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
130 Diabetes

120
Age-Adjusted
Death Rate 110
Relative to Cancer
1980 100
90 Cardiovascular
Disease
80 Stroke
70
60
1980 1982 1984 1986 1988 1990 1992 1994 1996
Year
 Risk of myocardial infarction is
increased in type 2 diabetes
50% 45.0%*
Risk of fatal or nonfatal
myocardial infarction

No prior myocardial infarction

40% Prior myocardial infarction

30%
18.8% * 20.2%
20%

10%
3.5%
0%
Nondiabetic subjects Type 2 diabetic subjects
(n = 1,373) (n = 1,059)

Seven-year incidence in a Finnish-based cohort.

*P < 0.001 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
0.9 P <.01 (n = 191)

0.8 Microalbuminuria
Survival P <.05 (n = 86)
(all-cause
mortality) 0.7
Macroalbuminuria*
(n = 51)
0.6

0.5
0 1 2 3 4 5 6
Years
*P < 0.001 normoalbuminuria vs macroalbuminuria.
Gall MA et al. Diabetes. 1995;44:1303-1309.
 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 & 1 0.85 1.11 1.89 <0.001

CV death (0.63-1.14) (0.86-1.43) (1.52-2.63)
All cause 1 0.86 1.41 2.38 <0.001
mortality (0.58-1.28) (1.01-1.95) (1.80-3.20)
CHF 1 0.72 1.83 3.65 <0.001
(0.32-1.63) (0.98-3.43) (2.06-6.46)

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 & 1 1.24 1.54 1.83 <0.001

CV death (1.03-1.49) (1.29-1.85) (1.52-2.20)
All cause 1 1.17 1.49 2.27 <0.001
mortality (0.93-1.47) (1.19-1.87) (1.82-2.82)
CHF 1 1.45 1.86 2.93 <0.001
(0.87-2.44) (1.12-3.10) (1.79-4.81)

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 Glomerulonephritis
10% 13%
700
Diabetes Hypertension
600 50% 27%

500
No. of Dialysis
Patients 400
(thousands) Patients (n)
300 520,240
Projection 281,355
200 95% CI
243,524
100 r2 = 99.8%
0
1984 1988 1992 1996 2000 2004 2008
United States Renal Data System. USRDS 2000 Annual Data Report. June 2000.
Annual Transition Rates
Through Stages of DN
No nephropathy
1.4%
2.0% (1.3% to 1.5%)
(1.9% to 2.2%)

Microalbuminuria
3.0%
2.8% (2.6% to 3.4%)
(2.5% to 3.2%)

Macroalbuminuria
4.6%
2.3% (3.6% to 5.7%)
(1.5% to 3.0%)

Elevated plasma creatinine or

Renal replacement therapy
19.2%
DN = diabetic nephropathy. (14.0% to 24.4%)
Adler et al. Kidney Int. 2003;63:225-232.
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 18 (49) 13 (72) 2 (11) 3 (17)
(n = 37)

NIDDM with
normoalbuminuria 18 (17) 13 (32) 0 (0) 11 (61)
(n = 109)

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 Mothers
(n=156) (n=178)
All offspring (n=478)
AER 2915 3112
AER adjusted for SBP 2715 3413

Sons (n=225)
AER 1517 3515
AER adjusted for SBP 1218 3916

Daughters (n=253)
AER 3419 2916
AER adjusted for SBP 3120 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 p value

ACR 8.38±0.2 41.6±2.9

mg/mmol

CRP mg/l 3.8±0.15 5.37±0.47 0.0018

Fibrinogen 278.2±1.6 295.7±4 0.0001

mg/dl

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)*
vWf
67.9% 1.02 (0.59-1.76)
111.9% 1.89 (1.17-3.08)*
CRP
1.9 mg/L 1.80 (1.06-3.08)†
5.5 mg/L 2.92 (1.76-4.85)*

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 ACE inhibitor Bradykinin

Angiotensin-
X converting X
enzyme
Angiotensin II
Angiotensin receptor X Degradation
blocker
products
AT1 receptor AT2 receptor

Glomerulosclerosis Vasoconstriction
Vasodilation Antiproliferation
Na/fluid retention SMC proliferation
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
160 153 153 153
145 143 142
140
120
mm Hg 100
80 90 90 91
84 84 84
60
Baseline
40 On Treatment (150 mg)
20 On Treatment (300 mg)
0
Control Irbesartan Irbesartan
(n = 201) 150 mg 300 mg
(n = 195) (n = 194)

IRMA-2 = Irbesartan in Patients with Type 2 Diabetes and Microalbuminura.

