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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.
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ABSTRACT
Background 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 intervention with
that of conventional treatment on modifiable risk factors for
cardiovascular disease in patients with type 2 diabetes and
microalbuminuria. Methods The primary end point of this open,
parallel trial was a composite of death from cardiovascular 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. Results 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 significantly 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). Conclusions
A target-driven, long-term, intensified intervention aimed at
multiple risk factors in patients with type 2 diabetes and
microalbuminuria reduces the risk of cardiovascular and microvascular
events by about 50 percent.
Patients with type 2 diabetes mellitus have a risk of death
from cardiovascular causes that is two to six times that among persons
without diabetes, and among white Americans, the age-adjusted prevalence
of coronary heart disease is twice as high among those with type 2
diabetes as among those without diabetes.1,2,3,4
The cardiovascular events associated with type 2 diabetes and the
high incidence of other macrovascular complications, such as strokes
and amputations, are a major cause of illness and an enormous
economic burden.
Multiple modifiable risk factors for late complications in
patients with type 2 diabetes, including hyperglycemia,
hypertension, and dyslipidemia, increase the risk of a poor outcome.5
Randomized trials that investigated the effect of intensified
intervention involving a single risk factor in patients with type 2
diabetes demonstrated benefits in terms of both macrovascular and
microvascular complications in kidneys, eyes, and nerves.6,7,8,9,10 On
the basis of the results of these trials, recent guidelines from
the American Diabetes Association and other national guidelines recommend
an intensified multifactorial treatment approach, although the
effect of this approach has not been confirmed in long-term studies.
We undertoook a randomized study — the Steno-2 Study — to
evaluate the effect on cardiovascular disease of an intensified, targeted,
multifactorial intervention comprising behavior modification 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 involving multiple
risk factors.
Methods
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 intervention was the primary end point and a macrovascular analysis
in which a composite end point for macrovascular 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.11
Patients with persistent microalbuminuria were selected, since
microalbuminuria is a well-established independent risk factor for
cardiovascular disease (the primary end point) as well as for
nephropathy, retinopathy, and neuropathy (secondary end points).12,13
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 (Figure 1). Randomization
was performed with the use of sealed envelopes. Eighty patients were
randomly assigned to receive conventional treatment for multiple
risk factors from their general practitioner, according to the 1988
recommendations of the Danish Medical Association (which were
revised in 2000) (Table
1), with the possibility of being referred to specialists.14
The remaining 80 patients were randomly assigned to undergo
intensive multifactorial intervention involving strict treatment
goals (Table 1),
to be achieved through behavior modification and a stepwise
introduction of pharmacologic therapy 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 request 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 diabetes clinics per year for these 53 patients was
three. Patients in the conventional-therapy group who were treated
at the Steno Diabetes Center in accordance 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 in patients with Type 2 Diabetes and Microalbuminuria therapy
group were treated by the project team.
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Arterial hypertension was also treated with a stepwise approach. As
mentioned, all patients were prescribed an ACE inhibitor or an
angiotensin II–receptor antagonist because of the presence of
microalbuminuria. If a patient had hypertension, thiazides,
calcium-channel blockers, and beta-blockers were added as needed.
The combination of an ACE inhibitor and an angiotensin II–receptor
antagonist could also be used. Isolated instances of raised fasting
serum cholesterol concentrations or combined dyslipidemia were
treated with statins (atorvastatin, with a maximum of 80 mg daily,
or the equivalent). Fibrates were used for isolated cases of
hypertriglyceridemia, defined by a fasting serum triglyceride
concentration of more than 350 mg per deciliter (4.0 mmol per
liter), or were added to statin treatment if the fasting serum
triglyceride concentration was also elevated (350 mg per deciliter).
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Procedures, Measurements, and End Points
The macrovascular study ended as planned in December 2001.
Biochemical and clinical data were obtained every third month in the
intensive-therapy group. End-point examinations for both
macrovascular and microvascular complications were performed and
biochemical and clinical status was determined after four and eight
years of intervention in both groups.11
All blood samples were obtained at 8 a.m. after an overnight fast
and before the morning medication. Blood pressure was measured twice
after 20 minutes' rest while patients were supine, with use of a
Hawksley random-zero sphygmomanometer. The measurements were
obtained by a laboratory technician who was unaware of the patients'
treatment assignment. The primary study end point was a composite of
death from cardiovascular causes, nonfatal myocardial infarction,
coronary-artery bypass grafting, percutaneous coronary intervention,
nonfatal stroke, amputation as a result of ischemia, or vascular
surgery for peripheral atherosclerotic artery disease. All end points
specified in the protocol were adjudicated by an independent
committee whose members were unaware of the patients' treatment
assignments. Secondary end points indicative of microvascular
disease, which have previously been described in detail,11
were the incidence of diabetic nephropathy or the development or
progression of diabetic retinopathy or neuropathy. Diabetic
nephropathy was defined as a urinary albumin excretion of more than
300 mg per 24 hours in two of three consecutive sterile urine
specimens. Diabetic retinopathy was graded according to the
six-level grading scale of the European Community–funded Concerted
Action Programme into the Epidemiology and Prevention of Diabetes by
two independent ophthalmologists who were unaware of the patients' treatment
assignment.15
Peripheral neuropathy was measured with a biothesiometer, and the
diagnosis of autonomic neuropathy was based on a measurement of the
RR interval on the electrocardiogram during paced breathing and on
an orthostatic-hypotension test conducted by a laboratory technician
who was unaware of the patients' treatment assignments.
