Background Intensified multifactorial intervention — withtight glucose regulation and the use of renin–angiotensinsystem blockers, aspirin, and lipid-lowering agents —has been shown to reduce the risk of nonfatal cardiovasculardisease among patients with type 2 diabetes mellitus and microalbuminuria.We evaluated whether this approach would have an effect on therates of death from any cause and from cardiovascular causes.
Methods In the Steno-2 Study, we randomly assigned 160 patientswith type 2 diabetes and persistent microalbuminuria to receiveeither intensive therapy or conventional therapy; the mean treatmentperiod was 7.8 years. Patients were subsequently followed observationallyfor a mean of 5.5 years, until December 31, 2006. The primaryend point at 13.3 years of follow-up was the time to death fromany cause.
Results Twenty-four patients in the intensive-therapy groupdied, as compared with 40 in the conventional-therapy group(hazard ratio, 0.54; 95% confidence interval [CI], 0.32 to 0.89;P=0.02). Intensive therapy was associated with a lower riskof death from cardiovascular causes (hazard ratio, 0.43; 95%CI, 0.19 to 0.94; P=0.04) and of cardiovascular events (hazardratio, 0.41; 95% CI, 0.25 to 0.67; P<0.001). One patientin the intensive-therapy group had progression to end-stagerenal disease, as compared with six patients in the conventional-therapygroup (P=0.04). Fewer patients in the intensive-therapy grouprequired retinal photocoagulation (relative risk, 0.45; 95%CI, 0.23 to 0.86; P=0.02). Few major side effects were reported.
Conclusions In at-risk patients with type 2 diabetes, intensiveintervention with multiple drug combinations and behavior modificationhad sustained beneficial effects with respect to vascular complicationsand on rates of death from any cause and from cardiovascularcauses. (ClinicalTrials.gov number, NCT00320008
[ClinicalTrials.gov]
.)
Type 2 diabetes mellitus is associated with a high rate of complicationsrelated to cardiovascular disease and diabetic nephropathy,retinopathy, and neuropathy.1,2,3 The rate of death among patientswith type 2 diabetes is approximately twice as high as thatamong persons without the disorder.2,3 However, trials of interventionsfor single risk factors have shown efficacy in reducing thedevelopment and progression of complications.4,5,6,7,8,9 Furthermore,the risk of vascular complications was reduced by about halfin the Steno-2 Study, our previous prospective, randomized,open-label, blinded trial, during an average of 7.8 years ofintensified multitarget intervention aimed at concomitant riskfactors.10 The study encompassed treatment goals similar tothose recommended in the current guidelines of the AmericanDiabetes Association.11
Although the number of deaths was lower in the intensive-therapygroup in the Steno-2 Study, the relatively small number of patientswho reached that end point precluded a determination of whetherthis approach affected mortality. Therefore, this follow-upto the Steno-2 Study was designed to address the question ofmortality, as well as whether the risk reductions already achievedfor both macrovascular and microvascular diseases were maintainedduring follow-up in a community setting. In the follow-up study,patients were observed for a mean of 5.5 years after the initialtrial had ended.
Methods
Study Design
Detailed information about the Steno-2 Study has been reportedpreviously.10,12 Briefly, in 1993, a total of 160 white Danishpatients with type 2 diabetes (defined according to the criteriaof the World Health Organization) and persistent microalbuminuriawere randomly assigned to receive either conventional multifactorialtreatment, consistent with the guidelines of the Danish MedicalAssociation,13 or intensified, target-driven therapy involvinga combination of medications and focused behavior modification.The intensive-therapy group had defined targets consistent withthe latest guidelines of the American Diabetes Association.These targets included a glycated hemoglobin level of less than6.5%, a fasting serum total cholesterol level of less than 175mg per deciliter (4.5 mmol per liter), a fasting serum triglyceridelevel of less than 150 mg per deciliter (1.7 mmol per liter),a systolic blood pressure of less than 130 mm Hg, and a diastolicblood pressure of less than 80 mm Hg. Patients were treatedwith blockers of the renin–angiotensin system becauseof their microalbuminuria, regardless of blood pressure, andreceived low-dose aspirin as primary prevention.10,12 The numbersof patients who underwent randomization, were assigned to receivetreatment, and completed the study and follow-up are shown inFigure 1.
