Effects of linaclotide in the treatment of chronic constipation and irritable bowel syndrome with constipation: a meta-analysis

Abstract

Objective Linaclotide is a guanylate cyclase-C (GCC) agonist that is found in intestinal epithelial cells and is used when treating chronic constipation (CC) and irritable bowel syndrome with constipation (IBS-C). Several randomized controlled trials (RCTs) were conducted for evaluating its efficacy and safety.

Methods The PubMed, EMBASE, and Cochrane databases and the Web of Science were searched to find multiple RCTs of patients with CC or IBS-C. The Jadad scoring system was used for evaluating each study’s methodological quality, and RevMan5.3 was used for meta-analysis. The composite endpoint reaction approved by the FDA, abdominal pain and discomfort relief, symptom improvement, and diarrhea-related adverse reactions were chosen as observation indicators, and relative risk (RR) and 95% confidence interval (CI) were obtained for quantitative and comprehensive evaluation.

Results Eleven randomized controlled studies were included, consisting of 5 cases of CC and 6 cases of IBS-C. Linaclotide reached the composite endpoint response approved by FDA in the treatment of CC (RR = 3.26, 95% CI: 2.45–4.33), and the composite endpoint response approved by FDA for the treatment of IBS-C (RR = 2.26, 95% CI: 1.86–2.74) was greater than the placebo (both p < 0.00001). The main adverse reactions of linaclotide were gastrointestinal, mostly diarrhea, which was higher than that of the placebo when treating CC (RR = 3.56, 95% CI: 2.76–4.60) and IBS-C (RR = 8.23, 95% CI: 5.69–11.90) (both p < 0.00001).

Conclusion Linaclotide proved to be effective and safe for the treatment of CC and IBS-C compared to the placebo. However, diarrhea is the primary adverse reaction.

Zusammenfassung

Ziel Linaclotid ist ein Guanylatzyklase-C-Agonist, der in Darmepithelzellen vorkommt und bei der Behandlung von chronischer Obstipation und von Reizdarmsyndrom (RDS) mit Obstipation eingesetzt wird. Es wurden etliche randomisierte kontrollierte Studien durchgeführt, um dessen Wirksamkeit und Sicherheit zu evaluieren.

Methoden Die Datenbanken PubMed, EMBASE und Cochrane sowie das Web of Science wurden nach randomisierten kontrollierten Studien (RCTs) über Patienten mit chronischer Obstipation oder RDS mit Obstipation durchsucht. Für die Bewertung der methodischen Qualität der einzelnen Studien wurde das Jadad-Scoring-System verwendet und RevMan5.3 für die Meta-Analyse. Die Kriterien des von der FDA zugelassenen kombinierten Endpunkts – Linderung von Bauchschmerzen und -beschwerden, Symptomverbesserung und durchfallbedingte Nebenwirkungen, wurden als Beobachtungsindikatoren festgelegt und das relative Risiko (RR) und das 95%-Konfidenzintervall (CI) wurden für die quantitative und die umfassenden Bewertung ermittelt.

Ergebnisse Es wurden 11 randomisierte kontrollierte Studien eingeschlossen, darunter fünf über die Anwendung bei chronischer Obstipation und sechs bei RDS mit Obstipation. Linaclotid erreichte den von der FDA zugelassenen kombinierten Endpunkt bei der Behandlung von chronischer Obstipation (RR=3,26,95%CI:2,45–4,33). Bei der Behandlung von RDS mit Obstipation (RR=2,26,95%CI:1,86–2,74) erzielte Linaclotid für den von der FDA zugelassenen kombinierten Endpunkt ein höheres Ansprechen als Placebo (beide P < 0,00001). Die Hauptnebenwirkungen von Linaclotid waren gastrointestinale Reaktionen, hauptsächlich Diarrhö, die bei der Behandlung von chronischer Obstipation (RR=3,56,95% CI:2,76–4,60) und bei RDS mit Obstipation (RR=8,23,95% CI:5,69–11,90) stärker waren als unter Placebo (beide P < 0,00001).

Schlussfolgerung Linaclotid erwies sich bei der Behandlung von chronischer Obstipation und von RDS mit Obstipation im Vergleich zu Placebo als wirksam und sicher. Die Hauptnebenwirkung ist jedoch Diarrhö.

Schlüsselwörter

Linaclotid - chronische Obstipation - Reizdarmsyndrom mit Obstipation - randomisierte kontrollierte Studie - Meta-Analyse

