 Microalbuminuria.  Hypertension. Diabetes Mellitus.   Interventions.
Microalbuminuria
Hypertension*Cigarette smokingObesity* (BMI >30 kg/m2)Physical inactivityDyslipidemia*Diabetes mellitus*Microalbuminuriaes...
Definition of Adversal Albumin                Excretion    Measure              Normoalbuminuria                  Microalb...
Micro-        Macro-Parameter           Normal                                        albuminuria   albuminuriaUrine AER  ...
MAU is Independently Associated with a              Variety of CV Risk Factors       MAU can be found in 5 to 15% of the ...
Correlation Coefficient betweenmicoalbuminoria and different parameters    Parameters        r       PBlood pressures:    ...
Albuminuria and CV Diseases: the LIFE               Study                 40              8,029 subjects with hypertension...
Microalbuminuria Compared To Traditional Risk     Factors For Ischemic Heart Disease                 3                    ...
HOPE TRIAL:Independent Predictive Variables for Combined    Endpoints of CV Death, MI, and Stroke               Variable  ...
Low Levels of MAU are Predictive of CAD and                  Death                                            CHD incidenc...
Cardiovascular Events by Degree of Albuminuria in                     HOPE                   30                          A...
Microalbuminuria Screening is             Important!!   Marker of small vessel disease in both the kidney    and the hear...
Modifiable Risk Factors / Markers for Progression  of Microalbuminuria to Clinical Proteinuria Blood pressure Level of m...
Detection of Microalbuminuria          (American Diabetes Association)                                   Exclusion of arte...
Hypertension
Hypertension Has a High Prevalence That IsExpected To Rise Over the Coming Decades                     50with Hypertension...
Hypertension Burden on Healthcare   Worldwide, hypertension is responsible for     62% of strokes1     49% of heart att...
Elevated Blood Pressure Increases the Risk of           Cardiovascular Disease                                     Stroke ...
Hypertension (HTN) and Microalbuminuria (MAU)    HTN is associated with MAU. However, real prevalence of MAU in     hyper...
MAU is a Predictor of Ischemic Heart Disease          in Hypertensive Patients    Proportion without ischemic             ...
MAU Reduction in Hypertensive Patients is                            Accompanied by CV Event Reduction                    ...
Risk of Ischemic Heart Disease                Related to SBP and Microalbuminuria                                         ...
MAU Screening Recommended in             Patients with Hypertension    ESH/ESC Guidelines for the management of arterial ...
Recommendations by ADA, ISHIB, and NKF           consistent with JNC 7     Drug therapy is recommended for all patients w...
Diabetes
The Diabetes Epidemic189 mill. in 2003324 mill. Estimated for 202572% increase                                        38.2...
Type 2 diabetes increases the risk of             cardiovascular disease                                                  ...
The presence of diabetes was associated with a                higher CHD risk in the VA-HIT placebo group                 ...
Association of Systolic Blood Pressure  (SBP) and CV Death in Type 2 Diabetes                                             ...
Proteinuria levels predict stroke               and CHD events in type 2 diabetes      Survival curves      (CV mortality)...
Proteinuria as a Risk Factor for Mortality in              Type 2 Diabetes                                             1.0...
Relative prognostic value of MAU                         in type 2 diabetes                            10           10    ...
Therapeutic Approach
Effective Blood Pressure Control Reduces    Cardiovascular Morbidity and Mortality            Systolic-diastolic hypertens...
UKPDS Relative Risk Reduction forIntensive vs Less Intensive Glucose Control        0     -10                             ...
HOT-Study: Optimal blood pressure in       hypertensive and diabetics (Type II)   HOT = Hypertension Optimal Treatment    ...
Microalbuminuria Resets the Focus on CV         Risk Reduction Strategies BP <130/80 mmHg Evaluate lipids Normalize mic...
JNC-7 Guidelines Diabetic hypertension   Thiazide diuretics, ß-blockers, ACE inhibitors, ARBs    and CCBs have been shown...
JNC 7 - Algorithm for treatment of                        hypertension                                             Lifesty...
Start ACE inhibitor                                                                                         BP still not  ...
Chronic Renal Disease:        Initial Treatment Recommendations      Renal Insufficiency                                  ...
Importance of Long-Term BP-Control for                              MAU-Reduction                                         ...
The RAS showing ACE and non-ACE           pathwaysACE PATHWAY                                   NON-ACE PATHWAY   (< 30%) ...
Angiotensin II Formation                                              Alternate                                           ...
Mechanism of Action of Angiotensin II    Receptor Blockers (ARBs)                                                         ...
Angiotensin II effects at the AT1 and AT2                receptors                                         Angiotensin    ...
Interventions to ReduceMicroalbuminuria Non   Pharmacological measures:-  Weight Loss.  Exercise.  Eating a low fat diet...
ACE-I Provides Greater Renoprotection            Than Non-ACE-I in Patients with         Diabetic and Non-Diabetic Nephrop...
