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Background Intensified multifactorial intervention — with tight glucose regulation and the use of renin–angiotensin system blockers, aspirin, and lipid-lowering agents — has been shown to reduce the risk of nonfatal cardiovascular disease among patients with type 2 diabetes mellitus and microalbuminuria. We evaluated whether this approach would have an effect on the rates of death from any cause and from cardiovascular causes.
Methods In the Steno-2 Study, we randomly assigned 160 patients with type 2 diabetes and persistent microalbuminuria to receive either intensive therapy or conventional therapy; the mean treatment period was 7.8 years. Patients were subsequently followed observationally for a mean of 5.5 years, until December 31, 2006. The primary end point at 13.3 years of follow-up was the time to death from any cause.
Results Twenty-four patients in the intensive-therapy group died, 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 risk of death from cardiovascular causes (hazard ratio, 0.43; 95% CI, 0.19 to 0.94; P=0.04) and of cardiovascular events (hazard ratio, 0.41; 95% CI, 0.25 to 0.67; P<0.001). One patient in the intensive-therapy group had progression to end-stage renal disease, as compared with six patients in the conventional-therapy group (P=0.04). Fewer patients in the intensive-therapy group required 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, intensive intervention with multiple drug combinations and behavior modification had sustained beneficial effects with respect to vascular complications and on rates of death from any cause and from cardiovascular causes. (ClinicalTrials.gov number, NCT00320008
[ClinicalTrials.gov]
.)
Although the number of deaths was lower in the intensive-therapy group in the Steno-2 Study, the relatively small number of patients who reached that end point precluded a determination of whether this approach affected mortality. Therefore, this follow-up to the Steno-2 Study was designed to address the question of mortality, as well as whether the risk reductions already achieved for both macrovascular and microvascular diseases were maintained during follow-up in a community setting. In the follow-up study, patients were observed for a mean of 5.5 years after the initial trial had ended.
Methods
Study Design
Detailed information about the Steno-2 Study has been reported previously.10,12 Briefly, in 1993, a total of 160 white Danish patients with type 2 diabetes (defined according to the criteria of the World Health Organization) and persistent microalbuminuria were randomly assigned to receive either conventional multifactorial treatment, consistent with the guidelines of the Danish Medical Association,13 or intensified, target-driven therapy involving a combination of medications and focused behavior modification. The intensive-therapy group had defined targets consistent with the latest guidelines of the American Diabetes Association. These targets included a glycated hemoglobin level of less than 6.5%, a fasting serum total cholesterol level of less than 175 mg per deciliter (4.5 mmol per liter), a fasting serum triglyceride level of less than 150 mg per deciliter (1.7 mmol per liter), a systolic blood pressure of less than 130 mm Hg, and a diastolic blood pressure of less than 80 mm Hg. Patients were treated with blockers of the renin–angiotensin system because of their microalbuminuria, regardless of blood pressure, and received low-dose aspirin as primary prevention.10,12 The numbers of patients who underwent randomization, were assigned to receive treatment, and completed the study and follow-up are shown in Figure 1.
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Of the 160 patients who were enrolled in the Steno-2 Study, 27 died and 3 (including 1 patient in the intensive-therapy group) withdrew before the end-of-trial examinations in 2001. All 130 remaining patients provided written informed consent to continue participation in the observational follow-up study after the intervention study ended. The protocol for the follow-up study was in accordance with the provisions of the Declaration of Helsinki and was approved by the ethics committee of Copenhagen County, Denmark.
When the Steno-2 Study was completed, the structured treatment of patients in the intensive-therapy group stopped. However, all participating patients in both study groups were informed in detail about the benefits of intensified multifactorial treatment, and the diabetes specialists to whom the patients were referred were educated about the new national recommendations for intensified multitarget treatment on the basis of the results of the Steno-2 Study. This education took place both at regional and at national levels.14,15 This report includes follow-up data obtained from September 1, 2006, to December 31, 2006. At follow-up examination, 84% of patients in the intensive-therapy group and 87% of those in the conventional-therapy group were still being treated at diabetes clinics.
Procedures, Measurements, and End Points
End-point examinations were performed for both macrovascular and microvascular complications, and data regarding biochemical and clinical status were obtained in both study groups. The measurements were obtained by a single laboratory technician who was not aware of the original study-group assignments.
The primary end point in the follow-up trial was the time to death from any cause. It is mandatory by law for a physician to complete a death certificate for any death occurring in Denmark; the data are coded and retained in the computerized Danish Death Registry.16
The secondary end points were death from cardiovascular causes and a composite of cardiovascular disease events that included death from cardiovascular causes, nonfatal stroke, nonfatal myocardial infarction, coronary-artery bypass grafting, percutaneous coronary intervention or revascularization for peripheral atherosclerotic arterial disease, and amputation because of ischemia.17 An independent committee whose members were unaware of study-group assignments from the intervention portion of the Steno-2 Study adjudicated the specified end points.
