Acute and Chronic Effects of SGLT2 Inhibitor Empagliflozin on Renal Oxygenation and Blood Pressure Control in Nondiabetic Normotensive Subjects: A Randomized, Placebo-Controlled Trial

Abstract

Background The sodium/glucose cotransporter 2 inhibitor empagliflozin has cardiorenal protective properties through mechanisms beyond glucose control. In this study we assessed whether empagliflozin modifies renal oxygenation as a possible mechanism of renal protection, and determined the metabolic, renal, and hemodynamic effects of empagliflozin in nondiabetic subjects. Methods and Results In this double-blind, randomized, placebo-controlled study, 45 healthy volunteers underwent blood and urine sampling, renal ultrasound, and blood-oxygenation-level-dependent magnetic resonance imaging before and 180 minutes after administration of 10 mg empagliflozin (n=30) or placebo (n=15). These examinations were repeated after 1 month of daily intake. Cortical and medullary renal oxygenation were not affected by the acute or chronic administration of empagliflozin, as determined by 148 renal blood-oxygenation-level-dependent magnetic resonance imaging examinations. Empagliflozin increased glucosuria (24-hour glucosuria at 1 month: +50.1±16.3 g). The acute decrease in proximal sodium reabsorption, as determined by endogenous fractional excretion of lithium (-34.6% versus placebo), was compensated at 1 month by a rise in plasma renin activity (+28.6%) and aldosterone (+55.7%). The 24-hour systolic and diastolic ambulatory blood pressures decreased significantly after 1 month of empagliflozin administration (-5.1 and -2.0 mm Hg, respectively). Serum uric acid levels decreased (-28.4%), hemoglobin increased (+1.7%), and erythropoietin remained the same. Conclusions Empagliflozin has a rapid and significant effect on tubular function, with sustained glucosuria and transient natriuresis in nondiabetic normotensive subjects. These effects favor blood pressure reduction. No acute or sustained changes were found in renal cortical or medullary tissue oxygenation. It remains to be determined whether this is the case in nondiabetic or diabetic patients with congestive heart failure or kidney disease. REGISTRATION: URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT03093103.

Keywords: BOLD‐MRI; SGLT2; blood pressure; empagliflozin; renal oxygenation.

Figures

Figure 1

Placebo and empagliflozin R2* profile graphs summarizing the mean±SD R2* of the 12 layers. The percentage scale refers to the relative depth of each layer. The deepest layers are in the medulla and have a higher R2*, and thus lower oxygenation. A and B, Curves before and after the first tablet (acute phase, T0(AP) and T180(AP)). C and D, Curves before and after the last tablet (chronic phase, T0(CP) and T180(CP)). E and F, Curves at baseline and after 1 month of treatment (T0(AP) and T0(CP)).

Figure 2

Summary of significant variations from baseline to 1‐month treatment in placebo and empagliflozin groups. Data are expressed as mean±SEM. Delta variations in placebo and empagliflozin groups were compared by unpaired two‐sample t tests. BOLD‐MRI indicates blood oxygenation‐level–dependent magnetic resonance imaging; DBP, diastolic blood pressure; FELi, fractional excretion of lithium; PRA, plasma renin activity; and SBP, systolic blood pressure.