..

28.1.12

10-30% TYPE 1
30-50% TYPE 2
20-40% IGT
20-30% IGT
TYPE 2

Ta
:

..
..

Relative risk of stroke and of

CHD increases with increasing
DBP
Stroke
CHD
7 prospective observational studies:
843 events

9 prospective observational studies:

4856 events

Relative risk of stroke

4.00

Relative risk of CHD

4.00

2.00

2.00

1.00

1.00

0.50

0.50

0.25

Baseline DBP category

1 2 3 4 5
76 84 91 98 105 mmHg
Approx mean usual DBP

0.25

Baseline DBP category

1 2 3 4 5
76 84 91 98 105 mmHg
Approx mean usual DBP
MacMahon et al 1990

Impact of Diabetes on Cardiovascular

Mortality in MRFIT
140
120

125

Nondiabetic (n=342,815)
Diabetic (n=5,163)
91

100
80

59
60

47
31

40
20

12

22

None
One only Two only All three
Number of risk factors*
MRFIT=Multiple Risk Factor Intervention Trial
*Risk factors analyzed: smoking, hypercholesterolemia, and hypertension.
Stamler J, et al. Diabetes Care. 1993;16:434-444.

50

Causes of Death in
People With Diabetes
40

40
30
20

15

13

10
0

Geiss LS, et al. In: Diabetes in America.

National Institutes of Health;1995.

13

10
4

DIABETES:
THE MOST COMMON CAUSE OF ESRD
Primary Diagnosis for Patients Who Start Dialysis
Other
10%

No. of dialysis patients

(thousands)

700

Glomerulonephritis
13%

Diabetes
50.1%

600

No. of patients
Projection
95% CI

Hypertension
27%

500
400
520,240

300
281,355

200
243,524

100
0

r2=99.8%
1984

1988

1992

United States Renal Data System. Annual data report. 2000.

1996

2000

2004

2008

Meta Analysis: Lower Mean BP

Results in Slower Rates of Decline in
GFR in Diabetics and Non-Diabetics
MAP (mmHg)

GFR (mL/min/year)

95
0

98

101

104

107

-2

110

113

116

119

r = 0.69; P < 0.05

-4
-6
Untreated
HTN

-8

-10
-12
130/85

140/90

Parving HH, et al. Br Med J. 1989. Moschio G, et al. N Engl J Med.

-14
1996.
Viberti GC, et al. JAMA. 1993.
Bakris GL, et al. Kidney Int.
1996.
Klahr S, et al. N Eng J. Med 1994. Bakris GL. Hypertension. 1997.
Hebert L, et al. Kidney Int. 1994. The GISEN Group. Lancet. 1997.
Lebovitz H, et al. Kidney Int. 1994.
Bakris GL, et al. Am J Kidney Dis. 2000;36(3):646-661.
Reprinted by permission, Harcourt Inc.

(mmHg)
(max 3 )

<130
<80
130-139 80-89

ADA, Position Statement Diabetes Care, Jan 2010

>140

>90

Events per 1000 patient yrs

UKPDS Event Rates for Select Endpoints With

Tight vs Less Tight Blood Pressure Control
80
70

P=0.005

Tight (n=758) mean

achieved BP 144/82 mmHg

60

Less tight (n=390) mean

achieved BP 154/87 mmHg

50
40
30

P=0.02

P=0.01

20

P=0.009

10
0

Any diabetesDiabetesrelated endpoint related death

Stroke

Microvascular
complications

UKPDS Group. BMJ. 1998;317:703713.

UKPDS: Relationship Between BP Control And

Diabetes--Related Deaths
Diabetes

Hazard ratio

p<0.0001
17% decrease per 10 mmHg decrement in
0.5 BP
110 120 130 140 150 160 170
Mean systolic blood pressure (mmHg)
Adler AI, et al. BMJ. 2000;321:412-419.
Reprinted by permission, BMJ Publishing Group.

HOT Diabetic Subgroup

Reduction in Cardiovascular Events
P=0.005

(mmHg)

Achieved Achieved
systolic diastolic
BP
BP

# of
patients
with
diabetes

(mmHg)

(mmHg)

90

143.7

85.2

501

85

141.4

83.2

501

80

139.7

81.1

499

mean

of all blood pressures for all study

patients in BP subgroups from 6 months of
follow-up to end of study

*Includes all myocardial infarction, all

strokes, and all other cardiovascular
deaths

25

Number of events*
per 1000 patient-yrs

Target
diastolic
BP

20
15
10
5
0

Hansson L, et al. Lancet. 1998;351:17551762.

