1 Giuseppe Remuzzi Prevention of progression and remission/regression strategies of chronic renal diseases: can we do better now than 5 years ago? Bellagio, March 16, 2004
Dec 19, 2015
1
Giuseppe Remuzzi
Prevention of progression and remission/regression strategies of chronic renal
diseases: can we do better now than 5
years ago?
Bellagio, March 16, 2004
2
There are 1,065,000 people on dialysis worldwide
90 % of them live in North America, Japan, and Europe, whose population is less than 20 % of world population
3Lysaght et al., J Am Soc Nephrol, 2002
1200
600
0
Te
n ye
ar
me
dic
al c
ost
s o
f d
ialy
sis
pop
ula
tion
$ (
bill
ions
)
1981-1990 1991-2000 2001-2010
800
1000
$
$
$
PREDICTED DIALYSIS COST OF APPROXIMATELY $ 1.1 TRILLION FOR THE COMING DECADE
400
200
4
1,000,000 deaths
5
PROGRESSION OF RENAL FAILURE IN 9 DIABETICS
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)
6
Time (months after UNx)
Sur
viva
l (%
)
UNx
Control
UNx + Lis
0 3 6 9 1 2 1 50
20
40
60
80
100
ACE INHIBITION PREVENTS RENAL FAILURE AND DEATH IN UNINEPHRECTOMIZED MWF/ZTM RATS
Urin
ary
Pro
tein
Exc
retio
n (
mg
/24
hrs
)
Per
cen
tag
e o
f gl
omer
uli
affe
cted
by
scle
rosi
s
0
20
40
60
80
100
UNxControl UNx + Lis
0
100
200
300
400
500
600
700
UNxControl UNx + Lis
*
**
*
**
* p < 0.05, **p < 0.01 vs control Remuzzi et al., Kidney Int, 1995
7
EFFECT OF ACE-I THERAPY ON RISK OF DEATH IN NON-DIABETIC CHRONIC RENAL DISEASE
- Zucchelli et al., 1992
- Kamper et al., 1992
- Brenner et al., 1993
- Toto et al., 1993
- van Essen et al.,1994
- Hannedouche et al., 1994
- Bannister et al., 1994
- Hansson et al., 1995
- Ihle et al., 1996
- Maschio et al., 1996
Author, year Patients
- OVERALL
121
70
112
124
103
100
51
260
70
583
1594
Giatras et al, J Am Soc Nephrol, 1997
Risk Ratio & C.I.
ACE-I better ACE-I worse
1 5 20 1000.20.050.01
Pooled Risk Ratio (95% CI)
1.24 (0.55 - 2.83)
Risk of death
Pat
ient
s w
ith p
rote
inur
ia (
%)
0
30
60
< 0.5 0.5 - 3 ≥ 3
Proteinuria (g/24 h)
50 %
35 %
15 %
8
REIN CORE
Rate of GFR decline according to base-line proteinuria - Interim analysis on 177 patients
STRATUM - 1U. Prot. < 3 g/24 h
STRATUM - 2U. Prot. ≥ 3 g/24 h
0.5
1.0
0
Rat
e o
f G
FR
dec
line
(m
l/min
/mo
nth
)
p=0.001
0.25±0.08
0.67±0.08
GISEN Group, Lancet, 1997
Conventional
0.89±0.11
Ramipril
0.39±0.100.5
1.0
0
Rat
e o
f G
FR
dec
lin
e(m
l/m
in/m
on
th)
p=0.001
Kidney survival: Conventional 54 %
Ramipril 77 %
9
REIN CORE
GISEN Group, Lancet, 1997
Conventional
Ramipril1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0%
pat
ient
s w
ith d
oubl
ing
of b
ase-
line
crea
tinin
e or
ES
RF
Mea
n ra
te o
f GF
R d
eclin
e (m
l/min
/mon
th)
70
60
50
40
30
20
10
0
3 - 4.5 4.5 - 7 ≥ 7 3 - 4.5 4.5 - 7 ≥ 7
Baseline proteinuria (g/24 h) Baseline proteinuria (g/24 h)
10
AN ARTIFICIAL NEURAL NETWORK TO MODEL INDIVIDUAL OUTCOME OF PATIENTS WITH CHRONIC NEPHROPATHIES ON THE BASIS OF DATA FROM THE REIN STUDY
Besides serum creatinine, the model identified proteinuria and Ca*P product as the strongest predictors of ESRD
