Antihypertensive Treatment In Diabetics

Calcium Channel Blockers

Dr.Nabil Elkafrawy MD.Professor of Internal Medicine, Diabetes Unit,

Menofieya University

Classification of BP in European Adults:ESHESC Guidelines

BP category Systolic (mmHg) Diastolic (mmHg)

Optimal <120 and <80

Normal 120–129 and 80–84

High normal 130–139 or 85–89

Hypertension

Grade 1 (mild) 140–159 or 90–99

Grade 2 (moderate) 160–179 or 100–109

Grade 3 (severe) 180 or 110

Guidelines Committee. J Hypertens 2003;21:101153

Classification of BP in US Adults:JNC VII Guidelines

BP category Systolic (mmHg) Diastolic (mmHg)

Normal <120 and <80

Pre-hypertension 120–139 or 80–89

Hypertension, stage 1 140–159 or 90–99

Hypertension, stage 2 160 or 100

Chobanian et al. JAMA 2003;289:256072

JNC VII and ESHESC Summary: Target BP Goals

Type of hypertension BP goal (mmHg)

Uncomplicated <140/90

Complicated

Diabetes mellitus <130/80

Kidney disease <130/80

Chobanian et al. JAMA 2003;289:256072Guidelines Committee. J Hypertens 2003;21:101153

Approximately 70% of Patients* in Europe Do Not Reach Blood Pressure 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

100

BP goal achieved BP goal not achievedPatients (%)

England Sweden Germany Spain Italy

Global Health Burden of Blood Pressure

62

49

76

14

0

20

40

60

80

Stroke Ischaemic heartdisease

Hypertensivedisease*

Other CVD

• Worldwide this equates to 7.1 million deaths (12.8% of total deaths) and 64.3 million disability-adjusted life years (4.4% of the total)

Lawes et al. J Hypertens 2006;24:423–30*Hypertensive disease includes essential hypertension, hypertensive heart disease and hypertensive renal disease

Events attributable to SBP >115 mmHg (%)

Lewington et al. Lancet 2002;360:1903–13

Cardiovascular Mortality Risk Doubles with Each 20/10 mmHg Increment in Systolic/Diastolic Blood Pressure*

CV mortality risk

0

2

4

8

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

6

Systolic BP/Diastolic BP (mmHg)

*Individuals aged 40–69 years

2X risk

4X risk

8X risk

1X risk

Blood Pressure Reduction of 2 mmHg Decreases the Risk of Cardiovascular Events by 7–10%

• Meta-analysis of 61 prospective, observational studies• 1 million adults• 12.7 million person-years

2 mmHg decrease in mean SBP 10% reduction in risk

of stroke mortality

7% reduction in risk of ischaemic heart disease mortality

Lewington et al. Lancet 2002;360:1903–13

Elliott. J Clin Hypertens 2003;5(Suppl. 2):313

‘Controlling blood pressure with medication is unquestionably one of the most cost-effective methods of reducing premature CV morbidity and mortality’

Lifestyle modifications

Chobanian et al. JAMA 2003;289:2560–72

Not at goal blood pressure (BP)*

Hypertension without compelling indications

Hypertension with compelling indications

Stage 1

Thiazide-type diuretics for most. May consider ACE inhibitor, ARB, β-blocker,

CCB, or combination

Stage 2

Two-drug combination for most (usually including thiazide-type diuretic)

If not at goal, optimise dosages or add additional drugs until goal BP is achieved. Consider consultation with hypertension specialist

JNC VII: Algorithm for Treatment of Hypertension

Drug(s) for the compelling indications

Other antihypertensive drugs (diuretics, ACE

inhibitor, ARB, β-blocker, CCB) as needed

*BP goal <140/90 mmHg or <130/80 mmHg for thosewith diabetes or chronic kidney disease

Consider: BP level before treatmentAbsence or presence of TOD and risk factors

2-drug combination at low dose

Choose between:

