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Clinical Trials in Clinical Trials in Hypertension and Hypertension and

Renal DiseasesRenal Diseases

Placebo + Other Antihypertensive Therapy

(excluding ACEI, AIIA)

Maintain prior antihypertensiv

e therapy (excluding ACEI,

AIIA)

Los 100 mg + Other Antihypertensive Therapy

(excluding ACEI, AIIA)

Los 100 mg

Goal BP< 140/90 mmHg

n = 1520

Los 50 mg

Placebo

NIDDM Patientswith proteinuria

Placebo



The Dual Significance of ProteinuriaThe Dual Significance of Proteinuria

• Proteinuria (albuminuria) results from injury to glomerular circulation Increased proteinuria (albuminuria) is

associated with progressive kidney disease• In diabetes and hypertension, proteinuria

(albuminuria) is also an indicator of injury in the systemic circulation Proteinuria (albuminuria) is associated with

increased cardiovascular risk



Renal Disease and HypertensionRenal Disease and HypertensionCore Concepts of TreatmentCore Concepts of Treatment

• Hypertension and proteinuria (albuminuria) are both independent variables that predict long-term decline in renal function Renal disease is both a cause and

consequence of hypertension Reduction of blood pressure reduces

cardiovascular risk and renal risk Reduction of proteinuria (albuminuria) may

lower both cardiovascular risk and renal risk



Meta Analysis: Lower Mean BP Meta Analysis: Lower Mean BP Results in Slower Rates of Decline in Results in Slower Rates of Decline in GFR in Diabetics and Non-DiabeticsGFR in Diabetics and Non-Diabetics

9595 9898 101101 104104 107107 110110 113113 116116 119119

r = 0.69; P < 0.05

MAP (mmHg)

GF

R (

mL

/min

/yea

r)

130/85 140/90

UntreatedHTN

00

-2-2

-4-4

-6-6

-8-8

-10-10

-12-12

-14-14 Parving HH, et al. Br Med J. 1989. Moschio G, et al. N Engl J Med. 1996.Viberti GC, et al. JAMA. 1993. Bakris GL, et al. Kidney Int. 1996.Klahr S, et al. N Eng J. Med 1994. Bakris GL. Hypertension. 1997.Hebert L, et al. Kidney Int. 1994. The GISEN Group. Lancet. 1997.Lebovitz H, et al. Kidney Int. 1994.

Bakris GL, et al. Am J Kidney Dis. 2000;36(3):646-661.Reprinted by permission from WB Saunders.



Meta Analysis: Lower Systolic BP Meta Analysis: Lower Systolic BP Results in Slower Rates of Decline in Results in Slower Rates of Decline in GFR in Diabetics and Non-DiabeticsGFR in Diabetics and Non-Diabetics

130 134 138 142 146 150 154 170 180

r = 0.69; P < .05

SBP (mmHg)

GF

R (

mL

/min

/yea

r)

UntreatedHTN

0

-2

-4

-6

-8

-10

-12

-14

Bakris GL, et al. Am J Kidney Dis. 2000;36(3):646-661.

Parving HH, et al. Br Med J. 1989. Moschio G, et al. N Engl J Med. 1996.

Viberti GC, et al. JAMA. 1993. Bakris GL, et al. Kidney Int. 1996.Klahr S, et al. N Eng J Med. 1994. Bakris GL. Hypertension. 1997.Hebert L, et al. Kidney Int. 1994. The GISEN Group. Lancet. 1997.Lebovitz H, et al. Kidney Int. 1994.



Goal BP Recommendations for Goal BP Recommendations for Patients with DM or Renal DiseasePatients with DM or Renal Disease

Organization Year Systolic

BPDiastolic

BPAmerican Diabetes Association 2001 <130 <80

National Kidney Foundation 2000 <130 <80

Canadian Hypertension Society 1999 <130 <80

British Hypertension Society 1999 <140 <80WHO & International

Society of Hypertension1999 <130 <85

Joint National Committee (JNC VI)

1997 <130 <85



JNC-VI General Goals for BP ControlJNC-VI General Goals for BP Control

Pre-existing condition

% achievedBP goals

BP goals (mmHg)

Essential Hypertension

27% <140/90

Diabetes 11% <130/85

Renal Disease and proteinuria>1.0 gram/24 h

<10% <125/75

Coresh J, et al. Arch Intern Med. 2001;161(9):1207-1216.



