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Amlodipine Valsartan: The Rational Combination In Diabetic Hypertensive

Patients

By

Adel A El-Sayed MD

Page 2

Hypertension affecting 20–60% of patients with diabetes.

In type 2 diabetes, hypertension is often present as

part of the metabolic syndrome while in type 1 diabetes, hypertension may reflect the onset of diabetic nephropathy.

Hypertension substantially increases the risk of both macrovascular and microvascular complications.

Hypertension & Diabetes

Adapted from UKPDS BMJ 1998;317:703–713.

Page 6

0

50

100

150

200

250

300

≥200180–199160–179140–159120–139<120

Systolic blood pressure (mmHg)

CV

D d

eath

rate

(p

er 1

0,00

0 pe

rson

-yea

rs)

Without diabetesWith diabetes

Adapted from Stamler J et al Diabetes Care 1993;16(2):435–444.

*This analysis by Stamler et al included a cohort of more than 342,000 men aged 35 to 57 years who did not have diabetes, and a cohort of 5163 men who did have diabetes at baseline. The health status of study participants was followed through an average of 12 years .

Page 8

aMulticenter, randomized, controlled trialbMean blood pressures: 144/82 mmHg (tight control) and 154/87 mmHg (less-tight control)cp<0.05 vs. less-tight control dp<0.01 vs. less-tight controlAdapted from UKPDS BMJ 1998;317:703–713.

%R

isk

redu

ctio

n w

ith

tight

vs.

less

-tigh

t con

trol

Study 1Tight blood pressure controlb

–50

0

–10

–20

–30

–40

20

10

Aggregate EndpointsStroke

Microvascular disease Any diabetes-related endpoint

Death related to diabetes

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aMulticenter, randomized, controlled trialbGoal fasting blood glucose: <6.0 mmol/L (intensive control) and <15.0 mmol/L (conventional treatment)

cp<0.05 vs. less-tight controldp<0.01 vs. less-tight control

Adapted from UKPDS Lancet 1998;352:837–853.

%R

isk

redu

ctio

n w

ith

tight

vs.

less

-tigh

t con

trol

Study 2Intensive blood glucose controlb

–50

0

–10

–20

–30

–40

20

10

Aggregate EndpointsStroke

Microvascular disease Any diabetes-related endpoint

Death related to diabetes

Page 10

–80

–60

–40

–20

0

Stroke p<0.13

Total mortality

p<0.04

Cardiovascular mortality p<0.02

Cardiovascular events p<0.01

With diabetes

–55%

–76%–69%

–73%

Adapted from Tuomilehto J et al. N Engl J Med 1999;340:677–84

–38%

–6%–13%

–26%

Without diabetes

Red

uctio

n in

inci

denc

e)%

(

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Unmet Need in the Treatment of Hypertension

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Approximately 70-80 % of hypertensive diabetic Patients* in Europe Do Not Reach BP Goal

Wolf-Maier et al. Hypertension 2004;43:10–17

*Treated for hypertensionBP goal is <140/90 mmHg

60 79 70 81 72

0

20

40

60

80

100BP goal achieved BP goal not achievedPatients (%)

England Sweden Germany Spain Italy

Back to section content

Multiple Antihypertensive Agents are Needed to Reach BP Goal

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Average no. of antihypertensive medications

1 2 3 4

Trial (SBP achieved)

Bakris et al. Am J Med 2004;116(5A):30S–8 Dahlöf et al. Lancet 2005;366:895–906; Jamerson et al. Blood Press 2007;16:80–6

ASCOT-BPLA (136.9 mmHg)

ALLHAT (138 mmHg)

IDNT (138 mmHg)

RENAAL (141 mmHg)

UKPDS (144 mmHg)

ABCD (132 mmHg)

MDRD (132 mmHg)

HOT (138 mmHg)

AASK (128 mmHg)

ACCOMPLISH* (132 mmHg)Initial 2-drug combination therapy*Interim 6-month data

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Rationale for Multiple-mechanism Therapy in Hypertension diabetic

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Recommendations for Multiple-mechanism Therapy: What the Treatment Guidelines Say: ESH–ESC

More than one agent is necessary to achieve target BP in the majority of patients

Treatment can be initiated with monotherapy or a combination of two drugs at low doses• Drug dose or number of drugs may be increased if necessary

A combination of two drugs at low doses preferred 1st step when• Initial BP in grade 2–3 range

• Total CV risk high/very high

Fixed combinations of two drugs simplify treatment/favor compliance

Task Force of ESH/ESC. J Hypertens 2007;25:1105–87

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Enhanced antihypertensive efficacy

Potential for attenuation of certain class-specific adverse events

May improve patient compliance (multiple-mechanism agent in a single pill versus free combination therapy)

Potentially cost effective

Recommended by treatment guidelines

Advantages of Multiple-mechanism Therapy

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Rationale for Dual-mechanism Therapy with Amlodipine/Valsartan:

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Amlodipine: Wealth of CV Outcomes Data

