1

Prevention and Treatment of Cardiovascular and Renal Disease

in Hypertensive Patients With Type 2 Diabetes

Michael B. Ganz, MD

Director, Clinical Research Center

Clevland Clinic

.

2

Prevention and Treatment of Cardiovascular and Renal Disease in Hypertensive Patients

With Type 2 Diabetes

After taking part in this activity, participants will be better able to:

• Monitor hypertensive patients with type 2 diabetes for cardiovascular and renal disease risk factors

• Identify the various stages of severity of chronic kidney disease

• Determine the presence of chronic kidney disease as manifested by albuminuria and reduced glomerular filtration rate

• Select the appropriate antihypertensive agent to reduce cardiovascular and renal disease in hypertensive patients with type 2 diabetes

• Apply various approaches to prevention and treatment of cardiovascular and renal disease in hypertensive patients with type 2 diabetes

Learning Objectives

3

Epidemiology and Potential Risks of Untreated

or Inadequately Treated Hypertension

4

Systolic Blood Pressure Increases With Age: NHANES III

Age (y)

≥80

Men

18-29

30-39

40-49

50-59

60-69

70-79

0

70

80

110

130

150

DBP

SBP

Women

70

80

110

130

150

018-29

30-39

40-49

50-59

60-69

70-79

≥80

DBP

SBP

mm

Hg

mm

Hg

African American

White

Mexican American

DBP = diastolic blood pressure; SBP = systolic blood pressure. Adapted with permission from Burt VL, et al. Hypertension. 1995;25:305-313.

5

100

60

20

0

80

40

Ris

k o

f H

yper

ten

sio

n (

%)

Follow-up (y)

Men

0 12 202 164 6 8 10 14 18

Women

Residual Lifetime Risk of Hypertension in Women and Men Aged 65 Years

Adapted with permission from Vasan RS, et al. JAMA. 2002;287:1003-1010.

6

CV

Mo

rtal

ity

Ris

k

SBP/DBP (mm Hg)

0

1

2

3

4

5

6

7

8

115/75 135/85 155/95 175/105

CV = cardiovascular; DBP = diastolic blood pressure; SBP = systolic blood pressure.*Individuals aged 40-69 years, starting at BP 115/75 mm Hg.Lewington S, et al; Prospective Studies Collaboration. Lancet. 2002;360:1903-1913.

CV Mortality Risk Doubles WithEach 20/10 mm Hg BP Increment*

7

Percent Chance of Cardiovascular Event in 5 Years: No Diabetes

4 5 6 7 8 4 5 6 7 8

MenWomenNonsmoker Smoker

Total Chol.:HDL-C

Age70

Nonsmoker SmokerTotal Chol.:HDL-C

Age60

180/105160/95140/85120/75

180/105160/95140/85120/75

Age50

180/105160/95140/85120/75

44 55 66 77 88 44 55 66 77 88

>20%

15-20%10-15%5-10%2.5-5%<2.5%

Adapted with permission from Jackson R. BMJ. 2000;320:709-710.

BP(mm Hg)

8

Percent Chance of Cardiovascular Event in 5 Years: Diabetes

Adapted with permission from Jackson R. BMJ. 2000;320:709-710.

>20%

15-20%10-15%5-10%2.5-5%

Age70

Age60

180/105160/95140/85120/75

180/105160/95140/85120/75

Age50

180/105160/95140/85120/75

BP(mm Hg)

MenWomenNonsmoker Smoker

Total Chol.:HDL-CNonsmoker Smoker

Total Chol.:HDL-C4 5 6 7 8 4 5 6 7 8 44 55 66 77 88 44 55 66 77 88

9

JNC 7 Algorithm for the Treatment of Hypertension

Not at goal BP

Optimize dosages or add drugs to reach goal BP Consider consultation with HTN specialist

Without compelling indications

Stage 2 HTN SBP ≥ 160, DBP ≥ 100 mm Hg

2-drug combo for most (usually thiazide-type diuretic and

ACEI, or ARB, or BB, or CCB)

Stage 1 HTNSBP 140-159, DBP 90-99 mm Hg Thiazide-type diuretics for most.

