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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 . Background. The Steno-2 study was designed in 1990

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multifactorial intervention and cardiovascular disease in patients with type 2 diabetes

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
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
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

STENO-2

steno 2 aim
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

STENO-2

steno 2 design
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

Endpointexaminations

4 years

8 years

80

Intensive group assigned to Steno Diabetes Center

STENO-2

steno 2 microvascular endpoints after 4 yrs
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 353;617-622, 1999

STENO-2

steno 2 relative risk reduction at year 7 8

63%

70

61%

58%

53 %

60

50

40

30

20

10

0

cardiovascular

nephropathy

retinopathy

autonomic

disease

neuropathy

Steno-2: Relative risk reduction at year 7.8

Relative risk reduction in intensive therapy group

STENO-2

N Engl J Med 348:383-93, 2003

slide8

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

STENO-2

steno 2 baseline characteristics
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

STENO-2

the intensive therapy group what s the difference
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

STENO-2

steno 2 treatment goals
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

No

Yes

Aspirin, primary prevention

* Guidelines from the Danish Medical Association

STENO-2

lifestyle change in the intensive therapy group
Lifestyle change in the intensive-therapy group

Patients and spouses were motivated to join smoking cessation courses

Nicotine substitutes were given for free

STENO-2

food advice to the intensive therapy group
Food advice to the intensive therapy-group

Have some kind of seafood every day

Cut down on animal fat

STENO-2

food advice to the intensive therapy group14
Food advice to the intensive-therapy group

5-6 servings of vegetables and fruits/day

STENO-2

exercise advice to the intensive therapy group
Exercise advice to the intensive-therapy group

Enjoy physical performance more than 150 min/week

STENO-2

slide16

p=0.58

p=0.02

p=0.13

p=0.09

LIFESTYLEPercentage of patients obtaining treatment goals for the intensive-therapy group after 7.8 yrs

Saturated fat

<10% E

Exercise

>150 min/week

Fat intake

<30% E

Non-smokers

Intensive Convent

Intensive Convent

Intensive Convent

Intensive Convent

STENO-2

higher intake of fish and vegetables fruits in the intensive therapy group after 7 8 yrs
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

STENO-2

relative failures
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

STENO-2

drug treatment stepwise and target driven
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

STENO-2

stepwise treatment of hyperglycaemia
Stepwise treatment of hyperglycaemia

Gliclazide

+

NPH insulin

BMI <27

Diet

Gliclazide

Gliclazide

+

Metformin

Metformin

+

NPH insulin

BMI ≥27

Metformin

Diet

Time

STENO-2

slide21

Stepwise approach to the treatment of hypertension

Severity of hypertension

Other

ß-blocker

Calcium antagonist

Diuretics

ACE inhibitor/Angiotensin II antagonist

STENO-2

differences in drug treatment at the end of study
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

STENO-2

biochemical risk factors at year 7 8 in conventional c versus intensive i group
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

STENO-2

percentage of patients achieving treatment goals set for the intensive therapy group at 7 8 yr
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

STENO-2

steno 2 endpoints at 7 8 years
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

STENO-2

primary composite cardiovascular endpoint
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

0

12

24

36

48

60

72

84

96

Months of follow-up

STENO-2

steno 2
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

CVD death

Stroke

Intensive

Conventional

STENO-2

stroke
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

STENO-2

stroke time to first stroke
StrokeTime 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

STENO-2

myocardial infarction time to first mi
Myocardial infarctionTime to first MI

Log-rank test P=0.08

25

Hazard ratio 0.41 (0.14-1.15); p = 0.09

20

Conventional

15

10

Probability for MI (%)

Intensive

5

0

0

12

24

36

48

60

72

84

96

Months of follow-up

STENO-2

coronary interventions time to first pci or cabg
Coronary interventionsTime 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

0

0

12

24

36

48

60

72

84

96

Months of follow-up

STENO-2

estimated impact of single risk factor interventions to reduce cvd in patients with type 2 diabetes
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 diabetes33
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

microvascular complications in steno 2 accumulated incidence during 7 8 years
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

0.5

1.5

2.0

2.5

In favor of intensive

In favor of conventional

STENO-2

steno 2 kidney disease
Steno-2:Kidney disease

Patients who progressed to nephropathy

P=0.003

ESRD

(Dialysis)

P=NS

Intensive

Conventional

Intensive

Conventional

STENO-2

steno 2 eye complications
Steno-2Eye 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

Intensive

Conventional

Conventional

Intensive

Conventional

STENO-2

steno 2 neuropathy
Steno-2:Neuropathy

Intensive n=67

Conventional n=63

p-value

STENO-2

steno 2 adverse effects
Steno-2:Adverse effects?

Polypharmacy?

One patient in the intensive- therapy group had a bleeding gastric ulcer

Hypoglycaemia?

No difference

Weight gain?

No difference

STENO-2

steno 2 hypoglycaemia
Steno-2:Hypoglycaemia

Intensive n=67

Conventional n=63

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

STENO-2

steno 2 weight gain body composition
Steno-2: Weight gain/body composition

Intensive n=67

Conventional n=63

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

STENO-2

steno 2 summary
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%

STENO-2

the steno 2 therapeutic package
’The Steno-2 therapeutic package’
  • Repetitive risk assessments
  • Ambitious treatment goals
  • Progressive and aggressive drug treatment
  • Proactive behaviour modelling
  • Continued patient education and motivation

STENO-2

further information
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

STENO-2