The efficacy and safety of SGLT2 inhibitors in diabetic and non-diabetic kidney transplant recipients: a multicentric study

Background and Aims The impact of SGLT2 inhibition on long term kidney outcomes as well as their safety in kidney transplant recipients (KTRs) have generated significant interest in recent years. Most of the existing evidence concerning the use of SGLT2 inhibitors (SGLT2i) in kidney transplantation is mostly derived from observational studies and only one small randomized controlled trial, which were mainly performed in diabetic patients. Our aim was to test the efficacy and safety of SGLT2i in diabetic and non-diabetic patients. Method We conducted a retrospective multicentric observational study including a cohort of 289 adult, diabetic and non-diabetic KTRs transplanted before 1 December 2022 and in follow up until 16 September 2024 at the outpatient Nephrology Clinic of the San Martino Hospital, Genoa, the Sant'Orsola Hospital, Bologna, and the Maggiore della Carità Hospital, Novara. A propensity score matching (caliper 0.1 with no replacement), using gender and 24 hours proteinuria as matching criteria, was conducted obtaining a match (1:1): 124 subjects on SGLT2i (cases) and 124 subjects without SGLT2i (controls). Our primary outcome was to compare changes in eGFR (CKD-EPI estimated glomerular filtration rate) and 24 hours proteinuria between cases and controls from baseline to 6- and 12 months. Secondary outcomes included changes from baseline in glycated hemoglobin, hemoglobin (Hb), uric acid, potassium, magnesium, body mass index (BMI), body weight and blood pressure control between the two subgroups. Safety data regarding 139 patients on SGLT2i were also reported. Categorical variables are presented as the number of patients with a proportion and were compared with the Chi square test. Continuous variables are described as means with standard deviation, we performed paired t-test for parametric and Wilcoxon test for non-parametric data, as appropriate. A p-value less than 0.05 was considered statistically significant. Results The mean follow-up of patients on SGLT2i was 13.3 ± 10.3 months. Baseline demographic and clinical characteristics of cases and controls are represented in Table 1. We observed a significant decrease in uric acid and systolic blood pressure values both at 6 months and at 12 months in KTRs on SGLT2i therapy. An increase in Hb values and a reduction in BMI were also reported in this subgroup. For what concerns proteinuria, no significant differences were observed in both cohorts between baseline and 6- and 12 months (Table 2). A decline in eGFR at 6 months was observed in cases (p = 0.007), but eGFR partially recovered at 12 months (Fig. 1). Urinary tract infections were the most common adverse effect, withdrawal of the drug occurred in 27% of the patients, but 21% restarted the therapy during follow up (Table 3). Conclusion With a study design which allowed us to obtain solid results and partially overcome the absence of randomization, our findings show that SGLT2i in KTRs may be effective in terms of nephroprotection as evidenced by the transient decline in eGFR and the stabilization of proteinuria levels. According to the available evidence, we also confirmed cardioprotective effects represented by favorable metabolic changes in KTRs on SGLT2i therapy. The safety profile seems acceptable, but has to be proven in the long term.