1. The evolving role of Microalbuminuria (MAU)
MAU as an early and reliable marker of organ damage
and a strong predictor of cardiovascular risk

2. Oxidative Stress: Endothelial
Dysfunction and CAD/Renal Risk Factors
Smoking LDL Homocysteine Estrogen
Hypertension Diabetes
deficiency
 O2 Endothelial Cells and
 H2O2 Vascular Smooth Muscle
Endothelial Dysfunction
Lipid VSMC Thrombosis
Apoptosis
Leukocyte deposition growth
adhesion Vasoconstriction

3. Pathologic Processes Leading to Glomerular
Injury and Proteinuria
Glucose Urinary protein
Glycoxidation
(glycation)
AGEs =angiotensin AT1
receptor
Increased
glomerular Efferent
pressure arteriolar
constriction
Ang II Ang II

4. Pathways Leading To
Progressive Renal Failure
Renal injury
Renal growth factor &
cytokine activation Systemic
Nephron mass hypertension
Filtration of plasma
Glomerular hypertension proteins
(Proteinuria)
Transdifferentiation of Progressive Loss of
renal cells to fibroblast Filtration Surface Area
phenotype  Proximal tubule
protein uptake
Influx of monocytes Hyperlipidemia
and macrophages GFR
Renal
microvascular
Fibrogenesis
Renal scarring injury
Brenner BM, Keane WF. 2001.

5. Angiotensin II and thrombospodin(TSP1)
both can stimulate the production of
transforming growth factor-b (TGF-)
by tubuloepithelial cells and fibroblasts.
TGF- TGF- plays a key
role in extracellular
matrix formation in
mesangium
and interstitium that
leads to fibrosis and
loss of nephron units

6. •
O2
Ang II
bFGF PDGF
TSP1
TGF- •
O2
TGF- plays a key role in
extracellular matrix
formation in mesangium
and interstitium that leads
to fibrosis and loss of
nephron units

7. Aldosterone Promotes Renal Fibrosis
by Multiple Mechanisms
Angiotensin II
Adrenal Vascular
Aldosterone
PAI-1
Stimulates Nitric oxide
Inhibits
synthesis
Na+ influx
into VSMC
Fibroblast collagen Norepinephrine
synthesis uptake
AT1R binding
into VSMC
of Ang II

8. MAU in the cardio-renal continuum: A strong and
independent risk factor for cardio-renal disease
Clinical Disease
Established Diabetes
Subclinical Claudication
Recent
Organ Damage Diabetes Cardiovascular
Angina Event
LVH
Proteinuria TIA
IMT
Myocardial
Risk End Organ
Moderate Infarction
Factors Failure
Renal Disease
Stroke
Mild Renal Microalbuminuria End-Stage Chronic
Disease Renal Disease Heart Failure
(MAU)
 Hypertension  Diabetes/Metabolic Syndrome
 Increased LDL  Smoking
IMT = intima media thickness; LVH = left ventricular hypertrophy; TIA = transient ischaemic event; LDL = low-density lipoprotein;
CV = cardiovascular
The cardio-renal continuum is the interrelated progression of CV and renal disease
MAU is an early integrated sign of target organ damage
Dzau VJ, et al. Circulation. 2006;114:2850-70.

9. Albuminuria: The role of the RAAS
 Evidence points to a major role for the RAAS in pathophysiological
changes that lead to progressive renal and cardiovascular disease
Renin inhibitor
Angiotensinogen
Ang I
Renin ACEIs
ACE
Compensatory Ang II
feedback ARBs
AT1 receptor Aldosterone
Aldosterone
Reactive oxygen species inhibitor
Inflammatory mediators (e.g. IL-6)
Adhesion molecules (e.g. IL-6)
Cellular growth and apoptosis
Endothelial dysfunction
ALBUMINURIA
Ang = angiotensin; AT1 = angiotensin II type 1; ACEI = ACE inhibitor; ARB = AT receptor blocker;
IL-6 = interleukin 6; ICAN-1 = intercellular adhesion molecule.
Basi S , et al. Am J Kidney Dis. 2006;47(6):927-46.

