1

Diabetes Symposium

Primary prevention of diabetic nephropathy:

pharmacological intervention

Piero Ruggenenti

Mario Negri Institute for Pharmacological ResearchUnit of Nefrology and Dialysis,

Azienda Ospedaliera Ospedali Riuniti, Bergamo,Italy

Malaga, October 10 2005

DEVELOPINGCOUNTRIES

DEVELOPEDCOUNTRIES

0500

100015002000250030003500400045005000

1990 2020Yusuf et al. Circulation 2001

Deaths (x 1000)

Cardiovascular diseases are the fastest growing cause of death in developing countries and by the year 2020 they would take the lead

PROJECTED CHANGES OF ISCHEMIC HEART DISEASE MORTALITY WORLDWIDE(1990 to 2020)

3

- Diabetes

- High Blood Pressure

- Chronic Renal Disease

4

World

20002030

154 m370 m

55 m84 m

Developed Developing

99 m286 m

16.733.8

32.9

18.2

52.430.7

28.3

9.1

80.9

22.8

42.3

18.6

0.9 1.6

2000

2030

* In million subjects

102%

81%

71%

211%

255%

127%

78%

THE GLOBAL BURDEN OF DIABETES (2000-2030)

WHO, March 2003

5

INCREASING DEATHS DUE TO DIABETES

U.S. National Center for Health Statistics, 1999

140

120

100

80

60

Ag

e-ad

just

ed d

eath

rat

e re

lati

ve t

o 1

980

1980 1984 1988 1992 1996

Diabetes

Cancer

Cardiovascular diseaseStroke

6

HALF-CENTURY’S EXPERIENCE IN DIABETES MELLITUS

Joslin EP, B Med J, 1950

30

90

(%)

60

Diabetic comaCardiovascular complications

1910-20 1920-30 1930-400

1940-50

7

PROTEINURIA IS AN INDEPENDENT RISK FACTOR FOR CARDIOVASCULAR DISEASE

Nelson et al., Diabetes, 1988

0

25

50

75

100

125

150

Healthysubjects

Non proteinuricdiabetics

Proteinuricdiabetics

Ag

e- a

nd

sex

-ad

just

ed d

eath

s(x

10

00

pe

rso

n-y

ea

r)

Age adjusted cardiovascular mortality in PIMA indians

Juomilehto et al., Diabetologia, 1998

0

2

4

6

8

10

12

12 24

Years of diabetes

CH

D(%

)

Cumulative incidence of CHD in type 1 diabetes

22201816140

With proteinuria

Without proteinuria

8

40 % of type 1 and of type 2 diabetics are at risk of overt nephropathy

THE FACT

9

PROGRESSION OF RENAL FAILURE IN 9 DIABETICS

Modified from Jones et al., Lancet, 1979

0

20

40

60

80

0 10 20 30 40 50

Time (months)

1/C

r x

10 3

(µm

ol/l)

10 Riser et al., Am J Pathol, 1996

Mechanical stress

Podocyte proliferation

Podocyte number

GLOMERULAR HYPERTENSION

Scarring

Durvasula et al, Kidney Int, 2004

Control0

0.2

0.4

0.6

0.8

1.2

Pg

of

An

g I

I p

er

µg

of

cell

lysa

te

1.0*

Stress

Pore dimension

11

GLOMERULAR PERMEABILITY TO MACROMOLECULES

Protein traffic

Glomerular hypertension

0.10

0.00

0.01

0.02

0.03

0.04

0.05

0.06

0.07

0.08

0.09

Po

re r

ad

ii d

istr

ibu

tion

0 20 30 40 50 60

Pore radius (Å)

10

Diabetic

Control

P GC

63mmHg

53mmHg

12A. Remuzzi et al., J Am Soc Nephrol, 1993

0.010

0.100

1.000

20 30 40 50

0.500

0.200

0.050

0.020

0.005

Fic

oll

Fra

ctio

nal

Cle

aran

ce

Vehicle

Angiotensin II

Effective Molecular Radius (A)°

Lapinski et al., J Am Soc Nephrol, 1996

Fra

ctio

nal d

extr

an c

lear

ance

1

Controls

Diabetes

0.1

0.01

0.001

24 28 32 36 40 44 48 52 56 60

Effective Molecular Radius (A)