Albumin excretion rate in hypertensive diabetic patients        treated with lercanidipine or ramipril.                   ...
Benefit of Angiotensin Receptor Blockers in                 Diabetes:Important Findings of 3 Major Clinical Trials   RENA...
ARB (Losartan) Reduces Urinary Albumin and      TGF-1 in Type 2 Diabetes with             Microalbuminuria        160    ...
Benefit of Angiotensin Receptor Blockers in                 Diabetes:Important Findings of 3 Major Clinical Trials   RENA...
The IRbesartan MicroAlbuminuria Type 2 Diabetes In           Hypertensive Patients Study IRMA II Objectives     Randomize...
IRMA II Incidence of Progression                                             to Diabetic Nephropathy                      ...
IRMA II Change in                                Urinary Albumin Excretion*                      20                      1...
IRMA II Irbesartan vs Placebo                  Secondary Endpoints  • During the first 3 months, the decline in creatinine...
IRMA II                  Adverse outcomes                                No. of adverse outcomes (%)                      ...
IRMA II               Summary of Important Findings    Irbesartan significantly reduces the rate of     progression from ...
Benefit of Angiotensin Receptor Blockers in                 Diabetes:Important Findings of 3 Major Clinical Trials   RENA...
Time to Doubling of Serum Creatinine, ESRD, or Death  IDNT Primary Endpoint                                  RRR 23%      ...
RECOMMENDATIONS FOR THERAPY                  SUMMARY   Guidelines are consistent in aiming to reduce cardiovascular and r...
Thank You
Thank You
Microalbuminuria in diabetic and hypertensive patient2
Microalbuminuria in diabetic and hypertensive patient2
Microalbuminuria in diabetic and hypertensive patient2
Microalbuminuria in diabetic and hypertensive patient2
Microalbuminuria in diabetic and hypertensive patient2
Microalbuminuria in diabetic and hypertensive patient2
Upcoming SlideShare
Loading in …5
×

Microalbuminuria in diabetic and hypertensive patient2

2,104 views

Published on

microalbuminuria is early sign of general vasculopathy and hurbinger of ESRD, the significance of microalbuminuria in diabetic and hypertensive patients is risky sign for further cardiovascular diseases, in this discussion I aimed to discuss the therapeutic approach for these patients

Published in: Health & Medicine

Microalbuminuria in diabetic and hypertensive patient2

  1. 1.  Microalbuminuria.  Hypertension. Diabetes Mellitus.  Interventions.
  2. 2. Microalbuminuria
  3. 3. Hypertension*Cigarette smokingObesity* (BMI >30 kg/m2)Physical inactivityDyslipidemia*Diabetes mellitus*Microalbuminuriaestimated GFR <60 ml/minAge (older than 55 for men, 65 for women)Family history of premature CVD(men under age 55 or women under age 65) *Components of the metabolic syndrome. JAMA 2003:289:2560
  4. 4. Definition of Adversal Albumin Excretion Measure Normoalbuminuria Microalbuminuria Macroalbuminuria Albumin <30 mg/24 hours 30-300 mg/24hours >300 mg/24 hours excretion rate* <20 μg/minute 20-200 μg/minute >200 μg/minute <30 mg/g creatinine 30-300 mg/g creatinine >300 mg/g creatinine Albumin-to-creatinine ratio** Male <2.5 mg/mmol Male 2.5-30 mg/mmol ≥30 mg/mmol Female < 3.5mg/mmol Female 3.5-30 mg/mmol*24-hour collection**spot urine; normalizes for urine volume; low muscle mass: false positive results; high muscle mass: false negative results Tagle R et al. Cleave Clin J Med 2003; 70:225-265
  5. 5. Micro- Macro-Parameter Normal albuminuria albuminuriaUrine AER < 20 20 - 200 >200(g/min)Urine AER < 30 30 - 300 >300(mg/24h) Urine albumin/ < 30 30 - 300 >300 Cr# ratio (mg/gm) AER=Albumin excretion rate CR# =creatinine
  6. 6. MAU is Independently Associated with a Variety of CV Risk Factors  MAU can be found in 5 to 15% of the general population, and in 3 to 8% of apparently healthy individuals (without diabetes or hypertension).  Non modifiable  Male gender1  Older age 2  Modifiable  Diabetes 3  Obesity 4  Smoking 5  Insulin resistance syndrome 6  LVH (Left-Ventricular Hypertrophy)7  Left ventricular dysfunction 8  CRP (C-Reactive Protein) 91 Gould et al., BMJ,306:240-242, 1993; 2 Damsgaard et al., BMJ,300:297-300, 1990; 3 Viberti et al., Lancet 1:1430-1432, 1982;4 Valensi et al., Int J of Obesity,20:574-579, 1996 5 Cirillo et al., Archive of inter Med,158:1933-1939, 1998; 6 Mykkanen etal.,Diabetes,47:793-800, 1998; 7 Watchell et al., AHJ 2002. 143:319-326; 8 Liu et al., J Am Coll Cardiol. 2003;41(11):2022-8., 9 Barzilay et al., Am J Kidney disease 2004 Jul;44(1):25-34.
