cardiovascular risk in chronic renal disease giancarlo viberti, md professor of diabetes and...
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Cardiovascular risk in
Chronic Renal Disease
Giancarlo Viberti, MDProfessor of Diabetes and Metabolic Medicine
GKT School of MedicineGuy’s Hospital
King’s College LondonLondon, UK
Excess Mortality With Hypertensionand Proteinuria in Type 2 Diabetes
StandardizedMortality Ratio
Status of Hypertension (H) and Proteinuria (P) in Type 2 Diabetes
Wang SL et al. Diabetes Care. 1996;19:305-312.
0
500
1000
P-H- P-H+ P+H- P+H+ P-H- P-H+ P+H- P+H+Men Women
Increasing Death Rate Due to Diabetes
Diabetes
Cancer
CardiovascularDisease
Stroke
Year
140
130
120
110
100
90
80
70
60
Age-AdjustedDeath RateRelative to
1980
1980 1982 1984 1986 1988 1990 1992 1994 1996
Seven-year incidence in a Finnish-based cohort.*P < 0.001
Risk of myocardial infarction is increased in type 2 diabetes
3.5%
20.2%18.8%
45.0%
0%
10%
20%
30%
40%
50%
Nondiabetic subjects (n = 1,373)
Type 2 diabetic subjects (n = 1,059)
Ris
k o
f fa
tal
or
no
nfa
tal
myo
card
ial
infa
rcti
on No prior myocardial infarction
Prior myocardial infarction
*
*
Adapted from Haffner SM. New Engl J Med 1998; 339:229–234.
Proteinuria is an Independent Risk Factor for Mortality in Type 2 Diabetes
**P P < 0.001 normoalbuminuria vs macroalbuminuria.< 0.001 normoalbuminuria vs macroalbuminuria.Gall MA et al. Diabetes. 1995;44:1303-1309.
1.0
0.9
0.8
0.7
0.6
0.5
0 1 2 3 4 5 6
Years
Survival(all-cause mortality)
Normoalbuminuria(n = 191)
Microalbuminuria(n = 86)
Macroalbuminuria*(n = 51)
P <.01
P <.05
Relative risk of CVD and mortality in3498 DM by quartile of albuminuria (ACR)
Gerstein et al. JAMA 2001
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
ACR (mg/mmol) quartiles RR (95% CI)
Relative risk of CVD and mortality in5545 patients without diabetes by quartile of
albuminuria (ACR)
Gerstein et al. JAMA 2001
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
ACR (mg/mmol) quartiles RR (95% CI)
The Metabolic Syndrome: a network of atherogenic factors
Adapted from McFarlane S, et al. J Clin Endocrinol Metab. 2001; 86:713–718.
Atherosclerosis
Genetic factorsEnvironmentalfactors
Insulin Resistance
Hyperglycemia/IGT
Dyslipidemia
Hypertension
Endothelial dysfunction/ Microalbuminuria
Hypofibrinolysis
Inflammation
PWV and mortality in patients with ESRD on RRTPWV and mortality in patients with ESRD on RRT
Blacher J et al. Kidney Int; 63Blacher J et al. Kidney Int; 63 :1852, 2003 :1852, 2003
Diabetes: The Most Common Cause of ESRDPrimary Diagnosis for Patients Who Start Dialysis
United States Renal Data System. USRDS 2000 Annual Data Report. June 2000.
Diabetes50%
Hypertension27%
Glomerulonephritis
13%
Other
10%
Patients (n)Projection95% CI
1984 1988 1992 1996 2000 2004 20080
100
200
300
400
500
600
700
r2 = 99.8%243,524
281,355520,240
No. of Dialysis Patients
(thousands)
DN = diabetic nephropathy.Adler et al. Kidney Int. 2003;63:225-232.
Annual Transition Rates Through Stages of DN
No nephropathy
Microalbuminuria
Macroalbuminuria
Elevated plasma creatinine or Renal replacement therapy
2.0%(1.9% to 2.2%)
2.8%(2.5% to 3.2%)
2.3%(1.5% to 3.0%)
1.4%(1.3% to 1.5%)
3.0%(2.6% to 3.4%)
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
NIDDM withmicroalbuminuria (n = 37)
NIDDM withnormoalbuminuria(n = 109)
18 (49) 13 (72) 2 (11) 3 (17)
NIDDM = non–insulin-dependent diabetes mellitus.Mattock MB et al. Diabetes. 1998; 47:1786-1792.
