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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.
Am J Gastroenterol 2018; 113(3):329-338AJ

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.

Authors+Show Affiliations

Division of Gastroenterology, University of Michigan, Ann Arbor, MI, USA.Center for Statistical Consultation and Research, University of Michigan, Ann Arbor, MI, USA.Division of Gastroenterology, University of Michigan, Ann Arbor, MI, USA. John D. Dingell VA Medical Center, Detroit, MI, USA.

Pub Type(s)

Journal Article
Meta-Analysis
Systematic Review

Language

eng

PubMed ID

29380823

Citation

Shah, Eric D., et al. "Efficacy and Tolerability of Guanylate Cyclase-C Agonists for Irritable Bowel Syndrome With Constipation and Chronic Idiopathic Constipation: a Systematic Review and Meta-Analysis." The American Journal of Gastroenterology, vol. 113, no. 3, 2018, pp. 329-338.
Shah ED, Kim HM, Schoenfeld P. Efficacy and Tolerability of Guanylate Cyclase-C Agonists for Irritable Bowel Syndrome with Constipation and Chronic Idiopathic Constipation: A Systematic Review and Meta-Analysis. Am J Gastroenterol. 2018;113(3):329-338.
Shah, E. D., Kim, H. M., & Schoenfeld, P. (2018). Efficacy and Tolerability of Guanylate Cyclase-C Agonists for Irritable Bowel Syndrome with Constipation and Chronic Idiopathic Constipation: A Systematic Review and Meta-Analysis. The American Journal of Gastroenterology, 113(3), pp. 329-338. doi:10.1038/ajg.2017.495.
Shah ED, Kim HM, Schoenfeld P. Efficacy and Tolerability of Guanylate Cyclase-C Agonists for Irritable Bowel Syndrome With Constipation and Chronic Idiopathic Constipation: a Systematic Review and Meta-Analysis. Am J Gastroenterol. 2018;113(3):329-338. PubMed PMID: 29380823.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Efficacy and Tolerability of Guanylate Cyclase-C Agonists for Irritable Bowel Syndrome with Constipation and Chronic Idiopathic Constipation: A Systematic Review and Meta-Analysis. AU - Shah,Eric D, AU - Kim,Hyungjin Myra, AU - Schoenfeld,Philip, Y1 - 2018/01/30/ PY - 2017/04/01/received PY - 2017/11/28/accepted PY - 2018/1/31/pubmed PY - 2019/8/7/medline PY - 2018/1/31/entrez SP - 329 EP - 338 JF - The American journal of gastroenterology JO - Am. J. Gastroenterol. VL - 113 IS - 3 N2 - 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. SN - 1572-0241 UR - https://www.unboundmedicine.com/medline/citation/29380823/Efficacy_and_Tolerability_of_Guanylate_Cyclase_C_Agonists_for_Irritable_Bowel_Syndrome_with_Constipation_and_Chronic_Idiopathic_Constipation:_A_Systematic_Review_and_Meta_Analysis_ L2 - http://Insights.ovid.com/pubmed?pmid=29380823 DB - PRIME DP - Unbound Medicine ER -