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Microalbuminuria in diabetic and hypertensive patient2
 Microalbuminuria.
  Hypertension.
 Diabetes Mellitus.
   Interventions.
Microalbuminuria
Microalbuminuria in diabetic and hypertensive patient2
Hypertension*
Cigarette smoking
Obesity* (BMI >30 kg/m2)
Physical inactivity
Dyslipidemia*
Diabetes mellitus*
Microalbuminuria
estimated GFR <60 ml/min
Age (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
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
Micro-        Macro-
Parameter           Normal
                                        albuminuria   albuminuria

Urine 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
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) 9
1 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 et

al.,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.
Microalbuminuria in diabetic and hypertensive patient2
Correlation Coefficient between
micoalbuminoria and different parameters
    Parameters        r       P
Blood pressures:
    Systolic BP     0.678    <0.01
    Diastolic BP    0.133     NS


Blood Glucose:
    FBS             0.201    <0.05
    PPBS            0.218    <0.05


Lipogram:
    T.Cholesterol   0.443    <0.05
    Triglycerides   0.179     NS
     HDL – C        -0.319   <0.05
     LDL – C        0.134     NS
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
Microalbuminuria Compared To Traditional Risk
     Factors For Ischemic Heart Disease

                 3
                                                     N=2,085; 10 year follow-up
                2.5
Relative Risk




                 2

                1.5

                 1




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Borch-Johnsen K, et al.
Arterioscler Thromb Vasc Biol. 1999;19(8):1992-1997.
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                                   1.13

Mann JFE, et al. Ann Intern Med. 2001;134(8):629-636.
Low Levels of MAU are Predictive of CAD and
                  Death
                                            CHD incidence                                                                      CHD mortality
Cumulative 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
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 Deciles
Gerstein et al. JAMA 2001;286:421-6.
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 years

American Diabetes Association. Diabetes Care 2002;25:S85-S89
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)
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 management
ADA. Diabetes Care 1996; 19:S103-S105
Microalbuminuria in diabetic and hypertensive patient2
Hypertension
Hypertension Has a High Prevalence That Is
Expected To Rise Over the Coming Decades
                     50
with 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
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 priority
1.WHO, 2002; 2. AHA, 2004
2.AHA. Heart Disease and Stroke Statistics -- 2004 Update
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
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
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
                                                                Years
204 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
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 an
end point).
Primary composite end points (CEP): the first occurrence of cardiovascular death, nonfatal stroke, and
nonfatal myocardial infarction.
LIFE Study: Double-blind, randomized trial to compare the effects of losartan
and atenolol on cardiovascular morbidity and mortality in high-risk patients with
hypertension and left ventricular hypertrophy (LVH)
                                                                 Ibsen et al., Hypertension. 2005;45:198-202
Risk of Ischemic Heart Disease
                Related to SBP and Microalbuminuria
                                                N=2,085; 10 year follow-up
                6

                5
Relative 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.
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
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 goal

American 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.
Diabetes
Microalbuminuria in diabetic and hypertensive patient2
The Diabetes Epidemic
189 mill. in 2003
324 mill. Estimated for 2025
72% 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.
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
                                                                                 2.3

Adjusted for age, race, income, cholesterol, systolic blood pressure, smoking
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
Association of Systolic Blood Pressure
  (SBP) and CV Death in Type 2 Diabetes
                                              250
                                              225              No diabetes
                                                               Diabetes
                                              200
               (deaths/10,000 person-years)




                                              175
CV 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.
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/L

7-year follow-up of 1,056 patients with type 2 diabetes with or without hypertension

Miettinen H et al. Stroke 1996;27:2033–9.                    U-Prot = Urinary protein concentration
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     6
P<0.01 normoalbuminuria vs microalbuminuria                                      Years
P<0.001 normoalbuminuria vs macroalbuminuria
P<0.05 microalbuminuria vs macroalbuminuria
Gall MA, et al. Diabetes. 1995;44:1303-1309.
Copyright ©1995, American Diabetes Association. Reprinted with permission.
Relative prognostic value of MAU
                         in type 2 diabetes

                            10
           10

             8
                                          6.5
Mortality 6
from 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.
Microalbuminuria in diabetic and hypertensive patient2
Therapeutic Approach
Effective Blood Pressure Control Reduces
    Cardiovascular Morbidity and Mortality
            Systolic-diastolic hypertension                          Isolated-systolic hypertension