Statistical Analysis
Given a constant rate of events of 6 percent per year, 160
patients were needed to permit us to detect a 35 percent reduction
in the relative risk of the primary composite end point with a power
of 0.7 and a type 1 error rate of 0.05 during the planned mean
follow-up period of eight years. The primary end point was analyzed
according to the intention-to-treat principle, with event curves for
the time to the first event based on Kaplan–Meier analysis, and treatments
were compared with the use of the log-rank test. A Cox regression
model was used to calculate the hazard ratio for the primary end
point. Since the secondary end points occurred at some point between
base line and four years or between four and eight years, the rate
ratio was estimated with use of a grouped survival model (binary
regression with complementary log-log link). Separate effects of
treatment were estimated for the two periods, whereas the effect of
the control variables was assumed to be constant. Analyses were
adjusted for age, the duration of diabetes, sex, and end-point
status at base line. Measured variables were compared by means of
analysis of covariance, with base-line values as covariates to
adjust for differences between the groups at randomization. In the
case of a nongaussian distribution, the Mann–Whitney test was used.
A chi-square test was used to compare categorical variables.
Results
The base-line demographic and clinical characteristics and
biochemical status of the patients in the conventional-therapy group
and the intensive-therapy group were similar (as shown in the Supplementary
Appendix 1, available with the full text of this article at
http://www.nejm.org). The mean age of the patients was 55.1 years.
Changes in lifestyle (behavioral variables) and clinical and
biochemical variables in the two groups and differences between
groups during the mean follow-up period of 7.8 years (range, 6.9 to
8.8) are shown in Table
3. The changes in lifestyle were moderate; the only significant
differences between groups were in the relative intake of
carbohydrate and fat. The changes in body-mass index did not differ
significantly between groups.
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The groups differed significantly with
respect to glycosylated hemoglobin values, fasting plasma glucose
concentrations, fasting serum lipid concentrations, systolic and
diastolic blood pressure, and urinary albumin excretion rate. As
shown in Figure 2A,
the differences in the values of various risk factors between the
two groups were maintained throughout the follow-up period. Figure 2B shows
the percentage of patients in each group who achieved the various recommended
treatment goals of the intensive regimen after 7.8 years of
follow-up.
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A total of 118 cardiovascular events
occurred during follow-up. There were 85 events among 35 patients
(44 percent) in the conventional-therapy group (7 deaths from
cardiovascular causes, 17 nonfatal myocardial infarctions, 10
coronary-artery bypass grafts, 5 percutaneous coronary
interventions, 20 nonfatal strokes, 14 amputations, and 12 surgical
interventions for peripheral atherosclerotic artery disease), as
compared with 33 events among 19 patients (24 percent) in the
intensive-therapy group (7 deaths from cardiovascular causes, 5
nonfatal myocardial infarctions, 5 coronary-artery bypass grafts, 3
nonfatal strokes, 7 amputations, and 6 vascular surgical
interventions). A breakdown of first events showed a similar
distribution in the conventional-therapy group (1 death from
cardiovascular causes, 8 nonfatal myocardial infarctions, 6
coronary-artery bypass grafts, 3 percutaneous coronary interventions, 11
nonfatal strokes, 3 amputations, and 3 vascular surgical interventions)
and the intensive-therapy group (3 deaths from cardiovascular
causes, 4 nonfatal myocardial infarctions, 4 coronary-artery bypass
grafts, 3 nonfatal strokes, 2 amputations, and 3 vascular surgical
interventions). The time-to-first-event curves for the primary
composite end point continued to diverge during follow-up (Figure 3A). The
unadjusted hazard ratio for the intensive-therapy group as compared with
the conventional-therapy group was 0.47 (95 percent confidence interval,
0.24 to 0.73; P=0.008). Adjustment for the duration of diabetes,
age, sex, smoking status, and presence or absence of cardiovascular
disease at base line had no substantial effect (hazard ratio, 0.47;
95 percent confidence interval, 0.22 to 0.74; P=0.01). When a
composite end point was used that excluded revascularizations so as
to avoid potential physician bias in this unblinded trial, the
hazard ratio was 0.45 (95 percent confidence interval, 0.23 to 0.91;
P=0.02). In a hypothetical worst-case analysis in which death from
any cause except cancer was included, instead of death from
cardiovascular causes, the patient who withdrew consent in the
intensive-therapy group was considered to have had an event, and the
two patients in the conventional-therapy group who withdrew were
considered to have completed follow-up without events (Figure 1), the
hazard ratio was 0.50 (95 percent confidence interval, 0.29 to 0.86;
P=0.01).