Parving H-H et al. N Engl J Med. 2001;345:870-878.
IRMA 2: Incidence of Diabetic
Nephropathy
20
RR = 70%
Placebo
15

Incidence of Irbesartan*
Diabetic 10 150 mg/d
Nephropathy (%)

5
Irbesartan*
300 mg/d
0
0 6 12 18 22 24
Follow-up (mo)
*P < 0.01 vs placebo.
Parving H-H et al. N Engl J Med. 2001;345:870-878.
 IRMA 2: Renoprotective Effects of
Angiotensin II Blockade Independent
of BP Lowering

20

10 Placebo
0
*
-10
% Change
in UAER 150 mg irbesartan
-20

-30

-40 300 mg irbesartan

*
-50
0 3 6 12 18 24

Follow-up (mo)
*P < 0.001 vs placebo.
Adapted from Parving HH et al. N Eng J Med. 2001;345: 870-878.
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 Amlodipine
Adapted from Viberti G et al. Circulation. 2002;106:672-678.
 Valsartan Corrects Microalbuminuria to a
Greater Extent than Amlodipine in Type 2 DM

35
% of Patients Returning to

29.9%*
30
Normoalbuminuria

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
-10.4 -10.7
Mean Reduction
-15 -14.1
in BP (mm Hg)
-16.3 -16.7
-20

-25 Candesartan 16mg qd

Lisinopril 20mg qd -25.3
-30 Combination

Mogensen CE et al. BMJ. 2000;321:1440-1444.

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/
Enalapril
Indapamide
(n = 233) (n = 224)
100
- 42% - 27%

80 P = 0.002
Urinary AER
(final/baseline) 60
(%)
Residual AER
40

20

0
[- 50%,- 33%] [- 37%,- 16%]
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 (%) RR (95% CI)
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
Dietary control of hyperglycemia 631 19.0
Insulin 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

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
Doubling of Serum Creatinine ESRD
Placebo Placebo
30 RR 25% 30
% With Event

% With Event
P = 0.006 RR 28%
P = 0.002
20 20
Losartan

10 10 Losartan

0 0
0 12 24 36 48 0 12 24 36 48
Months Months
P (+CT) 762 689 554 295 36 P (+CT) 762 715 610 347 42
L (+CT) 751 692 583 329 52 L (+CT) 751 714 625 375 69

ESRD or Death
50
Placebo
40
% With Event

RR 20%
P = 0.010
30
20
Losartan
10
0
0 12 24 36 48
Months
P (+CT) 762 715 610 347 42
L (+CT) 751 714 625 375 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.
RENAAL: Change From Baseline
in Proteinuria*
40

20 Placebo

Median 0
Percent
Change -20 P = 0.0001
35% overall reduction

-40
Losartan
-60
0 12 24 36 48
Months

P (+CT) 762 632 529 390 130

L (+CT) 751 661 558 438 167

*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
20 Risk Reduction: 32%
p=0.005 P
% with event

15

10 L

0
0 12 24 36 48
Months
P (+CT) 762 685 616 375 53
L (+CT) 751 701 637 388 74
Brenner et al. NEJM 2001
Antihypertensive and Antiproteinuric
Responses to Increasing ACE-I Dose
Lisinopril Dose (mg)
5 mg 10 mg 15 mg 20 mg
0

-10
-20

-30
% Reduction -40
vs. Control
-50
-60

-70
BP Urine protein
-80

Adapted from Palla R et al. Int J Clin Pharmacol Res. 1994;14:35-43.

Effect of 40 wk ACEi on ACR in 45 Type 2 DM with
early DN with or without aldosterone escape

Variable Baseline Escape neg. Escape pos.

(27) (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
Variable Relative Risk P Value
(95% CI)

Nephropathy 0.39 (0.17-0.87) 0.003

Retinopathy 0.42 (0.21-0.86) 0.02

Autonomic 0.37 (0.18-0.79) 0.002

neuropathy

Peripheral 1.09 (0.54-2.22) 0.66

neuropathy

0.0 0.5 1.0 1.5 2.0 2.5

Intensive Conventional
Therapy Therapy
Better Better
Gaede P et al. N Engl J Med. 2003;348:383-393.
 Steno 2: Intensive Therapy Reduces
the Risk of CVD Morbidity and
Mortality
60
Conventional therapy
50
Hazard ratio = 0.47
40 (95% CI 0.24 to 0.73; P = 0.008)

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