11
RISK OF PROGRESSION TO ESRD OVER 20 MONTHS FOLLOW-UP IN PROTEINURIC CHRONIC NEPHROPATHIES
Predicted risk in 3 explicative cases
0
20
40
60
%
Serum creat mg /dl
Proteinuria g /24 h
CaxP mg2/dl2
1.2
1.9
24.3
2.1
3.9
35.1
3.5
5.2
37.2
80
12
3 MONTHS PROTEINURIA REDUCTION PREDICTS LONG-TERM GFR DECLINE The REIN study
Ramipril
Overall
Conventional
* Corrected for GFR
> 3 gr/24 h
GF
R (m
l/min
/mo
nth
)
3 ye
ars
- 20
- 0.6
-0.5
- 0.4
-0.3
- 0.8
- 0.7
- 0.9
-0.20 20 40
proteinuria *( percent change vs .baseline)
3 monthsPerna et al., J Am Soc Nephrol, 2000
13
CORRELATION BETWEEN CHANGES IN PROTEINURIA AND GFR DECLINE
1 - 3 gr/24 h
p
rote
inu
ria
*(p
erce
nt c
hang
e vs
. ba
selin
e)3
mo
nth
s
- 20
0
20
40
- 0.2 -0.3 - 0.4
Overall PlaceboRamipril
* Corrected for GFR
> 3 gr/24 h
GFR (ml/min/month)
3 years
- 0.6-0.5- 0.4-0.3 - 0.8- 0.7 0.9-0.2
- 20
0
20
40
p
rote
inu
ria
*(
perc
ent
chan
ge v
s .b
asel
ine)
3 m
on
ths
Perna et al., J Am Soc Nephrol, 2000
14
6 MONTHS PROTEIN/CREATININE RATIO REDUCTION PREDICTS RENAL AND CARDIOVASCULAR EVENTSThe RENAAL study
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
15
PROTEINURIA AND RISK OF DEVELOPING ESRD
Iseki et al., Kidney Int, 2003
Community-based screening in 106,177 general population
Follow-up: 17 years
16
14
12
10
8
6
4
2
0
Cum
ulat
ive
inci
denc
e of
ES
RD
(%
)
Proteinuria
Number of screened
Number of ESRD
-
86,253
185
+
10,000
38
+
4,007
55
2+
1,072
76
>3+
357
55
16
RISK OF ESRD: PREDICTIVE VALUE OF BASELINE GFR AND PROTEINURIA1993 mass screening conducted by the Okinawa General Health Maintenance Association (OGHMA)
Subjects
Inclusion criteria
Baseline parameters
Follow-up
End point
95,255
> 20 years of ageGFR > 15 ml/min
Dipstick proteinuriaCalculated GFR (Cockcroft-Gault method)
7 years
ESRD
Iseki et al., J Am Soc Nephrol, 2003
17
Proteinuria (+)
Proteinuria (-)
Number of screened
Number of ESRD1,125
8481111
7177
8006
3,453108
Number of screened
Number of ESRD21,872
2222,254
1822,312
122,229
388,667
44
Cum
ulat
ive
Inci
denc
e of
ES
RD
per
1,00
0 sc
reen
ed in
7 y
ears
GFR, ml/min/1.73m2
0
20
40
60
80
15.0-57.1 57.2-77.6 77.7-102.6 ≥102.7 Total
Fig3
Proteinuria (+)
Proteinuria (-)
18
EFFECTS OF LOSARTAN ACCORDING TO RACE:Post-hoc analyses of the RENAAL study
Asian
Black
White
Hispanic
Other
Overall
Primary end point (Doubling s. creat, ESRD or death)
252
230
734
277
19
1,261
n°Region
0.5 0.750.25 1.0 1.25 1.5
Losartan better Losartan worse
Hazard ratio (95 % C.I.)
p
0.024
0.94
0.07
0.99
0.76
0.18
The whole effect of Losartan was fully driver by Asian patients
19
1-YEAR PROTEINURIA REDUCTION IN TYPE 2 DIABETICS ENROLLED IN THE RENAAL STUDY ACCORDING TO RACE
-20
-10
-15
-5
0
Med
ian
(I.Q
. ran
ge)
prot
einu
ria
redu
ctio
n vs
bas
elin
e (
%)
-19 (-56 to 36)
ASIAn = 252
p = 0.03 (ANCOVA)
Non-ASIAn = 1,261
-9 (-51 to 40)
20
Asian
Non Asian
Reduced proteinuria
YES
NO
YES
NO
YES
NO
NO
NO
Outcome improved
Risk reduction (95 % C.I.)
