Cardiovascular risk in Chronic Renal Disease

1
Cardiovascular risk in Chronic Renal Disease

• Giancarlo Viberti, MDProfessor of Diabetes and
  Metabolic MedicineGKT School of MedicineGuys
  HospitalKings College LondonLondon, UK

2
Excess Mortality With Hypertensionand
Proteinuria in Type 2 Diabetes
Status of Hypertension (H) and Proteinuria (P) in
Type 2 Diabetes
1000
StandardizedMortality Ratio
500
0
P-H- P-H PH- PH
P-H- P-H PH- PH
Men
Women
Wang SL et al. Diabetes Care. 199619305-312.
3
Increasing Death Rate Due to Diabetes
140 130 120 110 100 90 80 70 60
Diabetes
Age-AdjustedDeath Rate Relative to 1980
Cancer
Cardiovascular Disease
Stroke
1980
1982
1984
1986
1988
1990
1992
1994
1996
Year
4
Risk of myocardial infarction is increased in
type 2 diabetes

50
45.0
No prior myocardial infarction
40
Prior myocardial infarction
Risk of fatal or nonfatal myocardial infarction
30

20.2
18.8
20
10
3.5
0
Nondiabetic subjects (n 1,373)
Type 2 diabetic subjects (n 1,059)
Seven-year incidence in a Finnish-based
cohort. P lt 0.001
Adapted from Haffner SM. New Engl J Med 1998
339229234.
5
Proteinuria is an Independent Risk Factor for
Mortality in Type 2 Diabetes
1.0
Normoalbuminuria (n 191)
0.9
P lt.01
Microalbuminuria (n 86)
0.8
Survival (all-cause mortality)
P lt.05
0.7
Macroalbuminuria (n 51)
0.6
0.5
0
1
2
3
4
5
6
Years
P lt 0.001 normoalbuminuria vs macroalbuminuria. G
all MA et al. Diabetes. 1995441303-1309.
6
Relative risk of CVD and mortality in3498 DM by
quartile of albuminuria (ACR)
ACR (mg/mmol) quartiles RR (95 CI)
Gerstein et al. JAMA 2001
7
Relative risk of CVD and mortality in5545
patients without diabetes by quartile of
albuminuria (ACR)
ACR (mg/mmol) quartiles RR (95 CI)
Gerstein et al. JAMA 2001
8
The Metabolic Syndrome a network of atherogenic
factors
Genetic factors Environmental factors
Hyperglycemia/IGT Dyslipidemia Hypertension Endoth
elial dysfunction/ Microalbuminuria Hypofibrinolys
is Inflammation
Insulin Resistance
Atherosclerosis
Adapted from McFarlane S, et al. J Clin
Endocrinol Metab. 2001 86713718.
9
PWV and mortality in patients with ESRD on
RRT
Blacher J et al. Kidney Int 63 1852, 2003
10
Diabetes The Most Common Cause of ESRD
Primary Diagnosis for Patients Who Start Dialysis
Glomerulonephritis
Other
10
13
700
600
500
No. of Dialysis Patients (thousands)
400
520,240
300
281,355
200
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.
11
Annual Transition Rates Through Stages of DN
No nephropathy
1.4(1.3 to 1.5)
Microalbuminuria
3.0(2.6 to 3.4)
DEATH
Macroalbuminuria
4.6(3.6 to 5.7)
Elevated plasma creatinine or Renal replacement
therapy
19.2(14.0 to 24.4)
DN diabetic nephropathy. Adler et al. Kidney
Int. 200363225-232.
12
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) NIDDM
with normoalbuminuria (n 109)
18 (49) 13 (72) 2 (11) 3 (17)
18 (17) 13 (32) 0 (0) 11 (61)
NIDDM noninsulin-dependent diabetes
mellitus.Mattock MB et al. Diabetes. 1998
471786-1792.
13
Rate of Progression of AER Predicts CVD Mortality
in Type 2 DM With Microalbuminuria
Slow progressors (AER lt4 mg/mmol/y)
100
80
Fast progressors (AER gt4 mg/mmol/y)
60
Survival ()
40
20
0
20 40 60 80 100
Follow-up (mo)
CVD cardiovascular disease AER albumin
excretion rate. Adapted from Spoelstra-de Man A
et al. Diabetes Care. 2001242097-2101.
14
Heritability of AER in families of type 2
diabetic patients
Percent Resemblance
Fathers Mothers (n156)
(n178)
All offspring (n478) AER 29?15
31?12 AER adjusted for SBP
27?15
34?13 Sons (n225) AER
15?17
35?15 AER adjusted for
SBP 12?18
39?16 Daughters (n253) AER