13

14

Renal injury

Glomerular-capillary hypertension

Increased filtration of plasma proteins

Excessive tubular reabsorption

Nuclear signals for NF-kB-dependent and independent vasoactive and inflammatory genes. Corresponding protein products then released

into interstitium

Tubular cell transdifferentiation

Fibroblast proliferation

Fibrogenesis

Increased glomerular permeability to macromolecules

Proteinuria

Renal scarring

Reduction of nephron numbers

PATHOPHYSIOLOGY OF PROGRESSIVE NEPHROPATHIES

Remuzzi and Bertani, N Engl J Med, 1998

15Remuzzi et al., J Am Soc Nephrol, 1993

Angiotensin II receptor blocker by limiting urinary protein traffic - through a reduction in dimension of large unselective pores - also reduced tubulointerstitial and glomerulosclerosis injury

400

200

100

300

0

Urin

ary

prot

ein

excr

e tio

n (m

g/24

h)

0 4 8 12

Dia

bet

es

Dia

bet

es +

Lo

sart

an

months

**

*

P GC

63mmHg

53mmHg

16

SBP (mmHg)DBP (mmHg)GFR (ml/min/1.73sqm)RPF (ml/min/1.73sqm)FF (%) Urinary protein excretion (g/24h)Albumin fractional clearance (x10-5)IgG fractional clearance (x10-5)

* p < 0.05 Basal vs.Enalapril; ** p < 0.01 Basal vs. Enalapril

CLINICAL AND KIDNEY FUNCTIONAL PARAMETERSBasal Enalapril

152 ± 19 83 ± 9 23 ± 11

366 ± 164 7.0 ± 3.5 3.0 ± 1.9

455 ± 394 138 ± 156

149 ± 1481 ± 6

24 ± 12 357 ± 212 7.2 ± 3.0 2.2 ± 1.3

248 ± 355 * 78 ± 131 **

EnalaprilDiabetes30

35

40

45

50

55

60 u (Å)

0

1.0

2.0

3.0

4.0

5.0

6.0

EnalaprilDiabetes

mean size of membrane poresfiltrate volume fraction that would pass through the shunts if plasma protein were absent

u

o

Remuzzi A et al., J Nephrol, 1993

o x 10 -3

Control Control

17

Decrease in Mean Blood

Pressure (mm Hg)

- 2 –

0 –

- 2 –

- 4 –

- 6 –

- 8 –

- 40 –

- 20 –

0 –

- 20 –

- 40 –

- 60 –

% Reduction in

Proteinuria

P <.001

% with Doubling of

Baseline Creatinine

Baseline creatinine > 1.5 mg/dl

0

25

50

75

100

0 1 2 3 4

Captopril

Conventional therapy

Lewis et al. N Engl J Med. 1993;329:1456-1462.

NS

ACE-I IS BETTER THAN CONVENTIONAL THERAPY IN TYPE 1 DIABETES

18

Decrease in Mean Blood

Pressure (mm Hg)

+ 2 –

0 –

- 2 –

- 4 –

- 6 –

- 8 –

- 9 –

- 10 –

+ 40 –

+ 20 –

0 –

- 20 –

- 40 –

- 60 –

% Reduction in

Proteinuria

p <.001

% with Doubling of

Baseline Creatinine+ ESRD+ death

0

25

50

75

100

0 1 2 3 4

Losartan

Conventional therapy

Brenner et al, N Engl J Med., 2001.

