Prevention and Treatment of Cardiovascular and Renal Disease in ...

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 1 Prevention and Treatment of Cardiovascular and Renal Disease in Hypertensive Patients With Type 2 Diabetes Learning Objectives 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 2 Epidemiology and Potential Risks of Untreated or Inadequately Treated Hypertension 3 Systolic Blood Pressure Increases With Age: NHANES III Men 150 150 Women SBP 130 African American White Mexican American SBP 130 mm Hg mm Hg DBP 110 80 70 0 18- 30- 40- 50- 60- 70- ≥80 29 39 49 59 69 79 110 80 70 0 DBP 18- 30- 40- 50- 60- 70- ≥80 29 39 49 59 69 79 Age (y) DBP = diastolic blood pressure; SBP = systolic blood pressure. Adapted with permission from Burt VL, et al. Hypertension. 1995;25:305-313. 4 Residual Lifetime Risk of Hypertension in Women and Men Aged 65 Years 100 Risk of Hypertension (%) 80 60 40 20 0 0 2 4 6 8 10 12 14 16 18 20 Follow-up (y) Adapted with permission from Vasan RS, et al. JAMA. 2002;287:1003-1010. 5 Men Women CV Mortality Risk Doubles With Each 20/10 mm Hg BP Increment* 8 7 CV Mortality Risk 6 5 4 3 2 1 0 115/75 135/85 155/95 175/105 SBP/DBP (mm Hg) 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. 6 Percent Chance of Cardiovascular Event in 5 Years: No Diabetes Men BP (mm Hg) 4 5 6 7 Women Nonsmoker Smoker Total Chol.:HDL-C 8 4 5 6 7 8 4 5 6 7 8 Nonsmoker Smoker Total Chol.:HDL-C 8 4 5 6 7 180/105 160/95 140/85 120/75 180/105 160/95 140/85 120/75 180/105 160/95 140/85 120/75 Age 70 Age 60 >20% 15-20% 10-15% 5-10% 2.5-5% <2.5% Age 50 7 Adapted with permission from Jackson R. BMJ. 2000;320:709-710. Percent Chance of Cardiovascular Event in 5 Years: Diabetes Men BP (mm Hg) 4 5 6 7 Women Nonsmoker Smoker Total Chol.:HDL-C 8 4 5 6 7 8 4 5 6 7 8 Nonsmoker Smoker Total Chol.:HDL-C 8 4 5 6 7 180/105 160/95 140/85 120/75 180/105 160/95 140/85 120/75 180/105 160/95 140/85 120/75 Age 70 Age 60 >20% 15-20% 10-15% 5-10% 2.5-5% Age 50 8 Adapted with permission from Jackson R. BMJ. 2000;320:709-710. JNC 7 Algorithm for the Treatment of Hypertension Lifestyle modifications Initial drug choices Without compelling indications Not at goal BP (<140/90 mm Hg or <130/80 mm Hg for those with diabetes or chronic kidney disease) With compelling indications Stage 1 HTN SBP 140-159, DBP 90-99 mm Hg Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination SBP ≥ 160, DBP ≥ 100 mm Hg 2-drug combo for most (usually thiazide-type diuretic and ACEI, or ARB, or BB, or CCB) Stage 2 HTN Drugs for compelling indications Other antihypertensives (diuretics, ACEI, ARB, BB, CCB) as needed Not at goal BP Optimize dosages or add drugs to reach goal BP Consider consultation with HTN specialist 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. 9 JNC Reclassification of BP Based on Risk JNC VI BP (mm Hg) JNC 7 BP (mm Hg) Optimal Normal Borderline <120/80 120-129/80-84 130-139/85-89 Normal <120/80 Prehypertension 120-139/80-89 Hypertension Stage 1 Stage 2 Stage 3 140-159/90-99 160-179/100-109 ≥180/110 Stage 1 Stage 2 140-159/90-99 ≥160/100 Source for JNC VI: Arch Intern Med. 1997;157:2413-2446. Adapted with permission from Chobanian AV, et al. Hypertension. 2003;42:1206-1252. 10 ADA and NKF 2004 Guidelines for Treating Hypertension in Patients With Type 2 Diabetes Kidney Status Microalbuminuria (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. 11 Interrelationships Between Hypertension, Diabetes, CKD, and CVD 12 Morbidity and Mortality Along the Renal Continuum Microalbuminuria Macroproteinuria Endothelial Dysfunction Nephrotic Proteinuria CVD Risk Factors Diabetes Hypertension End-Stage Renal Disease Death 13 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 CKD = chronic kidney disease; CVD = cardiovascular disease; ESRD = end-stage renal disease. 