STENO-2

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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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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Steno-2: Idea and Frames

An attempt to validate the efficacy ofdaily 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

Intensive group assigned to Steno Diabetes Center

Endpoint examinations

Microvascular Macrovascular

4 years 8 years

80

80

n=160

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Number of patients developing/progressing in microvascular endpointNumber of patients developing/progressing in microvascular endpoint

Nephropathy

Conv - Int

Retinopathy

Conv - Int

Neuropathy

Conv - Int

OVERALL A 50% RELATIVE RISK REDUCTION

The Lancet 353;617-622, 1999

Steno-2: Microvascular endpoints after 4 yrs

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Steno-2: Relative risk reduction at year 7.8

53 %

61%58%

63%

0

10

20

30

40

50

60

70

cardiovasculardisease

nephropathy retinopathy autonomicneuropathy

N Engl J Med 348:383-93, 2003

Relative risk reduction in Relative risk reduction in intensive therapy groupintensive therapy group

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160 patients stratified according to urinaryalbumin 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 withdrew2 withdrew 1 withdrew

63 patients completed the study after 7.8 yrs

67 patients completedthe study after 7.8 yrs

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Conventional n=80

Intensive 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: Baseline characteristics

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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 (%) <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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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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Food advice to the intensive therapy-group

Have some kind of seafood every day

Cut down on animal fat

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Food advice to the intensive-therapy group

5-6 servings of vegetables and fruits/day

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Exercise advice to the intensive-therapy group

Enjoy physical performance more than

150 min/week

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LIFESTYLEPercentage of patients obtaining treatment goals

for the intensive-therapy group after 7.8 yrs

Fat intakeFat intake<30% E<30% E

Saturated fatSaturated fat<10% E<10% E

Non-smokersNon-smokers ExerciseExercise>150 min/week>150 min/week

Intensive Convent Intensive Convent Intensive Convent Intensive Convent

p=0.09p=0.02 p=0.13

p=0.58

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Higher intake of fish and vegetables/fruits in the intensive-therapy group after 7.8 yrs

Conventional Conventional IntensiveIntensive

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 More than difficult due to CVD and osteoarthritisosteoarthritis

Quit smoking:

Unhealthy habits in middle-aged people are Unhealthy habits in middle-aged people are tough to eliminate and replacetough to eliminate and replace

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Drug treatment: stepwise and target driven

Hyperglycaemia: GliclazideMetformin

Insulin

Dyslipidaemia: StatinsFibrates

Hypertension: ACE-inhibitorsAngiotensin II receptor blockersDiureticsCalcium antagonistsBeta-blockers

Microalbuminuria: ACE-inibitorsACE-inibitors

Other CVD prevention: Aspirin Folic acid

= ’PolyPill’ = ’PolyPill’ plus insulinplus insulin

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Stepwise treatment of hyperglycaemia

Diet

Diet

Gliclazide

Metformin

Gliclazide+

NPH insulin

Metformin+

NPH insulin

Time

BMI <27

BMI ≥27

Gliclazide+

Metformin

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ACE inhibitor/Angiotensin II antagonist

Diuretics

Calcium antagonist

ß-blocker

OtherSeverity of hypertension

Stepwise Stepwise approach to the approach to the

treatment of treatment of hypertension hypertension

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Differences in drug treatment at

the end of study

0

10

20

30

40

50

60

70

OHA Insulin Both ACE-I ARB Both Statin Aspirin Folic acid

IntensiveConventional

Number of patientsNumber of patients

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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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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

Int Conv

%

p<0.0001 p=0.21

Int Conv Int Conv Int Conv Int Conv

p=0.06

p=0.19

p=0.001

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Steno-2: Endpoints at 7.8 years

Primary: Cardiovascular diseasePrimary: Cardiovascular disease• Cardiovascular mortality• Non-fatal myocardial infarction• Coronary artery bypass graft• Non-fatal stroke• Revascularization• Amputation

Secondary: Microvascular diseaseSecondary: 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%) 85 CVD events in 35 ’conventional’ patients (44%)

33 CVD events in 19 ’intensive’ patients (24%)33 CVD events in 19 ’intensive’ patients (24%)

12 24 36 48 60 72 84 96 0

Months of follow-up

Hazard ratio 0.47 (0.24 to 0.73); p=0.007

Conventional

Intensive

Probability for primary endpoint

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PCI or CABG

Vascular surgery Amputation

Steno-2: 85 CVD events in 35 ’conventional’ patients

33 CVD events in 19 ’intensive’ patients

StrokeCVD deathMyocardial infarction

Number of eventsNumber of events

Intensive Conventional

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Stroke

3 patients (4%) in the intensive and 11 patients (14%) in 3 patients (4%) in the intensive and 11 patients (14%) in the conventional group had strokes during follow-upthe conventional group had strokes during follow-up

Total number of strokesNumber of strokes per

patient (Recurrence rate)

