supra rx dose of arbs
TRANSCRIPT
Supratherapeutic Doses of Supratherapeutic Doses of Angiotensin Receptor BlockersAngiotensin Receptor Blockers
Beneficial and Controversy
Thitisak Kitthaweesin MD.Department of Medicine
Phramongkutklao Hospital and College of Medicine
Adjusted incident rates & annual percent change
Incident ESRD patients; rates adjusted for age, gender, & race.
USRDS Annual Data Report 2007
International Comparison: Where we are ….Prevalence 2002
USRDSYearly Incidence 2002
USRDS
Thailand(2004)
236 pMp
Thailand(2004)
121 pMp
TRT Registry 2005www.nephrothai.org
Prevalent counts & adjusted ratesby primary diagnosis
December 31 point prevalent ESRD patients; rates adjusted for age, gender, & race.
USRDS Annual Data Report 2007
Diabetes:The Most Common Cause of ESRD
Primary Diagnosis for Patients Who Start Dialysis
Diabetes50.1%
Hypertension27%
Glomerulonephritis
13%
Other
10%
United States Renal Data System. Annual data report. 2000.
No. of patientsProjection95% CI
1984 1988 1992 1996 2000 2004 20080
100
200
300
400
500
600
700
r2=99.8%243,524
281,355520,240
No.
of
dia
lysi
s p
atie
nts
(t
hou
sand
s)
Projected growth of incident & prevalent ESRD populations through 2020,
by primary diagnosis (Markov model)
Counts projected using a Markov model. Original projection uses data through 2000; new projection uses data through 2005.
USRDS Annual Data Report 2007
Proteinuria Is an Independent Risk Factor for Mortality in Type 2 Diabetes
1.0
0.9
0.8
0.7
0.6
0.5
0 1 2 3 4 5 6
Years
Su
rviv
al(a
ll-ca
use
mor
talit
y)
Normoalbuminuria(n=191)
Microalbuminuria(n=86)
Macroalbuminuria(n=51)
Gall, MA et al. Diabetes 1995;44:1303P<0.01 normo vs. micro- and macroalbuminuriaP<0.05 micro vs. macroalbuminuria
Proteinuria is an independent Proteinuria is an independent predictor of kidney disease predictor of kidney disease
progressionprogression
Copyright ©2005 American Society of Nephrology
Zhang, Z. et al. J Am Soc Nephrol 2005;16:1775-1780
Figure 1. Risk associated with increasing proteinuria for (1) the primary endpoint of doubling of serum creatinine concentration, ESRD, or death; (2) ESRD or death; and (3) ESRD
Copyright ©2005 American Society of Nephrology
Zhang, Z. et al. J Am Soc Nephrol 2005;16:1775-1780
Figure 3. Kaplan-Meier curves for ESRD for the total Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan study population by treatment group (original; A) and adjustment for proteinuria as a
continuous variable (adjusted; B)
Urinary protein excretion rate is the best independent predictor of ESRF in non-diabetic
proteinuric chronic nephropathies
Progression to end-stage renal failure per tertile of baseline urinary protein excretion rate. Symbols are: ( ) lowest; ( ) middle; ( ) highest tertile.
Ruggenenti et al. Kidney Inter 1998;53:1209-16MDRD studyMDRD study
Urinary protein excretion rate is the best independent predictor of
ESRF in non-diabetic proteinuric chronic nephropathies
Progression to end-stage renal failure per tertile of baseline urinary protein excretion rate and mean arterial pressure (MAP).
Ruggenenti et al. Kidney Inter 1998;53:1209-16
Proteinuria is a risk marker Proteinuria is a risk marker for cardiovascular diseasefor cardiovascular disease
0
10
20
30
0-10 mg/L 10-20 mg/L 20-200 mg/L > 200 mg/L
CV death
All cause
CV death
Non CV death
All cause
Urinary Albumin Excretion Predicts Cardiovascular and
Noncardiovascular Mortality in General Population
Crude Incidence Rates per 1000 Person-Years for All-Cause, CV, and Non-CV Mortality by UAC
Hillege HL et al. PREVEND study group. Circulation 2002;106:1777-1782.
Risk of Ischemic Heart Disease Related to SBP and Microalbuminuria
0
1
2
3
4
5
6
SBP <140 SBP 140-160 SBP>160
Rela
tive R
isk Normoalbuminuria Microalbuminuria
Borch-Johnsen K, et al. Arterioscler Thromb Vasc Biol. 1999;19(8):1992-1997.
