supra rx dose of arbs

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.


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.


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


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


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



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


0 12 24 36 48

0

10

20

30

40

50

0 12 24 36 480

10

20

30


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


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%


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.


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


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)


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)


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



Figure 1. Study flow diagram

N=167+172, non-DM CKD



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)


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


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


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



Figure 3. Proteinuria throughout the whole study period



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


Uri

ne K

(mm

ol/d

)

5.3 5

3.5

5

0

2

4

6


U A

ldo

V (u

g/d)

67

7268 67

50

55

6065

70

75

80


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

supra rx dose of arbs

Health & Medicine