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 SGLT2 SGLT1 90% 10%
Glucose reabsorption
Loop of Henle Up to ~ 90% of glucose ~ 10% of glucose Minimal is reabsorbed is reabsorbed glucose from the S1/S2 segments from the S3 segment excretion Possible mechanisms responsible for cardiovascular and renal protection with SGLT2 inhibition
SGLT2 inhibition
Glycosuria Natriuresis
↓Blood ↓Plasma Negative caloric balance ↑Uricosuria pressure ↑Tubuloglomerular volume feedback
↓Myocardial
↓HbA1c ↓ Afferent stretch ↓
↓Plasma uric ↓Arterial ↓ arteriole acid stiffness ↑ constriction ↓Total body fat mass ↓Inflammation ↓Glucose toxicity ↓Epicardial fat ↓Intraglomerular hypertension ↓Ventricular ↓Hyperfiltration arrhythmias ↓Atherosclerosis Activation of ACE2 – Ang1/7 ↑Cardiac contractility ↓Inflammation No sympathetic nervous system activation ↓Fibrosis Cardiac and renal protection
Heerspink HJ et al, Circulation 2016 Tonneijck et al, J Am Soc Nephrol 2017 Diabetic nephron Diabetic nephron with SGLT2 i 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 0,072 1800 1641 0,08 200 ) 1600
2 172 0,07 1400 0,054 1156 0,06 150 139 1200 0,05 1000 0,04 100 800 600 0,03 50 400 0,02
200 0,01
Mean RVR (mmHg/L/min) RVR Mean Mean RBV (ml/min/1.73 m2) (ml/min/1.73 RBV Mean 0 0 0 Mean GFR (ml/min/1.73 m (ml/min/1.73 GFR Mean T1D-H (Euglycemia) RBF 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 Efferent arteriole • Decreased glomerular pressure Afferent • Reduction in albuminuria vasoconstriction Due to increased Na+ delivery Glomerular capillaries to the macula densa1-3 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 dependent reabsorption of glucose 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 Transport work Kidney growth 2 Renal O2 consumption Albuminuria Blood Albuminuria Inflammation glucose 1 2 ? GFR PBow SGLT2 NHE3
+ ‒ + 4 [NA /CI /K ]MD
Insulin need/levels HIF Glucosuria Natriuresis Glucagon Osmotic diuresis Uricosuria 3 5 ? 6 3 Lipolysis and hepatic 3 gluconeogenesis ECV/blood pressure ? 5 Kidney/heart Uric acid levels Mild ketosis protection 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