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Managing patients with
renal disease
Hiddo Lambers Heerspink, MD University Medical Centre Groningen,
The Netherlands
Asian Cardio Diabetes ForumApril 23 – 24, 2016 – Kuala Lumpur, Malaysia
Diabetic Kidney Disease is common
De Boer IH et al. JAMA 2011;305:2532
0
2
4
6
8
1988–1994 1999–2004 2005–2008
Pre
va
len
t c
ase
s, in
mill
ion
s, ±
95
% C
I All diabetic kidney disease
Persistent albuminuria only(ACR ≥ 30 mg/g)
Impaired eGFR only (< 60 ml/min/1.73 m2)
Albuminuria and impaired eGFR
18% prevalence increase
34% prevalence increase
Prevalence of kidney disease is projected to
increase
CKD3, CKD stage 3; CKD4, CKD stage 4; CKD5, CKD stage 5
*Austria, Belgium, Denmark, Finland, Greece, Iceland, Italy, Netherlands, Norway, Spain, Sweden, UK
Est
ima
ted
re
lativ
e p
rev
ale
nc
e r
ate
(p
er
millio
n p
op
ula
tio
n)
0
20.000
40.000
60.000
80.000
100.000
120.000
140.000
160.000
180.000
200.000
2010 2015 2020 2025
Projection of CKD in patients with diabetes in 12 European countries*
0
2.000
4.000
6.000
8.000
10.000
12.000
14.000
2010 2015 2020 2025
Year Year
CKD3
CKD4
CKD5
Kainz A et al. Nephrol Dial Transplant 2015;30:iv1113
Prevalence of ESRD around the world
RegionWorld
Lynage Lancet 2015
Despite RAAS blockade high residual
risk for dialysis and mortality
0
20
40
60
80
100
120
140
160
BENEDICT ROADMAP IRMA-2 RENAAL IDNT
ES
RD
/Death
(E
vent R
ate
, %
)Early Intermediate Late Intervention
RAAS intervention
Conventional treatment
BP ↑ MA -
BP ↑ MA +
BP ↑ Prot + GFR ↓
ALL Cancers
New drugs for diabetic kidney disease
• Low Protein Diet (MDRD, no formal additive effect tested)
• NSAID’s (proteinuria reduction, no hard endpoint trials)
• Combination ACEi/ARB (alb red, hard endpoints, NEPHRON; STOPPED)
• Renin-inhibitors (alb red, hard endpoints, ALTITUDE; CV/renal, STOPPED)
• Erythropoietin (Hb rise; hard endpoint trial; TREAT; CV/renal; NO EFFECT)
• GAG’s(prot reduction; hard endpoint trial; SUN-Overt; renal; STOPPED)
• Statins (hard endpoint trial; SHARP;CV/renal; CV but NO RENAL EFFECT)
• Statins (prot reduction and GFR decline; PLANET trial; renal)
• Nrf2 agonist (rise in eGFR; hard endpoint; BEACON; renal; STOPPED)
• Endothelin Antagonist (alb red; hard endpoint ; ASCEND; renal; STOPPED
SONAR; ONGOING)
• SGLT2 inhibition (EMPAREG, CV benefit; CRENDENCE ongoing)
Effects of SGLT2i on urinary glucose excretion depends on renal function
0 120
0
20
40
60
80
Da
y 1
, Δ
UG
E0-2
4h
(g)
GFR (mL/min/1.73m2)
eGFR Normal Renal Function (n=3)
≥90 mL/min/1.73m2
eGFR Mild Renal Impairment (n=10)
60 to 89 mL/min/1.73m2
eGFR Moderate Renal Impairment (n=9)
30 to 59 mL/min/1.73m2
eGFR Severe Renal Impairment (n=10)
15 to 29 mL/min/1.73m2
y = -12.2 + 0.697 (r2adj: 0.783)
95% Confidence Band
20 40 60 80 100
Effects of SGLT2i attenuates at lower
eGFR
4 8 12 16 20 24
10
20
30
40
50
60
BL
2
2
Study week
2
45 to <60 mL/min/1.73m
60 to <90 mL/min/1.73m
90 mL/min/1.73m
4 8 12 16 20 24-0.8
-0.6
-0.4
-0.2
0.0
Study week
BL
Hb
a1
c (
%)
ch
an
ge
Heerspink et.al. ADA 2016
Urin
ary
glu
co
se:c
rea
tin
ine
ra
tio
(m
g/m
g)
Effects of SGLT2i on volume related