Single agent at low dose

If goal BP not achieved

Previous agentat full dose

Switch todifferent agent

at low dose

Previouscombinationat full dose

Add athird drug

at low dose

If goal BP not achieved

2–3 drugcombination

3-drug combinationat effective doses

ESH–ESC: Algorithm for Treatment of Hypertension

ESH–ESC Guidelines. J Hypertens 2003;21:1779–86

Full-dosemonotherapy

TOD = target organ damage

http://www.nice.org.uk/download.aspx?o=CG034fullguideline.Accessed June 2006

Updated UK NICE Guidelines for the Treatment of Newly Diagnosed Hypertension

*If ACE inhibitor (ACEI) not tolerated

ACEI (or ARB*) + CCB orACEI (or ARB*) + thiazide diuretic

<55 years

ACEI (or ARB*) + CCB + diuretic

CCB or thiazide-type diureticACEI (or ARB*)

55 years or black patients at any age

Add further diuretic therapy, α-blocker, or β-blocker.Consider seeking specialist advice

Step 1

Step 2

Step 3

Step 4

Average no. of antihypertensive medications1 2 3 4

Multiple Antihypertensive Agents are Needed to Reach BP Goal

Trial (SBP achieved)

Bakris et al. Am J Med 2004;116(5A):30S–8 Dahlöf et al. Lancet 2005;366:895–906

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)

Advantages of Multiple-mechanism Therapy: Efficacy

• Components with a different mechanism of action interact on complementary pathways of BP control1

• Each component can potentially neutralize counter-regulatory mechanisms, e.g.– Diuretics reduce plasma volume, which in turn stimulates the

renin angiotensin system (RAS) and thus increases BP; addition of a RAS blocker attenuates this effect1,2

• Multiple-mechanism therapy may result in BP reductions that are additive2

1Sica. Drugs 2002;62:443622Quan et al. Am J Cardiovasc Drugs 2006;6:10313

Multiple-mechanism therapy results in a greater BP reduction than seen with its single-mechanism components1,2

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

• JNC VII1

– “Most patients with hypertension will require two or more antihypertensive agents to achieve their BP goals”

– “When BP is more than 20 mmHg above systolic goal or 10 mmHg above diastolic goal, consideration should be given to initiate therapy with 2 drugs, either as separate prescriptions or in fixed-dose combinations”

• ESHESC2

– “To reach target blood pressures, it is likely that a large proportion of patients will require therapy with more than one agent”

1Chobanian et al. JAMA 2003;289:2560–722ESH–ESC Guidelines. J Hypertens 2003;21:1011–53

ESHESC Recommendations for Combining BP-lowering Drugs

ESH–ESC Guidelines. J Hypertens 2003;21:1011–53

Diuretics

Angiotensinreceptor blockers(ARBs)

Calcium channelblockers (CCBs)

Angiotensin-converting enzyme (ACE) inhibitors

b-blockers

a-blockers

Most rational combinationsCombinations used as necessary

Diabetes And Hypertension

Adapted from Curb JD et al. JAMA. 1996;276:1886-1892; Hansson L et al. Lancet. 1998;351:1755-1762; Tuomilehto J et al. N Engl J Med. 1999:340:677-684.

Diabetes Approximately Doubles CVD Risk in Patients With Hypertension

Study

Patients With Diabetes

Patients Without Diabetes

Ratio(events per 1000 pt-yr)

Systolic Hypertension in the Elderly Program (SHEP)

CV events 63.0 36.8 1.71

Stroke 28.8 15.0 1.92

CHD events 32.2 15.2 2.12

Systolic Hypertension in Europe (Syst-Eur)

CV events 55.0 28.9 1.90

Stroke 26.6 12.3 2.16

CHD events 23.1 12.4 1.87

Hypertension Optimal Treatment (HOT) (DBP <90 mm Hg)

CV events 24.0 9.8 2.45

Target DBP (mm Hg)

Stro

ke, M

I, or

CV

Dea

th

(per

100

0 pa

tient

-yea

rs)

80 85 900

5

10

15

20

25 P = .005

Patients with hypertension and diabetes were given baseline felodipine, plus other agents in a 5-step regimen. Study N = 18,790; diabetes n = 1501.HOT = Hypertension Optimal Treatment; MI = myocardial infarction.Adapted from Hansson L et al, for the HOT Study Group. Lancet. 1998;351:1755-1762.