10. MAU: an important and sensitive marker
of early kidney dysfunction
 Albumin is one of the
smallest plasma proteins
and accounts for ~60%
of total plasma protein1
Clinical significance of albuminuria
 Albumin is the first to appear in the urine during kidney dysfunction2
 MAU occurs in the earliest stages of kidney disease and reflects
vascular damage3
 MAU can indicate dysfunction, even during early chronic kidney disease
(CKD), while eGFR may remain within the normal range2
1. Gekle M. News Physiol Sci. 1998;13:5-11. 2. Levey AS. Ann Intern Med. 2003;139:137-47. 3. Cerasola G, et al. J Hypertens. 2010 Sep 16.

11. Measuring MAU: Sampling
Methods for sampling/measuring albumin:1
Measures Practicalities
Recommended, most practical, reliable
Morning spot-urine sample (mg/l)
and easy to use method
Still gold standard but not practical
24-hour urine collection (mg/24h)
and subject to collection errors
Timed overnight urine collection (µg/min) Easy but not practical
A urine dipstick test in a morning spot-urine sample
is the recommended method for initial screening2
1. De Jong PE, Curhan GC. J Am Soc Nephrol. 2006;17:2120-6. 2. Busby DE , et al. J Clin Hypertens 2004;6(11 suppl. 3):8-12.

12. MAU is emerging as an early and more sensitive
marker than eGFR
MAU eGFR
CV
risk
factors
 Both MAU and eGFR are independent predictors of a progressive
loss in renal function1
 When MAU is present and detectable, GFR is typically normal,
elevated or only modestly impaired (stage 1 or 2 CKD)2
MAU = microalbuminuria; CV = cardiovascular; eGFR = estimated glomerular filtration rate; CKD = chronic kidney disease.
1. Ninomiya T, et al. J Am Soc Nephrol. 2009;20(8):1813-21. 2. De Jong PE, et al. J Am Soc Nephrol. 2006;17:2120-6.

13. Conventional threshold levels for MAU
using different methods
24-hour Overnight (First morning void) spot urine
urinary urinary
albumin albumin Albumin* Urinary albumin/creatinine ratio (UACR)
excretion excretion (mg/L)
(mg/24 h) (µg/min) Gender mg/mmol mg/g
M 1.25 to <2.5 10 to <20
High normal 15 to <30 10 to <20 10 to <20
F 1.75 to <3.5 15 to <30
Micro-
M 2.5 to <25 20 to <200
albuminuria 30 to <300 20 to <200 20 to <200
F 3.5 to <35 30 to <300
(MAU)
*Measured, for example, using dipstick test.
MAU is defined as a spot urinary albumin measurement of 20 to <200 mg/l
De Jong PE, Curhan GC. J Am Soc Nephrol. 2006;17:2120-6.

14. Who should be screened?
People at risk of MAU
 In individuals with MAU, the aim of treatment is to manage the risk factors
Major risk factors for MAU
Hypertension*
Diabetes
Obesity
Gender and age
Family history of chronic kidney disease
Smoking
Genetic factors
* Primary risk factors
Management of these risk factors individually is beneficial,
hence they should be treated aggressively
Zelmanovitz T, et al. Diabetol Metab Syndr. 2009;1(1):10.

15. When to screen?
Guideline recommendations for MAU testing
Organisation Patient Group Frequency
ESH-ESC All people with: • Routine assessment at screening for
Guidelines CV risk and during treatment
2009 Reappraisal • Hypertension
(SBP 140 mmHg or DBP • Patient should be assessed routinely
90 mmHg) using:
– Serum creatinine
• Metabolic syndrome & – Estimated creatinine clearance
– Urinalysis (complemented by MAU via
high-normal BP (SBP 130–139
dipstick test and microscopic examination)
mmHg or DBP 80–85 mmHg) – Electrocardiogram
• MAU should be examined during
treatment as well as during screening
ESH/ESC = European Society of Hypertension/European Society of Cardiology; SBP = systolic blood pressure; DBP = diastolic blood pressure;
CV = cardiovascular; MAU = microalbuminuria; BP = blood pressure.
Current ESH-ESC guidelines recommend routine testing for MAU in
patients with hypertension and in metabolic syndrome with high-normal BP
1. Mancia G, et al. J Hypertens. 2007;25:1105-87. 2. Mancia G, et al. J Hypertens. 2009;27:2121-58.