N=2,085; 10 year follow-up
0.5
1
1.5
2
2.5
3
Rela
tive R
isk
Microalbuminuria Compared To Traditional Risk Factors For Ischemic Heart Disease
N=2,085; 10 year follow-up
Borch-Johnsen K, et al. Arterioscler Thromb Vasc Biol. 1999;19(8):1992-1997.
A/C ra
tio >
0.65
mg/
mm
ol
> 7
.0
mm
ol/L
> 1
60
mm
Hg
Monitoring and detectionMonitoring and detection
Definitions of Microalbuminuria and Macroalbuminuria
Parameter NormalMicro-
albuminuriaMacro-
albuminuria
Urine AER
(g/min)< 20 20 - 200 >200
Urine AER
(mg/24h)< 30 30 - 300 >300
Urine albumin/
Cr# ratio (mg/gm)
< 30 30 - 300 >300
AER=Albumin excretion rate CR# =creatinine
Reproducibility of Renal Function Measurement
Protein excretion
Protein/creatinine ratio
Agarwal R. Am J Nephrol 2007;27:92-100
Strategies for TreatmentStrategies for Treatment
Pathways Leading To Progressive Renal Failure
Renal growth factor & cytokine activation
Fibrogenesis
Systemic hypertension
Progressive Loss of Filtration Surface Area
GFR
Renal injury
Nephron mass
Glomerular hypertension
Renal scarring
Hyperlipidemia
Filtration of plasma
proteins
Proteinuria
Proximal tubule
protein uptake
Renal microvascular
injury
Influx of monocytes and macrophages
Transdifferentiation of renal cells to fibroblast
phenotype
Brenner BM, Keane WF. 2001.
Pathologic Processes Leading to Glomerular Injury and Proteinuria
Ang II
IncreasedGlomerular
Pressure
Ang II
Urinary proteinGlucose
AGEs
Glycoxidation (glycation)
Efferent arteriolar
constriction
=angiotensin AT1 receptor
Role of Angiotensin II in Chronic Renal Disease
Adhesion molecules Chemotactic factors Cell growth Apoptosis TGF-, CTGF PAI-1
Glomerular capillarypressure
Single nephron GFR
Macrophageinfiltration
Angiotensin IIAngiotensin II
•Mechanical stress•Mesangial changes•Oxidative stress•Proteinuria•NF-B activation
Glomerulosclerosis
& Tubulo-interstitial
fibrosis
Renaldisease
Nephronloss
ACEI and ARBACEI and ARB
Afferent arteriole, BP drop
Renin
Negative feedback
Increasedblood
pressure
Sodiumretention
Aldosterone
Inactivefragments
Bradykinin ACE
Angiotensin II
Angiotensinogen
Angiotensin INon-ACEpathway
Tissue Chymase
Cathepsin G
AT1 RECEPTORS ADRENAL GLAND
AT1 RECEPTORS BLOOD VESSELS
VASOCONSTRICTION
The Lancet; Vol 355, Feb 2000
KK//DOQI Clinical Practice Guidelines on DOQI Clinical Practice Guidelines on Hypertension and Antihypertensive Hypertension and Antihypertensive Agents in Chronic Kidney DiseaseAgents in Chronic Kidney Disease
Am J Kidney Dis 2004; 43:S65-S223 (suppl 1)
ACEI and ARBACEI and ARB
Clinical Endpoint Data for ESRD in Type 2 Diabetes with ACE Inhibitors Are Lacking
Endpoints StudiedACE Inhibitor Trialsin Type 2 Diabetics Total Reduction of Reduction of Reduction in Risk with >1 Year Follow-Up Sample Proteinuria GFR Decline of ESRD*
Ravid et al Ann Intern Med 1993 94 Yes YesNoLebovitz et al Kidney Int 1994 121 Yes YesNoBakris et al Kidney Int 1996 52 Yes YesNoAhmad et al Diabetes Care 1996 103 Yes YesNoNielsen et al Diabetes Care 1997 36 Yes YesNoUKPDS et al Br Med J 1998 758 Yes NoNoFogari et al J Hum Hypertens 1999 107 Yes NoNo ABCD Diabetes Care 2000 470 Yes YesNoRuggenenti et al (REIN) 352 (27)** Yes Yes Yes**Am J Kidney Dis 2000 MICRO-HOPE** Lancet 2000 3577 Yes NoYes***
GFR=glomerular filtration rate
*Reduction in the risk of end-stage renal disease (renal transplant or dialysis) **Only 27 (8%) of the 352 patients in this study were Type 2 diabetics***In this study there was no reduction of risk for renal dialysis for ramipril compared to placebo (p=0.70)