HOT Study: Fewer Major CV Events in Patients With Diabetes Randomized to

Lower BP Goal

Patients with hypertension received nitrendipine enalapril or HCTZ. N = 4695. Diabetes n = 492. Syst-Eur = Systolic Hypertension in Europe; CV = cardiovascular.Adapted from Tuomilehto J et al. N Engl J Med. 1999;340:677-684.

Syst-Eur: CV Protection Resulting From BP Lowering Was Greatest in Patients With Diabetes

Redu

ctio

n in

Eve

nt R

ate

for

Activ

e Tr

eatm

ent G

roup

(%)

Overall Mortality

CVDMortality

All CVEvents

Fatal and NonfatalStroke

Fatal and Nonfatal

Cardiac Events0

–10

–20

–30

–70

–40

–5041%

P = .09

8%P = .55

70%P = .01

16%P = .37

62%P = .002

25%P = .02

69%P = .02

36%P = .02

–60 57%P = .06

22%P = .10

Diabetic Nondiabetic

UKPDS: Tight Glucose Versus Tight BP Control and CV Outcomes

Ptients had hypaertension and Type 2 diabetes. N = 1148.

Tight glucose control (goal <6.0 mmol/L or 108 mg/dL)

Tight BP control (average 144/82 mm Hg)

*P <.05 compared to tight glucose control

StrokeAny Diabetic

End PointDM

DeathsMicrovascularComplications

-50

-40

-30

-20

-10

0

Rela

tive

Risk

Red

uctio

n (%

)

32%37%

10%

32%

12%

24%

5%

44%*

*

**

UKPDS = United Kingdom Prospective Diabetes Study.Bakris GL et al. Am J Kidney Dis. 2000;36:646-661.

22

ADA 2009 Recommendations

Calcium Channel Blockers

Mechanism of Action of Amlodipine

• Amlodipine inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle– Inhibition is selective, with a greater effect on vascular

smooth muscle cells • It binds to both dihydropyridine and

nondihydropyridine binding sites• Amlodipine is also a peripheral arterial vasodilator

– Acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and a reduction in BP

http://www.pfizer.com/pfizer/download/uspi_norvasc.pdf

Amlodipine: Wealth of CV Outcome 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

Dahlöf et al. Lancet 2005;366:895–906

CV Events with Amlodipine Compared with Atenolol: ASCOT-BPLA

Hazard ratio (95% CI)

Atenolol betterAmlodipine better

0.6 0.7 0.8 0.9 1.0 1.45

Non-fatal MI (including silent) + fatal CHD p=0.1052

Non-fatal MI (excluding silent) + fatal CHD p=0.0458

Total coronary endpoints p=0.0070

Total CV endpoints and procedures p<0.0001

All-cause mortality p=0.0247

Cardiovascular mortality p=0.0010

Fatal and non-fatal stroke p=0.0003

Fatal and non-fatal heart failure p=0.1257

ASCOT-BPLA = Anglo-Scandinavian CardiacOutcomes Trial-Blood Pressure Lowering Arm

n=9,639 n=9,618

Primary endpoint

Secondary endpoints

New-onset Diabetes Mellitus with Amlodipine Compared with Atenolol: ASCOT-BPLA

Dahlöf et al. Lancet 2005;366:895–906

4

8

Proportion of events (%)

0

6

10

0Time (years)

2

1 2 3 4 5 6

Amlodipine-based regimen

Atenolol-based regimen

HR=0.70 (95% CI: 0.63–0.78)p<0.0001

Amlodipine(567 events)

9,639 9,383 9,165 8,966 8,726 7,618

Atenolol(799 events)

9,618 9,295 9,014 8,735 8,455 7,319

Number at risk

28Elliott and Meyer. Lancet 2007;369:201–7

0.57 (0.46–0.72) p<0.0001

0.67 (0.56–0.80) p<0.0001

0.75 (0.62–0.90) p=0.002

0.77 (0.63–0.94) p=0.009

0.90 (0.75–1.09) p=0.30

Referent

ARB

ACE inhibitor

CCB

Placebo

β-blocker

Diuretic

Odds ratio of incident diabetes Incoherence=0.0000170.50 0.70 0.90 1.26

Effects of Different Antihypertensive Agents on Incidence of Diabetes

Network meta-analysis assessing the effects of differentantihypertensive agents on incidence of diabetes in 48 randomised groups from 22

clinical trials* (n=143,153)

