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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).
Diabetes care 2006;29 Suppl:S4-S42
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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
Diabetes care 2006;29 Suppl:S4-S42
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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
Parving H-H, et al. N Engl J Med2001;345:870-878.
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
Parving H-H, et al. N Engl J Med2001;345:870-878.
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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
Parving H-H, et al. N Engl J Med2001;345:870-878.
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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
Lewis EJ et al. N Engl J Med2001;345:851-860.
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)
Lewis EJ et al. N Engl J Med2001;345:851-860.
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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
Lewis EJ et al. N Engl J Med2001;345:851-860.
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
Lewis EJ et al. N Engl J Med2001;345:851-860.
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
Parving H-H, et al. N Engl J Med2001;345:870-878.
Lewis EJ et al. N Engl J Med2001;345:851-860.
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..
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 (2)from studies of irbesartan, in patients with diabetes (2)
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.
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 (3)from studies of irbesartan, in patients with diabetes (3)
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.
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 p
from studies of irbesartan, in patients with diabetes (4)from studies of irbesartan, in patients with diabetes (4)
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..
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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
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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
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