Three patients withdrew during follow-up because they moved to other regions: one patient in the intensive-therapy group withdrew after 3.2 years, and two patients in the conventional-therapy group withdrew after 0.4 and 4.7 years. No other patients were lost to follow-up.
Study Population
Of the 160 patients who were enrolled in the Steno-2 Study,27 died and 3 (including 1 patient in the intensive-therapygroup) withdrew before the end-of-trial examinations in 2001.All 130 remaining patients provided written informed consentto continue participation in the observational follow-up studyafter the intervention study ended. The protocol for the follow-upstudy was in accordance with the provisions of the Declarationof Helsinki and was approved by the ethics committee of CopenhagenCounty, Denmark.
When the Steno-2 Study was completed, the structured treatmentof patients in the intensive-therapy group stopped. However,all participating patients in both study groups were informedin detail about the benefits of intensified multifactorial treatment,and the diabetes specialists to whom the patients were referredwere educated about the new national recommendations for intensifiedmultitarget treatment on the basis of the results of the Steno-2Study. This education took place both at regional and at nationallevels.14,15 This report includes follow-up data obtained fromSeptember 1, 2006, to December 31, 2006. At follow-up examination,84% of patients in the intensive-therapy group and 87% of thosein the conventional-therapy group were still being treated atdiabetes clinics.
Procedures, Measurements, and End Points
End-point examinations were performed for both macrovascularand microvascular complications, and data regarding biochemicaland clinical status were obtained in both study groups. Themeasurements were obtained by a single laboratory technicianwho was not aware of the original study-group assignments.
The primary end point in the follow-up trial was the time todeath from any cause. It is mandatory by law for a physicianto complete a death certificate for any death occurring in Denmark;the data are coded and retained in the computerized Danish DeathRegistry.16
The secondary end points were death from cardiovascular causesand a composite of cardiovascular disease events that includeddeath from cardiovascular causes, nonfatal stroke, nonfatalmyocardial infarction, coronary-artery bypass grafting, percutaneouscoronary intervention or revascularization for peripheral atheroscleroticarterial disease, and amputation because of ischemia.17 An independentcommittee whose members were unaware of study-group assignmentsfrom the intervention portion of the Steno-2 Study adjudicatedthe specified end points.
The tertiary end points were incident diabetic nephropathy orthe development or progression of diabetic retinopathy or neuropathy.12Diabetic nephropathy was defined as a urinary albumin excretionrate of more than 300 mg per 24 hours in two of three consecutivesterile urine specimens measured at baseline; after 1.9, 3.8,and 7.8 years; and at the end of the follow-up period.
Diabetic retinopathy was graded according to the six-level gradingscale of the European Community-funded Concerted Action Programmeinto the Epidemiology and Prevention of Diabetes (EURODIAB)by two independent eye specialists who were unaware of the patients'study-group assignments (see the table in the Supplementary Appendix,available with the full text of this article at www.nejm.org).18Progression of retinopathy was defined as an increase of atleast one level in the EURODIAB grading scale in either eye,as reported previously.12 The need for laser treatment of eitherproliferative retinopathy or macular edema was evaluated byophthalmologists at the eye clinic of the Steno Diabetes Center,who were unaware of study-group assignments. Blindness was definedaccording to the criteria of the World Health Organization asa maximally corrected visual acuity of less than 6/60 in eithereye (less than 20/200 on the Snellen visual-acuity scale).