NS

RENAAL: ARB IS BETTER THAN CONVENTIONAL

THERAPY IN TYPE 2 DIABETIC NEPHROPATHY

+ 19

- 45-9.2 -9.6

19

In diabetic renal disease a major achievement has been already to limit progression from macroalbuminuria to the need of dialysis

1 -

20

Heart Failure

MI

Stroke

CV Death

RENAAL Secondary Composite Endpoint and Components

Losartan n=751

n

89

50

47

90

Placebo n=762

n

127

68

50

79

% RiskLosartan vs placebo

- 32

- 28

- 5

+12

21

HAZARD RATIO OF RENAL AND CARDIOVASCULAR EVENTS ACCORDING TO 6 MONTHS REDUCTION IN PROTEIN/CREATININE RATIO

ESRD

CV events

Heart failure

0.4 0.60.2 0.8 1 1.2

RENAAL Study group, 2002

Hazard ratio (95 % C.I.)

Decreased risk Increased risk

22

HAZARD RATIO FOR CARDIOVASCULAR EVENTS ACCORDING TO TREATMENT AND RESIDUAL (6 MONTHS) PROTEINURIA

RENAAL study group, 2002

Haz

ard

ratio

rel

ativ

e to

lo

wes

t pro

tein

uria

Protein/creatinine ratio at 6 months (g/g)

CV Endpoint

1

1.01

1.02

1.03

1.04

1.05

<0.4 2.0 3.0 4.1 ≥ 5.2

Losartan

Placebo

23

AT1 blockade

Angiotensin II

AT2 overstimulation

- BP reduction- vasodilation- antigrowth and antitrophic effects

- cardiovascular fibrosis

- Inhibition of coronary angiogenesis

Any disruption of angiogenesis that may arise from stimulation of AT2 receptors in the context of AT1 blockade could have serious implications in ischemic tissues such as a diseased myocardium or in lower limbs affected with peripheral arterial disease

Silvestre et al., Circ Res, 2002

Akishita et al., Circulation, 2000

24

A META-ANALYSIS OF 47 TRIALS OF 8,305 PATIENTS WITH DIABETIC NEPHROPATHY RANDOMIZED TO ACEi OR ARB THERAPY vs PLACEBO

ACEi

Patients

4,805

ARB 3,329

All cause mortality Relative Risk (95% C.I.)

Strippoli et al., J Am Soc Nephrol, 2003

0.7 0.80.6 0.9 1 1.1

Decreased risk Increased risk

1.2 1.3

25

ANGIOTENSIN RECEPTOR BLOCKADE VS ACE-I IN TYPE 2 DIABETES AND NEPHROPHATYA 5-years, randomized trial

Enalapril(n = 130)

GFR (ml/min/1.73 sqm)

CV events (%)(fatal//non fatal)

Barnett et al., N Engl J Med, 2004

Telmisartan(n = 120)

-14.9

21

-17.9

27

However: - more progression and events on telmisartan

- statistics ?

“These findings support the clinical equivalence of AII-RA and ACE-I in persons with type 2 diabetes and nephropathy”

26

ANNUAL MORTALITY AND ESRD IN SUBJECTS WITH TYPE 2 DIABETES AND NEPHROPATHY

Adler et al., Kidney Int, 2003

0

20

25

15

(%)

10

5

ESRD

*

Estimate from the ° UKPDS and the *RENAAL studies

Mortality

°

?U

KP

DS

RE

NA

AL

27

RISK OF CARDIOVASCULAR EVENTS ACCORDING TO RENAL OR CORONARY ARTERY DISEASE

Renal insufficiency and albuminuria

Coronary artery disease

R.R. (95 % C.I.)