  7. 7. Correlation Coefficient betweenmicoalbuminoria and different parameters Parameters r PBlood pressures: Systolic BP 0.678 <0.01 Diastolic BP 0.133 NSBlood Glucose: FBS 0.201 <0.05 PPBS 0.218 <0.05Lipogram: T.Cholesterol 0.443 <0.05 Triglycerides 0.179 NS HDL – C -0.319 <0.05 LDL – C 0.134 NS
  8. 8. Albuminuria and CV Diseases: the LIFE Study 40 8,029 subjects with hypertension and LV hypertrophy, mean age 66 years Normoalbuminuria 30 Microalbuminuria (Alb/Crea >3.5 mg/mmol)Prevalence (%) Macroalbuminuria (Alb/Crea >35 mg/mmol) 20 10 0 Diabetes Cerebrovascular Peripheral Coronary disease vascular vascular disease disease Wachtell et al. J Hypertens 2002;20:405–12
  9. 9. Microalbuminuria Compared To Traditional Risk Factors For Ischemic Heart Disease 3 N=2,085; 10 year follow-up 2.5Relative Risk 2 1.5 1 l a g BP r o 0.5 de in i er ur ok ic en st in ol Sm e m G st ol bu e Ch Sy al al M al ro t ic To MBorch-Johnsen K, et al.Arterioscler Thromb Vasc Biol. 1999;19(8):1992-1997.
  10. 10. HOPE TRIAL:Independent Predictive Variables for Combined Endpoints of CV Death, MI, and Stroke Variable Hazard Ratio Microalbuminuria 1.59 Creatinine > 1.4 mg/dL 1.40 CAD 1.51 PVD 1.49 Diabetes Mellitus 1.42 Male 1.20 Age 1.03 Waist-Hip Ratio 1.13Mann JFE, et al. Ann Intern Med. 2001;134(8):629-636.
  11. 11. Low Levels of MAU are Predictive of CAD and Death CHD incidence CHD mortalityCumulative CHD incidence (%) UAE ≥ 4.8μg/min Cumulative mortality (%) 30 30 20 20 UAE ≥ 4.8μg/min 10 10 UAE < 4.8μg/min UAE < 4.8μg/min 0 0 0 2 4 6 8 10 12 0 2 4 6 8 10 12 Years from entry Years from entry Cox-estimated age-adjusted curves of cumulative coronary Cox-estimated age-adjusted curves of cumulative mortality for heart disease (CHD) for a 60-year-old person based on 1734 a 60-year-old person based on 1734 hypertensive subjects with hypertensive subjects with microalbuminuria (UAE ≥ microalbuminuria 4.8µg/min; n=522) and normoalbuminuria (UAE < 4.8µg/min; (UAE ≥ 4.8µg/min; n=522) and normoalbuminuria n=1212; P<0.001). (UAE < 4.8µg/min; n=1212; P<0.001). Klausen et al., Hypertension. 2005; 46:33-37
  12. 12. Cardiovascular Events by Degree of Albuminuria in HOPE 30 All participants Microalbuminuria threshold With diabetes 25 Without diabetes 20 Incidence (%) 15 10 5 0 1&2 3 4 5 6 7 8 9 10 Albumin/creatinine Ratio DecilesGerstein et al. JAMA 2001;286:421-6.
