the knowns and unknowns of sglt2 inhibition in ckd · the knowns and unknowns of sglt2 inhibition...
TRANSCRIPT
![Page 1: The knowns and unknowns of SGLT2 inhibition in CKD · The knowns and unknowns of SGLT2 inhibition in CKD Paola Fioretto Department of Medicine University of Padova, Italy. Proximal](https://reader030.vdocuments.site/reader030/viewer/2022040205/5f02597f7e708231d403d5b2/html5/thumbnails/1.jpg)
The knowns and unknowns
of SGLT2 inhibition in CKD
Paola Fioretto, MD
Padua, Italy
June 14, 2019 - Budapest, Hungary
![Page 2: The knowns and unknowns of SGLT2 inhibition in CKD · The knowns and unknowns of SGLT2 inhibition in CKD Paola Fioretto Department of Medicine University of Padova, Italy. Proximal](https://reader030.vdocuments.site/reader030/viewer/2022040205/5f02597f7e708231d403d5b2/html5/thumbnails/2.jpg)
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
![Page 3: The knowns and unknowns of SGLT2 inhibition in CKD · The knowns and unknowns of SGLT2 inhibition in CKD Paola Fioretto Department of Medicine University of Padova, Italy. Proximal](https://reader030.vdocuments.site/reader030/viewer/2022040205/5f02597f7e708231d403d5b2/html5/thumbnails/3.jpg)
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%
![Page 4: The knowns and unknowns of SGLT2 inhibition in CKD · The knowns and unknowns of SGLT2 inhibition in CKD Paola Fioretto Department of Medicine University of Padova, Italy. Proximal](https://reader030.vdocuments.site/reader030/viewer/2022040205/5f02597f7e708231d403d5b2/html5/thumbnails/4.jpg)
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
![Page 5: The knowns and unknowns of SGLT2 inhibition in CKD · The knowns and unknowns of SGLT2 inhibition in CKD Paola Fioretto Department of Medicine University of Padova, Italy. Proximal](https://reader030.vdocuments.site/reader030/viewer/2022040205/5f02597f7e708231d403d5b2/html5/thumbnails/5.jpg)
Tonneijck et al, J Am Soc Nephrol 2017
![Page 6: The knowns and unknowns of SGLT2 inhibition in CKD · The knowns and unknowns of SGLT2 inhibition in CKD Paola Fioretto Department of Medicine University of Padova, Italy. Proximal](https://reader030.vdocuments.site/reader030/viewer/2022040205/5f02597f7e708231d403d5b2/html5/thumbnails/6.jpg)
Diabetic nephron Diabetic nephron with SGLT2 i
![Page 7: The knowns and unknowns of SGLT2 inhibition in CKD · The knowns and unknowns of SGLT2 inhibition in CKD Paola Fioretto Department of Medicine University of Padova, Italy. Proximal](https://reader030.vdocuments.site/reader030/viewer/2022040205/5f02597f7e708231d403d5b2/html5/thumbnails/7.jpg)
Effects of SGLT2 i on afferent arteriole tone: in vivo studieswith multiphoton microscope imaging techniques
Kidokoro K et al, Circulation 2019
![Page 8: The knowns and unknowns of SGLT2 inhibition in CKD · The knowns and unknowns of SGLT2 inhibition in CKD Paola Fioretto Department of Medicine University of Padova, Italy. Proximal](https://reader030.vdocuments.site/reader030/viewer/2022040205/5f02597f7e708231d403d5b2/html5/thumbnails/8.jpg)
Effects of SGLT2 i on SNGFR and afferent artery diameter: in vivo studies with multiphoton microscope imaging techniques
Kidokoro K et al, Circulation 2019
![Page 9: The knowns and unknowns of SGLT2 inhibition in CKD · The knowns and unknowns of SGLT2 inhibition in CKD Paola Fioretto Department of Medicine University of Padova, Italy. Proximal](https://reader030.vdocuments.site/reader030/viewer/2022040205/5f02597f7e708231d403d5b2/html5/thumbnails/9.jpg)
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
![Page 10: The knowns and unknowns of SGLT2 inhibition in CKD · The knowns and unknowns of SGLT2 inhibition in CKD Paola Fioretto Department of Medicine University of Padova, Italy. Proximal](https://reader030.vdocuments.site/reader030/viewer/2022040205/5f02597f7e708231d403d5b2/html5/thumbnails/10.jpg)
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
