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ΑΝΔΡΕΑΣ ΠΙΤΤΑΡΑΣ MD
Diabetes Prevalence
and Relative Risk
Prevalence of Diabetes
• Estimated prevalence in the United States*
– 17 million people (6.2%)
• 11.1 million diagnosed
• 5.9 million undiagnosed
– 20 years old = 151,000 (0.19%†)
– 20 years old = 16.9 million (8.6%†)
– 65 years old = 7.0 million (20.1%†)
• Estimated prevalence worldwide‡
– 124 million people (2.1%)
• 97% with type 2 diabetes
*In 2000
†Percentage
in age group
‡In
CDC. National Diabetes Fact Sheet. 2002.
Amos AF, et al. Diab Med. 1997;14:S1-S85.
1997
Estimates of Diabetes
Prevalence in World Regions
80
1995
2000
2025
70
60
50
40
30
20
10
0
Africa Americas Eastern Europe Southeast Western
Mediterranean
Asia
Pacific
WHO Report 1997. World Health Organization. Geneva;1997.
Adults With Diagnosed Diabetes*
1990
No data
available
Less than 4%
*Includes women with a history of gestational diabetes.
Mokdad AH, et al. Diabetes Care. 2000;23(9):1278-1283.
4%-6%
Above 6%
Adults With Diagnosed Diabetes*
2000
4%-6%
Above 6%
*Includes women with a history of gestational diabetes.
Mokdad AH, et al. JAMA. 2001;286(10):1195-1200.
Prevalence of Diabetes
by Age Group in the US
22%
25
19%
20
12%
15
10
5
0
3%
20-44
45-64
65-74
Age Group
75+
Source: 1997-1999 National Health Interview Survey and 1988-1994 National Health and
Nutrition Examination Survey (NHANES) estimates projected to year 2000
CDC. National Diabetes Fact Sheet. 2002.
Age-Adjusted Prevalence of Diabetes*
by Race/Ethnicity in the US
19%
15%
14%
7%
0
*In people 20+ years old
5
10
15
20
25
Percent
Sources: 1997-1999 National Health Interview Survey and 1988-1994 National Health and
Nutrition Examination Survey (NHANES) estimates projected to year 2000. 1998
outpatient database of the Indian Health Service
CDC. National Diabetes Fact Sheet. 2002.
Projected New Cases of Diagnosed
Diabetes in US Adults by Age Group
600
500
400
300
200
100
0
20-44
45-64
65+
Age Group
Source: 1997-1999 National Health Interview Survey and 1988-1994 National Health and
Nutrition Examination Survey (NHANES) estimates projected to year 2000.
CDC. National Diabetes Fact Sheet. 2002.
Distribution by Age of Persons
With Self-Reported Diabetes
NHANES III*
(n=1,026)
BRFSS†
(n=3,059)
21.8 %
21.8 %
30.3 %
31.6 %
47.9 %
18-44 years
46.7 %
45-64 years
 65
*NHANES III=Third US National Health and Nutrition Examination Survey (1988-1994)
†BRFSS=Behavioral Risk Factors Surveillance System (1995)
Saaddine JB, et al. Ann Intern Med. 2002;136:565-574.
Distribution by Ethnicity of Persons
With Self-Reported Diabetes
NHANES III*
(n=1,026)
BRFSS†
(n=3,059)
3%
6.4 %
6.2 %
12 %
16 %
71.5 %
Non-Hispanic White
69.4 %
15.6 %
Non-Hispanic Black
Hispanic or Mexican American
Other
*NHANES III=Third US National Health and Nutrition Examination Survey (1988-1994)
†BRFSS=Behavioral Risk Factors Surveillance System (1995)
Saaddine JB, et al. Ann Intern Med. 2002;136:565-574.
NHANES III 1988-1994 Prevalence of
Elevated Blood Pressure* in Diabetic Adults
0
20
40
60
80
100
Percent
NHANES III=Third US National Health and Nutrition Examination Survey (1988-1994)
*130/85 mmHg or current use of prescription medication for hypertension
Geiss LS, et al. Am J Prev Med. 2002;22:42-48.
Relative Risk for Type 2 Diabetes
in US Men by Age
2.5
2
1.5
1
0.5
>65
<65
0
Quintile 1
Quintile 2-4
Quintile 5
Quintile of Western Dietary Pattern Score
van Dam RM, et al. Ann Intern Med. 2002;136:201-209.
©2002 ACP-ASIM. Reprinted with permission.
Age
Relative Risk for Type 2 Diabetes
in US Men by Family History
4
3
2
1
0
No
Quintile 1
Quintile 2-4
Quintile 5
Quintile of Western Dietary Pattern Score
van Dam RM, et al. Ann Intern Med. 2002;136:201-209.
©2002 ACP-ASIM. Reprinted with permission.
Yes
Family
History
Relative Risk for Type 2 Diabetes
in US Men by Physical Activity Level
2
1.5
1
0.5
0
Quintile 1 Quintile 2-4 Quintile 5
Quintile of Western Dietary Pattern Score
van Dam RM, et al. Ann Intern Med. 2002;136:201-209.
©2002 ACP-ASIM. Reprinted with permission.
Quintile 1
Quintile 2-4
Quintile 5
Relative Risk for Type 2 Diabetes
in US Men by BMI
12
10
8
6
4
2
0
Quintile 1
Quintile 2-4
Quintile 5
Quintile of Western Dietary Pattern Score
van Dam RM, et al. Ann Intern Med. 2002;136:201-209.
©2002 ACP-ASIM. Reprinted with permission.
>30
25-29
<25
BMI,
kg/m2
Diabetes Impact on
Clinical Cardiovascular Disease
Clinical Impact of Diabetes Mellitus
Diabetes
A 2- to 4fold
increase in
cardiovascular
mortality
The leading
cause of new
cases of end
stage renal
disease
The leading
cause of new
cases of
blindness in
workingaged adults
The leading
cause of
nontraumatic
lower
extremity
amputations
Causes of Death in
People With Diabetes
50
40
40
30
20
15
13
10
0
Geiss LS, et al. In: Diabetes in America.
National Institutes of Health;1995.
13
10
4
5
Rate of Diabetes-Related
Complications in Elders
IHD
200
100
Stroke
50
Leg Infection
Acute MI
25
Gangrene
10
Amputation
0
65-69
70-74
IHD=ischemic heart disease
75-79
MI=myocardial infarction
80-84
85+
Age (Years)
Bertoni, et al. Diabetes Care. 2002:25;471-475.
Copyright ©2002, American Diabetes Association. Reprinted with permission.
WHO Percentage of CV Deaths in Type 2 Diabetic Men
Ischemic Heart Disease
Cerebrovascular Accident
Other
London
Switzerland
Warsaw
Berlin
Zagreb
Hong Kong
Tokyo
Havana
Oklahoma
Arizona
0%
20%
40%
60%
WHO = World Health Organization CV=cardiovascular
Morrish NJ, et al. Diabetologia. 2001;44[suppl 2]:S14-S21.
Copyright ©2001, Springer-Verlag. Reprinted with permission.
80%
100%
WHO Percentage of CV Deaths in Type 2 Diabetic Women
Ischemic Heart Disease
Cerebrovascular Accident
Other
London
Switzerland
Warsaw
Berlin
Zagreb
Hong Kong
Tokyo
Havana
Oklahoma
Arizona
0%
20%
WHO = World Health Organization
40%
CV=cardiovascular
60%
Morrish NJ, et al. Diabetologia. 2001;44[suppl 2]:S14-S21.
Copyright ©2001, Springer-Verlag. Reprinted with permission.
80%
100%
OASIS Study Mortality
by Diabetes and CVD Status
0.25
Event rate
0.2
Diabetes/CVD (n=1,148)
RR=2.88 (2.37-3.49)
No Diabetes/CVD (n=3,503)
Diabetes/No CVD (n=569)
No Diabetes/No CVD (n=2,796)
RR=1.99 (1.52-2.60)
0.15
RR=1.71 (1.44-2.04)
0.1
RR=1.00
0.05
0
3
6
9
12
15
18
21
OASIS=Organization to Assess Strategies for Ischemic Syndromes
CVD=cardiovascular disease RR=relative risk (95% confidence intervals)
Malmberg K, et al. Circulation. 2000;102:1014-1019.
24
Months
Impact of Diabetes on
Cardiovascular Mortality in MRFIT
140
120
Diabetic (n=5,163)
91
100
80
59
60
47
31
40
20
0
125
Nondiabetic (n=342,815)
6
None
12
22
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.
Systolic BP and CV Death in MRFIT
250
225
200
175
150
125
100
75
50
25
0
Nondiabetic (n=342,815)
Diabetic (n=5,163)
<120 120-139 140-159 160-179 180-199
200
Systolic BP (mmHg)
BP= blood pressure CV=cardiovascular MRFIT=Multiple Risk Factor Intervention Trial
Stamler J, et al. Diabetes Care. 1993;16:434-444.