Peripheral neuropathy was measured with a biothesiometer. Thediagnosis of autonomic neuropathy was based on a measurementof the RR interval on an electrocardiogram obtained during pacedbreathing and on an orthostatic-hypotension test, with progressiondefined as reported previously.12
Statistical Analysis
The protocol for the follow-up trial specified that no analysesof death from any cause would be performed until at least 60patients had died, as verified by online death registration,and until at least half the patients in either the intensive-therapygroup or the conventional-therapy group had died. It was estimatedthat this plan for analyzing death from any cause would providea statistical power of 0.75 and a type I error rate of 0.05in detecting a reduction in the relative risk of death of 40%in the intensive-therapy group. Continuous reporting from theDanish Death Registry to the Steno Diabetes Center confirmedthat this milestone was reached in June 2006.
All end points were analyzed according to the intention-to-treatprinciple. For the primary and secondary end points, event curvesfor the time to the first event were based on Kaplan–Meieranalysis, and treatments were compared by means of the log-ranktest. The hazard ratio for the comparison of intensive withconventional therapy and 95% confidence intervals were estimatedwith the use of a proportional-hazards model. We determinedwhether the hazard ratio at the end of the formal interventionsubsequently changed. If so, the time since randomization wasused as the time scale in an adjusted model.19 Data regardingtertiary end points were censored according to prespecifiedintervals and analyzed with the use of a proportional-hazardsmodel, with adjustment for age, duration of diabetes, sex, andmicrovascular status at baseline; these results are expressedas relative risks. Changes in measured variables within groupswere compared by means of analysis of covariance, with baselinevalues as covariates. The Mann–Whitney test was used forany instances of non-Gaussian distribution. A chi-square testwas performed to compare categorical variables. All reportedP values are two-sided.
Results
Patients
Behavioral, clinical, and biochemical characteristics of thepatients at baseline, at the end of the trial (at 7.8 years),and at the end of the follow-up period (at 13.3 years) are shownin Table 1. The two study groups were similar at baseline butdiffered significantly at the end of the intervention period,indicating that intensive therapy was superior to conventionaltherapy in controlling the level of glycated hemoglobin; fastingserum levels of total cholesterol, low-density lipoprotein cholesterol,and triglycerides; systolic and diastolic blood pressures; andrate of urinary albumin excretion (Table 1). At the end of thefollow-up period, the differences in risk factors between thegroups had narrowed, primarily because of intensified treatmentamong patients in the original conventional-therapy group (Figure 1A).In contrast, risk factors in the intensive-therapy group remainedthe same as they had been during the original trial, exceptfor systolic blood pressure, which increased (P=0.001) (Figure 2A).Time curves for risk factors showed a similar pattern for the93 patients who were followed during the entire 13.3-year period(data not shown). No significant differences were observed betweenthe two groups with respect to habits related to exercise andsmoking, and only minor (although significant) changes wereseen in the intake of carbohydrates and fat. There were alsono significant differences in body weight or waist circumference(Table 1).
Figure 2. Changes in Selected Risk Factors during the Interventional Study and Follow-up Period.
Panel A shows mean (±SE) values for selected risk factors during the interventional part of the study for all patients (solid lines) and during the follow-up period (dashed lines). In the conventional-therapy group, mean values were obtained at baseline, at 3.8 years, at 7.8 years, and at 13.3 years. At these intervals, the total numbers of patients in both study groups were 160, 149, 130, and 93, respectively. Panel B shows the percentage of patients in each group in whom the treatment goals for the intensive-therapy group were reached at the end of the study. Only one patient (in the intensive-therapy group) reached all five treatment goals at the end of follow-up. To convert the values for cholesterol to millimoles per liter, multiply by 0.02586. To convert the values for triglycerides to millimoles per liter, multiply by 0.01129. LDL denotes low-density lipoprotein.
