Cardiovascular risk
in
Chronic Renal Disease
Giancarlo Viberti, MD
Professor of Diabetes and Metabolic Medicine
GKT School of Medicine
Guy’s Hospital
King’s College London
London, UK
Excess Mortality With Hypertension
and Proteinuria in Type 2 Diabetes
Status of Hypertension (H) and Proteinuria (P) in Type 2 Diabetes
1000
Standardized
Mortality Ratio
500
0
P-H- P-H+ P+H- P+H+
P-H- P-H+ P+H- P+H+
Men
Women
Wang SL et al. Diabetes Care. 1996;19:305-312.
Increasing Death Rate Due to
Diabetes
140
Diabetes
130
Age-Adjusted
Death Rate
Relative to
1980
120
110
Cancer
100
90
80
Cardiovascular
Disease
Stroke
70
60
1980
1982
1984
1986
1988
1990
Year
1992
1994
1996
Risk of fatal or nonfatal
myocardial infarction
Risk of myocardial infarction is
increased in type 2 diabetes
50%
40%
45.0%*
No prior myocardial infarction
Prior myocardial infarction
30%
18.8% *
20%
10%
20.2%
3.5%
0%
Nondiabetic subjects
(n = 1,373)
Seven-year incidence in a Finnish-based cohort.
*P < 0.001
Type 2 diabetic subjects
(n = 1,059)
Adapted from Haffner SM. New Engl J Med 1998; 339:229–234.
Proteinuria is an Independent Risk
Factor for Mortality in Type 2 Diabetes
1.0
Normoalbuminuria
(n = 191)
P <.01
0.9
Survival
(all-cause
mortality)
0.8
P <.05
Microalbuminuria
(n = 86)
0.7
Macroalbuminuria*
(n = 51)
0.6
0.5
0
1
2
3
Years
*P < 0.001 normoalbuminuria vs macroalbuminuria.
Gall MA et al. Diabetes. 1995;44:1303-1309.
4
5
6
Relative risk of CVD and mortality in
3498 DM by quartile of albuminuria (ACR)
ACR (mg/mmol) quartiles RR (95% CI)
1st
2nd
3rd
4th
Variable
<0.22
0.22-0.57
0.58-1.62
>1.62
P for trend
MI, Stroke &
CV death
1
0.85
(0.63-1.14)
1.11
(0.86-1.43)
1.89
(1.52-2.63)
<0.001
All cause
mortality
1
0.86
(0.58-1.28)
1.41
(1.01-1.95)
2.38
(1.80-3.20)
<0.001
CHF
1
0.72
(0.32-1.63)
1.83
(0.98-3.43)
3.65
(2.06-6.46)
<0.001
Gerstein et al. JAMA 2001
Relative risk of CVD and mortality in
5545 patients without diabetes by quartile of
albuminuria (ACR)
ACR (mg/mmol) quartiles RR (95% CI)
1st
2nd
3rd
4th
Variable
<0.22
0.22-0.57
0.58-1.62
>1.62
P for trend
MI, Stroke &
CV death
1
1.24
(1.03-1.49)
1.54
(1.29-1.85)
1.83
(1.52-2.20)
<0.001
All cause
mortality
1
1.17
(0.93-1.47)
1.49
(1.19-1.87)
2.27
(1.82-2.82)
<0.001
CHF
1
1.45
(0.87-2.44)
1.86
(1.12-3.10)
2.93
(1.79-4.81)
<0.001
Gerstein et al. JAMA 2001
The Metabolic Syndrome: a
network of atherogenic factors
Genetic factors
Environmental
factors
Hyperglycemia/IGT
Dyslipidemia
Hypertension
Insulin Resistance
Endothelial dysfunction/
Microalbuminuria
Hypofibrinolysis
Inflammation
Atherosclerosis
Adapted from McFarlane S, et al. J Clin Endocrinol Metab. 2001; 86:713–718.
PWV and mortality in patients with ESRD on RRT
Blacher J et al. Kidney Int; 63 :1852, 2003
Diabetes: The Most Common
Cause of ESRD
Primary Diagnosis for Patients Who Start Dialysis
Other
10%
700
Glomerulonephritis
13%
Hypertension
27%
Diabetes
50%
600
500
No. of Dialysis
400
Patients
(thousands)
300
Patients (n)
Projection
95% CI
200
281,355
243,524
100
0
520,240
r2 = 99.8%
1984
1988
1992
1996
2000
United States Renal Data System. USRDS 2000 Annual Data Report. June 2000.
