1. 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
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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
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3. 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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4. 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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5. 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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6. Steno-2: Microvascular endpoints after 4 yrs
Number of patients developing/progressing in microvascular endpoint
OVERALL A 50% RELATIVE RISK REDUCTION
Nephropathy
Conv - Int
Retinopathy
Conv - Int
Neuropathy
Conv - Int
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The Lancet 353; , 1999

7. Steno-2: Relative risk reduction at year 7.8
Relative risk reduction in intensive therapy group
53 %
61%
58%
63% 10 20 30 40 50 60 70
cardiovascular
disease
nephropathy
retinopathy
autonomic
neuropathy
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N Engl J Med 348:383-93, 2003

8. 160 patients stratified according to urinary
albumin excretion rate and then randomly
assigned to treatment groups
80 patients received
conventional therapy
80 patients received
intensive therapy
15 died
7 of CVD
5 of cancer
3 of other causes
12 died
7 of CVD
2 of cancer
3 of other causes
2 withdrew
1 withdrew
63 patients completed
the study after 7.8 yrs
67 patients completed
the study after 7.8 yrs
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9. 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 s -
-cholesterol (mmol/l)
5.8
5.4
Blood pressure (mm Hg)
149/86
146/85
Albumin excretion rate (mg/24 h) 69 78
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10. 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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11. Steno-2: Treatment goals
Conventional *
Intensive
Haemoglobin A1c (%)
<7.5
<6.5
F-s-cholesterol (mmol/l)
<6.5
<4.5
F-s-triglycerides (mmol/l)
<2.2
<1.7
Systolic BP (mm Hg)
<160
<130
Diastolic BP (mm Hg)
<95
<80
ACEi irrespective of BP No
Yes
Aspirin, primary prevention No
Yes
* Guidelines from the Danish Medical Association
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12. Lifestyle change in the intensive-therapy group
Patients and spouses were motivated to join smoking cessation courses
Nicotine substitutes were given for free
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13. Food advice to the intensive therapy-group
Have some kind of seafood every day
Cut down on animal fat
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14. Food advice to the intensive-therapy group
5-6 servings of vegetables and fruits/day
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15. Exercise advice to the intensive-therapy group
Enjoy physical performance more than 150 min/week
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16. LIFESTYLE Percentage of patients obtaining treatment goals for the intensive-therapy group after 7.8 yrs
Fat intake
<30% E
Saturated fat
<10% E
Non-smokers
Exercise
>150 min/week
p=0.09
p=0.02
p=0.13
p=0.58
Intensive Convent
Intensive Convent
Intensive Convent
Intensive Convent
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17. Higher intake of fish and vegetables/fruits in the intensive-therapy group after 7.8 yrs
Conventional Intensive
Vegetables (g/day)
Fruits (g/day)
Fish (times/week)
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18. More than difficult due to CVD and osteoarthritis
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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19. 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
Microalbuminuria: ACE-inibitors
Other CVD prevention: Aspirin
Folic acid
= ’PolyPill’ plus insulin
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20. Stepwise treatment of hyperglycaemia
Gliclazide +
NPH insulin
BMI <27
Diet
Gliclazide
Gliclazide +
Metformin
Metformin +
NPH insulin
BMI ≥27
Metformin
Diet
Time
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21. Stepwise approach to the treatment of hypertension
Severity of hypertension
Other
ß-blocker
Calcium antagonist
Diuretics
ACE inhibitor/Angiotensin II antagonist
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22. Differences in drug treatment at the end of study
Number of patients 70
Intensive
Conventional 60 50 40 30 20 10
OHA
Insulin
Both
ACE-I
ARB
Both
Statin
Aspirin
Folic acid
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23. Biochemical risk factors at year 7
Biochemical risk factors at year 7.8 in conventional (C) versus intensive (I) group
Haemoglobin A1c
Systolic BP
Diastolic BP
Total-cholesterol
LDL-cholesterol
Triglycerides
Urinary albumin
9.0 in C versus 7.9 % in I
146 versus 131 mm Hg
78 versus 73 mm Hg
5.6 versus 4.1 mmol/l
3.3 versus 2.1 mmol/l
3.0 versus 1.7 mmol/l
126 versus 26 mg/24h
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24. Percentage of patients achieving treatment goals set for the intensive-therapy group at 7.8 yr