parameters independent of eGFR
Hematocrit Systolic BP
Body Weight
4 8 12 16 20 240
1
2
3
4
BL
Study week
4 8 12 16 20 240
1
2
3
4
BL
2
2
Study week
4 8 12 16 20 24-4
-3
-2
-1
0
BL
Study week
Albuminuria
Heerspink et.al. ADA 2016
Δ H
ct
(%)
ΔSyst
olic
BP
(m
mH
g)
ΔB
W (
Kg
)
4 8 12 16 20 24
-80
-60
-40
-20
0
20
40
BL
Study week
ΔU
AC
R (
%)
45 to <60 mL/min
60 to <90 mL/min/
90 mL/min/
3-point MACE: subgroup analysis by eGFR
Empagliflozin Placebo
All patients 4687 2333
Age, years 0.01
<65 2596 1297
≥65 2091 1036
Sex 0.81
Male 3336 1680
Female 1351 653
Race 0.09
White 3403 1678
Asian 1006 511
Black/African-American 237 120
HbA1c, % 0.01
<8.5 3212 1607
≥8.5 1475 726
Body mass index, kg/m2 0.06
<30 2279 1120
≥30 2408 1213
eGFR, mL/min/1.73m2 0.20
≥90 1050 488
60 to <90 2425 1238
<60 1212 607
Hazard ratio (95%CI)
Zinman et.al. NEJM 2015
EMPAREG CV death: subgroup analyses by eGFR
Empagliflozin Placebo
All patients 4687 2333
Age, years 0.21
<65 2596 1297
≥65 2091 1036
Sex 0.32
Male 3336 1680
Female 1351 653
Race 0.43
White 3403 1678
Asian 1006 511
Black/African-American 237 120
HbA1c, % 0.51
<8.5 3212 1607
≥8.5 1475 726
Body mass index, kg/m2 0.05
<30 2279 1120
≥30 2408 1213
eGFR, mL/min/1.73m2 0.15
≥90 1050 488
60 to <90 2425 1238
<60 1212 607
Zinman et.al. NEJM 2015
Diabetes causes glomerular hypertension
Afferent arteriole
Efferent
arteriolePT: Proximal tubule
GL: Glomerulus
MD: Macula densa
Loop of Henle
PT
GFR
Na+/glucose co-
transport
Glucose
SGLT2SGLT2
SGLT2
Renal hemodynamics under hyperglycemia
Glomerular pressure
Adapted from: Cherney D et al. Circulation 2014;129:587
Empagliflozin lowers intra-glomerular
pressure
Renal hemodynamics with empagliflozin
SGLT2
SGLT2
Afferent arteriole
Efferent
arteriolePT: Proximal tubule
GL: Glomerulus
MD: Macula densa
Loop of Henle
GFR
Glucose
SGLT inhibitor
blocks SGLT2
SGLT2
PT
Glomerular pressure
Adapted from: Cherney D et al. Circulation 2014;129:587
Tubular Na reabsorption in T1 diabetes
mellitus
Pollock CA et al (1991) Am. J. Physiol. 260: F946-F952
Normalisation in GFR after phlorizin treatment in
type 1 diabetes experimental model
Pollock CA et al. Tubular sodium handling and tubuloglomerular feedback
in experimental diabetes mellitus. (1991) Am. J. Physiol. 260: F946-F952
0
10
20
30
40
50
60
Fra
ctio
na
l So
diu
m d
eliv
ery
dia
tal tu
ble
(%
)
0
0,2
0,4
0,6
0,8
1
1,2
1,4
GFR
(m
l/m
in/1
00g
Control Diabetes D+Phlorizin Control Diabetes D+Phlorizin
40
50
60
70
80
Me
an
intr
ag
lom
eru
larp
ress
ure
mm
Hg
Empagliflozin reduces intra-glomerular
pressure
Intra-glomerular pressure recorded at baseline and after 8 weeks treatment with empagliflozin
*
Glomerular pressure T1D-H (mmHg) Baseline EMPA p valueChange from
baseline
Euglycaemia (mmHg) 67.4 ± 5.4 61.0 ± 5.2 <0.0001 9.5%
Hyperglycaemia (mmHg) 69.3 ± 6.5 61.6 ± 6.3 <0.0001 11.1%
*p<0.0001
~6−8 mmHg
Skrtic M et al. Diabetologia 2014;57:2599
Baseline
Empagliflozin
Euglycemia Hyperglycemia
Empagliflozin attenuates glomerular
hyperfiltration
Type 1 diabetes patients with hyperfiltration. Mean GFR recorded at baseline and after 8 weeks treatment with empagliflozin 25 mg QD
