Microalbuminuria in Diabetic and hypertensive

patients: Therapeutic approach

By Dr.Abdelsalam Sherif

Consultant Cardiologist RNH

Microalbuminuria. Hypertension.

Diabetes Mellitus. Interventions.

Microalbuminuria

JNC 7: CVD RISK FACTORS

Hypertension*

Cigarette smoking

Obesity* (BMI >30 kg/m2)

Physical inactivity

Dyslipidemia*

Diabetes mellitus*

Microalbuminuria

estimated GFR <60 ml/min

Age (older than 55 for men, 65 for women)

Family history of premature CVD (men under age 55 or women under age 65)

JAMA 2003:289:2560

*Components of the metabolic syndrome.

>300 mg/g creatinine30-300 mg/g creatinine<30 mg/g creatinineAlbumin-to-creatinine

ratio** Male 2.5-30 mg/mmolFemale 3.5-30 mg/mmol

30-300 mg/24hours20-200 μg/minute

Microalbuminuria

≥30 mg/mmolMale <2.5 mg/mmol

Female < 3.5mg/mmol

>300 mg/24 hours>200 μg/minute

<30 mg/24 hours<20 μg/minute

Albumin excretion

rate*

Macroalbuminuria

Normoalbuminuria

Measure

Definition of Adversal Albumin Excretion

*24-hour collection**spot urine; normalizes for urine volume; low muscle mass: false positive results; high muscle mass: false

negative results

Tagle R et al. Cleave Clin J Med 2003; 70:225-265

DEFINITIONS OF MICROALBUMINURIA

AND MACROALBUMINURIAParameter Normal Micro-

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

1 Gould et al., BMJ,306:240-242, 1993; 2 Damsgaard et al., BMJ,300:297-300, 1990; 3 Viberti et al., Lancet 1:1430-1432, 1982; 4 Valensi et al., Int J of Obesity,20:574-579, 1996 5 Cirillo et al., Archive of inter Med,158:1933-1939, 1998; 6 Mykkanen et al.,Diabetes,47:793-800, 1998; 7 Watchell et al., AHJ 2002. 143:319-326; 8 Liu et al., J Am Coll Cardiol. 2003;41(11):2022-8., 9 Barzilay et al., Am J Kidney disease 2004 Jul;44(1):25-34.

MAU is Independently Associated with a Variety of CV Risk Factors

MAU can be found in 5 to 15% of the general population, and in 3 to 8% of apparently healthy individuals (without diabetes or hypertension).

Non modifiable Male gender1 Older age 2

Modifiable Diabetes 3 Obesity 4 Smoking 5 Insulin resistance syndrome 6 LVH (Left-Ventricular Hypertrophy)7 Left ventricular dysfunction 8 CRP (C-Reactive Protein) 9

Correlation Coefficient between micoalbuminoria and different parameters

P r Parameters

Blood pressures:<0.01 0.678 Systolic BP

NS 0.133 Diastolic BP

Blood Glucose:

<0.05 0.201 FBS

<0.05 0.218 PPBS

Lipogram:<0.05 0.443 T.Cholesterol

NS 0.179 Triglycerides

<0.05 -0.319 HDL – C

NS 0.134 LDL – C

Wachtell et al. J Hypertens 2002;20:405–12

8,029 subjects with hypertension and LV hypertrophy,

mean age 66 years

Pre

vale

nce (

%)

40

30

20

10

0

Diabetes Cerebrovascular Peripheral Coronarydisease vascular vascular

disease disease

NormoalbuminuriaMicroalbuminuria (Alb/Crea >3.5 mg/mmol)Macroalbuminuria (Alb/Crea >35 mg/mmol)

Albuminuria and CV Diseases: the LIFE Study

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

HOPE TRIAL:Independent Predictive Variables for

Combined Endpoints 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.

Klausen et al., Hypertension. 2005; 46:33-37

30

20

10

0

30

20

10

00 2 4 6 8 10 12

0 2 4 6 8 10 12

CHD incidence CHD mortality

Cum

ula

tive C

HD

inci

dence

(%

)

Cum

ula

tive m

ort

alit

y (

%)

UAE ≥ 4.8μg/min

UAE < 4.8μg/min

UAE ≥ 4.8μg/min

UAE < 4.8μg/min

Years from entry Years from entry

Cox-estimated age-adjusted curves of cumulative mortality for a 60-year-old person based on 1734 hypertensive subjects with microalbuminuria(UAE ≥ 4.8µg/min; n=522) and normoalbuminuria(UAE < 4.8µg/min; n=1212; P<0.001).