2004
2008
Annual Transition Rates
Through Stages of DN
No nephropathy
2.0%
(1.9% to 2.2%)
1.4%
(1.3% to 1.5%)
Microalbuminuria
2.8%
(2.5% to 3.2%)
3.0%
(2.6% to 3.4%)
Macroalbuminuria
2.3%
(1.5% to 3.0%)
Elevated plasma creatinine or
Renal replacement therapy
DN = diabetic nephropathy.
Adler et al. Kidney Int. 2003;63:225-232.
4.6%
(3.6% to 5.7%)
19.2%
(14.0% to 24.4%)
Mortality Among Patients With Type 2 DM
With and Without Microalbuminuria
(7-year follow-up)
All-Cause
CHD
Stroke
Other
n (%)
n (%)
n (%)
n (%)
NIDDM with
microalbuminuria
(n = 37)
18 (49)
13 (72)
2 (11)
3 (17)
NIDDM with
normoalbuminuria
(n = 109)
18 (17)
13 (32)
0 (0)
11 (61)
NIDDM = non–insulin-dependent diabetes mellitus.
Mattock MB et al. Diabetes. 1998; 47:1786-1792.
Heritability of AER in families
of type 2 diabetic patients
Percent Resemblance
Fathers
(n=156)
Mothers
(n=178)
All offspring (n=478)
AER
AER adjusted for SBP
2915
2715
3112
3413
Sons (n=225)
AER
AER adjusted for SBP
1517
1218
3515
3916
Daughters (n=253)
AER
AER adjusted for SBP
3419
3120
2916
3516
Data are age and FBG adjusted
Forsblom 1999
Association of microalbuminuria with non
traditional cardiovascular risk factors in
1481 subjects in the IRAS
Variable
MA neg
MA pos
ACR
mg/mmol
8.38±0.2
41.6±2.9
CRP mg/l
3.8±0.15
5.37±0.47
0.0018
278.2±1.6
295.7±4
0.0001
Fibrinogen
mg/dl
p value
Festa et al. Kidney Int. 2000
Risk Factors for Mortality in Patients With
Type 2 DM – 9 Year Follow-up
RR (95% CI) adjusted for conventional risk factors
AER
Micro
2.36 (1.54-3.63)*
Macro
4.74 (2.82-7.96)*
67.9%
1.02 (0.59-1.76)
111.9%
1.89 (1.17-3.08)*
1.9 mg/L
1.80 (1.06-3.08)†
5.5 mg/L
2.92 (1.76-4.85)*
vWf
CRP
N = 328 patients; *P < 0.01; †P < 0.05. vWf = von Willebrand factor; CRP = C-reactive protein.
Stehouwer et al. Diabetes. 2002;51:1157-1165.
The Renin System and
Therapeutic Intervention
Angiotensinogen
Renin
Angiotensin I
X
Angiotensin receptor
blocker
Angiotensin II
X
AT1 receptor
Glomerulosclerosis
ACE inhibitor
Angiotensinconverting
enzyme
AT2 receptor
X
Degradation
products
Vasoconstriction
Vasodilation
Na/fluid retention
Bradykinin
SMC proliferation
Antiproliferation
Effects of ACE-Is in Type 1
Diabetes With Microalbuminuria*
• ACE-Is reduced progression to macroalbuminuria by
62%
• ACE-Is increased regression to normoalbuminuria
threefold
• AER-lowering effect depended on baseline AER
– 18% at 20 µg/min, 48% at 50 µg/min
– 63% at 100 µg/min, 74% at 200 µg/min
• ACE-I effects independent of age, gender, BP,
HbA1c, and duration of DM
*Meta-analysis of 10 trials: 326 patients on ACE-Is, 320 on placebo.
ACE Inhibitors in Diabetic Nephropathy Trialist Group. Ann Intern Med. 2001;134:370-379.
IRMA-2: Blood Pressure Reduction
200
180
160
153
145
153
143
153
142
140
120
mm Hg 100
80
90
84
90
84
60
91
84
40
Baseline
On Treatment (150 mg)
20
On Treatment (300 mg)
0
Control
(n = 201)
Irbesartan
150 mg
(n = 195)
IRMA-2 = Irbesartan in Patients with Type 2 Diabetes and Microalbuminura.
Parving H-H et al. N Engl J Med. 2001;345:870-878.
