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What is the Impact of PRIME inClinical Practice of Diabetic

Nephropathy patient ?

Harsinen SanusiDivision of Endocrinology &

Metabolic Department of InternalMedicine Faculty of Medicine

Hasanuddin University Dr WahidinSudirohusodo Hospital Makassar

East Indonesia EndoMetabolism Up date 27-28 May 2006


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The Diabetes Epidemic

151 million patients with diabetes, 221million estimated by 2010

2.1% of worldwide population

97% are Type 2 DM patients

Diabetic nephropathy ESRD ESRD high risk Cardio Vascular Death 65% of people with diabetes die of CVD

Complications of diabetes include Coronary artery disease Peripheral vascular disease

Diabetic nephropathy

Stroke


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Pathogenesis Of

Diabetic Nephropathy

MultifactorialGenetic

Metabolic Factor

Haemodynamic Factors


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Metabolic Hemodynamic

Intracelellular signalling molecules

Growth Factors & Cytokines

Diabetic Complications

Cooper,ME Diabetologis 2001;44:1957

Glucose

Advanced glycationOxidative stress

Flow/pressure

Renin Angiotensin


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Glycemic control

DIABETES MELLITUS

End Stage Renal

Disease

HYPERTENSION

MICROALBUMINURIA

Blood pressure control


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Functional changes*

Natural History of Type 2 Diabetic

Nephropathy

Proteinuria

End-stage ginjal disease

Clinical type 2 diabetes

Structural changes

Rising blood pressure

Rising serum creatinine levels

Cardiovascular death

Microalbuminuria

Onset of

diabetes

2 5 10 20 30

Years

* Kidney size , GFR . GBM thickening , mesangial ekspansion , microvascular changes+/-.


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Normal urinary

albumin

secretion

Proteinuria

End Stage

Renal Disease

(ESRD)

Death

Microalbuminuria

50%

(5-10 years)

20%

(20 year)

40%


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Risk Factors for Cardiovascular Disease

Association with type 2 Diabetes

Specific Non Specific Microalbuminuria

Glycated LDL

Glycated HDL

Hypertriglyceridemia

Small dense LDL

Cardiac autonomic neuropathy

Endothelial dysfunction

Altered fibrinolysis and

thrombosis

Hypertension

Lipids

Decreased HDL

Obesity

Renal failure

Felig P, Froshman LA. Endocrinology and Metabolism 2001;909


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Diabetic Nephropathy(ADA 2006)

Parameter Urine AER Urine AER Albumen

(g/min) (mg/24 h) urine/creat

mg/gr

Normal 300

Diabetes care 2006;29 Suppl:S4-S42


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U-Prot, urinary protein concentration.

Miettinen H et al. Stroke. 1996;27:20332039.

1.0

0.

90.8

0.7

0.6

0.5

00 10 20 30 40 50 60 70 80 90 Stroke CHD

events

P


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0.5

0.6

0.7

0.8

0.9

1

0 1 2 3 4 5 6

Years

Gall MA, et al. Diabetes. 1995;44:1303-9

Normoalbuminuria

Microalbuminuria

Macroalbuminuria

n=191

n=86

n=51

*p


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Cumulativ

eincidenceof ESRD

(%)

0

5

10

15

20

25

30

0 2 4 6 8 10 12 14 16 18 20

Years from diagnosis of persistent proteinuria

ESRD in type 2 diabetes mellitus

Humphrey et al. Ann Int Med1989;111:788-796.


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Screening for microalbuminuria is veryScreening for microalbuminuria is very

important for the following reasons:important for the following reasons:

Microalbuminuria has a prevalence rateMicroalbuminuria has a prevalence rate

ofof30%30% -- 40%40%in patients with diabetes.in patients with diabetes.

Microalbuminuria progresses within 5 toMicroalbuminuria progresses within 5 to

10 years to10 years to overt proteinuria inovert proteinuria in 50%50% ofof

patients with type 2 diabetes.patients with type 2 diabetes.

Microalbuminuria is an indicator ofMicroalbuminuria is an indicator of

vascular injury.vascular injury.