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. 14 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 CKD = chronic kidney disease; CVD = cardiovascular disease; ESRD = end-stage renal disease. Sarnak MJ, et al. Hypertension. 2003;42:1050-1065. 15 Incidence of ESRD by Cause Primary Diagnosis for Patients Who Start Dialysis Diabetic Nephropathy Other 15% 13% 33% 39% Diabetic Nephropathy + Hypertension 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. 16 Stages of Chronic Kidney Disease Stage Description Kidney damage with normal or increased GFR Kidney damage with mildly decreased GFR Moderately decreased GFR Severely decreased GFR Kidney failure GFR, mL/min/1.73 m2 ≥90 US Prevalence, 1000s 5900 US Prevalence*, % 3.3 1 2 3 4 5 60–89 30–59 15–29 <15 or dialysis 5300 7600 400 300 3.0* 4.3 0.2 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. 17 Accessed November 9, 2005. Adapted with permission from the National Kidney Foundation. Relative Risk of Death per GFR Level Age-Standardized Rate of Death From Any Cause (per 100 person-yr) 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 14.14 11.36 4.76 0.76 1.08 60 45-59 30-44 15-29 <15 Estimated GFR (mL/min/1.73 m2) No. of Events 25,803 11,569 7802 4408 1842 GFR = glomerular filtration rate. Reproduced with permission from Go AS, et al. N Engl J Med. 2004;351:1296-1305. 18 Renal Dysfunction Predicts Increased Mortality After Acute MI 1.0 0.9 0.8 0.7 <40 mL/min Mortality 0.6 0.5 0.4 0.3 0.2 0.1 0 0 1 2 3 40–55 56–70 71–85 Creatinine clearance ≤70 mL/min predicted significantly worse outcome after adjustment for covariables* N = 6252* >85 4 5 6 Years *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. 19 Renal Dysfunction Predicts Increased Mortality After Acute Stroke 1.0 N = 2042 Cumulative Survival 0.8 >66 mL/min 0.6 0.4 0.2 0 0 1 2 3 4 5 6 7 51–66 mL/min 39–51 mL/min <39 mL/min CrCl <51 mL/min predicted significantly worse outcome, even after adjustment for confounders* Time to Death (years) *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. 20 Reproduced with permission from MacWalter RS, et al. Stroke. 2002;33:1630-1635. With All This Important News, What Do We Need to Do Differently? • Estimate GFR • Quantitate: albuminuria/proteinuria • Control risk factors for CKD/CVD progression 21 Relationship Between Serum Creatinine and GFR Implications of Doubling of Serum Creatinine Creatinine Clearance Ucr V Pcr 125 100 75 50 25 0 0 1 2 3 4 5 6 Pcr — Serum Creatinine (mg/dL) GFR = glomerular filtration rate; Pcr = plasma creatinine Ucr = urinary creatinine; V = volume. 22 Equations to Predict GFR Based on Serum Creatinine (140–Age) x Weight x (0.85 if 72 x SCr female) Cockcroft-Gault equation CCr(mL/min) = Abbreviated MDRD Study equation 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. 23 Definitions of Proteinuria Urine Collection Method Total protein Spot urine dipstick Spot urine protein-to-creatinine ratio (varies with method) <30 mg/dL <200 mg/g NA NA ≥ 30 mg/dL ≥ 200 mg/g Normal Microalbuminuria Albuminuria or Clinical Proteinuria Albumin Spot urine albumin-specific dipstick Spot urine albumin-to-creatinine ratio (varies by sex) <3 mg/dL <17 mg/g (men) <25 mg/g (women) >3 mg/dL 17–250 mg/g (men) 25–355 mg/g (women) NA >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. 24 Microalbuminuria and Ischemic Heart Disease Risk 6 Normoalbuminuria Relative Risk of Ischemic Heart Disease 5 4 3 2 1 0 Microalbuminuria <140 140–160 >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. 