the knowns and unknowns of sglt2 inhibition in ckd · the knowns and unknowns of sglt2 inhibition...
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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 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