May consider ACEI, ARB, BB, CCB, or combination

Drugs for compelling indications

Other antihypertensives (diuretics, ACEI, ARB, BB, CCB)

as needed

With compelling indications

Initial drug choices

Lifestyle modifications Not at goal BP (<140/90 mm Hg or <130/80 mm Hg for those

with diabetes or chronic kidney disease)

ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin II receptor blocker; BB = -blocker;

CCB = calcium channel blocker; DBP = diastolic blood pressure; SBP = systolic blood pressure.Adapted with permission from Chobanian AV, et al. Hypertension. 2003;42:1206-1252.

10

JNC Reclassification of BP Based on Risk

Source for JNC VI: Arch Intern Med. 1997;157:2413-2446.Adapted with permission from Chobanian AV, et al. Hypertension. 2003;42:1206-1252.

JNC VIBP (mm Hg)

JNC VIBP (mm Hg)

Optimal

JNC 7BP (mm Hg)

JNC 7BP (mm Hg)

Normal<120/80 <120/80

Stage 1

HypertensionStage 1140-159/90-99 140-159/90-99

Normal

BorderlinePrehypertension

120-129/80-84

130-139/85-89120-139/80-89

Stage 2

Stage 3Stage 2

160-179/100-109

≥180/110≥160/100

11

ADA and NKF 2004 Guidelines for Treating Hypertension in

Patients With Type 2 Diabetes

Kidney StatusMicroalbuminuria

(30–300 mg/day*)

Albuminuria

(>300 mg/day*)

Normal Renal Function (<1.4 mg/dL†)

Goal: <130/80 mm Hg

ACE inhibitor

Goal: <130/80 mm Hg

ACE inhibitor or ARB

Renal Insufficiency (≥ 1.4 mg/dL†)

Goal: <130/80 mm Hg

ACE inhibitor or ARB

Goal: <130/80 mm Hg

ARB

*Albumin in urine.†Serum creatinine.

American Diabetes Association. Diabetes Care. 2004;27(suppl 1):S65-S67. Kidney Disease Outcomes Quality Initiative (K/DOQI). Am J Kidney Dis. 2004;43(5 suppl 1):S1-S290.

12

Interrelationships Between Hypertension,

Diabetes, CKD, and CVD

13

Morbidity and Mortality Along the Renal Continuum

Risk FactorsDiabetes

Hypertension

EndothelialDysfunction

Micro- albuminuria

Macro-proteinuria

NephroticProteinuria

End-Stage Renal Disease

CVD

Death

14

CKD, CVD, and DM

• CKD is a worldwide public health problem

• Rising incidence, poor outcomes, increased cost

• High prevalence of early stages of CKD expected to fuel the growth of more patients treated for ESRD

• Increase would be even greater were it not for the competitive hazard for CVD and death in patients with CKD

US Renal Data System. USRDS 2005 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. NIH, NIDDKS, Bethesda, Md, 2005. Available at: http://www.usrds.org/adr.htm. Accessed December 7, 2005.

CKD = chronic kidney disease; CVD = cardiovascular disease; ESRD = end-stage renal disease.

15

CKD, CVD, and DM (cont.)

• Patients with CKD are more likely to die of CVD than to develop kidney failure

• CKD appears to be a risk factor for CVD

• Mortality due to CVD is 10–30 times higher in the ESRD population compared with the general population

• Patients with diabetes mellitus and CKD are 5 times as likely to die than reach ESRD

Sarnak MJ, et al. Hypertension. 2003;42:1050-1065.

CKD = chronic kidney disease; CVD = cardiovascular disease; ESRD = end-stage renal disease.