16. 重點
1. Microalbuminuria 是早期器官受損的指標，它反映出endothelial
dysfunction ;早期測得MAU並加以治療可以延緩腎臟功能惡化的速度，
延緩Microalbuminuria發生更可以降低心血管疾病和腎臟疾病的發生‧
2. 一般測尿液白蛋白尿(Urine Albumin)最常見為測 morming spot urine，
即
早晨第一泡尿‧
男性< 10mg/g ; 女性< 15mg/g 為正常‧
男性10~20mg/g ;女性 15~30mg/g 為正常偏高‧
男性20~200mg/g ;女性 30~300mg/g 為微量白蛋白尿
(Microalbuminuria)‧
男性>200mg/g ;女性 > 300mg/g 為巨量白蛋白尿(Macroalbuminuria)‧
3. Hypertension、DM、Metabolic syndrome 皆為MAU的risk factor ;
目前ESH guideline 建議這些病人需要定期監測‧

17. Prevalence of MAU in the general population, and
in diabetic and hypertensive patients

18. MAU* is present in ~5−7% of the general population†
PREVEND (Netherlands)1 n=40,619
NHANES III (USA)2 n=22,244 HUNT (Norway)3 n=2,089
10
in general population (%)
7.8
8 7.2
Prevalence of MAU
6.6
6 5.1 5.2
4
2
0
General population Non-diabetic, non-hypertensive‡
* Morning urinary albumin 20–200 mg/L in the PREVEND Study, urinary albumin/creatinine ratio 30–299 mg/g in NHABES III, and urinary
albumin/creatinine ratio >22 µg in the HUNT Study.
† Aged 28–75 years in the PREVEND Study, ≥6 years in NHANES III, and ≥20 years in the HUNT Study.
‡ In NHANES III, the non-diabetic, non-hypertensive cohort also excluded subjects with cardiovascular disease or elevated serum creatinine levels.
Restricting screening to high-risk groups in PREVEND
(e.g. hypertension, diabetes, CVD and the elderly) failed to identify
45% of individuals with MAU and macroalbuminuria4
1. Hillege HL, et al. J Intern Med. 2001;249:519-26. 2. Jones CA, et al. Am J Kidney Dis. 2002;39(3):445-59. 3. Romundstad S, et al. Am J Kidney Dis. 2003;42:466-73. 4. Menne J, et al.
J Hypertens. 2010;28(10):1983-94.

19. MAU* is present in ~16−40% of the population
with diabetes†‡
45
in population with diabetes (%)
39.0
40
35
Prevalence of MAU
28.8
30
25 21.0
20 16.4
15
10
5
0
PREVEND NHANES III DEMAND AusDiab
(Netherlands)1 (US)2 (Global)3 (Australia)4
* Morning urinary albumin 20–200 mg/L in the PREVEND Study, urinary albumin/creatinine ratio 22–220 mg/g in males and 31–220 mg/g in females in the
AusDiab study, urinary albumin/creatinine ratio 31–299 mg/g in NHANES III and the DEMAND Study.
† Aged 28–75 years in the PREVEND Study, ≥6 years in NHANES III, and 18–80 years in the DEMAND Study.
‡ PREVEND, AusDiab and NHANES III were true population based studies; DEMAND studied a clinical /medical centre-based referred cohort (mainly in a
primary-care setting).
The DEMAND study, in patients with type 2 diabetes and no known
nephropathy, identified MAU in 39% and macroalbuminuria in 10% of
participants, respectively3
1. Hillege HL, et al. J Intern Med. 2001;249:519-26. 2. Jones CA et al. Am J Kidney Dis. 2002;39(3):445-59. 3. Parving HH, et al. Kidney Int. 2006;69(11):2057-63. 4. Tapp RJ, Am J
Kidney Dis. 2004;44(5):792-8.

