Multifactorial Intervention and Cardiovascular Disease in Patients with Type 2 Diabetes

1
Multifactorial Intervention and Cardiovascular
Disease in Patients with Type 2 Diabetes

• N Engl J Med 348383-93, 2003
• Peter Gæde, Pernille Vedel, Nicolai Larsen,
  Gunnar Jensen, Hans-Henrik Parving, and Oluf
  Pedersen

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

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

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

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 GPs or intensive
  care at Steno Diabetes Center

Conventional group assigned to GPs
80
Microvascular
Macrovascular
Endpoint examinations
n160
4 years
8 years
80
Intensive group assigned to Steno Diabetes Center
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
The Lancet 353617-622, 1999
7
Steno-2 Relative risk reduction at year 7.8
Relative risk reduction in intensive therapy group
N Engl J Med 348383-93, 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
9
Steno-2 Baseline characteristics

Conventional

Intensive


n80

n80

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


10
The intensive-therapy group - whats the
difference?
Individualised risk assessment Ambitious goal
setting Focused behaviour modification More
drugs/higher dose Continued patient
education/motivation
11
Steno-2 Treatment goals


Conventional
Intensive
Haemoglobin A1c ()

lt7.5

lt6.5

F-s-cholesterol (mmol/l)

lt6.5


lt4.5

F-s-triglycerides (mmol/l)

lt2.2


lt1.7

Systolic BP (mm Hg)

lt160

lt130

Diastolic BP (mm Hg)
lt95

lt80

ACEi irrespective of BP

No

Yes

No
Yes
Aspirin, primary prevention





Guidelines from the Danish Medical Association
12
Lifestyle change in the intensive-therapy group
Patients and spouses were motivated to join
smoking cessation courses Nicotine substitutes
were given for free
13
Food advice to the intensive therapy-group
Have some kind of seafood every day Cut down on
animal fat
14
Food advice to the intensive-therapy group
5-6 servings of vegetables and fruits/day
15
Exercise advice to the intensive-therapy group
Enjoy physical performance more than 150 min/week
16
LIFESTYLEPercentage of patients obtaining
treatment goals for the intensive-therapy group
after 7.8 yrs
Saturated fat lt10 E
Exercise gt150 min/week
Fat intake lt30 E
Non-smokers
Intensive Convent
Intensive Convent
Intensive Convent
Intensive Convent
17
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
18
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
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
20
Stepwise treatment of hyperglycaemia
Gliclazide NPH insulin
BMI lt27
Diet
Gliclazide
Gliclazide Metformin
Metformin NPH insulin
BMI 27
Metformin
Diet
Time
21
Stepwise approach to the treatment of
hypertension
Severity of hypertension
Other
ß-blocker
Calcium antagonist
Diuretics
ACE inhibitor/Angiotensin II antagonist
22
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
23
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
24
Percentage of patients achieving treatment goals
set for the intensive-therapy group at 7.8 yr
HbA1clt6.5
Cholesterol lt4.5 mM
Triglycerides lt1.7 mM
Systolic BP lt130 mm Hg
Diastolic BP lt80 mm Hg

plt0.0001
p0.21
p0.19
p0.001
p0.06
Int Conv
Int Conv
Int Conv
Int Conv
Int Conv
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

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) p0.007
12
24
36
48
60
72
84
96
0
Months of follow-up


27
Steno-2
85 CVD events in 35 conventional patients 33
CVD events in 19 intensive patients
Number of events
Vascular surgery
Myocardial infarction
PCI or CABG
Amputation
Stroke
CVD death
Intensive
Conventional
28
Stroke
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
29
StrokeTime to first stroke
Log-rank test P0.02
Hazard ratio 0.25 (0.07 0.89) p 0.03
Conventional
Probability for stroke ()
Intensive
Months of follow-up
30
Myocardial infarctionTime to first MI
Log-rank test P0.08
25
Hazard ratio 0.41 (0.14-1.15) p 0.09
20
Conventional
15
10
Probability for MI ()
Intensive
5
0
12
24
36
48
60
72
84
96
0
Months of follow-up
31
Coronary interventionsTime to first PCI or CABG
Log-rank test P0.07
25
Hazard ratio 0.40 (0.14 1.12) p 0.08
20
Conventional
15
Probability for intervetnion ()
10
Intensive
5
0
12
24
36
48
60
72
84
96
0
Months of follow-up
32
Estimated impact of single risk factor
interventions to reduce CVD in patients with type
2 diabetes

• Relative risk 2-yrs 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 2001111633-642 Turner
R.C. BMJ 1998316823-828 He et al. JAMA
19992822027-2034 Antitrombotic Trialits BMJ
200232471-86
33
Microvascular complications in Steno-2Accumulated
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
0
2.5
2.0
1.5
In favor of intensive
In favor of conventional
34
Steno-2Kidney disease
Patients who progressed to nephropathy
P0.003
ESRD (Dialysis)
PNS
Intensive
Conventional
Intensive
Conventional
35
Steno-2Eye complications
New retinopathy
Progression in retinopathy
Blindness in one eye
P0.03
P0.02
P0.02
Number of patients
Number of patients
Intensive
Intensive
Conventional
Conventional
Intensive
Conventional
36
Steno-2 Neuropathy
Intensive n67
Conventional n63
p-value
37
Steno-2Adverse effects?
Polypharmacy? One patient in the intensive-
therapy group had a bleeding gastric
ulcer Hypoglycaemia? No difference Weight
gain? No difference
38
Steno-2Hypoglycaemia
Intensive n67
Conventional n63
p-value
NS
42
39
At least one minor episode
0.07
5
12
At least one major episode
NS
4
9
Major episode during insulin treatment
Data are number of patients
39
Steno-2 Weight gain/body composition
Intensive n67
Conventional n63
p-value
0.49
3.1
2.0
Average weight gain (kg)
Increase in waist (cm)
0.23
3
4
Men
0.81
6
5
Women
Data are number of patients
40
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 RRRs 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
41
The Steno-2 therapeutic package

• Repetitive risk assessments
• Ambitious treatment goals
• Progressive and aggressive drug treatment
• Proactive behaviour modelling
• Continued patient education and motivation

42
Further information

• Contact
• Professor Oluf Pedersen, MD, DMSCi
• Principal Investigator of the Steno-2 Trial
• Steno Diabetes Center
• 2820 Gentofte, Copenhagen,
• Denmark
• oluf_at_steno.dk