16

39%

33%

13%15%

Incidence of ESRD by CausePrimary Diagnosis for Patients Who Start Dialysis

Hypertension

OtherDiabeticNephropathy

Diabetic Nephropathy+

Hypertension

ESRD = end-stage renal disease; Other = cystic kidney disease plus glomerulonephritis.United States Renal Data System. 2003 Annual Report. Figure 2.9. Available at: http://www.usrds.org/slides.htm. Accessed September 29, 2005.

17

Stages of Chronic Kidney Disease

Stage DescriptionGFR,

mL/min/1.73 m2

USPrevalence,

1000s

USPrevalence*, %

1Kidney damage with

normal or increased GFR≥90 5900 3.3

2Kidney damage with

mildly decreased GFR60–89 5300 3.0*

3 Moderately decreased GFR 30–59 7600 4.3

4 Severely decreased GFR 15–29 400 0.2

5 Kidney failure <15 or dialysis 300 0.1

GFR = glomerular filtration rate.

*Prevalence data for stages 1 and 2 are based on NHANES III patients with persistent albuminuria and are likely underestimated.

National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Part 4. Definition and classification of stages of chronic kidney disease. Available at: http://www.kidney.org/professionals/KDOQI/guidelines_ckd/p4_class_g1.htm. Accessed November 9, 2005. Adapted with permission from the National Kidney Foundation.

18GFR = glomerular filtration rate.Reproduced with permission from Go AS, et al. N Engl J Med. 2004;351:1296-1305.

No. of Events 25,803 11,569 7802 4408 1842

Estimated GFR (mL/min/1.73 m2)

Relative Risk of Death per GFR Level

0.76 1.08

4.76

11.36

14.14

0123456789

101112131415

60 45-59 30-44 15-29 <15Ag

e-S

tan

dar

diz

ed R

ate

of

Dea

th F

rom

An

y C

aus

e (p

er 1

00 p

ers

on

-yr)

19

N = 6252*

Creatinine clearance ≤70 mL/min predicted significantly worse outcome after adjustment for covariables*

Renal Dysfunction Predicts Increased Mortality After Acute MI

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 1 2 3 4 5 60

Years

Mo

rtal

ity

<40 mL/min

40–5556–70

71–85

>85

*Adjusted for age, high BP, diabetes, history of angina, previous MI, current smoker, anterior acute MI, ventricular fibrillation, CHF, wall motion index, and thrombolytic therapy.

Reproduced with permission from Sorensen CR, et al. Eur Heart J. 2002;23:948-952.

20

0

0.2

0.4

0.6

0.8

1.0

0 1 2 3 4 5 6 7

Time to Death (years)

Cu

mu

lati

ve S

urv

ival

CrCl <51 mL/min predicted significantly worse outcome, even after adjustment for confounders*

>66 mL/min

51–66 mL/min

39–51 mL/min

<39 mL/min

N = 2042

Renal Dysfunction Predicts Increased Mortality After Acute Stroke

*Adjusted for age, neurologic score, high BP or ischemic heart disease, smoking, and diuretic use; Kaplan-Meier survival analysis (log-rank test, P<.0001). CrCL = creatinine clearance.Reproduced with permission from MacWalter RS, et al. Stroke. 2002;33:1630-1635.

21

With All This Important News, What Do We Need to Do Differently?

• Estimate GFR

• Quantitate: albuminuria/proteinuria

• Control risk factors for CKD/CVD progression

22

Implications of Doubling of Serum Creatinine

0 1 2 3 4 5 6

25

50

75

100

125

0

Cre

atin

ine

Cle

aran

ce

Pcr — Serum Creatinine (mg/dL)

Ucr V

Pcr

Relationship Between Serum Creatinine and GFR

GFR = glomerular filtration rate; Pcr = plasma creatinine Ucr = urinary creatinine; V = volume.

23

Equations to Predict GFR Based on Serum Creatinine

Cockcroft-Gault equation

Abbreviated MDRD Study equation

(140–Age) x Weight72 x SCr

CCr(mL/min) = x (0.85 if female)

GFR (mL/min-1 per 1.73 m2) = 186 x (SCr)-1.154 x (Age)-0.203 x (0.742 if female) x (1.210 if black)

Age is given in years and weight in kilograms.