During the entire 13.3 years of follow-up, 24 patients (30%)in the intensive-therapy group died, as compared with 40 patients(50%) in the conventional-therapy group, which correspondedto an absolute risk reduction of 20% (P=0.02 by the log-ranktest) (Figure 3A). The hazard ratio for death in the intensive-therapygroup, as compared with the conventional-therapy group, was0.54 (95% confidence interval [CI], 0.32 to 0.89; P=0.02). Therewas no evidence of a change in the hazard ratio after the formalintervention was stopped (P=0.27). Deaths from cancer were asexpected on the basis of data from the Danish Cancer Registryand did not differ significantly between the two study groups(two deaths in the intensive-therapy group and five in the conventional-therapygroup).
Figure 3. Kaplan–Meier Estimates of the Risk of Death from Any Cause and from Cardiovascular Causes and the Number of Cardiovascular Events, According to Treatment Group.
Panel A shows the cumulative incidence of the risk of death from any cause (the study's primary end point) during the 13.3-year study period. Panel B shows the cumulative incidence of a secondary composite end point of cardiovascular events, including death from cardiovascular causes, nonfatal stroke, nonfatal myocardial infarction, coronary-artery bypass grafting (CABG), percutaneous coronary intervention (PCI), revascularization for peripheral atherosclerotic artery disease, and amputation; Panel C shows the number of events for each component of the composite end point. In Panels A and B, the I bars represent standard errors.
Nine patients in the intensive-therapy group died from cardiovascularcauses, as compared with 19 in the conventional-therapy group(P=0.03 by the log-rank test) (Table 2). The hazard ratio fordeath from cardiovascular causes in the intensive-therapy groupwas 0.43 (95% CI, 0.19 to 0.94; P=0.04). The hazard ratio fordeath from cardiovascular disease tended to decrease in theintensive-therapy group after the end of the original trial,but the difference between the groups did not reach significance(P=0.06). However, because of the borderline significance, wealso analyzed the data according to an adjusted model that includedtime since randomization as the time scale. The derived results(hazard ratio, 0.43; 95% CI, 0.19 to 0.95; P=0.04) were similarto those derived from the unadjusted model.
Table 2. Numbers of Deaths from Any Cause, Deaths from Cardiovascular Causes, and Cardiovascular Events at 13.3 Years.
A total of 209 cardiovascular events occurred during the 13.3years of observation (Table 2 and Figure 3B). In the intensive-therapygroup, the absolute risk reduction was 29%, with a hazard ratioof 0.41 (95% CI, 0.25 to 0.67; P<0.001). There was no evidenceof a change in the hazard ratio after the formal interventionstudy ended (P=0.20). There were 51 events in 25 patients inthe intensive-therapy group and 158 events in 48 patients inthe conventional-therapy group (Table 2 and Figure 3C). Themean number of major cardiovascular events was 0.6 in the intensive-therapygroup and 2.0 in the conventional-therapy group. The averagenumber of recurrent events among patients with cardiovascularevents was 2.0 in the intensive-therapy group and 3.3 in theconventional-therapy group.
During the entire observation period, diabetic nephropathy developedin 20 patients in the intensive-therapy group, as compared with37 patients in the conventional-therapy group (relative risk,0.44; 95% CI, 0.25 to 0.77; P=0.004) (Figure 4). One patientin the intensive-therapy group had progression to end-stagerenal disease requiring dialysis, as compared with six patientsin the conventional-therapy group (P=0.04).
Figure 4. Patients with Development or Progression of Diabetic Nephropathy, Retinopathy, Autonomic Neuropathy, and Peripheral Neuropathy.
The bars labeled "Post-Trial" refer to the number of patients in whom the condition progressed during the period from the end of the original intervention trial to the end-point examination after an average of 13.3 years of study and follow-up.
Progression of diabetic retinopathy occurred in 41 patientsin the intensive-therapy group and in 54 patients in the conventional-therapygroup (relative risk, 0.57; 95% CI, 0.37 to 0.88; P=0.01). Lasertreatment for proliferative retinopathy or macular edema wasadministered to 14 patients in the intensive-therapy group and27 patients in the conventional-therapy group (relative risk,0.45; 95% CI, 0.23 to 0.86; P=0.02); blindness in at least oneeye was diagnosed in 2 patients in the intensive-therapy groupand in 7 patients in the conventional-therapy group (relativerisk, 0.51; 95% CI, 0.17 to 1.53; P=0.23).