20. Hypertension and glucose status are associated
with increased risk for MAU: The AusDiab Study
No HTN HTN
30 n=10,596 patients
25.4
Proportion with MAU (%)
25
20
18.3
13.8
15
10.3
10 8.3
3.7 4.8
5 2.5
0
DM IGT IFG NG
AusDiab = Australian Diabetes, Obesity and Lifestyle; MAU = microalbuminuria; DM = diabetes mellitus; IGT = impaired glucose tolerance;
IFG = impaired fasting glucose; NG = normal glucose; HTN = hypertension; T2D = type 2 diabetes.
Impaired fasting glucose − as well as type 2 diabetes − is associated with
a significantly increased risk of albuminuria after adjusting for age, sex
and other known albuminuria risk factors
Tapp RJ, et al. Am J Kidney Dis. 2004;44(5):792-8.

21. Albuminuria – a marker of renal damage – is associated
with increased CV morbidity and mortality
The UKPDS
Annual transition rates through stages of albuminuria
in patients with type 2 diabetes
No nephropathy
1.4%
2.0% (1.3-1.5%)
(1.9-2.2%)
Microalbuminuria (MAU)
Death
3.0%
2.8% (2.6-3.4%)
(2.5-3.2%)
Macroalbuminuria
4.6%
2.3% (3.6-5.7%)
(1.5-3.0%)
↑ Plasma creatinine or
renal replacement therapy 19.2%
(14.0-24.4%)
Data from the United Kingdom Prospective Diabetes Study (UKPDS). Data presented as annual transition rates with 95% confidence intervals. Adler A, et al. Kidney Int. 2003;63:225-32.

22. Albuminuria indicates vascular damage at different
stages of renal impairment leading to end-organ damage
Renal event Cardiovascular event
Odds ratio (age and sex adjusted)
Odds ratio (age and sex adjusted)
*
6 6
*
4 4
* *
* *
2 2 *
0 0
<15 15-30 30-150 150-300 >300 <15 15-30 30-150 150-300 >300
UAE (mg/24hr) UAE (mg/24hr)
N 4,132 796 574 51 57 N 6,013 1,279 1,023 121 134
n 143 42 49 9 13 n 252 121 150 20 25
*P < 0.05 versus patients with a urinary albumin excretion (UAE) 15 mg/day.
N = Number of patients with follow-up data available.
n = Number of patients with an event.
Gansevoort RT, et al. J Am Soc Nephrol. 2009;20(3):465-8.

23. LIFE sub-study: Kaplan-Meier plots on accumulated
freedom of CV events according to UACR and LV mass
UACR ≥1.406, LV mass ≥ 264
UACR ≥1.406, LV mass <194 UACR <1.406, LV mass <194
1.00
0.95
Freedom of CV events
0.90
0.85
0.80
0 12 24 36 48 60
Months
CV = cardiovascular; UACR = urine albumin: creatinine ratio; LV = left ventricular; MI = myocardial infarction.
CV events – CV death, non-fatal stroke or non- fatal MI –
increase throughout the LV mass, both in patients with UACR
above and below the median value
Olsen MH, et al. J Hum Hypertens. 2004;18:453-59.

24. Urinary albumin excretion is a strong predictor
of all-cause mortality in the general population
The PREVEND study
High Normal MAU (UAC = 20 to <200 mg/L)
Macroalbuminuria
6.0
5.5 CV death
5.0
4.5
4.0
Hazard ratio
3.5
Non-CV
3.0
death
2.5
2.0
1.5
1.0
0.5
0.0
1 10 100 1000
Urinary albumin concentration (mg/L)
The relationship between urinary albumin concentration and CV mortality
is already apparent at albuminuria levels considered to be normal
Hillege HL, et al. Circulation 2002;106:1777-82.

25. MAU and gross proteinuria associated
with significantly higher risks of CV mortality in T2D
The WESDR study
Normoalbuminuria (n=460) (<30 mg/L urinary albumin)
MAU (n=208) (30–300 mg/L urinary albumin)
Gross proteinuria (n=172) (>300 mg/L urinary protein)
1.0
Proportion surviving
0.8
0.6
0.4
0.2
0
0 2 4 6 8 10 12
Years of follow up
Log-Rank test p<0.001
Gross proteinuria (>300 mg/L) > Macroalbuminuia (>200 mg/L)
The relative risk of CV mortality associated with MAU
(30–300 mg urinary albumin) was 1.8
Valmadrid CT, et al. Arch Intern Med. 2000;160:1093-100.