The tertiary end points were incident diabetic nephropathy or the development or progression of diabetic retinopathy or neuropathy.12 Diabetic nephropathy was defined as a urinary albumin excretion rate of more than 300 mg per 24 hours in two of three consecutive sterile 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 grading scale of the European Community-funded Concerted Action Programme into 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).18 Progression of retinopathy was defined as an increase of at least one level in the EURODIAB grading scale in either eye, as reported previously.12 The need for laser treatment of either proliferative retinopathy or macular edema was evaluated by ophthalmologists at the eye clinic of the Steno Diabetes Center, who were unaware of study-group assignments. Blindness was defined according to the criteria of the World Health Organization as a maximally corrected visual acuity of less than 6/60 in either eye (less than 20/200 on the Snellen visual-acuity scale).
Peripheral neuropathy was measured with a biothesiometer. The diagnosis of autonomic neuropathy was based on a measurement of the RR interval on an electrocardiogram obtained during paced breathing and on an orthostatic-hypotension test, with progression defined as reported previously.12
Statistical Analysis
The protocol for the follow-up trial specified that no analyses of death from any cause would be performed until at least 60 patients had died, as verified by online death registration, and until at least half the patients in either the intensive-therapy group or the conventional-therapy group had died. It was estimated that this plan for analyzing death from any cause would provide a statistical power of 0.75 and a type I error rate of 0.05 in detecting a reduction in the relative risk of death of 40% in the intensive-therapy group. Continuous reporting from the Danish Death Registry to the Steno Diabetes Center confirmed that this milestone was reached in June 2006.
All end points were analyzed according to the intention-to-treat principle. For the primary and secondary end points, event curves for the time to the first event were based on Kaplan–Meier analysis, and treatments were compared by means of the log-rank test. The hazard ratio for the comparison of intensive with conventional therapy and 95% confidence intervals were estimated with the use of a proportional-hazards model. We determined whether the hazard ratio at the end of the formal intervention subsequently changed. If so, the time since randomization was used as the time scale in an adjusted model.19 Data regarding tertiary end points were censored according to prespecified intervals and analyzed with the use of a proportional-hazards model, with adjustment for age, duration of diabetes, sex, and microvascular status at baseline; these results are expressed as relative risks. Changes in measured variables within groups were compared by means of analysis of covariance, with baseline values as covariates. The Mann–Whitney test was used for any instances of non-Gaussian distribution. A chi-square test was performed to compare categorical variables. All reported P values are two-sided.
Results
Patients
Behavioral, clinical, and biochemical characteristics of the patients 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 shown in Table 1. The two study groups were similar at baseline but differed significantly at the end of the intervention period, indicating that intensive therapy was superior to conventional therapy in controlling the level of glycated hemoglobin; fasting serum levels of total cholesterol, low-density lipoprotein cholesterol, and triglycerides; systolic and diastolic blood pressures; and rate of urinary albumin excretion (Table 1). At the end of the follow-up period, the differences in risk factors between the groups had narrowed, primarily because of intensified treatment among patients in the original conventional-therapy group (Figure 1A). In contrast, risk factors in the intensive-therapy group remained the same as they had been during the original trial, except for systolic blood pressure, which increased (P=0.001) (Figure 2A). Time curves for risk factors showed a similar pattern for the 93 patients who were followed during the entire 13.3-year period (data not shown). No significant differences were observed between the two groups with respect to habits related to exercise and smoking, and only minor (although significant) changes were seen in the intake of carbohydrates and fat. There were also no significant differences in body weight or waist circumference (Table 1).
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During the entire observation period, diabetic nephropathy developed in 20 patients in the intensive-therapy group, as compared with 37 patients in the conventional-therapy group (relative risk, 0.44; 95% CI, 0.25 to 0.77; P=0.004) (Figure 4). One patient in the intensive-therapy group had progression to end-stage renal disease requiring dialysis, as compared with six patients in the conventional-therapy group (P=0.04).
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Autonomic neuropathy progressed in 39 patients in the intensive-therapy group and in 52 patients in the conventional-therapy group (relative risk, 0.53; 95% CI, 0.34 to 0.81; P=0.004), and peripheral neuropathy progressed 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 episode of symptomatic hypoglycemia was reported in 80% of patients in the intensive-therapy group and in 70% of patients in the conventional-therapy group (P=0.15). There was no statistical difference in major hypoglycemia episodes (13% in the intensive-therapy group and 17% in the conventional-therapy group, P=0.52). A bleeding gastric ulcer developed in one patient in the intensive-therapy group. Two patients in the intensive-therapy group and one in the conventional-therapy group reported having muscle pain after statin treatment; however, no elevation of the serum creatine kinase level was seen. Five patients in the intensive-therapy group and four patients in the conventional-therapy group reported having a cough during treatment with angiotensin-converting–enzyme inhibitors. The cough disappeared in all patients after a change to an angiotensin II antagonist. The average number of physician-prescribed drugs for type 2 diabetes or its complications in the intensive-therapy group at the end of the follow-up period was 5.5, as compared with 5.7 in the conventional-therapy group (P=0.64).
