Integrating Aggressive CV Risk Management in Primary Care

1
Integrating Aggressive CV Risk Management in
Primary Care
2
High prevalence of multiple CV risk factors in
US adults
Behavioral Risk Factor Surveillance System, 2003
27.032.9
33.035.9
36.039.9
40.046.2
2 of hypertension, hypercholesterolemia,
diabetes, smoking, physical inactivity, obesity
CDC. MMWR. 200554113-40.
3
INTERHEART Exponential rise in CV disease with
added risk factors
2.9
2.4
1.9
3.3
13.0
42.3
68.5
182.9
333.7
512
256
128
64
Odds ratio for1st MI (99 CI)
32
16
8
4
2
1
All 9 riskfactors
Smk(1)
DM(2)
HTN(3)
ApoB/A1 ratio (4)
123
All 4
All 4 Obes
All 4 Ps
Smk smoking DM diabetes HTN hypertension
Obes obesity Ps psychosocial
factors Plotted on a doubling scale
Yusuf S et al. Lancet. 2004364937-52.
4
INTERHEART Any smoking increases CV risk
N 27,098 from 52 countries
8
4
Odds ratio for first MI
2
1
-0.75
12
34
56
78
910
1112
1314
1516
1718
1920
Never
21
Cigarettes smoked (n/day)
vs never smoked
Teo KK et al. Lancet. 2006368647-58.
5
Lifetime CVD risk estimate and risk factor burden
Men(n 3564)
Women (n 4362)
70
70
69
60
60
50
50
50
50
Adjusted cumulative incidence of CVD()
46
39
40
40
36
30
30
27
20
20
10
10
8
5
0
0
50
60
70
80
90
50
60
70
80
90
Attained age (years)
2 Major RFs
1 Elevated RF
All optimal RFs
1 Major RF
1 Not optimal RF
Lloyd-Jones DM et al. Circulation. 2006113791-8.
6
Additive risk of age with hypertension
hypercholesterolemia
NHANES 2001-2002 N 2864
?2-fold in higher age group

Wong ND et al. Am J Cardiol. 200698204-8.
7
Clinical manifestations of obesity
Insulinresistance Glucotoxicity Lipotoxicity ?Adi
ponectin ?Leptin
Atherosclerosis
Courtesy of Selwyn AP, Weissman PN. 2006.
8
Metabolic consequences of visceral obesity

• Visceral/abdominal obesity
• Correlates more strongly with insulin resistance
  than lower body obesity
• Is associated with ?plasma levels of fatty acids
  and accompanying ?TG
• ?Insulin resistance
• ?Altered hepatic fat accumulation and metabolism
• ?Dyslipidemia
• ?Proinflammatory adipokines (?insulin
  resistance, ?risk for CV disease)
• Visceral fat correlates more strongly with
  insulin resistance than subcutaneous fat

Grundy SM et al. Circulation. 20051122735-52. De
sprés J-P et al. BMJ. 2001322716-20.
9
Visceral obesity in CV risk
CT scans from men matched for BMI and total body
fat White visceral fat area (VFA) black
subcutaneous fat
Visceral obesity Fat mass 19.8 kg VFA 155 cm2
Visceral obesitydrives CV risk progression
independent of BMI
Subcutaneous obesity Fat mass 19.8 kg VFA 96
cm2
Després J-P. Eur Heart J Suppl. 20068(suppl
B)B4-12.
10
Optimal marker(s) for visceral adiposity
Measurement of waist circumference may offer a
more useful surrogate marker of visceral
adiposity than waist-hip ratio
Després JP et al. BMJ. 2001322716-720.
11
Measuring waist circumference
Iliac crest
NHLBI. www.nhlbi.nih.gov.
12
CDC Projections 2005 to 2050 Diabetes focus
32.1 million new diabetes patients by 2050
?220
?174
?470
Individuals with diabetes (millions)
?423
?Diabetes2005-2050 ()
2050
2005
?606 in blacks 75 yr
Revised projection appears more alarming than
previously estimated
Narayan KMV et al. Diabetes Care. 2006292114-6.
13
Multiple risk factors Undertreated and poorly
controlled
NHANES 2001-2002 n 638 with hypertension and
hypercholesterolemia

Wong ND et al. Am J Cardiol. 200698204-8.
14
Sudden cardiac death Too often the first sign
of CV disease
50 of sudden cardiac deaths occur in persons
with no CV disease history
Fox CS et al. Circulation. 2004110522-7.
15
Call to action
Identify all risk factors
Base treatment on global risk assessment
Treat multiple risk factors aggressively
16
ABCs of multiple risk factor management
Hypertension
Dyslipidemia
Hyperglycemia/ Insulin resistance
Platelet activationand aggregation
Adapted from Cohen JD. Lancet. 2001357972-3.
Beckman JA et al. JAMA. 20022872570-81.
17
AHA diet and lifestyle recommendations

• Healthy diet
• Fruits, vegetables, legumes, whole grains,
  non-fat/low-fat dairy, fish, poultry, limited
  alcohol intake
• Physical activity
• 30 min on most days
• No smoking
• Avoid use of and exposure to tobacco products