HbA1c<6.5%
Cholesterol
<4.5 mM
Triglycerides
<1.7 mM
Systolic BP
<130 mm Hg
Diastolic BP
<80 mm Hg %
p<0.0001
p=0.21
p=0.19
p=0.001
p=0.06
Int Conv
Int Conv
Int Conv
Int Conv
Int Conv
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25. 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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26. Primary composite cardiovascular endpoint
85 CVD events in 35 ’conventional’ patients (44%)
33 CVD events in 19 ’intensive’ patients (24%)
Probability for primary endpoint
Conventional
Intensive
Hazard ratio 0.47 (0.24 to 0.73); p=0.007 12 24 36 48 60 72 84 96
Months of follow-up
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27. Steno-2: 85 CVD events in 35 ’conventional’ patients
33 CVD events in 19 ’intensive’ patients
Number of events
Myocardial infarction
PCI or CABG
Vascular surgery
CVD death
Stroke
Amputation
Intensive
Conventional
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28. patient (Recurrence rate) Total number of strokes
3 patients (4%) in the intensive and 11 patients (14%) in the conventional group had strokes during follow-up
Number of strokes per
patient (Recurrence rate)
Total number of strokes
Intensive Convent
Intensive Convent
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29. Stroke Time to first stroke
Log-rank test: P=0.02
Hazard ratio 0.25 (0.07 – 0.89); p = 0.03
Conventional
Probability for stroke (%)
Intensive
Months of follow-up
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30. Myocardial infarction Time to first MI
Log-rank test P=0.08 25
Hazard ratio 0.41 ( ); p = 0.09 20
Conventional 15 10
Probability for MI (%)
Intensive 5 12 24 36 48 60 72 84 96
Months of follow-up
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31. Coronary interventions Time to first PCI or CABG
Log-rank test P=0.07 25
Hazard ratio 0.40 (0.14 – 1.12); p =0.08 20
Conventional 15
Probability for intervetnion (%) 10
Intensive 5 12 24 36 48 60 72 84 96
Months of follow-up
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32. Estimated impact of single risk factor interventions to reduce CVD in patients with type 2 diabetes
Relative risk yr’s event
reduction rate
None …… %
Cholesterol (down by 0.6 mmol/l) 25 % %
BP (down by 5/2 mm Hg) % %
HbA1c (down by 0.9 %) % %
Aspirin % %
Cumulative relative risk reduction of about 57%
Huang et al. Am J Med 2001;111:
Turner R.C. BMJ 1998;316:
He et al. JAMA 1999;282:
Antitrombotic Trialits BMJ 2002;324:71-86
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33. Estimated impact of single risk factor interventions to reduce CVD in patients with type 2 diabetes
Relative risk yr’s event
reduction rate
None …… %
Cholesterol (down by 0.6 mmol/l) 25 % %
BP (down by 5/2 mm Hg) % %
HbA1c (down by 0.9 %) % %
Aspirin % %
Cumulative relative risk reduction of about 57%
Huang et al. Am J Med 2001;111:
Turner R.C. BMJ 1998;316:
He et al. JAMA 1999;282:
Antitrombotic Trialits BMJ 2002;324:71-86
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34. Microvascular complications in Steno-2 Accumulated incidence during 7
Microvascular complications in Steno-2 Accumulated incidence during 7.8 years
Relative risk
Nephropathy
(NNT 4)
0.39
Retinopathy
(NNT 5)
0.42
Auto. neuropathy
(NNT 3)
0.37
1.09
Periph. neuropathy
1.0
0.5
1.5
2.0
2.5
In favor of intensive
In favor of conventional
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35. Steno-2: Kidney disease
Patients who progressed to nephropathy
P=0.003
ESRD
(Dialysis)
P=NS
Intensive
Conventional
Intensive
Conventional
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36. Steno-2 Eye complications
Progression in retinopathy
New retinopathy
Blindness in one eye
P=0.03
P=0.02
P=0.02
Number of patients
Number of patients
Intensive
Conventional
Intensive
Conventional
Intensive
Conventional
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37. Steno-2: Neuropathy
Conventional n=63
Intensive n=67
p-value
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38. Steno-2: Adverse effects?
Polypharmacy?
One patient in the intensive- therapy group had a bleeding gastric ulcer
Hypoglycaemia?
No difference
Weight gain?
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39. Steno-2: Hypoglycaemia
Conventional n=63
Intensive 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 treatment 9 4 NS
Data are number of patients
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40. Steno-2: Weight gain/body composition
Conventional n=63
Intensive n=67
p-value
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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41. 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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42. ’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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43. Further information Contact: Professor Oluf Pedersen, MD, DMSCi
Principal Investigator of the Steno-2 Trial
Steno Diabetes Center
2820 Gentofte, Copenhagen,
Denmark
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