Autonomic neuropathy progressed in 39 patients in the intensive-therapygroup and in 52 patients in the conventional-therapy group (relativerisk, 0.53; 95% CI, 0.34 to 0.81; P=0.004), and peripheral neuropathyprogressed in 44 and 46 patients in the two groups, respectively(relative risk, 0.97; 95% CI, 0.62 to 1.51; P=0.89).
During the 13.3 years of observation, at least one minor episodeof symptomatic hypoglycemia was reported in 80% of patientsin the intensive-therapy group and in 70% of patients in theconventional-therapy group (P=0.15). There was no statisticaldifference in major hypoglycemia episodes (13% in the intensive-therapygroup and 17% in the conventional-therapy group, P=0.52). Ableeding gastric ulcer developed in one patient in the intensive-therapygroup. Two patients in the intensive-therapy group and one inthe conventional-therapy group reported having muscle pain afterstatin treatment; however, no elevation of the serum creatinekinase level was seen. Five patients in the intensive-therapygroup and four patients in the conventional-therapy group reportedhaving a cough during treatment with angiotensin-converting–enzymeinhibitors. The cough disappeared in all patients after a changeto an angiotensin II antagonist. The average number of physician-prescribeddrugs for type 2 diabetes or its complications in the intensive-therapygroup at the end of the follow-up period was 5.5, as comparedwith 5.7 in the conventional-therapy group (P=0.64).
Discussion
After a mean of 13.3 years (7.8 years of multifactorial interventionand an additional 5.5 years of follow-up), there was an absoluterisk reduction for death from any cause of 20% among patientswith type 2 diabetes and microalbuminuria who received intensivetherapy, as compared with those who received conventional therapy.The absolute risk of death from cardiovascular causes was reducedby 13% among those receiving intensive therapy. During the entirefollow-up period, the rate of death among patients in the conventional-therapygroup was 50%, a finding that underscores the poor prognosisfor such patients in the absence of intensive treatment.20
In comparison with the results of trials involving treatmentof single risk factors in patients with type 2 diabetes, theachieved risk reductions in our trial were considerable. However,in secondary interventions, individual therapy with aspirin,antihypertensive agents, and lipid-lowering drugs each reducedthe relative risk of cardiovascular events by about 25%, andthe effects appeared to be additive.21,22 Therefore, the reductionsin risk — a 59% reduction in the relative risk and a 29%reduction in the absolute risk — in the composite of cardiovascularevents fit with projections from trials involving single riskfactors.21
Our study was not designed to identify which elements of intensivediabetes therapy contributed most to the reduction in cardiovascularrisk. However, using a risk calculator based on epidemiologicand interventional data from patients with type 2 diabetes inthe United Kingdom Prospective Diabetes Study,23 we concludedthat the use of statins and antihypertensive drugs might havehad the largest effect in reducing cardiovascular risk duringthe 7.8 years of intervention, with hypoglycemic agents andaspirin the next most important interventions.24
Even though the significant differences in the levels of riskfactors for cardiovascular disease between the study groupsat the end of our interventional study had disappeared by theend of the follow-up period (Table 1 and Figure 2), the Kaplan–Meiercurves for the time to the first cardiovascular event continuedto diverge (Figure 3B). A similar outcome was reported in theDiabetes Control and Complications Trial (DCCT),25 involvingpatients with type 1 diabetes, in which the effects of intensiveinsulin therapy and conventional insulin therapy were comparedduring a 6.5-year period. After an average follow-up of 17 years,the original intensive-therapy treatment was associated withan absolute risk reduction of 2.8% for a composite cardiovascularend point. In the DCCT follow-up trial, glucose regulation deterioratedin the original intensive-therapy group and improved in thecontrol group, resulting in a convergence of the glycemic levelsin the two groups.