26. Risk associated with a given level of eGFR is independently
increased in patients with higher levels of proteinuria
The Alberta study
End-stage renal disease Doubling of serum creatinine
Normal Microalbuminuria Macroalbuminuria
Rate per 1000 person years
100 60
Rate per 1000 person years
50
80
40
60
30
40
20
20 10
0 0
≥60 45-59.9 30-44.9 15-29.9 ≥60 45-59.9 30-44.9 15-29.9
eGFR (mL/min/1.73 m2) eGFR (mL/min/1.73 m2)
The risks of mortality, myocardial infarction, and progression to kidney failure
associated with a given level of eGFR are independently increased in patients
with higher levels of proteinuria
Hemmelgarn BR, et al. JAMA. 2010;303(5):423-9.

27. Key clinical studies evaluating the predictive value
of MAU on CV and renal risk
Change of MAU as a predictor
Year Study name Author/s Title Patient #
Proteinuria, a target for renoprotection in patients
De Zeeuw D,
2004 RENAAL with type 2 diabetic nephropathy: lessons from N=1,513
et al.
RENAAL.
De Zeeuw D, Albuminuria, a therapeutic target for CV protection N=1,513
2004 RENAAL
et al. in type 2 diabetic patients with nephropathy.
Reduction in albuminuria translates to reduction in
Ibsen H, CV events in hypertensive patients: losartan
2005 LIFE N=8,206
et al. intervention for endpoint reduction in hypertension
study.
Schmieder R, Changes in albuminuria predict mortality and
2010 ONTARGET N=23,480
et al. morbidity in patients with vascular disease.

28. Antiproteinuric effect predicts nephroprotection
in patients with type 2 diabetes
The RENAAL study
<0% (increase) 0%-30% >30% decrease
70
60 0-30% vs <0% p=0.0118
% with renal endpoint
50 >30% vs <0% p<0.0001
40
30
20
10
0
0 12 24 36 48
Months of follow-up
The larger the treatment reduction of proteinuria, the lower the risk for renal endpoints
De Zeeuw D, et al. Kid Int. 2004;65:2309-20.

29. Reduction of proteinuria predicts cardiovascular
prognosis in people with type 2 diabetes
The RENAAL study
Cardiovascular event Congestive heart failure
>0 <30% <0% >30% >0 <30% <0% >30%
60 60
Patients (%)
40 40
Patients (%)
20 20
0 0
0 12 24 36 48 0 12 24 36 48
Months Months
Kaplan-Meier Curves of CV events and congestive heart failure stratified according to the change of proteinuria after 6 months:
<0% (n=631), >0 and <30% (n=393) and >30% (n=489).
The larger the treatment reduction of proteinuria, the lower the risk for CV endpoints
de Zeeuw D, et al. Circulation. 2004;11:921-7.

30. Increasing albuminuria is associated with
an increased risk of CV events
The LIFE study
Composite CV endpoint rates stratified baseline albuminuria
measurement (UACR)*3 X 8.84 to US measures, mg/g
24 >3 mg/mmol (n=2435, 1708, 1760)
22 1-3 mg/mmol (n=2219, 1827, 1946)
20 0.5-1 mg/mmol (n=1591, 1587, 1814)
≤ 0.5 mg/mmol (n=1961, 3385, 2458)
Endpoint rate (%)
18
16
14
12
10
8
6
4
2
0
0 6 12 18 24 30 36 42 48 54 60 66
Month
*Composite endpoint = first occurrence of cardiovascular death, nonfatal stroke, and nonfatal myocardial infarction;
UACR = urinary albumin/creatinine ratio; The numbers in parentheses are the numbers of at-risk patients in each range of UACR at baseline, Years 2 and4.
Reducing UACR is associated with a reduction
in CV events in patients with hypertension
Ibsen H, et al. Hypertension. 2005;45:198-202.

