Reduced risk of heart failure with intensified multifactorial intervention in individuals with type 2 diabetes and microalbuminuria: 21 years of follow-up in the randomised Steno-2 study

Abstract

Aims/hypothesis: In type 2 diabetes mellitus, heart failure is a frequent, potentially fatal and often forgotten complication. Glucose-lowering agents and adjuvant therapies modify the risk of heart failure. We recently reported that 7.8 years of intensified compared with conventional multifactorial intervention in individuals with type 2 diabetes and microalbuminuria in the Steno-2 study reduced the risk of cardiovascular disease and prolonged life over 21.2 years of follow-up. In this post hoc analysis, we examine the impact of intensified multifactorial intervention on the risk of hospitalisation for heart failure.

Methods: One hundred and sixty individuals were randomised to conventional or intensified multifactorial intervention, using sealed envelopes. The trial was conducted using the Prospective, Randomised, Open, Blinded Endpoints (PROBE) design. After 7.8 years, all individuals were offered intensified therapy and the study continued as an observational follow-up study for an additional 13.4 years. Heart-failure hospitalisations were adjudicated from patient records by an external expert committee blinded for treatment allocation. Event rates were compared using a Cox regression model adjusted for age and sex.

Results: Eighty patients were assigned to each treatment group. Ten patients undergoing intensive therapy vs 24 undergoing conventional therapy were hospitalised for heart failure during follow-up. The HR (95% CI) was 0.30 (0.14, 0.64), p = 0.002 in the intensive-therapy group compared with the conventional-therapy group. Including death in the endpoint did not lead to an alternate overall outcome; HR 0.51 (0.34, 0.76), p = 0.001. In a pooled cohort analysis, an increase in plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) during the first two years of the trial was associated with incident heart failure.

Conclusions/interpretation: Intensified, multifactorial intervention for 7.8 years in type 2 diabetic individuals with microalbuminuria reduced the risk of hospitalisation for heart failure by 70% during a total of 21.2 years of observation.

Trial registration: ClinicalTrials.gov NCT00320008.

Keywords: Complications; Heart failure; Microalbuminuria; Multifactorial intervention; NT-proBNP; Type 2 diabetes.

Conflict of interest statement

Since completion of the Steno-2 21.2 years follow-up data acquisition, data management and interpretation, JO has been employed by Novo Nordisk Scandinavia A/B, Region Denmark. PR reports having given lectures for Astra Zeneca, Bayer and Boehringer Ingelheim, has served as a consultant for AbbVie, Astra Zeneca, Bayer, Eli Lilly, Boehringer Ingelheim, Astellas, Janssen and Novo Nordisk (all fees given to the Steno Diabetes Center) and has equity interest in Novo Nordisk. HHP has equity interest in Merck and receives 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 centre at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation. PG, RR and LK declare that there is no duality of interest associated with this manuscript.

Figures

Fig. 1

CONSORT diagram showing patient flow throughout the trial. The first 7.8 years were the active intervention period, after which time the randomisation was neutralised and continued as a post-trial observational follow-up study with all remaining patients being offered the same treatment as in the original intensive-therapy group

Fig. 2

CIF plot of hospitalisation for heart failure. Dashed line, conventional therapy; solid line, intensive therapy. The unadjusted relative hazard reduction was 69% in the intensive-therapy group. Logrank p = 0.001

Fig. 3

CIF plots of the secondary outcomes. Dashed line, conventional therapy; solid line, intensive therapy. (a) Heart failure or cardiovascular death. The unadjusted relative hazard reduction was 61% in the intensive-therapy group. Logrank p < 0.001. (b) Heart failure or death from all causes. The unadjusted relative hazard reduction was 48% in the intensive-therapy group. Logrank p = 0.001

Fig. 4

Transition frequencies from entry to MI, HF and/or death. (a) Intensive-therapy group and (b) conventional-therapy group: arrows terminate at the event and originate from the original state of the patients. The black number at the arrow end is the number with the given event coming from the state at arrow origin. The coloured number in the bottom right corner is the number of patients not progressing from the given state. Example: ten intensive-therapy patients developed HF (pale orange box, Fig. 4a). Eight had no previous MI; two developed HF after previous MI. One developed MI after HF, six died after HF and three ended the observation alive with HF. Twenty-seven patients died without prior MI or HF. In the primary analysis of data from the 21.2 years of follow-up, 26 patients in the intensive-therapy and 29 in the conventional-therapy group were classified as having died from non-CV causes and 12 vs 26 patients died from CV causes, respectively. Thirty-seven patients in the intensive-therapy group and 20 patients in the conventional-therapy group ended follow-up alive and with no incident HF or MI during follow-up. (c) Intensive-therapy group and (d) conventional-therapy group: survival frequencies without MI/HF. Both MI and HF were more frequent in the conventional-therapy group (b) and the difference in HF was not driven primarily by increased MI risk. DM2, type 2 diabetes mellitus; HF, heart failure