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The bad companions...The bad companions...

Hipertensi is associated witha doublingof the presence of

Microalbuminuria LVH

ECG signs of MI

and a prior historyof overt CV events

Kaplan NM. In Ellenberg and Rifkins DiabetesMellitus: Theory and Practice, 5th ed. 1997.

Coexistence of Hipertension in

Diabetes


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Microalbuminuria in persons aged 50-75 years

Dis Manage Health outcomes 2000;7(5):267-88

25

10

5

15

20

Type 2

DMHiper

tensi

Non

diabeticNormo

tensi

21.3 20.1

7.5

5.8

Type2 DM+

HPT

Type

2 DM

30 31.7

9.6

Preva

lensi(%

)

JNC VI T Bl d P


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Patient Population Target Pressure

Essential Hypertension


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National Kidney Foundation Recommendations on Treatment of

HTN and Diabetes

Blood pressure lowering medicationsshould reduce both blood pressure +proteinuria

Therapies that reduce both bloodpressure and proteinuria have beenknown to reduce renal disease

progression and incidence ofischemic heart disease


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AMERICAN DIABETES ASSOCIATION

(ADA) 2006

Reduce the risk and/or slow theprogression of DN

Optimize Glucose controlBlood pressure control

Reduce the risk of DN protein intake

(0,8 gr/kg).



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T2DM + Hypertension + microalbuminuriaACE inhibitors / ARBs delay the

progression to macroalbuminuria T2DM + Hypertension +macroalbuminuria

and renal insufficiency (serum creatinine

>1.5 mg/dl)

ARBs

delay theprogression of nephropathy

AMERICAN DIABETES ASSOCIATION

(ADA) 2006



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Practice points The earliest sign of renal involvement in

diabetic patients microalbuminuria

In incipient DN+hypertensionaccelerate

development & progression of overt ND ARBs are effective in slowing the

progression of kidney disease with

microalbuminuria due T2DM

Akira YT Wu. In Medical Progress 2005;32: 270274.


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AA PRPRogram forogram for IIrrbesartanbesartan MMortalityortality

and Morbidityand Morbidity EEvaluationvaluation


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Time Course of Type 2 DiabeticRenal Disease

Early Stage Late Stage End Stage

Kidney Disease

IRMA 2 IDNTMicroalbuminuria Proteinuria ESRD

Cardiovascular Morbidity and Mortality

Prevention Protection

PRIME


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The IRbesartan MicroAlbuminuriaType 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 IIreceptor antagonist irbesartan in hypertensive patients with

type 2 diabetes and microalbuminuriaPopulation

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.


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Double-blind Treatment

Up to 5 weeks

Screening/Enrollment

Irbesartan 150 mg*

Irbesartan 300 mg*

Follow-up: 2 years

Control group*

IRMA 2

Study Design

590 pasien hipertensi, type 2 diabetes, microalbuminuria(albumin excretion rate 20200 g/min)

* Adjunctive antihypertensive therapies (excluding ACE inhibitors, angiotensin II receptor antagonists,and dihydropyridine calcium channel blockers) could be added to all groups to help achieve equal bloodpressure levels.

Parving H-H, et al. N Engl J Med2001;345:870-878.


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Placebon=201

Irbesartan150 mg

n=195

Irbesartan300 mg

n=194Mean age (yrs) 58.3 58.4 57.3

Male (%) 68.7 66.2 70.6

Mean Systolic BP (mmHg)Mean Diastolic BP (mmHg)

15390

15390

15391

Mean BMI (kg/m2) 30.3 29.9 30.0

Mean urinary albuminexcretion ( g/min) 54.8 58.3 53.4

Mean serum creatinine (mg/dl)

Menwomen

1.10.9

1.10.9

1.11.0

Mean glycosylated hemoglobin (%) 7.1 7.3 7.1

*The differences between the treatment groups were not statistically significant

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

IRMA 2 Baseline Characteristics


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0

70

130

160

0 3 6 9 12 15 18 21 24 27Months

Mean SeSBP

and SeDBP

(mm Hg)

80

90

100

110120

140

150

Control SeDBP

Irbesartan 150 mgSeDBP

Irbesartan 300 mg

SeDBP

Control SeSBP

Irbesartan 150 mg

SeSBPIrbesartan 300 mg

SeSBP

Blood Pressure Response


Concomitant antihypertensive agents received by 56% of patients in thecontrol group, 45% in the irbesartan 150 mg group, and 43% in the

irbesartan 300 mg group.