31. Controlling progression of MAU as a means
of reducing CV risk
The LIFE study
Prognosis after reduction of albuminuria
Composite endpoint of CV death, stroke and myocardial infarction
0.20 N= 9,193 hypertensive patients with LVH
High Alb at BL/High at Yr 1 13.5%
Proportion reaching
composite endpoint
0.15
High Alb at BL/Low at Yr 1 9.4%
0.10 Low Alb at BL/High at Yr 1 8.6%
0.05 Low Alb at BL/Low at Yr 1 5.5%
0.00
0 20 40 60
Time (Months)
CV = cardiovascular; LVH = left ventricular hypertrophy; Ab at BL = albuminuria at baseline/value after 1 year (Yr 1)
Reducing UACR during treatment is associated with a reduction
in CV death, stroke and myocardial infarction in patients with hypertension
Ibsen H, et al. Hypertension 2005;45:198-202.

32. Change in MAU as a predictor of CV and renal
outcomes in patients with vascular disease
The ONTARGET/TRANSCEND study programme
A) CV death
decrease >50% vs minor change 0.140
minor change
increase >100% vs minor change <0.0001
B) Composite CV endpoint
decrease >50% vs minor change 0.032
minor change
increase >100% vs minor change <0.0001
C) Combined renal endpoint
decrease >50% vs minor change 0.019
minor change
increase >100% vs minor change 0.005
0 1 2
Adjusted HR* (95 CI%) of changes in UACR
from baseline to 2 year visit
Analyses were adjusted for age, gender, BMI, smoking, alcohol consumption, eGFR, plasma glucose,
BP and HR at baseline, BP change within 2 years and for baseline albuminuria.
The risk of CV and renal outcomes is increased significantly if MAU
is increased and is decreased if MAU is reduced
Schmieder RE, et al. JASN 2011; In press.

33. Change in MAU as a predictor of all-cause mortality
in patients with vascular disease
The ONTARGET/TRANSCEND study programme
All-cause mortality
Decrease >50% vs minor change 0.026
Minor change
Increase >100% vs minor change <0.0001
0 1 2
Adjusted HR* (95 CI%) of changes in UACR
from baseline to 2 year visit
Analyses were adjusted for age, gender, BMI, smoking, alcohol consumption, eGFR, plasma glucose,
BP and HR at baseline, BP change within 2 years and for baseline albuminuria.
The risk of all-cause mortality is increased significantly if MAU
is increased and is decreased if MAU is reduced
Schmieder RE, et al. JASN 2011; In press.

34. Understanding the clinical implications of MAU
Summary
• The RAAS plays a major role in development of albuminuria in
accordance with the Steno hypothesis (Albuminuria reflects
widespread vascular damage ).
 MAU is a strong and independent risk factor for cardio-renal disease
 UACR and eGFR are multiplicatively and independently associated with
mortality risk without evidence of interaction
 Albumin is a continuous predictor of mortality starting at low levels,
whereas eGFR is predictive only above a certain threshold
 Reducing proteinuria/MAU leads to a decreased risk in CV and renal
outcomes and all-cause mortality.

35. Combining antihypertensive therapy prevents MAU
in people with T2D and HT and normoalbuminuria
The BENEDICT Study
Proportion (%) of participants with MAU during treatment with trandolapril or placebo
Placebo Trandolapril
15
microalbuminuria (%)
Subjects with
10
5
0
0 6 12 18 24 30 36 42 48
Follow-up (Months)
MAU = microalbuminuria; T2D = type 2 diabetes; HT = hypertension; BP = blood pressure; RAAS = renin-angiotensin-aldosterone system
*Defined as UACR ≥20g/min in at least 2 of 3 consecutive overnight urine collections and confirmed after approx. 2 months in at least 3
consecutive overnight urine collections; †Significant difference (p=0.01) vs. placebo after adjusting for pre-specified covariates.
Treatment with an ACE inhibitor reduces the incidence
of MAU in individuals with T2D and hypertension
verapamil
Ruggenenti P, et al. N Engl J Med. 2004;351(19):1941-51.

36. ARB therapy delays/prevents first occurrence of MAU
The ROADMAP Study
Placebo Olmesartan n=4,447
Cumulative proportion of patients
0.22
0.20
Hazard Ratio Risk reduction P value
with microalbuminuria
0.18
0.16 0.770 -23% 0.0104
0.14
0.12
0.10
0.08
0.06
0.04
0.02
0.00
0 3 6 12 18 24 30 36 42 48
Time (months)
Subjects: type 2 diabetes (T2D) and ≥1 additional CV risk factor (e.g. dyslipidaemia, hypertension, obesity, smoking).
94% of participants had blood pressure below 130/80 mmHg or were receiving antihypertensive treatment with a
non-RAAS medication
ARB therapy significantly delays the onset of MAU –
by 23% compared with placebo in individuals with T2D
(After correction for diastolic and systolic blood pressure, the risk reduction with olmesartan dropped to 18% and 17%, respectively, losing statistical significance )
Haller H et al. Olmesartan for the Delay or Prevention of Microalbuminuria in Type 2 Diabetes. New Engl J Med 2011; 364:907-17.

