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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 Grade 1 (mild) 140–159 or 90–99 Grade 2 (moderate) 160–179 or 100–109 180 or 110 Hypertension Grade 3 (severe) Guidelines Committee. J Hypertens 2003;21:101153 Classification of BP in US Adults: JNC VII Guidelines BP category Normal Systolic (mmHg) Diastolic (mmHg) <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 Uncomplicated BP goal (mmHg) <140/90 Complicated Diabetes mellitus <130/80 Kidney disease <130/80 Chobanian et al. JAMA 2003;289:256072 Guidelines Committee. J Hypertens 2003;21:101153 Approximately 70% of Patients* in Europe Do Not Reach Blood Pressure Goal Patients (%) 100 BP goal achieved BP goal not achieved 60 79 70 81 72 England Sweden Germany Spain Italy 80 60 40 20 0 *Treated for hypertension BP goal is <140/90 mmHg Wolf-Maier et al. Hypertension 2004;43:10–17 Global Health Burden of Blood Pressure Events attributable to SBP >115 mmHg (%) 76 80 62 60 49 40 14 20 0 Stroke • Ischaemic heart disease Hypertensive disease* 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) *Hypertensive disease includes essential hypertension, hypertensive heart disease and hypertensive renal disease Lawes et al. J Hypertens 2006;24:423–30 Cardiovascular Mortality Risk Doubles with Each 20/10 mmHg Increment in Systolic/Diastolic Blood Pressure* CV mortality risk 8 8X risk 6 4 4X risk 2 0 1X risk 2X risk 115/75 135/85 155/95 175/105 Systolic BP/Diastolic BP (mmHg) *Individuals aged 40–69 years Lewington et al. Lancet 2002;360:1903–13 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 7% reduction in risk of ischaemic heart disease mortality 10% reduction in risk of stroke mortality Lewington et al. Lancet 2002;360:1903–13 ‘Controlling blood pressure with medication is unquestionably one of the most costeffective methods of reducing premature CV morbidity and mortality’ Elliott. J Clin Hypertens 2003;5(Suppl. 2):313 JNC VII: Algorithm for Treatment of Hypertension Lifestyle modifications Not at goal blood pressure (BP)* Hypertension without compelling indications Hypertension with compelling indications Stage 1 Stage 2 Thiazide-type diuretics for most. May consider ACE inhibitor, ARB, β-blocker, CCB, or combination Two-drug combination for most (usually including thiazide-type diuretic) Drug(s) for the compelling indications Other antihypertensive drugs (diuretics, ACE inhibitor, ARB, β-blocker, CCB) as needed If not at goal, optimise dosages or add additional drugs until goal BP is achieved. Consider consultation with hypertension specialist *BP goal <140/90 mmHg or <130/80 mmHg for those with diabetes or chronic kidney disease Chobanian et al. JAMA 2003;289:2560–72 ESH–ESC: Algorithm for Treatment of Hypertension Consider: BP level before treatment Absence or presence of TOD and risk factors Choose between: Single agent at low dose 2-drug combination at low dose If goal BP not achieved Previous agent at full dose Switch to different agent at low dose Previous combination at full dose Add a third drug at low dose If goal BP not achieved 2–3 drug combination Full-dose monotherapy TOD = target organ damage 3-drug combination at effective doses ESH–ESC Guidelines. J Hypertens 2003;21:1779–86 Updated UK NICE Guidelines for the Treatment of Newly Diagnosed Hypertension Step 1 <55 years 55 years or black patients at any age ACEI (or ARB*) CCB or thiazide-type diuretic Step 2 ACEI (or ARB*) + CCB or ACEI (or ARB*) + thiazide diuretic Step 3 ACEI (or ARB*) + CCB + diuretic Step 4 Add further diuretic therapy, α-blocker, or β-blocker. Consider seeking specialist advice *If ACE inhibitor (ACEI) not tolerated http://www.nice.org.uk/download.aspx?o=CG034fullguideline. Accessed June 2006 Multiple Antihypertensive Agents