*17 trials enrolled patients with hypertension, three enrolled high-risk patients and one enrolled patients with heart failure (HF)ARB=angiotensin receptor blocker; ACE=angiotensin-converting enzyme; CCB=calcium channel blocker

0

−3

−2

1

4

−1

2

3

Relative risk reduction for total CHD/non-fatal MI (%)

Equivalence of Amlodipine to ACE Inhibitors or Diureticsfor Coronary Heart Disease/Non-Fatal Myocardial

Infarction: ALLHAT

ALLHAT Collaborative Research Group.JAMA 2002;288:298197

ALLHAT = Antihypertensive and Lipid-LoweringTreatment to Prevent Heart Attack Trial

Lisinopril (n=9,054) vschlorthalidone (n=15,255)

Amlodipine (n=9,048) vschlorthalidone (n=15,255)

−1%

−2%

Total CHD/non-fatal MI

p=NS

30

Reduction of pill-burden an d blood pressure with the fixed-dose combination of Amlodipine /Valsartan in hypertensive

patient s with different risk profiles (EXZELLENT Study).

31

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

77.184.4

78.485.2

69.7

80

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 (In press)

Copyright © 2008, with permission from Blackwell Publishing

32

Interaction of CCBs and ARBs on Vascular and Renal Function, SNS and RAS Activity

CCB ARB

Vasodilation

Natriuresis

Arterial Arterial +Venous

RAS ↓

SNS ↓

↑ RAS

↑ SNS

Opie et al. In: Opie LH, editor. Drugs for the Heart. 3rd ed. 1991:4273White et al. Clin Pharmacol Ther 1986;39:438

Gustaffson. J Cardiovasc Pharmacol 1987;10(Suppl 1):S12131

Arterialdilation

No venousdilation

Fluid leakage

Fluid leakage

Capillary bed

Peripheral Edema Associated with CCBs

Complementary Effects of a CCB/Angiotensin-receptor Blocker (ARB): Reduction of CCB-associated Edema

Opie. In: Opie LH, editor. Drugs for the Heart. 3rd ed. 1991:4273White et al. Clin Pharmacol Ther 1986;39:438; Gustaffson. J Cardiovasc Pharmacol

1987;10(Suppl. 1):S12131; Messerli et al. Am J Cardiol 2000;86:11827

Arterialdilation

(CCB andARB)

Venousdilation(ARB)

Capillary bed

SynergisticBP reduction

Complementaryclinical benefits

CCB· Arteriodilation· Peripheral edema· Effective in low-renin patients· Reduces cardiac ischemia

CCB· RAS activation· No renal or CHF

benefits

CCB–ARB: Synergy of Counter-regulation

ARB· Venodilation· Attenuates peripheral edema· Effective in high-renin patients· No effect on cardiac ischemia

ARB· RAS blockade· CHF and renal benefits

BP

CONCLUSION

• 1. Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are associated with favorable effects on renal function and may improve insulin sensitivity, making them ideal first choices in treatment for patients with both diabetes and hypertension

©2007 AACE. All rights reserved.

• 2. Combination therapy is generally required to achieve the stricter BP goals set for most patients with diabetes mellitus: systolic BP below 130 mmHg and diastolic BP below 80 mmHg (≤120/75 in the presence of significant proteinuria).

• 3. In addition to lifestyle modification, the use of an ACEI or ARB in combination with a low-dose diuretic, CCB, and/or third generation BB currently appears to be the preferred starting regimen for patients with diabetes.

• 4. AACE recommends an early aggressive approach in the management of hypertension as part of overall risk factor reduction

©2007 AACE. All rights reserved.

5. Calcium channel blockers (CCBs) .

• have been associated with several benefits as a potent antihypertensive treatment for diabetics to reach the target.

• Nondihydropyridine type (i.e., diltiazem, verapamil) may reduce microalbuminuria to an extent comparable to the ACEIs .

• Although not considered optimal agents for first-line or monotherapy in patients with diabetes, have all proven safe and effective in combination regimens with ACEIs, diuretics, and/or BBs

©2007 AACE. All rights reserved.

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