TrialTrial NumberNumber BP goalBP goal Rx comparatorRx comparator Major FindingsMajor Findings
T2DM with microalbuminuriaT2DM with microalbuminuria
MARVAL<2002>
3320.5 yr
< 135/85< 135/85 Valsartan vsAmlodipine
baseline albuminuria, 56% vs 92%
IRMA-2<2001>
5902.0 yrs
< 135/85< 135/85 Irbesartan vsPlacebo
incidence of progression to macroal-buminuria (hazard ratio = 0.30, 0.14-0.61)
INNOVATION<2007>
6751.0 yr
Telmisartan vs Placebo
↓ transition to overt nephropathy, 55%, 66% in 40, 80 mg
Lozano<2001>
4220.5 yr
< 140/90< 140/90 Losartan 43% of baseline albuminuria
CALM<2000>
199 0.5 yr
Candesartan vs lisinopril + both
24% of proteinuria with mono Rx 50% with combined Rx
Evidence for ARBs and Renoprotection in Diabetes
Evidence for ARBs and Renoprotection in Diabetes
TrialTrial NumbNumberer BP goalBP goal Rx comparatorRx comparator Major FindingsMajor Findings
T2T2DM with oDM with overt nephropathyvert nephropathyDETAIL<2004>
199 5 yrs
Telmisartan vsEnalapril
No inferiority in the change in GFR from baseline
VIVALDI<2003>
8001 yr
Telmisartan vs Valsartan
↓ proteinuria , comparable
AMADEO<2003>
8001 yr
Telmisartan vs Losartan
↓ proteinuria 29% vs 19%
RENAAL<2001>
15133.4 yrs
< 140/90< 140/90 Losartan vsPlacebo
16% risk of composite end point (doubling SCr/ESRD/death) 25% risk of doubling SCr, 28% ESRD
IDNT<2001>
17152.6 yrs
< 135/85< 135/85 Irbesartan vsAmlodipine vsPlacebo
20-23% risk of composite end point (doubling SCr/ESRD/death) 29-39% risk of doubling SCr
Evidence for ARBs and Renoprotection in Diabetes
Evidence for ARBs and Renoprotection in Diabetes
RENAAL
Reduction of Endpoint in NIDDM with the Angiotensin II Antagonist Losartan
Study
Brenner B et al. N Engl J Med. 2001;345:861-869.
RENAAL: Reduction of Endpoint in NIDDM with the Angiotensin II Antagonist Losartan Study
• 1513 patients with type 2 diabetes– Proteinuria (urine alb/cr >300 mg/g, >25 mg/mmol)– Serum Creatinine: 1.3-3.0 mg/dl– Mean age 60 years old
• Multicenter, randomized, double-blind, placebo-controlled – Placebo +normal AHT– Losartan 50-100 mg OD + Normal AHTAHT excluded ACEI and other ARBTarget BP: SBP<140 mm Hg, DBP<90 mm Hg
• Primary outcome measurement– Doubling of serum creatinine– ESRD– ESRD and death
RENAAL Study Design
qd=once daily
*CT=conventional therapy: Open-label calcium-channel blocker, diuretic, beta blocker, alpha blocker, or centrally acting agents.
Adapted from Brenner BM et al J Renin-Angiotens-Aldoster Syst 2000;1(4):328-334.
4 wk
Losartan 100 mg qd(+CT)
Maintain conventional antihypertensive therapy (CT)*
(excluding ACE inhibitors, AII antagonists)
Losartan 100 mg qd (+CT)
Placebo(+CT)
Goal trough BP:<140/<90 mmHg
n=1513
Placebo (+CT)
Losartan 50 mg qd(+CT)
Placebo(+CT)
8 wk 6 wk
Mean follow-up 3.4 years
*Lower limit 1.5 mg/dl (133 µmol/L) in male patients >60 kg
Brenner BM et al J Renin-Angio-Aldo System 2000;1(4):328-335.
RENAAL: Inclusion/Exclusion Criteria
Inclusion criteria• Type 2 diabetes • Age 31-70 years• Proteinuria:
urine alb:cr >300 mg/g, >25 mg/mmol
• Serum Creatinine: 1.3-3.0 mg/dl, 115-265 µmol/L*
Exclusion criteria• Type 1 diabetes • Known non-diabetic renal
disease or renal artery stenosis
• Recent history of MI, CABG, PTCA, CVA, TIA
• History of heart failure
• HbA1c >12%
RENAAL: Blood Pressure Changes
Baseline Study End
152/82 mm Hg 140/74 mm HgLosartan+ usual AHT
153/82 mm Hg 142/74 mm HgPlacebo+ usual AHT
AHT = antihypertensive therapy (excluding ACEIs and other ARBs).
