Multifactorial Intervention and
Cardiovascular Disease in Patients with
Type 2 Diabetes
N Engl J Med 348:383-93, 2003
Peter Gæde, Pernille Vedel, Nicolai Larsen,
Gunnar Jensen, Hans-Henrik Parving,
and Oluf Pedersen
STENO-2
Background
The Steno-2 study was designed in 1990
There was no evidence base for the treatment of type 2
diabetes
Some diabetes educators were suffering from
therapeutic nihilism
Intervention studies including the UKPDS were
ongoing
STENO-2
Steno-2:
Idea and Frames
An attempt to validate the efficacy of
daily clinical practice, i.e. the
multifactorial treatment of type 2
diabetes
High risk type 2 diabetes patients
A single center study
An organisation which allowed for
intensive intervention
Longterm intervention
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Steno-2: Aim
To investigate the impact on
microvascular and cardiovascular
disorders of a target driven
behaviour modification and
polypharmacy as compared to a
conventional multifactorial
treatment of high-risk type 2
diabetic patients with the metabolic
syndrome including
microalbuminuria
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Steno-2: Design
A PROBE design was applied, i.e.
a Prospective, Randomized, Open, Blinded Endpoint study
160 patients with type 2 diabetes and the metabolic syndrome
including microalbuminuria were with consealed randomization
allocated conventional therapy at their GP’s or intensive care at Steno
Diabetes Center
Conventional group assigned to GPs
80
Microvascular Macrovascular
n=160 Endpoint examinations
4 years 8 years
80
Intensive group assigned to Steno Diabetes Center
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Steno-2: Microvascular endpoints after 4 yrs
Number of patients developing/progressing in microvascular endpoint
35
30
OVERALL
25 A 50%
20 RELATIVE
RISK
15 REDUCTION
10
5
0
Nephropathy Retinopathy Neuropathy
1 2 3
Conv - Int Conv - Int Conv - Int
STENO-2 The Lancet 353;617-622, 1999
Steno-2: Relative risk reduction at year 7.8
Relative risk reduction in
intensive therapy group 63%
70
61%
58%
60 53 %
50
40
30
20
10
0
cardiovascular nephropathy retinopathy autonomic
disease neuropathy
STENO-2 N Engl J Med 348:383-93, 2003
160 patients stratified according to urinary
albumin excretion rate and then randomly
assigned to treatment groups
80 patients received 80 patients received
conventional therapy intensive therapy
15 died 12 died
7 of CVD 7 of CVD
5 of cancer 2 of cancer
3 of other causes 3 of other causes
2 withdrew 1 withdrew
63 patients completed 67 patients completed
the study after 7.8 yrs the study after 7.8 yrs
STENO-2
Steno-2:
Baseline characteristics
Conventional Intensive
n=80 n=80
Gender (M/F) 56/24 63/17
Age (yrs) 55 55
Known DM (yrs) 6 6
Body mass index (kg/m2) 30 30
Haemoglobin A1c (%) 8.8 8.4
Fasting --cholesterol (mmol/l)
s 5.8 5.4
Blood pressure (mm Hg) 149/86 146/85
Albumin excretion rate (mg/24 h) 69 78
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The intensive-therapy group
- what’s the difference?
