Transcript Dia 1

Benefits of intensive
multiple risk factor
intervention
Potential benefits of multifactorial
approaches
Adherence to multiple therapies is more likely
if initiated simultaneously
Early aggressive therapy targeting multiple
risk factors could potentially have a major impact
on CVD prevention
Chapman RH et al. Arch Intern Med. 2005;165:1147-1152.
Wald NJ, Law MR. BMJ. 2003;326:1419.
Age adjusted CVD death rate per
10,000 person years
MRFIT: CVD mortality by diabetes status
and number of baseline risk factors
140
120
Nondiabetic
Diabetic
100
80
60
40
20
0
none
one only
two only
all three
Stamler J et al. Diabetes Care 1993;16:434-443
Evidence base for multiple risk factor
intervention: the STENO-2 study
Conventional
Intensive
p
FPG (mmol/L)
–1.0
–2.9
<0.001
HbA1C (%)
+0.2
–0.5
<0.001
SBP (mmHg)
–3
–14
<0.001
DBP (mmHg)
–8
–12
0.006
Tot-C (mmol/L)
+0.2
–1.1
<0.001
LDL-C (mmol/L)
–0.3
–1.2
<0.001
TG (mmol/L)
+0.1
–0.5
0.015
Gaede P et al. NEJM 2003;348:383-93
STENO-2 study: Clinical outcomes
Cardiovascular disease
Autonomic neuropathy
Retinopathy
Nephropathy
0
0.2
0.4
0.6
0.8
1.0
Hazard ratio and 95% CI
Gaede P et al. NEJM 2003;348:383-93
STENO-2 study: Residual CV risk
Intensive Risk Management in Patients With Diabetes
60
Primary Composite End Point* (%)
P = 0.007
Conventional Therapy
50
Hazard ratio = 0.47
(95 percent CI., 0.24
to 0.73; P = 0.008)
40
30
20
Intensive therapy
10
0
12
24
36
48
60
72
84
96
Months of Follow-up
*From nonfatal MI, CABG, PCI, nonfatal stroke, amputation, or surgery for PAD .
Gaede P, et al. NEJM 2003; 348: 383-93
Risk factors for coronary artery disease
Stepwise selection of major risk factors for 280 coronary
artery disease events in 2,693 UKPDS patients followed for 10 years
Potentially modifiable





LDL cholesterol
HDL cholesterol
HbA1C
Systolic blood pressure
Smoking
p
<0.0001
0.0001
0.0022
0.0065
0.056
Age and gender were also significant risk factors but not body mass index, fasting plasma insulin,
waist/hip ratio or microalbuminuria
Turner RC et al. BMJ 1998;316:823-8
Summary
 Type 2 diabetes is characterised by a complex and evolving
pathophysiology
 Most patients die from a cardiovascular cause, but
microvascular complications are also important
 Integrated strategies to control multiple risk factors are
crucial to improve patient outcomes
Approaches to CVD prevention in diabetes
Lipid
modification
Lifestyle
intervention
Optimal
CV risk
Reduction ?
Glucose
lowering
BP
lowering
The prevention of CV complications:
a complex and multifactorial problem
Patients routinely
underestimate their
own CV risk
CV complications start to
develop early in disease
course
Patients pick and
choose which pills to
take
Dysfunctional
microcirculation and
macrocirculation
Complications are
usually already
present at diagnosis
The problem
Abnormal insulin sensitivity,
haemostasis, BP, vascular
function, weight, lipids, all
drive adverse outcomes
Frequently used therapies in diabetes
Drug Therapy
Primary Indication
Statins
Dyslipidaemia
Antihypertensives
Blood pressure
Oral antidiabetics
Glucose control
Long-acting insulins
Glucose control
Key findings from recent lipidlowering trials
IDEAL
ALLHAT-LLT
ASCOT-LLA
CARDS
Neutral effect in HTN Benefit in high-risk HTN Benefit in DM
regardless of baseline
with mild
LDL-C
lipid lowering
2002
2003
HPS
Benefit
in CVD and DM
regardless of baseline
LDL-C
2004
4D
Neutral effect
in ESRD
2005
PROVE IT-TIMI 22
TNT
Early and late benefit of
intensive vs moderate
lipid lowering in ACS
Benefit of
intensive vs
moderate
lipid lowering
in stable CAD
A to Z
Primary prevention
Secondary prevention (ACS)
Secondary prevention (stable CAD)
Benefit of intensive vs
moderate lipid lowering
in stable CAD
Late benefit of
intensive vs moderate
lipid lowering in ACS
Statins reduce all-cause death:
Meta-analysis of 14 trials
Cause of death
Events (%)
Treatment
Control
(n = 45,054)
(n = 45,002)
Treatment
better
Control
better
Vascular causes:
CHD
3.4
4.4
0.81
Stroke
Other vascular
Any non-CHD vascular
0.6
0.6
1.2
0.6
0.7
1.3
0.91
0.95
0.93
Any vascular
4.7
5.7
0.83
Nonvascular causes:
Cancer
Respiratory
Trauma
Other/unknown
Any nonvascular
2.4
0.2
0.1
1.1
3.8
2.4
0.3
0.1
1.2
4.0
1.01
0.82
0.89
0.87
0.95
Any death
8.5
9.7
0.88
0.5
1.0
Relative risk
1.5
CTT Collaborators. Lancet. 2005;366:1267-78
Benefits of aggressive LDL-C
lowering in diabetes
Aggressive lipidlowering
better
Primary event rate (%)
TNT
Diabetes, CHD
Treatment
Control
13.8
17.9
P
Difference in
LDL-C
(mg/dL)
0.026
22*
0.036
35†
0.001
46†
<0.0001
39†
0.0003
39†
0.75
ASCOT-LLA
Diabetes, HTN
9.2
11.9
CARDS
Diabetes, no CVD
5.8
9.0
HPS
All diabetes
Aggressive lipidlowering
worse
0.77
0.63
0.73
9.4
12.6
9.3
13.5
0.67
Diabetes, no CVD
0.5
0.7
0.9 1
Relative risk
1.7
* 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.