Diabetic nephropathy developed in 31
patients in the conventional-therapy group and 16 patients in the
intensive-therapy group (Figure 3B).
Three patients in the conventional-therapy group had progression to
end-stage renal disease requiring dialysis, as compared with none in
the intensive-therapy group. Retinopathy developed or progressed in
51 patients in the conventional-therapy group, as compared with 38
in the intensive-therapy group. The groups also differed with
respect to the proportion of patients in whom retinopathy developed
(38 patients in the conventional-therapy group, as compared with 27
in the intensive-therapy group; P=0.02). Seven patients in the
conventional-therapy group became blind in one eye, as compared with
one patient in the intensive-therapy group (P=0.03). Autonomic
neuropathy progressed in 43 patients in the conventional-therapy group,
as compared with 24 in the intensive-therapy group; peripheral neuropathy
progressed in 37 and 40 patients, respectively. The groups did not
differ significantly with respect to the number of patients who
reported at least one minor episode of hypoglycemia at the four- or
eight-year examination (39 in the conventional-therapy group and 42
in the intensive-therapy group, P=0.50). Twelve patients in the
conventional-therapy group and five in the intensive-therapy group
had at least one major hypoglycemic event that impaired
consciousness and required help from another person (P=0.12). More
than 75 percent of major events occurred in insulin-treated
patients. One patient in the intensive-therapy group was
hospitalized for a bleeding gastric ulcer. Otherwise, no major
adverse events were reported.
Discussion
We found that a targeted, long-term (mean, 7.8 years),
intensified intervention involving multiple risk factors reduced the
risk of cardiovascular events among patients with type 2 diabetes
and microalbuminuria. The continued divergence in the rates of
the primary end point suggests that therapy for even longer periods
may result in an even better prognosis. Our data suggest that five
patients need to be treated for this length of time to prevent one
cardiovascular event. In addition, the reductions in the risk of
nephropathy, retinopathy, and autonomic neuropathy obtained after
four years of the intervention were maintained at eight years.11
Serious adverse events were few. The study design precludes us from
drawing conclusions about which treatment component was the most
crucial in reducing the incidence of diabetes-related complications.
The absolute 20 percent reduction in the risk of cardiovascular events
is higher than that in studies applying single-factor intervention
strategies aimed at hyperglycemia, hypertension, or dyslipidemia.7,16,17,18,19,20,21,22,23
Yet, the populations studied in these trials varied considerably, as
did the durations of the intervention and the composite end points.
The United Kingdom Prospective Diabetes Study, involving intensive
treatment of hyperglycemia in patients with newly diagnosed type 2
diabetes over a 10-year period, found an absolute reduction in the
risk of myocardial infarction of borderline significance (3
percent), with an absolute difference of 0.9 percent in glycosylated
hemoglobin values.6 The
study did not find significant reductions in any other macrovascular
outcomes.6
Intensive treatment of hypertension in patients with newly diagnosed
diabetes during an eight-year period, which decreased systolic and
diastolic blood pressure by 10 and 5 mm Hg, respectively, significantly
reduced both the absolute risk of stroke and the combined end point
of diabetes-related death, death from vascular causes, and death
from renal causes by 5 percent.7 The
Hypertension Optimal Treatment Study, which treated elevations in
diastolic blood pressure for an average of 3.7 years, reported
similar reductions in the risk of composite end points for
macrovascular disease in subgroup analyses of patients with type 2
diabetes.17
Treatment of systolic hypertension for 4.7 years in the Systolic Hypertension
in the Elderly Program trial and 2 years in the Systolic
Hypertension in Europe Trial reduced the absolute risk of
cardiovascular events by 8 percent18
and that of death from cardiovascular causes by 5 percent.19
Subgroup analysis showed a large reduction in the absolute risk of cardiovascular
events (19 percent) among diabetic patients with elevated serum
total cholesterol concentrations who took statins for 5.4 years for
secondary cardiovascular prevention.8
Other subgroup analyses in secondary-prevention trials of statins or
fibrates have not been associated with such marked effects.20,21,22,23
In our study, the reductions in the risk of microvascular complications
after eight years of intervention were similar to the reductions seen
after four years of intervention, demonstrating long-term beneficial
