microalbuminuria is early sign of general vasculopathy and hurbinger of ESRD, the significance of microalbuminuria in diabetic and hypertensive patients is risky sign for further cardiovascular diseases, in this discussion I aimed to discuss the therapeutic approach for these patients
5. 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)
*Components of the metabolic syndrome.
JAMA 2003:289:2560
6. Definition of Adversal Albumin
Excretion
Measure Normoalbuminuria Microalbuminuria Macroalbuminuria
Albumin <30 mg/24 hours 30-300 mg/24hours >300 mg/24 hours
excretion rate* <20 μg/minute 20-200 μg/minute >200 μg/minute
<30 mg/g creatinine 30-300 mg/g creatinine >300 mg/g creatinine
Albumin-to-
creatinine ratio** Male <2.5 mg/mmol Male 2.5-30 mg/mmol
≥30 mg/mmol
Female < 3.5mg/mmol Female 3.5-30 mg/mmol
*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
8. 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
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.
9.
10. Correlation Coefficient between
micoalbuminoria and different parameters
Parameters r P
Blood pressures:
Systolic BP 0.678 <0.01
Diastolic BP 0.133 NS
Blood Glucose:
FBS 0.201 <0.05
PPBS 0.218 <0.05
Lipogram:
T.Cholesterol 0.443 <0.05
Triglycerides 0.179 NS
HDL – C -0.319 <0.05
LDL – C 0.134 NS
11. Albuminuria and CV Diseases: the LIFE
Study
40 8,029 subjects with hypertension and LV hypertrophy,
mean age 66 years
Normoalbuminuria
30 Microalbuminuria (Alb/Crea >3.5 mg/mmol)
Prevalence (%)
Macroalbuminuria (Alb/Crea >35 mg/mmol)
20
10
0
Diabetes Cerebrovascular Peripheral Coronary
disease vascular vascular
disease disease
Wachtell et al. J Hypertens 2002;20:405–12
12. Microalbuminuria Compared To Traditional Risk
Factors For Ischemic Heart Disease
3
N=2,085; 10 year follow-up
2.5
Relative Risk
2
1.5
1
l
a
g
BP
r
o
0.5 de
in
i
er
ur
ok
ic
en
st
in
ol
Sm
e
m
G
st
ol
bu
e
Ch
Sy
al
al
M
al
ro
t
ic
To
M
Borch-Johnsen K, et al.
Arterioscler Thromb Vasc Biol. 1999;19(8):1992-1997.
13. 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 1.49
Diabetes Mellitus 1.42
Male 1.20
Age 1.03
Waist-Hip Ratio 1.13
Mann JFE, et al. Ann Intern Med. 2001;134(8):629-636.
14. Low Levels of MAU are Predictive of CAD and
Death
CHD incidence CHD mortality
Cumulative CHD incidence (%)
UAE ≥ 4.8μg/min
Cumulative mortality (%)
30 30
20 20
UAE ≥ 4.8μg/min
10 10
UAE < 4.8μg/min
UAE < 4.8μg/min
0 0
0 2 4 6 8 10 12 0 2 4 6 8 10 12
Years from entry Years from entry
Cox-estimated age-adjusted curves of cumulative coronary Cox-estimated age-adjusted curves of cumulative mortality for
heart disease (CHD) for a 60-year-old person based on 1734 a 60-year-old person based on 1734 hypertensive subjects with
hypertensive subjects with microalbuminuria (UAE ≥ microalbuminuria
4.8µg/min; n=522) and normoalbuminuria (UAE < 4.8µg/min; (UAE ≥ 4.8µg/min; n=522) and normoalbuminuria
n=1212; P<0.001). (UAE < 4.8µg/min; n=1212; P<0.001).
Klausen et al., Hypertension. 2005; 46:33-37
15. Cardiovascular Events by Degree of Albuminuria in
HOPE
30
All participants Microalbuminuria
threshold
With diabetes
25
Without diabetes
20
Incidence (%)
15
10
5
0
1&2 3 4 5 6 7 8 9 10
Albumin/creatinine Ratio Deciles
Gerstein et al. JAMA 2001;286:421-6.
16. 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
17. 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)
18. Detection of Microalbuminuria
(American Diabetes Association)
Exclusion of artefacts
(exercise, urinary infections, fever etc.)
Microalbuminuria ?
(> 30 mg/24 h; > 20 g/min; > 20 mg/l; > 2 mg/mmol creatinine)
yes no
no
2 of 3 Repeat
Repeat 2 x in 3 months
positive tests at 1 y
yes
Diagnosis of microalbuminuria
start management
ADA. Diabetes Care 1996; 19:S103-S105
21. Hypertension Has a High Prevalence That Is
Expected To Rise Over the Coming Decades
50
with Hypertension
40.7
37.4 37.2
39.1 Men
40 35.3 34.8
Women
% Population
30 26.9 28.3
23.7 22.6
20.6 20.9 22
19.7
20 17
14.5
10
0
50 45.9 44.5
41.642.5
with Hypertension
39.1 40.2
40
% Population
30 27 27.7 27 27 28.2
22.9 23.6 24
18.8
20 17.1
2025
10
0
Hypertension is an important public health challenge worldwide.