-25 1 25 50 75
Decreased risk Increased risk
-50-75
0.016
0.27
0.59
0.35
pBaseline proteinuria
(alb/creat g/g)
1.535
1.167
21
BASELINE CHARACTERISTICS OF ASIAN AND NON-ASIAN PATIENTS OF RENAAL STUDY
Asian(257)
60+7
102+11
25+4
Non-Asian(1256)
60+7
106+11
31+5
p
0.72
<0.005
<0.0001
Age (yrs)
MAP (mmHg)
BMI (Kg/m2)
22
45
30
25
40
35GF
R(m
l/min
/mon
th)
RamiprilRamipril
GFR = -0.44 ± 0.54
GFR = -0.10 ± 0.50
GFR = -0.81 ± 1.12 GFR = -0.14 ± 0.87
RamiprilConventional
CORE FOLLOW-UP
Ruggenenti et al., Lancet, 1998
23
0,10 ml/min/month
24
Slopes refer to 26 patients on continuated Ramipril treatment since randomization who had at least 6 GFR measurements (≥ 3 on Core and ≤ 3 on Follow-up study)
16 patients with stable GFR
Remission Regression
10 patients with increasing GFR90
80
70
60
50
40
30
20
10
0
months0 10 20 30 40 50 60
GF
R (
ml/m
in/m
on
th)
90
80
70
60
50
40
30
20
10
0
months0 10 20 30 40 50 60
GF
R (
ml/m
in/m
on
th)
25
Pro
tein
uria
red
uctio
n vs
pr
e-br
eakp
oint
val
ues
(%)
Remissionn = 16
RELATIONSHIP BETWEEN REMISSION/REGRESSION AND POST-BREAKPOINT CHANGES IN PROTEINURIAPost hoc analyses of the REIN study
Regressionn = 10
- 40
0
- 20
- 60
-31 %
-52 %
The further improvement in GFR during continued ramipril therapy was always associated with further proteinuria reduction
The extent of GFR amelioration was associated with the extent of proteinuria reduction
Ruggenenti et al., J Am Soc Nephrol, 1999
26
0
10
20
30
40
50
0 6 18 30 36 48 5412 24 42
*
GF
R (
ml/1
.73
sq
m)
Y= 0.0092x - 0.6033x2 + 45.586
Y1 = - 0.3291x + 44.794 Y2 =0.387x + 19.677
* p (y1 vs y2 ): < 0.01 (F-test)
months
REGRESSION OF THE DISEASE IN PATIENTS ON CONTINUED RAMIPRIL
27
MWF 60 w
0
20
40
60
80
100
0% <25% 25-50% 50-75% >75%
MWF 50 w
0
20
40
60
80
100
0% <25% 25-50% 50-75% >75%
Num
ber
of
Glo
mer
uli
(%
)
MWF 60 w + LIS
0
20
40
60
80
100
0% <25% 25-50% 50-75% >75%
EVIDENCE FOR GLOMERULAR CAPILLARY REGENERATION AND REABSORPTION OF SCLEROSIS AREAS
Remuzzi et al., J Am Soc Nephrol, 2003
28
Intensify blood pressure control
Up-titrate ACE inhibitor dose
Combine with other antiproteinuric agents
Vasopeptidase inhibitors
protein traffic
- Non-dihydropyridinic Ca-channel blockers- Ang II receptor blockers- Aldosterone antagonists
consequences of protein trafficDrugs targeted to inflammatory or vasoactive genes which are up-regulated by protein reabsorption
- ET-1 receptor antagonists- TGF inhibitors- Lipid lowering agents
CAN WE DO BETTER?
29
* No correlation between proteinuria and BP changes
THE EFFECT ON PROTEINURIA AND BLOOD PRESSURE OF INCREASING DOSES OF ACE INHIBITORS
v
s. n
o tr
eatm
ent
(%)
151050 20-60
-50
-40
-20
-10
0
-30
y=-1.23x - 12.07
24 h Proteinuria*
Ramipril dose (mg/day)
M.A.P.*
151050 20
-30
-20
0
+10
+20
-10
-30
Ramipril dose (mg/day)
r =-1.23; p<0.02
30
THE COURSE OF THE EFFECT OF ANG II ANTAGONISM ON BLOOD PRESSURE AND URINARY PROTEIN EXCRETION
Blood pressure
Urinary protein excretion
Gansevoort et al., Kidney Int, 1994
31
LDL Cholesterol
Serum Albumin
Lisinopril dose (mg/day)
Ch
ang
es
vs. b
asa
l (%
) + 40
+ 30
+ 20
+ 10
0
0 10 20 30 40 10 0
- 10
- 20
- 30
EFFECTS OF UP-TITRATING LISINOPRIL IN MEMBRANOUS NEPHROPATHY
Ruggenenti et al., Circulation, 2003
32
DUAL RENIN-ANGIOTENSIN SYSTEM BLOCKADE IS HIGHLY EFFECTIVE TO IN NON-DIABETIC PROTEINURICS
Laverman et al., Kidney Int, 2002
9 non-diabetic renal patients (6 weeks treatment per dose)
