Efficacy and safety of Guanylyl cyclase C agonists (linaclotide and plecanatide) in patients with irritable bowel syndrome with constipation: a systematic review and meta-analysis of randomized controlled trials.

Background and Objectives: Guanylyl cyclase C (GCC) agonists, including linaclotide and plecanatide, induce prosecretory and analgesic effects by elevating cGMP levels in the intestinal lumen, rendering them significant treatment alternatives for constipation-predominant irritable bowel syndrome (IBS-C). Nonetheless, disparities in efficacy and safety across medications and dosages necessitate a thorough assessment using systematic reviews and meta-analyses, primarily focusing on composite efficacy endpoints approved by the U.S. Food and Drug Administration (FDA). Methods: A systematic search of PubMed, Embase, the Cochrane Library, Web of Science, and ClinicalTrials.gov databases was conducted to identify randomized controlled trials comparing the aforementioned GCC agonists with placebo for the treatment of IBS-C. The search timeframe spans from the establishment of each database to 7 September 2025. Three researchers independently performed literature screening, data extraction, and methodological quality assessment (using the Cochrane Risk of Bias Assessment Tool). The primary endpoint is the proportion of patients achieving the FDA composite endpoint. Secondary endpoints include indicators related to abdominal pain and constipation. The safety outcome was the incidence of diarrhea. Statistical analyses were performed using RevMan 5.4 and Stata 18.0 software. Results: A total of 6 linaclotide and 3 plecanatide trials were included, involving 5,718 patients with IBS-C. Compared with placebo, GCC agonists significantly increased the proportion of patients achieving the FDA composite endpoint (linaclotide 290 μg [relative risk (RR) = 1.78, 95% CI 1.51-2.09]; plecanatide 3 mg [RR = 1.63, 95% CI 1.35-1.96]; plecanatide 6 mg [RR = 1.67, 95% CI 1.36-2.05]). GCC agonists also demonstrated significant advantages across all secondary outcome measures. However, the incidence of diarrhea was significantly higher in both drug groups compared to the placebo group (linaclotide 290 μg [relative risk (RR) = 6.20, 95% CI 4.39-8.76]; plecanatide 3 mg [RR = 5.29, 95% CI 1.59-17.64]; plecanatide 6 mg [RR = 4.00, 95% CI 1.52-10.51]). Conclusion: Linaclotide and plecanatide are effective medications for treating IBS-C, significantly improving both abdominal pain and constipation symptoms while increasing the risk of diarrhea. Their efficacy and safety should be carefully weighed when used clinically. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/view/CRD420251168079, Identifier CRD420251168079.