Introduction: Heart failure with preserved ejection fraction (HFpEF) is a prevalent comorbidity among patients with end-stage kidney disease. Although sodium-glucose cotransporter 2 inhibitors are validated in treating heart failure and ameliorating left ventricular hypertrophy among non-dialysis patients, the effects on dialysis patients are unknown. We previously investigated the pharmacokinetics of henagliflozin in patients undergoing haemodialysis (HD) or peritoneal dialysis (PD) and clarified its safety. Methods and analysis: This multicentre, randomised, double-blind, placebo-controlled trial is being conducted at three hospitals in Shanghai, China. A target of 108 HD or PD patients with HFpEF are randomly allocated to treatment group (henagliflozin 5 mg/day in addition to standard therapy) or control group (placebo with standard therapy) at a ratio of 1:1. All subjects will be followed up for 24 weeks. The primary outcome is change in echocardiography-measured left ventricular mass index. The secondary interests include changes in left atrial volume index, E/e’, e’ and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Intergroup comparisons of change in echocardiography-related outcomes from baseline to 24 weeks are based on a linear regression model adjusted for baseline values (analysis of covariance), and repeated measure analysis of variance with Bonferroni adjustment is employed for comparison of change in NT-proBNP. Subgroup analyses of the primary and secondary outcomes are conducted to determine whether the effect of henagliflozin varies according to dialysis modality. The χ ² method is used to compare the occurrence of adverse events and severe adverse events. Ethics and dissemination: This trial has been approved by the Ethics Committee of Renji Hospital, School of Medicine, Shanghai Jiao Tong University (LY2023-127-B). All participants provide written informed consent before screening. The results of the trial will be disclosed completely in international peer-reviewed journals. Both positive and negative results will be reported. Trial registration number: ChiCTR2300073169.

Key Points: This trial evaluated the effects of henagliflozin on cardiac structure and its safety in patients with heart failure with preserved ejection fraction on dialysis. At week 24, henagliflozin achieved a statistically significant reduction in left ventricular mass index versus placebo (−5.27 g/m ² ; 95% confidence interval, −10.02 to −0.53 g/m ² ). Henagliflozin was tolerable in the peritoneal dialysis and hemodialysis settings. Background: Few effective drug treatments exist for patients with heart failure with preserved ejection fraction (HFpEF) on dialysis. The aim of this study was to evaluate the effects of henagliflozin, a sodium–glucose cotransporter 2 inhibitor, on cardiac structure and its safety in such population. Methods: In this multicenter, randomized, double-blind, placebo-controlled trial, patients with HFpEF on dialysis were randomly assigned (1:1) to receive henagliflozin or placebo for 24 weeks. All enrolled participants received conventional therapy. The primary outcome was change in left ventricular mass index (LVMI) from baseline to week 24. The secondary outcomes were changes in the left atrial volume index, E/e’, e’, and N -terminal pro-brain natriuretic peptide and safety. Efficacy was assessed in the intention-to-treat population. Safety was assessed in the as-treated population. Analysis of covariance was used to assess treatment effects. Results: A total of 112 participants were randomly assigned to the henagliflozin group ( n =56) and placebo group ( n =56). Of these, 60 participants were on hemodialysis and 52 were on peritoneal dialysis. From baseline to week 24, henagliflozin resulted in a greater reduction in least-squares mean (±SEM) change in LVMI than placebo (−3.27±1.71 g/m ² versus 2.01±1.69 g/m ² ), with a between-group difference of −5.27 g/m ² (95% confidence interval [CI], −10.02 to −0.53 g/m ² ; P = 0.03). In the prespecified subgroup by dialysis modality, the between-group difference in LVMI change from baseline to week 24 was −6.86 g/m ² (95% CI, −14.02 to 0.29 g/m ² ) among participants on peritoneal dialysis and −3.91 g/m ² (95% CI, −10.45 to 2.63 g/m ² ) among participants on hemodialysis. No between-group differences in secondary outcomes were observed. The incidence of adverse events was similar between the henagliflozin and placebo groups (36% versus 34%). Conclusions: Henagliflozin was associated with a greater reduction in LVMI at week 24 compared with placebo and was tolerable in patients with HFpEF on dialysis. Larger studies are needed to confirm the LVMI-lowering effect of henagliflozin. Clinical Trial registry name and registration number: ChiCTR2300073169.