Abstract
KEY POINTS: In this post hoc analysis of Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation, canagliflozin reduced the risk of first and subsequent all-cause hospitalization by 14%. Sodium-glucose cotransporter 2 inhibitor reduced the risk of hospitalization by 15%, with consistent effects irrespective of kidney function, albuminuria, and diabetes status. Absolute reductions in hospitalizations with sodium-glucose cotransporter 2 inhibitor in patients with CKD are substantial, with major implications for individuals and health systems. BACKGROUND: Unplanned hospitalization, irrespective of cause, is a meaningful outcome for patients, caregivers, clinicians, and health systems. The effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on all-cause hospitalization in patients with CKD have not been systematically evaluated. METHODS: We conducted a post hoc analysis of the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation trial to evaluate the effect of canagliflozin on nonelective all-cause hospitalization using Cox proportional hazards models, with recurrent events analysis to assess effects on first and subsequent hospitalizations. We performed inverse variance weighted meta-analysis of three placebo-controlled SGLT2 inhibitor CKD-focused trials to assess the relative and absolute effects of SGLT2 inhibitors on first and subsequent all-cause hospitalizations overall and across clinically relevant subgroups. For analyses of cause-specific hospitalization, adverse events that were reported by investigators but not adjudicated were used. RESULTS: Over a median follow-up of 2.6 years, 3015 hospitalizations occurred among 1543 of 4401 (35%) participants in the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation trial. Compared with placebo, canagliflozin reduced the risk of first all-cause hospitalization (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.80 to 0.98; P = 0.02) and first and subsequent hospitalizations (HR, 0.86; 95% CI, 0.76 to 0.96; P = 0.007). In a meta-analysis of three placebo-controlled SGLT2 inhibitor CKD-focused trials, SGLT2 inhibitors reduced the risk of first and subsequent hospitalizations from any cause by 15% (HR, 0.85; 95% CI, 0.78 to 0.95; P < 0.001), with consistent effects irrespective of diabetes, baseline kidney function, and albuminuria (all P interactions > 0.50). Reductions were driven by hospitalizations due to infection, cardiac, renal or urinary, and metabolism or nutritional disorders. We estimated that SGLT2 inhibition in CKD would prevent 36 (95% CI, 13 to 56) unplanned hospitalizations per 1000 patient-years of treatment, across a broad range of patients. CONCLUSIONS: SGLT2 inhibitors reduce the risk of hospitalizations from any cause in patients with CKD, irrespective of diabetes status, kidney function, and degree of albuminuria. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: NCT02065791.