  13. 13. Microalbuminuria Screening is Important!! Marker of small vessel disease in both the kidney and the heart Marker of increased cardiovascular morbidity and mortality for both diabetics and the general population Progresses to overt proteinuria in up to 40% of patients with type 2 diabetes within 5 to 10 yearsAmerican Diabetes Association. Diabetes Care 2002;25:S85-S89
  14. 14. Modifiable Risk Factors / Markers for Progression of Microalbuminuria to Clinical Proteinuria Blood pressure Level of microalbumin excretion rate Hemoglobin A1c Serum cholesterol Drugs that block the renin-angiotensin- aldosterone system (RAAS)
  15. 15. Detection of Microalbuminuria (American Diabetes Association) Exclusion of artefacts (exercise, urinary infections, fever etc.) Microalbuminuria ? (> 30 mg/24 h; > 20 g/min; > 20 mg/l; > 2 mg/mmol creatinine) yes no no 2 of 3 Repeat Repeat 2 x in 3 months positive tests at 1 y yes Diagnosis of microalbuminuria start managementADA. Diabetes Care 1996; 19:S103-S105
  16. 16. Hypertension
  17. 17. Hypertension Has a High Prevalence That IsExpected To Rise Over the Coming Decades 50with Hypertension 40.7 37.4 37.2 39.1 Men 40 35.3 34.8 Women% Population 30 26.9 28.3 23.7 22.6 20.6 20.9 22 19.7 20 17 14.5 10 0 50 45.9 44.5 41.642.5 with Hypertension 39.1 40.2 40 % Population 30 27 27.7 27 27 28.2 22.9 23.6 24 18.8 20 17.1 2025 10 0 Hypertension is an important public health challenge worldwide. Prevention, detection, treatment and control should receive high priority Kearney PM, et al. Lancet 2005; 365:217–223
  18. 18. Hypertension Burden on Healthcare Worldwide, hypertension is responsible for  62% of strokes1  49% of heart attacks1 Hypertension is the third leading risk factor for disease  Causes 7.1 million premature deaths each year1  4.5% of global burden of disease1 Hypertension represents a high burden on healthcare expenditure  In 2004, the direct and indirect cost of high blood pressure in the US was $55.5 billion; drug costs accounted for $21 billion2 Thus, hypertension management is a public health priority1.WHO, 2002; 2. AHA, 20042.AHA. Heart Disease and Stroke Statistics -- 2004 Update
  19. 19. Elevated Blood Pressure Increases the Risk of Cardiovascular Disease Stroke CAD 4.00 4.00 2.00 2.00 Relative Risk Relative Risk 1.00 1.00 0.50 0.50 0.25 0.25 123 136 148 162 175 123 136 148 162 175 76 84 91 98 85 76 84 91 98 85 Approximate mean usual BP Approximate mean usual BP Collins R et al. Br Med Bull 1994;50: 272–298
  20. 20. Hypertension (HTN) and Microalbuminuria (MAU)  HTN is associated with MAU. However, real prevalence of MAU in hypertensive patients is unknown  In patients with HTN, MAU is an independent risk marker for cardio- vascular events like ischemic heart disease and stroke, but also all- cause mortality  MAU is a marker of generalized endothelial dysfunction which is considered as an early stage of Atherothrombosis  Screening for MAU is simple and easy to perform and is recommended by international treatment guidelines  RAS-blockade and adequate BP-control are the cornerstone for the treatment of MAU and HTN
  21. 21. MAU is a Predictor of Ischemic Heart Disease in Hypertensive Patients Proportion without ischemic 100 heart disease (%) 95 Normoalbuminuria 90 85 80 75 Microalbuminuria (UA/Cr ratio > 1.07 mg/mmol) 70 0 1 2 3 4 5 6 7 8 9 10 Years204 hypertensive subjects drawn from 2085 general population subjects.No previous CV events, no diabetes.No renal or urinary disease.Follow up from 1983–1984 till 1993.18 coronary events. Jensen et al., Hypertension.2000;35:898-903
  22. 22. MAU Reduction in Hypertensive Patients is Accompanied by CV Event Reduction Analysis from LIFE trial Fraction suffering CEP 0.20 High baseline/high year 1 0.15 High baseline/low year 1 0.10 Low baseline/high year 1 Low baseline/low year 1 0.05 0.00 0 10 20 30 40 50 60 70 Time (months)Kaplan–Meier plot for the composite end point by UACR categories (fractions of patients experiencing from anend point).Primary composite end points (CEP): the first occurrence of cardiovascular death, nonfatal stroke, andnonfatal myocardial infarction.LIFE Study: Double-blind, randomized trial to compare the effects of losartanand atenolol on cardiovascular morbidity and mortality in high-risk patients withhypertension and left ventricular hypertrophy (LVH) Ibsen et al., Hypertension. 2005;45:198-202
  23. 23. Risk of Ischemic Heart Disease Related to SBP and Microalbuminuria N=2,085; 10 year follow-up 6 5Relative Risk Normoalbuminuria Microalbuminuria 4 3 2 1 0 SBP <140 SBP 140-160 SBP>160 Borch-Johnsen K, et al. Arterioscler Thromb Vasc Biol. 999;19(8):1992-1997. With permission from Lippincott Williams & Wilkins.
  24. 24. MAU Screening Recommended in Patients with Hypertension ESH/ESC Guidelines for the management of arterial hypertension, 2003 1: “…searching for microalbuminuria is recommended, because of the mounting evidence that it may be a sensitive marker of organ damage, not only in diabetes but also in hypertension.” The JNC-7 Report, The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure, 2003 2: “Optional tests include measurement of urinary albuminuria excretion or albumin/creatinine ratio.”1ESH/ESC guidelines, Journal of hypertension 2003,21:1011-1053; 2 The JNC 7 Hypertens.2003;42:1206-1252
  25. 25. Recommendations by ADA, ISHIB, and NKF consistent with JNC 7  Drug therapy is recommended for all patients with hypertension (SBP/DBP >140/90 mmHg)  BP goals  <140/90 mmHg  <130/80 mmHg for patients with diabetes mellitus or chronic kidney disease  Multiple drug therapy with 2 or more agents at adequate doses (thiazide diuretic, ACE inhibitor, ARB, beta-blocker, CCB) is usually required to achieve BP targets  ISHIB guidelines: consider initiating treatment with 2 drugs if BP is 15/10 mmHg above goalAmerican Diabetes Association (ADA). Diabetes Care 2005; 28:S4–S36.The International Society on Hypertension in Blacks (ISHIB). Arch Intern Med 2003;163:525–541.The National Kidney Foundation (NKF). Am J Kidney Dis 2000; 36:646–661.
