Renal and systemic hemodynamic effects of empagliflozin: Three randomized, double blind, placebo controlled cross-over trials

Abstract Background Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve renal outcomes in type 2 diabetes mellitus (DM2) and chronic kidney disease (CKD). A decrease in renal blood flow (RBF) with attenuation of glomerular hyperfiltration may contribute to this. We examined renal and systemic hemodynamic effects of SGLT2i in relevant patient categories. Methods Using a double-blind placebo controlled cross-over design we randomized patients with DM2 and estimated glomerular filtration rate (eGFR) >60 ml/min/1.73m 2 (n=16), patients with DM2 and eGFR 20-60 ml/min/1.73m 2 (n=17) and patients with non-diabetic CKD and eGFR 20-60 ml/min/1.73m 2 (n=16) to empagliflozin 10 mg daily or placebo for four weeks and crossed over to the opposite treatment after two-week washout. RBF was measured with 82 Rubidium positron emission tomography/computed tomography ( 82 Rb-PET/CT), GFR as plasma clearance of 99m Technetium-diethylene-triamine-pentaacetate, while 24-hour blood pressure (BP) and total peripheral vascular resistance (TVR) were recorded using the commercially available Mobil-O-graph. Results Compared to placebo empagliflozin reduced RBF by 6% in the DM2-CKD group (p<0.001), while there were non-significant decreases of 4% in the DM2 group and 1% in the CKD group (p=0.29 and 0.72). Empagliflozin reduced GFR, BP and TVR in all groups. Although total renal vascular resistance (RVR) remained unchanged, calculations based on Gomez’ equations revealed a reduction of post-glomerular resistance in the DM2 and CKD groups. Conclusion Short-term empagliflozin treatment reduced RBF in patients with DM2 and CKD, whereas GFR, BP and TVR were reduced in all groups. The lack of reduction in total RVR together with a decrease in post-glomerular resistance and systemic BP suggest SGLT2i protect the glomerulus due to relative pre-glomerular vasoconstriction and post-glomerular vasodilation. Registration EU Clinical Trials Register 2019-004303-12, 2019-004447-80 and 2019-004467-50 Clinical Perspective What is new? This is the first study of the hemodynamic effects of sodium-glucose cotransporter 2 inhibitors in diabetic and non-diabetic chronic kidney disease. We found that the sodium-glucose cotransporter 2 inhibitor empagliflozin reduced renal blood flow in patients with type 2 diabetes and chronic kidney disease. Empagliflozin reduced blood pressure and total vascular resistance in patients with type 2 diabetes both with and without chronic kidney disease and in patients with non-diabetic chronic kidney disease. What are the clinical implications? This is the first time sodium-glucose cotransporter 2 inhibitors have been shown to decrease renal blood flow in patients with type 2 diabetes, corroborating the hypothesis that they exert clinical benefits through attenuation of hyperfiltration Our findings suggest a combined pre- and post-glomerular hemodynamic response that may underlie the beneficial clinical effects. The reduction in blood pressure and total peripheral resistance point to a novel vascular effect of empagliflozin that is present in both patients with and without type 2 diabetes or chronic kidney disease.