Effect of ACE Inhibition on Nephropathy

in Patients with Type 1 Diabetes
40

Captopril
Placebo

Progression
to death,
dialysis or
transplant
(%)

30

20

*
10

0
0
Collaborative Study Group
* p = 0.006 vs placebo.

2
Follow-up (y)

Lewis EJ et al. N Engl J Med 1993;329:1456-1462.

20

HOPE Study Outcomes:

Events
Per
Patient
Group
RR=22%
P<0.001

15

RR=26%
P<0.001

RR=20%
P<0.001

Placebo

Ramipril

RR=16%
P=0.005

10

RR=32%
P<0.001
5

RR=0%
P=NS

0
Combined
Primary
Outcome*

Cardiovascular
Death

Myocardial
Infarction

StrokeNon-Cardiovascular
Death

*The occurrence of myocardial infarction, stroke or cardiovascular death

RR=Relative risk reduction

Yusuf S, et al. N Engl J Med. 2000;342:145-153.

Total
Mortality

Events per patient group (%)

MICRO-HOPE Events Per Patient Group

MICROfor Primary Endpoint* and Components
25

RR=25%
P<0.001

20

Placebo

Ramipril

RR=22%
P=0.01

15

RR=37%
P<0.001

RR=33%
P=0.007

10
5
0

Combined
primary
endpoint*

Myocardial
infarction

Stroke

Cardiovascular
death

*The occurrence of myocardial infarction, stroke or cardiovascular death

RR=Relative risk reduction
HOPE Study Investigators. Lancet. 2000;355:253-259.

www.hypertensiononline.
org

IRMA 2 Primary Endpoint

Time to Overt Proteinuria
20

Subjects
(%)

Control
Irbesartan 150 mg
Irbesartan 300 mg

15
10
5
0
0

Parving H-H, et al. N Engl J Med 2001;345:870878.

12
Follow-up (mo)

18

22

24

17

IDNT primary endpoint

Time to doubling of serum
creatinine, ESRD, or death

70

Irbesartan

RRR = 23%
p = 0.006
RRR = 20%
p = 0.02
p = NS

60
Amlodipin
e

50

Control

40
Subjects
(%) 30
20
10

RRR: Relative Risk Reduction

0
0

12

18

24

30

36

42

48

54

60

Follow-up (months)
Lewis EJ et al. N Engl J Med 2001;345(12):85160.

RENAAL

: 25%
p=0.006

30

: 28%
p=0.002

20

10

12

P (+ CT) 762
L (+ CT) 751

20

30

L
10
0
0

P (+ CT) 762
L (+ CT) 751

12
689
692

24
M
554
583

36
295
329

48
36
52

715
714

24
M
610
625

36

48

347
375

42
69

50
%

40

: 20%
p=0.010
P

30

20
10
0
0

Brenner BM et al New Engl J Med 2001;345(12):861-869.

P (+ CT) 762
L (+ CT) 751

12
715
714

24

610
625

36
347
375

48
42
69

A. BARNETT, JM, 2004

Time to Primary Outcome

# at Risk Yr 1
8576
T&R 8502

8214
8134

Yr 3

Yr 4

7832
7740

7473
7377

7095
7023

0.15
0.05

0.10

Ramipril
Tel. & Ram.

0.0

Cumulative Hazard Rates

0.20

0.25

Yr 2

Years of Follow-up

ONTARGET

Effects of ARBs in type 2 diabetes:

Renal and CV outcomes
Study
(N)

Primary outcome:
Renal disease
progression*

ARB

Secondary
outcomes
(CV)

Average
duration
(years)

IDNT
(N = 1715)

Irbesartan
300 mg/d vs
amlodipine
10 mg

20% vs placebo,
(P = 0.02) and 23%
vs amlodipine
(P = 0.006)

Combined CV
outcomes: NS

2.6

RENAAL
(N = 1514)

Losartan
100 mg/d
vs placebo

16% (P = 0.02)

CV morbidity
and mortality:
NS HF
hospitalization
32%

3.4

IRMA-2
(N = 590)

Irbesartan 150
300 mg
vs placebo

39% with
150 mg (P = 0.08)
70% with
300 mg (P < 0.001)

Nonfatal CV
events: NS

*Doubling of baseline serum creatinine, end-stage

renal disease (IDNT, RENAAL): progression to
diabetic nephropathy (IRMA-2)

Lewis EJ et al. N Engl J Med. 2001;345:851-60.