Frequency of Proteinuria Frequency of Proteinuria (Albuminuria) in the United States(Albuminuria) in the United States

Adults With Proteinuria

QuantitationTotal adults(in millions)

% of adultsin US

Increased urine ratioalbumin/creatinine

(>30 mg/gm)

20.2 11.7

Proteinuria(>300mg/24h)

18.3 10.6

Microalbuminuria(30-300 mg/24h)

1.9 1.1

Keane WF, Eknoyan G. Am J Kidney Dis. 1999;33(5):1004-1010



Impact of Blood Pressure Reduction Impact of Blood Pressure Reduction on Mortality in Diabeteson Mortality in Diabetes

TrialConventiona

lcare

Intensivecare

Risk reduction

P-value

UKPDS

154/87 144/82 32% 0.019

HOT 144/85 140/81 66% 0.016

Turner RC, et al. BMJ. 1998;317:703-713. Hansson L, et al. Lancet. 1998;351:1755–1762.

Mortality endpoints are:UK Prospective Diabetes Study (UKPDS) – “diabetes related deaths”Hypertension Optimal Treatment (HOT) Study – “cardiovascular deaths” in diabetics



UK Prospective Diabetes Study (UKPDS) UK Prospective Diabetes Study (UKPDS) Major Results: Powerful Risk ReductionsMajor Results: Powerful Risk Reductions

Better blood pressure control reduces…• Strokes by > one third• Serious deterioration of vision by > one third• Death related to diabetes by one third

Better glucose control reduces… • Early kidney damage by one third• Major diabetic eye disease by one fourth

Turner RC, et al. BMJ. 1998;317:703-713.



Diabetes: Tight Glucose vs Tight BP Diabetes: Tight Glucose vs Tight BP Control and CV Outcomes in UKPDSControl and CV Outcomes in UKPDS

StrokeAny Diabetic

EndpointDM

DeathsMicrovascularComplications

-50

-40

-30

-20

-10

0

% R

ed

ucti

on

In

Rela

tive R

isk

Tight Glucose Control (Goal <6.0 mmol/l or 108 mg/dL)

Tight BP Control (Average 144/82 mmHg)

32%

37%

10%

32%

12%

24%

5%

44%

*

*

*

**P <0.05 compared to tight glucose control

Bakris GL, et al. Am J Kidney Dis. 2000;36(3):646-661.Reprinted by permission from WB Saunders.



17% decrease per 10 mmHg decrement in BP

p<0.0001

0.5

1

5

110 120 130 140 150 160 170

UKPDS: Relationship Between BP Control UKPDS: Relationship Between BP Control And Diabetes-Related DeathsAnd Diabetes-Related Deaths

Mean systolic blood pressure (mmHg)

Haza

rd r

ati

o

Adler AI, et al. BMJ. 2000;321:412-419.Reprinted by permission, BMJ Publishing Group.



HOT Trial: BP Control Reduces HOT Trial: BP Control Reduces Cardiovascular Events in DiabeticsCardiovascular Events in Diabetics

Hansson L, et al. Lancet. 1998;351:1755–1762.

Maj

or

CV

eve

nts

*10

00 p

atie

nt-

yrs

30

25

20

15

10

5

0

P < .005

24.4

18.6

11.9

*includes all myocardial infarction, all strokes, and all other CV deaths

Diabetes SubgroupTarget

Diastolic BP

(mmHg)

Number of Patients

Achieved†

SystolicBP

(mmHg)

Achieved†

DiastolicBP

(mmHg)

90 501 143.7 85.2

85 501 141.4 83.2

80 499 139.7 81.1

† Achieved = Mean of all BPs from 6 months of follow-up to end of study



Landmark ACE Inhibitor Landmark ACE Inhibitor Trials in DiabeticsTrials in Diabetics

Study Drug N DosingStudy years

Endpoint P-value

Lewis Captopril 409 25 mg tid ~ 3Doubling of

serum creatinine

P=0.007

Lebovitz Enalapril 1655-40 mg qd

~ 3Correlation of MAP w/ rate of change in GFR

P=0.026

ABCD Trial

Enalapril 4705-40 mg qd

524-hr creatinine

clearanceNS

Lewis EJ, et al. N Engl J Med. 1993;329(20):1456-1462. Lebovitz HE, et al. Kidney Int. 1994;45(suppl45):S150-S155.Estacio RO, et al. Diabetes Care. 2000;23(suppl2):B54-B64.

