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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
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.
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.