37. Time to first occurrence of MAU
ROADMAP: Correction for BP differences
BP-independent olmesartan effect:
Analysis HR RR P-value
DBP AUC DBP last mean
Treatment 0.770 -23% p=0.0104
SBP AUC SBP last mean
Treatment
DBP
0 corrected* 0.823 -18% p=0.0596
(AUC)
-5
Risk reduction (%)
SBP corrected*
(AUC)
0.834 -17% p=0.0789
-10
DBP
-15 corrected 0.810 -19% p=0.0398
(Last mean)
-20 -17%
-18% -19% -19% SBP corrected
(Last mean)
0.814 -19% p=0.0451
-25 -23%
* AUC = Area under the curve (SBP/DBP) from baseline to last
assessment in DB period.
Last mean SBP/DBP before MAU event.
Haller H et al. Olmesartan for the Delay or Prevention of Microalbuminuria in Type 2 Diabetes. New Engl J Med 2011; 364:907-17.

38. Prevention of MAU: Realistic achievements in daily
clinical practice
Summary
 Current guidelines advocate early and aggressive individual management
of risk factors in order to prevent progression to MAU
 Lifestyle modifications are important in the early intervention of CV risk
 MAU acts as a target for RAAS inhibition and prevention of cardio-renal
damage
 Large clinical studies provide evidence that intervening in the
development of MAU in high-risk patients prevents or delays renal and
CV complications
 RAAS inhibitors (ARBs and ACE inhibitors) prevent/delay the
development of MAU in patients with hypertension and/or diabetes

39. Key clinical studies evaluating prevention and treatment
of different levels of albuminuria and kidney disease
Normal Microalbuminuria Proteinuria Proteinuria ESRD
Stage 1 Stage 2 Stage 3 Stage 4 Stage 5
Mild Moderate Severe Dialysis
IRMA 2 IDNT
BENEDICT MARVAL RENAAL

40. Nephroprotective effects of olmesartan in hypertension:
Reducing inflammatory markers
Decreased serum hsCRP Decreased serum TNF-a
Change of serum hsTNF-alpha (%)
15 15
Change of serum hsCRP (%)
10 Week 6 Week 12 10 Week 6 Week 12
Olmesartan Placebo Olmesartan Placebo Olmesartan Placebo Olmesartan Placebo
5 5
0 0
-5 -5
-10 -10
*
-15 -15 #§
-20 * -20
-25 ** -25
Weeks 0−6: olmesartan (20 mg/day) or placebo
Weeks 7−12: pravastatin 20 mg added to both treatment regimens
*p<0.05, **p<0.02, #p<0.01 vs baseline; $p<0.05 olmesartan vs placebo
hsCRP = high sensitivity C-reactive protein; TNF-α = tumor necrosis factor- α
ARB treatment significantly reduces vascular microinflammation
in patients with hypertension by as early as Week 6 of therapy
Fliser D, et al. Circulation. 2004;110:1103-7.

41. Achieving treatment goals in MAU-positive people:
ESH-ESC guideline recommendations
ESH-ESC guidelines: recommended intervention
(patients with subclinical organ damage)
Microalbuminuria ACEI , ARB,
Renal dysfunction ACEI , ARB
Left ventricular hypertrophy ACEI, CA, ARB
Asymptomatic atherosclerosis CA, ACEI
ACEI = Angiotensin converting enzyme inhibitor; ARB = Angiotensin II receptor blocker; CA = Calcium antagonist.
RAAS inhibition by ACEIs or ARBs provides nephroprotection
beyond blood pressure control
Mancia G, et al. J Hypertens. 2007;25(6):1105-87.

