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Harsinen Sanusi
Division of Endocrinology &
Metabolic Department of Internal
Medicine Faculty of Medicine
Hasanuddin University Dr Wahidin
Sudirohusodo Hospital Makassar
MICROALBUMINURIA
Structural changes†
Proteinuria
Cardiovascular death
Onset of 2 5 10 20 30
diabetes
Years
* Kidney size , GFR
†
GBM thickening , mesangial ekspansion , microvascular
changes +/-.
Normal urinary
albumin
secretion
Microalbuminuria 40%
50%
Proteinuria (5-10 years)
20%
(20 year)
End Stage
Renal Disease
(ESRD)
Death
Risk Factors for Cardiovascular Disease
Association with type 2 Diabetes
1. 40
0 P<0.001
0.
9 30
Survival 0.8 A
curves B Incidence
for CV 0.7 (%) 20
mortality
0.6
C 10
0. Overall: P<0.001
5
0 0
0 10 20 30 40 50 60 70 80 90 Stroke CHD
Months events
U-Prot, urinary protein concentration.
Miettinen H et al. Stroke. 1996;27:2033–2039.
Albuminuria and Mortality in
NIDDM
1 Normoalbuminuria
n=191
0.9 Microalbuminuria
Survival
0.8 n=86
Macroalbuminuria
0.7
* n=51
0.6
*p<0.05: normo. vs. micro. and macroalbuminuria
0.5
0 1 2 3 4 5 6
Years
25
Cumulativ 20
e
incidence 15
of ESRD
(%) 10
0 2 4 6 8 10 12 14 16 18 20
Years from diagnosis of persistent proteinuria
ECG signs of MI
Microalbuminuria LVH and a prior history
of overt CV events
Kaplan NM. In Ellenberg and Rifkin’s Diabetes
Mellitus: Theory and Practice, 5th ed. 1997.
30 31.7
25
20 21.3 20.1
Prevalensi (%)
15
10 9.6
7.5
5 5.8
Recommendations
PRIME
Prevention Protection
IRMA 2 IDNT
Microalbuminuria Proteinuria ESRD
Cardiovascular Morbidity and Mortality
Kidney Disease
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 2
Study Design
20
Control
Irbesartan 150 mg
15 Irbesartan 300 mg
Subjects
(%)
10
0
0 3 6 12 18 22 24
Follow-up (mo)
PRIME
Prevention Protection
IRMA 2 IDNT
Microalbuminuria Proteinuria ESRD
Kidney
Disease
IDNT
Study Design
• 1,715 pasien hipertensi, diabetes type 2, dan
proteinuria 900 mg/hari, creatinine 1.0-3.0 mg/dl
Control group*
Up to 5 weeks
Amlodipine*
* Adjunctive antihypertensive therapies (excluding
ACE Minimum follow-up:
inhibitors, angiotensin II receptor antagonists, approximately 2 years
and
calcium channel blockers) could be added to all (average follow-up 2.6 years)
groups to help achieve equal blood pressure
levels.
*The differences between the treatment groups were not statistically significant,
except for the smaller number of females in the placebo group (P=0.02)
140
Blood pressure (mmHg)
130
Irbesartan
120 Mean Arterial Pressure Amlodipine
(P=0.001 for both treatment groups compared to Placebo
110 placebo for visits after baseline)
100
90 Diastolic
80
70
0 6 12 18 24 30 36 42 48 54
Months of Follow-up
Lewis EJ, et al. N Engl J Med. 2001;345(12):851-860.
©2001 Massachusetts Medical Society. All rights reserved.
IDNT Primary Endpoint :Time to Doubling of Serum
Creatinine, ESRD, or Death
70
Irbesartan
RRR 23%
60 P=0.006
RRR 20%
Amlodipine P=0.02
50 P=NS
Control
Subjects
(%) 40
30
20
Primary Composite
10
end point
0
0 6 12 18 24 30 36 42 48 54 60
Lewis EJ et al. N Engl J Med 2001;345:851-860. Follow-up (mo)
IDNT : Primary Endpoint
Primary Endpoint = Doubling Creatinine, ESRD, orall cause mortality
50
-23%
Composite
-20% (p=0.006)
Patients Reaching Primary
(p=0.02)
40
Outcome (%)
30
20
10
0
Placebo Irbesartan Amlodipine
(n=569) (n=579) (n=567)
Irbesartan
60 RRR 37%
P<0.001 RRR 33%
Amlodipine P=0.003
50 P=NS
Subject 40 Control
s (%)
30
20
10
0
0 6 12 18 24 30 36 42 48 54 60
Irbesartan
RRR 23%
30 Control +
P=0.04
Subjects amlodipine
(%)
20
10
0
0 6 12 18 24 30 36 42 48 54 60
Follow-up (mo)
Data on file, Bristol-Myers Squibb and Sanofi-
Synthelabo.
IDNT
Time to CHF
30
Irbesartan
RRR 37%
P<0.001
Amlodipin RRR 23%
P=0.15
e
20
Subjects Control
(%)
10
0
0 6 12 18 24 30 36 42 48 54 60
Follow-up (mo)
Lewis EJ et al. N Engl J Med 2001;345:851-860.
Data on file, Bristol-Myers Squibb and Sanofi-
Synthelabo.
IDNT
Summary
Irbesartan successfully reduced the risk of
progression of renal disease and total
mortality, independent of its blood pressure-
lowering effects
– 20% reduction in the primary endpoint vs. control
– 23% reduction vs. amlodipine, despite similar BP
reduction
In normotensive,
• Subgroup 1, irbesartan 6 mmHg, placebo 3 mmHg,
• Subgroup 2, irbesartan 1 mmHg, placebo 3 mmHg.
In normotensive,
• Subgroup 1, irbesartan 1 mmHg, placebo 1 mmHg,
• Subgroup 2, irbesartan 1 mmHg, placebo 0 mmHg.
Figure 2—AER in the two subgroups of normotensive (A) and hypertensive (B) diabetic subjects. *P<0.01.
RESULTS—
Of the 124 patients were randomized. AER was significantly reduced (P<0.01)
in :
• Hypertensive
• in subgroup 1, irbesartan 36 g/min, placebo 5 g/min,
• in subgroup 2, irbesartan 35 g/min, placebo 3 g/min.
• Normotensive
• in subgroup 1, irbesartan 31 g/min, placebo 2 g/min,
• in subgroup 2, irbesartan 40 g/min, placebo 5 g/min.
RESULTS—
CONCLUSIONS—
Thank you
Impact of Blood Pressure Reduction
on Mortality in Diabetes
Conventional Intensive Risk
Trial P-value
care care reduction
UKPD
154/87 144/82 32% 0.019
S
HOT 144/85 140/81 66% 0.016
Renal Insufficiency
Clcr <60 mL/min 130/80
CrSerum >1.4 mg/dL*
ACE Inhibitor
or ARB
Microalbuminuria Start
(only Abnormality) 130/80 And
Titrate
To Maximum
Proteinuria Tolerable
Dose
Diabetes Mellitus
*for women, CRSerum >1.2 mg/dL
PRIME
Objectives
• IRMA 2
– To determine whether irbesartan can prevent or slow
the progression from microalbuminuria to overt
nephropathy 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, total
mortality, and cardiovascular morbidity in patients at a
later stage of type 2 diabetic renal disease