n engl j med
established in 1812
vol. 348no. 5
Multifactorial Intervention and Cardiovascular Disease
in Patients with Type 2 Diabetes
Peter Gæde, M.D., Pernille Vedel, M.D., Ph.D., Nicolai Larsen, M.D., Ph.D., Gunnar V.H. Jensen, M.D., Ph.D.,
Hans-Henrik Parving, M.D., D.M.Sc., and Oluf Pedersen, M.D., D.M.Sc.
From the Steno Diabetes Center, Copen-
hagen (P.G., P.V., N.L., H.-H.P., O.P.); Her-
lev County Hospital, Herlev (N.L.); Amtssy-
gehuset Roskilde, Roskilde (G.V.H.J.); and
the Faculty of Health Science, Aarhus Uni-
versity, Aarhus (H.-H.P., O.P.) — all in Den-
mark. Address reprint requests to Dr. Ped-
ersen at the Steno Diabetes Center, Niels
Steensens Vej 2, 2820 Gentofte, Denmark,
or at email@example.com.
N Engl J Med 2003;348:383-93.
Copyright © 2003 Massachusetts Medical Society.
Cardiovascular morbidity is a major burden in patients with type 2 diabetes. In the
Steno-2 Study, we compared the effect of a targeted, intensified, multifactorial interven-
tion with that of conventional treatment on modifiable risk factors for cardiovascular
disease in patients with type 2 diabetes and microalbuminuria.
The primary end point of this open, parallel trial was a composite of death from cardio-
vascular causes, nonfatal myocardial infarction, nonfatal stroke, revascularization, and
amputation. Eighty patients were randomly assigned to receive conventional treatment
in accordance with national guidelines and 80 to receive intensive treatment, with a
stepwise implementation of behavior modification and pharmacologic therapy that
targeted hyperglycemia, hypertension, dyslipidemia, and microalbuminuria, along with
secondary prevention of cardiovascular disease with aspirin.
The mean age of the patients was 55.1 years, and the mean follow-up was 7.8 years.
The decline in glycosylated hemoglobin values, systolic and diastolic blood pressure,
serum cholesterol and triglyceride levels measured after an overnight fast, and urinary
albumin excretion rate were all significantly greater in the intensive-therapy group than
in the conventional-therapy group. Patients receiving intensive therapy also had a signif-
icantly lower risk of cardiovascular disease (hazard ratio, 0.47; 95 percent confidence
interval, 0.24 to 0.73), nephropathy (hazard ratio, 0.39; 95 percent confidence interval,
0.17 to 0.87), retinopathy (hazard ratio, 0.42; 95 percent confidence interval, 0.21 to
0.86), and autonomic neuropathy (hazard ratio, 0.37; 95 percent confidence interval,
0.18 to 0.79).
A target-driven, long-term, intensified intervention aimed at multiple risk factors in pa-
tients with type 2 diabetes and microalbuminuria reduces the risk of cardiovascular and
microvascular events by about 50 percent.
n engl j med
new england journal
atients with type 2 diabetes melli
tus have a risk of death from cardiovascular
causes that is two to six times that among
persons without diabetes, and among white Amer-
icans, the age-adjusted prevalence of coronary heart
disease is twice as high among those with type 2 di-
abetes as among those without diabetes.
cardiovascular events associated with type 2 dia-
betes and the high incidence of other macrovascu-
lar complications, such as strokes and amputations,
are a major cause of illness and an enormous eco-
Multiple modifiable risk factors for late compli-
cations in patients with type 2 diabetes, including
hyperglycemia, hypertension, and dyslipidemia, in-
crease the risk of a poor outcome.
als that investigated the effect of intensified inter-
vention involving a single risk factor in patients with
type 2 diabetes demonstrated benefits in terms of
both macrovascular and microvascular complica-
tions in kidneys, eyes, and nerves.
of the results of these trials, recent guidelines from
the American Diabetes Association and other na-
tional guidelines recommend an intensified multi-
factorial treatment approach, although the effect of
this approach has not been confirmed in long-term
We undertoook a randomized study — the
Steno-2 Study — to evaluate the effect on cardio-
vascular disease of an intensified, targeted, multi-
factorial intervention comprising behavior modifi-
cation and polypharmacologic therapy aimed at
several modifiable risk factors in patients with type 2
diabetes and microalbuminuria; we compared this
approach with a conventional intervention involv-
ing multiple risk factors.
On the basis
patients and study design
The study protocol specified two major analyses, a
microvascular analysis in which the development of
diabetic nephropathy after four years of interven-
tion was the primary end point and a macrovascular
analysis in which a composite end point for macro-
vascular disease after eight years of intervention was
the primary end point. The results of the original
microvascular part of the study have been reported
elsewhere, together with detailed information about
the study design and base-line phenotypic data.
Patients with persistent microalbuminuria were se-
lected, since microalbuminuria is a well-established
independent risk factor for cardiovascular disease
(the primary end point) as well as for nephropa-
thy, retinopathy, and neuropathy (secondary end
points). All patients provided written informed
consent. The protocol was in accordance with the
Declaration of Helsinki and was approved by the
ethics committee of Copenhagen County, Denmark.
The study was a randomized, open, parallel trial
(Fig. 1). Randomization was performed with the use
of sealed envelopes. Eighty patients were randomly
assigned to receive conventional treatment for mul-
tiple risk factors from their general practitioner, ac-
cording to the 1988 recommendations of the Dan-
ish Medical Association (which were revised in
2000) (Table 1), with the possibility of being referred
The remaining 80 patients were ran-
domly assigned to undergo intensive multifactorial
intervention involving strict treatment goals (Table
1), to be achieved through behavior modification
and a stepwise introduction of pharmacologic ther-
apy overseen by a project team (doctor, nurse, and
dietitian) at the Steno Diabetes Center. On average,
patients in the intensive-therapy group were offered
individual consultations every third month during
the eight-year follow-up. All hospital admissions in
the conventional-therapy group occurred at the re-
quest of the patients’ personal physicians.
At some point during follow-up, 45 patients in
the conventional-therapy group (56 percent) were
treated at the outpatient clinic at the Steno Diabetes
Center in accordance with the national guidelines
and 8 (10 percent) were referred to other diabetes
clinics. The mean number of consultations at diabe-
tes clinics per year for these 53 patients was three.
Patients in the conventional-therapy group who
were treated at the Steno Diabetes Center in accord-
ance with the national guidelines did not differ from
typical patients with type 2 diabetes who were seen
at the center; they had a similar duration of diabetes
and similar levels of hyperglycemia, blood pressure,
and serum lipids after an overnight fast (data not
shown). None of the patients in the conventional-
therapy group were treated by the project team.
interventions in the intensive-therapy
The aim of dietary intervention was a total daily in-
take of fat that was less than 30 percent of the daily
energy intake and an intake of saturated fatty acids
that was less than 10 percent of the daily energy in-
take. Light-to-moderate exercise for at least 30 min-
utes three to five times weekly was recommended,
n engl j med
multifactorial intervention in type 2 diabetes
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Copyright © 2003 Massachusetts Medical Society.