Prevention, detection, treatment and control should receive high priority
Kearney PM, et al. Lancet 2005; 365:217–223
22. Hypertension Burden on Healthcare
Worldwide, hypertension is responsible for
62% of strokes1
49% of heart attacks1
Hypertension is the third leading risk factor for disease
Causes 7.1 million premature deaths each year1
4.5% of global burden of disease1
Hypertension represents a high burden on healthcare
expenditure
In 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, 2004
2.AHA. Heart Disease and Stroke Statistics -- 2004 Update
23. Elevated Blood Pressure Increases the Risk of
Cardiovascular Disease
Stroke CAD
4.00 4.00
2.00 2.00
Relative Risk
Relative Risk
1.00 1.00
0.50 0.50
0.25 0.25
123 136 148 162 175 123 136 148 162 175
76 84 91 98 85 76 84 91 98 85
Approximate mean usual BP Approximate mean usual BP
Collins R et al. Br Med Bull 1994;50: 272–298
24. 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
25. MAU is a Predictor of Ischemic Heart Disease
in Hypertensive Patients
Proportion without ischemic
100
heart disease (%)
95
Normoalbuminuria
90
85
80
75 Microalbuminuria
(UA/Cr ratio > 1.07 mg/mmol)
70
0 1 2 3 4 5 6 7 8 9 10
Years
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.
Jensen et al., Hypertension.2000;35:898-903
26. MAU Reduction in Hypertensive Patients is
Accompanied by CV Event Reduction
Analysis from LIFE trial
Fraction suffering CEP
0.20
High baseline/high year 1
0.15
High baseline/low year 1
0.10
Low baseline/high year 1
Low baseline/low year 1
0.05
0.00
0 10 20 30 40 50 60 70
Time (months)
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
27. Risk of Ischemic Heart Disease
Related to SBP and Microalbuminuria
N=2,085; 10 year follow-up
6
5
Relative Risk
Normoalbuminuria Microalbuminuria
4
3
2
1
0
SBP <140 SBP 140-160 SBP>160
Borch-Johnsen K, et al. Arterioscler Thromb Vasc Biol. 999;19(8):1992-1997. With permission
from Lippincott Williams & Wilkins.
28. 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.”
1ESH/ESC guidelines, Journal of hypertension 2003,21:1011-1053; 2 The JNC 7 Hypertens.2003;42:1206-1252
29. 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.
32. The Diabetes Epidemic
189 mill. in 2003
324 mill. Estimated for 2025
72% increase
38.2
44.2
16% 81.8
25.0 156.1
39.7 91%
59%
18.2
35.9
13.6 97%
26.9
10.4 98%
19.7
1.1
88%
1.7
59%
From Zimmet P et al. Diabet Med. 2003;20:693-702.
33. Type 2 diabetes increases the risk of
cardiovascular disease
No diabetes n = 342,815
Rates (per 10,000 person-year)
Diabetes n = 5,163
75
50
25
0
Relative Total CVD CHD Stroke Other
risk 3.0 3.2 2.8 CVD
2.3
Adjusted for age, race, income, cholesterol, systolic blood pressure, smoking
34. The presence of diabetes was associated with a
higher CHD risk in the VA-HIT placebo group
age-adujested 5 year incidence of major cardiovascular events
in the VA-HIT palcebo groupby dlucose group
40% 36.5%
cumulative event rate %
34.3%
30% 23.8
21 %
%
20%
10%
0%
normal Impaired Undiagnos Diagnosed
fasting ed diabetes
glucose diabetes
35. Association of Systolic Blood Pressure
(SBP) and CV Death in Type 2 Diabetes
250
225 No diabetes
Diabetes
200
(deaths/10,000 person-years)
175
CV Mortality
150
125
100
75
50
25
0
120 120–139 140–159 160–179 180–199 200
SBP (mm Hg)
Adapted from Stamler J et al. Diabetes Care. 1993;16:434-444.