Cox-estimated age-adjusted curves of cumulative coronary heart disease (CHD) for a 60-year-old person based on 1734 hypertensive subjects with microalbuminuria (UAE ≥ 4.8µg/min; n=522) and normoalbuminuria (UAE < 4.8µg/min; n=1212; P<0.001).

Low Levels of MAU are Predictive of CAD and Death

Cardiovascular Events by Degree of Albuminuria in HOPE

Gerstein et al. JAMA 2001;286:421-6.

Incid

en

ce (

%)

30

25

20

15

10

5

0

All participants

With diabetes

Without diabetes

Microalbuminuriathreshold

Albumin/creatinine Ratio Deciles

1 & 2 3 4 5 6 7 8 9 10

Microalbuminuria Screening is Important!!

Marker of small vessel disease in both the kidney and the heart

Marker of increased cardiovascular morbidity and mortality for both diabetics and the general population

Progresses to overt proteinuria in up to 40% of patients with type 2 diabetes within 5 to 10 years

American Diabetes Association. Diabetes Care 2002;25:S85-S89

Modifiable Risk Factors / Markers for Progression of Microalbuminuria to

Clinical Proteinuria

Blood pressure Level of microalbumin excretion rate Hemoglobin A1c

Serum cholesterol Drugs that block the renin-angiotensin-

aldosterone system (RAAS)

Exclusion of artefacts(exercise, urinary infections, fever etc.)

Microalbuminuria ?(> 30 mg/24 h; > 20 mg/min; > 20 mg/l; > 2 mg/mmol

creatinine)

Repeat 2 x in 3 months

2 of 3 positive tests

Repeatat 1 y

yes

yes

nono

Diagnosis of microalbuminuriastart management

ADA. Diabetes Care 1996; 19:S103-S105

Detection of Microalbuminuria(American Diabetes Association)

Hypertension

Hypertension Has a High Prevalence That Is Expected To Rise Over the Coming Decades

Kearney PM, et al. Lancet 2005; 365:217–223

Hypertension is an important public health challenge worldwide. Prevention, detection, treatment and control should receive high priority

2000

2025

Esta

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hed

Mar

ket Ec

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ies

Form

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Econ

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Cre

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37.435.3

20.6

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17

26.9

37.239.1

20.9

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23.719.7

14.5

28.3

0

10

20

30

40

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MenWomen

41.639.1

22.9

44.5

2427.7

18.8

27

42.545.9

23.6

40.2

27 27

17.1

28.2

0

10

20

30

40

50

Hypertension Burden on Healthcare

Worldwide, hypertension is responsible for62% of strokes1

49% of heart attacks1

Hypertension is the third leading risk factor for diseaseCauses 7.1 million premature deaths each year1

4.5% of global burden of disease1

Hypertension represents a high burden on healthcare expenditureIn 2004, the direct and indirect cost of high blood

pressure in the US was $55.5 billion; drug costs accounted for $21 billion2

Thus, hypertension management is a public health priority

1.WHO, 2002; 2. AHA, 20042.AHA. Heart Disease and Stroke Statistics -- 2004 Update

0.25

0.50

1.00

2.00

4.00

12376

13684

14891

16298

17585

Approximate mean usual BP Approximate mean usual BP

Stroke CAD

Rela

tive R

isk

Elevated Blood Pressure Increases the Risk of Cardiovascular Disease

Collins R et al. Br Med Bull 1994;50: 272–298

12376

13684

14891

16298

17585

0.25

0.50

1.00

2.00

4.00

Rela

tive R

isk

Hypertension (HTN) and Microalbuminuria (MAU)

HTN is associated with MAU. However, real prevalence of MAU in

hypertensive patients is unknown

In patients with HTN, MAU is an independent risk marker for cardio-vascular

events like ischemic heart disease and stroke, but also all-cause mortality

MAU is a marker of generalized endothelial dysfunction which is considered

as an early stage of Atherothrombosis

Screening for MAU is simple and easy to perform and is recommended by

international treatment guidelines

RAS-blockade and adequate BP-control are the cornerstone for the

treatment of MAU and HTN

Normoalbuminuria

Microalbuminuria(UA/Cr ratio > 1.07 mg/mmol)

0 1 2 3 4 5 6 78 9 10

100

95

90

85

80

75

70

Pro

port

ion w

ithout

isch

em

icheart

dis

ease

(%

)

Jensen et al., Hypertension.2000;35:898-903

204 hypertensive subjects drawn from 2085 general population subjects.No previous CV events, no diabetes.No renal or urinary disease.Follow up from 1983–1984 till 1993.18 coronary events.

