of SGLT2 inhibition in CKD Paola Fioretto, MD Padua, Italy June - PowerPoint PPT Presentation

The knowns and unknowns of SGLT2 inhibition in CKD Paola Fioretto, MD Padua, Italy June 14, 2019 - Budapest, Hungary

SGLT2 inhibition in CKD: Discussing the key questions and evidence Budapest, june 14 2019 The knowns and unknowns of SGLT2 inhibition in CKD Paola Fioretto Department of Medicine University of Padova, Italy

180 g of glucose filtered Glomerulus Proximal tubule Distal tubule Collecting duct each day S1 S2 Glucose filtration S3 SGLT1 SGLT2 10% 90% Glucose reabsorption Loop of Henle Minimal Up to ~ 90% of glucose ~ 10% of glucose glucose is reabsorbed is reabsorbed excretion from the S1/S2 segments from the S3 segment

Possible mechanisms responsible for cardiovascular and renal protection with SGLT2 inhibition SGLT2 inhibition Glycosuria Natriuresis ↓ Blood ↓ Plasma Negative caloric balance ↑ Uricosuria ↑ Tubuloglomerular pressure volume feedback ↓ Myocardial ↓ ↓ HbA 1c Afferent stretch ↓ Plasma uric ↓ Arterial ↓ arteriole ↓ ↑ acid stiffness constriction ↓Total body fat mass ↓Inflammation ↓Glucose toxicity ↓ Epicardial fat ↓Intraglomerular ↓ Ventricular hypertension arrhythmias ↓Hyperfiltration ↓ Atherosclerosis Activation of ACE2 – Ang1/7 ↑ Cardiac contractility No sympathetic nervous ↓ Inflammation system activation ↓ Fibrosis Cardiac and renal protection Heerspink HJ et al, Circulation 2016

Tonneijck et al, J Am Soc Nephrol 2017

Diabetic nephron with SGLT2 i Diabetic nephron

Effects of SGLT2 i on afferent arteriole tone: in vivo studies with multiphoton microscope imaging techniques Kidokoro K et al, Circulation 2019

Effects of SGLT2 i on SNGFR and afferent artery diameter: in vivo studies with multiphoton microscope imaging techniques Kidokoro K et al, Circulation 2019

Effects of Empagliflozin on renal hemodynamics in type 1 diabetes Glomerular filtration rate Renal blood flow Renal vascular resistance Baseline Empagliflozin Baseline Empagliflozin Baseline Empagliflozin 1800 0,072 0,08 1641 Mean RBV (ml/min/1.73 m2) 200 1600 Mean RVR (mmHg/L/min) 172 0,07 Mean GFR (ml/min/1.73 m 2 ) 1400 0,054 0,06 1156 139 150 1200 0,05 1000 0,04 800 100 0,03 600 400 0,02 50 200 0,01 0 0 0 RBF T1D-H (Euglycemia) RVR Cherney D et al , Circulation 2014

SGLT2 inhibition and RAAS blockade both reduce glomerular pressure by complimentary mechanisms Afferent arteriole CLINICAL IMPLICATIONS SGLT2 inhibitors • Decreased glomerular pressure Efferent arteriole • Reduction in albuminuria Afferent vasoconstriction Due to increased Na+ delivery Glomerular capillaries to the macula densa 1-3 Bowman’s capsule Afferent arteriole • Decreased glomerular pressure • Reduction in albuminuria RAAS blockade Efferent arteriole Efferent vasodilation Glomerular capillaries Bowman’s capsule

Potential pathways of renal protective effects Dekkers CCJ et al, Current Diabetes Reports , 2018

Improvement of hypoxia with phlorizin O’Neill J et al, Am J Physiol Renal Physiol. 2015

SGLT2 inhibitors reduce excessive energy demands in tubules T2DM T2DM with SGLT2 inhibitors Proximal tubular epithelial cells are Proximal tubular epithelial cells are overoaded by excessive energy- relieved from the burden of excessive reabsorption of glucose dependent reabsorption of glucose Sano M, J of Cardiology , 2018

Effects of 12 w treatment with dapagliflozin vs hydrochlorothiazide Heerspink H et al, Diabetes, Obesity and Metabolism 2013

Acute renal failure and acute kidney injury Wanner C et al, N Engl J Med 2016

Dapagliflozin attenuates renal ischemia-reperfusion injury Chang YK et al, PlosOne 2016

Luseogliflozin attenuates capillary injury and fibrosis by a VEGF- dependent pathway in a ischemia-reperfusion injury model Zhang Y et al, Kidney Int 2018

Van Raalte DH et al, Kidney Int 2018

Additional mechanisms of SGLT2i-mediated organ protection 5 Kidney protection 2 Transport work Kidney growth Renal O 2 consumption Albuminuria Blood Albuminuria Inflammation glucose 2 1 ? GFR P Bow SGLT2 NHE3 4 [NA + /CI ‒ /K + ] MD HIF Insulin need/levels Glucosuria Natriuresis Glucagon Osmotic diuresis Uricosuria 3 5 ? 6 3 Lipolysis and hepatic 3 gluconeogenesis ECV/blood pressure 5 Kidney/heart ? Uric acid levels protection Mild ketosis Body fat and weight 5 Vallon V et al, Diabetologia 2017

Summary • RCT have demonstrated a reduction in renal endpoints with SGLT2 inhibitors in patients with type 2 diabetes • Possible nephroprotective pathways: • Largely independent from the glucose lowering effect • Inducing natriuresis/diuresis • Restoring tubulo-glomerular feedback • Improving renal oxygen tension and hypoxia • Reducing AKI