ABCD = Appropriate Blood Pressure Control in Diabetes Trial



ACE-I Is More Renoprotective Than ACE-I Is More Renoprotective Than Conventional Therapy in Type 1 Diabetes Conventional Therapy in Type 1 Diabetes

% with doubling of

baseline creatinine

100

75

50

25

00 1 2 3 4

Baseline creatinine >1.5 mg/dL

Captopriln=207

Placebon=202

P<.001

Lewis EJ, et al. N Engl J Med. 1993;329(20):1456-1462. Copyright © 1993 Massachusetts Medical Society. Adapted with permission.

Years of follow-up



ACE-I Is More Renoprotective than ACE-I Is More Renoprotective than Conventional Therapy in Type 1 Diabetes Conventional Therapy in Type 1 Diabetes

% c

han

ge in

pro

tein

uri

a

40

20

0

-20

-40

-60CaptoprilPlacebo

P<.001

Decr

ease

in

mean

art

eri

al

pre

ssu

re (

mm

Hg

)

2

0

2

-4

-6

-8CaptoprilPlacebo

NS

Lewis EJ, et al. N Engl J Med. 1993;329(20):1456-1462.



Relationship of Achieved Mean Arterial Relationship of Achieved Mean Arterial Pressure to Parameters of Renal Function Pressure to Parameters of Renal Function

in Type 1 Diabetesin Type 1 DiabetesMean

arterialpressure(mmHg)*

nFinal total

proteinuria(mg/24h)

Serumcreatinin

e(mg/dL)

GFR(mL/min)

# patients with final

proteinuria <500 mg/24h

< 92 47 1,073 + 1,535† (418) +0.14† -5.2† 27

92.1–99.9 41 1,830 + 1,701 (1,798) +0.38 -6.2 11

100–107 32 4,249 + 4,754 (2,659) +0.38 -11.6 2

107.1 6 4,882 + 2,878 (5,825) +0.92 -11.0 0

Note: Values expressed as mean + SD. Data based on achieved blood pressures, not randomized blood pressure goals.*Mean of all pressure readings observed during the trial for each patient.† P < 0.05 when < 92 group is compared with these patients with MAP >92.1 mmHg.

Reprinted from Lewis JB, et al. Am J Kidney Dis. 1999;34(5):809-817 with permission from National Kidney Foundation.



125

140

155

170

Baseline 1 Month 5.6 Yrs Month offACE-I

+Clonidine

SB

P (

mm

Hg

)Impact of ACE-I on BP and GFR:Impact of ACE-I on BP and GFR:

Acute and Chronic EffectsAcute and Chronic Effects

60

65

70

75

80

85

90

Baseline 1 Month 5.6 Yrs Month offACE-I

+Clonidine

*P<0.05 compared to baseline

Bakris GL, Weir MR. Arch Intern Med. 2000;160(5):685-93.©American Medical Association

GFR

ml/m

in/1

.73m

2

*

* *

*

*



ARB (Losartan) Reduces Urinary Albumin and ARB (Losartan) Reduces Urinary Albumin and TGF-TGF-1 in Type 2 Diabetes with Microalbuminuria1 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

/mL



Landmark Trials in Diabetics and Non-Diabetics Landmark Trials in Diabetics and Non-Diabetics with ESRD/Death as an Endpointwith ESRD/Death as an Endpoint

Trial YearEndpoint

significanceAchieved BP

Captopril 1993 P=0.007 141/82

AIPRI 1996 P<0.001 139/82

REIN 1997 P=0.03 142/84

RENAAL 2001 P=0.01 142/77

IDNT 2001 results pending results pending

Lewis EJ, et al. N Engl J Med. 1993;329(20):1456-1462. Maschio G, et al. N Engl J Med. 1996;334(15):939-945. The GISEN Group. Lancet. 1997;349:1857–1863.



Landmark Renal Trials inLandmark Renal Trials inNon-Diabetics with ACE InhibitorsNon-Diabetics with ACE Inhibitors

Study Drug DosingSurvival Benefit

Study Duration

AIPRI Benazepril 10-20mg qd

P<0.001 ~3.0 years

REIN Ramipril 5-10 mg qd

P=0.03 ~ 3.5 years

AIPRI = ACE Inhibition in Progressive Renal Insufficiency StudyREIN = Ramipril Efficacy In Nephropathy Study

Maschio G, et al. N Engl J Med. 1996;334(15):939-945.The GISEN Group. Lancet. 1997;349:1857-1863.