IRMA 2


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0

5

10

15

20

0 3 6 12 18 22 24Follow-up (mo)

Subjects

(%)

Control

Irbesartan 150 mg

Irbesartan 300 mg

IRMA 2 Primary EndpointTime to Overt Proteinuria

Parving H-H, et al. N Engl J Med2001;345:870-

878.


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14

18

16

1210

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


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IRMA 2 Normalization of Urinary Albumin Excretion Rate

35

45

40

30

25

20

15

10

50

Subjects(%)

Control

(n=201)

150 mg

(n=195)

300 mg

(n=194)

Irbesartan

24

34

21

P=0.006



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Conclusion IRMA 2

Irbesartan is renoprotective, independent ofits blood pressure-lowering effects 70% risk reduction in the progression from

microalbuminuria to overt diabetic nephropathy withirbesartan 300 mg

Regression to normoalbuminuria was more frequentwith irbesartan 300 mg

Irbesartan is safe and well tolerated Fewer non-fatal CV events, serious AEs, and

discontinuations due to AEs in the irbesartan groups



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Early Stage Late Stage End Stage

Kidney

Disease

IRMA 2 IDNTMicroalbuminuria Proteinuria ESRD

Cardiovascular Morbidity and Mortality

Prevention Protection

PRIME

Time Course of Type 2 DiabeticRenal Disease


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Study Design

1,715 pasien hipertensi, diabetes type 2, danproteinuria 900 mg/hari, creatinine 1.0-3.0 mg/dl

Double-blind Treatment

Up to 5 weeks

Screening/Enrollment

Control group*

Amlodipine*

Minimum follow-up:approximately 2 years

(average follow-up 2.6 years)

Irbesartan*

* Adjunctive antihypertensive therapies (excludingACEinhibitors, angiotensin II receptor antagonists,andcalcium channel blockers) could be added to allgroups to help achieve equal blood pressurelevels.

Lewis EJ et al. N Engl J Med2001;345:851-860.

IDNT B li Ch i i *


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IDNT Baseline Characteristics*Irbesartan

Groupn=579

AmlodipineGroupn=567

PlaceboGroupn=569

Mean age (yrs) 59.3 59.1 58.3

Male (%) 65 63 71

Mean Systolic BP (mmHg)Mean Diastolic BP (mmHg)

16087

15987

15887

Mean BMI (kg/m2) 31.0 30.9 30.5

Median urinary albuminexcretion (g/24hr) 1.9 1.9 1.9

Mean serum creatinine (mg/dl) 1.67 1.65 1.69

Mean glycosylated hemoglobin (%) 8.1 8.2 8.2

Lewis EJ, et al. N Engl J Med. 2001;345(12):851-860.

*The differences between the treatment groups were not statistically significant,except for the smaller number of females in the placebo group (P=0.02)


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IDNT Average Systolic, Mean Arterial andDiastolic Blood Pressures

70

80

90

100

110

120

130

140

150

160

Bloodp

ressure(mmHg

)

Months of Follow-up

0 6 12 18 24 30 36 42 48 54

Irbesartan

Amlodipine

Placebo

Systolic

Mean Arterial Pressure(P=0.001 for both treatment groups compared to

placebo for visits after baseline)

Diastolic

Lewis EJ, et al. N Engl J Med. 2001;345(12):851-860.2001 Massachusetts Medical Society. All rights reserved.