MAU is a Predictor of Ischemic Heart Disease in Hypertensive Patients

Years

Kaplan–Meier plot for the composite end point by UACR categories (fractions of patients experiencing from an end point). Primary composite end points (CEP): the first occurrence of cardiovascular death, nonfatal stroke, and nonfatal myocardial infarction. LIFE Study: Double-blind, randomized trial to compare the effects of losartan and atenolol on cardiovascular morbidity and mortality in high-risk patients with hypertension and left ventricular hypertrophy (LVH)

Ibsen et al., Hypertension. 2005;45:198-202

Low baseline/low year 1

Analysis from LIFE trial

0.20

0.15

0.10

0.05

0.00

Fract

ion s

uff

eri

ng C

EP

Time (months)

High baseline/high year 1

High baseline/low year 1Low baseline/high year 1

MAU Reduction in Hypertensive Patients is Accompanied by CV Event Reduction

0 10 20 30 40 50 60 70

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. 999;19(8):1992-1997. With permission from Lippincott Williams & Wilkins.

N=2,085; 10 year follow-up

1ESH/ESC guidelines, Journal of hypertension 2003,21:1011-1053; 2 The JNC 7 Hypertens.2003;42:1206-1252

MAU Screening Recommended in Patients with Hypertension

ESH/ESC Guidelines for the management of arterial hypertension, 2003 1:“…searching for microalbuminuria is recommended, because of the mounting evidence that it may be a sensitive marker of organ damage, not only in diabetes but also in hypertension.”

The JNC-7 Report, The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure, 2003 2:“Optional tests include measurement of urinary albuminuria excretion or albumin/creatinine ratio.”

Recommendations by ADA, ISHIB, and NKF consistent with JNC 7

Drug therapy is recommended for all patients with hypertension (SBP/DBP >140/90 mmHg)

BP goals <140/90 mmHg <130/80 mmHg for patients with diabetes mellitus or chronic

kidney disease

Multiple drug therapy with 2 or more agents at adequate doses (thiazide diuretic, ACE inhibitor, ARB, beta-blocker, CCB) is usually required to achieve BP targets

ISHIB guidelines: consider initiating treatment with 2 drugs if BP is 15/10 mmHg above goal

American Diabetes Association (ADA). Diabetes Care 2005; 28:S4–S36.The International Society on Hypertension in Blacks (ISHIB). Arch Intern Med 2003;163:525–541.The National Kidney Foundation (NKF). Am J Kidney Dis 2000; 36:646–661.

Diabetes

From Zimmet P et al. Diabet Med. 2003;20:693-702.

25.039.759%

10.419.788%

38.244.216%

1.11.7

59%

13.626.998%

81.8 156.191%

18.2 35.997%

189 mill. in 2003324 mill. Estimated for 202572% increase

The Diabetes Epidemic

Rat

es (

per

10,

000

per

son

-yea

r)

Adjusted for age, race, income, cholesterol, systolic blood pressure, smoking

Total CVD CHD Stroke Other CVD

75

50

25

0

Diabetes

No diabetes

Relative risk 3.0 3.2 2.8 2.3

Type 2 diabetes increases the risk of cardiovascular disease

n = 342,815

n = 5,163

The presence of diabetes was associated with a higher CHD risk in the VA-HIT placebo group

normal Impaired fasting glucose

Undiagnosed

diabetes

Diagnosed diabetes

0%

10%

20%

30%

40%

cum

ula

tive

eve

nt

rate

%

age-adujested 5 year incidence of major cardiovascular events in the VA-HIT palcebo groupby dlucose group

36.5%34.3%

23.8%21

%

0

25

50

75

100

125

150

175

200

225

250

SBP (mm Hg)

CV

Mort

ality

(death

s/1

0,0

00

pers

on

-years

) No diabetesDiabetes

120 120–139 140–159 160–179 180–199 200

Adapted from Stamler J et al. Diabetes Care. 1993;16:434-444.