Intensive Convent Intensive Convent

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StrokeTime to first stroke

0 ,0 0

0 ,0 5

0 ,1 0

0 ,1 5

0 ,2 0

0 ,2 5

0 1 2 2 4 3 6 4 8 6 0 7 2 8 4 9 6

Months of follow-up

Pro

bab

ilit

y f

or

str

oke (

%)

Intensive

Conventional

Log-rank test: P=0.02

Hazard ratio 0.25 (0.07 – 0.89); p = 0.03

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Myocardial infarctionTime to first MI

Months of follow-up

Pro

bab

ilit

y f

or

MI

(%)

Intensive

Conventional

12 24 36 48 60 72 84 960

0

5

10

15

20

25Log-rank test P=0.08

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

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Coronary interventionsTime to first PCI or CABG

Months of follow-up

Pro

bab

ilit

y f

or

inte

rvetn

ion

(%

)

Intensive

Conventional

12 24 36 48 60 72 84 960

0

5

10

15

20

25Log-rank test P=0.07

Hazard ratio 0.40 (0.14 – 1.12); p =0.08

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Estimated impact of single risk factor interventions to reduce CVD in patients with

type 2 diabetes

Relative risk Relative risk 2-yr’s event 2-yr’s event reduction ratereduction 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;111:633-642Turner R.C. BMJ 1998;316:823-828He et al. JAMA 1999;282:2027-2034Antitrombotic Trialits BMJ 2002;324:71-86

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Estimated impact of single risk factor interventions to reduce CVD in patients with

type 2 diabetes

Relative risk Relative risk 2-yr’s event 2-yr’s event reduction ratereduction 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;111:633-642Turner R.C. BMJ 1998;316:823-828He et al. JAMA 1999;282:2027-2034Antitrombotic Trialits BMJ 2002;324:71-86

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0.50 2.52.01.51.0

Microvascular complications in Steno-2Accumulated incidence during 7.8 years

Nephropathy(NNT 4)

Retinopathy(NNT 5)

Auto. neuropathy (NNT 3)

Periph. neuropathy

Relative risk

0.39

0.42

0.37

1.09

In favor of intensive In favor of conventional

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Steno-2:Kidney disease

Intensive Conventional Intensive Conventional

Patients who progressed to nephropathyPatients who progressed to nephropathy

ESRD(Dialysis)

P=0.003

P=NS

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Steno-2Eye complications

New retinopathy

Blindness in one eye

Intensive Conventional Intensive Conventional

Nu

mb

er

of

pati

en

ts

Nu

mb

er

of

pati

en

ts

P=0.02 P=0.03P=0.02

Progression in retinopathy

Intensive Conventional

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Steno-2: Neuropathy

Conventional n=63

Intensive n=67 p-value

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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 n=63

Intensive n=67 p-value

NS4239At least one minor episode

NS49Major episode during insulin treatment

0.07512At least one major episode

Data are number of patients

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0.493.12.0Average weight gain (kg)

0.8165 Women

0.2334 Men

Increase in waist (cm)

Steno-2: Weight gain/body composition

Conventional n=63

Intensive n=67 p-value

Data are number of patients

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Steno-2: Summary

Compared with a conventional multifactorial treatment Compared with a conventional multifactorial treatment an intensive and target driven behaviour modelling and an intensive and target driven behaviour modelling and

polypharmacy for 7.8 yrs induced an absolute risk polypharmacy for 7.8 yrs induced an absolute risk reduction of 20% (RRR 0.53; NNT 4) in CVD in patients reduction of 20% (RRR 0.53; NNT 4) in CVD in patients

with type 2 DM and the metabolic syndrome incl. with type 2 DM and the metabolic syndrome incl. microalbuminuriamicroalbuminuria

The RRR’s found for microvascularThe RRR’s found for microvascularevents after 4 years were main-events after 4 years were main-

tained at a similar level after 7.8 tained at a similar level after 7.8 years of intervention: nephropathy years of intervention: nephropathy 61%, retinopathy 58% and autono-61%, retinopathy 58% and autono-

mic neuropathy 63%mic neuropathy 63%

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’The Steno-2 therapeutic package’

•Repetitive risk assessmentsRepetitive risk assessments•Ambitious treatment goalsAmbitious treatment goals•Progressive and aggressive drug Progressive and aggressive drug treatmenttreatment•Proactive behaviour modellingProactive behaviour modelling•Continued patient education and Continued patient education and motivationmotivation

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Further information

Contact:Contact:

Professor Oluf Pedersen, MD, DMSCiProfessor Oluf Pedersen, MD, DMSCi

Principal Investigator of the Steno-2 TrialPrincipal Investigator of the Steno-2 Trial

Steno Diabetes CenterSteno Diabetes Center

2820 Gentofte, Copenhagen,2820 Gentofte, Copenhagen,

DenmarkDenmark

oluf@steno.dkoluf@steno.dk