GFR = glomerular filtration rate; CCr = creatinine clearance; MDRD = Modification of Diet in Renal Disease; Scr = serum creatinine in mg/dL.

National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Guideline 4. Estimation of GFR. Available at: http://www.kidney.org/professionals/kdoqi/guidelines_ckd/p5_lab_g4.htm.

24

Definitions of Proteinuria

Urine Collection Method Normal MicroalbuminuriaAlbuminuria or

Clinical Proteinuria

Total protein

Spot urine dipstick <30 mg/dL NA ≥ 30 mg/dL

Spot urine protein-to-creatinine ratio(varies with method) <200 mg/g NA ≥ 200 mg/g

Albumin

Spot urine albumin-specific dipstick <3 mg/dL >3 mg/dL NA

Spot urine albumin-to-creatinine ratio(varies by sex)

<17 mg/g (men) <25 mg/g (women)

17–250 mg/g (men)25–355 mg/g (women)

>250 mg/g (men)>355 mg/g (women)

NA = not applicable.National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Guideline 1. Definition and stages of chronic kidney disease.Available at: http://www.kidney.org/professionals/kdoqi/guidelines_ckd/p4_class_g1.htm. Adapted with permission from the National Kidney Foundation.

25

Normoalbuminuria

Microalbuminuria

Microalbuminuria and Ischemic Heart Disease RiskR

elat

ive

Ris

k o

f I

sch

emic

Hea

rt D

isea

se

<140 140–1600

1

2

3

4

5

6

>160

Systolic BP (mm Hg)N = 2085; 10-year follow-up; prospective, open-ended, population-based cohort.

Adapted with permission from Borch-Johnsen K, et al. Arterioscler Thromb Vasc Biol. 1999;19:1992-1997.

26

Why Is Microalbuminuria Such a Powerful Predictor of CVD Outcomes

in Patients With Diabetes?

• Higher prevalence of traditional risk factors (independent adverse prognostic risk factor even after adjustment)

• May reflect generalized endothelial dysfunction and increased vascular permeability or abnormalities in the coagulation and fibrinolytic systems

• May denote greater severity of target organ damage

27

Kidney Disease and the Metabolic Syndrome: Parallels

Metabolic Syndrome

• Truncal obesity

• Low HDL cholesterol

• High triglycerides

• Insulin resistance

• Hypertension

• Microalbuminuria

• Markers of inflammation

• Endothelial dysfunction

Renal Disease

• May not be obese

• Low HDL cholesterol

• High triglycerides

• Insulin resistance

• Hypertension

• Micro- or overt albuminuria

• Markers of inflammation

• Endothelial dysfunction

Hunsicker LG. Personal communication.

28

Glomerular Structure

MesangialCell

Endothelial Cell

Capillary Loop

AfferentArteriole

Juxtaglomerular Apparatus

EfferentArteriole

29

CKD Resets the Focus on CV Risk-Reduction Strategies

• BP <130/80 mm Hg

• Evaluate lipids

• Extinguish microalbuminuria/proteinuria

• Reduction in dietary salt/saturated fat

• Intensify glycemic control

• Control anemia

• Control calcium/phosphorus balance

• Antiplatelet therapy

30

Primary Outcome, MI, CV Death, and All Death for Patients With a Serum Creatinine Concentration

<1.4 mg/dL or at Least 1.4 mg/dLMyocardial Infarction

Serum CreatinineConcentration

<1.4 mg/dL

Serum CreatinineConcentration

≥ 1.4 mg/dL

605040302010

0

All Death

Serum CreatinineConcentration

<1.4 mg/dL

Serum CreatinineConcentration

≥1.4 mg/dL

60

50

40

30

20

10

0

Primary Outcome

Serum CreatinineConcentration

<1.4 mg/dL

Serum CreatinineConcentration

≥1.4 mg/dL

80

60

40

20

0

Cardiovascular Death

Serum CreatinineConcentration

<1.4 mg/dL

Serum CreatinineConcentration

≥1.4 mg/dL

40

30

20

10

0

Eve

nts

per

10

00 P

erso

n-Y

ears

(n

)

Eve

nts

per

10

00 P

erso

n-Y

ears

(n

)

All patients

Patients taking placebo

Patients taking ramipril

Reproduced with permission from Mann JF, et al. Ann Intern Med. 2001;134:629-636.