Increased Risk of CV Events
Over 7 years in Type 2 Diabetics
50
45
40
35
30
25
20
15
10
5
0
Myocardial
Infarction
Stroke
CV Death
Nondiabetic –MI (n=1,304)
Diabetic –MI (n=890)
P<0.001*
Nondiabetic +MI (n=69)
Diabetic +MI (169)
P<0.001*
P<0.001*
-MI=no prior myocardial infarction/+MI=prior myocardial infarction
CV=cardiovascular
*For diabetes vs. no diabetes and prior MI vs. no prior MI
Haffner SM, et al. N Engl J Med. 1998;339:229-234.
Framingham Heart Study
CVD Events in Diabetics
Men
Women
12
10
*
8
*
6
4
*
*
2
*
*
*
*
†
0
Total
CVD
CHD
Cardiac
failure
Intermittent
claudication
Stroke
CVD=cardiovascular disease CHD=coronary heart disease *P<0.01 †P<0.05
Wilson PWF, Kannel WB. In: Hyperglycemia, Diabetes and Vascular Disease.
Ruderman N, et al. eds. Oxford;1992. ©Copyright 1992, American
Physiological Society. Used by permission of Oxford University Press, Inc.
Age-Adjusted CVD Mortality by Number
of Risk Factors in Type 2 Diabetics
None
40
35
30
25
20
15
10
5
0
One only
Two only
All three
†
No proteinuria
Proteinuria
†
*
*
*
Men
Women
Men
Women
‡
Men
Women
Men
CVD=cardiovascular disease
For comparison of risk factors to “none” *P<0.05 †P<0.01 ‡P<0.001
Fuller JH, et al. Diabetologia. 2001;44[suppl2]:S54-S64.
Copyright ©2001, Springer-Verlag. Reprinted with permission.
Women
Presence of CVD and Increased Mortality
80
68.7
Normal
IGT
60
53.7
Diabetic
40
20
0
40
41.3
30.7
24.4
9.8
12.8
17.8
No Subclinical CVD Subclinical CVD
CVD=cardiovascular disease
IGT=Impaired glucose tolerance
Kuller LH, et al. Arterioscler Thromb Vasc Biol. 2000;20:823-829.
Clinical CVD
Coronary Heart Disease
Risk Markers in Diabetes
Modifiable




Elevated LDL-C
Thrombogenic
factors
Low HDL-C
– PAI-1
Elevated blood
– Fibrinogen
pressure
– C-reactive
Elevated triglycerides protein
 Diet
 Tobacco smoking
 Excess alcohol
consumption
 Physical inactivity


Obesity
Pyorala K, et al. Eur Heart J. 1994;15:1300-1331.
Not modifiable

Age

Male gender

Family history
of CHD

Personal
history of CHD
Multivariate Relative Risk
of Fatal CHD in Women*
18
15
12
9
6
3
0
1
No DM
2.75
3.63
5.51
6.38
11.9
5
6-10 11-15 16-25 >25
Duration of diabetes, y
CHD=coronary heart disease DM=diabetes mellitus
*P<0.001 for trend across categories of duration
Hu FB, et al. Arch Intern Med. 2001;161:1717-1723.
Copyright ©2001, American Medical Association.
5.49
1
No
prior
CHD
Prior
CHD
Multivariate Relative Risk* of Fatal CHD in
Women With and Without History of CHD
35
30
Women with history of CHD
25
20
11.0
8.61
10
0
15.4
13.1
15
5
30.0
Women without history of CHD
1
No diabetes
3.07
5
4.24
7.59
6-10
11-15
Duration of diabetes, y
CHD=coronary heart disease
*P<0.001 for trend across categories of duration
Hu FB, et al. Arch Intern Med. 2001;161:1717-1723.
Copyright ©2001, American Medical Association.
8.66
>15
Increased CHF Prevalence in Diabetics
377
400
350
Diabetic subjects
300
224
250
200
135
150
68
100
50
0
8
33
4
12
105
241
300
250
Control subjects
44
<45 45-54 55-64 65-74 75-84 85-94
Age at baseline
CHF=congestive heart failure
Nichols GA, et al. Diabetes Care. 2001:24;1614-1619.
Copyright ©2002, American Diabetes Association. Reprinted with permission.
95+
7-Year Incidence
of Fatal and Nonfatal MI
45%
50
40
30
19%
20
10
0
20%
4%
No Prior MI* Prior MI No Prior MI* Prior MI
Nondiabetic
Diabetic
(n=1,373)
(n=1,059)
*At baseline
MI=myocardial infarction
P<0.001 for prior MI vs. no prior MI and for diabetes vs. no diabetes
Haffner SM, et al. N Eng J Med. 1998;339:229-234.
Minnesota Heart Survey
Post-MI Survival in Men*
100
Nondiabetic
n=1,628
Percent
90
80
70
Diabetic
n=228
60
50
40
0
5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80
MI=myocardial infarction
Time Since MI
*based on data collected in 1970, 1980, and 1985
Sprafka JM, et al. Diabetes Care. 1991;14:537-543.
Copyright ©1991, American Diabetes Association. Reprinted with permission.
(months)
Minnesota Heart Survey
Post-MI Survival in Women*
100
Percent
90
Nondiabetic
n=568
80
70
60
Diabetic
n=156
50
40
0
5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80
MI=myocardial infarction
Time Since MI
*based on data collected in 1970, 1980, and 1985
Sprafka JM, et al. Diabetes Care. 1991;14:537-543.
Copyright ©1991, American Diabetes Association. Reprinted with permission.
(months)
1-Year Mortality After First MI
45
Nondiabetic men
Nondiabetic women
Diabetic men
Diabetic women
30
15
0
Out-ofhospital
28 days
(hospitalized
patients)
MI=myocardial infarction
Miettinen H, et al. Diabetes Care. 1998;21:69-75.
1 year
(28-day
survivors)
Overall
1-year
deaths
Age-Adjusted CVD Mortality by Quintile*
of Fasting Serum Triglyceride (mmol/l)
25
Men
*
Women *
20
15
10
5
0
Q1 Q2 Q3 Q4 Q5
Q1 Q2 Q3 Q4 Q5
CVD=cardiovascular disease *P<0.01 compared to Q1
Q1<1.10; Q2=1.11-1.50; Q3=1.51-2.02; Q4=2.03-2.93; Q5>2.94.
Fuller JH, et al. Diabetologia. 2001;44[suppl2]:S54-S64.
Copyright ©2001, Springer-Verlag. Reprinted with permission.
Age-Adjusted CVD Mortality
by Quintile of Fasting Plasma Glucose
25
20
Men
Women
‡
*
‡
†
15
* *
10
5
0
Q1 Q2 Q3 Q4 Q5
Q1 Q2 Q3 Q4 Q5
CVD=cardiovascular disease *P<0.05 †P<0.01 ‡P<0.001, all compared to Q1
Q1<1.10; Q2=1.11-1.50; Q3=1.51-2.02; Q4=2.03-2.93; Q5>2.94.
Fuller JH, et al. Diabetologia. 2001;44[suppl2]:S54-S64.
Copyright ©2001, Springer-Verlag. Reprinted with permission.
Survival Without Major CHD Event
by Quintile of AUC Insulin
Proportion without
major CHD event
1.00
0.95
0.90
Q1
0.85
Q2
0.80
0.75
Log rank:
Overall P=0.001
Q5 vs Q1 P<0.001
Q3
Q4
Q5
0
0.70
0
5
10
15
Years
CHD=coronary heart disease
AUC=area under the plasma insulin response curve
Pyorala M, et al. Circulation. 1998;98:398-404.
20
25
CHD Incidence by HbA1c Levels
in Elderly Type 2 Diabetics
CHD death
Incidence (%)
25
25
20
CHD death
and nonfatal MI
†
20
*
15
15
10
10
5
5
0
0
Low
<6%
Middle
6%-7.9%
High
>7.9%
HbA1c tertile
Low
<6%
Middle
6%-7.9%
High
>7.9%
HbA1c tertile
CHD=coronary heart disease MI=myocardial infarction
*P<0.01 compared with lowest tertile; †P<0.05 compared with lowest tertile
Kuusisto J, et al. Diabetes. 1994;43:960–967.
Copyright ©1994, American Diabetes Association. Reprinted with permission.
Risk Factors for CAD* in UKPDS
Age
LDL-C
HDL-C
3
3
3
1
1
1
0.4
0.4
0.4
40
45
50
55
60
Years
65
70
95
135
175
115
155
195
mg/dL
(from mmol/l)
CAD=coronary artery disease
UKPDS=UK Prospective Diabetes Study
*Includes fatal and nonfatal myocardial infarction or angina with abnormal
electrocardiography (ECG).