Cha
nge
of p
rote
inur
ia (
%)
-100
-75
-50
-25
0
0 10 20 40
0 50 100 150 50 - 150
10 - 40
Losartan
LisinoprilCombined
33
-70
-60
-50
-40
-30
-20
-10
0
10
24 hrs Uprot excretion
MAP
VALSARTAN(160 mg/day)
BENAZEPRIL(20 mg/day)
BENAZEPRIL + VALSARTAN
(10 + 80 mg/day)
p = 0.002
p = 0.022
p = 0.024
Per
cen
t ch
ang
e fr
om
bas
elin
e
EFFECTS ON PROTEINURIA OF 8 WEEKS COMPARABLE BLOOD PRESSURE CONTROL ACHIEVED BY COMBINED THERAPY IN 23 PATIENTS WITH CHRONIC NON-DIABETIC NEPHROPATHIES
Campbell et al., 2002
34
Dextran clearance studies found no differences in size selective properties of the membrane but more reduction in renal vascular resistance (p = 0.046) in combination therapy compared to each drug alone
22 30 38 46 54 62 70
0.01
0.1
1.0
22 30 38 46 54 62 70
Basaline
Benazepril + Valsartan
Molecular radius (Å)
De
xtr
an
Fra
cti
on
al
Cle
ara
nc
e
Baseline
Valsartan***
**
**
**
**
**
*
**
**
**
**
**
*
***
****
**
**
**
**
**
*
*
**
Campbell et al., 2002
22 30 38 46 54 62 70
Baseline
Benazepril **
*
35
COOPERATE study: results
Nakao et al., Lancet, 2003
Pa
tient
s w
ithou
t eve
nts
* (%
)
Months after randomisation0 6 12 18 24 30 36
CombinationLosartanTrandolapril
40
80
100
60
20
0
* ESRD and doubling of serum creatinine
36
SEVERE PASSIVE HEYMANN NEPHRITIS (UNINEPHRECTOMY)
Zoja et al., J Am Soc Nephrol, 2002
LisinoprilVehicle Lis + AII-RA Lis + AII-RA+Cerivastatin
Treatment for 10 months (start treatment at 2 months)
Urin
ary
prot
ein
excr
etio
n (
mg/
day)
Control
0
200
400
600
800
*
*
Glo
mer
ulos
cler
osis
(%
)
20
40
60
80
**
*
37
EDITORIAL J Am Soc Nephrol 13:3024 - 3026, 2002
The Next Treatments of Chronic Kidney Disease: If We Find Them, can We Test Them?
THOMAS H. HOSTETTERNational Institute of Health, National Institute of Diabetes and Digestive and Kidney Diseases,Bethesda, Maryland
38
Add non-dihydropyridine CCBs (Verapamil/Diltiazem)
Up-titrate non-dihydropiridine CCBs to max tolerated dose
Up titrate concomitant antihypertensive agents to achieve the maximum tolerated blood pressure reduction
Add a lipid lowering agent
Start low-dose sodium diet
Add low-dose ACE i or AII RA
Up-titrate ACE i or AII RA to max tolerated dose
Add a diuretic
Add a low dose of another antiproteinuric agent
Add AII RA or ACE i
Up-titrate AII RA or ACE i to maximum dose
REMISSION CLINIC
K < 5.5 mEq/l K > 5.5 mEq/l
Ruggenenti et al., Lancet, 2001
39
Uri
nar
y pr
ote
in e
xcre
tion
(g
/24
hour
s)
Se
rum cre
atin
ine
(mg/dl)
months
FULL RESPONDERS (n=19)
- Full remission of nephrotic syndrome (U.prot. <1g/24 h) - Stable s. creatinine over 4 years
0 10 20 30 40 500
1
2
3
4
5
- 10
Remission clinic
0
2
4
6
8
40
Uri
nar
y pr
ote
in e
xcre
tion
(g
/24
hour
s)
Se
rum cre
atin
ine
(mg/dl)
PARTIAL RESPONDERS (n=7)
- Partial remission of nephrotic syndrome- s. creat increase < 0.2 mg/dl/year
Remission clinic
0
1
2
3
4
5
-10 0 10 20 30months
0
2
4
6
8
40
41
Targets of the multidrug approach:
Blood pressure < 120/80 mmHgProteinuria < 0.3 g/24 hLDL < 100 mg/dlLDL + VLDL < 130 mg/dlHbA1c < 7.5 % (diabetics)
Ruggenenti et al., Lancet, 2001
REMISSION CLINIC
42
OUTCOMES OF 160 TYPE 2 DIABETICS WITH MICROALBUMINURIA ACCORDING TO MULTIFACTORIAL OR CONVENTIONAL THERAPY
Gaede et al., N Engl J Med, 2003
Multifactorial therapy better
Multifactorial therapy worse
Fatal and non-fatal CV events
Nephropathy
Retinopathy
0.0 0.5 1.0 1.5
Relative risk (95 % C.I.)