Association of Systolic Blood Pressure (SBP) and CV Death in Type 2 Diabetes

Proteinuria levels predict stroke and CHD events in type 2 diabetes

> 300

< 150

150-300

U-Prot = Urinary protein concentrationMiettinen H et al. Stroke 1996;27:2033–9.

Survival curves(CV mortality) Incidence

(%)1.0

0.9

0.8

0.7

0.6

0.5

0

40

30

20

10

0

Stroke CHD events

Overall: p < 0.001

Time (months)10 20 30 40 50 60 70 80 900

U-Prot < 150 mg/L U-Prot 150-300 mg/L U-Prot > 300 mg/L

p < 0.001

7-year follow-up of 1,056 patients with type 2 diabetes with or without hypertension

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-c

au

se m

ort

ality

)

Normoalbuminuria(n=191)

Microalbuminuria(n=86)

Macroalbuminuria(n=51)

P<0.01 normoalbuminuria vs microalbuminuriaP<0.001 normoalbuminuria vs macroalbuminuriaP<0.05 microalbuminuria vs macroalbuminuria

Proteinuria as a Risk Factor for Mortality in Type 2 Diabetes

Gall MA, et al. Diabetes. 1995;44:1303-1309.Copyright ©1995, American Diabetes Association. Reprinted with permission.

Relative prognostic value of MAUin type 2 diabetes

Eastman RC, Keen H. Lancet 1997;350(Suppl 1):29–32.

MAU Smoking Diastolic BP

Mortality

from CHD

(odds ratio)

Cholesterol

10

6.5

2.33.2

10

8

6

4

2

0

Therapeutic Approach

Effective Blood Pressure Control Reduces Cardiovascular Morbidity and Mortality

ESH/ESC Guidelines. J Hypertens 2003; 21:1779–1786.

10

-40

-30

-20

-10

0

-50

Isolated-systolic hypertension

Stroke CHDAll

Causes CV Non CV Stroke CHDAll

Causes CV Non CV

Systolic-diastolic hypertension

Fatal and nonfatal events Mortality

Fatal and nonfatal events

Mortality

<0.001

<0.001

<0.001

<0.001

<0.01 <0.01NS

NS

0.02

0.01

Event reduction in patients on active antihypertensive treatment versus placebo or no treatment.

CHD: coronary heart disease; CV: cardiovascular

-33

-25

-21

-16

-12

-50

-40

-30

-20

-10

0

Microalbuminuria at 12 yrs Microvascular complicationsRetinopathy Myocardial InfarctionAny DM endpoint

% r

ela

tive r

isk r

ed

ucti

on

P=0.03

P<0.01

P<0.01

P=0.05

P=0.02

UKPDS Group. Lancet. 1998;352:837-853.

UKPDS Relative Risk Reduction for Intensive vs Less Intensive Glucose

Control

Over 10 years, HbA1c was 7.0% (6.2-8.2) in the intensive group (n=2,729) compared with 7.9% (6.9-8.8) in the conventional group (n=1,138).

Hypertensive diabetics profit most from stringentblood pressure control

HOT = Hypertension Optimal Treatment

0

5

10

15

20

25S

eri

ou

s c

ard

iovascu

lar

even

ts/1

000 p

at.

years

90 85 80

30

mm Hg diastolic target blood pressure

- 51% risk reduction

Hansson L at al. Lancet 1998; 351:1755-1762

HOT-Study: Optimal blood pressure in hypertensive and diabetics (Type II)

Microalbuminuria Resets the Focus on CV Risk Reduction Strategies

BP <130/80 mmHg Evaluate lipids Normalize microalbuminuria Reduction in dietary salt/saturated fat Intensify glycemic control Anti-platelet therapy

JNC-7 Guidelines Diabetic hypertension

Thiazide diuretics, ß-blockers, ACE inhibitors, ARBs and CCBs have been shown to reduce CVD and stroke incidence in diabetic hypertension

In diabetic hypertension, combinations of 2 or more medications are usually needed to achieve target BP of < 130/80 mmHg

ACE- and ARB-based treatments favourably affect the progression of diabetic nephropathy and reduce albuminuria

Chobanian AV et al. The seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure: the JNC 7 report. JAMA 2003;289:2560-72.