Turner RC, et al. BMJ. 1998;316:823-828.
Reprinted with permission from the BMJ Publishing Group.
35
40
45
50
55
mg/dL
Risk Factors for CAD* in UKPDS (cont’d)
HbA1c
3
Smoking
Status
Systolic BP
3
3
1
1
1
0.4
0.4
0.4
5
6
7
Percent
8
9
110
130
150
120
160
140
Never Ex Current
mmHg
CAD=coronary artery disease
UKPDS=UK Prospective Diabetes Study
*Includes fatal and nonfatal myocardial infarction or angina with abnormal
electrocardiography (ECG).
Turner RC, et al. BMJ. 1998;316:823-828.
Reprinted with permission from the BMJ Publishing Group.
Incidence of MI and Microvascular Endpoints
by Mean SBP and HbA1c in UKPDS
80
40
30
Myocardial
infarction
20
10
Microvascular
endpoints
0
110 120 130 140 150 160 170
Mean SBP (mmHg)
Adjusted incidence
per 1000 person-years (%)
Adjusted incidence
per 1000 person-years (%)
50
60
40
Myocardial
infarction
20
Microvascular
endpoints
0
5
6
7
8
9 10 11
Updated mean HbA1c concentration (%)
Adler AI, et al. BMJ. 2000;321:412-419.
Stratton IM, et al. BMJ. 2000;321:405-412.
Reprinted with permission from the BMJ Publishing Group.
MI=myocardial infarction
SBP=systolic blood pressure
Relationship of Fasting Insulin to
Relative Risk for Metabolic Disorders
Metabolic
Disorder
Baseline insulin
Low (%)
High (%)
Relative
risk
Hypertension
5.5
11.4
2.04
0.019
Hypertriglyceridemia
2.6
8.9
3.46
<0.001
Low HDL-C
16.2
26.3
1.63
0.012
High LDL-C
16.4
20.1
1.23
0.223
2.2
12.3
5.62
<0.001
Type 2 Diabetes
Haffner SM, et al. Diabetes. 1992;41:715-722.
P value
Survival (all-cause mortality)
Proteinuria as a Risk Factor
for Mortality in Type 2 Diabetes
1.0
Normoalbuminuria
(n=191)
0.9
Microalbuminuria
(n=86)
0.8
0.7
Macroalbuminuria
(n=51)
0.6
0.5
0
1
2
3
P<0.01 normoalbuminuria vs microalbuminuria
P<0.001 normoalbuminuria vs macroalbuminuria
P<0.05 microalbuminuria vs macroalbuminuria
4
5
6
Years
Gall MA, et al. Diabetes. 1995;44:1303-1309.
Copyright ©1995, American Diabetes Association. Reprinted with permission.
Proteinuria and Hypertension
in Type 2 Diabetes
1,000
Status of Proteinuria (P) and
Hypertension (H) in Type 2 Diabetics
500
0
-P-H -P+H +P-H +P+H
-P-H -P+H +P-H +P+H
Men
Women
Wang SL, et al. Diabetes Care. 1996;19:305-312.
Copyright ©1996, American Diabetes Association. Reprinted with permission.
Summary of Key Points
• Diabetics are at increased risk for all types of fatal
and non-fatal cardiovascular (CV) events
• The protection afforded nondiabetic women is lost
in diabetic women
• There is an increasingly negative impact on CV
morbidity and mortality as the number of risk
factors increases.
• The risk of myocardial infarction (MI) in a diabetic
without prior MI is as great as the risk of MI in a
nondiabetic with a previous MI
• Proteinuria is a potent predictor of cardiovascular
risk in diabetics, even more than in nondiabetics
Benefit of Diuretics in Diabetes:
Important Findings of 2 Major Clinical Trials
• SHEP (1991)
– Low doses of the diuretic chlorthalidone compared to
placebo reduced the risk of stroke in elderly patients
with isolated systolic hypertension
• ALLHAT (2000)
– In high-risk patients, the diuretic chlorthalidone compared to
the alpha-blocker doxazosin yielded equal risk of coronary
heart disease death and non-fatal myocardial infarction, but
significantly reduced the risk of combined cardiovascular
disease events, in particular congestive heart failure
SHEP
• The Systolic Hypertension in the Elderly Program (SHEP) was a
double-blind, randomized, placebo-controlled study enrolling
4,736 patients, 60 years old, with isolated systolic
hypertension (systolic BP160 mmHg; diastolic BP<90 mmHg),
for an average follow-up of 4.5 years
• Participants were randomized to low dose chlorthalidone, with
a step up to atenolol or reserpine, if needed
• Main outcome measures were fatal and non-fatal stroke
• Secondary endpoints were cardiovascular and coronary
morbidity and mortality, all-cause mortality, and quality of life
measures
• 583 patients had type 2 diabetes at baseline
SHEP Research Group. JAMA. 1991;265(24):3255-3264.
SHEP Morbidity and Mortality
Cumulative 5-Year Rate, Percent Per 100
Diabetics
Major CV events
RR (95% CI)
Non-fatal and fatal stroke
RR (95% CI)
Non-fatal MI and fatal CHD
RR (95% CI)
Major CHD events*
RR (95% CI)
All-cause mortality
RR (95% CI)
Active
(n=283)
Placebo
(n=300)
2.6
3.3
0.66 (0.46-0.94)
1.9
2.2
0.78 (0.45-1.34)
1.8
2.6
0.46 (0.24-0.88)
1.9
2.7
0.44 (0.25-0.77)
2.6
2.7
0.74 (0.46-1.18)
Nondiabetics
Active
Placebo
(n=2,080) (n=2,069)
0.9
1.0
0.66 (0.55-0.79)
0.5
0.7
0.62 (0.46-0.83)
0.6
0.6
0.77 (0.57-1.05)
0.7
0.7
0.81 (0.62-1.05)
0.7
0.8
0.85(0.68-1.06)
*P<0.05 for treatment effect in diabetics compared to nondiabetics
CV=cardiovascular, MI=myocardial infarction, CHD=coronary heart disease, RR=relative risk
Curb DJ, et al. JAMA. 1996;276(23):1886-1892.
Cumulative 5-y rate, per 100
SHEP Morbidity and Mortality
for Diabetics and Nondiabetics
35
Nondiabetic Active
Diabetic active
30
Nondiabetic placebo
Diabetic placebo
25
20
15
10
5
0
Major CV
events
Non-fatal & Non-fatal MI Major CHD
fatal strokes & fatal CHD
Events*
All-cause
mortality
*P<0.05 for treatment effect in diabetics compared to nondiabetics
CV=cardiovascular, MI=myocardial infarction, CHD=coronary heart disease
Curb DJ, et al. JAMA. 1996;276(23):1886-1892.
Benefit of Diuretics in Diabetes:
Important Findings of 2 Major Clinical Trials
• SHEP (1991)
– Low-doses of the diuretic chlorthalidone compared to
placebo reduced the risk of stroke in elderly patients
with isolated systolic hypertension
• ALLHAT (2000)
– In high-risk patients, the diuretic chlorthalidone
compared to the -andrenergic blocker doxazosin
yielded equal risk of coronary heart disease death and
non-fatal myocardial infarction, but significantly
reduced the risk of combined cardiovascular disease
events, in particular congestive heart failure
ALLHAT Blood Pressure Component
Doxazosin Arm
• The Antihypertensive and Lipid-Lowering Treatment to Prevent
Heart Attack Trial (ALLHAT) is a double-blind, active-controlled
trial that enrolled 42,448 patients, >55 years old, with
hypertension (SBP >140 mmHg and/or DBP >90 mmHg) and at
least 1 other coronary heart disease (CHD) risk factor
• ALLHAT was designed to determine the differences in the
incidence of the primary outcome between treatment with
diuretic (chlorthalidone) and 3 other agents, doxazosin,
lisinopril, and amlodipine
• The primary outcome was a composite of fatal CHD and nonfatal myocardial infarction (MI)
• Secondary outcomes were all-cause mortality, stroke, and all
major cardiovascular disease (CVD) events
• The doxazosin treatment arm of the blood pressure component
was stopped in January 2000, resulting in a median follow-up of
3.3 years for doxazosin compared to chlorthalidone
The ALLHAT Group. JAMA. 2000;283(15):1967-1975.
