Background Cardiovascular morbidity is a major burden in patientswith type 2 diabetes. In the Steno-2 Study, we compared theeffect of a targeted, intensified, multifactorial interventionwith that of conventional treatment on modifiable risk factorsfor cardiovascular disease in patients with type 2 diabetesand microalbuminuria.
Methods The primary end point of this open, parallel trial wasa composite of death from cardiovascular causes, nonfatal myocardialinfarction, nonfatal stroke, revascularization, and amputation.Eighty patients were randomly assigned to receive conventionaltreatment in accordance with national guidelines and 80 to receiveintensive treatment, with a stepwise implementation of behaviormodification and pharmacologic therapy that targeted hyperglycemia,hypertension, dyslipidemia, and microalbuminuria, along withsecondary prevention of cardiovascular disease with aspirin.
Conclusions A target-driven, long-term, intensified interventionaimed at multiple risk factors in patients with type 2 diabetesand microalbuminuria reduces the risk of cardiovascular andmicrovascular events by about 50 percent.
Patients with type 2 diabetes mellitus have a risk of deathfrom cardiovascular causes that is two to six times that amongpersons without diabetes, and among white Americans, the age-adjustedprevalence of coronary heart disease is twice as high amongthose with type 2 diabetes as among those without diabetes.1,2,3,4The cardiovascular events associated with type 2 diabetes andthe high incidence of other macrovascular complications, suchas strokes and amputations, are a major cause of illness andan enormous economic burden.
Multiple modifiable risk factors for late complications in patientswith type 2 diabetes, including hyperglycemia, hypertension,and dyslipidemia, increase the risk of a poor outcome.5 Randomizedtrials that investigated the effect of intensified interventioninvolving a single risk factor in patients with type 2 diabetesdemonstrated benefits in terms of both macrovascular and microvascularcomplications in kidneys, eyes, and nerves.6,7,8,9,10 On thebasis of the results of these trials, recent guidelines fromthe American Diabetes Association and other national guidelinesrecommend an intensified multifactorial treatment approach,although the effect of this approach has not been confirmedin 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 modificationand polypharmacologic therapy aimed at several modifiable riskfactors in patients with type 2 diabetes and microalbuminuria;we compared this approach with a conventional intervention involvingmultiple risk factors.
Methods
Patients and Study Design
The study protocol specified two major analyses, a microvascularanalysis in which the development of diabetic nephropathy afterfour years of intervention was the primary end point and a macrovascularanalysis in which a composite end point for macrovascular diseaseafter eight years of intervention was the primary end point.The results of the original microvascular part of the studyhave been reported elsewhere, together with detailed informationabout the study design and base-line phenotypic data.11 Patientswith persistent microalbuminuria were selected, since microalbuminuriais a well-established independent risk factor for cardiovasculardisease (the primary end point) as well as for nephropathy,retinopathy, and neuropathy (secondary end points).12,13 Allpatients provided written informed consent. The protocol wasin accordance with the Declaration of Helsinki and was approvedby 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 conventionaltreatment for multiple risk factors from their general practitioner,according to the 1988 recommendations of the Danish MedicalAssociation (which were revised in 2000) (Table 1), with thepossibility of being referred to specialists.14 The remaining80 patients were randomly assigned to undergo intensive multifactorialintervention involving strict treatment goals (Table 1), tobe achieved through behavior modification and a stepwise introductionof 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 individualconsultations every third month during the eight-year follow-up.All hospital admissions in the conventional-therapy group occurredat the request of the patients' personal physicians.
Three patients withdrew during follow-up because they moved to other regions: the two patients in the conventional-therapy group withdrew after 0.4 and 4.7 years of follow-up, respectively, and the patient in the intensive-therapy group withdrew after 3.2 years. CVD denotes cardiovascular disease.
Table 1. Treatment Goals for the Conventional-Therapy Group and the Intensive-Therapy Group.
At some point during follow-up, 45 patients in the conventional-therapygroup (56 percent) were treated at the outpatient clinic atthe Steno Diabetes Center in accordance with the national guidelinesand 8 (10 percent) were referred to other diabetes clinics.The mean number of consultations at diabetes clinics per yearfor these 53 patients was three. Patients in the conventional-therapygroup who were treated at the Steno Diabetes Center in accordancewith the national guidelines did not differ from typical patientswith type 2 diabetes who were seen at the center; they had asimilar duration of diabetes and similar levels of hyperglycemia,blood pressure, and serum lipids after an overnight fast (datanot shown). None of the patients in the conventional-therapygroup were treated by the project team.