Brenner B et al. N Engl J Med. 2001;345:861-869.
39
ESRD
Months
% w
ith
ev
ent
0 12 24 36 480
10
20
30
RR: 28%p=0.002
ESRD or Death
Months
% w
ith
ev
ent
sCr=serum creatinine; RR=risk reduction
Adapted from Brenner BM et al N Engl J Med 2001;345(12):861-869.
RENAAL Primary Components
Doubling of sCr
Months
% w
ith
ev
ent
RR: 25% p=0.006
Placebo (+CT) 762 689 554 295 36 Losartan (+CT) 751 692 583 329 52
RR: 20%p=0.010
Placebo (+CT) 762 715 610 347 42 Losartan (+CT) 751 714 625 375 69
0 12 24 36 48
0
10
20
30
40
50
0 12 24 36 480
10
20
30
Placebo (+CT) 762 715 610 347 42 Losartan (+CT) 751 714 625 375 69
Months
% w
ith
ev
ent
p=0.006Risk Reduction: 25%
751 692 583 329 52762 689 554 295 36P (+ CT)
L (+ CT)
0 12 24 36 480
10
20
30
P
L
Brenner BM et al . New Engl J Med 2001;345(12):861-869.
Primary Components : Doubling of Serum Creatinine
RENAAL: Reduction of Endpoint in NIDDM with the Angiotensin II Antagonist Losartan Study
Months
% w
ith
eve
nt
0 12 24 36 480
10
20
30
p=0.002
Risk Reduction: 28%
P
L
P (+ CT)L (+ CT) 751 714 625 375 69
762 715 610 347 42
Brenner BM et al . New Engl J Med 2001;345(12):861-869.
RENAAL: Primary Components, ESRD
ESRD or Death
P (+ CT)
L (+ CT)
Months
% w
ith
eve
nt
0 12 24 36 480
10
20
30
40
50
751 714 625 375 69762 715 610 347 42
P
L
p=0.010Risk Reduction: 20%
Brenner BM et al . New Engl J Med 2001;345(12):861-869.
RENAAL: Primary Components, ESRD or Death
0 12 24 36 48Months
Med
ian
% c
han
ge
–60
–40
–20
0
20
40
35% Overall reductionp<0.001
RENAALChange from Baseline in Proteinuria
Proteinuria measured as the urine albumin:creatinine ratio from a first morning void.
Adapted from Brenner BM et al N Engl J Med 2001;345(12):861-869.
Placebo (+CT) 762 632 529 390 130Losartan (+CT) 751 661 558 438 167
RENAALRate of Progression of Renal Disease
(median 1/sCr slope)
Losartan (+CT) Placebo (+CT)0
–0.02
–0.04
–0.06
–0.08
dl/m
g/y
r
–0.056
–0.069
p=0.0118% reduction
Adapted from Brenner BM et al N Engl J Med 2001;345(12):861-869.
ARB renoprotection in type 2 diabetesGFR decline with ARB treatment
-4.4-4.9
-5.5
-3.7
-6
-5
-4
-3
-2
-1
0
Losartan 100 mg Irbesartan 300 mg Irbesartan 300 mg Telmisartan 80 mg
RENAAL*
GF
R d
eclin
e (
mL/
min
/1.7
3m2 /
year
)
IDNT† DETAIL†§
*Median; †Mean§ Completers
IRMA2†
Barnett et al. N Engl J Med 2004;351:1952–1961Barnett et al. Acta Diabetol 2005; 42 Suppl 1:S42-S49
Treatment duration:
3.4 years 2.6 years 2 years 5 years
Optimal dose of Losartan for Renoprotection in Diabetic
Nephropathy
Anderson S et al. Nephrol Dial Transplant (2002)17:1413-1418
Table 1. Characteristics of 50 type 1 diabetic patients with diabetic nephropathy
Mean (SEM); *Geometric mean (95% CI).
