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

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

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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

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The knowns and unknowns

  • f SGLT2 inhibition in CKD

Paola Fioretto, MD Padua, Italy

June 14, 2019 - Budapest, Hungary

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SLIDE 2

SGLT2 inhibition in CKD: Discussing the key questions and evidence Budapest, june 14 2019

The knowns and unknowns

  • f SGLT2 inhibition in CKD

Paola Fioretto Department of Medicine University of Padova, Italy

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SLIDE 3

Proximal tubule

S1

Glomerulus Distal tubule Loop

  • f

Henle Collecting duct

Glucose filtration Glucose reabsorption

S3

~ 10% of glucose is reabsorbed from the S3 segment 180 g of glucose filtered each day Up to ~ 90% of glucose is reabsorbed from the S1/S2 segments

S2

Minimal glucose excretion SGLT2 90% SGLT1 10%

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SLIDE 4

Possible mechanisms responsible for cardiovascular and renal protection with SGLT2 inhibition

Heerspink HJ et al, Circulation 2016

SGLT2 inhibition

↑Tubuloglomerular

feedback

↓Blood

pressure

↓Arterial

stiffness Glycosuria

↓HbA1c ↑Uricosuria ↓Plasma uric

acid ↓Inflammation ↓Glucose toxicity Negative caloric balance ↓Total body fat mass

↓Epicardial fat ↑Cardiac

contractility

Cardiac and renal protection ↓Atherosclerosis

Afferent arteriole constriction ↓Intraglomerular hypertension ↓Hyperfiltration

↓Myocardial

stretch

↓Ventricular

arrhythmias Activation of ACE2 – Ang1/7 No sympathetic nervous system activation

↓Plasma

volume

↑ ↓ ↓ ↓

Natriuresis

↓Inflammation ↓Fibrosis

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SLIDE 5

Tonneijck et al, J Am Soc Nephrol 2017

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Diabetic nephron Diabetic nephron with SGLT2 i

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Effects of SGLT2 i on afferent arteriole tone: in vivo studies with multiphoton microscope imaging techniques

Kidokoro K et al, Circulation 2019

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Effects of SGLT2 i on SNGFR and afferent artery diameter: in vivo studies with multiphoton microscope imaging techniques

Kidokoro K et al, Circulation 2019

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Effects of Empagliflozin on renal hemodynamics in type 1 diabetes

Cherney D et al, Circulation 2014

172 139

50 100 150 200 T1D-H (Euglycemia) Mean GFR (ml/min/1.73 m2) Baseline Empagliflozin

1641 1156

200 400 600 800 1000 1200 1400 1600 1800

RBF

Mean RBV (ml/min/1.73 m2) Baseline Empagliflozin

0,054 0,072

0,01 0,02 0,03 0,04 0,05 0,06 0,07 0,08 RVR Mean RVR (mmHg/L/min) Baseline Empagliflozin

Renal blood flow Renal vascular resistance Glomerular filtration rate

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SLIDE 10

SGLT2 inhibition and RAAS blockade both reduce glomerular pressure by complimentary mechanisms

CLINICAL IMPLICATIONS

Efferent vasodilation

SGLT2 inhibitors RAAS blockade

  • Decreased glomerular pressure
  • Reduction in albuminuria
  • Decreased glomerular pressure
  • Reduction in albuminuria

Afferent vasoconstriction

Due to increased Na+ delivery to the macula densa1-3

Efferent arteriole Afferent arteriole Bowman’s capsule Glomerular capillaries Efferent arteriole Afferent arteriole Bowman’s capsule Glomerular capillaries

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SLIDE 11

Potential pathways of renal protective effects

Dekkers CCJ et al, Current Diabetes Reports, 2018

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Improvement of hypoxia with phlorizin

O’Neill J et al, Am J Physiol Renal Physiol. 2015

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T2DM Proximal tubular epithelial cells are

  • veroaded by excessive energy-

dependent reabsorption of glucose T2DM with SGLT2 inhibitors Proximal tubular epithelial cells are relieved from the burden of excessive reabsorption of glucose

Sano M, J of Cardiology, 2018

SGLT2 inhibitors reduce excessive energy demands in tubules

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Effects of 12 w treatment with dapagliflozin vs hydrochlorothiazide

Heerspink H et al, Diabetes, Obesity and Metabolism 2013

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SLIDE 15

Acute renal failure and acute kidney injury

Wanner C et al, N Engl J Med 2016

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Dapagliflozin attenuates renal ischemia-reperfusion injury

Chang YK et al, PlosOne 2016

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Luseogliflozin attenuates capillary injury and fibrosis by a VEGF- dependent pathway in a ischemia-reperfusion injury model

Zhang Y et al, Kidney Int 2018

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SLIDE 18

Van Raalte DH et al, Kidney Int 2018

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Additional mechanisms of SGLT2i-mediated organ protection

Vallon V et al, Diabetologia 2017

Kidney protection

Transport work Renal O2 consumption Albuminuria Kidney growth Albuminuria Inflammation

GFR

1

PBow Kidney/heart protection Blood glucose Insulin need/levels Glucagon

5 SGLT2

NHE3 Glucosuria Osmotic diuresis Natriuresis Uricosuria

2 2 4

ECV/blood pressure Uric acid levels Body fat and weight

3 3 3

HIF

6 ?

Lipolysis and hepatic gluconeogenesis

5

Mild ketosis

5 5 ?

[NA+/CI‒/K+]MD

?

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SLIDE 20

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