If patients were unable to maintain glycosylated hemoglobinvalues below 6.5 percent by means of diet and increased physicalactivity alone after three months, an oral hypoglycemic agentwas started. As the initial step, overweight patients (definedas those with a body-mass index [the weight in kilograms dividedby the square of the height in meters] above 25) received metformin(maximum, 1 g twice daily); lean patients, or overweight patientswho had contraindications to metformin therapy, received gliclazide(maximum, 160 mg twice daily). As the second step, metforminwas added to the regimen of lean patients and gliclazide tothat of overweight patients if hyperglycemia was not controlled.If the glycosylated hemoglobin value exceeded 7.0 percent despitemaximal doses of oral agents, the addition of neutral protamineHagedorn (NPH) insulin at bedtime was recommended. When insulinwas started, lean patients stopped metformin treatment and overweightpatients stopped gliclazide therapy unless it was the only oralhypoglycemic agent given. The insulin dose was adjusted on thebasis of the morning fasting blood glucose concentration. Ifthe daily dose of insulin exceeded 80 IU at bedtime or therewas no decrease in the glycosylated hemoglobin value, patientswere switched to regimens in which regular and NPH insulin wasgiven two to four times a day (Table 2).
The macrovascular study ended as planned in December 2001. Biochemicaland clinical data were obtained every third month in the intensive-therapygroup. End-point examinations for both macrovascular and microvascularcomplications were performed and biochemical and clinical statuswas determined after four and eight years of intervention inboth groups.11
All blood samples were obtained at 8 a.m. after an overnightfast and before the morning medication. Blood pressure was measuredtwice after 20 minutes' rest while patients were supine, withuse of a Hawksley random-zero sphygmomanometer. The measurementswere obtained by a laboratory technician who was unaware ofthe patients' treatment assignment.
The primary study end point was a composite of death from cardiovascularcauses, nonfatal myocardial infarction, coronary-artery bypassgrafting, percutaneous coronary intervention, nonfatal stroke,amputation as a result of ischemia, or vascular surgery forperipheral atherosclerotic artery disease. All end points specifiedin the protocol were adjudicated by an independent committeewhose members were unaware of the patients' treatment assignments.Secondary end points indicative of microvascular disease, whichhave previously been described in detail,11 were the incidenceof diabetic nephropathy or the development or progression ofdiabetic retinopathy or neuropathy. Diabetic nephropathy wasdefined as a urinary albumin excretion of more than 300 mg per24 hours in two of three consecutive sterile urine specimens.Diabetic retinopathy was graded according to the six-level gradingscale of the European Community–funded Concerted ActionProgramme into the Epidemiology and Prevention of Diabetes bytwo independent ophthalmologists who were unaware of the patients'treatment assignment.15 Peripheral neuropathy was measured witha biothesiometer, and the diagnosis of autonomic neuropathywas based on a measurement of the RR interval on the electrocardiogramduring paced breathing and on an orthostatic-hypotension testconducted by a laboratory technician who was unaware of thepatients' treatment assignments.
Statistical Analysis
Given a constant rate of events of 6 percent per year, 160 patientswere needed to permit us to detect a 35 percent reduction inthe relative risk of the primary composite end point with apower of 0.7 and a type 1 error rate of 0.05 during the plannedmean follow-up period of eight years. The primary end pointwas analyzed according to the intention-to-treat principle,with event curves for the time to the first event based on Kaplan–Meieranalysis, and treatments were compared with the use of the log-ranktest. A Cox regression model was used to calculate the hazardratio for the primary end point.
Since the secondary end points occurred at some point betweenbase line and four years or between four and eight years, therate ratio was estimated with use of a grouped survival model(binary regression with complementary log-log link). Separateeffects of treatment were estimated for the two periods, whereasthe 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 comparedby means of analysis of covariance, with base-line values ascovariates to adjust for differences between the groups at randomization.In the case of a nongaussian distribution, the Mann–Whitneytest was used. A chi-square test was used to compare categoricalvariables.
Results
The base-line demographic and clinical characteristics and biochemicalstatus of the patients in the conventional-therapy group andthe intensive-therapy group were similar (as shown in the Supplementary Appendix 1,available with the full text of this article athttp://www.nejm.org). The mean age of the patients was 55.1years. Changes in lifestyle (behavioral variables) and clinicaland biochemical variables in the two groups and differencesbetween 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 lifestylewere moderate; the only significant differences between groupswere in the relative intake of carbohydrate and fat. The changesin body-mass index did not differ significantly between groups.
Table 3. Changes in Clinical, Behavioral, and Biochemical Variables at the End of the Study.
The groups differed significantly with respect to glycosylatedhemoglobin values, fasting plasma glucose concentrations, fastingserum lipid concentrations, systolic and diastolic blood pressure,and urinary albumin excretion rate. As shown in Figure 2A, thedifferences in the values of various risk factors between thetwo groups were maintained throughout the follow-up period.Figure 2B shows the percentage of patients in each group whoachieved the various recommended treatment goals of the intensiveregimen after 7.8 years of follow-up.