36. Proteinuria levels predict stroke
and CHD events in type 2 diabetes
Survival curves
(CV mortality) Incidence (%) p < 0.001
1.0 40
< 150
0.9
30
0.8
150-300
0.7 20
0.6
> 300 10
0.5
Overall: p < 0.001
0 0
0 10 20 30 40 50 60 70 80 90 Stroke CHD events
Time (months)
U-Prot < 150 mg/L U-Prot 150-300 mg/L U-Prot > 300 mg/L
7-year follow-up of 1,056 patients with type 2 diabetes with or without hypertension
Miettinen H et al. Stroke 1996;27:2033–9. U-Prot = Urinary protein concentration
38. Relative prognostic value of MAU
in type 2 diabetes
10
10
8
6.5
Mortality 6
from CHD
(odds ratio)
4
3.2
2.3
2
0
MAU Smoking Diastolic BP Cholesterol
Eastman RC, Keen H. Lancet 1997;350(Suppl 1):29–32.
41. Effective Blood Pressure Control Reduces
Cardiovascular Morbidity and Mortality
Systolic-diastolic hypertension Isolated-systolic hypertension
Fatal and non Fatal and non
Mortality Mortality
10 fatal events fatal events
All All
Stroke CHD Causes CV Non CV Stroke CHD Causes CV Non CV
0
NS
-10
NS
<0.01 <0.01 0.02
-20
<0.001 0.01
<0.001
-30
<0.001
-40
Event reduction in patients on active antihypertensive
<0.001
-50 treatment versus placebo or no treatment.
CHD: coronary heart disease; CV: cardiovascular
ESH/ESC Guidelines. J Hypertens 2003; 21:1779–1786.
42. UKPDS Relative Risk Reduction for
Intensive vs Less Intensive Glucose Control
0
-10 -12
-16 P=0.03
-21 P=0.05
-20
-25 P=0.02
P<0.01
-30 -33
P<0.01
-40 Microalbuminuria at 12 yrs Microvascular complications
Retinopathy Myocardial Infarction
Any DM endpoint
-50
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).
UKPDS Group. Lancet. 1998;352:837-853.
43. HOT-Study: Optimal blood pressure in
hypertensive and diabetics (Type II)
HOT = Hypertension Optimal Treatment
30
Serious cardiovascular
25
events/1000 pat.years
20
- 51% risk reduction
15
10
5
90 85 80
0
mm Hg diastolic target blood pressure
Hypertensive diabetics profit most from stringent
blood pressure control
Hansson L at al. Lancet 1998; 351:1755-1762
44. 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
45. 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.
46. JNC 7 - Algorithm for treatment of
hypertension
Lifestyle modifications
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 Hypertension with compelling indications
indications
Stage 1 hypertension (SBP 140-159 Stage 2 hypertension (SBP ≥160 mmHg Drug(s) for compelling
or DBP 90-99 mmHg) or DBP ≥100 mmHg) indications
Thiazide-type diuretics for most 2-drug combination for most (usually Other antihypertensive drugs
May consider ACE inhibitor, ARB, thiazide-type diuretic and ACE (diuretics, ACE inhibitor, ARB,
-blocker, CCB, or combination inhibitor or ARB or -blocker or CCB) -blocker, CCB) as needed
Not at goal BP
Optimize dosages or add additional drugs until goal BP is achieved
Consider consultation with hypertension specialist
JNC 7 VII, Hypertens. 2003;42:1206-1252.
47. Start ACE inhibitor
BP still not
Blood pressure
titrate upwards at goal
>130/80 mm Hg
(130/80 mm Hg)
If BP still not Add Thiazide Diuretic
Baseline pulse 84 at goal or
(130/80 mm Hg) long-acting CCB*
If BP goal achieved, convert to fixed dose
Add low-dose beta blocker combinations (ACE inhibitor + CCB or ACE
or alpha/beta blocker Baseline pulse <84 inhibitor + diuretic)
Add other subgroup of CCB
BP still not at goal (ie, amlodipine-like agent if verapamil or
(130/80 mm Hg) diltiazem already being used and the
converse)
*If proteinuria present
(>300 mg per day) non-
DHP preferred. Refer to a
clinical hypertension specialist
Reprinted from Bakris GL, et al. Am J Kidney Dis. 2000;36(3):646-661 with permission from National Kidney
Foundation.
49. Importance of Long-Term BP-Control for
MAU-Reduction
SBP reduction leads to MAU-reduction
1.00
Cumulative hazard risk in
0.75
developing MAU
0.50
>139 mmHg
0.25
130–139 mmHg
<130mmHg
0.00
0 5 10 15
Time of follow-up
Pascual et al.,Hypertension. 2005;45:1132-1137
50. The RAS showing ACE and non-ACE
pathways
ACE PATHWAY NON-ACE PATHWAY
(< 30%) (> 70%)
Angiotensinogen
Chymase
Renin
Tonin
Angiotensin I Cathepsin
Kallikrein
ACE
Angiotensin
McConnaughey et al. J Clin Phamacol 1999;39: 547–59.
51. Angiotensin II Formation
Alternate
Pathways*
Angiotensinogen
Renin
Angiotensin I CAGE t-PA
ACE Cathepsin G Cathepsin G
Chymase Tonin
Angiotensin II
Angiotensin II Receptors
*The clinical significance of alternate pathways is unknown.