Cherney
172.0
139.0
0
20
40
60
80
100
120
140
160
180
200
T1D-H (Euglycemia)
Me
an
GFR
(m
l/m
in/1
.73 m
2)
Baseline
Empagliflozin
*p<0.01
GFR reduced by
-33 ml/min/1.73 m2
Glomerular filtration rate
*
Type 1 Diabetes:
Cherney D et al. Circulation 2014;129:587
Dapagliflozin causes a fall in mGFR in type 2
diabetes
60
80
100
120
baseline week 12
Me
an
GFR
(m
l/m
in/1
.73
m2
)
60
80
100
120
baseline week 12
Me
an
GFR
(m
l/m
in/1
.73
m2
)
Placebo
Type 2Diabetes:
Dapagliflozin
GFR reduced by
-10.1 ml/min/1.73m2
Heerspink et al. DOM 2013
-12
-10
-8
-6
-4
-2
0
0 26 52 78 104
Ch
an
ge
in e
GFR
(m
L/m
in/1
.73
m2)
Time (weeks)
Glimepiride
Canagliflozin 100 mg
Canagliflozin 300 mg-8
-6
-4
-2
0
2
eG
FR
slo
pe
(m
L/m
in/1
.73m
2/y
ea
r
Glimepiride
Cana 100 mg
Cana 300 mg
SGLT2i causes an acute fall in eGFR followed
by a complete stabilization
SGLT2i decreases risk of eGFR decline
endpoint
Favors Favors
Canagliflozin Glimepiride Canagliflozin Glimepiride p-value
Canagliflozin 100 mg vs glimepiride
Overall population
30% eGFR decline
UACR < 30 mg/g 25/403 29/400 0.83( 0.49-1.43) 0.51
UACR ≥ 30 mg/g 7/74 17/75 0.37( 0.15-0.90) 0.028
No. of events / patients Hazard Ratio
(95% CI)
40% eGFR decline 7/477 11/475 0.61( 0.24-1.57) 0.30
30% eGFR decline 32/477 46/475 0.66( 0.42-1.04) 0.070
0.2 0.5 0.8 1.0 1.5 2.0 3.0
Hazard Ratio (95%CI)
58
56
54
52
50
48
46
0 50 100 150 200
Ioth
ala
ma
teG
FR
(m
l/m
in)
Blood pressure lowering with ACEi or β-blocker
causes an acute and reversible fall in GFR
Apperloo et.al. Kidney Int 1998
Long-term (3 years) eGFR decline stratified by
initial (3 months) eGFR change
Tertiles of initial fall in eGFR
(-8.6)
-3.77-4.10
-4.82
-3.64-3.85
-4.40
p=0.009 p=0.049
Unadjusted analysis Adjusted analysis
Lon
g-t
erm
eG
FR
slo
pe
(ml/
min
/1.7
3m
2/y
ea
r)
-6
-5
-4
-3
-2
-
1
0(-2.4) (+4.2) (-8.6) (-2.4) (+4.2)
Holtkamp et.al. Kidney Int 2011
Increased intraglomerular pressure and hyperfiltration are key
steps in the progression of diabetic kidney disease
ACEi and ARB ↓ efferent
arteriole tone and ↓
intraglomerular pressure
SGLT2i ↑ tubuloglomerular
feedback, ↑ afferent arteriole
tone and ↓intraglomerular
pressure
Initial ↓ in eGFR followed by
stabilization
↓ albuminuria
Renal Protection
Initial ↓ in eGFR followed
by stabilization
↓ albuminuria
Renal Protection
(to be
determined)
Renoprotection by reducing intra-
glomerular pressure
EMPAREG: Empagliflozin lowers risk of
acute kidney injury
Placebo Empa 10 Empa 25 Empa pooled
Acute Kidney Injury 37 (1.6) 26 (1.1) 19 (0.8) 45 (1.0)*
*P<0.05 vs. placebo
Conclusions
• Effects of SGLT2i on glycemic control attenuate at lower renal function
• Effects on other CV risk factors are independent of GFR
• EMPAREG trial showed that effects of empagliflozinon CV outcomes are consistent regardless of eGFR
• Restoration of TGF, reduction in intra-glomerularpressure, and albuminuria contribute to long-termrenoprotective effects
• Future trials in patients with diabetic kidney disease(CREDENCE) will provide definitive answers onefficacy and safety in this population
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