Individualised risk
assessment
Ambitious goal setting
Focused behaviour
modification
More drugs/higher dose
Continued patient
education/motivation
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Steno-2: Treatment goals
Conventional * Intensive
Haemoglobin A1c (%) 150 min/week
80
p=0.58
70
60
p=0.02
50 p=0.13
p=0.09
40
30
20
10
0
Intensive Convent Intensive Convent Intensive Convent Intensive Convent
1
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Higher intake of fish and vegetables/fruits in
the intensive-therapy group after 7.8 yrs
Conventional Intensive
Vegetables (g/day) 100 160
Fruits (g/day) 125 265
Fish (times/week) 2 4
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Relative failures
Daily exercise:
More than difficult due to CVD and
osteoarthritis
Quit smoking:
Unhealthy habits in middle-aged people are
tough to eliminate and replace
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Drug treatment: stepwise and target driven
Hyperglycaemia: Gliclazide
Metformin
Insulin
Dyslipidaemia: Statins
Fibrates
Hypertension: ACE-inhibitors
Angiotensin II receptor blockers
Diuretics
Calcium antagonists
Beta-blockers
= ’PolyPill’
Microalbuminuria: ACE-inibitors plus insulin
Other CVD prevention: Aspirin
Folic acid
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Stepwise treatment of hyperglycaemia
Gliclazide
BMI Diet Gliclazide +
<27
NPH insulin
Gliclazide
+
Metformin
Metformin
BMI Metformin
Diet +
≥27
NPH insulin
Time
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Stepwise approach
Severity of to the treatment
hypertension Other of hypertension
ß-blocker
Calcium antagonist
Diuretics
ACE inhibitor/Angiotensin II antagonist
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Differences in drug treatment at
the end of study
Number of patients
70
Intensive
Conventional
60
50
40
30
20
10
0
OHA Insulin Both ACE-I ARB Both Statin Aspirin Folic acid
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Biochemical risk factors at year 7.8 in
conventional (C) versus intensive (I) group
Haemoglobin A1c 9.0 in C versus 7.9 % in I
Systolic BP 146 versus 131 mm Hg
Diastolic BP 78 versus 73 mm Hg
Total-cholesterol 5.6 versus 4.1 mmol/l
LDL-cholesterol 3.3 versus 2.1 mmol/l
Triglycerides 3.0 versus 1.7 mmol/l
Urinary albumin 126 versus 26 mg/24h
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Percentage of patients achieving treatment goals
set for the intensive-therapy group at 7.8 yr
HbA1c<6.5% Cholesterol Triglycerides Systolic BP Diastolic BP
% <4.5 mM <1.7 mM <130 mm Hg <80 mm Hg
80
p<0.0001 p=0.21
70
60 p=0.19
50 p=0.001
40
30
20 p=0.06
10
0
Int Conv Int Conv Int 1Conv Int Conv Int Conv
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Steno-2: Endpoints at 7.8 years
Primary: Cardiovascular disease
• Cardiovascular mortality
• Non-fatal myocardial infarction
• Coronary artery bypass graft
• Non-fatal stroke
• Revascularization
• Amputation
Secondary: Microvascular disease
• Progression to nephropathy
• Development of/progression in retinopathy
• Development of/progression in neuropathy
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Primary composite cardiovascular endpoint
85 CVD events in 35 ’conventional’ patients (44%)
33 CVD events in 19 ’intensive’ patients (24%)
Probability for primary endpoint
0,6
0,5
Conventional
0,4
0,3
0,2 Intensive
0,1
Hazard ratio 0.47 (0.24 to 0.73); p=0.007
0,0
0 18 36 54 73 91 10 12 14 16 18 20 21 23 25 27 29 31
0 12 24 36 48 60 72 84 96
3 5 8 0 3 95 78 60 43 25 08 90 73 55 38 20 03
Months of follow-up
Months of Study
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Steno-2:
85 CVD events in 35 ’conventional’ patients
33 CVD events in 19 ’intensive’ patients
Number of events
Myocardial PCI or Vascular
CVD death Stroke infarction CABG surgery Amputation
20
15
10
5
0
1 2 3 4 5 6
Intensive Conventional
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Stroke
3 patients (4%) in the intensive and 11 patients (14%)
in the conventional group had strokes during follow-up
Number of strokes per
Total number of strokes
patient (Recurrence rate)
20 3
15
2
10
1
5
0 0
Intensive 1 Convent Intensive
2 1 Convent
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Stroke
Time to first stroke
Log-rank test: P=0.02
0,25
Probability for stroke (%)
Hazard ratio 0.25 (0.07 – 0.89); p = 0.03
0,20
Conventional
0,15
0,10
0,05 Intensive
0,00
0 12 24 36 48 60 72 84 96
Months of follow-up
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Myocardial infarction