IDNT P i E d i t Ti t D bli f S


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Subjects(%)

0 6 12 18 24 30 36 42 48 54

Follow-up (mo)

60

0

10

20

30

40

50

60

70

IDNT Primary Endpoint :Time to Doubling of SerumCreatinine, ESRD, or Death

Irbesartan

Amlodipine

Control


RRR 20%

P=0.02P=NS

RRR 23%

P=0.006

Primary Composite

end point


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50

40

30

20

10

0Pa

tientsReac

hin

gP

rimary

Comp

osite

Outcom

e(%)

IDNT : Primary EndpointPrimary Endpoint = Doubling Creatinine, ESRD, orall cause mortality

Placebo

(n=569)

Irbesartan

(n=579)

Amlodipine

(n=567)

-23%

(p=0.006)-20%

(p=0.02)



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Subjects (%)

0 6 12 18 24 30 36 42 48 54

Follow-up (mo)

60

0

10

20

30

40

50

60

70

IDNTDoubling Serum Creatinine


Irbesartan

Amlodipine

Control

RRR 33%

P=0.003

P=NS

RRR 37%

P


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IDNTTime to ESRD

Subjects

(%)

Irbesartan

Control +

amlodipine

RRR 23%

P=0.04

0 6 12 18 24 30 36 42 48 54

Follow-up (mo)

60

0

10

30

40

20

Data on file, Bristol-Myers Squibb and Sanofi-Synthelabo.

IDNT


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Subjects(%)

Irbesartan

Amlodipine

Control

RRR 37%

P


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IDNT

SummaryIrbesartan successfully reduced the risk ofprogression of renal disease and total mortality,independent of its blood pressure-loweringeffects 20% reduction in the primary endpoint vs. control

23% reduction vs. amlodipine, despite similar BPreduction

Irbesartan was generally safe and welltolerated


PRIME


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PRIMEConclusions

PRIME is a comprehensive morbidity and/ormortality program in hypertensive patients with type2 diabetes

In IRMA 2, irbesartan prevents or slows theprogression to overt nephropathy in early stagediabetic renal disease

In IDNT, irbesartan protects against further renaldisease progression and death in later stages of

diabetic renal disease The renoprotective effects of irbesartan are above

and beyond its effect on systemic blood pressure



PRIME


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Treating 10 hypertensive patients with type 2diabetes and microalbuminuria with irbesartan 300mg for 2 years would prevent one patient fromdeveloping overt diabetic nephropathy within 2

years Treating 15 hypertensive patients with type 2

diabetes and proteinuria with irbesartan for 3 yearswould preventone patient from developing adoubling of serum creatinine, ESRD or death within3 years

PRIMEClinical Impact


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Summary

The earliest sign of renal involvementin diabetic patientsMicroalbuminuria

90 % Incipient diabetic nephropathyHypertension

Hypertension accelerate develop &progression diabetic nephropathy.


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Irbesartan diabetic hypertension +microalbuminuria (early intervention) overt nephropathy (late intervention):

Incidence ESRD decrease

Prolong of life

Saving of money

Summary

leads to adult obesityleads to adult obesity


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leads to adult obesityleads to adult obesity


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DiscussionDiscussion

In manyIn many tipe-2 diabetes mellitustipe-2 diabetes mellituspatientspatients (>50%),(>50%),microalbuminuriamicroalbuminuria does not represent a real incipientdoes not represent a real incipient

diabetic nephropathy, but only the presence of andiabetic nephropathy, but only the presence of anincreased CV riskincreased CV risk..

Treatment ofTreatment ofirbesartanirbesartan should be consideredshould be considered as anas anintegral component of the overall therapyintegral component of the overall therapy requiredrequired forforCV protectionCV protection..

Table 2. Several principles applicable to clinical practice can be derivedTable 2. Several p

rinciples applicable to clinical practice can be derived


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p p pp pp p pp p

from studies of irbesartan, in patients with diabetes (1)from studies of irbesartan, in patients with diabetes (1)

Patients with type 2 diabetesPatients with type 2 diabetes should beshould be screened forscreened for

microalbuminuriamicroalbuminuria at the time of diabetes diagnosisat the time of diabetes diagnosis

and annually thereafter as per ADA guidelinesand annually thereafter as per ADA guidelines Screening forScreening formicroalbuminuriamicroalbuminuria isis very importantvery important for thefor the

following reasons:following reasons: MicroalbuminuriaMicroalbuminuria has ahas a prevalenceprevalence rate ofrate of3030 toto 40%40%in patients within patients with

diabetes.diabetes.