![Page 11: The knowns and unknowns of SGLT2 inhibition in CKD · The knowns and unknowns of SGLT2 inhibition in CKD Paola Fioretto Department of Medicine University of Padova, Italy. Proximal](https://reader030.vdocuments.site/reader030/viewer/2022040205/5f02597f7e708231d403d5b2/html5/thumbnails/11.jpg)
Potential pathways of renal protective effects
Dekkers CCJ et al, Current Diabetes Reports, 2018
![Page 12: The knowns and unknowns of SGLT2 inhibition in CKD · The knowns and unknowns of SGLT2 inhibition in CKD Paola Fioretto Department of Medicine University of Padova, Italy. Proximal](https://reader030.vdocuments.site/reader030/viewer/2022040205/5f02597f7e708231d403d5b2/html5/thumbnails/12.jpg)
Improvement of hypoxia with phlorizin
O’Neill J et al, Am J Physiol Renal Physiol. 2015
![Page 13: The knowns and unknowns of SGLT2 inhibition in CKD · The knowns and unknowns of SGLT2 inhibition in CKD Paola Fioretto Department of Medicine University of Padova, Italy. Proximal](https://reader030.vdocuments.site/reader030/viewer/2022040205/5f02597f7e708231d403d5b2/html5/thumbnails/13.jpg)
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
![Page 14: The knowns and unknowns of SGLT2 inhibition in CKD · The knowns and unknowns of SGLT2 inhibition in CKD Paola Fioretto Department of Medicine University of Padova, Italy. Proximal](https://reader030.vdocuments.site/reader030/viewer/2022040205/5f02597f7e708231d403d5b2/html5/thumbnails/14.jpg)
Effects of 12 w treatment with dapagliflozinvs hydrochlorothiazide
Heerspink H et al, Diabetes, Obesity and Metabolism 2013
![Page 15: The knowns and unknowns of SGLT2 inhibition in CKD · The knowns and unknowns of SGLT2 inhibition in CKD Paola Fioretto Department of Medicine University of Padova, Italy. Proximal](https://reader030.vdocuments.site/reader030/viewer/2022040205/5f02597f7e708231d403d5b2/html5/thumbnails/15.jpg)
Acute renal failure and acute kidney injury
Wanner C et al, N Engl J Med 2016
![Page 16: The knowns and unknowns of SGLT2 inhibition in CKD · The knowns and unknowns of SGLT2 inhibition in CKD Paola Fioretto Department of Medicine University of Padova, Italy. Proximal](https://reader030.vdocuments.site/reader030/viewer/2022040205/5f02597f7e708231d403d5b2/html5/thumbnails/16.jpg)
Dapagliflozin attenuates renal ischemia-reperfusion injury
Chang YK et al, PlosOne 2016
![Page 17: The knowns and unknowns of SGLT2 inhibition in CKD · The knowns and unknowns of SGLT2 inhibition in CKD Paola Fioretto Department of Medicine University of Padova, Italy. Proximal](https://reader030.vdocuments.site/reader030/viewer/2022040205/5f02597f7e708231d403d5b2/html5/thumbnails/17.jpg)
Luseogliflozin attenuates capillary injury and fibrosis by a VEGF-dependent pathway in a ischemia-reperfusion injury model
Zhang Y et al, Kidney Int 2018
![Page 18: The knowns and unknowns of SGLT2 inhibition in CKD · The knowns and unknowns of SGLT2 inhibition in CKD Paola Fioretto Department of Medicine University of Padova, Italy. Proximal](https://reader030.vdocuments.site/reader030/viewer/2022040205/5f02597f7e708231d403d5b2/html5/thumbnails/18.jpg)
Van Raalte DH et al, Kidney Int 2018
![Page 19: The knowns and unknowns of SGLT2 inhibition in CKD · The knowns and unknowns of SGLT2 inhibition in CKD Paola Fioretto Department of Medicine University of Padova, Italy. Proximal](https://reader030.vdocuments.site/reader030/viewer/2022040205/5f02597f7e708231d403d5b2/html5/thumbnails/19.jpg)
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
?
![Page 20: The knowns and unknowns of SGLT2 inhibition in CKD · The knowns and unknowns of SGLT2 inhibition in CKD Paola Fioretto Department of Medicine University of Padova, Italy. Proximal](https://reader030.vdocuments.site/reader030/viewer/2022040205/5f02597f7e708231d403d5b2/html5/thumbnails/20.jpg)
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