?CV risk
Lichtenstein AH et al. Circulation.
200611482-96.
18
Weight loss improves CV risk factors
N 4047 with obesity
Conventional treatment (n 1660)
Gastric surgery (n 1845)
At 2 years
Sjöström L et al. N Engl J Med. 20043512683-93.
19
3-Week diet exercise regimen yields favorable
metabolic changes
N 31 overweight/obese men weight ?8.4 lbs
µU/mL
Baseline
Follow-up
P lt 0.01 P lt 0.05
Roberts CK. et al. J Appl Physiol.
20061001657-65.
20
Physical activity reduces CV and all-cause
mortality
N 9791 moderate physical activity vs little or
no physical activity
Adjusted HR (95 CI)
Favorsexercise
Favorsno exercise
Normal BP
0.75 (0.531.05)
All-cause death
0.76 (0.391.49)
CV death
Prehypertension
0.79 (0.650.97)
All-cause death
CV death
0.79 (0.581.09)
Hypertension
All-cause death
0.88 (0.800.98)
CV death
0.84 (0.730.97)
1.5
1.0
0.5
0
2.0
Hazard ratio
NHANES 1 Epidemiological Follow-up Survey
(19711992)
Fang J et al. Am J Hypertens. 200518751-8.
21
Dietary programs can be effective yet difficult
to maintain
N 160 overweight or obese with 1 CV risk factor
Dansinger ML et al. JAMA. 200529343-53.
22
Emerging strategies in weight control

• Lifestyle interventions must include both diet
  and exercise
• Even moderate weight loss (510) can
• Decrease cardiometabolic risk factors
• Encourage continued health-promoting behaviors
  and adherence to medical therapy
• Novel approaches to decreasing cardiometabolic
  risk factors are needed

Eckel RH et al. Circulation. 20061132943-6. Gelf
and EV, Cannon CP. J Am Coll Cardiol.
2006471919-26.
23
Goals for optimal health

AACE. Endocr Pract. 20028(suppl 1)40-82.
24
Steno-2 Rationale for Target-Driven Behavior
Modification and Polypharmacy
25
Steno-2 Goals of intensive pharmacologic strategy
Gæde P et al. N Engl J Med. 2003348383-93.
26
Steno-2 results Better control with intensive
therapy
350
170
P lt 0.001
P lt 0.001
250
150
SBP(mm Hg)
Total-C(mg/dL)
150
130
50
110
0
0
0
1
2
3
4
5
6
7
8
0
1
2
3
4
5
6
7
8
350
11
P 0.015
P lt 0.001
250
9
TG (mg/dL)
AlC()
150
7
50
5
0
0
0
1
2
3
4
5
6
7
8
0
1
2
3
4
5
6
7
8
Follow-up (years)
Follow-up (years)
Conventional therapy (n 80)
Intensive therapy (n 80)
Gæde P et al. N Engl J Med. 2003348383-93.
27
Steno-2 Multifactorial intervention improves
macrovascular outcomes
N 160 with type 2 diabetes and microalbuminuria
60
50
Conventional
NNT 5Absolute risk reduction 20
40
Primary composite outcome ()
30
20
Intensive
10
0
0
12
24
36
48
60
72
84
96
Follow-up (months)
CV death, MI, stroke, revascularization,
amputation, PAD surgery Unadjusted
Gæde P et al. N Engl J Med. 2003348383-93.
28
Steno-2 Intensive intervention improves vascular
and neuropathic outcomes
Intensivebetter
Conventionalbetter
Variable
RR
P
0.003
0.39
?Risk of microvascular complications after 4
years was maintained at 8 years
0.42
0.02
0.002
0.37
1.09
0.66
0.0
1.0
2.0
3.0
Relative risk
Gæde P et al. N Engl J Med. 2003348383-93.
29
Integrating Antihypertensive Agents in CV Risk
Reduction
30
Relation of BP to CV disease is continuous
Meta-analysis of 61 observational studies N
958,074
Systolic BP
Diastolic BP
Age at risk (y)
Age at risk (y)
256
256
8089
8089
128
128
7079
7079
64
64
6069
6069
IHDmortality(floatingabsoluterisk)
32
32
5059
5059
16
16
4049
4049
8
8
4
4
2
2
1
1
0
0
70
90
100
110
80
120
140
160
180
Usual SBP (mm Hg)
Usual DBP (mm Hg)
Plotted on a doubling scale
Prospective Studies Collaboration. Lancet.
20023601903-13.
31
BPLTTC Comparison of more- vs less-intensive BP
lowering
Meta-analysis of 4 trials 1998-2002 N162,341
Favorsmore intensive
Favorsless intensive
0.6
1.0
1.4
Relative risk
Blood Pressure Lowering Treatment Trialists
Collaboration. Lancet. 20033621527-35.
32
ASCOT-BPLA Rationale
Anglo-Scandinavian Cardiac Outcomes Trial-Blood
Pressure Lowering Arm