Hypertension with compelling indications

Stage 1 hypertension (SBP 140-159 or DBP 90-99

mmHg)

Thiazide-type diuretics for most

May consider ACE inhibitor, ARB, -blocker, CCB, or combination

Stage 2 hypertension (SBP ≥160 mmHg or DBP ≥100

mmHg)

2-drug combination for most (usually thiazide-type diuretic and ACE inhibitor or ARB or -blocker or CCB)

Drug(s) for compelling indications

Other antihypertensive drugs (diuretics, ACE inhibitor, ARB, -blocker, CCB) as needed

Not at goal BP

Lifestyle modifications

JNC 7 VII, Hypertens. 2003;42:1206-1252.

Not at goal BP (<140/90 mmHg or <130/80 mmHg for those with diabetes or chronic kidney disease)

Initial drug choices

Hypertension without compelling indications

Optimize dosages or add additional drugs until goal BP is achieved

Consider consultation with hypertension specialist

JNC 7 - Algorithm for treatment of hypertension

Reprinted from Bakris GL, et al. Am J Kidney Dis. 2000;36(3):646-661 with permission from National Kidney Foundation.

NATIONAL KIDNEY FOUNDATION ALGORITHM FOR ACHIEVING TARGET BP GOALS IN HYPERTENSIVE

DIABETIC PATIENTS

Start ACE inhibitor

titrate upwards

If BP still not at goal

(130/80 mm Hg)

BP still not at goal

(130/80 mm Hg)

Baseline pulse <84Add low-dose beta

blocker or alpha/beta blocker

Add other subgroup of CCB

(ie, amlodipine-like agent if verapamil or diltiazem already being used and the converse)

Refer to a clinical hypertension

specialist

BP still not at goal (130/80 mm Hg)

If BP goal achieved, convert to fixed dose combinations (ACE

inhibitor + CCB or ACE inhibitor + diuretic)

Baseline pulse 84Add Thiazide Diuretic or

long-acting CCB*

Blood pressure >130/80 mm Hg

*If proteinuria present (>300 mg per day) non-DHP preferred.

Chronic Renal Disease:Initial Treatment Recommendations

Renal InsufficiencyClcr <60 mL/min

CrSerum >1.4 mg/dL*

Microalbuminuria(only Abnormality)

Diabetes Mellitus

ACE Inhibitor(or ARB)

StartAnd

Titrate To Maximum

TolerableDose

130/80

130/80

Proteinuria

*for women, CRSerum >1.2 mg/dL

Importance of Long-Term BP-Control for

MAU-ReductionSBP reduction leads to MAU-reduction

Cum

ula

tive h

aza

rd r

isk

in

develo

pin

g M

AU

Time of follow-up

Pascual et al.,Hypertension. 2005;45:1132-1137

1.00

0.75

0.50

0.25

0.00

0 5 10 15

<130mmHg

130–139 mmHg

>139 mmHg

ACE PATHWAY(< 30%)

NON-ACE PATHWAY(> 70%)

Angiotensin

Angiotensinogen

ChymaseToninCathepsinKallikrein

Angiotensin I

Renin

ACE

McConnaughey et al. J Clin Phamacol 1999;39: 547–59.

The RAS showing ACE and non-ACE pathways

Angiotensin II Formation

Angiotensin II

Angiotensin I

Angiotensinogen

Angiotensin II Receptors

ACE

Renin

CAGECathepsin GChymase

t-PACathepsin GTonin

*The clinical significance of alternate pathways is unknown.Dzau VJ et al. J Hypertens. April 1993;11(suppl):S13-S18.

Alternate Pathways*

Mechanism of Action of Angiotensin II Receptor Blockers (ARBs)

Adapted from Unger T. Am J Cardiol 2002; 89 (suppl):3A-10A.

AT1 Receptor Na reabsorption Aldosterone release Sympathetic outflow Vasopressin secretionVasoconstrictionVascular and cardiac hypertrophy

Angiotensinogen

Angiotensin I

Angiotensin II

Non-ACE enzymes (cathepsin, chymase)

Renin

Bradykinin

ACEInactive Fragments

AT2 ReceptorVasodilati

onGrowth

inhibitionApoptosis

Blood Pressure

ARBs

Adapted from McConnaughey et al. J Clin Phamacol 1999;39: 547–59.