2.0
43
When to start, why never stop
44
0
40
50
70
Inci
den
ce o
f E
SR
D (
%)
Lowest(10.5 - 32.6 ml/min)
Middle(32.6 - 50.8 ml/min)
Highest(50.8 - 101.0 ml/min)
INCIDENCE OF ESRD IN 352 PATIENTS WITH PROTEINURIC, CHRONIC NEPHROPATHIES ACCORDING TO TREATMENT AND TERTILES OF BASAL GFR
60
30
20
10
60.0 %
40.4 %
21.4 %
13.4 % 10.9 %
0.0 %
p < 0.05
p < 0.01
Co
nv
enti
on
al
Ra
mip
ril
Ruggenenti et al., J Am Soc Nephrol, 2002
45
Hariprasad et al., Am J Kidney Dis, 2002
Co
sts
save
d (
$ b
illio
n)
- 10 % - 30 %0
10
20
30
40
50
60
70
18,56
60,61
* Predicted for patients with basal GFR ≤ 60ml/min
GFR reduction*
65,000
50,000
35,000
Pre
vale
nce
2000 2010
55,000
60,000
45,000
40,000
2005
661,330
466,438
ESRDPrevalence projections
7.56
-30 %
Predicted GFR
(ml/min/yrs)
615,767
-10 %
1998 - 2010PREDICTED ESRD PREVALENCE AND CUMULATIVE SAVINGS FOR DIFFERENT DEGREES OF GFR REDUCTIONS
46
GFR DECLINE ACCORDING TO DIFFERENT UNDERLYING RENAL DISEASE
Ruggenenti et al., Am J Kidney Dis, 2000
GF
R (
ml/
min
/mo
nth
)
0
0.2
0.4
0.6
0.8
1.0
1.2
0.53±0.09
0.31±0.07
Primary Glomerular Disease
0.55±0.13
0.36±0.09
IgA Nephropathy
0.49±0.11
0.31±0.09
Nephrosclerosis
ConventionalRamipril
% GFR reduction vs control
-42 -35 -37
47
DEVELOPMENT OF A LOW COST “POLYPILL” TO PREVENT RENAL PROGRESSION AND CARDIOVASCULAR EVENTS
• A single combination low cost pill containing six active components, including aspirin, a statin, three antihypertensive agents (a thiazide, a -blocker, an ACE inhibitor) at half standard dose, and folic acid has been proposed for the prevention of cardiovascular disease
Wald and Law, British Med J, 2003
48
Statin
Aspirin
ACE inhinitors
The superpill could be valuable also for patients with chronic nephropathies to limit both renal and cardiovascular events
49
A LOW COST POLYPILL COULD USE GENERIC COMPONENTS
Generic drugs are not subject to patent protection
This formulation may not have the lowest rate of adverse effects, but even if about 10% of people were intolerant of the formulation it would still have considerable public health merit
50
So far, treatment of renal patients has been aimed to limit or prevent progression to ESRD
51
ANNUAL ESRD AND MORTALITY IN TYPE 2 DIABETICS WITH OVERT NEPHROPATHY
Adler et al., Kidney Int, 2003
0
20
25
15
(%)
10
5
ESRD
*
Estimate from the °UKPDS and the *RENAAL studies
Mortality
°
?