Sex (m/f) 33/17
Age (years) 44 (2)
Diabetes duration (years) 32 (1)
Retinopathy (non-proliferative/proliferative) (%) 28/72
Albuminuria (mg/24 h)* 1138 (904–1432)
24-h systolic blood pressure (mmHg) 155 (3)
24-h diastolic blood pressure (mmHg) 81 (2)
24-h mean arterial blood pressure (mmHg) 105 (2)
Glomerular filtration rate (ml/min/1.73 m2) 91 (3)
Anderson S et al. Nephrol Dial Transplant (2002)17:1413-1418
Table 2. Kidney function and systemic blood pressure in 50 type 1 diabetic patients with diabetic nephropathy
Baseline Losartan 50 mg Losartan 100 mg Losartan 150 mg
Albuminuria (mg/24 h)*
1138 (904–1432)
796 (607–1043)
597 (438-814) 642 (467–882)
U-IgG (mg/24 h) 98 (74–130) 76 (56–104) 56 (40-79) 63 (47–85)
Albumin fractional clearance ( ) (10-6)
308 (234–405) 208 (148–291) 171 (121-241) 174 (123–247)
IgG fractional clearance ( ) (10-6)
108 (79–149) 79 (56–113) 67 (44–99) 66 (47–94)
Glomerular filtration rate (ml/min/1.73 m2)
91 (3) 89 (3) 87 (3) 87 (3)
24-h systolic blood pressure (mmHg)
155 (3) 148 (2) 143 (3) 145 (3)
24-h diastolic blood pressure (mmHg)
81 (2) 77 (2) 75 (2) 76 (2)
24-h mean arterial blood pressure (mmHg)
105 (2) 100 (2) 97 (2) 98 (2)
Anderson S et al. Nephrol Dial Transplant (2002)17:1413-1418
Optimal dose of Losartan for Renoprotection in Diabetic Nephropathy
0
20
40
60
80
100
120
Albuminuria (x10mg/day)
GFR (ml/min) MAP (mmHg) Serum K ( /10mEq/L)
Baseline
50 mg
100 mg
150 mg
Anderson S et al. Nephrol Dial Transplant (2002)17:1413-1418N=50, T1DM
Renoprotection of Optimal Antiproteinuric Doses (ROAD) Study: A Randomized
Controlled Study of Benazepril and Losartan
in Chronic Renal Insufficiency
Hou, F. F. et al. J Am Soc Nephrol 2007;18:1889-1898
Copyright ©2007 American Society of Nephrology
Hou, F. F. et al. J Am Soc Nephrol 2007;18:1889-1898
Figure 1. Study flow diagram
N=167+172, non-DM CKD
Copyright ©2007 American Society of Nephrology
Hou, F. F. et al. J Am Soc Nephrol 2007;18:1889-1898
Figure 2. Kaplan-Meier estimates of the percentage of patients who reached the primary composite end point of a doubling of the serum
creatinine level, ESRD, or death according to intention-to-treat (A) or per-protocol principal (B)
Hou, F. F. et al. J Am Soc Nephrol 2007;18:1889-1898
Figure 3. Median of changes in urinary proteinuria excretion (A), median of creatinine clearance (B), estimated GFR (eGFR; C), BP in all patients (D), median of systolic BP in patients with decline of
eGFR ({Delta}eGFR) >5 or <=5 ml/min per 1.73 m2 (E), and median of urinary excretion of urea and chloride (F)
Urinary protein
excretion
Median CrCl
EstimatedGFR
Table 3. Adverse events after randomization Group 1 (
n = 90)Group 2 (
n = 90)Group 3 (
n = 90)Group 4 (
n = 90)
Adverse events 23 25 7 9
Nonfatal cardiovascular event
4 5 5 4
Myocardial infarction 2 2 2 2
Heart failure 1 2 2 1
Stroke 1 1 1 1
Hyperkalemia 3 5 3 5
Acute decline in renal function
2 3 3 3
Dry cough 17 15 0 0
Hypotension 1 2 1 1
Hou, F. F. et al. J Am Soc Nephrol 2007;18:1889-1898
Enhanced renoprotective effects of ultrahigh doses of Irbesartan in patients with T2DM and micro
albuminuria
Rossing K et al. Kidney Int 2005;68:1190-1198
N=52, T2DM+microalbuminuria
Rossing K et al. Kidney Int 2005;68:1190-1198
Rossing K et al. Kidney Int 2005;68:1190-1198
Copyright ©2005 American Society of Nephrology
Schmieder, R. E. et al. J Am Soc Nephrol 2005;16:3038-3045
Additional Antiproteinuric Effect of Ultrahigh Dose Candesartan:
A Double-Blind, Randomized, Prospective Study
N=32Proteinuria 1-10 g/d
