Efficacy, Mechanisms and Safety of Sodium-Glucose Cotransporter-2 Inhibitors in Kidney Transplant Recipients: A Randomized, Double-Blind, Placebo-Controlled Trial

Background: Cardiovascular and kidney protective mechanisms with 12 weeks of sodium-glucose cotransporter-2 (SGLT2) inhibitor (dapagliflozin 10 mg daily) were assessed in kidney transplant recipients (KTR) with and without type 2 diabetes (T2D). 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 one week and 12 weeks of treatment. The primary objective was to evaluate blood pressure lowering with dapagliflozin. Secondary outcomes were: iohexol-measured glomerular filtration rate (GFR), natriuresis, body composition, non-invasive 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 T2D, 50% on renin-angiotensin-aldosterone system (RAAS) inhibitors and mean estimated GFR 68.2±24.4 mL/min/1.73m 2 . Compared to placebo, dapagliflozin did not lower systolic blood pressure at one or 12 weeks, though it did reduce mean arterial pressure after one week (3.9 mmHg 95% CI –7.5, –0.2). Dapagliflozin led to significant, placebo-adjusted reductions in iohexol-measured GFR from baseline to one week (4.2 ml/min/1.73m 2 ; 95% CI –7.14, –1.24 ml/min/1.73m 2 ) and 12 weeks (–3.49 ml/min/1.73m 2 ; 95% CI –6.33, –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, –1.1) were observed in the dapagliflozin group after 12 weeks, though this was not significant compared to 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. Conclusion: Dapagliflozin activated expected physiological pathways, though key differences observed in KTR might suggest mechanistic heterogeneity compared to non-transplant populations. Clinical trials evaluating SGLT2 inhibitors in KTR are important to determine whether these mechanistic effects translate to improvements in kidney and cardiovascular outcomes.