42. Interventions in MAU-positive individuals:
Evidence-based data, guidelines and practical
considerations for treatment
Summary
 Recent data have confirmed a link between MAU and CV disease in
people with and without diabetes – even at low levels once considered
to be ‘normal’
 Treatment goals in MAU-positive individuals should be to:
− Prevent/delay progression of CV and renal disease
− Reduce progression and increase regression of MAU
− Provide better control of renal and CV risk progression
 Therapies that inhibit RAAS (ACEIs and ARBs) have shown to help
achieve these treatment goals
 ESH-ESC guidelines recommend that patients with hypertension and
MAU should receive ACEIs and/or ARBs as the first-line treatment.

43. Take Home Message
1. 一般人Microalbuminuria 的盛行率約5~7%，糖尿病病人MAU盛行率約
16~40%；而且高血壓病人MAU 發生率較非高血壓發生率高。
2. 許多臨床證據證實UACR越高，心血管疾病和腎臟疾病發生率會越高。所
以降低UACR或延緩MAU的發生皆可以延緩腎臟惡化，進而有效降低心
血管疾病發生率及死亡率。
3. ARB和ACEI 皆有臨床證據證實可以延緩DM Nephropathy，不過只有
BENEDICT和ROADMAP study證實可以有效延緩DM 病人
Microalbuminuria的發生。
4. ESH-ESC guideline建議高血壓病人同時患有MAU需以ARB和ACEI 為第
一線治療。
5. Olmetec 有anti-inflammatory function，可以改善病人endothelial
function，甚至可以延緩DM 病人Microalbuminuria的發生。

44. Thanks for Your Attention

45. FDA reviews olmesartan safety record, cites CV deaths in trials
June 14, 2010 | Steve StilesWashington, DC –
The FDA is conducting a safety review of the angiotensin receptor blocker (ARB)
olmesartan(Benicar, Daiichi Sankyo) after determining that diabetic patients taking the drug in
two completed phase 3 trials may have had an excess risk of cardiovascular death, the
regulatory body has announced [1].
The safety announcement says that the FDA's review is "ongoing, and the agency has not
concluded that Benicar increases the risk of death. FDA currently believes that the
benefits of Benicar in patients with high blood pressure continue to outweigh its potential
risks." The agency also notes that "other controlled clinical trials evaluating Benicar and other
ARBs have not suggested an increased risk of cardiovascular-related death."
The primary end points of the two trials were dominated by measures of renal function.
In the Randomized Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study,
conducted in Europe, 4447 patients with diabetes and at least one additional cardiovascular
risk factor, but no evidence of renal dysfunction, were randomized to receive either olmesartan
at 40 mg/day (n=2232) or placebo (n=2215). The trial, sponsored by Sankyo Pharma, ended in
July 2009 [2].

46. There were 15 cardiovascular deaths—including seven cases of sudden death, five fatal MIs, two
fatal strokes, and one death related to coronary revascularization—in the olmesartan group
compared with a total of three CV deaths—one sudden death and two fatal strokes—in the
control group.
In the Olmesartan Reducing Incidence of End Stage Renal Disease in Diabetic Nephropathy Trial
(ORIENT), conduced in Japan and Hong Kong, 566 patients with diabetes and renal dysfunction
were randomized to receive olmesartan at 10 mg/day to 40 mg/day (n=282) or placebo (n=284).
Of the 10 cardiovascular deaths in the olmesartan group, five were sudden death, one was a fatal
MI, three were fatal strokes, and one was of unknown CV cause. Three patients in the control
group died, two from sudden death and one from MI. ORIENT, sponsored by Daiichi Sankyo, was
completed in February 2009 [3].
"In considering the results of these trials, it is important to remember that numerous clinical
trials with olmesartan as well as trials with other ARBs have not suggested an increased risk of
cardiovascular-related death," the FDA announcement notes. Still, the "FDA plans to review the
primary data from the two trials and the total clinical-trial data on olmesartan. Also, the agency
will evaluate additional ways to understand the findings from ROADMAP and ORIENT, in light of
information supporting the use of ARBs and angiotensin-converting enzyme (ACE) inhibitors in
certain patients at high risk for cardiovascular events."

47. Demography of ROADMAP

49. Primary End-point of ROADMAP

50. Secondary End-point

51. AE of ROADMAP