• Premise
• Multiple risk factors markedly increase CV
  disease severity
• Standard BP-lowering therapies (diuretics and
  ß-blockers) have not been proven to prevent CHD
  events
• ASCOT-BPLA compared newer vs older
  antihypertensive regimens in patients with 3
  risk factors
• Hypothesis
• Newer, aggressive combination BP-lowering agents
  will prevent more CV events

BPLTTC. Arch Intern Med. 20051651410-9.Dahlöf
B et al. Lancet. 2005366895-906.
33
ASCOT-BPLA Comparison of older vs newer therapy
BP 160/100 mm Hg (untreated) or BP 140/90 mm Hg
(treated) 3 other risk factors N 19,257
Amlodipine 510 mg perindopril 48 mg
Atenolol 50100 mg bendroflumethiazide 1.252.5
mg
RandomizedDouble-blind
Follow-up 5.5 years
Primary outcome Nonfatal MI and fatal CHD
Plus K supplement if needed
Dahlöf B et al. Lancet. 2005366895-906.
34
ASCOT patient profile
Hypertension Aged 55 years Male Microalbuminuria/
proteinuria Smoker Family history of CHD Plasma
TCHDL-C 6 Type 2 diabetes ECG
abnormalities LVH Prior cerebrovascular
events Peripheral vascular disease
0
10
20
30
40
50
60
70
80
90
100
Patients with risk factor ()
Sever PS et al. J Hypertens. 2001191139-47.
Sever PS et al. Lancet. 20033611149-58.
35
ASCOT-BPLA BP reductions over time
180
Systolic BP
160
BP
140
137.7 136.1
Mean difference 2.7, P lt 0.0001
120
Blood pressure(mm Hg)
100
Diastolic BP
80
79.2 77.4
Mean difference 1.9, P lt 0.0001
60
0
1.0
2.0
3.0
4.0
5.0
0
0.5
1.5
2.5
3.5
4.5
5.5
Time (years)
Atenolol 50100 mg bendroflumethiazide
1.252.5 mg/potassium
Amlodipine 510 mg perindopril 48 mg
Dahlöf B et al. Lancet. 2005366895-906.
36
ASCOT-BPLA Reduction in primary outcome
Nonfatal MI and fatal CHD
10
8
10 RRR HR 0.90 (0.791.02) P 0.1052
6
Proportionof events ()
4
2
0
1
2
3
4
5
6
0
Time (years)
Atenolol 50100 mg bendroflumethiazide 1.252.5
mg/potassium
Amlodipine 510 mg perindopril 48 mg

Dahlöf B et al. Lancet. 2005366895-906.
37
ASCOT-BPLA Additional reductions with
amlodipine-based regimen
Rate/1000 patient-years
Amlodipine-based(n 9639)
Atenolol-based (n 9618)
Amlodipine-based better
Atenolol-based better
Secondary endpoints Nonfatal MI (excluding
silent) 7.4 8.5 fatal CHD Total
coronary endpoint 14.6 16.8 Total CV events
and procedures 27.4 32.8 All-cause
mortality 13.9 15.5 CV mortality 4.9 6.5
Fatal/nonfatal stroke 6.2 8.1
Fatal/nonfatal HF 2.5 3.0 Tertiary
endpoints Development of diabetes 11.0 15.9
Development of renal impairment 7.7 9.1
P lt0.05 lt0.01 lt0.0001 lt0.05 0.001 lt0.001
NS lt0.0001 lt0.05
0.50
0.70
1.00
1.45
2.00
Unadjusted hazard ratio

Dahlöf B et al. Lancet. 2005366895-906.
38
CAFE Lower central aortic BP with newer vs older
antihypertensive regimen
Similar effects on brachial BP
140
Brachial SBP
135
130
Central aortic SBP
mm Hg
125
120
0
0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
5.0
5.5
6.0
Time (years)
Atenolol bendroflumethiazide Amlodipine
perindopril
CAFE Investigators. Circulation. 20061131213-25.
39
CAFE Summary

• Substantial and consistent differences in central
  aortic BP and hemodynamics with amlodipine
  perindopril vs atenolol bendroflumethiazide,
  despite similar brachial systolic BP effects
• Central aortic systolic BP and pulse pressure
  differences may explain ASCOT-BPLA outcomes
• Central aortic pulse pressure may be a
  determinant of CV outcomes

CAFE Investigators. Circulation. 20061131213-25.
40
Beyond BP Reduction Integrating RAAS Modulation
in Vascular Protection
41
Vascular protection Focus on ACE inhibition