Discussion
After a mean of 13.3 years (7.8 years of multifactorial intervention and an additional 5.5 years of follow-up), there was an absolute risk reduction for death from any cause of 20% among patients with type 2 diabetes and microalbuminuria who received intensive therapy, as compared with those who received conventional therapy. The absolute risk of death from cardiovascular causes was reduced by 13% among those receiving intensive therapy. During the entire follow-up period, the rate of death among patients in the conventional-therapy group was 50%, a finding that underscores the poor prognosis for such patients in the absence of intensive treatment.20
In comparison with the results of trials involving treatment of single risk factors in patients with type 2 diabetes, the achieved risk reductions in our trial were considerable. However, in secondary interventions, individual therapy with aspirin, antihypertensive agents, and lipid-lowering drugs each reduced the relative risk of cardiovascular events by about 25%, and the effects appeared to be additive.21,22 Therefore, the reductions in risk — a 59% reduction in the relative risk and a 29% reduction in the absolute risk — in the composite of cardiovascular events fit with projections from trials involving single risk factors.21
Our study was not designed to identify which elements of intensive diabetes therapy contributed most to the reduction in cardiovascular risk. However, using a risk calculator based on epidemiologic and interventional data from patients with type 2 diabetes in the United Kingdom Prospective Diabetes Study,23 we concluded that the use of statins and antihypertensive drugs might have had the largest effect in reducing cardiovascular risk during the 7.8 years of intervention, with hypoglycemic agents and aspirin the next most important interventions.24
Even though the significant differences in the levels of risk factors for cardiovascular disease between the study groups at the end of our interventional study had disappeared by the end of the follow-up period (Table 1 and Figure 2), the Kaplan–Meier curves for the time to the first cardiovascular event continued to diverge (Figure 3B). A similar outcome was reported in the Diabetes Control and Complications Trial (DCCT),25 involving patients with type 1 diabetes, in which the effects of intensive insulin therapy and conventional insulin therapy were compared during a 6.5-year period. After an average follow-up of 17 years, the original intensive-therapy treatment was associated with an absolute risk reduction of 2.8% for a composite cardiovascular end point. In the DCCT follow-up trial, glucose regulation deteriorated in the original intensive-therapy group and improved in the control group, resulting in a convergence of the glycemic levels in the two groups.
In our follow-up trial, the risk factors in the two study groups tended to converge (Figure 2). Only the control of systolic blood 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-therapy group, leaving the two study groups with similar levels of risk factors after 13.3 years. The design of our study did not allow us to estimate the exact time at which risk factors improved in the conventional-therapy group. However, since all patients were offered intensive treatment at the end of the trial, the improvement probably took place early during the follow-up period. The effect of blood-pressure reduction on cardiovascular end points usually occurs within months,26,27 whereas the effect of lipid lowering is evident after 1 to 2 years.8,28,29 The effect of glucose lowering on diabetes-related end points occurs even later.4 Thus, an effect of early intervention, as compared with late intervention, may be a likely explanation for the continuing divergence in cardiovascular end points, rather than a 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-therapy group took metformin or sulfonylurea, despite the similar levels of glycemia in the two groups. Therefore, differences in drugs or their combinations might have contributed to the long-term outcome.
Reductions in the progression of microvascular complications occurred after a mean of 3.8 years of intensified intervention,12 changes that were maintained at 13.3 years. Indeed, during continuous follow-up, this reduction translated into a significant absolute risk reduction of 6.3% in the need for dialysis, a condition that in many parts of the world is tantamount to death.30
We did not monitor adverse effects continuously. However, few serious adverse effects were reported during regular interviews with patients.10,12 In this respect, it is noteworthy that except for atorvastatin, generic drugs with well-known long-term side effects were prescribed. Whether newer and more expensive diabetes treatments would have additional beneficial long-term effects or risks remains to be determined.
Recent surveys have shown very slow progress in achieving treatment goals and in the use of recommended drugs for the prevention of diabetic vascular complications.31,32 Therefore, since intensive, multifactorial care of patients with type 2 diabetes leads to reduced rates of death and cardiovascular disorders, the early and meticulous implementation of current treatment guidelines remains a major challenge.
Supported by the Danish Health Research Council.
Dr. Parving reports receiving consulting and lecture fees from Merck, Novartis, Bristol-Myers Squibb, Pfizer, and Sanofi and grants from Merck, Novartis, and Bristol-Myers Squibb and having an equity interest in Novo Nordisk and Merck; and Dr. Pedersen, having an equity interest in Novo Nordisk. No other potential conflict of interest relevant to this article was reported.
We thank the patients who participated in the study and their families; Pernille Vedel, a coinvestigator in the early phase of 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 and A. Vølund for their statistical support; M. Frandsen, B.V. Hansen, B.R. Jensen, T.R. Juhl, L. Pietrascek, and U. Schmidt for their bioanalytical assistance; and J. Faber and P. Hildebrandt for their thorough examinations while serving on the end-point committee.
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.
References
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Related Letters:
Multifactorial Intervention and Mortality in Type 2 Diabetes
Schroeder S. A., Tayek J. A., Gæde P., Parving H.-H., Pedersen O.
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N Engl J Med 2008;
358:2292-2293, May 22, 2008.
Correspondence
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