34?19
29?16 AER adjusted for SBP
31?20
35?16
Data are age and FBG adjusted
Forsblom 1999
15
Association of microalbuminuria with non
traditional cardiovascular risk factors in 1481
subjects in the IRAS
Festa et al. Kidney Int. 2000
16
Risk Factors for Mortality in Patients With Type
2 DM 9 Year Follow-up
RR (95 CI) adjusted for conventional risk
factors
N 328 patients P lt 0.01 P lt 0.05. vWf von
Willebrand factor CRP C-reactive
protein. Stehouwer et al. Diabetes.
2002511157-1165.
17
The Renin System and Therapeutic Intervention
Angiotensinogen
Renin
Angiotensin I
Bradykinin
ACE inhibitor
Angiotensin- converting enzyme
X
X
Angiotensin II
X
Angiotensin receptor blocker
Degradation products
AT1 receptor
AT2 receptor
Glomerulosclerosis
Vasoconstriction
Antiproliferation
Vasodilation
Na/fluid retention
SMC proliferation
18
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. 2001134370-379.
19
IRMA-2 Blood Pressure Reduction
153
153
153
145
143
142
mm Hg
90
90
91
84
84
84
Baseline
On Treatment (150 mg)
On Treatment (300 mg)
(n 201)
150 mg (n 195)
300 mg (n 194)
IRMA-2 Irbesartan in Patients with Type 2
Diabetes and Microalbuminura. Parving H-H et al.
N Engl J Med. 2001345870-878.
20
IRMA 2 Incidence of Diabetic Nephropathy
20
RR 70
Placebo
15
Irbesartan150 mg/d
Incidence of Diabetic Nephropathy ()
10
5
Irbesartan 300 mg/d
0
0
6
12
18
22
24
Follow-up (mo)
P lt 0.01 vs placebo. Parving H-H et al. N Engl J
Med. 2001345870-878.
21
IRMA 2 Renoprotective Effects of Angiotensin II
Blockade Independent of BP Lowering
20
10
Placebo
0
Change in UAER

150 mg irbesartan
300 mg irbesartan

0
3
6
12
18
24
Follow-up (mo)
P lt 0.001 vs placebo. Adapted from Parving HH et
al. N Eng J Med. 2001345 870-878.
22
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
-11.2
-11.6
MARVAL MicroAlbuminuria Reduction with
Valsartan trial Viberti G. Circulation.
2002106672-678.
23
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 lt 0.001
60
UAER (µg/min)
50
40
30
20
10
0
Valsartan
Amlodipine
Adapted from Viberti G et al. Circulation.
2002106672-678.
24
Valsartan Corrects Microalbuminuria to a Greater
Extent than Amlodipine in Type 2 DM
of Patients Returning to Normoalbuminuria
Valsartan
Normoalbuminuria UAER lt 20 ?g/min P 0.001
vs. amlodipine Viberti G. Circulation.
2002106672-678.
25
CALM Study ARB and ACE Inhibitor Increase BP
Lowering
Mean Reduction in BP (mm Hg)
Mogensen CE et al. BMJ. 20003211440-1444.
26
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.
20003211440-1444.
27
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)
- 27
- 42
P 0.002
Urinary AER(final/baseline)()


- 37,- 16
- 50,- 33
95 CI
PREMIER Preterax in Albuminuria Regression.
Mogensen CE, Viberti GC et al. Hypertension.
2003411063-1071.
28
MICRO-HOPE Study Ramipril Reduces Risk of CVD
in Diabetic Patients With Microalbuminuria
MICRO-HOPE Microalbuminurea, Cardiovascular,
and Renal Outcomes HOPE Substudy. HOPE Study
Investigators. Lancet. 2000356860.
29
RENAAL Composite Primary End Point
Doubling of Serum Creatinine
ESRD
Placebo
RR 25
30
P 0.006
20
Losartan
With Event
10
0
0
12
24
36
48
Months
P (CT)
762
689
554
295
36
36
36
36
36
36
L (CT)
L (CT)
751
692
583
329
52
52
52
52
52
52
751
714
625
375
69
ESRD or Death
RENAAL Reduction of End Points in NIDDM with
the Angiotensin II Antagonist Losartan Brenner
BM et al. N Engl J Med. 2001345861-869.
30
RENAAL Change From Baseline in Proteinuria
40
Placebo
20
0
MedianPercent Change
P 0.0001 35 overall reduction
-20
-40
Losartan
-60
0
12
24
36
48
Months
P (CT)
762
632
529
390
130
130
130
130
130
130
L (CT)
751
661
558
438
167
167
167
167
167
167
Proteinuria measured as the urine
albumincreatinine ratio from a first morning
void. Brenner BM et al. N Engl J Med. 2001
345861-869.
31
RENAALFirst Hospitalization for Heart Failure
Risk Reduction 32 p0.005
P
with event
L
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
32
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 vs. Control
-40
-50
-60
-70
BP
Urine protein
-80
Adapted from Palla R et al. Int J Clin Pharmacol
Res. 19941435-43.
33
Effect of 40 wk ACEi on ACR in 45 Type 2 DM with
early DN with or without aldosterone escape

• Sato et al Hypertension 2003

34
Effect of spironolactone Rx (25mg/day) on AER in
ACEi- treated Type 2 DM with aldosterone escape
Individual AER
Mean AER
Sato et al Hypertension 2003
35
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)
Variable
P Value
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 Therapy Better
Conventional Therapy Better
Gaede P et al. N Engl J Med. 2003348383-393.
36
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 CompositeEnd Point ()
30
20
Intensive therapy
10
0
36
48
24
0
12
96
60
84
72
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. 2003348383-393.
37
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