  26. 26. Diabetes
  27. 27. The Diabetes Epidemic189 mill. in 2003324 mill. Estimated for 202572% increase 38.2 44.2 16% 81.8 25.0 156.1 39.7 91% 59% 18.2 35.9 13.6 97% 26.9 10.4 98% 19.7 1.1 88% 1.7 59%From Zimmet P et al. Diabet Med. 2003;20:693-702.
  28. 28. Type 2 diabetes increases the risk of cardiovascular disease No diabetes n = 342,815 Rates (per 10,000 person-year) Diabetes n = 5,163 75 50 25 0 Relative Total CVD CHD Stroke Other risk 3.0 3.2 2.8 CVD 2.3Adjusted for age, race, income, cholesterol, systolic blood pressure, smoking
  29. 29. The presence of diabetes was associated with a higher CHD risk in the VA-HIT placebo group age-adujested 5 year incidence of major cardiovascular events in the VA-HIT palcebo groupby dlucose group 40% 36.5%cumulative event rate % 34.3% 30% 23.8 21 % % 20% 10% 0% normal Impaired Undiagnos Diagnosed fasting ed diabetes glucose diabetes
  30. 30. Association of Systolic Blood Pressure (SBP) and CV Death in Type 2 Diabetes 250 225 No diabetes Diabetes 200 (deaths/10,000 person-years) 175CV Mortality 150 125 100 75 50 25 0 120 120–139 140–159 160–179 180–199 200 SBP (mm Hg) Adapted from Stamler J et al. Diabetes Care. 1993;16:434-444.
  31. 31. Proteinuria levels predict stroke and CHD events in type 2 diabetes Survival curves (CV mortality) Incidence (%) p < 0.001 1.0 40 < 150 0.9 30 0.8 150-300 0.7 20 0.6 > 300 10 0.5 Overall: p < 0.001 0 0 0 10 20 30 40 50 60 70 80 90 Stroke CHD events Time (months) U-Prot < 150 mg/L U-Prot 150-300 mg/L U-Prot > 300 mg/L7-year follow-up of 1,056 patients with type 2 diabetes with or without hypertensionMiettinen H et al. Stroke 1996;27:2033–9. U-Prot = Urinary protein concentration
  32. 32. Proteinuria as a Risk Factor for Mortality in Type 2 Diabetes 1.0 Survival (all-cause mortality) Normoalbuminuria 0.9 (n=191) Microalbuminuria 0.8 (n=86) 0.7 Macroalbuminuria (n=51) 0.6 0.5 0 1 2 3 4 5 6P<0.01 normoalbuminuria vs microalbuminuria YearsP<0.001 normoalbuminuria vs macroalbuminuriaP<0.05 microalbuminuria vs macroalbuminuriaGall MA, et al. Diabetes. 1995;44:1303-1309.Copyright ©1995, American Diabetes Association. Reprinted with permission.
  33. 33. Relative prognostic value of MAU in type 2 diabetes 10 10 8 6.5Mortality 6from CHD (odds ratio) 4 3.2 2.3 2 0 MAU Smoking Diastolic BP Cholesterol Eastman RC, Keen H. Lancet 1997;350(Suppl 1):29–32.
  34. 34. Therapeutic Approach
  35. 35. Effective Blood Pressure Control Reduces Cardiovascular Morbidity and Mortality Systolic-diastolic hypertension Isolated-systolic hypertension Fatal and non Fatal and non Mortality Mortality10 fatal events fatal events All All Stroke CHD Causes CV Non CV Stroke CHD Causes CV Non CV 0 NS-10 NS <0.01 <0.01 0.02-20 <0.001 0.01 <0.001-30 <0.001-40 Event reduction in patients on active antihypertensive <0.001-50 treatment versus placebo or no treatment. CHD: coronary heart disease; CV: cardiovascularESH/ESC Guidelines. J Hypertens 2003; 21:1779–1786.
  36. 36. UKPDS Relative Risk Reduction forIntensive vs Less Intensive Glucose Control 0 -10 -12 -16 P=0.03 -21 P=0.05 -20 -25 P=0.02 P<0.01 -30 -33 P<0.01 -40 Microalbuminuria at 12 yrs Microvascular complications Retinopathy Myocardial Infarction Any DM endpoint -50Over 10 years, HbA1c was 7.0% (6.2-8.2) in the intensive group (n=2,729) compared with 7.9% (6.9-8.8) inthe conventional group (n=1,138). UKPDS Group. Lancet. 1998;352:837-853.
