Introduction
Type 2 diabetes mellitus is a complex disorder often featuring adiposity, hypertension, dyslipidaemia and increased blood platelet aggregation in addition to hyperglycaemia, giving rise to an increased risk of macro- and microvascular damage and reduced life expectancy. Over the past two decades, a number of single-risk-factor intervention and post-trial studies have provided evidence for recommending multifactorial treatment of this common disorder (as reviewed in [
1]). Still, patients with type 2 diabetes mellitus have increased risk for early mortality [
2] and may suffer from multiple organ damage with recurrent event rates of up to 15% per year during follow-up of various trials [
3‐
8] even though recent surveys suggest favourable changes in diabetes-related complications including death [
9,
10].
Therefore, this follow-up, a randomised trial of intensified vs standard multifactorial intervention for 7.8 years in patients with type 2 diabetes mellitus and microalbuminuria, was designed to address the median differences in lifespan with and without incident cardiovascular events between the originally intensified vs conventionally treated patients. We use the term ‘years of life gained’ to emphasise the decreased life expectancy in patients with type 2 diabetes mellitus and microalbuminuria.
In the present follow-up study the patients were observed for a median of 13.2 years after the formal interventional part of the study ended.
Methods
Statistical analyses
All statistical analyses were conducted using the intention-to-treat principle. Adherence to the treatment was assessed at study visits in both groups based on interviews with patients.
Overall cumulative survival, as well as CVD-free survival, by time since randomisation was calculated for the two treatment groups by the Kaplan–Meier estimator. Median survival time from randomisation was compared between the treatment groups. CIs for the medians were calculated using bootstrapping. We specifically chose difference in median survival time between groups to make a clear statement in easily understandable terms in addition to the more extensively used, but more difficult to interpret, HR and RR reduction.
Proportional hazards Poisson models were fitted for mortality (both from cardiovascular causes and from other causes) and cardiovascular events, taking treatment group, age, sex and current CVD status into account, using smooth underlying hazards (time since baseline). Current CVD status was included in models for all-cause mortality as 0, 1, 2 or 3 or more cardiovascular events after randomisation. Thus, we modelled both death and (extra) CVD events as outcome, and the models were used to compute the average years of life lived and the years of life free of CVD during the study period and thereby the average number of years gained by intensive treatment. Models were checked for proportional hazards between randomisation groups by likelihood-ratio tests. Diabetes duration at baseline, as well as the interaction with treatment allocation, was included in a model to assess the effect of diabetes duration on mortality.
Except for end-stage renal disease (where exact date of transplantation or first dialysis treatment was known), the status of microvascular complications was only assessed at study visits, and the exact event date is therefore unknown. For analysis purposes a random date between the last day without and first day with the specified complication was imputed as the event date. When the progression between states jumped more than one category (e.g. from EURODIAB-score 2 to 5 between two observation points), random dates between the two observations for the steps were generated and used in analyses of transition rates. Sensitivity analyses were performed by repeating the random allocation of dates.
Transition rates between states and group comparison were analysed as for cardiovascular events. For each of the four types of outcome (retinopathy, autonomic neuropathy, peripheral neuropathy and albuminuria) we estimated the rates of transition between states of increasing severity and used these to construct plots showing the fraction of patients in each state at different times after randomisation.
A fuller account of statistical approaches and detailing of analyses can be found in
ESM Sections 4–7. For the anthropometric, biochemical and physiological variables, the
t test, Mann–Whitney
U test and χ
2 statistics were applied for the comparison of means, medians and proportions, respectively. In the results section all estimates are followed by 95% CIs in parentheses. Analyses were conducted using R, version 3.3.0, using the Epi package version 2.5 or Stata/IC version 14.1 for Windows (StataCorp LP, College Station, TX, USA).
Discussion
In the current report from the Steno-2 study we demonstrate that intensified treatment for 7.8 years was associated with a 7.9 years longer median lifespan over a period of 21.2 years follow-up. Furthermore, the increased lifespan was matched by the years gained free from incident CVD. The reduced mortality was caused by a decreased risk of incident CVD and cardiovascular mortality.
Absolute risk and RR reductions for all endpoints were well in line with earlier reported findings, confirming the durability of the intensified, multifactorial approach [
13].
