORCID
Venue
American Journal of Gastroenterology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2018-03
Volume
113
Issue
3
Pages
329-338
ISSN
0002-9270 (ISSN-L)
DOI
10.1038/ajg.2017.495
PMC
PMC7213047
OpenAlex
W2789261715
Cited by
119
References
28
Citations by year
2026: 3 · 2025: 10 · 2024: 8 · 2023: 17 · 2022: 13 · 2021: 26 · 2020: 16 · 2019: 12 · 2018: 14
FWCI
3.03
Type
journal article
Language
en
Open access
Locations
  • The American Journal of Gastroenterology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Ironwood Pharmaceuticals, Incorporated
  • National Institute of Diabetes and Digestive and Kidney Diseases (K24DK084208, T32DK062708)
Topics
  • Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
  • Health Sciences › Medicine › Rheumatology › Pelvic floor disorders treatments
  • Health Sciences › Medicine › Surgery › Congenital gastrointestinal and neural anomalies
Keywords
guanylate cyclase-C agonist, linaclotide, plecanatide, irritable bowel syndrome with constipation, chronic idiopathic constipation, diarrhea, drug tolerability, drug efficacy, meta-regression
MeSH terms
Guanylyl Cyclase C Agonists, Chronic Disease, Constipation, Diarrhea, Humans, Peptides, Randomized Controlled Trials as Topic, Irritable Bowel Syndrome, Natriuretic Peptides

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