Keywords

linaclotide - CC - IBS-C - RCT - meta-analysis

Publication History

Received: 20 November 2020

Accepted after revision: 25 April 2021

Article published online:
02 July 2021

• References

• 1 Nee JW, Johnston JM, Shea EP. et al. Safety and tolerability of linaclotide for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation: pooled Phase 3 analysis. Expert Rev Gastroenterol Hepatol 2019; 13: 397-406 DOI: 10.1080/17474124.2019.1575203. (PMID: 30791771)
• 2 Hannig G, Tchernychev B, Kurtz CB. et al. Guanylate cyclase-C/cGMP: an emerging pathway in the regulation of visceral pain. Front Mol Neurosci 2014; 7: 31 DOI: 10.3389/fnmol.2014.00031. (PMID: 24795564)
• 3 Silos-Santiago I, Hannig G, Eutamene H. et al. Gastrointestinal pain: unraveling a novel endogenous pathway through uroguanylin/guanylate cyclase-C/cGMP activation. Pain 2013; 154: 1820-1830 DOI: 10.1016/j.pain.2013.05.044. (PMID: 23748116)
• 4 Linaclotide (Linzess) for constipation. Med Lett Drugs Ther 2012; 54: 91-92 (PMID: 23183319)
• 5 Sonu I, Triadafilopoulos G, Gardner JD. Persistent constipation and abdominal adverse events with newer treatments for constipation. BMJ Open Gastroenterol 2016; 3: e000094 DOI: 10.1136/bmjgast-2016-000094. (PMID: 27486521)
• 6 Fukudo S, Miwa H, Nakajima A. et al. High-dose linaclotide is effective and safe in patients with chronic constipation: a phase III randomized, double-blind, placebo-controlled study with a long-term open-label extension study in Japan. Neurogastroenterol Motil 2019; 31: e13487 DOI: 10.1111/nmo.13487. (PMID: 30353619)
• 7 Schoenfeld P, Lacy BE, Chey WD. et al. Low-dose linaclotide (72 μg) for chronic idiopathic constipation: a 12-week, randomized, double-blind, placebo-controlled trial. Am J Gastroenterol 2018; 113: 105-114 DOI: 10.1038/ajg.2017.230. (PMID: 29091082)
• 8 Fukudo S, Miwa H, Nakajima A. et al. Dose-finding study of linaclotide in Japanese patients with chronic constipation: a phase II randomized, double-blind, and placebo-controlled study. Neurogastroenterol Motil 2018; 30: e13442 DOI: 10.1111/nmo.13442. (PMID: 30084233)
• 9 Lacy BE, Schey R, Shiff SJ. et al. Linaclotide in chronic idiopathic constipation patients with moderate to severe abdominal bloating: a randomized, controlled trial. PLoS One 2015; 10: e0134349 DOI: 10.1371/journal.pone.0134349. (PMID: 26222318)
• 10 Lembo AJ, Schneier HA, Shiff SJ. et al. Two randomized trials of linaclotide for chronic constipation. N Engl J Med 2011; 365: 527-536 DOI: 10.1056/NEJMoa1010863. (PMID: 21830967)
• 11 Yang Y, Fang J, Guo X. et al. Linaclotide in irritable bowel syndrome with constipation: a phase 3 randomized trial in China and other regions. J Gastroenterol Hepatol 2018; 33: 980-989 DOI: 10.1111/jgh.14086. (PMID: 29319191)
• 12 Fukudo S, Nakajima A, Fujiyama Y. et al. Determining an optimal dose of linaclotide for use in Japanese patients with irritable bowel syndrome with constipation: a phase II randomized, double-blind, placebo-controlled study. Neurogastroenterol Motil 2018; 30: e13275 DOI: 10.1111/nmo.13275. (PMID: 29278278)
• 13 Fukudo S, Miwa H, Nakajima A. et al. A randomized controlled and long-term linaclotide study of irritable bowel syndrome with constipation patients in Japan. Neurogastroenterol Motil 2018; 30: e13444 DOI: 10.1111/nmo.13444. (PMID: 30136447)
• 14 Rao S, Lembo AJ, Shiff SJ. et al. A 12-week, randomized, controlled trial with a 4-week randomized withdrawal period to evaluate the efficacy and safety of linaclotide in irritable bowel syndrome with constipation. Am J Gastroenterol 2012; 107: 1714-1724 DOI: 10.1038/ajg.2012.255. (PMID: 22986440)
• 15 Chey WD, Lembo AJ, Lavins BJ. et al. Linaclotide for irritable bowel syndrome with constipation: a 26-week, randomized, double-blind, placebo-controlled trial to evaluate efficacy and safety. Am J Gastroenterol 2012; 107: 1702-1712 DOI: 10.1038/ajg.2012.254. (PMID: 22986437)
• 16 Johnston JM, Kurtz CB, Macdougall JE. et al. Linaclotide improves abdominal pain and bowel habits in a phase IIb study of patients with irritable bowel syndrome with constipation. Gastroenterology 2010; 139: 1877-1886 e2
• 17 Bassotti G, Usai-Satta P, Bellini M. Linaclotide for the treatment of chronic constipation. Expert Opin Pharmacother 2018; 19: 1261-1266 DOI: 10.1080/14656566.2018.1494728. (PMID: 29985664)
• 18 Fukudo S, Miwa H, Nakajima A. et al. High-dose linaclotide is effective and safe in patients with chronic constipation: a phase III randomized, double-blind, placebo-controlled study with a long-term open-label extension study in Japan. Neurogastroenterol Motil 2019; 31: e13487 DOI: 10.1111/nmo.13487. (PMID: 30353619)
• 19 Wensel TM, Luthin DR. Linaclotide: a novel approach to the treatment of irritable bowel syndrome. Ann Pharmacother 2011; 45: 1535-1543 DOI: 10.1345/aph.1Q428. (PMID: 22045908)
• 20 Vazquez-Roque MI, Bouras EP. Linaclotide, novel therapy for the treatment of chronic idiopathic constipation and constipation-predominant irritable bowel syndrome. Adv Ther 2013; 30: 203-211 DOI: 10.1007/s12325-013-0012-9. (PMID: 23436110)
• 21 Jani B, Marsicano E. Constipation: evaluation and management. Mo Med 2018; 115: 236-240 (PMID: 30228729)