       Fatal and non                                              Fatal and non
                                    Mortality                                                 Mortality
10      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: cardiovascular
ESH/ESC Guidelines. J Hypertens 2003; 21:1779–1786.
UKPDS Relative Risk Reduction for
Intensive 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
     -50
Over 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) in
the conventional group (n=1,138).
                                                                   UKPDS Group. Lancet. 1998;352:837-853.
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 control

Hansson L at al. Lancet 1998; 351:1755-1762
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
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.
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
                 indications

Stage 1 hypertension (SBP 140-159      Stage 2 hypertension (SBP ≥160 mmHg              Drug(s) for compelling
      or DBP 90-99 mmHg)                        or DBP ≥100 mmHg)                            indications
Thiazide-type diuretics for most      2-drug combination for most (usually          Other antihypertensive drugs
May 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.
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 dose
Add 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.
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
Importance of Long-Term BP-Control for
                              MAU-Reduction
                                                SBP reduction leads to MAU-reduction
                            1.00
Cumulative 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
The RAS showing ACE and non-ACE
           pathways

ACE 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.
Angiotensin II Formation

                                              Alternate
                                              Pathways*
        Angiotensinogen
Renin

           Angiotensin I                         CAGE             t-PA
ACE                                              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.
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 hypertrophy




Adapted from Unger T. Am J Cardiol 2002; 89 (suppl):3A-10A.
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.
Interventions to Reduce
Microalbuminuria

 Non   Pharmacological measures:-
  Weight Loss.
  Exercise.
  Eating a low fat diet
 Pharmacological     agents:-
  Statins.
  ACE inhibitors.
  ARBs.
  Cobination of ACEI and ARBs.
  CCBs
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 the
Bjork et al   1992   amount of albuminuria.
                     In Type I diabetics, ACE-I reduced proteinuria, risk of
Lewis 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 from
MicroHOPE 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.
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
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
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.
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
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.
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-up
Placebo (n)        201    201         164                    154                                  139         129    36
Irbesartan
150 mg (n)         195    195         167                    161                                  148         142    45
Irbesartan
300 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.
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.
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 placebo




Parving HH, et al. N Engl J Med. 2001;345(12):870-878.
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.
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.
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
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.
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
Thank You
Thank You

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Microalbuminuria in diabetic and hypertensive patient2

