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 unknownsof SGLT2 inhibition in CKD

Paola Fioretto

Department of Medicine

University of Padova, Italy

Proximal tubule

S1

Glomerulus Distal tubule

Loopof

Henle

Collecting duct

Glucosefiltration

Glucosereabsorption

S3

~ 10% of glucoseis 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

Minimalglucose

excretion

SGLT290%

SGLT110%

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

Afferentarteriole

constriction

↓Intraglomerular hypertension

↓Hyperfiltration

↓Myocardial

stretch

↓Ventricular

arrhythmias

Activation of ACE2 – Ang1/7

No sympathetic nervous system activation

↓Plasma

volume

↑

↓

↓

↓

Natriuresis

↓Inflammation

↓Fibrosis

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 studieswith 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

Cherney D et al, Circulation 2014

172

139

0

50

100

150

200

T1D-H (Euglycemia)Me

an

GF

R (

ml/m

in/1

.73

m2)

Baseline Empagliflozin1641

1156

0

200

400

600

800

1000

1200

1400

1600

1800

RBF

Me

an

RB

V (

ml/

min

/1.7

3 m

2)

Baseline Empagliflozin

0,054

0,072

0

0,01

0,02

0,03

0,04

0,05

0,06

0,07

0,08

RVR

Me

an

RV

R (

mm

Hg

/L/m

in)

Baseline Empagliflozin

Renal blood flow Renal vascular resistance Glomerular filtration rate

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

vasoconstrictionDue to increased Na+ delivery

to the macula densa1-3

Efferent arteriole

Afferent arteriole

Bowman’s capsule

Glomerular capillaries

Efferent arteriole

Afferent arteriole

Bowman’s capsuleGlomerular capillaries

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

T2DM

Proximal tubular epithelial cells are

overoaded by excessive energy-

dependent reabsorption of glucose

T2DM with SGLT2 inhibitorsProximal tubular epithelial cells are relieved from the burden of excessivereabsorption of glucose

Sano M, J of Cardiology, 2018

SGLT2 inhibitors reduce excessive energydemands in tubules

Effects of 12 w treatment with dapagliflozinvs 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

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

33

HIF

6?Lipolysis and hepatic

gluconeogenesis

5

Mild ketosis

5

5?

[NA+/CI‒/K+]MD

?

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