  37. 37. HOT-Study: Optimal blood pressure in hypertensive and diabetics (Type II) HOT = Hypertension Optimal Treatment 30 Serious cardiovascular 25 events/1000 pat.years 20 - 51% risk reduction 15 10 5  90  85  80 0 mm Hg diastolic target blood pressure Hypertensive diabetics profit most from stringent blood pressure controlHansson L at al. Lancet 1998; 351:1755-1762
  38. 38. Microalbuminuria Resets the Focus on CV Risk Reduction Strategies BP <130/80 mmHg Evaluate lipids Normalize microalbuminuria Reduction in dietary salt/saturated fat Intensify glycemic control Anti-platelet therapy
  39. 39. JNC-7 Guidelines Diabetic hypertension Thiazide diuretics, ß-blockers, ACE inhibitors, ARBs and CCBs have been shown to reduce CVD and stroke incidence in diabetic hypertension In diabetic hypertension, combinations of 2 or more medications are usually needed to achieve target BP of < 130/80 mmHg ACE- and ARB-based treatments favourably affect the progression of diabetic nephropathy and reduce albuminuria Chobanian AV et al. The seventh report of the Joint National Committee on prevention, detection,evaluation, and treatment of high blood pressure: the JNC 7 report. JAMA 2003;289:2560-72.
  40. 40. JNC 7 - Algorithm for treatment of hypertension Lifestyle modifications Not at goal BP (<140/90 mmHg or <130/80 mmHg for those with diabetes or chronic kidney disease) Initial drug choices Hypertension without compelling Hypertension with compelling indications indicationsStage 1 hypertension (SBP 140-159 Stage 2 hypertension (SBP ≥160 mmHg Drug(s) for compelling or DBP 90-99 mmHg) or DBP ≥100 mmHg) indicationsThiazide-type diuretics for most 2-drug combination for most (usually Other antihypertensive drugsMay consider ACE inhibitor, ARB, thiazide-type diuretic and ACE (diuretics, ACE inhibitor, ARB,-blocker, CCB, or combination inhibitor or ARB or -blocker or CCB) -blocker, CCB) as needed Not at goal BP Optimize dosages or add additional drugs until goal BP is achieved Consider consultation with hypertension specialist JNC 7 VII, Hypertens. 2003;42:1206-1252.
  41. 41. Start ACE inhibitor BP still not Blood pressure titrate upwards at goal >130/80 mm Hg (130/80 mm Hg) If BP still not Add Thiazide Diuretic Baseline pulse 84 at goal or (130/80 mm Hg) long-acting CCB* If BP goal achieved, convert to fixed doseAdd low-dose beta blocker combinations (ACE inhibitor + CCB or ACE or alpha/beta blocker Baseline pulse <84 inhibitor + diuretic) Add other subgroup of CCB BP still not at goal (ie, amlodipine-like agent if verapamil or (130/80 mm Hg) diltiazem already being used and the converse)*If proteinuria present(>300 mg per day) non-DHP preferred. Refer to a clinical hypertension specialist Reprinted from Bakris GL, et al. Am J Kidney Dis. 2000;36(3):646-661 with permission from National Kidney Foundation.
  42. 42. Chronic Renal Disease: Initial Treatment Recommendations Renal Insufficiency 130/80 Clcr <60 mL/min ACE Inhibitor CrSerum >1.4 mg/dL* (or ARB) Start Microalbuminuria (only Abnormality) 130/80 And Titrate Proteinuria To Maximum Tolerable Diabetes Mellitus Dose*for women, CRSerum >1.2 mg/dL
  43. 43. Importance of Long-Term BP-Control for MAU-Reduction SBP reduction leads to MAU-reduction 1.00Cumulative hazard risk in 0.75 developing MAU 0.50 >139 mmHg 0.25 130–139 mmHg <130mmHg 0.00 0 5 10 15 Time of follow-up Pascual et al.,Hypertension. 2005;45:1132-1137
  44. 44. The RAS showing ACE and non-ACE pathwaysACE PATHWAY NON-ACE PATHWAY (< 30%) (> 70%) Angiotensinogen Chymase Renin Tonin Angiotensin I Cathepsin Kallikrein ACE Angiotensin McConnaughey et al. J Clin Phamacol 1999;39: 547–59.
  45. 45. Angiotensin II Formation Alternate Pathways* AngiotensinogenRenin Angiotensin I CAGE t-PAACE Cathepsin G Cathepsin G Chymase Tonin Angiotensin II Angiotensin II Receptors *The clinical significance of alternate pathways is unknown. Dzau VJ et al. J Hypertens. April 1993;11(suppl):S13-S18.
  46. 46. Mechanism of Action of Angiotensin II Receptor Blockers (ARBs) Angiotensinogen Renin Angiotensin I Bradykinin ACE Non-ACE enzymes Inactive (cathepsin, chymase) Fragments Angiotensin II ARBs AT1 Receptor AT2 Receptor Na reabsorption Aldosterone release Vasodilation Blood Pressure Sympathetic outflow Growth Vasopressin secretion inhibition Vasoconstriction Apoptosis Vascular and cardiac hypertrophyAdapted from Unger T. Am J Cardiol 2002; 89 (suppl):3A-10A.