31

Progression to Cardiovascular and Renal Disease

CV EventsDeath

Overt Proteinuria

Microalbuminuria

Doubling of Creatinine

End-Stage Renal Disease

32

Renin-Angiotensin System (RAS)

Angiotensinogen

Angiotensin I

AT1 receptor

ARBs AT2 receptor

ACE inhibitorsACE

Renin

• CAGE• Cathepsin G• Chymase

• tPA• Cathepsin G• Tonin

Angiotensin II

ACE inhibitors

Bradykinin(active)

Bradykinin1-7

(inactive)

CAGE = chymostatin-sensitive angiotensin-generating enzyme; tPA = tissue plasminogen activator.Figure adapted with permission from Dzau VJ, et al. J Hypertens. 1993;11(suppl 3):S13-S18.

33

Possible Mechanisms for the Benefits of A-II Blockade: Hemodynamic Hypothesis

• Hyperglycemia and/or reduced renal mass lead to dilation of the glomerular afferent arteriole and impaired glomerular autoregulation

• Reduced glomerular afferent arteriolar tone, particularly in the presence of systemic hypertension, leads to increased glomerular capillary blood pressure and flow

• The increased glomerular capillary pressure leads to progressive glomerular injury and scarring

34

Possible Mechanisms for the Benefits of A-II Blockade: Proteinuria Hypothesis

• Angiotensin II increases glomerular permeability to proteins, increasing both proteinuria and tubular reabsorption of filtered proteins

• Reabsorption of protein stimulates the tubules to secrete TGF- and other cytokines into the renal interstitium, leading to interstitial fibrosis

• The closest correlate to decreased kidney function is interstitial fibrosis and tubular atrophy, not the glomerular changes of CKD

35

Possible Mechanisms for the Benefits of A-II Blockade: Aldosterone Hypothesis• Aldosterone, released in response to plasma A II, also

induces vascular smooth muscle proliferation1

– In animals, the benefit of captopril in protecting against vascular disease is negated by coadministration of aldosterone

• Aldosterone is similarly implicated in renal damage in the remnant kidney model2

• In studies of human diabetic nephropathy, the rate of progression correlated most strongly with plasma aldosterone levels3

1. Rocha R, et al. Hypertension. 1998;31(1 Pt 2):451-458.2. Greene EL, et al. J Clin Invest. 1996;98:1063-1068.3. Walker WG. Am J Kidney Dis. 1993;22:164-173.

36

Treatment of Hypertension in Patients With Type 2 Diabetes,

CVD, and Stroke

37

Compelling Indications for Individual Drug Classes

Compelling IndicationInitial Therapy

OptionsClinical Trial Basis

DiabetesTHIAZ, BB, ACEI, ARB, CCB

NKF-ADA Guideline, UKPDS, ALLHAT

Chronic kidney disease ACEI, ARBNKF Guideline, Captopril Trial, RENAAL, IDNT, REIN, AASK

Recurrent stroke prevention

THIAZ and ACEI PROGRESS

ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; BB = β-blocker; CCB = calcium channel blocker; THIAZ = thiazide diuretic.Adapted with permission from Chobanian AV, et al. Hypertension. 2003;42:1206-1252.

38

Compelling Indications for Individual Drug Classes (cont.)