ALLHAT Blood Pressure Component
Doxazosin Arm Outcomes
4-year rate per 100 (SE)
Chlorthalidone
(n=15,268)
Doxazosin
(n=9,067)
Relative Risk
(95 % CI)
P
value
Primary outcome*
6.30 (0.36)
6.26 (0.30)
1.03 (0.90-1.17)
0.71
All-cause mortality
9.08 (0.35)
9.62 (0.49)
1.03 (0.90-1.15)
0.56
11.97 (0.38)
13.06 (0.53)
1.10 (1.00-1.12)
0.05
3.61 (0.22)
4.23 (0.32)
1.19 (1.01-1.40)
0.04
21.76 (0.49)
25.45 (0.68)
1.25 (1.17-1.33)
<0.001
4.45 (0.26)
8.13 (0.43)
2.04 (1.79-2.32)
<0.001
5.20 (0.27)
6.21 (0.39)
1.15 (1.00-1.32)
0.05
10.19 (0.35)
11.54 (0.48)
1.16 (1.05-1.27)
<0.001
Combined CHD†
Stroke
Combined CVD‡
CHF
Coronary
revascularization
Angina
*Coronary heart disease (CHD) and non-fatal myocardial infarction (MI)
†Combined CHD consists of CHD death, non-fatal MI, coronary revascularization procedures, and angina with
hospitalization
‡Combined cardiovascular disease (CVD) consists of CHD death, nonfatal MI, stroke, coronary revascularization
procedures, angina, congestive heart failure (CHF), and peripheral arterial disease
The ALLHAT Group. JAMA. 2000;283(15):1967-1975.
ALLHAT Blood Pressure Component
4-Year Outcome Rates Per 100
Primary outcome*
Chlorthalidone
Doxazosin
All-cause mortality
Combined CHD†
Stroke
P=0.04
Combined CVD‡
P<0.001
CHF
P<0.001
Coronary revascularization
P<0.001
Angina
0
5
10
15
20
25
30
*Coronary heart disease (CHD) and non-fatal myocardial infarction (MI)
†Combined CHD consists of CHD death, non-fatal MI, coronary revascularization procedures, and angina with
hospitalization
‡Combined cardiovascular disease (CVD) consists of CHD death, nonfatal MI, stroke, coronary revascularization
procedures, angina, congestive heart failure (CHF), and peripheral arterial disease
The ALLHAT Group. JAMA. 2000;283(15):1967-1975.
ALLHAT BP Component Doxazosin Arm
Relative Risk For Diabetics*
Relative risk
(95% CI)*
P
value
1.25 (1.17-1.33)
<0.001
Diabetes
1.24 (1.12-1.38)
<0.001
No diabetes
1.26 (1.16-1.37)
<0.001
2.04 (1.79-2.32)
<0.001
Diabetes
2.14 (1.76-2.59)
<0.001
No diabetes
1.99 (1.65-2.37)
<0.001
Combined CVD
CHF
*for doxazosin compared to chlorthalidone, as of December 1999
The ALLHAT Group. JAMA. 2000;283(15):1967-1975.
Benefit of Beta-Blockers in Diabetes:
Important Findings of 1 Major Clinical Trial
• UKPDS (1998)
– Captopril and atenolol were equally effective in
reducing blood pressure to a mean of 144/83 mmHg
and 143/81 mmHg, respectively, and had a similar
effect on diabetic complications
UKPDS Outcomes by Treatment
Group for Patients Randomized to
Tight Blood Pressure Control*
Captopril Atenolol
(n=400) (n=358)
Any DM-related endpoint
Relative Risk†
(95% CI)
141
118
1.10 (0.86-1.41)
Diabetes-related death
48
34
1.27 (0.82-1.97)
All-cause mortality
75
59
1.14 (0.81-1.61)
Myocardial infarction
61
46
1.20 (0.82-1.76)
Stroke
21
17
1.12 (0.59-2.12)
Peripheral vascular disease
5
3
1.48 (0.35-6.19)
Microvascular complications
40
28
1.29 (0.80-2.10)
*The differences between the treatment groups were not statistically significant
†For captopril compared to atenolol
UKPDS Group. BMJ. 1998;317:713–720.
Patients with events (%)
UKPDS Kaplan-Meier Plots of Proportion of
Patients with Any Diabetes-Related Endpoint
50
Less tight blood pressure control
40
Captopril
Atenolol
30
20
10
0
0
No. of patients at risk:
Captopril
Atenolol
P=0.43
400
358
1
2
3
4
5
6
7
Years from randomization
327
314
UKPDS Group. BMJ. 1998;317:713–720.
Reprinted with permission from the BMJ Publishing Group.
257
237
8
9
124
112
Patients with events (%)
UKPDS Kaplan-Meier Plots of Proportion of
Patients Who Died of Disease Related to Diabetes
20
Less tight blood pressure control
Captopril
15
Atenolol
10
5
0
0
No. of patients at risk:
Captopril
Atenolol
P=0.28
400
358
1
2
3
4
5
6
7
8
Years from randomization
383
346
UKPDS Group. BMJ. 1998;317:713–720.
Reprinted with permission from the BMJ Publishing Group.
328
303
9
172
154
Benefit of Calcium Channel Blockers in Diabetes:
Important Findings of 2 Major Clinical Trials
• HOT (1998)
– Intensive diastolic blood pressure lowering (based on
comparison of diastolic blood pressures of 80 vs 85 vs
90 mmHg) with the calcium channel blocker felodipine
lead to fewer cardiovascular events and less
cardiovascular mortality
• Syst-Eur (1997)
– Treatment with the calcium channel blocker nitrendipine
significantly decreased rate of cardiovascular complications
in diabetics
– In older diabetic patients with isolated systolic hypertension,
dihydropyridine-based calcium channel blocker treatment
with nitrendipine was beneficial (1999)
HOT Study
• The Hypertension Optimal Treatment (HOT) Study enrolled
18,790 patients to assess the optimal target diastolic blood
pressure for hypertensive patients over a period of 4.9 years
(average follow-up 3.8 years)
• Patients were randomized to felodipine + placebo or felodipine +
aspirin
• Principal aims of this study were to assess: the association
between major cardiovascular events (non-fatal myocardial
infarction, non-fatal stroke, and cardiovascular death) and the
target BPs of 90 mmHg, 85 mmHg, and 80 mmHg; the
association between major cardiovascular events and diastolic BP
achieved during treatment; and the impact of the addition of
acetylsalicylic acid to antihypertensive treatment on the rate of
major cardiovascular events
• 1,501 patients had diabetes at baseline
Hansson L, et al. Lancet. 1998;351:1755–1762.
HOT Outcomes by
Target Blood Pressure Group*
Number of events
250
 90
 85
 80
200
150
100
50
0
Major
cardiovascular
events
All
myocardial
infarction
All
stroke
Cardiovascular
Mortality
Total
Mortality
*The outcomes for different blood pressure groups were not statistically significant
Hansson L, et al. Lancet. 1998;351:1755–1762.
HOT Diabetic Subgroup
Reduction in Cardiovascular Events
P=0.005
Achieved†
systolic
BP
Achieved†
diastolic
BP
(mmHg)
(mmHg)
 90
143.7
85.2
501
 85
141.4
83.2
501
 80
139.7
81.1
499
(mmHg)
# of
patients
with
diabetes
†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
Hansson L, et al. Lancet. 1998;351:1755–1762.
25
Number of events*
per 1000 patient-yrs
Target
diastolic BP
20
15
10
5
0
Benefit of Calcium Channel Blockers in Diabetes:
Important Findings of 2 Major Clinical Trials
• HOT (1998)
– Intensive diastolic blood pressure lowering (based on
comparison of diastolic blood pressures of 80 vs 85 vs 90
mmHg) with the calcium channel blocker felodipine lead to
fewer cardiovascular events and less cardiovascular
mortality
• Syst-Eur (1997)
– Treatment with the calcium channel blocker
nitrendipine significantly decreased rate of
cardiovascular complications in diabetics
– In older diabetic patients with isolated systolic
hypertension, dihydropyridine-based calcium channel
blocker treatment with nitrendipine was beneficial
(1999)
Syst-Eur Trial
• The Systolic Hypertension in Europe (Syst-Eur) Trial enrolled
4,695 patients 60 years old, with hypertension, for a median
follow-up of 24 months (range 1-97 months)
• Participants were randomly assigned to nitrendipine, plus
enalapril and hydrochlorothiazide if needed, or to placebo
• The primary endpoint was a composite of fatal and non-fatal
stroke
• Other endpoints included congestive heart failure, myocardial
infarction, sudden death, and all cardiac endpoints (a composite
of congestive heart failure, myocardial infarction and sudden
death)
• 492 patients had diabetes at baseline
Staessen JA, et al. Lancet. 1997;350:757-764.
Syst-Eur Fatal and Non-Fatal
Endpoints Combined
% relative risk reduction
Stroke
Cardiac
endpoints*
Heart
failure
All
Myocardial cardiovascular
infarction
endpoints
0
-5
-10
-15
-20
- 26
-25
-30
P=0.03
-35
-40
-45
- 29
P=0.12
- 42
- 30
- 31
P=0.12
P<0.001
P=0.003
*Includes fatal and non-fatal heart failure, fatal and non-fatal myocardial infarction,
and sudden death
Staessen JA, et al. Lancet. 1997;350:757-764.