MicroalbuminuriaMicroalbuminuria is anis an indicatorindicatorof vascularof vascularinjuryinjury..

MicroalbuminuriaMicroalbuminuria progressesprogresses within 5 to 10 yearswithin 5 to 10 years to overt proteinuriato overt proteinuria inin50% of patients with type 2 diabetes.50% of patients with type 2 diabetes.

ProgressionProgression to overt proteinuria can beto overt proteinuria can be reducedreduced byby 70%70% with 300mg ofwith 300mg of

irbesartanirbesartan..




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p p pp pp p pp p


IrbesartanIrbesartan has alreadyhas already provenproven effectiveeffective for the treatment offor the treatment of

hypertension in patients withhypertension in patients with type 2 diabetestype 2 diabetes. Irbesartan has. Irbesartan has

been shown to bebeen shown to be effectiveeffective as a treatment for patients withas a treatment for patients with renalrenal

diseasedisease as well.as well.

TheThe PRIMEPRIME studies havestudies have increasedincreased the knowledgethe knowledge of how bestof how bestto treat diabetic nephropathy or with microalbuminuria whileto treat diabetic nephropathy or with microalbuminuria while

optimally treating hypertension. Recall thatoptimally treating hypertension. Recall that IDNTIDNT, irbesartan, irbesartan

achieved a 23% risk reduction compared with amlodipine on theachieved a 23% risk reduction compared with amlodipine on the

primary endpointprimary endpoint; the composite of :; the composite of : time to a doubling of the baseline serum creatinine level (DSC),time to a doubling of the baseline serum creatinine level (DSC),

the onset of ESRD,the onset of ESRD,

death from any cause.death from any cause.




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p p pp pp p pp p


IrbesartanIrbesartan has demonstratedhas demonstrated therapeutictherapeutic valuevalue atat anyany stagestage ofof

renal disease in patients with diabetes.renal disease in patients with diabetes. CliniciansClinicians shouldshould routinelyroutinely considerconsidertreatmenttreatment with irbesartanwith irbesartan whenwhen

patients present withpatients present with diabetic nephropathydiabetic nephropathy or withor with microalbuminuriamicroalbuminuria..

IrbesartanIrbesartan should beshould be used by cliniciansused by clinicians as first-lineas first-line option in theoption in the

treatment of diabetic nephropathy.treatment of diabetic nephropathy.

AIIRAs are safe and well-tolerated therapy the treatment ofAIIRAs are safe and well-tolerated therapy the treatment of

diabetic nephropathy, anddiabetic nephropathy, and irbesartanirbesartan has been shown to havehas been shown to have

superiorsuperiorefficacyefficacy andand persistencepersistence as compared to other AIIRAs.as compared to other AIIRAs.

IrbesartanIrbesartan, in the treatment of diabetic nephropathy, was, in the treatment of diabetic nephropathy, was

independentindependent of blood pressure lowering.of blood pressure lowering.




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p p pp p


IrbesartanIrbesartan, in the treatment of diabetic nephropathy, was, in the treatment of diabetic nephropathy, was

independentindependent of blood pressure lowering.of blood pressure lowering. AIIRAs, such asAIIRAs, such as irbesartanirbesartan, have value, have value beyondbeyond being an anti-being an anti-

hypertensive.hypertensive.

The AIIRA,The AIIRA, irbesartanirbesartan could be used in the treatment of diabeticcould be used in the treatment of diabetic

nephropathynephropathy regardlessregardless of any concomitantof any concomitant hypertensionhypertension..

TheThe PRIMEPRIME studies highlight thestudies highlight the discrepancydiscrepancy betweenbetween

recommendations andrecommendations and realityreality in diabetic nephropathy treatment.in diabetic nephropathy treatment.

AIIRAs may help to combat the growing trend that showsAIIRAs may help to combat the growing trend that shows

diabetic nephropathydiabetic nephropathy to be on theto be on the increaseincrease, globally., globally.

