Effect of linaclotide in irritable bowel syndrome with constipation (IBS-C): a systematic review and metaanalysis

BackgroundTreatment options for constipation-predominant irritable bowel syndrome (IBS-C) are limited. While linaclotide improved IBS-C symptoms in randomized controlled trials (RCTs), results vary among studies and the magnitude of benefit is unclear. MethodsTwo investigators independently extracted data on study participants, methods and outcomes (i.e., symptoms, quality of life, and adverse events) from eligible articles i.e., RCTs comparing linaclotide with placebo in adult patients with IBS-C with a follow-up of 12weeks or longer. The grading of recommendations assessment, development and evaluation (GRADE) methodology was used to rate the quality of evidence. Key ResultsOf 182 identified citations, three RCTs enrolling 1773 patients met the inclusion criteria. Compared with placebo, fewer patients on linaclotide failed to achieve responses i.e., FDA endpoint (1604 patients, risk ratio [RR]=0.80; 95%CI 0.76-0.85), adequate IBS symptom relief (1773 patients, RR=0.73; 95%CI 0.65-0.82), and clinically meaningful improvement in IBS-QOL (1659 patients, RR=0.78; 95%CI 0.72-0.86). The incidence of diarrhea leading to discontinuation of treatment was higher for linaclotide (1773 patients, RR=14.75; 95%CI 4.04-53.81). The quality of evidence was rated as moderate for FDA endpoint and adequate relief response, high for diarrhea, and low for IBS-QOL. Generalizability may be limited by the study population (i.e., predominantly white female patients), lack of data regarding prior therapy, and availability of few RCTs. The number of patients is insufficient to identify rare adverse events. Conclusions & InferencesLinaclotide is moderately effective in improving symptoms of IBS-C with diarrhea being the major side effect. Further studies are needed to evaluate the long-term efficacy and safety of linaclotide for IBS-C.