1 1.25 1.5 2.0 2.50.5Increased risk

28

00

*

*300

200

0 31-33 35-37 39-41

EVIDENCE THAT ACE-I HAS A DIFFERENT EFFECT ON GLOMERULAR INJURY ACCORDING TO THE DIFFERENT PHASE OF THE DISEASE AT WHICH THE TREATMENT IS STARTED

Pro

tein

uri

a (m

g/2

4h)

Pro

tein

uri

a (m

g/2

4h)

Perico et al., J Am Soc Nephrol, 1994

Time (weeks) Time (weeks)

0 20-24 24-28 28-32

Diabetes

Diabetes + ACEi

ACEi

ACEiDiabetes

Diabetes + ACEi100

200

200

160

120

80

40

29

RENAALIDNT

IRMA 2

ESRDNormoalbuminuria Micro Macro

0 25

Duration of diabetes (years)

< 20 20 - 200 > 200UAE µg/min

13 18

30

EFFECT OF ANGIOTENSIN II ANTAGONISM ON PROGRESSION TO MACROALBUMINURIA IN SUBJECTS WITH TYPE 2 DIABETES AND MICROALBUMINURIA

Parving et al., N Engl J Med, 2001

Inci

den

ce o

f m

acro

alb

um

inu

ria

(%)

Months of follow-up

0 3 6 12 18 22 240

5

10

15

20

Placebo

Irbesartan

31

The second important step was to reduce the number of patients who progress from microalbuminuria to overt nephropathy

2 -

32

THE ASSOCIATION OF MICROALBUMINURIA AND MORTALITY IN TYPE 2 DIABETES

An overview of 2.138 patients of 8 clinical trials from 1992 to 1995

R.R. (95 % C.I.)

1 4 160.5

Micro worse

64 256

33

Preventing nephropathy is more important than retarding progression

34

RENAALIDNT

IRMA 2BENEDICT

ESRDNormoalbuminuria Micro Macro

0 25

Duration of diabetes (years)

< 20 20 - 200 > 200UAE µg/min

13 18

35

1.200 hanno preso parte allo studio

The BENEDICT trial

6.500 pazienti studiati

36

To assess whether microalbuminuria can be prevented in people with type 2 diabetes and normal urinary albumin excretion

PRIMARY AIM

37

Type 2 diabetes mellitus

Arterial hypertension

Normoalbuminuria

Serum creatinine

WHO criteriaAge ≥ 40 yrsDuration < 25 yearsHbA1c < 11 %

Systolic BP > 130 mmHg and/or

Diastolic BP > 85 mmHg and/or

need for antihypertensive agents

UAE < 20 µg/min (in at least 2 of 3 consecutive overnight urine collections)

< 1.5 mg/dl

Inclusion criteria

The BENEDICT group, CCT 2003Ruggenenti et al., N Engl J Med, 2004

38Ravid et al., Ann Intern Med 1998

EFFECTS OF ENALAPRIL (10 mg/day) IN NON-OBESE SUBJECTS WITHTYPE 2 DIABETES, NORMAL BLOOD PRESSURE ANDNORMOALBUMINURIA

110

105

100

95

900 1 2 3 4 5 6

Me

an

Blo

od

Pre

ss

ure

(m

mH

g)

Years

40

30

20

10

0

UA

E

(mg

/24

h)

Enalapril (n=77)

Placebo (n=79)

*

*

* p < 0.05 vs. enalapril

39

Cha

nge

vs. b

asal

(%

)

Bakris et al., Kidney Int 2004

EFFECTS OF CALCIUM ANTAGONIST SUBCLASSES ON MARKERS OF NEPHROPATHY PROGRESSIONA systematic review of randomized trials of dCCBs and ndCCBs in hypertensive adults with proteinuria

MAP

-30

-20

-10

0

dCCBs ndCCBs

Proteinuria

-30

-20

-10

0

dCCBs ndCCBs

10

0

10

p < 0.01

40

THE EFFECT OF 6 MONTH TREATMENT WITH TRANDOLAPRIL AND ITS FIXED-DOSE COMBINATION WITH VERAPAMIL ON PROTEINURIA IN 60 NORMOTENSIVE ADULTS WITH TYPE 2 DIABETES