Syst-Eur Outcomes in Diabetic
and Nondiabetic Patients
Overall
mortality
% relative risk reduction
0
Mortality from
cardiovascular causes
-6
-10
All Cardiovascular
events*
-13
-20
-26
-30
-40
-50
-55
P=0.04
-60
Diabetic (n=492)
-70
Nondiabetic (n=4,203)
P=0.02
P=0.01
-69
-76
-80
*Includes fatal and non-fatal events
Tuomilehto J, et al. N Eng J Med. 1999;340:677-684.
Benefit of ACE Inhibitors in Diabetes:
Important Findings of 5 Major Clinical Trials
•
•
•
•
UKPDS (1998)
– Tight blood pressure control with captopril or atenolol compared to
less tight control lowered the rates of stroke, any diabetes endpoint,
microvascular outcomes, and death
– Intensive compared to conventional glucose control lowered risk of
any diabetes-related endpoint, microvascular endpoints and
myocardial infarction
HOPE & MICRO-HOPE Substudy (2000)
– Ramipril compared to placebo added to usual care reduces the occurrence of
death, myocardial infarction, and stroke in both diabetics and nondiabetics
– Ramipril decreased progression of proteinuria in diabetics
ABCD (1998)
– Enalapril compared to nisoldipine provided comparable blood pressure control
and better protection against myocardial infarction
ABCD, CAPPP, FACET and UKPDS meta-analysis (2000)
– ACEIs compared to other agents significantly reduced the frequency of acute
myocardial infarction, cardiovascular events, and all-cause mortality
UKPDS Impact of Tight* vs Less Tight† Blood
Pressure Control on Diabetes-Related Endpoints
Relative risk
for tight control
(95% CI)
P Value
Any DM-related
endpoint
0.76 (0.62–0.92)
0.005
DM-related deaths
0.68 (0.49–0.94)
0.02
All-cause mortality
0.82 (0.63–1.08)
0.17
Myocardial infarction 0.79 (0.59–1.07)
0.13
Stroke
0.56 (0.35–0.89)
0.01
Peripheral vascular
disease
0.51 (0.19–1.37)
0.17
Microvascular
complications
0.63 (0.44–0.89)
0.009
*n=758 (mean achieved blood pressure of 144/82 mmHg)
†n=390 (mean achieved blood pressure of 154/87 mmHg)
Adapted from UKPDS Group. BMJ. 1998;317:703–713.
Reprinted with permission from the BMJ Publishing Group.
Relative risk
reduction
(95% CI)
0.1
Favors tight
control
1
10
Favors less
tight control
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
20
P=0.01
P=0.009
10
0
Any diabetesDiabetesrelated endpoint related death
UKPDS Group. BMJ. 1998;317:703–713.
Stroke
Microvascular
complications
UKPDS Relative Risk Reduction for
Tight* vs Less Tight† Blood Pressure Control
% Relative risk
reduction
P
value
Any diabetes-related endpoint
Diabetes-related deaths
24
32
0.005
0.02
Heart failure
Stroke
Myocardial infarction
56
44
21
0.004
0.01
NS
Microvascular complications
Retinopathy progression
Deterioration of vision
37
34
47
0.009
0.004
0.004
Endpoint
*n=758 (mean achieved blood pressure of 144/82 mmHg)
†n=390 (mean achieved blood pressure of 154/87 mmHg)
UKPDS Group. BMJ. 1998;317:703–713.
UKPDS Outcomes by Treatment
Group for Patients Randomized to
Tight Blood Pressure Control*
Captopril Atenolol
(n=400) (n=358)
Any DM-related endpoint
Relative Risk†
(95% CI)
141
118
1.10 (0.86-1.41)
Diabetes-related death
48
34
1.27 (0.82-1.97)
All-cause mortality
75
59
1.14 (0.81-1.61)
Myocardial infarction
61
46
1.20 (0.82-1.76)
Stroke
21
17
1.12 (0.59-2.12)
Peripheral vascular disease
5
3
1.48 (0.35-6.19)
Microvascular complications
40
28
1.29 (0.80-2.10)
*the differences between the treatment groups were not statistically significant
†for captopril compared to atenolol
UKPDS Group. BMJ. 1998;317:713–720.
Patients with events (%)
UKPDS Kaplan-Meier Plots of Proportion of
Patients with Any Diabetes-Related Endpoint
50
Less tight blood pressure control
Captopril
40
Atenolol
30
20
10
0
0
N.o of patients at risk:
Captopril
Atenolol
P=0.43
400
358
1
2
3
4
5
6
7
Years from randomization
327
314
UKPDS Group. BMJ. 1998;317:713–720.
Reprinted with permission from the BMJ Publishing Group.
257
237
8
9
124
112
Patients with events (%)
UKPDS Kaplan-Meier Plots of Proportion of
Patients Who Died of Disease Related to Diabetes
20
Less tight blood pressure control
Captopril
15
Atenolol
10
5
0
0
No. of patients at risk:
Captopril
Atenolol
P=0.28
400
358
1
2
3
4
5
6
7
8
Years from randomization
383
346
UKPDS Group. BMJ. 1998;317:713–720.
Reprinted with permission from the BMJ Publishing Group.
328
303
9
172
154
UKPDS Relative Risk Reduction for
Intensive vs Less Intensive Glucose Control
% Relative
risk
reduction
Relative risk
reduction
(95% CI)
P value
Any DM-related
endpoint
12
0.03
DM-related deaths
10
0.34
All-cause mortality
6
0.44
Myocardial infarction
16
0.05
Microvascular
complications
25
<0.01
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.
Reprinted with permission from Elsevier Science.
0.5
Favors
intensive
1
2
Favors
conventional
UKPDS Relative Risk Reduction for
Intensive vs Less Intensive Glucose Control
0
-12
-10
-16
-21
-20
-25
P=0.03
P=0.05
P=0.02
P<0.01
-30
-33
P<0.01
-40
-50
Microalbuminuria at 12 yrs
Retinopathy
Any DM endpoint
Microvascular complications
Myocardial Infarction
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.
UKPDS Findings on Tight Blood Pressure
Control and Intensive Glucose Control
• Tight vs less tight blood pressure control reduces risk of
– Any diabetes-related endpoint
24%
P=0.005
– Microvascular complications
37%
P=0.009
– Stroke
44%
P=0.01
Tight control (using captopril or atenolol) mean achieved BP 144/82 mmHg (n=758)
Less tight control (avoiding ACEIs and ß-blockers) mean achieved BP 154/87 mmHg (n=390)
• An intensive compared to conventional glucose control
policy reduces risk of
– Any diabetes-related endpoint
12%
P=0.03
– Microvascular complications
25%
P<0.01
– Myocardial infarction
16%
P=0.05
Over 10 years, HbA1c was 7.0% (6.2-8.2) in the intensive group treated
with sulfonylurea or insulin (n=2,729) compared with 7.9% (6.9-8.8)
in the conventional group (n=1,138) with diet modifications
UKPDS Group. BMJ. 1998;317:703–712.
UKPDS Group. Lancet. 1998;352:837-853.
Benefit of ACE Inhibitors in Diabetes:
Important Findings of 5 Major Clinical Trials
•
•
•
•
UKPDS (1998)
– Tight blood pressure control with captopril or atenolol compared to less tight
control lowered the rate of stroke, any diabetes endpoint, microvascular
outcomes, and death
– Intensive compared to conventional glucose control lowered risk of any
diabetes-related endpoint, microvascular endpoints and myocardial infarction
HOPE & MICRO-HOPE Substudy (2000)
– Ramipril compared to placebo added to usual care reduces the
occurrence of death, myocardial infarction, and stroke in both
diabetics and nondiabetics
– Ramipril decreased progression of proteinuria in diabetics
ABCD (1998)
– Enalapril compared to nisoldipine provided comparable blood pressure control
and better protection against myocardial infarction
ABCD, CAPPP, FACET and UKPDS meta-analysis (2000)
– ACEIs compared to other agents significantly reduced the frequency of acute
myocardial infarction, cardiovascular events, and all-cause mortality
HOPE Study
• The Heart Outcomes Prevention Evaluation (HOPE) Study was
a multicenter, randomized trial enrolling 9,297 patients 55
years old with a history of cardiovascular disease, or diabetes
plus at least one other cardiovascular risk factor
• Patients were treated with ramipril or placebo and vitamin E or
placebo for an average of 4.5 years
• Combined primary endpoint was the development of myocardial
infarction, stroke, or cardiovascular death
• Secondary endpoints were total mortality, admission to hospital
for congestive heart failure or unstable angina, complications
related to diabetes, and cardiovascular revascularization
Yusuf S, et al. N Engl J Med. 2000;342:145-153.