TheThe PRIMEPRIME results haveresults have importantimportant health economic implicationshealth economic implications

implying that increased AIIRA use will bringimplying that increased AIIRA use will bring massive savingsmassive savings toto

society-cost savings ofsociety-cost savings of$ 2.5 billion$ 2.5 billion withinwithin 3 years3 years..


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FERDINANDO C. SASSO, et al.,FERDINANDO C. SASSO, et al., Diabetes CareDiabetes Care 25:19091913, 200225:19091913, 2002

OBJECTIVEOBJECTIVE


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OBJECTIVEOBJECTIVE

ACE-isACE-is delaydelay the progressionthe progressionfrom incipient to overtfrom incipient to overt

diabetic nephropathy anddiabetic nephropathy and reducereduce albumin excretionalbumin excretionrate (rate (AERAER),), independentlyindependently of blood pressure.of blood pressure.

A-II type 1 receptor antagonists produceA-II type 1 receptor antagonists produce similarsimilareffectseffects on MAU and mean arterial pressure.on MAU and mean arterial pressure.

The aim of this study was to evaluate the effect ofThe aim of this study was to evaluate the effect of

irbesartanirbesartan on MAUon MAU and blood pressureand blood pressure ininhypertensivehypertensiveandandnormotensivenormotensive type 2 diabetictype 2 diabeticpatients.patients.

RESEARCH DESIGN AND METHODSRESEARCH DESIGN AND METHODS


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RESEARCH DESIGN AND METHODSRESEARCH DESIGN AND METHODS

Sixty-four MAUSixty-four MAU hypertensivehypertensive (group 1)(group 1) and 60 MAUand 60 MAU

normotensivenormotensive (group 2)(group 2) type 2 diabetic maletype 2 diabetic malepatients, matched for age, BMI, HbA1c, andpatients, matched for age, BMI, HbA1c, and

diabetes duration, were enrolled.diabetes duration, were enrolled.

Each group was divided intoEach group was divided into two subgroupstwo subgroupsreceiving either irbesartan (150 mg b.i.d. orally) orreceiving either irbesartan (150 mg b.i.d. orally) or

placebo for 60 days.placebo for 60 days.

AfterAfter15 days of washout,15 days of washout, irbesartan was given toirbesartan was given tothe subgroupsthe subgroups whowho had receivedhad received the placebo, andthe placebo, andvice versavice versa, in a randomized double-blind, in a randomized double-blind crossovercrossover

study.study.


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ADA Guidelines

Patients with type 2 diabetesPatients with type 2 diabetesshould be screenedshould be screened forfor

microalbumin uria at the time ofmicroalbumin uria at the time ofdiabetes diagnosis anddiabetes diagnosis and

annually thereafterannually thereafter

The 24-h meanThe 24-h mean systolicsy

stolic BP in Diabetic patientsBP in Diabetic pa

tients


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y p

In hypertensive,In hypertensive,was significantly reduced (P


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Figure 2Figure 2AER in the two subgroups of normotensive (AER in the two subgroups of normotensive (AA) and hypertensive () and hypertensive (BB))diabetic subjects. *diabetic subjects. *P


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RESULTSRESULTS

In MAUIn MAU hypertensivehypertensive type 2 diabetic subjects,type 2 diabetic subjects,

irbesartanirbesartan reducedreduced 24-h24-h mean systolic and diastolicmean systolic and diastolicpressurepressure andand AERAER..

In MAUIn MAU normotensivenormotensivetype 2 diabetic patients,type 2 diabetic patients,

irbesartanirbesartan reducedreduced AERAER..

CONCLUSIONSCONCLUSIONS

These results indicate theThese results indicate the beneficial effects ofbeneficial effects ofirbesartan on AERirbesartan on AER in type 2 diabetic subjects,in type 2 diabetic subjects,independentlyindependently of its antihypertensive effects.of its antihypertensive effects.