Time to first MI
Log-rank test P=0.08
0,25
25
Hazard ratio 0.41 (0.14-1.15); p = 0.09
0,20
20
Conventional
Probability for MI (%)
15
0,15
0,10
10
Intensive
5
0,05
0
0,00
0
0 12
12 24
24 36
36 48
48 60
60 72
72 84
84 96
96
Months of follow-up
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Coronary interventions
Time to first PCI or CABG
Log-rank test P=0.07
0,25
25
Probability for intervetnion (%)
Hazard ratio 0.40 (0.14 – 1.12); p =0.08
0,20
20
Conventional
15
0,15
0,10
10
Intensive
5
0,05
0
0,00
0
0 12
12 24
24 36
36 48
48 60
60 72
72 84
84 96
96
Months of follow-up
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Estimated impact of single risk factor
interventions to reduce CVD in patients with
type 2 diabetes
Relative risk 2-yr’s event
reduction rate
None …… 11.0 %
Cholesterol (down by 0.6 mmol/l) 25 % 8.3 %
BP (down by 5/2 mm Hg) 27 % 6.0 %
HbA1c (down by 0.9 %) 13 % 5.2 %
Aspirin 9% 4.7 %
Cumulative relative risk reduction of about 57%
Huang et al. Am J Med 2001;111:633-642
Turner R.C. BMJ 1998;316:823-828
He et al. JAMA 1999;282:2027-2034
Antitrombotic Trialits BMJ 2002;324:71-86
STENO-2
Estimated impact of single risk factor
interventions to reduce CVD in patients with
type 2 diabetes
Relative risk 2-yr’s event
reduction rate
None …… 11.0 %
Cholesterol (down by 0.6 mmol/l) 25 % 8.3 %
BP (down by 5/2 mm Hg) 27 % 6.0 %
HbA1c (down by 0.9 %) 13 % 5.2 %
Aspirin 9% 4.7 %
Cumulative relative risk reduction of about 57%
Huang et al. Am J Med 2001;111:633-642
Turner R.C. BMJ 1998;316:823-828
He et al. JAMA 1999;282:2027-2034
Antitrombotic Trialits BMJ 2002;324:71-86
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Microvascular complications in Steno-2
Accumulated incidence during 7.8 years
Relative risk
Nephropathy
0.39
(NNT 4)
Retinopathy 0.42
(NNT 5)
Auto. neuropathy
0.37
(NNT 3)
Periph. neuropathy 1.09
0 0.5 1.0 1.5 2.0 2.5
0 0,5 1 1,5 2 2,5
In favor of intensive In favor of conventional
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Steno-2:
Kidney disease
Patients who progressed to nephropathy
35
P=0.003
30
25
20
15 ESRD
(Dialysis)
10
P=NS
5
0
Intensive 1Conventional Intensive 2 Conventional
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Steno-2
Eye complications
Progression in New Blindness
retinopathy retinopathy in one eye
P=0.03
P=0.02 P=0.02
60 10
50 8
Number of patients
Number of patients
40
6
30
4
20
2
10
0 0
Intensive Conventional Intensive Conventional Intensive Conventional
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Steno-2:
Neuropathy
Conventional Intensive
n=63 n=67 p-value
Progression in
43 24 0.01
autonomic neuropathy
Progression in
37 40 0.81
peripheral neuropathy
Values are number of patients
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Steno-2:
Adverse effects?
Polypharmacy?
One patient in the intensive- therapy group had a
bleeding gastric ulcer
Hypoglycaemia?
No difference
Weight gain?
No difference
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Steno-2:
Hypoglycaemia
Conventional Intensive
n=63 n=67 p-value
At least one minor episode 39 42 NS
At least one major episode 12 5 0.07
Major episode during insulin 9 4 NS
treatment
Data are number of patients
STENO-2
Steno-2:
Weight gain/body composition
Conventional Intensive
n=67 p-value
n=63
Average weight gain (kg) 2.0 3.1 0.49
Increase in waist (cm)
Men 4 3 0.23
Women 5 6 0.81
Data are number of patients
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Steno-2:
Summary
Compared with a conventional multifactorial treatment
an intensive and target driven behaviour modelling and
polypharmacy for 7.8 yrs induced an absolute risk
reduction of 20% (RRR 0.53; NNT 4) in CVD in patients
with type 2 DM and the metabolic syndrome incl.
microalbuminuria
The RRR’s found for microvascular
events after 4 years were main-
tained at a similar level after 7.8
years of intervention: nephropathy
61%, retinopathy 58% and autono-
mic neuropathy 63%
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’The Steno-2 therapeutic package’
•Repetitive risk assessments
•Ambitious treatment goals
•Progressive and aggressive drug
treatment
•Proactive behaviour modelling
•Continued patient education and
motivation
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Further information
Contact:
Professor Oluf Pedersen, MD, DMSCi
Principal Investigator of the Steno-2 Trial
Steno Diabetes Center
2820 Gentofte, Copenhagen,
Denmark
oluf@steno.dk
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