Irbesartan
300 mg
(n = 194)
IRMA 2: Incidence of Diabetic
Nephropathy
20
RR = 70%
Placebo
15
Incidence of
Diabetic
10
Nephropathy (%)
Irbesartan*
150 mg/d
5
Irbesartan*
300 mg/d
0
0
6
12
Follow-up (mo)
*P < 0.01 vs placebo.
Parving H-H et al. N Engl J Med. 2001;345:870-878.
18
22
24
IRMA 2: Renoprotective Effects of
Angiotensin II Blockade Independent
of BP Lowering
20
10
Placebo
0
% Change
in UAER
*
-10
150 mg irbesartan
-20
-30
300 mg irbesartan
-40
*
-50
0
3
6
12
Follow-up (mo)
*P < 0.001 vs placebo.
Adapted from Parving HH et al. N Eng J Med. 2001;345: 870-878.
18
24
MARVAL: Mean BP Effects in Type 2 Diabetic
Patients with MicroAlbuminuria
SBP
DBP
Mean Change
from Baseline
(mm Hg)
at 24 weeks
-6.6
-6.5
Valsartan
Amlodipine
-11.2
-11.6
MARVAL = MicroAlbuminuria Reduction with Valsartan trial
Viberti G. Circulation. 2002;106:672-678.
Valsartan Reduces UAER to a
Greater Extent than Amlodipine in
Type 2 DM
Primary End Point
Baseline
Valsartan 24 Wks
Amlodipine 24 Wks
70
P < 0.001
60
50
UAER 40
(µg/min)
30
20
10
0
Valsartan
Adapted from Viberti G et al. Circulation. 2002;106:672-678.
Amlodipine
% of Patients Returning to
Normoalbuminuria
Valsartan Corrects Microalbuminuria to a
Greater Extent than Amlodipine in Type 2 DM
35
29.9%*
30
25
20
14.5%
15
10
5
0
Valsartan
Amlodipine
Normoalbuminuria = UAER < 20 g/min; *P = 0.001 vs. amlodipine
Viberti G. Circulation. 2002;106:672-678.
CALM Study: ARB and ACE
Inhibitor Increase BP Lowering
Diastolic BP
Systolic BP
0
-5
-10
Mean Reduction
in BP (mm Hg)
-10.4
-10.7
-15
-14.1
-16.3
-20
-25
-30
Candesartan 16mg qd
Lisinopril 20mg qd
Combination
Mogensen CE et al. BMJ. 2000;321:1440-1444.
-16.7
-25.3
CALM: Combined Therapy of ARBs
and ACE-Is: Effect on Proteinuria
197 Type 2 DM
With Microalbuminuria
Lisinopril 20 mg
Candesartan 16 mg
Lisinopril 20 mg
Candesartan 16 mg
39%
24%
50%
Reduction in Urinary Albumin: Creatinine Ratio (%)
CALM = Candesartan and Lisinopril Microalbuminuria Study.
Mogensen CE et al. BMJ. 2000;321:1440-1444.
PREMIER Study: Effect of Perindopril /
Indapamide vs Enalapril on Urinary AER in
Type 2 DM With Early DN
Perindopril/
Indapamide
(n = 233)
Enalapril
(n = 224)
- 42%
- 27%
100
80
Urinary AER
(final/baseline)
(%)
P = 0.002
60
Residual AER
40
20
0
[- 37%,- 16%]
[- 50%,- 33%]
95% CI
PREMIER = Preterax in Albuminuria Regression.
Mogensen CE, Viberti GC et al. Hypertension. 2003;41:1063-1071.
MICRO-HOPE Study: Ramipril Reduces
Risk of CVD in Diabetic Patients With
Microalbuminuria
Group
n
Placebo (%)
Overall
3577
19.8
Microalbuminuria positive
1140
28.6
Microalbuminuria negative
2437
15.5
Cardiovascular disease
2458
23.9
No cardiovascular disease
1119
9.9
631
19.0
1852
19.3
Oral hyperglycemics
914
21.6
Insulin plus oral hyperglycemics
180
18.5
Type 1 diabetes
81
25.5
Type 2 diabetes
3496
19.7
Dietary control of hyperglycemia
Insulin
RR (95% CI)
0.2 0.4 0.6 0.8 1.0 1.2
MICRO-HOPE = Microalbuminurea, Cardiovascular, and Renal Outcomes HOPE Substudy.
HOPE Study Investigators. Lancet. 2000;356:860.