AIPRI: Baseline Prognostic Factors and Reduction of AIPRI: Baseline Prognostic Factors and Reduction of Risk for Progressive Renal Insufficiency with ACE-IRisk for Progressive Renal Insufficiency with ACE-I

≤1gm >1 to <3gm ≥3gm

24-Hr Urine Protein Excretion

-80

-70

-60

-50

-40

-30

-20

-10

0

% r

isk

re

du

cti

on

>45 ml/min ≤45 ml/min

Creatinine Clearance

71%

46%

31%

53%

66%

Maschio G, et al. N Engl J Med. 1996;334(15):939-945.



REIN Study: ACE Inhibition in Proteinuric REIN Study: ACE Inhibition in Proteinuric Non-Diabetic NephropathyNon-Diabetic Nephropathy

Baseline SBP ∆ SBPBaseline

DBP∆ DBP

Ramipril

149.8 -5.8 mmHg 92.4 -4.2 mmHg

Placebo 148.0 -3.4 mmHg 91.3 -3.4 mmHg

00 66 1212 1818 2424 3030 3636

100

80

60

40

20

0

100

80

60

40

20

0

RamiprilRamipril

PlaceboPlacebo

P=0.02P=0.02

Reprinted from The GISEN Group. Lancet. 1997;349:1857–1863 with permission from Elsevier.

% o

f pati

ents

wit

hout

com

bin

ed e

ndp

oin

t*

*Combined endpoint = doubling of baseline serum creatinine concentration or end stage renal failure



REIN Study: ACE Inhibition in Proteinuric REIN Study: ACE Inhibition in Proteinuric Non-Diabetic NephropathyNon-Diabetic Nephropathy

Mea

n r

ate

of

GF

R d

ecli

ne

(mL

/min

/mo

nth

)

1.61.41.21.00.80.60.40.20.0

Baseline urinary protein excretion

(g/24 h)

n = 613–4.5

n = 364.5–7.0

n = 20 7.0

% p

ts w

ith

do

ub

lin

go

f b

asel

ine

Cr

or

ES

RD 70

60

50

40

30

20

10

0

Baseline urinary protein excretion

(g/24 h)

n = 873–4.5

n = 484.5–7.0

n = 31 7.0

Placebo

Ramipril

Reprinted from The GISEN Group. Lancet. 1997;349:1857–1863 with permission from Elsevier.



REIN Study: Ramipril Group Median REIN Study: Ramipril Group Median Change in Urinary Protein ExcretionChange in Urinary Protein Excretion

-60

-50

-40

-30

-20

-10

0

0 1 3 6 12 24 36

% c

han

ge in

uri

nary

p

rote

in e

xcre

tion

Months

The GISEN Group. Lancet. 1997;349:1857–1863.



ACE-I Provides Greater Renoprotection ACE-I Provides Greater Renoprotection Than Non-ACE-I in Patients with Than Non-ACE-I in Patients with

Diabetic and Non-Diabetic NephropathyDiabetic and Non-Diabetic Nephropathy

Study YearConclusions about

ACE inhibitors (ACE-I)

Bjork et al 1992 ACE-I reduced both the rate of decline in GFR and the amount of albuminuria.

Lewis et al 1993In Type I diabetics, ACE-I reduced proteinuria, risk of doubling serum creatinine, and risk of ESRD+Death. But, ESRD alone was not reduced.

REIN 1997In non-diabetics, ACE-I reduced proteinuria, risk of doubling serum creatinine, and risk of ESRD+Death. But, ESRD alone was not reduced.

MicroHOPE 2000ACE-I reduced progression of proteinuria from normoalbuminuria to microalbuminuria and from microalbuminuria to macroalbuminuria.

AASK 2001ACE-I was superior to amlodipine in reducing proteinuria among non-diabetic African Americans with hypertension and kidney disease.



AASK: The African American Study AASK: The African American Study of Kidney Disease and Hypertensionof Kidney Disease and Hypertension

• The AASK trial enrolled 1,094 African American patients with renal disease at 21 US centers, and randomized them to receive one of 3 study drugs:– Ramipril – ACEI or– Amlodipine – CCB or– Metoprolol – Beta-blocker

• Results– After adjustments for covariates, the risk

reduction for ramipril vs amlodipine groups in the clinical composite outcomes (GFR, dialysis, or death) was 38% (p=0.005)

Agodoa L, et al. JAMA. 2001;285(21):2719-2728.