Copyright ©2005 American Society of Nephrology
Schmieder, R. E. et al. J Am Soc Nephrol 2005;16:3038-3045
Figure 3. Proteinuria throughout the whole study period
Copyright ©2005 American Society of Nephrology
Schmieder, R. E. et al. J Am Soc Nephrol 2005;16:3038-3045
Figure 4. Scatterplot of changes in proteinuria versus changes in BP
Studies of High Dose ARB
Berl T. Nephrol Dial Transplant (August) 2008;23:2443-2447
ConclusionConclusion
• CKD is common progressive disease that lead to ESRD and CVD
• DM and HT are most common cause of CKD• Proteinuria is predictor of CKD progression and
cardiovascular risk marker• Targeting at RAAS is strategy for CKD treatment• ARB and ACEi are beneficial in proteinuric
nephropathy (DM/non-DM)• High dose ARB is one of options for maximize
inhibition of RAAS to retard renal progression
Thank youThank you
SafetySafety
Hyperkalemia in ARB and ACEI
Bakris et al. Val-K study group. Kidney Int Nov 2000;58:2084-92
Hyperkalemia in ARB and ACEI
4.4 4.44.6
4.3
3.5
4
4.5
5
5.5
Lisinopril Valsartan
Ser
um K
(mm
ol/L
)
40
33
43
49
30
40
50
60
Lisinopril Valsartan
Uri
ne K
(mm
ol/d
)
5.3 5
3.5
5
0
2
4
6
Lisinopril Valsartan
U A
ldo
V (u
g/d)
67
7268 67
50
55
6065
70
75
80
Lisinopril Valsartan
GFR
(ml/m
in/1
.73
m2)
Baseline Week 4Bakris et al.Val-K study group. Kidney Int Nov 2000;58:2084-92.
Effects of ACEI Compared to ARB in Patient with Hypertension and GFR>60
3.9
4
4.1
4.2
4.3
4.4
Lisinopril Valsatan
Serum K
mE
q/L
Baseline
One month
2
3
4
5
6
7
8
9
Lisinopril Valsatan
Plasma aldosterone
pg
/ml
Bakris et al.Val-K study group. Kidney Int Nov 2000;58:2084-92.
Effects of ACEI Compared to ARB in Patient with Hypertension and GFR<60
4.2
4.3
4.4
4.5
4.6
4.7
4.8
4.9
5
Lisinopril Valsatan
Serum K
mE
q/L
Baseline
One month
2
3
4
5
6
7
8
9
Lisinopril Valsatan
Plasma aldosterone
pg
/ml
Bakris et al. Val-K study group. Kidney Int Nov 2000;58:2084-92
*
*
* p<0.05 compared to baseline
Albuminuria Response to Very High Dose Valsartan in T2DM
Hollenberg et al. J Hypertens 2007;25:1921-6
Hollenberg et al. J Hypertens 2007;25:1921-6
Long-Term Renoprotective Effects of Standard Versus High Doses
of Telmisartan in Hypertensive Nondiabetic Nephropathies
Arandra P. et al. Am J Kidney Dis 2005;46:1074-1079
Arandra P. et al. Am J Kidney Dis 2005;46:1074-1079
Studies of High Dose ACEi
IDNT
Irbesartan Diabetic Nephropathy Trial
Lewis E et al. N Engl J Med. 2001;345:851-860.
IDNT: Irbesartan Diabetic Nephropathy Trial
• 1715 patients with type 2 diabetes (>15 years)– 24-hour urine protein excretion >900 mg (mean 4,016 mg)
– Serum creatinine 1.0-3.0 mg/dl (mean 1.7 mg/dl)
– Mean age 59 years old
• 210 centers, prospective, randomized, double-blind– Irbesartan 75-300 mg OD + AHT– Amlodipine 2.5-10 mg OD + AHT– Placebo + AHT (BP target = 135/85 mmHg)
• Primary outcome measurement– Doubling of serum creatinine– ESRD– All cause mortality
Lewis E et al. N Engl J Med. 2001;345:851-860.
IDNT: Irbesartan Diabetic Nephropathy Trial
• Inclusions– Type 2 hypertensive diabetic subjects– 30-70 years of age– 24-hour urine protein excretion >900 mg– Serum creatinine 1.0-3.0 mg/dL
• Exclusions– Age of onset of diabetics <20 years– Type 1 diabetes– Absolute requirement for ACEI, ARB, or CCB– CV disease– Abnormal serum potassium
IDNT: Blood Pressure Changes
Baseline Study End
160/88 mm Hg 140/77 mm HgIrbesartan + AHT
158/87 mm Hg 141/77 mm HgAmlodipine + AHT
158/87 mm Hg 144/80 mm HgPlacebo + AHT
AHT = other antihypertensive therapy (excluding ACEIs, ARBs, and CCBs).Lewis E et al. N Engl J Med. 2001;345:851-860.
