Years of life gained by multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: 21 years follow-up on the Steno-2 randomised trial

Abstract

Aims/hypothesis: The aim of this work was to study the potential long-term impact of a 7.8 years intensified, multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria in terms of gained years of life and years free from incident cardiovascular disease.

Methods: The original intervention (mean treatment duration 7.8 years) involved 160 patients with type 2 diabetes and microalbuminuria who were randomly assigned (using sealed envelopes) to receive either conventional therapy or intensified, multifactorial treatment including both behavioural and pharmacological approaches. After 7.8 years the study continued as an observational follow-up with all patients receiving treatment as for the original intensive-therapy group. The primary endpoint of this follow-up 21.2 years after intervention start was difference in median survival time between the original treatment groups with and without incident cardiovascular disease. Non-fatal endpoints and causes of death were adjudicated by an external endpoint committee blinded for treatment allocation.

Results: Thirty-eight intensive-therapy patients vs 55 conventional-therapy patients died during follow-up (HR 0.55 [95% CI 0.36, 0.83], p = 0.005). The patients in the intensive-therapy group survived for a median of 7.9 years longer than the conventional-therapy group patients. Median time before first cardiovascular event after randomisation was 8.1 years longer in the intensive-therapy group (p = 0.001). The hazard for all microvascular complications was decreased in the intensive-therapy group in the range 0.52 to 0.67, except for peripheral neuropathy (HR 1.12).

Conclusions/interpretation: At 21.2 years of follow-up of 7.8 years of intensified, multifactorial, target-driven treatment of type 2 diabetes with microalbuminuria, we demonstrate a median of 7.9 years of gain of life. The increase in lifespan is matched by time free from incident cardiovascular disease.

Trial registration: ClinicalTrials.gov registration no. NCT00320008.

Funding: The study was funded by an unrestricted grant from Novo Nordisk A/S.

Keywords: Albuminuria; Cardiovascular disease; Diabetes complications; Diabetes mellitus, type 2; Diabetic nephropathy; Diabetic neuropathy; Diabetic retinopathy; Follow-up studies; Humans.

Conflict of interest statement

Funding

The study was funded by an unrestricted grant from Novo Nordisk A/S. Novo Nordisk A/S were not in any way involved in study design or in data collection, analysis or interpretation, but have had the opportunity to read and comment on the manuscript before submission.

Duality of interest

BC is employed at Steno Diabetes Center, which is owned by Novo Nordisk A/S, and has equity share in Novo Nordisk A/S. PR has equity interest in Novo Nordisk A/S, research contracts with AbbVie, Novo Nordisk and Novartis and has received consulting honoraria from AstraZeneca, BMS, Boehringer Ingellheim, Eli Lilly, Novo Nordisk, Astellas and AbbVie) (all to institution). HLA is a consultant at Steno Diabetes Center. HHP has equity interest in Merck and has received consulting honoraria from AbbVie and Novartis. OP has equity interest in Novo Nordisk A/S. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (www.metabol.ku.dk). All other authors declare that there is no duality of interest associated with their contribution to this manuscript.

Contribution statement

OP conceived and designed the original Steno-2 study, devised and supervised the 21.2 years follow-up, acquired all funding throughout the study and provided key content to the manuscript. HHP contributed to the conception and supervision of the original Steno-2 study and provided key content to the manuscript. PG acquired all data up to the 13.3 years examination, handled patient care during the intervention period, planned the 21.2 years follow-up and supervised data acquisition and processing in the present follow-up. JO coordinated and performed the 21.2 years follow-up, acquired all data for the 21.2 years follow-up, supervised laboratory work and patient evaluations, processed data and performed statistical work. BC planned, conducted and supervised statistical work, provided additional analyses and figures, contributed to data interpretation and compiled the ESM. PR supervised and facilitated all work performed at Steno Diabetes Center (i.e. the patient assessments for the long-term follow-up), was responsible for quality assurance/quality control of the performed measures, provided key intellectual content to the discussion section and critically reviewed the manuscript. HLA provided and interpreted data regarding retinopathy, provided key intellectual content and critically reviewed the manuscript. The manuscript was drafted by PG and JO with contributions from all other authors. All authors gave final approval for the paper to be published. OP, HHP and PG are guarantors of this work.

Figures

Fig. 1

Consort diagram of patient flow throughout the entire observation period. Procedures for enrolment and randomisation are described in [11]. Numbers lost to follow-up are cumulative

Fig. 2

Cumulative mortality (a) and cumulative incidence of the composite cardiovascular or death endpoint (b). Solid lines, patients in the intensive-therapy group; dashed lines, patients in the conventional-therapy group; vertical dotted lines, end of trial and start of intensification of conventional-therapy group patients’ treatment; horizontal dashed lines intersect with survival curves at median survival time (a) and median CVD-free survival time (b). The median survival time in the original intensive-therapy group was at least 7.9 years longer than in the conventional-therapy group (48% of patients in the intensive-therapy group died during follow-up, so formally this might be an underestimate, since 50% mortality is required to calculate the median). The median difference in survival before first CVD event was 8.1 years in favour of the original intensive-therapy group

Fig. 3

Forest plot of the HR (95% CI) for secondary and tertiary endpoints. Intensive vs conventional treatment. We found significant risk reductions for all-cause mortality, CVD mortality, CVD events and progression of retinopathy, autonomic neuropathy and macroalbuminuria. No difference was observed for non-CVD mortality, death after specific number of CVD events (Death | CVD state—i.e. no difference in mortality after first, second or third CVD event was observed between groups) and progression of peripheral neuropathy

Fig. 4

Distribution of type of first event by treatment allocation. White bars, intensive-therapy patients; black bars, conventional-therapy patients. *p < 0.05 and **p < 0.01 for difference between groups; revasc., revascularisation

Fig. 5

Progression of microvascular complications. The black line is the smoothed survival estimate. Green areas under the curves depict the probability of being alive without (progression in) the specified microvascular complication and the different shades of orange represent progression to the specified progression state after the given follow-up duration. The lightly coloured areas above the black curve depict the fraction of patients who died after progression corresponding to the specified disease states Both the ‘survival without progression’ area (dark green) and the total ‘survival’ area (area under the black curve) are significantly larger in the intensive-therapy group for autonomic neuropathy, retinopathy and nephropathy (albuminuria) (i.e. the risk of disease progression is decreased for these outcomes in the intensive-therapy group). No significant difference in the progression of peripheral neuropathy between groups was observed. An example of interpretation: for autonomic neuropathy, it is shown that the fraction of patients that died with no progression is similar in the two groups (light green), but the fraction of patients who died after progression (light orange) was significantly larger in the conventional-therapy group