  • 2.  Microalbuminuria.  Hypertension.  Diabetes Mellitus.  Interventions.
  • 5. Hypertension* Cigarette smoking Obesity* (BMI >30 kg/m2) Physical inactivity Dyslipidemia* Diabetes mellitus* Microalbuminuria estimated GFR <60 ml/min Age (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
  • 6. 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
  • 7. Micro- Macro- Parameter Normal albuminuria albuminuria Urine 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
  • 8. 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) 9 1 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 et al.,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.
  • 10. Correlation Coefficient between micoalbuminoria and different parameters Parameters r P Blood pressures: Systolic BP 0.678 <0.01 Diastolic BP 0.133 NS Blood Glucose: FBS 0.201 <0.05 PPBS 0.218 <0.05 Lipogram: T.Cholesterol 0.443 <0.05 Triglycerides 0.179 NS HDL – C -0.319 <0.05 LDL – C 0.134 NS
  • 11. 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
  • 12. Microalbuminuria Compared To Traditional Risk Factors For Ischemic Heart Disease 3 N=2,085; 10 year follow-up 2.5 Relative 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 M Borch-Johnsen K, et al. Arterioscler Thromb Vasc Biol. 1999;19(8):1992-1997.
  • 13. 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 1.13 Mann JFE, et al. Ann Intern Med. 2001;134(8):629-636.
  • 14. Low Levels of MAU are Predictive of CAD and Death CHD incidence CHD mortality Cumulative 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
  • 15. 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 Deciles Gerstein et al. JAMA 2001;286:421-6.
  • 16. 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 years American Diabetes Association. Diabetes Care 2002;25:S85-S89
  • 17. 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)
  • 18. 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 management ADA. Diabetes Care 1996; 19:S103-S105
  • 21. Hypertension Has a High Prevalence That Is Expected To Rise Over the Coming Decades 50 with 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
  • 22. 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 priority 1.WHO, 2002; 2. AHA, 2004 2.AHA. Heart Disease and Stroke Statistics -- 2004 Update
  • 23. 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
  • 24. 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
  • 25. 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 Years 204 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
  • 26. 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 an end point). Primary composite end points (CEP): the first occurrence of cardiovascular death, nonfatal stroke, and nonfatal myocardial infarction. LIFE Study: Double-blind, randomized trial to compare the effects of losartan and atenolol on cardiovascular morbidity and mortality in high-risk patients with hypertension and left ventricular hypertrophy (LVH) Ibsen et al., Hypertension. 2005;45:198-202
  • 27. Risk of Ischemic Heart Disease Related to SBP and Microalbuminuria N=2,085; 10 year follow-up 6 5 Relative 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.
  • 28. 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
  • 29. 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 goal American 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.
  • 32. The Diabetes Epidemic 189 mill. in 2003 324 mill. Estimated for 2025 72% 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.
  • 33. 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 2.3 Adjusted for age, race, income, cholesterol, systolic blood pressure, smoking
  • 34. 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
  • 35. Association of Systolic Blood Pressure (SBP) and CV Death in Type 2 Diabetes 250 225 No diabetes Diabetes 200 (deaths/10,000 person-years) 175 CV 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.
  • 36. 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/L 7-year follow-up of 1,056 patients with type 2 diabetes with or without hypertension Miettinen H et al. Stroke 1996;27:2033–9. U-Prot = Urinary protein concentration
  • 37. 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 6 P<0.01 normoalbuminuria vs microalbuminuria Years P<0.001 normoalbuminuria vs macroalbuminuria P<0.05 microalbuminuria vs macroalbuminuria Gall MA, et al. Diabetes. 1995;44:1303-1309. Copyright ©1995, American Diabetes Association. Reprinted with permission.
  • 38. Relative prognostic value of MAU in type 2 diabetes 10 10 8 6.5 Mortality 6 from 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.
  • 41. Effective Blood Pressure Control Reduces Cardiovascular Morbidity and Mortality Systolic-diastolic hypertension Isolated-systolic hypertension Fatal and non Fatal and non Mortality Mortality 10 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: cardiovascular ESH/ESC Guidelines. J Hypertens 2003; 21:1779–1786.
  • 42. UKPDS Relative Risk Reduction for Intensive 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 -50 Over 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) in the conventional group (n=1,138). UKPDS Group. Lancet. 1998;352:837-853.
  • 43. 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 control Hansson L at al. Lancet 1998; 351:1755-1762
  • 44. 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
  • 45. 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.
  • 46. 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 indications Stage 1 hypertension (SBP 140-159 Stage 2 hypertension (SBP ≥160 mmHg Drug(s) for compelling or DBP 90-99 mmHg) or DBP ≥100 mmHg) indications Thiazide-type diuretics for most 2-drug combination for most (usually Other antihypertensive drugs May 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.
  • 47. 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 dose Add 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.
  • 48. 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
  • 49. Importance of Long-Term BP-Control for MAU-Reduction SBP reduction leads to MAU-reduction 1.00 Cumulative 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
  • 50. The RAS showing ACE and non-ACE pathways ACE 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.
  • 51. Angiotensin II Formation Alternate Pathways* Angiotensinogen Renin Angiotensin I CAGE t-PA ACE 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.
  • 52. 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 hypertrophy Adapted from Unger T. Am J Cardiol 2002; 89 (suppl):3A-10A.
  • 53. 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.
  • 54. Interventions to Reduce Microalbuminuria  Non Pharmacological measures:- Weight Loss. Exercise. Eating a low fat diet  Pharmacological agents:- Statins. ACE inhibitors. ARBs. Cobination of ACEI and ARBs. CCBs
  • 55. 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 the Bjork et al 1992 amount of albuminuria. In Type I diabetics, ACE-I reduced proteinuria, risk of Lewis 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 from MicroHOPE 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.
  • 56. 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
  • 57. 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
  • 58. 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.
  • 59. 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
  • 60. 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.
  • 61. 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-up Placebo (n) 201 201 164 154 139 129 36 Irbesartan 150 mg (n) 195 195 167 161 148 142 45 Irbesartan 300 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.
  • 62. 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.
  • 63. 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 placebo Parving HH, et al. N Engl J Med. 2001;345(12):870-878.
  • 64. 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.
  • 65. 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.
  • 66. 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
  • 67. 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.
  • 68. 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