The Adaptive Renal Response for Volume Homeostasis During 2 Weeks of Dapagliflozin Treatment in People With Type 2 Diabetes and Preserved Renal Function on a Sodium-Controlled Diet

INTRODUCTION: Proximal tubule sodium uptake is diminished following sodium glucose cotransporter 2 (SGLT2) inhibition. We previously showed that during SGLT2 inhibition, the kidneys adapt by increasing sodium uptake at distal tubular segments, thereby maintaining body sodium balance. Despite continuous glycosuria, we detected no increased urine volumes. We therefore assessed the adaptive renal responses to prevent excessive fluid loss. METHODS: We conducted a mechanistic open-label study in people with type 2 diabetes mellitus with preserved kidney function, who received a standardized sodium intake (150 mmol/d) to evaluate the effects of dapagliflozin on renin-angiotensin-aldosterone system (RAAS) hormones, volume-related biomarkers, urinary albumin-to-creatinine ratio (UACR), and estimated glomerular filtration rate (eGFR), at start of treatment (day 4), end of treatment (day 14), and follow-up (day 18). RESULTS: A total of 14 people were enrolled. Plasma renin and angiotensin II and urinary aldosterone and angiotensinogen were acutely and persistently increased during treatment with dapagliflozin. Plasma copeptin level was numerically increased after 4 days (21%). Similarly, fractional urea excretion was significantly decreased at start of treatment (−17%). Free water clearance was significantly decreased after 4 days (−74%) and 14 days (−41%). All changes reversed after dapagliflozin discontinuation. CONCLUSION: Dapagliflozin-induced osmotic diuresis triggers kidney adaptive mechanisms to maintain volume and sodium balance in people with type 2 diabetes and preserved kidney function. ClinicalTrials.gov (identification: NCT03152084).