HOPE Study Outcomes:
Events Per Patient Group
20
RR=22%
P<0.001
RR=20%
P<0.001
15
RR=26%
P<0.001
10
Placebo
RR=32%
P<0.001
5
0
Combined
Primary
Outcome*
Cardiovascular
Death
Myocardial
Infarction
Stroke
Ramipril
RR=0%
P=NS
NonTotal
Cardiovascular Mortality
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.
RR=16%
P=0.005
MICRO-HOPE Substudy
• The MIcroalbuminuria, Cardiovascular, and Renal Outomes
HOPE Study enrolled 3,577 diabetics who participated in the
larger HOPE Study (n=9,541)
– MICRO-HOPE had the same study design, duration and
endpoints as HOPE, with the addition of the development of
overt nephropathy as an endpoint
HOPE Study Investigators. Lancet. 2000;355:253-259.
MICRO-HOPE Baseline Characteristics
Ramipril
n=1,808
Placebo
n=1,769
65.3
65.6
Males (n)
1,112
1,143
Type 2 diabetes (n)
Mean duration of diabetes (years)
1,774
11.1
1,722
11.8
Therapy for hyperglycemia (n)
•
Dietary therapy alone
•
Insulin therapy alone
•
Oral agents alone
•
Insulin + oral agents
331
432
957
88
300
482
895
92
Microalbuminuria (n)
555
587
Mean HbA1C (% of ULN*)
Mean serum creatinine (mol/L†)
123
93.8
124
94.0
Mean age (yrs)
*Measured at local laboratories; HbA1C is reported as percentage above ULN (upper limit
of normal) for local laboratory.
†Conversion factor of 88.4 mol/L=1 milligram per deciliter
HOPE Study Investigators. Lancet. 2000;355:253-259.
Events per patient group (%)
MICRO-HOPE Events Per Patient Group for
Primary Endpoint* and Components
25
20
RR=25%
P<0.001
Placebo
Ramipril
RR=22%
P=0.01
15
RR=33%
P=0.007
10
RR=37%
P<0.001
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.
MICRO-HOPE Combined
Primary Endpoint* in Subgroups
Total
#
% in
placebo
group
631
19.0
1,852
19.3
Oral hypoglycemics†
914
21.6
Insulin and oral
hypoglycemics†
180
18.5
Microalbuminuria‡
1,140
28.6
Cardiovascular disease‡
2,458
23.9
Dietary hyperglycemic
control†
Insulin†
*The occurrence of myocardial infarction, stroke or
0.2
cardiovascular death
†During study
‡At baseline
Adapted from HOPE Study Investigators. Lancet. 2000;355:253-259.
Reprinted with permission from Elsevier Science.
Relative risk
reduction
(95% CI)
0.4 0.6 0.8 1.0 1.2
Events per patient group (%)
MICRO-HOPE Events Per Patient
Group for Secondary Endpoints
18
16
14
12
10
8
6
4
2
0
RR=24%
P=0.004
RR=17%
P=0.03
Placebo
Ramipril
NS
RR=24%
P=0.03
NS
Total Revascularization Overt
mortality
nephropathy*
Heart
failure†
Unstable
angina†
*Based on positive 24h urine collection or albumin/creatinine ratio 36 mg/mmol
†Requiring hospital admission
RR=Relative risk reduction
NS 0.05
HOPE Study Investigators. Lancet. 2000;355:253-259.
MICRO-HOPE Combined Primary
Endpoint* Event Rates
Kaplan-Meier rates
0.25
0.20
RR=25%
P<0.001
0.15
0.10
0.05
Placebo
Ramipril
0.00
0
200
400
600
800
1000 1200 1400 1600
1800
Duration of follow-up (days)
*The occurrence of myocardial infarction, stroke or cardiovascular death
HOPE Study Investigators. Lancet. 2000;355:253-259.
Reprinted with permission from Elsevier Science.
RR=Relative risk reduction
Change from baseline (mmHg)
MICRO-HOPE
Change in Systolic Blood Pressure
1
0.6
0.55
0
-1.3
-1
-2
-1.9*
-2.7*
-3
-4
-5
-6
-5.3*
1 month
Ramipril
2 years
*P<0.001
†Study
duration was 4.5 years
HOPE Study Investigators. Lancet. 2000;355:253-259.
Placebo
Final visit†
Benefit of ACE Inhibitors in Diabetes:
Important Findings of 5 Major Clinical Trials
•
•
•
•
UKPDS (1998)
– Tight blood pressure control with captopril or atenolol compared to less tight
control lowered the rate of stroke, any diabetes endpoint, microvascular
outcomes, and death
– Intensive compared to conventional glucose control lowered risk of any
diabetes-related endpoint, microvascular endpoints and myocardial infarction
HOPE & MICRO-HOPE Substudy (2000)
– Ramipril compared to placebo added to usual care reduces the occurrence of
death, myocardial infarction, and stroke in both diabetics and nondiabetics
– Ramipril decreased progression of proteinuria in diabetics
ABCD (1998)
– Enalapril compared to nisoldipine provided comparable blood
pressure control and better protection against myocardial infarction
ABCD, CAPPP, FACET and UKPDS meta-analysis (2000)
– ACEIs compared to other agents significantly reduced the frequency of acute
myocardial infarction, cardiovascular events, and all-cause mortality
ABCD Trial
• The Appropriate Blood Pressure Control in Diabetes (ABCD)
Trial enrolled 950 non-insulin-dependent diabetics with
minimally reduced renal function to compare the effect of
moderate BP control (target diastolic BP of 80 to 89 mmHg) to
intensive BP control (target diastolic BP of 75 mmHg) over 5.3
years of follow-up
• Nisoldipine and enalapril also were compared as first-line
antihypertensive agents in the prevention and progression of
complications of diabetes
• Primary outcome measure was glomerular filtration rate as
assessed by 24hr creatinine clearance
• Secondary outcome measures were urinary albumin excretion,
left ventricular hypertrophy, retinopathy, and neuropathy
• In hypertensive subgroup (n=470), the endpoint of the
incidence of myocardial infarction was analyzed
Estacio RO, et al. N Eng J Med. 1998;338:645-652.
ABCD Hypertensive Subgroup Change in
Blood Pressure by Treatment Group
Blood pressure (mmHg)
Intensive-Treatment Group
Moderate-Treatment Group
160
150
Systolic
Systolic
140
130
120
110
100
Diastolic
90
Diastolic
80
70
6
18
30
42
54
Month
Nisoldipine
6
18
Enalapril
Estacio RO, et al. N Engl J Med. 1998;338:645-652.
©1998 Massachusetts Medical Society. All rights reserved.
30
42
54
ABCD Trial CV Outcomes and Death
in Hypertensive Subgroup
Number of events
30
P=0.03
25
P=0.03
Nisoldipine (n=235)
Enalapril (n=235)
20
15
P=NS
10
P=NS
P=NS
5
0
Fatal or
non-fatal MI
Non-fatal
MI
Congestive
heart failure
MI=myocardial infarction
CV=cardiovascular
Estacio RO, et al. N Engl J Med. 1998;338:645-652.
Schrier RW, Estacio RO. N Engl J Med. 2000;343:1969.
Death from
CV causes
Death from
any cause
Benefit of ACE Inhibitors in Diabetes:
Important Findings of 5 Major Clinical Trials
•
•
•
•
UKPDS (1998)
– Tight blood pressure control with captopril or atenolol compared to less tight
control lowered the rate of stroke, any diabetes endpoint, microvascular
outcomes, and death
– Intensive compared to conventional glucose control lowered risk of any
diabetes-related endpoint, microvascular endpoints and myocardial infarction
HOPE & MICRO-HOPE Substudy (2000)
– Ramipril compared to placebo added to usual care reduces the occurrence of
death, myocardial infarction, and stroke in both diabetics and nondiabetics
– Ramipril decreased progression of proteinuria in diabetics
ABCD (1998)
– Enalapril compared to nisoldipine provided comparable blood pressure control
and better protection against myocardial infarction
ABCD, CAPPP, FACET and UKPDS meta-analysis (2000)
– ACEIs compared to other agents significantly reduced the frequency
of acute myocardial infarction, cardiovascular events, and all-cause
mortality
ABCD, CAPPP, FACET
and UKPDS Meta-Analysis
• To assess whether ACE inhibitors are superior to other agents in
the prevention of cardiovascular events in hypertensive type 2
diabetics
• Review and meta-analysis of randomized controlled trials of
patients treated with ACEIs or other agents, followed for 2
years, with adjudicated cardiovascular events
• 4 trials eligible
– ABCD (n=470) compared enalapril with nisoldipine
– CAPPP (n=572) compared captopril with diuretic or betablockers
– FACET (n=380) compared fosinopril with amlodipine
– UKPDS (n=758) compared captopril with atenolol
Pahor M, et al. Diabetes Care. 2000;23:888-892.