The frequency of recurrent events was high in both groups, but patients in the original conventional-therapy group experienced more than twice as many cardiovascular events per person than patients from the original intensive-therapy group. Only a few studies have reported results on recurrent events; none of these have been exclusively in patients with type 2 diabetes [
2,
3] and the follow-up periods were much shorter, hence direct comparison is difficult.
In the Steno-2 study, we observed high rates of progression for microvascular complications with the vast majority of patients progressing in one or more complication types. Yet, we found significant and clinically relevant risk reductions for autonomic neuropathy, nephropathy, and retinopathy, as well as blindness, and a trend towards reduced risk for end-stage renal disease. Retinopathy grading was not corrected for cataract development and surgery, which made the longitudinal comparison less exact. For the rarer and later-onset complications (i.e. end-stage renal disease and blindness) competing risk from death might be a serious issue, underestimating the true effect of the intervention.
The risk reductions reported are high compared with those reported in single-risk-factor intervention trials [
18‐
21]. Concomitant treatment of multiple risk factors seems to be of profound importance. A recent report from VADT (Veterans Affairs Diabetes Trial) demonstrated larger risk reductions in patients with diabetes mellitus achieving both HbA
1c and LDL-cholesterol goals compared with patients achieving only one of these goals [
22]. Similar findings have been reported from the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation) trial examining a combined approach of intensified blood pressure lowering and intensive glucose control [
23] as well as from registry-based studies [
2,
10]. In addition, analysis of the relation between number of risk factors simultaneously in control and cardiovascular outcomes in the BARI-2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) trial found a clear beneficial effect of having more risk factors in control [
24], further supporting the concept of multifactorial treatment.
Long-term beneficial effects of glucose-lowering treatment in reducing microvascular complications have been demonstrated beyond the duration of a clinical trial in both type 1 and type 2 diabetes [
20,
25,
26]. Lipid-lowering treatment has proven long-term beneficial effects with regards to CVD reduction [
6]. However, the beneficial effects on cardiovascular outcomes of blood pressure- and glucose-lowering treatments seem to attenuate when treatment is relaxed post intervention [
19,
21,
27]. Long-term beneficial effects in these trials have been termed ‘metabolic memory’ or ‘legacy effect’. In these trials, intensified intervention according to protocol was stopped at the end of the trial and the subsequent risk factor control was relaxed or not reported. In contrast, patients in the Steno-2 study’s intensive-therapy group continued treatment according to the original treatment goals while patients in the original conventional-therapy group started intensified treatment with identical targets during the follow-up period. Thus, from year 8 onwards all patients in both treatment arms in the Steno-2 study received identical treatment with similar post-trial risk factor levels in the two groups. We interpret the continuing beneficial effects seen in the trial as a direct consequence of early intervention intensification in patients at lower absolute risk for late diabetic complications compared with a situation wherein increased vascular damage is already present with intensification in later stages of the disease. This concept of early intervention in patients at lower risk has just proven beneficial for combined treatment of lipid and blood pressure lowering in patients at intermediate risk of, but without, CVD [
28].
The Steno-2 study is robust in the sense that data on endpoints are considered complete due to the quality of relevant databases combined with low dropout rate and endpoint adjudication by an external expert committee blinded for treatment allocation. Additionally, the study design resembles a real-life situation, where researchers did not have direct influence on medicine compliance or lifestyle.
In conclusion, we found that intensified, multifactorial treatment of type 2 diabetes with microalbuminuria for 7.8 years compared with conventional treatment increases median life length by 7.9 years over 21.2 years of follow-up, and that these gained years were matched by years free from cardiovascular complications.
We must emphasise the significance of early, intensified risk factor control in patients with complicated type 2 diabetes. This approach is already broadly implemented according to clinical guidelines and the present findings should lead to even more focus on the potential preventive effects.
Acknowledgements
We thank the patients who participated in the study and their families. I. Holstein, G. Lademann, B. B. Nielsen, M. Valerius and B. R. Jensen are thanked for their technical and managerial assistance (all Steno Diabetes Center, Gentofte, Denmark or Novo Nordisk Foundation Centre for Basic Metabolic Research, Copenhagen, Denmark). We thank J. Faber (Herlev Hospital, Denmark) and P. Hildebrandt (Frederiksberg Heart Clinic, Denmark) for their thorough examinations while serving on the endpoint committee and E. A. M. Gale (University of Bristol, UK) for critically reviewing the manuscript prior to submission.
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