HOPE Study Investigators. N Engl J Med.
2000. EUROPA Investigators. Lancet. 2003. PEACE
Trial Investigators. N Engl J Med. 2004.
or diabetes 1 CV risk factor LVEF left
ventricular ejection fraction
42
HOPE, EUROPA, PEACE Concomitant CV therapies at
baseline
HOPE Study Investigators. N Engl J Med. 2000.
EUROPA Investigators. Lancet. 2003. PEACE Trial
Investigators. N Engl J Med. 2004.
43
HOPE, EUROPA, PEACE Primary outcomes
HOPE
PEACE
EUROPA
Placebo
Placebo
Placebo
20
14
22 RR P lt 0.001
4 RR P 0.43
20 RR P 0.0003
30
12
25
15
10
20
8
Patients ()
10
6
15
Ramipril 10 mg
4
Trandolapril 4 mg
Perindopril 8 mg
10
5
2
5
0
0
0
0
2
4
1
3
1
2
3
4
5
6
1
3
4
0
5
2
Time (years)
HOPE Study Investigators. N Engl J Med.
2000. EUROPA Investigators. Lancet. 2003. PEACE
Trial Investigators. N Engl J Med. 2004.
RR risk reduction
44
HOPE, EUROPA, PEACE Reduction in all-cause
mortality
Favors ACEI
Favors placebo
0.6
1.0
1.4
Odds ratio (95 CI)
Dagenais GR et al. Lancet. 2006368581-8.
45
HOPE, EUROPA Benefit consistent across ancillary
therapy
4-year rates in placebo groups
ACEI better
ACEI worse
Patients (n)
Subgroup
PInteraction
0.003 0.651 0.139 0.078
AntiplateletsNo antiplatelets Lipid-lowering
agentsNo lipid-lowering agents ?-blockersNo
?-blockers RevascularizationNo revascularization
18,3313184 948912,026 11,32310,192 10,39411,12
3
13.217.9 10.616.4 13.414.3 11.516.0
1.1
1.0
0.5
0.9
0.6
0.7
0.8
Odds ratio (95 CI)
CV death, nonfatal MI, or stroke
Adapted from Dagenais GR et al. Lancet.
2006368581-8.
46
HOPE, EUROPA, PEACE Benefit of ACEIs across
broad spectrum of risk
CV death, nonfatal MI or stroke
ACEI worse
ACEI better
-5
20
40
5
30
15
35
25
10
0
Odds reduction ()
Or total mortality in AIRE, TRACE, SOLVD, SAVE
trials
Dagenais GR et al. Lancet. 2006368581-8.
47
ACEIs vs ARBs Comparative effect on stroke, HF,
and CHD
Blood Pressure Lowering Treatment Trialists
Collaboration meta-analysisN 137,356 21
randomized clinical trials
ACEI
RRR
StrokeP 0.6
Stroke
-1 (9 to -10)
HF
10 (10 to 0)
HF P 0.4
CHD
9 (14 to 3)
ARB
CHD P 0.001
Stroke
2 (33 to -3)
HF
16 (36 to -5)
CHD
-7 (7 to -24)
0
30
30
Decrease
Increase
Risk
Turnbull F. 15th European Meeting on
Hypertension. 2005.Adapted by Strauss MH, Hall
AS. Circulation. 2006114838-54.
CHD MI and CV death
48
ACEIs in vascular disease Conclusions

• ACEIs reduce mortality, MI, HF, and stroke in
  patients with vascular disease with/without LVSD
  or HF
• Benefit in addition to antiplatelet agents,
  ß-blockers, and lipid-lowering agents
• Combining ACEIs with these agents provides
  greatest benefit
• Benefit in patients across a broad range of risk
  for CV events
• Annual rate in placebo groups of 1.422.6

• Consider ACEIs in all patients with vascular
  disease
• Assess risk/benefits and tolerability
• Use doses proven in clinical trials

Dagenais GR et al. Lancet. 2006368581-8. Fox K
et al. Eur Heart J. 2006272154-7.
49
Integrating Statinsin CV Risk Reduction
50
Statins reduce all-cause death
Cholesterol Treatment Trialists Collaboration N
90,056
Events ()
Treatment better
Controlbetter
Treatment(n 45,054)
Control(n 45,002)
Cause of death
Vascular causes
3.4
0.81
4.4
CHD
0.91
Stroke
0.6
0.6
0.95
Other vascular
0.6
0.7
0.93
Any non-CHD vascular
1.2
1.3
Any vascular
4.7
5.7
0.83
Nonvascular causes
2.4
2.4
Cancer
1.01
0.2
0.3
0.82
Respiratory
0.1
0.1
0.89
Trauma
1.1
1.2
0.87
Other/unknown
3.8
4.0
0.95
Any nonvascular
8.5
9.7
0.88
Any death
1.5
1.0
0.5
Relative risk
Meta-analysis of 14 trials
CTT Collaborators. Lancet. 20053661267-78.
51
HPS Assessing statin benefit in high-risk
patients
Heart Protection Study
Total-C ?135 mg/dL and diabetes, CAD, stroke,
PAD, or treated hypertension (if male, aged 65
years)N 20,536
Simvastatin 40 mg
Placebo
RandomizedOpen-label Blinded outcome
Follow-up 5 years
Primary outcomesMortality (overall analysis)
Fatal/nonfatal vascular events (subcategory
analysis)
HPS Collaborative Group. Lancet. 20023607-22.
52
HPS Statins confer benefit independent of
baseline LDL-C
N 20,536 Fatal/nonfatal vascular events
Placebo n ()
Statin n ()
Baseline LDL-C (mg/dL)
Statin better
Placebo better
358 (21.0)
282 (16.4)
lt100
871 (24.7)
668 (18.9)
100 to lt130
1356 (26.9)
1083 (21.6)
130
24 reduction 2P lt 0.00001
2585 (25.2)
2033 (19.8)
All patients
Rate ratio (95 CI)
Patients with multiple risk factors may develop
CV disease at LDL-C levels lt100 mg/dL
HPS Collaborative Group. www.hpsinfo.org.
53
ASCOT-LLA Rationale
Anglo-Scandinavian Cardiac Outcomes Trial-Lipid
Lowering Arm