1Pitt et al. Circulation 2000;102:1503–10; 2Nissen et al. JAMA 2004;292:2217–26; 3Dahlof et al. Lancet 2005;366:895–906 4Williams et al. Circulation 2006;113:1213–25; 5Leenen et al. Hypertension 2006;48:374–84

PREVENT1

825 CAD patients (≥30%): Multicenter, randomized, placebo controlled

Primary outcome: No difference in mean 3 yr coronary angiographic changes vs. placebo

35% hospitalization for heart failure + angina33% revascularization procedures

CAMELOT2

1,991 CAD patients (>20%): Double-blind, randomized study vs. placebo and enalapril 20 mg

Primary outcome: 31% in CV events vs. placebo

41% hospitalization for angina27% coronary revascularization

ASCOT-BPLA/CAFE3,4

19,257 HTN patients: Multicenter, randomized, prospective study vs. atenolol

Primary outcome: 10% in non-fatal MI & fatal CHD

16% total CV events and procedures30% new-onset diabetes27% stroke11% all-cause mortality

central aortic pressure by 4.3 mmHg

ALLHAT5

18,102 HTN patients: Randomized, prospective study vs. lisinopril

Primary outcome: No difference in composite of fatal CHD + non-fatal MI vs. lisinopril6% combined CVD23% stroke

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Valsartan: Wealth of CV Outcomes Data

1Julius et al. Lancet 2004;363:2022–31; 2Pfeffer et al. N Engl J Med 2003;349:1893–906; 3Maggioni et al. Am Heart J 2005;149:548–57; 4Wong et al. J Am Coll Cardiol 2002;40:970–5; 5Cohn et al. N Engl J Med 2001;345:1667–7;6Mochizuki et al. Lancet 2007;369:1431–9

VALUE1

15,245 high-risk HTN patients; Double-blind, randomized study vs. amlodipine

No difference in composite of cardiac mortality and morbidity (primary)

23% new-onset diabetes

VALIANT2

14,703 post-myocardial infarction patients; Double- blind, randomized study vs. captopril and vs. captopril + valsartan

No difference vs. captopril in all-cause mortality (primary)

(valsartan is as effective as standard of care)

Val-HeFT3–5

5,010 heart failure II–IV patients; Double-blind, randomized study vs. placebo

13% morbidity and mortality (primary) left ventricular remodeling37% atrial fibrillation occurrence heart failure signs/symptoms28% heart failure hospitalization

JIKEI HEART6

3,081 Japanese patients on conventional treatment for hypertension, coronary heart disease, heart failure or combination of these; Multicenter, randomized, controlled trial comparing addition of valsartan vs. non-ARB to conventional treatment

39% composite CV mortality and morbidity40% Stroke/transient ischemic attack47% Hospitalization for heart failure65% Hospitalization for angina

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Amlodipine/Valsartan: BP Reductions Across All Grades of Hypertension - (Exzellent Trial1)

DBP ↓ (mmHg) –17 –18 –29

n = n = 18001800

n = n = 22932293

n = n = 890890

1Schrader J et al. PS38 Late Breaking Abstracts Session. ESH/ISH Congress, 14 June 2008.

-19

-32

-49

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Amlodipine/Valsartan FDC: BP Reductions for Patients with Diabetes– (Exzellent Trial1)

n = n = 639639

n = n = 795795 n = n =

295295

1Schrader J et al. PS38 Late Breaking Abstracts Session. ESH/ISH Congress, 14 June 2008.

-19

-32

-48

DBP ↓ (mmHg) –11 –15 –18

syst

.BP

redu

ctio

n (m

mH

g)

Amlodipine/Valsartan: Up to 9 Out of 10 Patients Reach BP Goal <140/90 mmHg

77.184.4

78.485.2

69.780

0

20

40

60

80

100All patients Non-diabetic patients Diabetic patients

Amlodipine/Valsartan 5/160 mg Amlodipine/Valsartan 10/160 mg

Diabetic patients with BP <130/80 mmHg at Week 8 were 47.0% and 49.2% for 5/160 mg and 10/160 mg doses, respectively

Patie

nts

(%)

Data shown are at Week 8No hydrochlorothiazide add-on was permitted until after Week 8Randomized, double-blind, multinational, parallel-group, 16-week study

n=440 n=369 n=71 n=449 n=375 n=74

80.0

Adapted fromAllemann et al. J Clin Hypertens 2008;10:185–94

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Tolerability

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Tolerability and Risk Factor Modification: CCB-induced Peripheral Edema Minimized by the ARB

Single mode of action of the CCB

Dual mode of action of the CCB/ARB

Illustration modified from www.lotrel.com

ARB dilates arteries and veins

ReducesCCB-induced

peripheral edema

Capillary overload

forces fluid into

surrounding tissue

CCB dilates arteries

Veins remain constricted

Messerli et al. Am J Hypertens 2001;14:978–9

ConclusionsCoexistence of diabetes and hypertension

is common and serious condition.

Aggressive treatment of hypertension in diabetic patients is important to avoid serious and potentially fatal complications.

Amlodipine Valsartan combination is a rational, safe and effective therapy for this serious health problem.