Tenapanor for Irritable Bowel Syndrome With Constipation (IBS-C): A Systematic Review of Randomized Trials Assessing...

Tenapanor, a minimally absorbed inhibitor of intestinal Sodium/Hydrogen Exchanger 3 (NHE3), is approved for IBS with constipation (IBS‑C). We systematically reviewed randomized trials that used Food and Drug Administration (FDA)‑aligned weekly composite responders to consolidate the evidence on their efficacy, durability of benefit, and risk of bias. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020, we searched major databases and trial registries (January 2015 - August 2025) for adult, placebo‑controlled parallel‑group randomized controlled trials (RCTs) (≥12 weeks) of oral Tenapanor in IBS‑C. The primary endpoint was the FDA composite (≥30% abdominal pain reduction and ≥1 additional complete spontaneous bowel movement in the same week, sustained ≥6/12 or ≥13/26 weeks). Patient‑reported outcomes were collected via daily e‑diaries. Risk of bias (RoB) was assessed with RoB-2; certainty with grading of recommendations, assessment, development, and evaluation (GRADE). Synthesis was narrative with supportive pooled estimates from the evidence profile. We found six studies that met our inclusion criteria: three double‑blind RCTs (one Phase 2b, two Phase 3) plus an open‑label extension and two post‑hoc pooled analyses. Across RCTs using the approved 50 mg twice‑daily dose, composite responder rates favored Tenapanor: Phase 2b 50.0% vs 23.6%; Tenapanor IBS-C Phase 3 clinical program (T3MPO)‑1 27.0% vs 18.7%; T3MPO‑2 36.5% vs 23.7% (placebo‑adjusted differences 8-26%). Durable response also favored Tenapanor (e.g., 9/12 weeks: 13.7% vs 3.3% and 18.4% vs 5.3%; 13/26 weeks: 35.5% vs 24.3%). Pooled estimates indicated a higher likelihood of response [composite relative risk (RR) 1.59, 95% confidence interval (CI) 1.33-1.90; abdominal‑pain responder RR 1.32, 95% CI 1.17-1.49] with minimal heterogeneity. Diarrhea was the principal adverse event (≈13-16%) and the most common reason for discontinuation; serious events were uncommon. Overall risk of bias was low to some concerns; certainty of evidence was moderate. In conclusion, Tenapanor confers clinically meaningful, durable improvements in pain and bowel function for adults with IBS‑C, with predictable mechanism‑related diarrhea as the main tolerability trade‑off. Head‑to‑head trials versus other prosecretory agents and longer‑term pragmatic studies are priorities, but current evidence supports Tenapanor as a patient‑centered option within guideline‑directed care.