Efficacy, Mechanisms, and Safety of Sodium-Glucose Cotransporter-2 Inhibitors in Kidney Transplant Recipients

KEY POINTS: The effIcacy, mechaNisms and saFety of SGLT2 INhibitors in kIdney Transplant recIpients trial assessed the physiologic effects of sodium-glucose cotransporter-2 inhibitors in kidney transplant recipients. In kidney transplant recipients, sodium-glucose cotransporter-2 inhibitors lowered mean arterial pressure after 1 week, reduced GFR, increased glucosuria, and were safe. Dapagliflozin was well tolerated in kidney transplant recipients, showing similar cardio-kidney effects seen in other groups; outcome trials in kidney transplant recipients are now needed. BACKGROUND: Cardiovascular and kidney protective mechanisms with 12 weeks of sodium-glucose cotransporter-2 inhibitor treatment (dapagliflozin 10 mg daily) were assessed in kidney transplant recipients (KTR) with and without type 2 diabetes. METHODS: This randomized double-blind, parallel-group, placebo-controlled study enrolled 52 KTR and comprised three sequential physiologic assessments under clamped euglycemia (4-6 mmol/L): baseline, at 1, and 12 weeks of treatment. The primary objective was to evaluate BP lowering with dapagliflozin. Secondary outcomes were iohexol-measured GFR, natriuresis, body composition, noninvasive cardiac output monitoring, arterial stiffness, heart rate variability, neurohormones, and safety. RESULTS: Fifty-one KTR completed the study-mean age 53±13 years, 62% with hypertension, 57% with type 2 diabetes, 50% on renin-angiotensin-aldosterone system inhibitors, and mean eGFR 68.2±24.4 ml/min per 1.73 m 2 . Compared with placebo, dapagliflozin did not lower systolic BP at 1 or 12 weeks, although it did reduce mean arterial pressure after 1 week (3.9 mm Hg; 95% confidence interval [CI], -7.5 to -0.2). Dapagliflozin led to significant, placebo-adjusted reductions in iohexol-measured GFR from baseline to 1 week (4.2 ml/min per 1.73 m 2 ; 95% CI, -7.14 to -1.24 ml/min per 1.73 m 2 ) and 12 weeks (-3.49 ml/min per 1.73 m 2 ; 95% CI, -6.33 to -0.64). Dapagliflozin significantly increased glucosuria without altering proximal sodium handling or evidence of sympathetic activation. Acute decreases in arterial stiffness (carotid augmentation index, -3.5%; 95% CI, -6.0 to -1.1) were observed in the dapagliflozin group after 12 weeks, although this was not significant compared with placebo. Dapagliflozin was generally safe and well tolerated. No episodes of urinary tract or genitourinary infections were observed in either treatment group throughout the trial. CONCLUSIONS: Dapagliflozin activated expected physiologic pathways, although key differences observed in KTR might suggest mechanistic heterogeneity compared with nontransplant populations. Clinical trials evaluating sodium-glucose cotransporter-2 inhibitors in KTR are important to determine whether these mechanistic effects translate to improvements in kidney and cardiovascular outcomes. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: ClinicalTrials.gov, NCT04965935 . PODCAST: This article contains a podcast at https://dts.podtrac.com/redirect.mp3//www.asn-online.org/media/podcast/JASN/2026_02_09_KTS_February2026.mp3.