52
Preventing nephropathy is more important than retarding progression
PROJECTED CHANGES OF ISCHEMIC HEART DISEASE MORTALITY WORLDWIDE (1990 to 2020)
DEVELOPINGCOUNTRIES
DEVELOPEDCOUNTRIES
0500
100015002000250030003500400045005000
1990 2020Yusuf et al. Circulation 2001
Deaths (x 1000)
54
The obstacle in providing adequate health care to millions of people in poor countries are multiple
- Poor infrastructures- Famine and malnutrition- Cultural attitudes- Inadequate public health systems- War
55
However, lack of access to essential drugs is a most striking aspect that underlines dramatically the existence of two different world
56
COST OF 1 YR OF THE PROJECT $ 6,200COST PER PATIENT $ 0.27PER CAPITA HEALTH EXPENDITURE $ 7.7IN INDIA
THE KIDNEY HELP TRUST PROJECT IN INDIA
Mani, Kidney Int, 2003
25,000 people were screened for high blood pressure, diabetes, chronic kidney disease in the region of Tamil Nadu (India)
The screening campaign was conducted by 6 trained social workers and 2 doctors
Patients with high blood pressure, diabetes or kidney diseases were put on cheap medications and followed
India
Tamil Nadu
---
57
The community programme of mass screening and free drug therapy, reported from India would not be sustainable if replicated across the whole of India
58
STARTING TO WORK FOR A LARGE-SCALE PREVENTION PROGRAM OF ESRD IN MOLDOVA
Health Authorities
Mario Negri Institute
Moldova Society of Nephrology
Igor Codreanu
ISN-COMGAN
Activation of a 4 yr program
4,762,000 population
Chisinau
Bergamo
MOLDOVA
Network between existing health care structures under the coordination of the Republican Clinical Hospital Chisinau
Large--scale screening
Intervention treatment
Continuous education
33,700 Km2
Income per month: 70 $
59
VIRTUAL NETWORKS OF EXCELLENCE TO LINK THE SCIENTIFIC TALENTS OF ENTIRE REGIONS
Virtual networks of excellence are based on research programs jointly sponsored and conducted by research institutes in different geographical locations
InterAcademic Council, 2004
60
CREATING AUTONOMOUS CENTERS OF EXCELLENCE TO ADDRESS LOCAL CHALLENGES
Center of excellence - whether of local, national, regional, or international status - should be created or planned in the near future in every developing nation in order for its science capacity to grown
InterAcademic Council, 2004
61
THE EFFECT OF RAMIPRIL TRIALS ON ACE INHIBITOR PRESCRIBING IN ONTARIO (CANADA)
REIN, HOPE
All ACE inhibitors
Ramipril
62
63
0
20
10
%
5
TelecomPharmaceutical
PERCENT PROFIT OF TOP COMPANIES IN EACH SECTOR
Fortune 500, 2000
15
Airlines Chemicals Automobiles
18,6
11,7
5,7 5,1
3,5
64
0
30
20
Pe
rce
nt o
f in
com
e
10
ResearchMarketing
PHARMACEUTICAL COMPANIES
Year 2000
Fortune 500, 2000
65
Pre-clinical studies
Infrastructures
Expertise - physicians - nurses - other professionals
Angell, N Engl J Med, 2000
INVESTMENT OF PUBLIC INSTITUTIONS ON INNOVATIVE DRUGS
66
It is no unlikely that the pre-clinical research could account for as much as 20 to 25% of a company’s research budget
Gerth and Stolberg, New York Times, 2000
67
It is becoming increasingly intolerable to know that innumerable lives are lost in poor countries only because relatively simple measures are not available because of their cost
The contribution of pharmaceutical industry is fundamental to starting a new era of hope
68
A GLOBAL FUND FOR KIDNEY DISEASE
69
Pharmaceutical companies that profit from selling renoprotective drugs take the lead in establishing the fund
The makers of drugs with renoprotective effects - not just ACE inhibitors and ARBs, but also blood pressure, diabetes, and cholesterol drugs - could donate 1 % of profit from sales of these drugs
70
WHAT TO DO WITH GLOBAL FUND?
Further ISN prevention/education program and add primary care physicians and health professionals
Begins centers of excellence with infrastructures so we can apply to agencies for funds
Raise public awareness to renal survival
71
The one % solution:
Compassionate capitalism benefits the shareholders, the employees and the needy people
Marc Benioff, Salesforce
CORPORATE SOCIAL RESPONSIBILITY
1 % of equity1 % of profit1 % of employees’ paid hours are devoted to philanthropy
72
73
Helping patients of a less developed country is a way to thank the contribution of so many volunteers
74
The industry's impact on public health is so great, and the subsidies and protections offered by governments so generous, that the industry should consider its social responsibilities
75
76
These slides are belonging to Giuseppe Remuzzi, M.D.
Mario Negri Institute for Pharmacological Research, Bergamo,
Italy.
Using these slides is only authorized by mentioning the source
77
BASELINE PROTEINURIA PREDICTS THE RESPONSE TO RAS BLOCKADE Post-hoc analyses of the RENAAL study
> 1.25
< 1.25
Overall
Primary end-point(doubling, ESRD or death)
757
756
1,513
n°Alb/creat ratio (g/g)
0.5 0.75 1.0 1.25 1.5
Hazard ratio (95 % C.I.)