18 (17) 13 (32) 0 (0) 11 (61)
n (%) n (%) n (%) n (%)
Heritability of AER in families of type 2 diabetic patients
Percent Resemblance
Fathers Mothers(n=156) (n=178)
All offspring (n=478)AER 2915 3112AER adjusted for SBP 2715 3413
Sons (n=225)AER 1517 3515AER adjusted for SBP 1218 3916
Daughters (n=253)AER 3419 2916AER adjusted for SBP 3120 3516
Data are age and FBG adjusted Forsblom 1999
Association of microalbuminuria with non traditional cardiovascular risk factors in
1481 subjects in the IRAS
Festa et al. Kidney Int. 2000
Variable MA neg MA pos p value
ACR mg/mmol
8.38±0.2 41.6±2.9
CRP mg/l 3.8±0.15 5.37±0.47 0.0018
Fibrinogen mg/dl
278.2±1.6 295.7±4 0.0001
Risk Factors for Mortality in Patients With Type 2 DM – 9 Year Follow-up
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.
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)*
RR (95% CI) adjusted for conventional risk factors
The Renin System and Therapeutic Intervention
Angiotensinogen
Angiotensin I
Angiotensin II
ACE inhibitorACE inhibitor
XXAngiotensin receptor blocker
Angiotensin receptor blocker
Angiotensin- converting
enzyme
Angiotensin- converting
enzymeXX
Bradykinin
Degradationproducts
Vasodilation
Vasoconstriction
Renin
Na/fluid retention SMC proliferation
GlomerulosclerosisAntiproliferation
AT1 receptor AT2 receptor
XX
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 = Irbesartan in Patients with Type 2 Diabetes and Microalbuminura.Parving H-H et al. N Engl J Med. 2001;345:870-878.
IRMA-2: Blood Pressure Reduction
0
20
40
60
80
100
120
140
160
180
200
Control Irbesartan Irbesartan
9084
153145
9084
153143
9184
153142
(n = 201) 150 mg(n = 195)
300 mg(n = 194)
mm Hg
BaselineOn Treatment (150 mg)
On Treatment (300 mg)
IRMA 2: Incidence of Diabetic Nephropathy
*P < 0.01 vs placebo.Parving H-H et al. N Engl J Med. 2001;345:870-878.
0
5
10
15
20
0 6 12 18 22 24
Follow-up (mo)
Incidence of Diabetic
Nephropathy (%)
Placebo
Irbesartan*150 mg/d
Irbesartan* 300 mg/d
RR = 70%
*P < 0.001 vs placebo.Adapted from Parving HH et al. N Eng J Med. 2001;345: 870-878.
0 3 6 12 18 24-50
-40
-30
-20
-10
0
10
20
Follow-up (mo)
% Change in UAER
*
*
Placebo
IRMA 2: Renoprotective Effects of Angiotensin II Blockade Independent of BP Lowering
150 mg irbesartan
300 mg irbesartan
MARVAL: Mean BP Effects in Type 2 Diabetic Patients with MicroAlbuminuria
Valsartan
Amlodipine
Mean Changefrom Baseline
(mm Hg)at 24 weeks
MARVAL = MicroAlbuminuria Reduction with Valsartan trialViberti G. Circulation. 2002;106:672-678.
-11.2 -11.6
-6.6 -6.5
SBP DBP
Valsartan Reduces UAER to a Greater Extent than Amlodipine in Type 2 DM
UAER (µg/min)
Adapted from Viberti G et al. Circulation. 2002;106:672-678.
0
10
20
30
40
50
60
70
Valsartan Amlodipine
P < 0.001
Baseline Valsartan 24 Wks Amlodipine 24 Wks
Primary End Point
Valsartan Corrects Microalbuminuria to a Greater Extent than Amlodipine in Type 2 DM
0
5
10
15
20
25
30
35
Amlodipine
14.5%
29.9%*
Normoalbuminuria = UAER < 20 g/min; *P = 0.001 vs. amlodipineViberti G. Circulation. 2002;106:672-678.