• Premise
• High prevalence of dyslipidemia in hypertensive
  patients
• Most CV disease events occur in patients with BP
  and lipid concentrations deemed normal
• Hypothesis
• Lipid lowering will benefit hypertensive patients
  not conventionally deemed dyslipidemic

Sever PS et al. Lancet. 20033611149-58.
54
ASCOT-LLA Design
BP 160/100 mm Hg (untreated) or BP 140/90 mm Hg
(treated) 3 other risk factors N 19,257
Amlodipine 510 mg perindopril 48 mg
Atenolol 50100 mg bendroflumethiazide 1.252.5
mg
RandomizedDouble-blind
Total-C 250 mg/dLn 10,305
Atorvastatin 10 mg
Placebo
Dahlöf B et al. Lancet. 2005366895-906.Sever
PS et al. Lancet. 20033611149-58.
Plus K supplement if needed
55
ASCOT-LLA Statin reduces primary outcome in
hypertension

n 10,305
4
Placebo
36 RRRHR 0.64 (0.500.83) P 0.0005
3
Patients ()
2
Atorvastatin
1
0
0
1.0
1.5
3.0
3.5
2.0
2.5
0.5
Follow-up (years)
Mean baseline LDL-C 133 mg/dL Nonfatal MI and
fatal CHD
Sever PS et al. Lancet. 20033611149-58.
56
ASCOT-LLA post hoc analysis Time to benefit
n 10,305
Event rate
Atorvastatinbetter
Placebobetter
RRR ()
Censoring time
Atorvastatin
Placebo
30 days 90 days 180 days 1 year 2 years End of
study
83 2.4 14.2 67 5.5 16.6 48 7.5 14.3 45 6.6 12.
0 38 5.9 9.5 36 6.0 9.4
0
0.5
1.0
1.5
2.0
Hazard ratio
Per 1000 patient-years
Sever PS et al. Am J Cardiol. 200596(suppl)39F-4
4F.
57
ASCOT Integration of antihypertensive regimens
with statin
Primary endpoint Nonfatal MI and fatal CHD
Amlodipine 510 mg perindopril 48 mg
Atenolol 50100 mg bendroflumethiazide 1.252.5
mg/K
4.0
4.0
HR 0.47 (0.320.69)P 0.001
HR 0.84 (0.601.17)P 0.30
3.0
3.0
Cumulativeincidence()
2.0
2.0
1.0
1.0
0
0
0
1.0
2.0
3.0
3.5
0
1.0
2.0
3.0
3.5
Years
Placebo
Atorvastatin
Courtesy of Appel G, 2006.Adapted from Dahlöf B
et al. www.ascotstudy.org.
58
ASCOT Total CV events and procedures
Amlodipine 510 mg perindopril 48 mg
Atenolol 50100 mg bendroflumethiazide 1.252.5
mg/K
12.0
12.0
10.0
10.0
HR 0.85 (0.711.02) P 0.08
HR 0.73 (0.600.88) P 0.001
8.0
8.0
Cumulativeincidence()
6.0
6.0
4.0
4.0
2.0
2.0
0
0
0
1.0
2.0
3.0
3.5
0
1.0
2.0
3.0
3.5
Years
Placebo
Atorvastatin
Courtesy of Appel G, 2006.Adapted from Dahlöf B
et al. www.ascotstudy.org.
59
HPS, ASCOT Summary and implications

• Statins reduced CV events in moderate- to
  high-risk patients with normal LDL-C
• Global CV risk, not absolute LDL-C level,
  determines need for statin therapy
• Occlusive vascular disease
• Hypertension plus 3 other risk factors