78
LESS NEED OF DIALYSIS FOR NON-DIABETIC AND DIABETIC RENAL DISEASE WITH RENIN-ANGIOTENSIN SYSTEM BLOCKADE
Re
lativ
e r
isk
(%)
- 50
RENAAL(n = 1,513)
- 28 %
REIN(n = 352)
- 48 %
- 40
- 30
- 20
- 10
0
IDNT(n = 1,715)
- 20 %
CAPTOPRIL(n = 409)
- 45 %
79
There is little doubt that ACE-I and ARBs have guaranteed substantial revenues, and their development costs have been largely paid off, since their sale is in the order of billions of dollars worldwide
80
Inci
den
ce o
f E
SR
D (
%)
INCIDENCE OF ESRD IN 1513 PATIENTS WITH TYPE 2 DIABETIC NEPHROPATHY ACCORDING TO TREATMENT AND TERTILES OF BASAL SERUM CREATININE (data from the RENAAL study)
0
40
50
30
20
10
Pla
ce
bo
Lo
sart
an
S. Creatinine (mg/dl)
GFR (ml/min)
2.1 - 3.6
19 - 34
1.6 - 2.0
35 - 44
0.9 - 1.5
45 - 77
81
INCIDENCE OF HEART FAILURE IN 1513 PATIENTS WITH TYPE 2 DIABETIC NEPHROPATHY ACCORDING TO TREATMENT AND TERTILES OF BASAL SERUM CREATININE (data from the RENAAL study)
25
20
15
10
5
0
Inci
dence
(%
)
13.4
9.011.0
19.3
11.3
21.3
p < 0.003
Lowest Middle Highest
TERTILES
p < 0.01
Pla
ce
bo
Lo
s
2.1 - 3.6 1.6 - 2.0 0.9 - 1.6S. creat
82
400
200
100
300
0U
rinar
y pr
otei
n ex
cre
tion
(mg/
24 h
)0 4 8 12
Co
ntr
ol
Dia
bet
es
months
**
*
0.10
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
Por
e r
adi
i dis
trib
utio
n
0 20 30 40 50 60
Pore radius (Å)
10
Diabetic
Control
P GC
63mmHg
53mmHg
Remuzzi et al., J Am Soc Nephrol, 1993
83
0
-2
-4
-6
-8
-10
-12
-14
GF
R (
ml/m
in/y
ear)
95 98 113110107104101 119116
130/85 140/90 Untreated HTN
r = 0.69; p < 0.05
MAP (mmHg)
Parving et al., Br Med J, 1989Viberti et al., JAMA, 1993Hebert et al., Kidney Int, 1994Lebovitz et al., Kidney Int, 1994Bakris et al., Kidney Int, 1996Bakris et al., Hypertension, 1997
Klahr et al., N Engl J Med, 1993Maschio et al., N Engl J Med, 1996GISEN Group, Lancet, 1997
Bakris et al., Am J Kidney Dis, 2000
Diabetes Non-diabetes
84
ACHIEVED BLOOD PRESSURE CONTROL IN MAJOR TRIALS ON NEPHROPATHY TYPE 2 DIABETES
Trial SPB/DBP (mmHg) Study drug
RENAAL
IDNT
IRMA
142/74
142/84
144/77
Losartan
Irbesartan
Irbesartan
85
CHINA
In the 2010Diabetes 30 millions
High blood pressure/chronic renal disease 80 millions
Need of dialysis 1 million
86
ANGIOTENSIN II PARTICIPATES TO THE DEVELOPMENT OF GLOMERULAR CAPILLARY HYPERTENSION
Acute infusion of Ang II in normal rats raises intraglomerular capillary pressure
Following 5/6 nephrectomy in rats endogenous Ang II local activity increases
Myers et al., Circ Res, 1975
Mackie et al, Kidney Int, 2001
87
ESRD
0 12 24 36 48
Months
% w
ith e
vent
0
10
20
30
p=0.002
Risk Reduction: 28%
P
L
- 1513 type 2 diabetes
- Age 31-70 years
- Alb/Cr ratio >300 mg/g,
- S Creat 1.3-3.0 mg/dL,
RENAALReduction of Endpoints in NIDDM with the AII Antagonist Losartan
88
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
89
THE PROGRAMS OF PREVENTING RENAL DISEASE PROGRESSION WORLDWIDE
The funding of such programs is probably on the top of list of the difficulties
90
A GLOBAL FUND TO FIGHT RENAL AND VASCULAR DISEASES
ISN: initiator and advisory body in creating the Fund and executing the programs
Governed by WHO
The notion of health as a good to be bought and sold be cannot be a substitute for the notion of health as a fundamental human right
92
EFFECTS OF LOSARTAN ACCORDING TO THE GEOGRAPHIC AREA:Post-hoc analyses of the RENAAL study
North America
Europe
Latin America
Asia
Overall (but Asia)
Primary end point (Doubling s. creat, ESRD or death)
687
295
274
257
1,256
n°Region
0.5 0.750.25 1.0 1.25 1.5
Losartan better Losartan worse
Hazard ratio (95 % C.I.)