25 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 26 Kidney Disease and the Metabolic Syndrome: Parallels Metabolic Syndrome Renal Disease • • • • • • • • Truncal obesity Low HDL cholesterol High triglycerides Insulin resistance Hypertension Microalbuminuria Markers of inflammation Endothelial dysfunction • • • • • • • • May not be obese Low HDL cholesterol High triglycerides Insulin resistance Hypertension Micro- or overt albuminuria Markers of inflammation Endothelial dysfunction 27 Hunsicker LG. Personal communication. Glomerular Structure Mesangial Cell Capillary Loop Endothelial Cell Afferent Arteriole Efferent Arteriole Juxtaglomerular Apparatus 28 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 29 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/dL 80 60 Primary Outcome Events per 1000 Person-Years (n) 60 50 40 30 20 10 0 Myocardial Infarction All patients Patients taking placebo Patients taking ramipril Events per 1000 Person-Years (n) 40 20 0 Serum Creatinine Concentration <1.4 mg/dL Serum Creatinine Concentration ≥1.4 mg/dL Serum Creatinine Concentration <1.4 mg/dL Serum Creatinine Concentration ≥ 1.4 mg/dL 40 30 Cardiovascular Death 60 50 40 30 20 10 0 All Death 20 10 0 Serum Creatinine Concentration <1.4 mg/dL Serum Creatinine Concentration ≥1.4 mg/dL Serum Creatinine Concentration <1.4 mg/dL Serum Creatinine Concentration ≥1.4 mg/dL Reproduced with permission from Mann JF, et al. Ann Intern Med. 2001;134:629-636. 30 Progression to Cardiovascular and Renal Disease Microalbuminuria Overt Proteinuria Doubling of Creatinine CV Events Death End-Stage Renal Disease 31 Renin-Angiotensin System (RAS) Angiotensinogen Renin Bradykinin (active) ACE inhibitors Angiotensin I ACE Bradykinin1-7 (inactive) ACE inhibitors • CAGE • Cathepsin G • Chymase • tPA • Cathepsin G • Tonin Angiotensin II ARBs AT1 receptor AT2 receptor 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. 32 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 • 33 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 34 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. 35 Treatment of Hypertension in Patients With Type 2 Diabetes, CVD, and Stroke 36 Compelling Indications for Individual Drug Classes Compelling Indication Initial Therapy Options THIAZ, BB, ACEI, ARB, CCB Clinical Trial Basis Diabetes NKF-ADA Guideline, UKPDS, ALLHAT Chronic kidney disease ACEI, ARB NKF 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. 37 Compelling Indications for Individual Drug Classes (cont.) Compelling Indication Initial Therapy Options Clinical Trial Basis ACC/AHA Heart Failure Guideline, MERIT-HF, COPERNICUS, CIBIS, SOLVD, AIRE, TRACE, ValHEFT, RALES, CHARM ACC/AHA Post-MI Guideline, BHAT, SAVE, Capricorn, EPHESUS ALLHAT, HOPE, ANBP2, LIFE, CONVINCE, EUROPA, INVEST Heart failure THIAZ, BB, ACEI, ARB, ALDO ANT Post–myocardial infarction BB, ACEI, ALDO ANT High coronary disease risk THIAZ, BB, ACEI, CCB 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. 38 IDNT and RENAAL Trial Results: Major End Points Relative Risk Reduction (%) RENAAL1 Mean follow-up: 3.4 yrs IDNT2 Mean follow-up: 2.6 yrs Losartan vs Control Doubling of Creatinine, ESRD, or Death Doubling of Creatinine ESRD Death CV Morbidity and Mortality Irbesartan vs Control Irbesartan vs Amlodipine Amlodipine vs Control 16 (P=.02) 20 (P=.02) 23 (P=.006) -4 (P=.69) 25 (P=.006) 28 (P=.002) -2 (P=.88) 10 (P=.26) 33 (P=.003) 23 (P=.07) 8 (P=.57) 9 (P=.40) 37 (P<.001) 23 (P=.07) -4 (P=.80) -3 (P=.79) -6 (P=.60) 0 (P=.99) 12 (P=.40) 12 (P=.29) 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. 39 Simultaneous Effect of Follow-up Systolic Blood Pressure and Treatment on Renal Outcomes Relative Risk of Renal End Point 1.800 1.200 0.600 Amlodipine Placebo Irbesartan <134 134-140 >149 141-149 Reproduced with permission from Pohl MA, et al; IDNT Study Group. J Am Soc Nephrol. 2005;16:3027-3027. 40 Simultaneous Effects of Follow-up Systolic and Diastolic BP on Renal Outcomes Relative Risk of Renal End Point 2 1.5 1 0.5 >149 141149 >89 134140 79-89 74-78 <134 <74 Follow-up Systolic BP Hunsicker LG; IDNT Study Group. Personal communication. 