HOPE TRIAL:HOPE TRIAL:Independent Predictive Variables for Combined Independent Predictive Variables for Combined

Endpoints of CV Death, MI, and StrokeEndpoints of CV Death, MI, and Stroke

Variable Hazard Ratio

Microalbuminuria 1.59

Creatinine > 1.4 mg/dL 1.40

CAD 1.51

PVD 1.49Diabetes Mellitus 1.42

Male 1.20Age 1.03

Waist-Hip Ratio 1.13

Mann JFE, et al. Ann Intern Med. 2001;134(8):629-636.



0

10

20

30

40

0

10

20

30

40

50

60

0

10

20

30

40

50

60

0

20

40

60

80

<1.4 mg/dL

All Patients Placebo

Even

ts p

er

1000 P

ers

on

-Years

, n Primary

Outcome*Myocardial Infarction*

CardiovascularDeath*

All Death*

>1.4 mg/dL <1.4 mg/dL >1.4 mg/dL

<1.4 mg/dL >1.4 mg/dL<1.4 mg/dL >1.4 mg/dL

Ramipril

HOPE Trial: HOPE Trial: Main Outcomes and Serum CreatinineMain Outcomes and Serum Creatinine

Mann JFE, et al. Ann Intern Med. 2001;134(8):629-636.Reprinted by permission, ACP-ASIM.

*p=<0.001



0

20

40

60

80

100

0

20

40

60

80

100

0

20

40

60

80

100

0

20

40

60

80

100

<1.4 mg/dL

Placebo Ramipril

Even

ts p

er

1000 P

ers

on

-Years

, n

DiabeticPatients

Hypertensive Patients

Non-Diabetic Patients Normotensive Patients

>1.4 mg/dL <1.4 mg/dL >1.4 mg/dL

<1.4 mg/dL >1.4 mg/dL<1.4 mg/dL >1.4 mg/dL

HOPE Trial: HOPE Trial: Primary Outcomes and Serum CreatininePrimary Outcomes and Serum Creatinine

Mann JFE, et al. Ann Intern Med. 2001;134(8):629-636.Reprinted by permission, ACP-ASIM.



Comparison of Anti-Hypertensive Comparison of Anti-Hypertensive Regimens on Proteinuria Regimens on Proteinuria

With similar reductions of blood pressure…

• Dihydropyridine calcium channel blockers (DHPCCB) increase proteinuria− Ref: Mimran A, et al. Diabetes Care. 1988;11:850-853.− Ref: Demarie BK, Bakris GL. Ann Intern Med. 1990;113:987-988.− Ref: Agodoa L, et al. JAMA. 2001;285(21):2719-2728.

• Non-DHPCCB reduces proteinuria when a DHPCCB produces no change or increase in proteinuria– Ref: Smith AC, et al. Kidney Int. 1998;54:889-896.– Ref: Kloke H, et al. Kidney Int. 1998; 53:1559-1573.



Mean Changes in Albuminuria and Mean Changes in Albuminuria and Mean Arterial Pressure (MAP) in Studies Mean Arterial Pressure (MAP) in Studies

of Patients with HTN and Proteinuriaof Patients with HTN and Proteinuria

-50

-40

-30

-20

-10

0

10

20

Pe

rce

nt

Ch

an

ge

MAP(mmHg) Albuminuria

N=173 N=121 N=111 N=723

Nifedipine

OtherDihydropyridine

CCBs

Diltiazem &Verapamil

CCBsAll

ACE Inhibitors

Kloke H, et al. Kidney Int. 1998;53:1559-1573.



ACE-I + Verapamil: Additive Reduction of ACE-I + Verapamil: Additive Reduction of Proteinuria in Type 2 Diabetes at 1 YearProteinuria in Type 2 Diabetes at 1 Year

Trandolapril (5.5 mg/d)

Verapamil (315 mg/d)

Trandolapril (2.9 mg/d) + Verapamil (219 mg/d)

-70

-60

-50

-40

-30

-20

-10

0

MAP Proteinuria

*

Bakris GL, et al. Kidney Int. 1998;54:1283-1289. Reprinted by permission, Blackwell Science, Inc.

-33%

-27%

-62%

*p <0.001 combination vs either monotherapy

Perc

en

t re

du

cti

on

n=12 n=11 n=14

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