CARDS:
cumulative hazard for any CVD endpoint
Relative Risk = -32% (95% CI -45, -15)
p=0.001
Cumulative Hazard (%)
20
Placebo
189 events
15
Atorvastatin
134 events
10
5
0
0
Placebo
Atorva
1410
1428
1
1334
1372
2
1275
1337
3
4
4.75
992
1040
621
663
287
306
Years
Colhoun H.M. et.al. Lancet 2004; 364: 685-696
Key findings from recent
BP-lowering trials
ALLHAT
Benefit regardless
of drug class
2002
INVEST
CCB + ACEI
equivalent to
-blocker
+ diuretic in
hypertension
+ CAD
VALUE
Importance
of prompt
BP control
ASCOT-BPLA
Benefit of
CCB + ACEI vs
-blocker + diuretic
in high-risk
hypertension
without CAD
2003
2004
2005
CAMELOT
Evidence for
 BP goal in
hypertension
+ CAD
-blocker metaanalysis
Increased risk of
stroke vs other
antihypertensives
Greater benefit from hypertension
control in type 2 diabetes: Syst-Eur
study
All-cause
mortality
CV mortality
CV events
Favours treatment
p values compare
diabetic vs. non-diabetic
p=0.04
No diabetes
Diabetes
p=0.02
No diabetes
Diabetes
p=0.01
0
-0.5
Adjusted hazard ratio
No diabetes
Diabetes
0.5
Tuomilehto J et al. N Engl J Med 1999;340:677-84
Risk reductions from intervention
studies in type 2 diabetes
UKPDS
Captopril
Atenolol
n=1148
HOT
Felodipine
Aspirin
n=1501
4S
Simvastatin
n=202
HOPE
Ramipril
Diabetes-related deaths (%)
32
67
36
37
All-cause mortality (%)
18
43
43
24
All MI (%)
21
51
55
22
Fatal MI (%)
28
-
-
-
All stroke (%)
44
30
62
33
Fatal stroke (%)
58
-
-
-
Follow-up (years)
8.4
3.8
5.4
4.5
Clinical Outcomes
n=3577
UKPDS Group. BMJ 1998; 317: 713-20; HOT Study Group. Lancet 1998; 351(9118): 1755-62;
4S Group. Lancet 1994; 344: 1383-89; HOPE study investigators. Lancet 2000; 355; 253-59.
Targets for glycaemic control
HbA1C (%)
FPG (mmol/L)
ADA (USA)1
<7
< 6.7 (120)*
IDF (Europe)2
< 6.5
< 6.0 (110)*
AACE (USA)3
< 6.5
< 6.0 (110)*
*mg/dL
1American
Diabetes Association. Diabetes Care 1999; 22(Suppl 1):S1-S114;
Policy Group. Diabetic Medicine 1999;16:716-30;
3American Association of Clinical Endocrinologists. Endocrine Pract (2002) 8(Suppl. 1):40-82
2European Diabetes
Risk reduction in UKPDS 75
An intensive glucose control policy HbA1c 7.0 % vs 7.9 % reduces
risk of
–
–
–
any diabetes-related endpoints
12%
p=0.030
microvascular endpoints
25%
p=0.010
myocardial infarction
16%
p=0.052
A tight BP control policy 144 / 82 vs 154 / 87 mmHg reduces risk of
–
–
–
any diabetes-related endpoint
24%
p=0.005
microvascular endpoint
37%
p=0.009
stroke
44%
p=0.013
Stratton IM et al. Diabetologia 2006; 1761-9
UKPDS 34: Intensive glucose control
and CV protection
n = 1704 overweight, with diabetes; n = 342 metformin group
Aggregate endpoints
Favors metformin
or intensive
Favors
usual care
P*
All-cause mortality
Metformin
Intensive
0.02
Myocardial infarction
Metformin
Intensive
0.12
Stroke
Metformin
Intensive
0.08
0
*Metformin vs other intensive therapy
(sulfonylurea or insulin)
1
Relative risk
(95% CI)
2
UKPDS Group. Lancet. 1998;352:854-65.