IDNT: Irbesartan Diabetic Nephropathy TrialS
ub
ject
s (
%)
0 6 12 18 24 30 36 42 48 54
Follow-up (mo)
60
0
10
20
30
40
50
60
70
Irbesartan
Amlodipine
Control
RRR 33%P=0.003
P=NS
RRR 37% P<0.001
Lewis EJ et al. N Engl J Med 2001;345:851-860.
Primary End Point: Time to Doubling of Serum Creatinine
Su
bje
cts
(%
)
0 6 12 18 24 30 36 42 48 54
Follow-up (mo)
60
0
10
20
30
40
50
60
70
IDNT: Primary EndpointTime to Doubling of Serum Creatinine, ESRD, or Death
Irbesartan
Amlodipine
ControlRRR 20%
P=0.02P=NS
RRR 23%P=0.006
Lewis EJ et al. N Engl J Med 2001;345:851-860.
IRMA 2
Irbesatan Reduce MicroAlbuminuria in Type 2
Diabetes
Parving HH et al. N Engl J Med. 2001;345:870-878.
IRMA 2: Irbesatan Reduce MicroAlbuminuria in Type 2 Diabetes
• 590 patients with type 2 diabetics– Hypertensive (DBP>85 mmHg or SBP>135 mmHg)
– Microalbuminuria (UAER 20-200 µg/min, mean 55 µg/min)
– Normal kidney function (serum creatinine <1.6 mg/dl in men <1.2 mg/dl in women)
• Randomization– Irbesartan 150 mg + AHT*– Irbesartan 300 mg + AHT*– Placebo + AHT (excluding ACEIs, other ARBs, and DHP
CCBs)
• Primary outcome measurement– Development of overt proteinuria
IRMA 2: Blood Pressure Changes
Baseline Study End
153/90 mm Hg 143/84 mm HgIrbesartan 150 mg+ usual AHT
153/91 mm Hg 142/84 mm HgIrbesartan 300 mg+ usual AHT
153/90 mm Hg 145/84 mm HgPlacebo + usual AHT
Parving HH et al. N Engl J Med. 2001;345:870-878.
84
IRMA 2: Irbesatan Reduce MicroAlbuminuria in Type 2 Diabetes
Parving H-H, et al. N Engl J Med 2001;345:870-878.
14
18
16
12
10
8
6
4
2
0
Subjects(%)
Control (n=201)
150 mg(n=195)
300 mg(n=194)
Irbesartan
9.7
5.2
14.9
RRR=39%P=0.08
RRR=70%P<0.001
NNT = 10
Primary Endpoint : Development of Overt Proteinuria
ARB (Losartan) Reduces Urinary Albumin and TGF-1 in Type 2 Diabetes with Microalbuminuria
Esmatjes E, et al. Nephrol Dial Transplant. 2001;16(Suppl1):90-93.
160
140
130
120
24-hour Systolic BPP<0.01 vs baseline
mm
Hg
4 Weeks
90
80
70
60
24-hour Diastolic BPP<0.03 vs baseline
Baseline 8 Weeks
mm
Hg
50
Urinary Albumin ExcretionP<0.01 vs baseline
100
90
80
70
60
mcg
/min
6
5
4
3
2
1
TGF-P<0.005 vs baseline
Baseline 4 Weeks 8 Weeks
ng/m
L
www.hypertensiononline.org
Effect of ARB vs ACE-I in Reduction in Progression of Urinary Albumin Excretion in Type 2 Diabetic Patients
Muirhead N, et al. Curr Ther Research 1999;60(12):650-660
-16.7
-10.8
11.5
-30
-20
-10
0
10
20
Valsartan80mg(n=27)
Captopril25mg tid
(n=29)
Placebo
(n=28)
%
Ch
an
ge
in
AE
R f
rom
bas
elin
e (
µg
/min
)
Effects of ARB vs ACEI: Progression to Proteinuria
3.7
0
3.4
10.7
0
5
10
15
Valsartan 80 mg Valsartan 160 mg Captopril 25 mg tid Placebo
Perc
ent
Muirhead et al, J Am Coll Cardiol, 1999.
Prospective study122 patients Type 2 DMMicroalbuminuriaFU for 52 weeks
Progression to proteinuria(two AER > 300 ug/min within 6 mo)
Effects of ARB on GFR: Non-DM
0
5
10
15
20
25
Valsartan Placebo
GFR
(ml/m
in)
Baseline
End point
Castelao et al, JASN, 1999.