41 UKPDS Mean Blood Pressures Baseline (mm Hg) Less tight control Tight control 160/94 159/94 Mean BP Over 9 Yrs (mm Hg) 154/87 144/82 Difference P 1/0 NS 10/5 P<.0001 UK Prospective Diabetes Study Group. BMJ. 1998;317:703-713. 42 Difference in Risk Reduction: Tight vs Less Tight BP Control (-10/-5 mm Hg) 0 –10 –20 –30 Deaths Related to Diabetes All-Cause Mortality MI Stroke % Risk Reduction –18% –21% –32% –40 –50 UK Prospective Diabetes Study Group. BMJ. 1998;317:703-713. –44% 43 Effect of Tight Glucose and BP Control on Cardiovascular Risk Reduction in the UKPDS Stroke 10 11 Any Diabetes- Death Related Microvascular Related to Diabetes Complications End Point % Risk Reduction 0 –10 –20 –30 –40 –50 -12 -10 * -24 -25 -32 * * -44 * -37 * Tight vs Conventional Blood-Glucose Control1 Tight vs Conventional BP Control2 44 * *P <.05, tight vs conventional control. 1. UK Prospective Diabetes Study Group. Lancet. 1998;352:837-853. 2. UK Prospective Diabetes Study Group. BMJ. 1998;317:703-713. Steno-2: Effects of Multifactorial Intervention on Macrovascular and Microvascular Outcomes 160 Patients With Type 2 Diabetes and Microalbuminuria 60 50 Conventional therapy Nephropathy Variable Relative Risk (95% CI) 0.39 (0.17-0.87) 0.42 (0.21-0.86) 0.37 (0.18-0.79) 1.09 (0.54-.2.22) P Primary Composite End Point* (%) .003 40 30 20 10 0 0 53% risk reduction P=.01 Retinopathy Autonomic neuropathy .02 .002 Intensive therapy† Peripheral neuropathy .66 12 24 36 48 60 72 84 96 0.0 0.5 1.0 1.5 2.0 2.5 Intensive Conventional therapy therapy better better Months of Follow-up *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. 45 Hypertensives on Treatment 5 Out of 10 Treated Hypertensive Patients Are Not at Goal BP Controlled 53% Uncontrolled 47% 69% of hypertensive Americans are aware of their disease 58% 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. 46 Multiple Antihypertensive Agents Are Often Needed to Achieve Target BP Trial UKPDS1 ABCD2 MDRD3 HOT4 AASK5 IDNT6 ALLHAT7 Target BP (mm Hg) No. of Antihypertensive Agents 1 2 3 4 DBP 85 DBP 75 MAP 92 DBP 80 MAP 92 SBP 135/DBP 85 SBP 140/DBP 90 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. 47 Efficacy: Uptitration vs Combination 0 -2 T T 40 mg 80 mg T T 40/HCTZ V V 40 mg 12.5 mg 80 mg 160 mg V V 80/HCTZ 80 mg 12.5 mg Change in SBP (mm Hg) -4 -6 -8 -10 -12 -12.2 -14 -16 -18 -20 -18.8 -16.8 -12.6 -6.9 -6.9 -8.2 -8.2 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. 48 SBP Response to HCTZ 12.5 mg vs HCTZ 25 mg in Combination With ARBs 0 Change in SBP (mm Hg) Irbesartan 150 mg1 Irbesartan 300 mg1 Irbesartan 300 mg/ Irbesartan 300 mg/ HCTZ 12.5 mg2 HCTZ 25 mg2 -5 -10 -15 -16 -20 -25 -23 49 -9 -10 1. Weber M, et al. J Hypertens. 1998;16(suppl 2):S129. 2. Kochar M, et al. Am J Hypertens. 1999;12:797-805. DBP and SBP Response Rates in African American Subgroup* Patients Achieving Response (%) 100 90 80 70 60 50 40 30 20 10 0 28 28 45 32 35 36 36 DBP SBP 77 69 56 42 † 73 † Placebo HCTZ 12.5 mg Telmisartan 40 mg Telmisartan 80 mg Telmisartan 40/ Telmisartan 80/ HCTZ 12.5 mg HCTZ 12.5 mg *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. 50 McGill JB, Reilly PA. Clin Cardiol. 2001;24:66-72. INCLUSIVE Study: Blood Pressure Goal* Attainment With Irbesartan/HCTZ at Week 18 SBP Goal DBP Goal 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. 51 INCLUSIVE Study: SBP Control Rates by Subgroup 100 Patients Controlled (%) 80 60 40 20 0 Total African Population Americans n=736 n=157 Hispanics/ Latinos n=110 Metabolic Syndrome n=345 Type 2 Diabetes n=227 Elderly (≥65 Years) n=184 Women n=370 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. 52 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 53 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 54