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