  47. 47. Angiotensin II effects at the AT1 and AT2 receptors Angiotensin II -sartan AT1 Receptor AT2 Receptor Vasoconstriction Activate sympathetic activity Antiproliferation Apotosis Increase sodium retention Endothelial cell growth Increase vasopressin release Vasodilation (NO mediated?)Promote myocyte hypertrophy and proliferation Stimulate renal bradykinin and NO Stimulate vascular and cardiac fibrosis Stimulate plasminogen activator inhibitor 1 Stimulate superoxide formation Adapted from McConnaughey et al. J Clin Phamacol 1999;39: 547–59.
  48. 48. Interventions to ReduceMicroalbuminuria Non Pharmacological measures:- Weight Loss. Exercise. Eating a low fat diet Pharmacological agents:- Statins. ACE inhibitors. ARBs. Cobination of ACEI and ARBs. CCBs
  49. 49. ACE-I Provides Greater Renoprotection Than Non-ACE-I in Patients with Diabetic and Non-Diabetic Nephropathy Conclusions about Study Year ACE inhibitors (ACE-I) ACE-I reduced both the rate of decline in GFR and theBjork et al 1992 amount of albuminuria. In Type I diabetics, ACE-I reduced proteinuria, risk ofLewis et al 1993 doubling serum creatinine, and risk of ESRD+Death. But, ESRD alone was not reduced. In non-diabetics, ACE-I reduced proteinuria, risk of REIN 1997 doubling serum creatinine, and risk of ESRD+Death. But, ESRD alone was not reduced. ACE-I reduced progression of proteinuria fromMicroHOPE 2000 normoalbuminuria to microalbuminuria and from microalbuminuria to macroalbuminuria. ACE-I was superior to amlodipine in reducing AASK 2001 proteinuria among non-diabetic African Americans with hypertension and kidney disease.
  50. 50. Albumin excretion rate in hypertensive diabetic patients treated with lercanidipine or ramipril. Lercanidipine P<0.05 Ramipril P<0.05 Change in Albumin Excreation Rate (AER) from baseline to the end point according to treatment groups: ( )Lercanidipine group p<0.05; (∆)Ramipril group p<0.05. From th comparison between groups, p<0.05 at baseline and NS at the endpoint Dalla Vestra M et al, Diab Nutr Metab, 2004
  51. 51. Benefit of Angiotensin Receptor Blockers in Diabetes:Important Findings of 3 Major Clinical Trials RENAAL (2001)  The angiotensin receptor blocker losartan compared to placebo reduced the risk of diabetic nephropathy developing to renal failure IRMA II (2001)  Higher doses of the angiotensin receptor blocker irbesartan reduced the risk of progression of renal insufficiency IDNT (2001)  The angiotensin receptor blocker irbesartan compared to the calcium channel blocker amlodipine provided better renal protection in hypertensive type 2 diabetics, reducing the chance of diabetic nephropathy developing to renal failure
  52. 52. ARB (Losartan) Reduces Urinary Albumin and TGF-1 in Type 2 Diabetes with Microalbuminuria 160 100 24-hour Systolic BP Urinary Albumin Excretion 90 P<0.01 vs baseline P<0.01 vs baseline mcg/min 140 80 mmHg 70 130 60 120 50 90 6 24-hour Diastolic BP TGF- P<0.03 vs baseline 5 P<0.005 vs baseline 80 ng/mL mmHg 4 3 70 2 60 1 Baseline 4 Weeks 8 Weeks Baseline 4 Weeks 8 Weeks Esmatjes E, et al. Nephrol Dial Transplant. 2001;16(Suppl1):90-93.
  53. 53. Benefit of Angiotensin Receptor Blockers in Diabetes:Important Findings of 3 Major Clinical Trials RENAAL (2001)  The angiotensin receptor blocker losartan compared to placebo reduced the risk of diabetic nephropathy developing to renal failure IRMA II (2001)  Higher doses of the angiotensin receptor blocker irbesartan reduced the risk of progression of renal insufficiency IDNT (2001)  The angiotensin receptor blocker irbesartan compared to the calcium channel blocker amlodipine provided better renal protection in hypertensive type 2 diabetics, reducing the chance of diabetic nephropathy developing to renal failure
  54. 54. The IRbesartan MicroAlbuminuria Type 2 Diabetes In Hypertensive Patients Study IRMA II Objectives  Randomized multi-site, double-blind, placebo-controlled study to evaluate the renal protective effect of the angiotensin II receptor antagonist irbesartan in hypertensive patients with type 2 diabetes and microalbuminuria Population  590 patients (30 to 70 years old)  Type 2 diabetes  Hypertension (a mean systolic BP >135 mmHg or a mean diastolic BP >85 mmHg, or both, on 2 of 3 consecutive measurements)  Persistent microalbuminuria ○ Albumin excretion rate of 20 to 200 g/min in 2 of 3 samples ○ Serum creatinine concentration of no more than 1.5 mg/dL for men and 1.1 mg/dL for women Parving HH, et al. N Engl J Med. 2001;345(12):870-878.