In our follow-up trial, the risk factors in the two study groupstended to converge (Figure 2). Only the control of systolicblood pressure deteriorated in the intensive-therapy group,whereas glucose levels, lipid levels, diastolic blood pressure,and the rate of urinary albumin excretion improved in the conventional-therapygroup, leaving the two study groups with similar levels of riskfactors after 13.3 years. The design of our study did not allowus to estimate the exact time at which risk factors improvedin the conventional-therapy group. However, since all patientswere offered intensive treatment at the end of the trial, theimprovement probably took place early during the follow-up period.The effect of blood-pressure reduction on cardiovascular endpoints usually occurs within months,26,27 whereas the effectof lipid lowering is evident after 1 to 2 years.8,28,29 Theeffect of glucose lowering on diabetes-related end points occurseven later.4 Thus, an effect of early intervention, as comparedwith late intervention, may be a likely explanation for thecontinuing divergence in cardiovascular end points, rather thana simple time-to-effect relationship.
The drugs used in our study differed between the study groups.For instance, a larger proportion of patients in the intensive-therapygroup took metformin or sulfonylurea, despite the similar levelsof glycemia in the two groups. Therefore, differences in drugsor their combinations might have contributed to the long-termoutcome.
Reductions in the progression of microvascular complicationsoccurred after a mean of 3.8 years of intensified intervention,12changes that were maintained at 13.3 years. Indeed, during continuousfollow-up, this reduction translated into a significant absoluterisk reduction of 6.3% in the need for dialysis, a conditionthat in many parts of the world is tantamount to death.30
We did not monitor adverse effects continuously. However, fewserious adverse effects were reported during regular interviewswith patients.10,12 In this respect, it is noteworthy that exceptfor atorvastatin, generic drugs with well-known long-term sideeffects were prescribed. Whether newer and more expensive diabetestreatments would have additional beneficial long-term effectsor risks remains to be determined.
Recent surveys have shown very slow progress in achieving treatmentgoals and in the use of recommended drugs for the preventionof diabetic vascular complications.31,32 Therefore, since intensive,multifactorial care of patients with type 2 diabetes leads toreduced rates of death and cardiovascular disorders, the earlyand meticulous implementation of current treatment guidelinesremains a major challenge.
Supported by the Danish Health Research Council.
Dr. Parving reports receiving consulting and lecture fees fromMerck, Novartis, Bristol-Myers Squibb, Pfizer, and Sanofi andgrants from Merck, Novartis, and Bristol-Myers Squibb and havingan equity interest in Novo Nordisk and Merck; and Dr. Pedersen,having an equity interest in Novo Nordisk. No other potentialconflict of interest relevant to this article was reported.
We thank the patients who participated in the study and theirfamilies; Pernille Vedel, a coinvestigator in the early phaseof the study; study assistants L. Askjær, M. Beck, J.Bengtsen, I. Holstein, A. Hoppe, S. Kohlwes, G. Lademann, J.Lohse, C. Lysén, G. Mortensen, S. Månsson, B.B.Nielsen, J. Obel, J. Poulsen, and K. Riemer; B. Carstensen andA. Vølund for their statistical support; M. Frandsen,B.V. Hansen, B.R. Jensen, T.R. Juhl, L. Pietrascek, and U. Schmidtfor their bioanalytical assistance; and J. Faber and P. Hildebrandtfor their thorough examinations while serving on the end-pointcommittee.
Source Information
From the Steno Diabetes Center, Copenhagen (P.G., H.L.-A., O.P.); Department of Ophthalmology, Glostrup University Hospital, Glostrup (H.L.-A.); Department of Medical Endocrinology, Rigshospitalet Copenhagen University Hospital, Copenhagen (H.-H.P.); and Faculty of Health Sciences, University of Aarhus, Aarhus (H.-H.P., O.P.) — all in Denmark.
Address reprint requests to Dr. Pedersen at the Steno Diabetes Center, 2820 Gentofte, Copenhagen, Denmark, or at oluf{at}steno.dk.
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