THE EFFECT OF TENAPANOR ON HYPERPHOSPHATEMIA IN DIALYSIS PATIENTS: AN UPDATED SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS

Hyperphosphatemia is a common complication in dialysis patients, associated with increased cardiovascular risk and vascular calcification, atherosclerosis, and bone disorders. Standard treatments include dietary changes, phosphate binders (PBs), and intensified dialysis, but these often fail due to hidden dietary phosphates, poor adherence, and side effects. Traditional phosphate binders (PBs) often fail due to pill burden and poor adherence. Tenapanor, a sodium/hydrogen exchanger isoform 3 (NHE3) inhibitor, offers a novel mechanism by reducing intestinal phosphate absorption. Previous meta-analyses included limited RCTs (5–7 studies), while this updated meta-analysis focuses solely on RCTs and includes a subgroup analysis of Japanese patients, supporting more personalized treatment strategies. The KDIGO guidelines now refer to “phosphate-lowering therapies” to reflect emerging options like tenapanor, despite limited evidence. This study aims to clarify tenapanor’s efficacy compared to placebo in dialysis patients.

This systematic review was prospectively registered with International Prospective Register of Systematic Reviews (PROSPERO) under the number CRD42024545282 and conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). We systematically searched Pubmed, Embase and Cochrane. Studies that reported levels of serum phosphorus, calcium, sodium, bicarbonate and other electrolytes were included. Also, reporting the incidence of adverse events, such as diarrhea, was also an inclusion criteria. Study quality was assessed using the Cochrane RoB-2 tool. Two authors independently evaluated bias risk, resolving disagreements with a third reviewer. Funnel plots were used to assess publication bias. The review followed Cochrane and PRISMA guidelines. Risk ratios (RR) and mean differences (MD), both with 95% confidence intervals (CI), were used to compare outcomes. Heterogeneity was assessed using Cochrane Q and I² tests, with significance set at p < 0.1 and I² > 25%. A random-effects model was applied, and analyses were performed using RevMan Web.

Our systematic search yielded 214 records. After removing duplicates and excluding studies by title/abstract that did not fit in our eligibility criteria, 35 records remained. Ultimately, we included 10 RCTs, with a total of 1627 patients, of whom 932 were in the tenapanor group and 695 were in the placebo group. Study baseline characteristics are presented in Table 1. Tenapanor significantly reduced serum phosphorus (MD -1.34 mg/dL; 95% CI -1.78 to -0.91; p < 0.00001) and sodium (MD -0.99 mEq/L; 95% CI -1.37 to -0.61; p < 0.00001). No significant changes were observed in bicarbonate, calcium, or iPTH levels. Tenapanor increased the likelihood of achieving target phosphorus levels (<5.5–6.0 mg/dL) nearly threefold (RR 2.97; 95% CI 2.07–4.27; p < 0.00001). Diarrhea was the most common adverse event (RR 4.13; 95% CI 3.23–5.26; p < 0.00001), generally mild to moderate. Overall adverse events were more frequent with tenapanor (RR 1.34; 95% CI 1.15–1.56; p = 0.0001), but discontinuation rates were not significantly different. Subgroup analysis suggested ethnicity may influence tenapanor’s phosphate-lowering effect, with Japanese patients showing more consistent responses. Once significant heterogeneity was detected in serum P levels analysis, we performed a subgroup analysis on this forest plot. In the first subgroup, we analyzed just Japanese patients, overcoming heterogeneity from 79% to 0%. In the second group, we analyzed non-Japanese patients, reducing heterogeneity from 79% to 27%. This analysis gave us a 0% heterogeneity. This scenario shows that tenapanor may have a different magnitude of P lowering effect depending on the population who is taking it. 

Tenapanor effectively lowers serum phosphorus and sodium levels in dialysis patients and improves achievement of target phosphorus levels. While associated with increased diarrhea and adverse events, its safety profile remains acceptable. Ethnicity may affect treatment response, supporting the need for individualized approaches. Tenapanor represents a promising alternative or adjunct to conventional phosphate-lowering therapies.