  55. 55. IRMA II Incidence of Progression to Diabetic Nephropathy 20 Incidence of Diabetic Nephropathy P<0.001 for difference between 300 mg irbesartan group and placebo 15 Placebo 150 mg of irbesartan 10 (%) 5 300 mg of irbesartan 0 0 3 6 12 18 22 24 Months of Follow-upPlacebo (n) 201 201 164 154 139 129 36Irbesartan150 mg (n) 195 195 167 161 148 142 45Irbesartan300 mg 194 194 180 172 159 150 49 Parving HH, et al. N Engl J Med. 2001;345(12):870-878. ©2001 Massachusetts Medical Society. All rights reserved.
  56. 56. IRMA II Change in Urinary Albumin Excretion* 20 10 Placebo% change in urinary albumin excretion 0 -10 150 mg of irbesartan -20 -30 300 mg of irbesartan -40 -50 0 3 6 12 18 22 24 Months of Follow-up*P<0.001 for difference between both irbesartan groups and placebo Parving HH, et al. N Engl J Med. 2001;345(12):870-878. ©2001 Massachusetts Medical Society. All rights reserved.
  57. 57. IRMA II Irbesartan vs Placebo Secondary Endpoints • During the first 3 months, the decline in creatinine clearance (mL/min/m2 body surface area per month) was greater than the decline between 3 and 24 months*  0.9 vs 0.1 for the placebo group  1.0 vs 0.2 for the 150 mg group  1.9 vs 0.2 for the 300 mg group • Irbesartan reduced the level of urine albumin excretion… 24% in the 150 mg group (P=NS)† 38% in the 300 mg group (P<0.001)†*Neither the initial nor long-term decline differed significantly among the 3 groups† Compared to placeboParving HH, et al. N Engl J Med. 2001;345(12):870-878.
  58. 58. IRMA II Adverse outcomes No. of adverse outcomes (%) Irbesartan Irbesartan Control (150 mg) (300 mg)Cardiovascular events 18 (8.7) 14 (6.9) 9 (4.5)Serious adverse events 47 (22.8) 32 (15.8) 30 (15.0)Discontinuations 19 (9.2) 18 (8.9) 11 (5.5)due to adverse events Parving H-H et al. N Engl J Med 2001;345:870–78.
  59. 59. IRMA II Summary of Important Findings Irbesartan significantly reduces the rate of progression from microalbuminuria to diabetic nephropathy. Renoprotection from irbesartan in patients with type 2 diabetes and microalbuminuria is independent of its blood pressure lowering effect. Antihypertensive treatment has a renoprotective effect in hypertensive patients with type 2 diabetes and microalbuminuria Parving HH, et al. N Engl J Med. 2001;345(12):870-878.
  60. 60. Benefit of Angiotensin Receptor Blockers in Diabetes:Important Findings of 3 Major Clinical Trials RENAAL (2001)  The angiotensin receptor blocker losartan compared to placebo reduced the risk of diabetic nephropathy developing to renal failure IRMA II (2001)  Higher doses of the angiotensin receptor blocker irbesartan reduced the risk of progression of renal insufficiency IDNT (2001)  The angiotensin receptor blocker irbesartan compared to the calcium channel blocker amlodipine provided better renal protection in hypertensive type 2 diabetics, reducing the chance of diabetic nephropathy developing to renal failure
  61. 61. Time to Doubling of Serum Creatinine, ESRD, or Death IDNT Primary Endpoint RRR 23% 60 P=0.006 23% RRR 20% 50 P=NS P=0.02 RRR P=0.006 Subjects (%) 40 30 Irbesartn 20 Amlodipie 10 Control 0 0 6 12 18 24 30 36 42 48 54 60 Follow-up (mo) Lewis EJ et al. N Engl J Med 2001;345:851-860.
  62. 62. RECOMMENDATIONS FOR THERAPY SUMMARY Guidelines are consistent in aiming to reduce cardiovascular and renal morbidity. „Goal‟ or „Target‟ BP’s consistent:  <140/90 mm Hg for all hypertensive patients  <130/80 mm Hg in diabetic patients. BP goals are not attained by many patients US and European guidelines recommend use of combination therapy early in the management of specific groups of patients US and European guidelines recommend use of combination therapy following failure to reach goal with monotherapy JNC 7 Report. JAMA 2003; 289: 2560-2572 ESH/ESC Guidelines. J Hypertens 2003; 21: 1011-1053 Guidelines Sub-Committee. 1999 WHO/ISH. J Hypertens 1999; 17:151–183
  63. 63. Thank You
  64. 64. Thank You

×