AngiotensinII

AT1 Receptor AT2 Receptor

-sartan

Angiotensin II effects at the AT1 and AT2 receptors

VasoconstrictionActivate sympathetic activity

Increase sodium retentionIncrease vasopressin release

Promote myocyte hypertrophy and proliferationStimulate vascular and cardiac fibrosis

Stimulate plasminogen activator inhibitor 1Stimulate superoxide formation

AntiproliferationApotosis

Endothelial cell growth

Vasodilation (NO mediated?)Stimulate renal bradykinin and NO

Interventions to Reduce Microalbuminuria

Non Pharmacological measures:- Weight Loss.

Exercise.

Eating a low fat diet Pharmacological agents:- Statins.

ACE inhibitors.

ARBs.

Cobination of ACEI and ARBs.

CCBs

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

Diabetic 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.

Albumin excretion rate in hypertensive diabetic patients treated with lercanidipine or ramipril.

Dalla Vestra M et al, Diab Nutr Metab, 2004

P<0.05

P<0.05

Lercanidipine

Ramipril

Change in Albumin Excreation Rate (AER) from baseline to the end point according to treatment groups: (□)Lercanidipine group p<0.05; (∆)Ramipril group p<0.05. From th comparison between groups, p<0.05 at baseline and NS at the endpoint

Benefit of Angiotensin Receptor Blockers in Diabetes:

Important Findings of 3 Major Clinical Trials RENAAL (2001)

The angiotensin receptor blocker losartan compared to placebo reduced the risk of diabetic nephropathy developing to renal failure

IRMA II (2001) Higher doses of the angiotensin receptor blocker irbesartan

reduced the risk of progression of renal insufficiency IDNT (2001)

The angiotensin receptor blocker irbesartan compared to the calcium channel blocker amlodipine provided better renal protection in hypertensive type 2 diabetics, reducing the chance of diabetic nephropathy developing to renal failure

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

/mL

Benefit of Angiotensin Receptor Blockers in Diabetes:

Important Findings of 3 Major Clinical Trials

RENAAL (2001) The angiotensin receptor blocker losartan compared to

placebo reduced the risk of diabetic nephropathy developing to renal failure

IRMA II (2001) Higher doses of the angiotensin receptor blocker

irbesartan reduced the risk of progression of renal insufficiency

IDNT (2001) The angiotensin receptor blocker irbesartan compared to the

calcium channel blocker amlodipine provided better renal protection in hypertensive type 2 diabetics, reducing the chance of diabetic nephropathy developing to renal failure

The IRbesartan MicroAlbuminuria Type 2 Diabetes In

Hypertensive Patients Study

IRMA II Objectives Randomized multi-site, double-blind, placebo-controlled study to evaluate the

renal protective effect of the angiotensin II receptor antagonist irbesartan in hypertensive patients with type 2 diabetes and microalbuminuria

Population 590 patients (30 to 70 years old)

Type 2 diabetes Hypertension (a mean systolic BP >135 mmHg or a mean diastolic BP >85

mmHg, or both, on 2 of 3 consecutive measurements) Persistent microalbuminuria

○ Albumin excretion rate of 20 to 200 g/min in 2 of 3 samples○ Serum creatinine concentration of no more than 1.5 mg/dL for men and 1.1

mg/dL for women

Parving HH, et al. N Engl J Med. 2001;345(12):870-878.

IRMA II Incidence of Progression to Diabetic Nephropathy

0

5

10

15

20

Incid

en

ce o

f D

iab

eti

c

Nep

hro

path

y (

%)

0 3 6 12 18 22 24

201 201 164 154 139

195 195 167 161 148

194 194 180 172 159

129

142

150

36

45

49

Placebo (n)Irbesartan 150 mg (n)Irbesartan 300 mg

Months of Follow-up

Placebo 150 mg ofirbesartan

300 mg ofirbesartan

P<0.001 for difference between 300 mg irbesartan group and placebo

Parving HH, et al. N Engl J Med. 2001;345(12):870-878.©2001 Massachusetts Medical Society. All rights reserved.