RENAAL: Composite Primary End Point
ESRD
Placebo
RR 25%
P = 0.006
30
20
% With Event
% With Event
Doubling of Serum Creatinine
Losartan
10
0
0
P (+CT) 762
L (+CT) 751
12
24
Months
36
689
692
554
583
295
329
Placebo
30
RR 28%
P = 0.002
20
10
0
48
Losartan
0
12
P (+CT) 762
L (+CT) 751
36
52
715
714
24
36
Months
610
347
625
375
ESRD or Death
% With Event
50
Placebo
40
RR 20%
P = 0.010
30
20
Losartan
10
0
0
P (+CT) 762
L (+CT) 751
12
24
36
Months
715
610
347
714
625
375
48
42
69
RENAAL = Reduction of End Points in NIDDM with the Angiotensin II Antagonist Losartan;
Brenner BM et al. N Engl J Med. 2001;345:861-869.
48
42
69
RENAAL: Change From Baseline
in Proteinuria*
40
Placebo
20
Median
Percent
Change
0
P = 0.0001
35% overall reduction
-20
-40
Losartan
-60
0
P (+CT) 762
L (+CT) 751
12
24
Months
36
48
632
661
529
558
390
438
130
167
*Proteinuria measured as the urine albumin:creatinine ratio from a first morning void.
Brenner BM et al. N Engl J Med. 2001; 345:861-869.
RENAAL
First Hospitalization for Heart Failure
% with event
20
Risk Reduction: 32%
p=0.005
P
15
10
L
5
0
P (+CT)
L (+CT)
Brenner et al. NEJM 2001
0
12
24
Months
36
48
762
751
685
701
616
637
375
388
53
74
Antihypertensive and Antiproteinuric
Responses to Increasing ACE-I Dose
Lisinopril Dose (mg)
5 mg
10 mg
15 mg
0
-10
-20
-30
% Reduction
vs. Control
-40
-50
-60
-70
BP
Urine protein
-80
Adapted from Palla R et al. Int J Clin Pharmacol Res. 1994;14:35-43.
20 mg
Effect of 40 wk ACEi on ACR in 45 Type 2 DM with
early DN with or without aldosterone escape
Variable Baseline Escape neg.
(27)
Escape pos.
(18)
SBP mmHg
150±15
136±13
135±12
DBP mmHg
89±14
84±11
83±10
ACR mg/g
389±109
119±95
368±142
PAC pg/ml
83.7±20
53.2±15.1
112±18.7
Sato et al Hypertension 2003
Effect of spironolactone Rx (25mg/day) on AER in
ACEi- treated Type 2 DM with aldosterone escape
Mean AER
Individual AER
Sato et al Hypertension 2003
Steno 2 Study: Intensive Therapy Reduces the
Relative Risk of Microvascular Disease in Patients
With Type 2 DM and Microalbuminuria –
Follow-up 7.8 Years
Relative Risk
(95% CI)
P Value
Nephropathy
0.39 (0.17-0.87)
0.003
Retinopathy
0.42 (0.21-0.86)
0.02
Autonomic
neuropathy
0.37 (0.18-0.79)
0.002
Peripheral
neuropathy
1.09 (0.54-2.22)
0.66
Variable
0.0
Gaede P et al. N Engl J Med. 2003;348:383-393.
0.5
Intensive
Therapy
Better
1.0
1.5
2.0
Conventional
Therapy
Better
2.5
Steno 2: Intensive Therapy Reduces
the Risk of CVD Morbidity and
Mortality
60
Conventional therapy
50
Hazard ratio = 0.47
(95% CI 0.24 to 0.73; P = 0.008)
40
Primary Composite 30
End Point (%)
20
Intensive therapy
10
0
0
12
24
36
48
60
72
84
96
Months of Follow-up
Composite end point = Death from CV causes, nonfatal MI, coronary artery bypass graft, percutaneous
coronary intervention, nonfatal stroke, amputation, or surgery for peripheral atherosclerotic artery disease.
Gaede P et al. N Engl J Med. 2003;348:383-393.
Conclusions
• Proteinuria and chronic renal disease
increase the risk of CVD mortality by 3-4 fold
• Reduction and normalization of arterial
hypertension and proteinuria are key
treatment goals for cardiorenal protection
• Blockade of the RAAS is critical for
preventing progression of renal disease
• Multifactorial treatment regimens should
include, whenever possible, agents that block
the RAAS