Relative Risk Reduction With ACEIs
in ABCD, CAPPP and FACET
0
Acute
Myocardial
Infarction
Cardiovascular
Event
All-cause
Mortality
Stroke
-10
-24
-20
NS
-30
-43
-40
-51
-50
-60
-70
-63
P<0.001
P<0.001
Pahor M, et al. Diabetes Care. 2000;23:888-892.
P=0.01
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 Reduction of Endpoints in NIDDM
With the Angiotensin II
Antagonist Losartan Study
RENAAL Overview
• Randomized multi-site, double-blind, placebo-controlled study to
evaluate the renal protective effects of the angiotensin II
receptor antagonist losartan in patients with type 2 diabetes and
nephropathy
Population
• 1,513 patients (31 to 70 years old)
– Diagnosed type 2 diabetes and nephropathy
• albumin/creatinine ratio 300 mg/g
• serum creatinine between 1.3–3.0 mg/dL (1.5–3.0 mg/dL
for men >60 kg)
Brenner BM, et al. N Engl J Med. 2001;345(12):861-869.
RENAAL Study Design
Losartan
50 mg qd†
Maintain
antihypertensive therapy*
(excluding ACE inhibitors
& angiotensin II receptor
antagonists)
n=1,513
Losartan
100 mg qd†
Losartan 100 mg qd†
Trough Blood Pressure Goal
<140/<90 mmHg
Placebo†
Placebo†
6 week
screening phase
*Open-label
Week
10
Week
14
Placebo†
Average follow-up
3.4 years
diuretic, calcium channel blocker, beta-blocker, alpha-blocker, or centrally acting agent
combination with open-label diuretic, calcium channel blocker, beta-blocker, alpha-blocker,
and/or centrally acting agent
Brenner BM, et al. J Renin Angiotens Aldo System. 2000;1:329–335.
†In
RENAAL Endpoints
Primary Endpoint
•
Composite of a doubling of serum creatinine, end stage renal
disease, or death
Secondary Endpoints
1. Composite of morbidity & mortality from cardiovascular causes
• Myocardial infarction
• Stroke
• First hospitalization for heart failure or unstable angina,
coronary or peripheral revascularization
• Death from cardiovascular causes
2. Proteinuria
3. Rate of progression of renal disease
Brenner BM, et al. N Engl J Med. 2001;345(12):861-869.
RENAAL Baseline Characteristics*
Losartan†
Group
n=751
Placebo†
Group
n=762
Mean Age (yrs)
60
60
Male (%)
62
65
152
82
153
82
30
29
1237
1261
Mean serum creatinine (mg/dL)
1.9
1.9
Mean glycosylated hemoglobin (%)
8.5
8.4
Mean Systolic BP (mmHg)
Mean Diastolic BP (mmHg)
Mean BMI (kg/m2)
Median urinary albumin:creatinine
ratio (mg/g)
*The differences between the treatment groups were not statistically significant
†In combination with open-label diuretic, calcium channel blocker, beta-blocker, alpha-blocker,
and/or centrally acting agent
Brenner BM, et al. N Engl J Med. 2001;345(12):861-869.
Blood Pressure and
Pulse Pressure (mmHg)
RENAAL Trends in Blood Pressure
and Pulse Pressure
160
Systolic
140
120
Mean arterial pressure (P<0.001 at 12 months)
100
Diastolic
80
60
Pulse pressure
0
12
24
36
Months
48
Placebo* (n) 762
658
532
313
71
Losartan* (n) 751
673
562
371
101
*In
combination with open-label diuretic, calcium channel blocker, beta-blocker,
alpha-blocker, and/or centrally acting agent
Brenner BM, et al. N Engl J Med. 2001;345(12):861-869.
RENAAL Impact of Losartan
on Primary Composite Endpoint*
Losartan†
Group
n=751
Placebo†
Group
n=762
n
%
n
%
Primary composite
endpoint*
327
43.5
359
Doubling of
serum creatinine
• ESRD
• Death
162
147
158
21.6
19.6
21.0
255
226
P
value
% Relative risk
reduction
(95% CI)
47.1
0.02
16 (2 to 28)
198
194
155
26.0
25.5
20.3
0.006
0.002
0.88
25 (8 to 39)
28 (11 to 42)
-2 (-27 to 19)
34.0
300
39.4
0.01
20 (5 to 32)
30.1
263
34.5
0.01
21 (5 to 34)
•
•
ESRD or Death
Doubling of serum
creatinine and ESRD
•
*Composite of a doubling of serum creatinine, end stage renal disease (ESRD), or death
†In combination with open-label diuretic, calcium channel blocker, beta-blocker, alpha-blocker,
and/or centrally acting agent
Brenner BM, et al. N Engl J Med. 2001;345(12):861-869.
Cumulative % of
patients with event
RENAAL Patients Reaching
the Primary Composite Endpoint*
50
Placebo
Risk reduction=16%
40
P=0.02
30
20
Losartan
10
0
0
12
24
Months
36
48
Placebo† (n) 762
689
554
295
36
Losartan† (n) 751
692
583
329
52
†In
combination with open-label diuretic, calcium channel blocker, beta-blocker, alpha-blocker,
and/or centrally acting agent
*doubling of serum creatinine, end stage renal disease, death
Brenner BM, et al. N Engl J Med. 2001;345(12):861-869.
©2001 Massachusetts Medical Society. All rights reserved.
RENAAL Impact of Losartan
on Secondary Endpoints
• 10% risk reduction in the secondary composite
endpoint* (P=0.26)
 32% risk reduction in first hospitalization for heart
failure (P=0.005)
• 35% average reduction in the level of proteinuria
(P<0.001 for the overall treatment effect)
• 18% reduction in the decline of renal function
(P=0.01)
 15.2% reduction in the estimated decline in the
glomerular filtration rate (P=0.01)
*Composite of cardiovascular morbidity and mortality, including myocardial infarction,
stroke, first hospitalization for heart failure or unstable angina, coronary or peripheral
revascularization, or death from cardiovascular causes
Brenner BM, et al. N Engl J Med. 2001;345(12):861-869.
RENAAL First Hospitalization
for Heart Failure
% of patients
with event
20
32% Risk reduction
P=0.005
15
10
5
0
Placebo* (n)
Losartan* (n)
0
12
24
Months
36
48
762
685
616
375
53
751
701
637
388
74
*In combination with open-label diuretic, calcium channel blocker, beta-blocker, alpha-blocker,
and/or centrally acting agent
Brenner BM, et al. N Engl J Med. 2001;345(12):861-869.
©2001 Massachusetts Medical Society. All rights reserved.
RENAAL
Summary of Important Findings
In patients with type 2 diabetes and nephropathy:
• Losartan, in combination with other antihypertensive therapy
(non-ACE or ARB), delayed the onset of the primary composite
endpoint* (P=0.02) and delayed progression to end stage renal
disease (P=0.002)
• Losartan reduced proteinuria (P<0.001) and the rate of decline in
renal function (P=0.01)
• Losartan reduced the incidence of first hospitalization for heart
failure (P=0.005)
• These benefits were above and beyond those attributable to blood
pressure reduction alone
*Composite of a doubling of serum creatinine, end stage renal disease, or death
Brenner BM, et al. N Engl J Med. 2001;345(12):861-869.
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 Study Design
Irbesartan
300 mg/qd
n=194
11 died or
had adverse
events
174
completed
study
590 patients
randomized
and followed
Irbesartan
150 mg/qd
n=195
18 had
adverse
events
168
completed
study
Target Blood
Pressure*
<135/85 mmHg
Placebo
n=201
18 died or
had adverse
events
171
completed
study
1,469
patients
screened
*3 months after
randomization
Follow-up of 2 years
Parving HH, et al. N Engl J Med. 2001;345(12):870-878.
IRMA II Endpoints
Primary Endpoint
• Onset of diabetic nephropathy
– urinary albumin excretion rate greater than 200 g per
minute and at least 30% higher than baseline in at least 2
consecutive measurements
Secondary Endpoints
• Changes in level of albuminuria
• Changes in creatinine clearance
• Restoration of normoalbuminuria
– urinary albumin excretion rate of <20 g/min by last exam
Parving HH, et al. N Engl J Med. 2001;345(12):870-878.
