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