HPS Collaborative Group. Lancet. 2003.Sever PS
et al. Circulation. 2005.Sever PS et al. AHA
Scientific Sessions. Nov 2005.
60
Extending the scope of aggressive lipid-lowering
TNT and IDEAL
TNT Treating to New Targets IDEAL Incremental
Decrease in End Points Through Aggressive Lipid
Lowering
LaRosa JC et al. N Engl J Med. 20053521425-35.P
edersen TR et al. JAMA. 20052942437-45.
61
Benefits of aggressive LDL-C lowering in stable
CAD
Reduction in primary end point
Favorshighdose
Favors standard dose
0.65
1
1.35
Hazard ratio
LaRosa JC et al. N Engl J Med. 20053521425-35.P
edersen TR et al. JAMA. 20052942437-45.
62
Low incidence of severe adverse events with
high-dose statin
Cannon CP et al. J Am Coll Cardiol.
200648438-45.
63
Integrating Aggressive Medical Therapy in
Diabetes
64
Aggressive medical therapy in diabetes
ACE inhibitorsARBs ß-blockersCCBsDiuretics
Hypertension
Atherosclerosis
StatinsFibric acid derivatives
Dyslipidemia
MetforminTZDsSulfonylureasNonsulfonylureasecre
tagogues Incretins Insulin
Hyperglycemia/ Insulin resistance
ASAClopidogrelTiclopidine
Platelet activationand aggregation
Adapted from Beckman JA et al. JAMA.
20022872570-81.
65
MICRO-HOPE, PERSUADE ACEIs reduce primary outcome
MICRO-HOPE
PERSUADE
(N 1502) CV death/MI/cardiac arrest
(N 3577) CV death/MI/stroke
20
25
Placebo
Placebo
19 RRRP 0.131
16
25 RRRP 0.0004
20
12
15
Perindopril 8 mg

Ramipril 10 mg
8
10
4
5
0
0
0
1
2
3
4
5
0
1
2
3
4
5
Follow-up (years)
HOPE Study Investigators. Lancet.
2000355253-9. Daly CA et al. Eur Heart J.
2005261369-78.
66
MICRO-HOPE, PERSUADE Relative risk reductions
in diabetes
Favors ACEI
Favors placebo
Primary outcome
Total mortality
CV mortality
MICRO-HOPE (N 3577)
All MI
PERSUADE (N 1502)
Stroke
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
Relative risk (95 CI)
HOPE Study Investigators. Lancet.
2000355253-9. Daly CA et al. Eur Heart J.
2005261369-78.
67
MICRO-HOPE ACEI improves renal and CV outcomes
in diabetes
N 3577 (32 with microalbuminuria)
Overt nephro-pathy
Mean albumin/ creatinine ratio
CV death
P 0.02
Stroke
MI
0
3.0
Placebo
-10
2.0
Relative risk reduction ()
Ramipril 10 mg
-20
1.0
P 0.001 at 1 yr
-30
P 0.01
P 0.027
0
-40
0
1
2
3
4.5
P 0.007
Years
P 0.0001
P values ACEI vs placebo
HOPE Study Investigators. Lancet. 2000355253-9.
68
Aggressive LDL-Clowering benefits in diabetes

Primary event rate ()
Difference in LDL-C(mg/dL)
Aggressive lipid-lowering better
Aggressive lipid-lowering worse
Control
Treatment
P
0.026 0.036 0.001 lt0.0001 0.0003
17.9 11.9 9.0 12.6 13.5
13.8 9.2 5.8 9.4 9.3
TNT Diabetes, CHD ASCOT-LLA Diabetes,
HTN CARDS Diabetes, no CVD HPS All
diabetes Diabetes, no CVD
22 35 46 39 35
0.75
0.77
0.63
0.78
0.67
0.7
0.9
1
0.5
1.7
Relative risk
Atorvastatin 10 vs 80 mg/day Statin vs placebo
Shepherd J et al. Diabetes Care. 2006 Sever PS
et al. Diabetes Care. 2005 HPS Collaborative
Group. Lancet. 2003 Colhoun HM et al. Lancet.
2004.
69
HPS Statin benefits irrespective of baseline
lipid level and diabetes status
Event rate ()
Placebo n 10,267
Simvastatin n 10,269
Statin better
Placebo better
LDL-C lt 116 mg/dL
With diabetes
15.7
20.9
No diabetes
18.8
22.9
LDL-C 116 mg/dL
With diabetes
23.3
27.9
No diabetes
20.0
26.2
24 reductionP lt 0.0001
25.2
19.8
All patients
0.4
1.0
1.4
0.6
0.8
1.2
Event rate ratio (95 CI)
HPS Collaborative Group. Lancet. 20033612005-16.
70
CARDS Assessment of lipid lowering in patients
with diabetes
Collaborative AtoRvastatin Diabetes Study
Type 2 diabetes and 1 of hypertension,
retinopathy, micro- or macroalbuminuria, current
smokerN 2838
RandomizedDouble-blind
Atorvastatin 10 mgn 1428
Placebo n 1410
Follow-up 4 years
Primary outcome Fatal/nonfatal MI, unstable
angina, acute CHD death, resuscitated cardiac
arrest, coronary revascularization, stroke
Colhoun HM et al. Lancet. 2004364685-96.
71
CARDS Statin reduces primary outcome in diabetes
Fatal/nonfatal MI, unstable angina, acute CHD
death, resuscitated cardiac arrest, coronary
revascularization, stroke
15
Placebo127 events
37 RRR (1752) P 0.001
10
Cumulativehazard()
Atorvastatin 10 mg83 events
5
0
0
1
2
3
4
4.75
Follow-up (years)
Mean baseline LDL-C 117 mg/dL
Colhoun HM et al. Lancet. 2004364685-96.
72
CARDS Safety considerations
Colhoun HM et al. Lancet. 2004364685-96.
73
Integrating Preventive Treatments in Diabetes
74
Diabetes Prevention Program Design
IFG or IGT, without diabetes N 3234
Randomized, double-blind
Intensive lifestyle modification
Metformin 850 mg bid
Placebo
Follow-up 2.8 years
Primary outcomeNew-onset diabetes
7 weight loss/maintenance 150 minutes
moderate physical activity weeklyPlus standard
lifestyle recommendations
DPP Research Group. N Engl J Med.
2002346393-403.
75
DPP Benefit of diet exercise or metformin on
diabetes prevention in at-risk patients
N 3234 with IFG and IGT without diabetes
40
Placebo
P
30
Metformin
lt 0.001
?31
Cumulative incidence of diabetes ()
20
Lifestyle
?58
lt 0.001
10
0
0
1.0
2.0
3.0
4.0
Years

