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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
Open accessAbstract
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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“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]
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“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]
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“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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Metadata
- Authors
- Shah, E. D., Kim, H. M., & Schoenfeld, P.
- Affiliations
- University of Michigan (US)
- Corresponding author
- Schoenfeld, Philip
- Venue
- American Journal of Gastroenterology
- Published
- 2018-03
- Volume
- 113
- Issue
- 3
- Pages
- 329-338
- ISSN
- 0002-9270 (ISSN-L)
- 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
- green
- www.ncbi.nlm.nih.gov
- 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 › Urology › 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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