% o
f Pa
tien
ts R
etu
rnin
g to
N
orm
oa
lbu
min
uria
Valsartan
CALM Study: ARB and ACE Inhibitor Increase BP Lowering
-10.4
-14.1
-10.7
-16.7-16.3
-25.3
-30
-25
-20
-15
-10
-5
0
Diastolic BP Systolic BP
Candesartan 16mg qd
Lisinopril 20mg qd
Combination
Mean Reductionin BP (mm Hg)
Mogensen CE et al. BMJ. 2000;321:1440-1444.
CALM: Combined Therapy of ARBs and ACE-Is: Effect on Proteinuria
197 Type 2 DM197 Type 2 DMWith MicroalbuminuriaWith Microalbuminuria
Lisinopril 20 mgLisinopril 20 mg Candesartan 16 mgCandesartan 16 mg Lisinopril 20 mgLisinopril 20 mgCandesartan 16 mgCandesartan 16 mg
CALM = Candesartan and Lisinopril Microalbuminuria Study. Mogensen CE et al. BMJ. 2000;321:1440-1444.
39% 24% 50%
Reduction in Urinary Albumin: Creatinine Ratio (%)Reduction in Urinary Albumin: Creatinine Ratio (%)
0
20
40
60
80
100
Urinary AER(final/baseline)
(%)
95% CI[- 50%,- 33%] [- 37%,- 16%]
- 27%- 42%
Perindopril/Indapamide
(n = 233)
Enalapril(n = 224)
Residual AER
PREMIER = Preterax in Albuminuria Regression. Mogensen CE, Viberti GC et al. Hypertension. 2003;41:1063-1071.
PP = 0.002= 0.002
PREMIER Study: Effect of Perindopril / Indapamide vs Enalapril on Urinary AER in Type 2 DM With Early DN
MICRO-HOPE = Microalbuminurea, Cardiovascular, and Renal Outcomes HOPE Substudy.HOPE Study Investigators. Lancet. 2000;356:860.
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
RENAAL: Composite Primary End Point
ESRD or Death
Doubling of Serum Creatinine
0 12 24 36 48Months
0
10
20
30
% W
ith
Ev
en
t
P = 0.006RR 25%
751 692 583 329 525252525252762 689 554 295 363636363636P (+CT)
L (+CT)
ESRD
751 714 625 375 69L (+CT)
0 12 24 36 48Months
% W
ith
Ev
en
t
0
10
20
30
762 715 610 347 42P (+CT)
P = 0.002RR 28%
Placebo
Losartan
P (+CT)L (+CT)
0 12 24 36 48Months
0
10
20
30
40
50
% W
ith
Ev
en
t
P = 0.010RR 20%
751 714 625 375 696969696969762 715 610 347 424242424242
Placebo
Losartan
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.
Placebo
Losartan
*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.
0 12 24 36 48Months
MedianPercent Change
-60
-40
-20
0
20
40
751 661 558 438 167167167167167167P (+CT)L (+CT)
762 632 529 390 130130130130130130
P = 0.0001 35% overall reduction
RENAAL: Change From Baseline in Proteinuria*
Placebo
Losartan
RENAALFirst Hospitalization for Heart Failure
0 12 24 36 48Months
0
5
10
15
20%
with
eve
ntRisk Reduction: 32%p=0.005
P (+CT)L (+CT)
762 685 616 375 53751 701 637 388 74
P
L
Brenner et al. NEJM 2001
Antihypertensive and Antiproteinuric Responses to Increasing ACE-I Dose
% Reduction vs. Control
-80
-70
-60
-50
-40
-30
-20
-10
05 mg 10 mg 15 mg 20 mg
Lisinopril Dose (mg)
BP Urine protein
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
Sato et al Hypertension 2003
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
Effect of spironolactone Rx (25mg/day) on AER in ACEi- treated Type 2 DM with aldosterone escape
Sato et al Hypertension 2003
Mean AERMean AER Individual AERIndividual AER
Variable 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 0.37 (0.18-0.79) 0.002neuropathy
Peripheral 1.09 (0.54-2.22) 0.66neuropathy
0.0 0.5 1.0 1.5 2.0 2.5
IntensiveTherapyBetter
ConventionalTherapyBetterGaede P et al. N Engl J Med. 2003;348:383-393.
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
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.
Primary CompositeEnd Point (%)
00 3612
966048 847224
60
30
40
20
10
50
Intensive therapy
Conventional therapy
Hazard ratio = 0.47 (95% CI 0.24 to 0.73; P = 0.008)
Steno 2: Intensive Therapy Reduces the Risk of CVD Morbidity and Mortality
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