IRMA II Change in Urinary Albumin Excretion*

-50

-40

-30

-20

-10

0

10

20

% c

han

ge in

uri

nary

alb

um

in e

xcre

tion

0 3 6 12 18 22 24

Months of Follow-up

150 mg of irbesartan

300 mg of irbesartan

Placebo

Parving HH, et al. N Engl J Med. 2001;345(12):870-878.©2001 Massachusetts Medical Society. All rights reserved.

*P<0.001 for difference between both irbesartan groups and placebo

IRMA II Irbesartan vs Placebo Secondary Endpoints

• During the first 3 months, the decline in creatinine clearance (mL/min/m2 body surface area per month) was greater than the decline between 3 and 24 months* 0.9 vs 0.1 for the placebo group 1.0 vs 0.2 for the 150 mg group 1.9 vs 0.2 for the 300 mg group

• Irbesartan reduced the level of urine albumin excretion…24% in the 150 mg group (P=NS)†

38% in the 300 mg group (P<0.001)†

Parving HH, et al. N Engl J Med. 2001;345(12):870-878.

*Neither the initial nor long-term decline differed significantly among the 3 groups

† Compared to placebo

IRMA II Adverse outcomes

Parving H-H et al. N Engl J Med 2001;345:870–78.Parving H-H et al. N Engl J Med 2001;345:870–78.

Cardiovascular events

Serious adverse events

Discontinuations due to adverse events

Cardiovascular events

Serious adverse events

Discontinuations due to adverse events

18

47

19

18

47

19

(8.7)

(22.8)

(9.2)

(8.7)

(22.8)

(9.2)

ControlControl

14

32

18

14

32

18

(6.9)

(15.8)

(8.9)

(6.9)

(15.8)

(8.9)

Irbesartan(150 mg)

Irbesartan(150 mg)

9

30

11

9

30

11

(4.5)

(15.0)

(5.5)

(4.5)

(15.0)

(5.5)

Irbesartan(300 mg)

Irbesartan(300 mg)

No. of adverse outcomes (%)No. of adverse outcomes (%)

IRMA IISummary of Important Findings

Irbesartan significantly reduces the rate of progression from microalbuminuria to diabetic nephropathy.

Renoprotection from irbesartan in patients with type 2 diabetes and microalbuminuria is independent of its blood pressure lowering effect.

Antihypertensive treatment has a renoprotective effect in hypertensive patients with type 2 diabetes and microalbuminuria

Parving HH, et al. N Engl J Med. 2001;345(12):870-878.

Benefit of Angiotensin Receptor Blockers in Diabetes:

Important Findings of 3 Major Clinical Trials

RENAAL (2001) The angiotensin receptor blocker losartan compared to

placebo reduced the risk of diabetic nephropathy developing to renal failure

IRMA II (2001) Higher doses of the angiotensin receptor blocker irbesartan

reduced the risk of progression of renal insufficiency IDNT (2001)

The angiotensin receptor blocker irbesartan compared to the calcium channel blocker amlodipine provided better renal protection in hypertensive type 2 diabetics, reducing the chance of diabetic nephropathy developing to renal failure

Subjects (%)

0 6 12 18 24 30 36 42 48 54Follow-up (mo)

60

0

10

20

30

40

50

60

IDNT Primary Endpoint

Irbesartn

Amlodipie

Control

RRR 20%P=0.02

P=NS

RRR 23%P=0.006 23%

RRRP=0.006

Time to Doubling of Serum Creatinine, ESRD, or Death

Lewis EJ et al. N Engl J Med 2001;345:851-860.

Guidelines are consistent in aiming to reduce cardiovascular and renal morbidity.

‘Goal’ or ‘Target’ BP’s consistent: <140/90 mm Hg for all hypertensive patients <130/80 mm Hg in diabetic patients.

BP goals are not attained by many patients

US and European guidelines recommend use of combination therapy early in the management of specific groups of patients

US and European guidelines recommend use of combination therapy following failure to reach goal with monotherapy

RECOMMENDATIONS FOR THERAPY SUMMARY

JNC 7 Report. JAMA 2003; 289: 2560-2572ESH/ESC Guidelines. J Hypertens 2003; 21: 1011-1053

Guidelines Sub-Committee. 1999 WHO/ISH. J Hypertens 1999; 17:151–183

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