Compelling IndicationInitial Therapy

OptionsClinical Trial Basis

Heart failureTHIAZ, BB, ACEI, ARB, ALDO ANT

ACC/AHA Heart Failure Guideline, MERIT-HF, COPERNICUS, CIBIS, SOLVD, AIRE, TRACE, ValHEFT, RALES, CHARM

Post–myocardial infarction BB, ACEI, ALDO ANTACC/AHA Post-MI Guideline, BHAT, SAVE, Capricorn, EPHESUS

High coronary disease risk THIAZ, BB, ACEI, CCBALLHAT, HOPE, ANBP2, LIFE, CONVINCE, EUROPA, INVEST

ACEI = angiotensin-converting enzyme inhibitor; ALDO ANT = aldosterone antagonist; ARB = angiotensin receptor blocker; BB = β-blocker; CCB = calcium channel blocker; THIAZ = thiazide diuretic.Adapted with permission from Chobanian AV, et al. Hypertension. 2003;42:1206-1252.

39

IDNT and RENAAL Trial Results:Major End Points

12 (P=.29)-3 (P=.79)9 (P=.40)10 (P=.26)CV Morbidity and Mortality

12 (P=.40)-4 (P=.80)8 (P=.57)-2 (P=.88)Death

0 (P=.99)23 (P=.07)23 (P=.07)28 (P=.002)ESRD

-6 (P=.60)37 (P<.001)33 (P=.003)25 (P=.006)Doubling of Creatinine

-4 (P=.69)23 (P=.006)20 (P=.02)16 (P=.02)Doubling of Creatinine, ESRD, or Death

Amlodipine vs Control

Irbesartan vs Amlodipine

Irbesartan vs Control

Losartanvs Control

IDNT2

Mean follow-up: 2.6 yrs RENAAL1

Mean follow-up: 3.4 yrs

Relative Risk Reduction (%)

1. Brenner BM, et al. N Engl J Med. 2001;345:861-869.2. Lewis EJ, et al. N Engl J Med. 2001;345:851-860.

40

<134134-140

141-149>149

Irbesartan

Placebo

Amlodipine

Simultaneous Effect of Follow-up Systolic Blood Pressure and Treatment

on Renal Outcomes

Quartile of Average Systolic BP

(mm Hg)

Rel

ati

ve

Ris

k o

f R

enal

En

d P

oin

t

1.800

1.200

0.600

Treatment

Reproduced with permission from Pohl MA, et al; IDNT Study Group. J Am Soc Nephrol. 2005;16:3027-3027.

41

Simultaneous Effects of Follow-up Systolic and Diastolic BP

on Renal Outcomes

<7474-78

79-89>89

<134

134-140

141-149

>149

Follow-up Diastolic BP

Rel

ati

ve

Ris

k o

f R

enal

E

nd

Po

int

2

1.5

0.5

Follow-up Systolic BP

1

Hunsicker LG; IDNT Study Group. Personal communication.

42

UKPDS Mean Blood Pressures

Baseline(mm Hg)

Mean BP Over 9 Yrs(mm Hg)

Less tight control 160/94 154/87

Tight control 159/94 144/82

Difference 1/0 10/5

P NS P<.0001

UK Prospective Diabetes Study Group. BMJ. 1998;317:703-713.

43

Difference in Risk Reduction: Tight vs Less Tight BP Control (-10/-5 mm Hg)

% R

isk

Red

uct

ion

0

–10

–20

–30

–40

–50

Deaths Related to Diabetes

Deaths Related to Diabetes

All-CauseMortalityAll-CauseMortality MIMI StrokeStroke

–32%–32%

–18%–18%–21%–21%

–44%–44%

UK Prospective Diabetes Study Group. BMJ. 1998;317:703-713.