p
0.64
0.76
0.54
0.0008
0.34
The whole effect of Losartan was fully driver by Asian patients
93
1-YEAR PROTEINURIA REDUCTION IN ASIA AND NON-ASIA TYPE 2 DIABETICS ENROLLED IN THE RENAAL STUDY
Less events in Asia patients were associated with more (double) short-term proteinuria reduction
-20
-10
-15
-5
0
Med
ian
(I.Q
. ran
ge)
prot
einu
ria
redu
ctio
n vs
bas
elin
e (
%)
-20 (-55 to 30)
ASIAn = 257
p < 0.05 (ANCOVA)
Non-ASIAn = 1,256
-9 (-51 to 43)
94
REIN: ACE-I IS MORE RENOPROTECTIVE THAN
CONVENTIONAL THERAPY IN NON-DIABETIC RENAL
DISEASE
% of patients without doubling of baseline creatinine or ESRF
60
40
20
00 6 12 18 24 30
80
100
36Follow-up
P=0.02
- 40 –
- 20 –
0 –
20 –
40 –
60 –
% Reduction in
Proteinuria
Diastolic Blood Pressure (mm Hg)
100 –
90 –
80 –
70 –
60 –
Ramipril
Conventional therapy
Gisen group; Lancet 1997
95
3 4 5 years-2 - 1 0 1 2
Mogensen et al., 1976* PA 200/120 mmHg
Glo
mer
ular
Filt
ratio
n R
ate
(ml/m
in/1
.73s
qm)
treatment *
GFR 20 ml/year
GFR 2 ml/year40
60
80
100
20
0DYALISIS
96
Diabetic nephropathy is irreversible in human
No cases of recovery or cure have been reported in the literature
Once the clinical signs of nephropathy have become manifest, the natural course is inexorably progressive to death
Kussman et al., JAMA, 1976
97
SWIMMING TO REDUCE PROTEINURIA?
Pechter et al., Nephrol Dial Transplant, 2003
20 patients: proteinuric chronic nephropathyTreatments: 12-week regular acquatic exercise
Blood pressure Proteinuria
p = 0.005
1.0
0.5
1.5
g /
24h
1.0+0.3
0.5+.03
Pre PostPre Post
mm
Hg
150
140
130
120
100
90
80
70
p < 0.01
p < 0.05
98
Seru
m creatin
ine
(mg
/dl)
Pro
tein
uri
a (g
/day
)
Renal biopsy *
AZA 100
… a 22 years old women with previous diagnosis of Systemic Lupus Erythematosus
* Severe chronic glomerulopathy with no signs of disease activity
1994 1995 1996 1997 19981993
10
8
6
4
2
0
MPD
3
2
1
0
Losartan 50 100 mg/day
Hydrochlorotiazide 25 mg/day
Low sodium diet 2 g/day
Enalapril 2.5 20 mg/day
Prednisone 25 5 mg/day
1999 2000 2001 2002 2003
99
PREVENTING NEPHROPATHY WILL PREVENT CV
MORTALITY?The BENEDICTstudy
BP>140/90 mmHgNormoalbuminuria
Fatal and non-fatal CV eventsProgression to microalbuminuria
BP<120/80mhgHbA1c <7,5%
July 2003
1200 type 2 diabetics:
Main end points:
Targets:
Study End:
Run-in
Ran
do
mis
atio
n
ACE-I
ndCCB
ACE-I + ndCCB
Placebo
0 1 2 3Years
Science brings imagination and vision to bear across the board allowing people to analyze present (and future) situations, make sounder choices, and invest their resources more wisely
InterAcademic Council, 2004
101
On August 30, 2003 World Trade Organization reaches agreement on generic medicines
102
IMPROVING ONLINE ACCESS TO MEDICAL INFORMATION FOR LOW-INCOME COUNTRIES
WHO helped to create the Health InterNetwork Access to Research Initiative (HINARI)
Low-income countries (GNP<$1,000) offered for free online access to a large library of important international journals
Additional countries (GNP $1,000-3,000) qualified for access to the journals at a very low price ($ 1,000 per year)
Total institutions in 100 countries (of a total of 113 eligible countries) have registered for the program
Publishers of scientific publishing have joined the Network Access to offer more than 2,300 journals and other full-text resources
69
44
47
1043
Aronson, N Engl J Med, 2004
103
Pharmaceutical companies are not the biggest industries in terms of revenues, but are very profitable
The pharmaceutical companies average profit is 18 % of revenues as compared to 11.6 % of financial companies
Henry and Lexchin, Lancet, 2002
104
The pharmaceutical industry nowadays is a very profitable enterprise, and its returns are on the average greater than those of other industries
105
RamiprilConventional
Base-line urinary protein excretion (g/ 24 hours)
Mea
n ra
te o
f G
FR d
eclin
e
(ml/
min
/mo
nth)
0.2
0.4
0.6
0.8
1.0
1.2
0
2-3 3-4.5 4.5
n=6 0 n=81 n=69
<2
n=115
RESPONSE TO ACE INHIBITION ACCORDING TO DIFFERENT LEVELS OF BASELINE PROTEINURIA