Brenner BM et al. N Engl J Med. 2001;345:861-9.
Parving HH et al. N Engl J Med. 2001;345:870-8.

ACCORD BP
Trial design: Type 2 diabetics were randomized to systolic BP <120 mm Hg (n = 2,362) vs.
systolic BP <140 mm Hg (n = 2,371). Mean follow-up was 4.7 years.

Results

% per year

(p = 0.20)

Systolic BP at 1 year: 119 mm Hg in intensive

group vs. 134 mm Hg in standard group
CV mortality, MI, or stroke: 1.9%/yr vs.
2.1%/yr, respectively

1.9

2.1

CV mortality: 1.3%/yr vs. 1.2%/yr (p = 0.55),

respectively
Serious adverse events: 3.3% vs. 1.3% (p <
0.001), respectively, due to increase in
hypokalemia and serum creatinine

Conclusions
0

CV mortality,
MI, or stroke
mace
Systolic BP
<120 mm Hg

Systolic BP
<140 mm Hg

Goal systolic BP <120 mm Hg was not

superior to a goal systolic BP <140 mm Hg
Similar incidence of CV outcomes in both
groups; however, more adverse events in the
intensive group
Presented by Dr. William Cushman at ACC.10/i2 Summit

Mean # Meds
Intensive:
Standard:

3.2
1.9

3.4
2.1

3.5
2.2

3.4
2.3

Average after 1st year: 133.5 Standard vs. 119.3 Intensive, Delta = 14.2

20

Primary Outcome

Patients with Events (%)

Nonfatal MI, Nonfatal Stroke or CVD Death

15

10

HR = 0.88
95% CI (0.73-1.06)

0
0

Years Post-Randomization

130-139 / 80 -89 mmHg 3

.
()
>140 / 90 mmHg
()
ACE-I ARBs +
(C)
(GFR < 30ml / min)
2

(B)

RAS
(E)
American Diabetes Association
Clinical Practice Recommendations 2009

130-139 / 80 -89 mmHg 3

.
()
>140 / 90 mmHg
()
ACE-I ARBs +
(C)
(GFR < 30ml / min)
2

(B)

RAS
(E)
American Diabetes Association
Clinical Practice Recommendations 2009

130-139 / 80 -89 mmHg 3

.
()
>140 / 90 mmHg
()
ACE-I ARBs +
(C)
(GFR < 30ml / min)
2

(B)

RAS
(E)
American Diabetes Association
Clinical Practice Recommendations 2009


.. ..

UKPDS (<85 mmHg

mmHg,,
))
MDRD (92 mmHg
mmHg,, MA
MA)
HOT (<80 mmHg
mmHg,,
))
AASK (<92 mmHg
mmHg,,
))
RENAAL (<140/90 mmHg
mmHg))
IDNT (135/85 mmHg
mmHg))
1

Bakris et al. Am J Kidney Dis. 2000;36:6462000;36:646-661
Brenner et al. NEJM 2001;345:8612001;345:861-869
Lewis et al. NEJM 2001; 345:851345:851-860

130-139 / 80 -89 mmHg 3

.
()
>140 / 90 mmHg
()
ACE-I ARBs +
(C)
(GFR < 30ml / min)
2

(B)

RAS
(E)
American Diabetes Association
Clinical Practice Recommendations 2009

ADA Recommentations 2012

Possible combinations 2007 ESC/ESH Guidelines for the

Management of Hypertension1
Thiazide diuretics

Angiotensin Receptor
antagonists

-blockers

-blockers

Calcium antagonists

ACE inhibitors
Possible combinations between some classes of antihypertensive drugs. The preferred combinations in the general hypertensive
population are represented as thick yellow lines. The frames indicate classes of agents proven to be beneficial in controlled
intervention trials.
1. Mancia G. et al. J Hypertens 2007;25:11051187

 .
+
HOPE

200

VALUE

190

HOT
FACET
STOP-2
RENAAL
LIFE
IDNT
IRMA
ABCD

120

110

180

Blood pressure (mmHg)

UKPDS

Blood pressure (mmHg)

CAPPP
INSIGHT

100

170
160
150
140

90

80
70

130
120

60

Baseline

Treatment

Baseline

Treatment

Mancia G et al. J Hypertens 2002;20:1461-4.