vs placebo
DPP Research Group. N Engl J Med.
2002346393-403.
76
DPP Benefit of diet exercise or metformin on
diabetes by race and ethnicity
N 3234 with IFG and IGT without diabetes
African American (n 645)
American Indian (n 171)
White (n 1768)
Hispanic (n 508)
Asian (n 142)
0
-20
Reduction in new-onset diabetes()
-40
-60
-80
Lifestyle vs metformin
Lifestyle vs placebo
Metformin vs placebo
DPP Research Group. N Engl J Med.
2002346393-403.
77
HOPE, EUROPA, PEACE Reduction in new-onset
diabetes (placebo-controlled trials)
n 23,340 free from diabetes at baseline
Overall14 RRR RR 0.86 (0.780.95) P 0.0023
Ramipril 10 mg
Perindopril 8 mg
Trandolapril 4 mg
(all trials)
Not a prespecified end point
Dagenais GR et al. Lancet. 2006368581-8.
78
DREAM Study design
Randomized, double-blind 2 2 factorial designN
5269 with IFG and/or IGT, free from CV disease
Ramipril 15 mg/d vs placebo AND Rosiglitazone 8
mg/d vs placebo
Primary outcomeDiabetes or death from any cause
Secondary outcomes ICV eventsCombined MI,
stroke, CV death, revascularization, HF, angina,
ventricular arrhythmia
Secondary outcomes II Renal eventsProgression
to micro- or macroalbuminuria, or ?30 CrCl
Secondary outcomes III Glucose status Glucose
levels, conversion to normoglycemia
Follow-up 35 years
Diabetes REduction Assessment with ramipril and
rosiglitazone Medication
DREAM Trial Investigators. Diabetologia.
2004471519-27.
79
DREAM 2 x 2 factorial design
N 5269 with IFG and/or IGT
Rosiglitazone
Placebo
Ramipril Rosiglitazone
Ramipril
Ramipril Placebo
Placebo
Rosiglitazone Placebo
Placebo Placebo
Ramipril 5 mg 2 months 10 mg 10 months 15
mg thereafterRosiglitazone 4 mg 2 months 8
mg thereafter
DREAM Trial Investigators. Diabetologia.
2004471519-27.
80
DREAM Baseline characteristics
Age (years) 54.7 (10.9) Women
() 58.5 Hypertension () 43.5 Hyperlipidemia
() 35.5 BP (mm Hg) 136/83 (18.6/11.3) BMI
(kg/m2) 30.5 (5.1) Waist circumference
(inches) Men 34.3 (10.8) Women 32.6
(11.9) Glucose FPG (mg/dL) 104 (12.6) IFG
() 42.4 2-hour (mg/dL) 157 (25.2) IGT
() 85.9
DREAM Trial Investigators. Diabetologia.
2004471519-27.
81
DREAM Effects of treatments on occurrence of
new-onset diabetes or death
0.6
0.6
Placebo
60 RRR HR 0.40 (0.350.46) P lt 0.0001
9 RRRHR 0.91 (0.811.03) P 0.15
0.5
0.5
Placebo
0.4
0.4
Cumulative hazard rate
0.3
0.3
0.2
0.2
Ramipril
0.1
0.1
Rosiglitazone
0.0
0.0
0
1
2
3
4
0
1
2
3
4
Follow-up (years)
DREAM Trial Investigators. Lancet.
20063681096-1105 N Engl J Med.
20063551551-62.
82
DREAM Safety

• Rosiglitazone vs placebo
• Increased incidence of HF (0.5 vs 0.1, P
  0.01)
• No cases of fatal HF
• No difference for other CV events
• Increased incidence of peripheral edema(6.8 vs
  4.9, P 0.003)
• 4.9-lb weight gain (P lt 0.0001)
• Increased hip circumference (?0.71 in, P lt
  0.0001)
• No difference in waist circumference
• Decreased waist-hip ratio (P lt 0.0001)
• No adverse hepatic effects
• Alanine aminotransferase (ALT) levels ?4.2 U/L at
  1 year (P lt 0.0001)
• Ramipril vs placebo
• Increased incidence of HF (0.5 vs 0.2)
• No adverse hepatic effects
• ALT levels ?1.1 U/L at 1 year (P 0.004)