Dzau VJ et al. J Hypertens. April 1993;11(suppl):S13-S18.
52. Mechanism of Action of Angiotensin II
Receptor Blockers (ARBs)
Angiotensinogen
Renin
Angiotensin I
Bradykinin
ACE Non-ACE enzymes
Inactive (cathepsin, chymase)
Fragments Angiotensin II
ARBs
AT1 Receptor AT2 Receptor
Na reabsorption
Aldosterone release Vasodilation
Blood Pressure Sympathetic outflow Growth
Vasopressin secretion inhibition
Vasoconstriction Apoptosis
Vascular and cardiac hypertrophy
Adapted from Unger T. Am J Cardiol 2002; 89 (suppl):3A-10A.
53. Angiotensin II effects at the AT1 and AT2
receptors
Angiotensin
II
-sartan
AT1 Receptor AT2 Receptor
Vasoconstriction
Activate sympathetic activity
Antiproliferation
Apotosis
Increase sodium retention Endothelial cell growth
Increase vasopressin release
Vasodilation (NO mediated?)
Promote myocyte hypertrophy and proliferation Stimulate renal bradykinin and NO
Stimulate vascular and cardiac fibrosis
Stimulate plasminogen activator inhibitor 1
Stimulate superoxide formation
Adapted from McConnaughey et al. J Clin Phamacol 1999;39: 547–59.
54. 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
55. ACE-I Provides Greater Renoprotection
Than Non-ACE-I in Patients with
Diabetic and Non-Diabetic Nephropathy
Conclusions about
Study Year
ACE inhibitors (ACE-I)
ACE-I reduced both the rate of decline in GFR and the
Bjork et al 1992 amount of albuminuria.
In Type I diabetics, ACE-I reduced proteinuria, risk of
Lewis et al 1993 doubling serum creatinine, and risk of ESRD+Death.
But, ESRD alone was not reduced.
In non-diabetics, ACE-I reduced proteinuria, risk of
REIN 1997 doubling serum creatinine, and risk of ESRD+Death.
But, ESRD alone was not reduced.
ACE-I reduced progression of proteinuria from
MicroHOPE 2000 normoalbuminuria to microalbuminuria and from
microalbuminuria to macroalbuminuria.
ACE-I was superior to amlodipine in reducing
AASK 2001 proteinuria among non-diabetic African Americans with
hypertension and kidney disease.
56. Albumin excretion rate in hypertensive diabetic patients
treated with lercanidipine or ramipril.
Lercanidipine
P<0.05
Ramipril
P<0.05
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
Dalla Vestra M et al, Diab Nutr Metab, 2004
57. 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
58. ARB (Losartan) Reduces Urinary Albumin and
TGF-1 in Type 2 Diabetes with
Microalbuminuria
160 100
24-hour Systolic BP Urinary Albumin Excretion
90
P<0.01 vs baseline P<0.01 vs baseline
mcg/min
140 80
mmHg
70
130
60
120 50
90 6
24-hour Diastolic BP TGF-
P<0.03 vs baseline 5 P<0.005 vs baseline
80
ng/mL
mmHg
4
3
70
2
60 1
Baseline 4 Weeks 8 Weeks Baseline 4 Weeks 8 Weeks
Esmatjes E, et al. Nephrol Dial Transplant.
2001;16(Suppl1):90-93.
59. 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
60. 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.
63. 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)†
*Neither the initial nor long-term decline differed significantly among the 3 groups
† Compared to placebo
Parving HH, et al. N Engl J Med. 2001;345(12):870-878.
64. IRMA II
Adverse outcomes
No. of adverse outcomes (%)
Irbesartan Irbesartan
Control (150 mg) (300 mg)
Cardiovascular events 18 (8.7) 14 (6.9) 9 (4.5)
Serious adverse events 47 (22.8) 32 (15.8) 30 (15.0)
Discontinuations 19 (9.2) 18 (8.9) 11 (5.5)
due to adverse events
Parving H-H et al. N Engl J Med 2001;345:870–78.
65. IRMA II
Summary 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.
66. 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
67. Time to Doubling of Serum Creatinine, ESRD, or Death
IDNT Primary Endpoint
RRR 23%
60 P=0.006 23%
RRR 20%
50 P=NS
P=0.02 RRR
P=0.006
Subjects
(%) 40
30
Irbesartn
20
Amlodipie
10
Control
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.
68. RECOMMENDATIONS FOR THERAPY
SUMMARY
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
JNC 7 Report. JAMA 2003; 289: 2560-2572
ESH/ESC Guidelines. J Hypertens 2003; 21: 1011-1053
Guidelines Sub-Committee. 1999 WHO/ISH. J Hypertens 1999; 17:151–183