SGLT2 inhibitors reduce the salt sensitivity of blood pressure in type 2 diabetes via enhanced postprandial natriuresis

Background: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) lower blood pressure (BP) and provide cardiovascular protection. In animal models, SGLT2i blunt sodium-induced BP elevation, but this effect remains unexplored in humans. We investigated whether SGLT2i reduce the salt sensitivity of BP in patients with type 2 diabetes (T2D) and explored the underlying mechanisms. Methods: In an open-label, non-randomized study, 26 patients with T2D (14 on treatment with SGLT2i, 12 controls) completed two sequential 7-day dietary phases consisting of a very-low-sodium background diet with the addition of either high sodium (HS, + 4,800 mg/day) or low sodium (LS, + 1,200 mg/day). Changes in twenty-four hour ambulatory BP monitoring (24-hour ABPM), postprandial natriuresis and diuresis, plasma renin and aldosterone concentrations, glycosuria, and hydration were assessed. Results: The median change in systolic BP between HS and LS diets was greater in controls (median [IQR] Δ24-h SBP: +5.6 [2.0, 20.3] mmHg, p = 0.005), than in the SGLT2i group (Δ24-h SBP: -1.2 [-3.6, 4.2] mmHg, p = 0.594; p = 0.007 between groups). Diastolic BP changes showed similar patterns (Δ24-h DBP: +4.6 [1.3, 9.8] mmHg vs. -1.2 [-3.1, 1.4] mmHg; p = 0.002 between groups). SGLT2i-treated participants showed enhanced postprandial natriuresis during both HS (median [IQR]: 55.0 [28.3, 126.6] µEq/min vs. -0.7 [-148.6, 109.0] µEq/min; p = 0.049) and the LS diet (18.4 [1.3, 42.2] µEq/min vs. -14.5 [-30.2, 15.7] µEq/min; p = 0.046), and postprandial diuresis during the HS diet (median [IQR]: 0.52 [0.10, 1.18] ml/min vs. -0.21 [-0.58, 0.45] ml/min p = 0.041). In response to the LS diet, renin and aldosterone levels increased markedly in controls but not in SGLT2i-treated patients. Hydration and glycosuria were unchanged and unrelated to natriuretic responses. Conclusions: In T2D, treatment with SGLT2 inhibitors is associated with a reduced BP response to high sodium intake, accompanied by enhanced postprandial sodium and water excretion, along with attenuated neurohormonal activation. These findings identify physiological associations that may contribute to the BP-lowering and cardiovascular protective effects of SGLT2 inhibition. Trial registration: NCT06007157 (registered on 18/08/2023).