DREAM Trial Investigators.Lancet.
20063681096-1105 N Engl J Med.
20063551551-62.
Adjudicated
83
DREAM results Summary

• Rosiglitazone
• 60 RRR in new-onset diabetes or death (P lt
  0.001) NNT 7
• Benefit consistent across ethnicity, gender, and
  age
• Increased conversion to normoglycemia vs placebo
  (50.5 vs 30.3) (HR 1.71, P lt 0.0001)
• ?BP vs placebo (1.7/1.4 mm Hg P lt 0.0001)
• Ramipril
• 9 RRR in new-onset diabetes or death (P 0.15)
• Increased conversion to normoglycemia vs placebo
  (42.5 vs 38.2) (HR 1.16, P 0.001)
• ?BP vs placebo (4.3/2.4 mm Hg P lt 0.001)
• When ACEIs are indicated, improved glucose
  metabolism may be added benefit

DREAM Trial Investigators. Lancet.
20063681096-1105 N Engl J Med.
20063551551-62.
FPG lt 110 mg/dL and 2-h glucose lt 140 mg/dL
84
ONTARGET Study design
ONgoing Telmisartan Alone and in combination with
Ramipril Global Endpoint Trial
N 25,62055 years with coronary,
cerebrovascular, or peripheral vascular disease,
or diabetes end-organ damage
Ramipril 10 mg
Telmisartan 80 mg
Ramipril 10 mg telmisartan 80 mg
Primary end pointCV death, MI, stroke, hosp for
HF
Secondary end pointNewly diagnosed diabetes
Results anticipated in 2007
ONTARGET/TRANSCEND Investigators. Am Heart J.
200414852-61.
85
TRANSCEND Study design
Telmisartan Randomized AssessmeNt Study in aCE
iNtolerant subjects with cardiovascular Disease
N 5776 ACEI-intolerant55 years with coronary,
cerebrovascular, or peripheral vascular disease,
or diabetes end-organ damage
Telmisartan 80 mg
Placebo
Primary end pointCV death, MI, stroke, hosp for
HF
Secondary end pointNewly diagnosed diabetes
Results anticipated in 2007
ONTARGET/TRANSCEND Investigators. Am Heart J.
200414852-61.
86
NAVIGATOR Study design
Nateglinide and Valsartan in Impaired Glucose
ToleranceOutcomes Research
N 9150 with IGT50 years with prior CV disease
or55 years with CV risk factorsRandomized,
double-blind 2 2 factorial design
Valsartan vs placebo AND Nateglinide vs placebo
Primary end pointsCV events, new-onset diabetes
NAVIGATOR Trial Steering Committee. Diabetes.
200352(suppl 1)A505.Skyler JS. Clin Diabetes.
200422162-6.
Insulin secretagogue
87
Drugs dont work in patients who wont take them
88
Involve the patient
Provider-centered approach may lead to missed
diagnoses and poor adherence
Patient-centered approach facilitates
identification of risk conditions
Enhanced communication improves patient
adherence, outcomes, and satisfaction
Barrier PA et al. Mayo Clin Proc. 200378211-4.
89
Consider patient adherence when prescribing
multiple therapies
?Medication adherence undermines BP, lipid,and
glucose control
As aggressive risk factor regimens increase in
complexity, adherence declines
Fixed-dose combination therapies that target
multiple risk factors without ?pill burden may
improve adherence
McDonald HP et al. JAMA. 20022882868-79.Sleight
P et al. Eur Heart J. 2006271651-6.
90
Poor adherence within 6 months of initial
treatment
N 8406 managed-care enrollees receiving
antihypertensive and lipid-lowering medications
50
44.7
40
35.9
Patientsadherentto both medications()
30
20
10
0
3
6
Time from initiation of therapy (months)
Chapman RH et al. Arch Intern Med.
20051651147-52.
91
Combination drugs for treatment of hypertension,
dyslipidemia, and diabetes
Numerous combinations
92
The polypill strategy Gemini Study andJEWEL
Programs
Blank R et al. J Clin Hypertens.
20057264-73.Hobbs FDR et al. Int J Cardiol.
2006110242-50.
Open-label, noncomparative
93
Gemini BP and LDL-C goals achieved
N 1220
Patients()
LDL-C goal(NCEP ATP III)
BP goal(JNC VI)
Both LDL-Cand BP goals
Blank R et al. J Clin Hypertens. 2005. Expert
Panel. NCEP ATP III. JAMA. 2001. JNC VI. Arch
Intern Med. 1997.
Amlodipine/atorvastatin single-pill therapy over
14 weeks
94
Integrating aggressive CV risk management in
primary care
Identify all risk factors
Base treatment on global risk assessment
Treat multiple risk factors aggressively
?CV events