I b t l ti bl k d f th A II t 1


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IrbesartanIrbesartan, selective blockade of the A-II type 1, selective blockade of the A-II type 1receptor :receptor :

ComparableComparable to ACE-Is in lowering BP and MAU.to ACE-Is in lowering BP and MAU. The beneficial effect :The beneficial effect :

ofofblocking A-IIblocking A-II generated bygenerated by nonACEnonACE pathwayspathways withoutwithout altering eitheraltering eitherbradykininbradykinin metabolismmetabolism

the potentialthe potential beneficial effects ofbeneficial effects ofAT2AT2 receptorreceptorstimulationstimulation.. AT2 receptor stimulation causesAT2 receptor stimulation causes

vasodilatation, inhibits cell proliferation,vasodilatation, inhibits cell proliferation, andand

promotespromotes cell differentiationcell differentiation throughthroughproduction of :production of : bradykinin, NO,bradykinin, NO, andand cGMPcGMP..

I b t fl ti bl k d f th A II t 1


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IrbesartanIrbesartan, selective blockade of the A-II type 1, selective blockade of the A-II type 1

receptor :receptor : Has doubleHas double antiproliferativeantiproliferative effect, botheffect, both direct AT1direct AT1

receptor mediated andreceptor mediated and indirect AT2indirect AT2 receptorreceptor

mediated AT1-RAs couldmediated AT1-RAs could protectprotect againstagainst mesangialmesangialexpansionexpansion..

Moreover, irbesartan seems toMoreover, irbesartan seems to decreasedecrease AERAER evenevenin ain a prehypertensiveprehypertensive phasephase.. The effect ofThe effect ofirbesartanirbesartan on MAU, even inon MAU, even in

normotensivenormotensive type 2 diabetic subjects, suggests thattype 2 diabetic subjects, suggests that

thethe nephroprotectionnephroprotection brought about by AT1-RAbrought about by AT1-RAcould be caused by thecould be caused by the directdirect actionaction on renalon renalhemodynamics andhemodynamics and glomerular morphologyglomerular morphology..

Potential Impact of IRBESARTAN on


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IDNT was powered for renal primary endpoints IDNT was not powered for composite CV secondary endpoint or its

components

Compared to amlodipine or other antihypertensive therapies, irbesartan wasshown to provide superior renoprotection and comparablecardiovascular protection benefits

The renoprotective benefits, shown to be independent of blood pressure,were statistically significantly superior to either amlodipine based orplacebo treatments,

Irbesartan isthe clear choice as the treatment of greatest benefit in type 2hypertensive diabetics

Potential Impact of IRBESARTAN onReal Life Clinical Practice


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Selecting an appropriateSelecting an appropriate

drug isdrug is more importantmore importantthan lowering bloodthan lowering blood

pressure per se.pressure per se.

Thank youThank you

I t f Bl d P R d ti


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Impact of Blood Pressure Reductionon Mortality in Diabetes

Trial Conventionalcare

Intensivecare

Riskreduction

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;351:17551762.

Mortality endpoints are:

UK Prospective Diabetes Study (UKPDS) diabetes related deaths

Hypertension Optimal Treatment (HOT) Study cardiovascular deaths in diabetics

Chronic Renal Disease:


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Renal InsufficiencyClcr 1.4 mg/dL*

Renal InsufficiencyClcr 1.4 mg/dL*

Microalbuminuria(only Abnormality)

Microalbuminuria(only Abnormality)

Diabetes MellitusDiabetes Mellitus

ACE Inhibitor

or ARBStartAnd

TitrateTo Maximum

TolerableDose

ACE Inhibitor

or ARBStartAnd

TitrateTo Maximum

TolerableDose

130/80130/80

130/80130/80

ProteinuriaProteinuria

*for women, CRSerum >1.2 mg/dL

Chronic Renal Disease:

Initial Treatment Recommendations

PRIME


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IRMA 2 To determine whether irbesartan can prevent or slow

the progression from microalbuminuria to overtnephropathy in patients at an early stage of type 2

diabetic renal disease

IDNT To compare the effects of irbesartan, amlodipine, and

a control group on renal disease progression, totalmortality, and cardiovascular morbidity in patients at alater stage of type 2 diabetic renal disease

Objectives

prime eies 06

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