Gut relief revisited: plecanatide in chronic idiopathic constipation and irritable bowel syndrome with constipation — a systematic review and meta-analysis with GRADE assessment

BACKGROUND: Chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C) are prevalent gastrointestinal disorders with limited effective treatment options. CIC affects approximately 14% of the population worldwide, particularly women, and is marked by difficult defecation, while IBS-C also includes abdominal pain as a core of symptom. Plecanatide, a guanylate cyclase-C (GC-C) agonist approved in 2017, has shown promise in improving stool consistency and symptoms; however, its optimal therapeutic dose remains unclear. METHODS: A comprehensive literature search was conducted through (PubMed, Cochrane CENTRAL, Scopus, Web of Science, and Embase) for randomized controlled trials comparing plecanatide with placebo until August 2025. Primary outcomes included changes in complete spontaneous bowel movements (CSBMs), spontaneous bowel movements (SBMs), and stool consistency. RESULTS: Plecanatide significantly increased the changes in complete spontaneous bowel movements (CSBMs) across all reported doses with mean differences (MDs) of (0.75, 0.92, 0.80, and 1.00, (P < 0.00001), with the greatest improvement observed at the 9 mg dose. Moreover, spontaneous bowel movements (SBMs) improved significantly at 1, 3, and 6 mg, with (MDs: 0.97, 1.50, and 1.58, (P < 0.00001). Stool consistency and reduction in abdominal pain and bloating were observed particularly at 3-6 mg. Furthermore, plecanatide demonstrated consistent efficacy across all doses, with both 1 mg and 9 mg showing significantly greater improvements in CSBMs and SBMs compared to the 0.3 mg dose. Diarrhea was the most frequent adverse event and the primary reason for treatment discontinuation, while other safety outcomes were not significantly affected. CONCLUSION: Plecanatide is generally well-tolerated in the treatment of CIC and IBS-C, with the 3 mg dose, offering the best balance between efficacy and safety. This meta-analysis supports its use as a viable treatment option, though diarrhea remains a dose-related concern. TRIAL REGISTRATION: This systematic review and meta-analysis was registered prospectively with PROSPERO (Registration number: CRD420251066097, Date of registration: 2025-6-10).