are Needed to Reach BP Goal Trial (SBP achieved) 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) 1 2 3 4 Average no. of antihypertensive medications Bakris et al. Am J Med 2004;116(5A):30S–8 Dahlöf et al. Lancet 2005;366:895–906 Advantages of Multiple-mechanism Therapy: Efficacy Multiple-mechanism therapy results in a greater BP reduction than seen with its single-mechanism components1,2 • Components with a different mechanism of action interact on complementary pathways of BP control1 • Each component can potentially neutralize counterregulatory 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. 2Quan Drugs 2002;62:44362 et al. Am J Cardiovasc Drugs 2006;6:10313 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 2ESH–ESC et al. JAMA 2003;289:2560–72 Guidelines. J Hypertens 2003;21:1011–53 ESHESC Recommendations for Combining BPlowering Drugs Diuretics b-blockers Angiotensin receptor blockers (ARBs) a-blockers Calcium channel blockers (CCBs) Angiotensin-converting enzyme (ACE) inhibitors Most rational combinations Combinations used as necessary ESH–ESC Guidelines. J Hypertens 2003;21:1011–53 Diabetes And Hypertension Diabetes Approximately Doubles CVD Risk in Patients With Hypertension Patients With Patients Without Diabetes Diabetes Study (events per 1000 pt-yr) Systolic Hypertension in the Elderly Program (SHEP) Ratio CV events Stroke 63.0 28.8 36.8 15.0 1.71 1.92 CHD events 32.2 15.2 2.12 28.9 1.90 Systolic Hypertension in Europe (Syst-Eur) CV events 55.0 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 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. HOT Study: Fewer Major CV Events in Patients With Diabetes Randomized to Lower BP Goal P = .005 (per 1000 patient-years) Stroke, MI, or CV Death 25 20 15 10 5 0 80 85 90 Target DBP (mm Hg) 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. Syst-Eur: CV Protection Resulting From BP Lowering Was Greatest in Patients With Diabetes Reduction in Event Rate for Active Treatment Group (%) Diabetic 0 –10 –20 Overall Mortality 8% P = .55 –30 –40 –50 –60 –70 Nondiabetic CVD Mortality 16% P = .37 All CV Events 25% P = .02 41% P = .09 62% P = .002 Fatal and Nonfatal Stroke Fatal and Nonfatal Cardiac Events 22% P = .10 36% P = .02 57% P = .06 69% 70% P = .02 P = .01 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. UKPDS: Tight Glucose Versus Tight BP Control and CV Outcomes Tight glucose control (goal <6.0 mmol/L or 108 mg/dL) Relative Risk Reduction (%) Tight BP control (average 144/82 mm Hg) Stroke 0 -10 Any Diabetic End Point DM Deaths Microvascular Complications 5% 10% 12% -20 24% * -30 32% * -40 -50 44% * *P <.05 compared to tight glucose control 32% 37% * Ptients had hypaertension and Type 2 diabetes. N = 1148. UKPDS = United Kingdom Prospective Diabetes Study. Bakris GL et al. Am J Kidney Dis. 2000;36:646-661. ADA 2009 Recommendations 22 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 PREVENT1 Primary outcome: No difference in mean 3 yr coronary angiographic changes vs. placebo 825 CAD patients (≥30%): Multicenter, randomized, 35% hospitalization for heart failure + angina placebo controlled 33% revascularization procedures CAMELOT2 1,991 CAD patients (>20%): Double-blind, randomized study vs. placebo and enalapril 20 mg ASCOT-BPLA/CAFE3,4 19,257 HTN patients: Multicenter, randomized, prospective study vs. atenolol ALLHAT5 18,102 HTN patients: Randomized, prospective study vs. lisinopril 1Pitt Primary outcome: 31% in CV events vs. placebo 41% hospitalization for angina 27% coronary revascularization Primary outcome: 10% in non-fatal MI & fatal CHD 16% 30% 27% 11% total CV events and procedures new-onset diabetes stroke all-cause mortality central aortic pressure by 4.3 mmHg Primary outcome: No difference in composite of fatal CHD + non-fatal MI vs. lisinopril 6% combined CVD 23% stroke 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 CV Events with Amlodipine Compared with Atenolol: ASCOT-BPLA n=9,639 n=9,618 Amlodipine better Atenolol better Primary endpoint Non-fatal MI (including silent) + fatal CHD p=0.1052 Secondary endpoints 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 0.6 ASCOT-BPLA = Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm 0.7 0.8 0.9 1.0 Hazard ratio (95% CI) 1.45 Dahlöf et al. Lancet 2005;366:895–906 New-onset Diabetes Mellitus with Amlodipine Compared with Atenolol: ASCOT-BPLA Atenolol-based regimen Proportion of events (%) 10 Amlodipine-based regimen 8 6 4 HR=0.70 (95% CI: 0.63–0.78) p<0.0001 2 0 0 Number at risk Amlodipine (567 events) Atenolol (799 events) 1 2 3 4 Time (years) 5 9,639 9,383 9,165 8,966 8,726 7,618 9,618 9,295 9,014 8,735 8,455 7,319 6 Dahlöf et al. Lancet 2005;366:895–906 Effects of Different Antihypertensive Agents on Incidence of Diabetes Network meta-analysis assessing the effects of different antihypertensive agents on incidence of diabetes in 48 randomised groups from 22 clinical trials* (n=143,153) ARB 0.57 (0.46–0.72) p<0.0001 ACE inhibitor 0.67 (0.56–0.80) p<0.0001 CCB 0.75 (0.62–0.90) p=0.002 Placebo 0.77 (0.63–0.94) p=0.009 β-blocker 0.90 (0.75–1.09) p=0.30 Diuretic Referent 0.50 0.70 0.90 Odds ratio of incident diabetes 1.26 Incoherence=0.000017 *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 Elliott and Meyer. Lancet 2007;369:201–7 28 Equivalence of Amlodipine to ACE Inhibitors or Diuretics for Coronary Heart Disease/Non-Fatal Myocardial Infarction: ALLHAT Relative risk reduction for total CHD/non-fatal MI (%) 4 Total CHD/non-fatal MI 3 2 p=NS 1 0 −1 −2 −3 −1% −2% Lisinopril (n=9,054) vs chlorthalidone (n=15,255) ALLHAT = Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial Amlodipine (n=9,048) vs chlorthalidone (n=15,255) ALLHAT Collaborative Research Group. JAMA 2002;288:298197 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). 30 Amlodipine/Valsartan: Up to 9 Out of 10 Patients Reach BP Goal <140/90 mmHg All patients Non-diabetic patients Diabetic patients 100 Patients (%) 80 77.1 84.4 85.2 n=449 n=375 78.4 80.0 80 69.7 60 n=440 n=369 n=71 n=74 40 20 0 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 Data shown are at Week 8 No hydrochlorothiazide add-on was permitted until after Week 8 Randomized, double-blind, multinational, parallel-group, 16-week study Adapted from 31 press) Allemann et al. J Clin Hypertens 2008 (In Copyright © 2008, with permission from Blackwell Publishing Interaction of CCBs and ARBs on Vascular and Renal Function, SNS and RAS Activity Natriuresis Vasodilation Arterial Arterial + Venous CCB ARB ↑ RAS RAS ↓ ↑ SNS SNS ↓ 32 Peripheral Edema Associated with CCBs Fluid leakage No venous dilation Arterial dilation Fluid leakage Capillary bed Opie et al. In: Opie LH, editor. Drugs for the Heart. 3rd ed. 1991:4273 White et al. Clin Pharmacol Ther 1986;39:438 Gustaffson. J Cardiovasc Pharmacol 1987;10(Suppl 1):S12131 Complementary Effects of a CCB/Angiotensin-receptor Blocker (ARB): Reduction of CCB-associated Edema Arterial dilation (CCB and ARB) Venous dilation (ARB) Capillary bed Opie. In: Opie LH, editor. Drugs for the Heart. 3rd ed. 1991:4273 White 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 CCB–ARB: Synergy of Counterregulation CCB Arteriodilation Peripheral edema Effective in low-renin patients Reduces cardiac ischemia ARB Venodilation Attenuates peripheral edema Effective in high-renin patients No effect on cardiac ischemia ARB RAS blockade CHF and renal benefits BP Synergistic BP reduction Complementary clinical benefits CCB RAS activation No renal or CHF benefits 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.