Trandolapril VeraTran Trandolapril VeraTran

pre

Pro

tein

uria

(g/

24 h

ours

)

post0

0.5

1.0

1.5

pre post

p < 0.01 p < 0.001

pre

GF

R (

ml/m

in)

post0

60

80

100

pre post

p < 0.05

40

20

Rubio-Guerra et al., Diabetes Care, 2004

41

Study design

Overnight UAE

Blood pressure and routine laboratory tests

RAS inhibitors withdrawal

Ran

do

mis

atio

n

0 6 12 18 24 30 36months

RUN-IN TREATMENT PERIOD

-6 -5 -4 -3 -2 -1 0weeks

ndCCBs withdrawal

Trandolapril (2mg/d)

Verapamil S.R. (240 mg/d)

Trandolapril (2mg/d) plus Verapamil S.R. (180 mg/d)

Placebo

42

0

5

10

15

0 6 12 18 24 30 36 42 48

Follow-up (months)

Placebo(30 events)

Trandolapril

plus

verapamil(17 events)

300

300

249

229

232

214

217

203

210

187

201

176

192

164

162

136

115

89

Cu

mu

lati

ve I

nci

de

nce

of

Mic

roal

bu

min

uri

a (%

)

No. at Risk

Trandolapril plus VerapamilPlacebo

A.F. (95 % C.I.) = 0.39 (0.19 - 0.80) p = 0.01

43

0

5

10

15

0 6 12 18 24 30 36 42 48

Cu

mu

lati

ve

inci

den

ce o

f m

icro

alb

um

inu

ria

(%)

Follow-up (months)

301

300

254

229

237

214

224

203

207

187

198

176

188

164

149

136

104

89

No. at Risk

Trandolapril

Placebo

Placebo(30 events)

Trandolapril (18 events)

A.F. (95 % C.I.) = 0.47 (0.26 - 0.83) p = 0.01

44

Cu

mu

lati

ve

inci

den

ce o

f m

icro

alb

um

inu

ria

(%)

0 6 12 18 24 30 36 42 48

Follow-up (months)

303

300

234

229

210

214

202

203

189

187

181

176

174

164

134

136

98

89

No. at Risk

Verapamil

Placebo

0

5

10

15

Placebo

(30 events)

Verapamil

(36 events)

45

ADVERSE EVENTS

Fatal

Cardiovascular

Non Fatal

Cardiovascular

Trandolapril VerapamilTrandolapril

plusverapamil

Placebo

41

8012

21

6713

20

6711

53

7012

N=301 N=303 N=300 N=300

46 Palmer et al., Diabetes Care, 2004

COST-EFFECTIVENESS OF RAS INHIBITION IN TYPE 2 DIABETES MODELED OVER 25 YEARS

0

20

25

15

10

5

Cu

mu

lati

ve in

cid

ence

(%

)

ESRD

0

30

15

10

U.S

. $

(x

1,00

0)

Per patient costs

20

25

5

No

rmo

B

EN

ED

ICT

?M

acro

Mac

ro

RAS-inhibition

Mic

ro

Placebo

?

Mac

ro

Mac

ro

RAS-inhibition

Mic

ro

Placebo

IRM

A-2

RE

NA

AL

IRM

A-2

RE

NA

AL

No

rmo

B

EN

ED

ICT

47

Broome

Bega, Kalgoorlie

Borroloola

Wadeye

Naiuyu

Tiwi Islands

Chronic Disease Outreach Program in Australia

Soweto, South Africa

Chennai, India

48 Hoy et al., J Am Soc Nephrol, 2003

A cost effectiveness analysis estimate savings of $ 800,000 AUS to $ 4,1 million at 2 years in cost of dialysis avoided or delayed

0

5

10

Eve

nts

per

10

0 p

erso

ns/y

ea

rs15

20Conventional Perindopril

ES

RD

De

ath

1990 1995 2000

49

Nicaragua

Moldova

Cuba

Nigeria

Bolivia

ChinaNepal

Philippines

Maroco

Armenia

Established programs

Programs in development

Indonesia

India

Paraguay

AustraliaSouth Africa

50

A new agenda for kidney doctors will be for the future preventing nephropathy with the final aim to limit cardiovascular events and death

3 -

51

Just kidney doctors ?