IRMA II Baseline Characteristics*
Placebo
n=201
Irbesartan Irbesartan
150 mg
300 mg
n=195
n=194
Mean age (yrs)
58.3
58.4
57.3
Male (%)
68.7
66.2
70.6
Mean Systolic BP (mmHg)
Mean Diastolic BP (mmHg)
153
90
153
90
153
91
Mean BMI (kg/m2)
30.3
29.9
30.0
Mean urinary albumin
excretion (g /min)
54.8
58.3
53.4
Mean serum creatinine (mg/dl)
Men
women
1.1
0.9
1.1
0.9
1.1
1.0
Mean glycosylated hemoglobin (%)
7.1
7.3
7.1
*The differences between the treatment groups were not statistically significant
Parving HH, et al. N Engl J Med. 2001;345(12):870-878.
IRMA II Irbesartan vs Placebo
Primary Endpoint at 2 Years
Total
# of
Patients
Progression to
Nephropathy
n
%
Unadjusted
Risk
Reduction
P
Value†
Adjusted*
Risk
Reduction
P
Value†
300 mg
Irbesartan
194
10
5.2
70%
<0.001
68%
<0.001
150 mg
Irbesartan
195
19
9.7
39%
0.08
44%
0.05
Placebo
201
30
14.9
-
-
-
-
†
For irbesartan vs placebo (the significance level for the primary endpoint was 0.025)
*Hazard ratios were adjusted for baseline level of microalbuminuria and blood pressure
achieved during the study
Parving HH, et al. N Engl J Med. 2001;345(12):870-878.
IRMA II Change in
Urinary Albumin Excretion*
% change in urinary
albumin excretion
20
Placebo
10
0
-10
150 mg of irbesartan
-20
-30
300 mg of irbesartan
-40
-50
0
3
6
12
Months of Follow-up
18
*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.
22
24
IRMA II Incidence of Progression
to Diabetic Nephropathy
Incidence of Diabetic
Nephropathy (%)
20
P<0.001 for difference between
300 mg irbesartan group and placebo
15
Placebo
150 mg of
irbesartan
10
5
0
300 mg of
irbesartan
0
3
6
12
Months of Follow-up
Placebo (n)
201
201
164
154
Irbesartan
150 mg (n)
195
195
167
161
Irbesartan
194
180
172
194
300 mg
Parving HH, et al. N Engl J Med. 2001;345(12):870-878.
©2001 Massachusetts Medical Society. All rights reserved.
18
22
24
139
129
36
148
142
45
159
150
49
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
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
The Irbesartan in Diabetic
Nephropathy Trial
IDNT overview
• Randomized, double-blind trial to determine if irbesartan, an
angiotensin II receptor blocker, and amlodipine, a calcium
channel blocker, slow the progression of nephropathy in type 2
diabetics
Population
• 1,715 patients (30 to 70 years old)
– Diagnosed type 2 diabetes
– Hypertension (systolic BP>135, diastolic BP >85 mmHg or
treatment w/ antihypertensive agents)
– Nephropathy (urinary protein excretion of at least 900
mg/24hrs and serum creatinine between 1.0–3.0 mg/dL in
women, and 1.2–3.0 mg/dL in men)
Lewis EJ, et al. N Engl J Med. 2001;345(12):851-860.
IDNT Study Design
Target Blood Pressure
≤135*/ ≤85 mmHg
Potential
participants
discontinue ACEIs,
ARBs and CCBs at
least 10 days prior
to screening
1,715 patients
randomized
and followed
Amlodipine
10 mg/qd
n=567
Placebo
n=569
(*or 10 mmHg lower than
the value at screening if it
was more than 145 mmHg)
Screening phase of up to 5 weeks
Irbesartan
300 mg/qd
n=579
Average follow-up of 2.6 years
Lewis EJ, et al. N Engl J Med. 2001;345(12):851-860.
IDNT Endpoints
Primary Endpoint
• Composite of a doubling of serum creatinine, end stage renal
disease (as indicated by starting dialysis, serum creatinine  6
mg/dl, or transplantation), or death
Secondary Cardiovascular Endpoint
• Composite of death from cardiovascular causes, nonfatal
myocardial infarction, heart failure resulting in hospitalization, a
permanent neurologic deficit caused by a cerebrovascular
event, or lower limb amputation above the ankle
Lewis EJ, et al. N Engl J Med. 2001;345(12):851-860.
IDNT Baseline Characteristics*
Irbesartan
Group
n=579
Amlodipine
Group
n=567
Placebo
Group
n=569
59.3
59.1
58.3
65
63
71
Mean Systolic BP (mmHg)
Mean Diastolic BP (mmHg)
160
87
159
87
158
87
Mean BMI (kg/m2)
31.0
30.9
30.5
1.9
1.9
1.9
1.67
1.65
1.69
8.1
8.2
8.2
Mean age (yrs)
Male (%)
Median urinary albumin
excretion (g/24hr)
Mean serum creatinine (mg/dl)
Mean glycosylated hemoglobin (%)
*The differences between the treatment groups were not statistically significant,
except for the smaller number of females in the placebo group (P=0.02)
Lewis EJ, et al. N Engl J Med. 2001;345(12):851-860.
IDNT Irbesartan vs Amlodipine
Primary and Secondary Endpoints
Irbesartan
Group
n=579
Primary
composite endpoint*
• Doubling of serum
creatinine
• End stage renal
disease
• Death
Secondary
composite endpoint‡
Amlodipine
Group
n=567
P value
Unadjusted
relative risk
(95% CI)
n
%
n
%
189
32.6
233
41.1
0.006
0.77 (0.63-0.97)
98
16.9
144
25.4
<0.001
0.63 (0.48-0.81)
82
87
14.2
15.0
104
83
18.3
14.6
0.07
0.80
0.77 (0.57-1.03)
1.04 (0.77-1.40)
138
23.8
128
22.6
0.79
1.03 (0.81-1.31)
*Composite of a doubling of serum creatinine, end stage renal disease, or death
‡Composite
of death from cardiovascular causes, nonfatal myocardial infarction, heart
failure resulting in hospitalization, a permanent neurologic deficit caused by a
cerebrovascular event, or lower limb amputation above the ankle
Lewis EJ, et al. N Engl J Med. 2001;345(12):851-860.
IDNT Irbesartan vs Placebo
Primary and Secondary Endpoints
Irbesartan
Group
n=579
Primary
composite endpoint*
• Doubling of serum
creatinine
• End stage renal
disease
• Death
Secondary
composite endpoint‡
Placebo
Group
n=569
P value
Unadjusted
relative risk
(95% CI)
n
%
n
%
189
32.6
222
39.0
0.020
0.80 (0.66-0.97)
98
16.9
135
23.7
0.003
0.67 (0.52-0.87)
82
87
14.2
15.0
101
93
17.8
16.3
0.070
0.570
0.77 (0.57-1.03)
0.92 (0.69-1.23)
138
23.8
144
25.3
0.400
0.91 (0.72-1.14)
*Composite of a doubling of serum creatinine, end stage renal disease, or death
‡Composite
of death from cardiovascular causes, nonfatal myocardial infarction, heart
failure resulting in hospitalization, a permanent neurologic deficit caused by a
cerebrovascular event, or lower limb amputation above the ankle
Lewis EJ, et al. N Engl J Med. 2001;345(12):851-860.
IDNT Proportion of Patients with the
Primary Composite Endpoint*
Proportion with
primary endpoint
0.7
0.6
P=0.02 for irbesartan compared to placebo
0.5
0.4
0.3
0.2
*Composite of a doubling of serum
creatinine, end stage renal disease,
or death
0.1
0.0
0
6
12
18
Irbesartan (n) 579
555
528
496
400
304
216
146
65
Amlodipine (n) 565
542
508
474
385
287
187
128
46
Placebo (n)
551
512
471
401
280
190
122
53
568
24
30
36
42
Months of Follow-up
Lewis EJ, et al. N Engl J Med. 2001;345(12):851-860.
©2001 Massachusetts Medical Society. All rights reserved.
48
54
IDNT Average Systolic, Mean Arterial
and Diastolic Blood Pressures
Blood pressure (mmHg)
160
Systolic
150
140
130
120
Mean Arterial Pressure
(P=0.001 for both treatment groups
compared to placebo for visits after baseline)
110
Irbesartan
Amlodipine
Placebo
100
90
Diastolic
80
70
0
6
12
18
24
30
36
Months of Follow-up
Lewis EJ, et al. N Engl J Med. 2001;345(12):851-860.
©2001 Massachusetts Medical Society. All rights reserved.
42
48
54
IDNT
Summary of Important Findings
In hypertensive, type 2 diabetics with nephropathy:
• Irbesartan reduced the incidence of the primary composite
endpoint of a doubling of serum creatinine, end stage
renal disease, or death by 23% vs amlodipine (P=0.006)
and 20% vs placebo (P=0.02)
• Proteinuria was reduced 33% in the irbesartan group
compared to 10% with placebo
• These benefits were above and beyond those attributable
to blood pressure reduction alone
Lewis EJ, et al. N Engl J Med. 2001;345(12):851-860.