Figure 2. Mean (±SE) Changes in Selected Risk Factors in the Intensive-Therapy Group and the Conventional-Therapy Group during Follow-up (Panel A) and the Percentage of Patients in Each Group Who Reached the Intensive-Treatment Goals at a Mean of 7.8 Years (Panel B).
In Panel A, mean annual values are shown for the patients in the intensive-therapy group, whereas mean values obtained at the three examinations — at base line, after four years, and after eight years — are shown for the conventional-therapy group. LDL denotes low-density lipoprotein, and BP blood pressure. To convert values for cholesterol to millimoles per liter, multiply by 0.02586. To convert values for triglycerides to millimoles per liter, multiply by 0.01129.
A total of 118 cardiovascular events occurred during follow-up.There were 85 events among 35 patients (44 percent) in the conventional-therapygroup (7 deaths from cardiovascular causes, 17 nonfatal myocardialinfarctions, 10 coronary-artery bypass grafts, 5 percutaneouscoronary interventions, 20 nonfatal strokes, 14 amputations,and 12 surgical interventions for peripheral atheroscleroticartery disease), as compared with 33 events among 19 patients(24 percent) in the intensive-therapy group (7 deaths from cardiovascularcauses, 5 nonfatal myocardial infarctions, 5 coronary-arterybypass grafts, 3 nonfatal strokes, 7 amputations, and 6 vascularsurgical interventions). A breakdown of first events showeda similar distribution in the conventional-therapy group (1death from cardiovascular causes, 8 nonfatal myocardial infarctions,6 coronary-artery bypass grafts, 3 percutaneous coronary interventions,11 nonfatal strokes, 3 amputations, and 3 vascular surgicalinterventions) and the intensive-therapy group (3 deaths fromcardiovascular causes, 4 nonfatal myocardial infarctions, 4coronary-artery bypass grafts, 3 nonfatal strokes, 2 amputations,and 3 vascular surgical interventions).
The time-to-first-event curves for the primary composite endpoint continued to diverge during follow-up (Figure 3A). Theunadjusted hazard ratio for the intensive-therapy group as comparedwith the conventional-therapy group was 0.47 (95 percent confidenceinterval, 0.24 to 0.73; P=0.008). Adjustment for the durationof diabetes, age, sex, smoking status, and presence or absenceof cardiovascular disease at base line had no substantial effect(hazard ratio, 0.47; 95 percent confidence interval, 0.22 to0.74; P=0.01). When a composite end point was used that excludedrevascularizations so as to avoid potential physician bias inthis unblinded trial, the hazard ratio was 0.45 (95 percentconfidence interval, 0.23 to 0.91; P=0.02). In a hypotheticalworst-case analysis in which death from any cause except cancerwas included, instead of death from cardiovascular causes, thepatient who withdrew consent in the intensive-therapy groupwas considered to have had an event, and the two patients inthe conventional-therapy group who withdrew were consideredto have completed follow-up without events (Figure 1), the hazardratio was 0.50 (95 percent confidence interval, 0.29 to 0.86;P=0.01).
Figure 3. Kaplan–Meier Estimates of the Composite End Point of Death from Cardiovascular Causes, Nonfatal Myocardial Infarction, Coronary-Artery Bypass Grafting, Percutaneous Coronary Intervention, Nonfatal Stroke, Amputation, or Surgery for Peripheral Atherosclerotic Artery Disease in the Conventional-Therapy Group and the Intensive-Therapy Group (Panel A) and the Relative Risk of the Development or Progression of Nephropathy, Retinopathy, and Autonomic and Peripheral Neuropathy during the Average Follow-up of 7.8 Years in the Intensive-Therapy Group, as Compared with the Conventional-Therapy Group (Panel B).
The P value in Panel A was calculated with the use of the log-rank test. The bars in Panel A show standard errors. CI denotes confidence interval.
Diabetic nephropathy developed in 31 patients in the conventional-therapygroup and 16 patients in the intensive-therapy group (Figure 3B).Three patients in the conventional-therapy group had progressionto end-stage renal disease requiring dialysis, as compared withnone in the intensive-therapy group.
Retinopathy developed or progressed in 51 patients in the conventional-therapygroup, as compared with 38 in the intensive-therapy group. Thegroups also differed with respect to the proportion of patientsin whom retinopathy developed (38 patients in the conventional-therapygroup, as compared with 27 in the intensive-therapy group; P=0.02).Seven patients in the conventional-therapy group became blindin one eye, as compared with one patient in the intensive-therapygroup (P=0.03).