effects of continuous intervention in terms of diabetic nephropathy,
retinopathy, and autonomic neuropathy. The fact that more than half
the patients in the conventional-therapy group were referred to
specialists at some point during follow-up may have diminished the
degree of separation in risk factors between the two treatment
groups. As a consequence, the reported reductions in the risk of
cardiovascular as well as microvascular complications may be
conservative. Our findings have considerable implications for the
treatment of type 2 diabetes. An approach such as the one we used,
involving a focused, multifactorial intervention with continued
patient education and motivation and strict targets and
individualized risk assessment, should be offered to patients with
type 2 diabetes and microalbuminuria who are at increased risk for
macrovascular and microvascular complications. Such patients may
represent about one third of the population of patients with type 2
diabetes.24
Since many national guidelines for the treatment of type 2 diabetes recommend
reducing the risk of multiple factors through the use of protocols
and therapeutic targets similar to ours, it may be difficult to
replicate our findings in other controlled clinical trials. However,
future studies might address several key questions, including which
type of care organization is most effective in implementing this
approach to treatment. Taken together, these data suggest that a
long-term, targeted, intensive intervention involving multiple risk
factors reduces the risk of both cardiovascular and microvascular
events by about 50 percent among patients with type 2 diabetes and
microalbuminuria. Drs. Gæde, Parving, and Pedersen have
reported having equity in NovoNordisk. Dr. Parving has reported
having equity in Merck; receiving consulting and lecture fees from
Merck, Bristol-Myers Squibb, Pfizer, and Sanofi; and receiving
grants from Merck and Bristol-Myers Squibb. We are
indebted to the participating patients; to the members of the
Steno-2 team: M. Beck, J. Bengtsen, A. Hoppe, S. Kohlwes, G. Lademann,
J. Lohse, C. Lysén, G. Mortensen, S. Månsson, B. Nielsen, J. Obel,
J. Poulsen, and K. Riemer; to B. Carstensen, R.T. Palacios, and P.
Hougaard for statistical advice; to S. Boesgård, F. Stensgård
Hansen, P. Flesner, and A. Nielsen for help in evaluating the data;
to J. Faber, P. Hildebrandt, and J. Aldershvile for thorough work on
the end-point committee; and to T. Hansen, L. Hansen, F.S. Nielsen,
P. Rossing, S. Urhammer, H. Lund-Andersen, C. Binder, J. Nerup, T.
Deckert, T. Mandrup-Poulsen, A. Vaag, and K. Borch-Johnsen and the
rest of the staff at the Steno Diabetes Center for constructive
advice and assistance.
Source
Information
From the Steno Diabetes Center, Copenhagen (P.G., P.V., N.L.,
H.-H.P., O.P.); Herlev County Hospital, Herlev (N.L.); Amtssygehuset Roskilde,
Roskilde (G.V.H.J.); and the Faculty of Health Science, Aarhus University,
Aarhus (H.-H.P., O.P.) — all in Denmark. Address reprint requests to Dr.
Pedersen at the Steno Diabetes Center, Niels Steensens Vej 2, 2820 Gentofte,
Denmark, or at oluf@steno.dk.
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Ahmed S. A., Manning D., McGurk C., Bassan M. M., Gæde P., Parving H.-H.,
Pedersen O.
N Engl J Med 2003; 348:1925-1927, May 8, 2003. Correspondence
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[Abstract] [Full Text] - Gill, G.V., Woodward, A.,
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(2003). Intensified treatment of type 2 diabetes--positive effects on
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A., Beckman, J. A., Cosentino, F. (2003). Diabetes and Vascular Disease:
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intensive, target driven intervention reduced cardiovascular and
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V. M., Rull-Rodrigo, J. A., Conyer, R. T. (2003). Characteristics of
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[Abstract] [Full Text] - Dandona, P., Aljada, A.,
Chaudhuri, A., Bandyopadhyay, A. (2003). The Potential Influence of
Inflammation and Insulin Resistance on the Pathogenesis and Treatment of
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[Full Text] - Ritz, E. (2003). Albuminuria
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[Full Text] - Myers, J., Atwood, J. E.,
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[Full Text] - Ahmed, S. A., Manning, D.,
McGurk, C., Bassan, M. M., Gaede, P., Parving, H.-H., Pedersen, O. (2003).
Multifactorial Intervention and Cardiovascular Disease in Type 2 Diabetes.
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[Full Text] - Wolf, G., Ritz, E. (2003).
Diabetic Nephropathy in Type 2 Diabetes Prevention and Patient Management.
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