Double blindPlacebo controlmulticenter study56 patients HT + CRFFU 6 months
Morbidity and Mortality Along the Renal Continuum
Risk FactorsRisk FactorsDiabetesDiabetes
HypertensionHypertension
EndothelialEndothelialDysfunctionDysfunction
Micro-Micro-Albuminuria Albuminuria
Macro-Macro-ProteinuriaProteinuria
Nephrotic Nephrotic Proteinuria,Proteinuria,
End-Stage End-Stage Renal DiseaseRenal Disease
DeathDeath
Adapted from Burgess
Morbidity and Mortality Along the Renal Continuum
Risk FactorsRisk FactorsDiabetesDiabetes
HypertensionHypertension
EndothelialEndothelialDysfunctionDysfunction
Micro-Micro-Albuminuria Albuminuria
Macro-Macro-ProteinuriaProteinuria
Nephrotic Nephrotic Proteinuria,Proteinuria,
End-Stage End-Stage Renal DiseaseRenal Disease
DeathDeath
Adapted from Burgess
IDNT RENAALMARVAL
IRMA-2
ARBs prevent diabetic renal disease progressionARBs prevent diabetic renal disease progressionAlbumin excretion in patients with microalbuminuria
0
10
20
30
40
50
60
70
80
90
100
Valsartan Amlodipine
Urin
ary
albu
min
exc
retio
n ra
te
(% o
f ba
selin
e)
Viberti et al. Circulation 2002;106:672–678
p<0.001
MARVAL
Telmisartan renoprotection in type 2 diabetic nephropathy
Reduced transition to overt nephropathy (INNOVATION)
Month0 3 6 9 12 15 18 21 24 27 30
0
0.2
0.4
0.6
0.8
Telmisartan 80 mg
Telmisartan 40mg
Placebo
16.7%
22.6%
49.9%
Tra
nsiti
on r
ate
p<0.0001RRR: 66%NNT: 3.0
p<0.0001RRR: 55%
NNT: 3.7
Patients with and without hypertension
RRR: relative risk reductionNNT: number needed to treat to prevent 1 transition Makino et al. Diabetes Care 2007
0
5
10
15
20
25
30
Irbesartan Amlodipine Placebo
0
5
10
15
20
25
30
Losartan Placebo
Dou
blin
g of
ser
um c
reat
inin
e co
ncen
trat
ion
(% o
f pa
tient
s)ARBs prevent diabetic renal disease progressionARBs prevent diabetic renal disease progression
Serum creatinine in patients with macroproteinuria
Brenner et al. N Engl J Med 2001;345:861–869. , Lewis et al. N Engl J Med 2001;345:851–860
RENAAL IDNT
p=0.003
p<0.001p=0.006
Combination therapy provides Combination therapy provides additive benefit – CALM studyadditive benefit – CALM study
0
2
4
6
8
10
12
14
16
18
SBP
Red
uctio
n fr
om b
asel
ine
(mm
Hg)
CandesartanLisinoprilCombination
0
10
20
30
40
50
60
Albumin/creatinine ratio
Red
uctio
n fr
om b
asel
ine
(%)
CandesartanLisinoprilCombination
Mogensen et al. BMJ 2000;321:1440–1444
Telmisartan renoprotection in type 2 DMTelmisartan renoprotection in type 2 DMReduces long-term decline in GFR (DETAIL)
Barnett et al. N Engl J Med 2004;351:1952–1961. Erratum in: N Engl J Med 2005;352:1731Barnett. Acta Diabetol 2005; 42 Suppl 1:S42–S49
0
10
20
30
40
50
60
70
80
90
100
Telmisartan Enalapril
Total GFR
†p = NS, telmisartan vs enalapril
p = NS†
-17.5
-15.0
-25
-20
-15
-10
-5
0
Telmisartan Enalapril
Change in GFR
p = NS†
Baseline After 5 years
ml/m
in/1
.73m
2
ml/m
in/1
.73m
2
National Kidney Foundation Recommendations on Treatment of HTN and Diabetes
• Blood pressure goal: 130/80 mmHg• Target blood pressure: 125/75 for patients with
>1 gram/day proteinuria• Blood pressure lowering medications should
reduce both blood pressure + proteinuria• Therapies that reduce both blood pressure and
proteinuria have been known to reduce renal disease progression and incidence of ischemic heart disease
Bakris GL, et al. Am J Kidney Dis. 2000;36(3):646-661.
www.hypertensiononline.org