Autonomic neuropathy progressed in 43 patients in the conventional-therapygroup, as compared with 24 in the intensive-therapy group; peripheralneuropathy progressed in 37 and 40 patients, respectively.
The groups did not differ significantly with respect to thenumber of patients who reported at least one minor episode ofhypoglycemia at the four- or eight-year examination (39 in theconventional-therapy group and 42 in the intensive-therapy group,P=0.50). Twelve patients in the conventional-therapy group andfive in the intensive-therapy group had at least one major hypoglycemicevent that impaired consciousness and required help from anotherperson (P=0.12). More than 75 percent of major events occurredin insulin-treated patients. One patient in the intensive-therapygroup 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), intensifiedintervention involving multiple risk factors reduced the riskof cardiovascular events among patients with type 2 diabetesand microalbuminuria. The continued divergence in the ratesof the primary end point suggests that therapy for even longerperiods may result in an even better prognosis. Our data suggestthat five patients need to be treated for this length of timeto prevent one cardiovascular event. In addition, the reductionsin the risk of nephropathy, retinopathy, and autonomic neuropathyobtained after four years of the intervention were maintainedat eight years.11 Serious adverse events were few. The studydesign precludes us from drawing conclusions about which treatmentcomponent was the most crucial in reducing the incidence ofdiabetes-related complications.
The absolute 20 percent reduction in the risk of cardiovascularevents is higher than that in studies applying single-factorintervention strategies aimed at hyperglycemia, hypertension,or dyslipidemia.7,16,17,18,19,20,21,22,23 Yet, the populationsstudied in these trials varied considerably, as did the durationsof the intervention and the composite end points. The UnitedKingdom Prospective Diabetes Study, involving intensive treatmentof hyperglycemia in patients with newly diagnosed type 2 diabetesover a 10-year period, found an absolute reduction in the riskof myocardial infarction of borderline significance (3 percent),with an absolute difference of 0.9 percent in glycosylated hemoglobinvalues.6 The study did not find significant reductions in anyother macrovascular outcomes.6
Intensive treatment of hypertension in patients with newly diagnoseddiabetes during an eight-year period, which decreased systolicand diastolic blood pressure by 10 and 5 mm Hg, respectively,significantly reduced both the absolute risk of stroke and thecombined end point of diabetes-related death, death from vascularcauses, and death from renal causes by 5 percent.7 The HypertensionOptimal Treatment Study, which treated elevations in diastolicblood pressure for an average of 3.7 years, reported similarreductions in the risk of composite end points for macrovasculardisease in subgroup analyses of patients with type 2 diabetes.17Treatment of systolic hypertension for 4.7 years in the SystolicHypertension in the Elderly Program trial and 2 years in theSystolic Hypertension in Europe Trial reduced the absolute riskof cardiovascular events by 8 percent18 and that of death fromcardiovascular causes by 5 percent.19 Subgroup analysis showeda large reduction in the absolute risk of cardiovascular events(19 percent) among diabetic patients with elevated serum totalcholesterol concentrations who took statins for 5.4 years forsecondary cardiovascular prevention.8 Other subgroup analysesin secondary-prevention trials of statins or fibrates have notbeen associated with such marked effects.20,21,22,23
In our study, the reductions in the risk of microvascular complicationsafter eight years of intervention were similar to the reductionsseen after four years of intervention, demonstrating long-termbeneficial effects of continuous intervention in terms of diabeticnephropathy, retinopathy, and autonomic neuropathy. The factthat more than half the patients in the conventional-therapygroup were referred to specialists at some point during follow-upmay have diminished the degree of separation in risk factorsbetween the two treatment groups. As a consequence, the reportedreductions in the risk of cardiovascular as well as microvascularcomplications may be conservative.
Our findings have considerable implications for the treatmentof type 2 diabetes. An approach such as the one we used, involvinga focused, multifactorial intervention with continued patienteducation and motivation and strict targets and individualizedrisk assessment, should be offered to patients with type 2 diabetesand microalbuminuria who are at increased risk for macrovascularand microvascular complications. Such patients may representabout one third of the population of patients with type 2 diabetes.24
Drs. Gæde, Parving, and Pedersen have reported havingequity in NovoNordisk. Dr. Parving has reported having equityin Merck; receiving consulting and lecture fees from Merck,Bristol-Myers Squibb, Pfizer, and Sanofi; and receiving grantsfrom Merck and Bristol-Myers Squibb.
We are indebted to the participating patients; to the membersof 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 theSteno 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{at}steno.dk.
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-tocopherol, 400 µg of folic acid, and 100 µg of chrome picolinate. Initially, 150 mg of aspirin per day was given as secondary prevention to patients with a history of ischemic cardiovascular disease, and after October 1999, all patients received aspirin (unless there were contraindications). 
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