44

Effect of Tight Glucose and BP Control on Cardiovascular Risk Reduction in the UKPDS

MicrovascularComplications

Death Related to Diabetes

Stroke Any Diabetes-Related

End Point

–50

–40

–30

–20

–10

0

*

*

**

% R

isk

Red

uc

tio

n

Tight vs Conventional Blood-Glucose Control1

Tight vs Conventional BP Control2

10

*

*

11

-44

-12

-24

-10

-32

-25

-37

1. UK Prospective Diabetes Study Group. Lancet. 1998;352:837-853.2. UK Prospective Diabetes Study Group. BMJ. 1998;317:703-713.

*P <.05, tight vs conventional control.

45

Steno-2: Effects of Multifactorial Intervention on Macrovascular and Microvascular Outcomes

160 Patients With Type 2 Diabetes and Microalbuminuria

60

50

40

30

20

10

0

Conventional therapy

Intensive therapy†

53% risk reductionP=.01

Pri

ma

ry C

om

po

sit

e

En

d P

oin

t* (

%)

0 12 24 36 48 60 72 84 96

Months of Follow-up Intensivetherapybetter

Conventionaltherapybetter

0.0 0.5 1.0 1.5 2.0 2.5

.661.09

(0.54-.2.22)Peripheral neuropathy

.0020.37

(0.18-0.79)Autonomicneuropathy

.020.42

(0.21-0.86)Retinopathy

.0030.39

(0.17-0.87)Nephropathy

PRelative

Risk(95% CI)

Variable

*CV death, MI, stroke, revascularization, amputation. †Total fat intake <30%, <30 min exercise 3-5x weekly, ACE inhibitor, aspirin, BP <130/80 mm Hg, total-C <175 mg/dL, TG <150 mg/dL, A1c <6.5%.Reproduced with permission from Gaede P, et al. N Engl J Med. 2003;348:383-393.

46

Hypertensives on Treatment

Controlled53%

Uncontrolled47%

5 Out of 10 Treated Hypertensive Patients Are Not at Goal BP

69% of hypertensive Americans are aware of their disease58% of hypertensive Americans are receiving treatment for their disease

Hajjar I, Kotchen TA. JAMA. 2003;290:199-206.Burt VL, et al. Hypertension. 1995;25:305-313.Hyman DJ, Pavlik VN. N Engl J Med. 2001;345:479-486.

47

Multiple Antihypertensive Agents Are Often Needed to Achieve Target BP

1

No. of Antihypertensive Agents2 3 4

SBP 140/DBP 90ALLHAT7

SBP 135/DBP 85IDNT6

MAP 92AASK5

DBP 80HOT4

MAP 92MDRD3

DBP 75ABCD2

DBP 85 UKPDS1

Target BP (mm Hg)

Trial

1. UK Prospective Diabetes Study Group. BMJ. 1998;317:703-713.2. Estacio RO, et al. Am J Cardiol. 1998;82:9R-14R.3. Lazarus JM, et al. Hypertension. 1997;29:641-650.4. Hansson L, et al. Lancet. 1998;351:1755-1762.5. Kusek JW, et al. Control Clin Trials. 1996;16:40S-46S.6. Lewis EJ, et al. N Engl J Med. 2001;345:851-860.7. ALLHAT. JAMA. 2002;288:2998-3007.

48

Efficacy: Uptitration vs Combination

-6.9 -6.9

-8.2 -8.2

-12.2

-18.8

-12.6

-16.8

-20

-18

-16

-14

-12

-10

-8

-6

-4

-2

0

Ch

ang

e in

SB

P (

mm

Hg

)T

40 mgT

80 mgT

40 mgT 40/HCTZ 12.5 mg

V80 mg

V80 mg

V160 mg

V 80/HCTZ 12.5 mg

HCTZ = hydrochlorothiazide; SBP = systolic blood pressure; T = telmisartan; V = valsartan.McGill JB, Reilly PA. Clin Cardiol. 2001;24:66-72. Benz JR, et al. J Hum Hypertens. 1998;12:861-866.

49

SBP Response to HCTZ 12.5 mg vs HCTZ 25 mg in Combination With ARBs

Irbesartan 150 mg1

Irbesartan 300 mg1

Irbesartan 300 mg/HCTZ 12.5 mg2

Irbesartan 300 mg/HCTZ 25 mg2

Ch

ang

e in

SB

P (

mm

Hg

)

1. Weber M, et al. J Hypertens. 1998;16(suppl 2):S129. 2. Kochar M, et al. Am J Hypertens. 1999;12:797-805.

-9-10

-16

-23-25

-20

-15

-10

-5

0

50

Pat

ien

ts A

chie

vin

g R

esp

on

se (

%)

0

10

20

30

40

50

60

70

80

90

100

DBP SBP ††

Placebo HCTZ 12.5 mg Telmisartan 40 mg

Telmisartan 80 mg

Telmisartan 40/ HCTZ 12.5 mg

Telmisartan 80/ HCTZ 12.5 mg

28 28

42

32 35

45

36 36

69

56

7773

DBP and SBP Response Ratesin African American Subgroup*

*DBP response defined as supine DBP 90 mm Hg and/or a 10 mm Hg reduction from baseline; SBP response defined as 10 mm Hg reduction from baseline in supine SBP.†P.05 combination vs both monotherapies. McGill JB, Reilly PA. Clin Cardiol. 2001;24:66-72.

51

DBP GoalSBP Goal

INCLUSIVE Study: Blood Pressure Goal* Attainment With Irbesartan/HCTZ at Week 18

77% 83%

*Goal = systolic blood pressure (SBP) <140 mm Hg, diastolic blood pressure (DBP) <90 mm Hg, except patients with type 2 diabetes: SBP <130 mm Hg, DBP <80 mm Hg.Intent-to-treat (ITT) population, n = 736.Week 18 aggregate data for irbesartan/HCTZ 150/12.5 mg and 300/25 mg include all patients whose BP was controlled from baseline. Some patients were at goal DBP at baseline. Neutel JM, et al. J Clin Hypertens. 2005;7:578-586.

52

0

20

40

60

80

100

Pat

ien

ts C

on

tro

lled

(%

)

AfricanAmericans

n=157

Hispanics/Latinosn=110

MetabolicSyndrome

n=345

Type 2Diabetes

n=227

Elderly(≥65 Years)

n=184

Women

n=370

TotalPopulation

n=736

INCLUSIVE Study: SBP Control Rates by Subgroup

Goal = systolic blood pressure (SBP) <140 mm Hg, diastolic blood pressure (DBP) <90 mm Hg except patients with type 2 diabetes: SBP <130 mm Hg, DBP <80 mm Hg.Intent-to-treat (ITT) population. Race/ethnicity designation was self-identified.Week 18 aggregate data for irbesartan/HCTZ 150/12.5 mg and 300/25 mg include all patients whose BP was controlled from baseline. Neutel JM, et al. J Clin Hypertens. 2005;7:578-586.

53

Summary

• Hypertension, impaired renal function, and proteinuria are commonly associated with diabetes and play a major role in the development of cardiovascular and renal damage

• Hypertension is the main cause of the decline in renal function and progression to ESRD in patients with diabetic nephropathy

• Tight BP control (<130/80 mm Hg) is essential for patients with diabetes to reduce the progression of diabetic nephropathy and the risks of cardiovascular and renal disease

• Specific classes of antihypertensive drugs may provide additional organ protection beyond BP control

• Pharmacologic blockade of the renin-angiotensin system has been shown to convey renal and cardiovascular protection

54

Summary (cont.)

• Both ACEIs and ARBs prevent progression from microalbuminuria to clinical proteinuria in patients with type 2 diabetes

• ARBs provide better renal protection in patients with overt nephropathy

• Several studies have shown that ACEIs provide cardiovascular protection in patients with type 2 diabetes

• Large randomized clinical trials, including IDNT, RENAAL, and LIFE, have shown that ARBs provide both renal and cardiovascular protection in patients with type 2 diabetes

• Patients with difficult-to-treat hypertension may require treatment with a combination of antihypertensive drugs