Does training of general practitioners for intensive treatment of people with screen-detected diabetes have a spillover effect on mortality and cardiovascular morbidity in 'at risk' individuals with normoglycaemia? Results from the ADDITION-Denmark cluster-randomised controlled trial

Abstract

Aims/hypothesis: Within a trial of intensive treatment of people with screen-detected diabetes, we aimed to assess a potential spillover effect of the trial intervention on incident cardiovascular disease (CVD) and all-cause mortality among people who screened positive on a diabetes risk questionnaire but who were normoglycaemic.

Methods: In the Anglo-Danish-Dutch Study of Intensive Treatment In People with Screen-Detected Diabetes in Primary Care (ADDITION)-Denmark trial, 175 general practices were cluster-randomised into: (1) screening plus routine care of individuals with screen-detected diabetes (control group); or (2) screening plus training and support in intensive multifactorial treatment of individuals with screen-detected diabetes (intervention group). We identified all individuals who screened positive on a diabetes risk questionnaire in ADDITION-Denmark but were normoglycaemic following biochemical testing for use in this secondary analysis. After a median 8.9 years follow-up, we used data from national registers to compare rates of first CVD events and all-cause mortality in individuals in the routine care group with those in the intensive treatment group.

Results: In total, 21,513 individuals screened positive for high risk of diabetes but were normoglycaemic on biochemical testing in ADDITION-Denmark practices between 2001 and 2006 (10,289 in the routine care group and 11,224 in the intensive treatment group). During 9 years of follow-up, there were 3784 first CVD events and 1748 deaths. The incidence of CVD was lower among the intensive treatment group compared with the routine care group (HR 0.92 [95% CI 0.85, 0.99]). This association was stronger among individuals at highest CVD risk (heart SCORE ≥ 10; HR 0.85 [95% CI 0.75, 0.96]). There was no difference in mortality between the two treatment groups (HR 1.02 [95% CI 0.92, 1.14]).

Conclusions/interpretation: Training of general practitioners to provide target-driven intensive management of blood glucose levels and other cardiovascular risk factors showed some evidence of a spillover effect on the risk of CVD over a 9 year period among individuals at high risk of diabetes. The effect was particularly pronounced among those at highest risk of CVD. There was no effect on mortality.

Trial registration: ClinicalTrials.gov NCT00237549.

Keywords: Cardiovascular disease; Diabetes; High risk; Intensive treatment; Normoglycaemic; Routine care; Screening; Spillover; Trial.

Conflict of interest statement

Data availability

The data used in this paper was a combination of data obtained from the ADDITION study and data from national Danish Registers at Denmark Statistics (DST). The ADDITION study data were obtained after a written application to the data owner, A. Sandbæk (Institute of Public Health, Aarhus University, Aarhus, Denmark; annelli.sandbaek@ph.au.dk). Data from DST were made available following an application to DST (www.dst.dk/en/TilSalg/Forskningsservice). Data from ADDITION and DST were merged by DST and analyses were performed via a secure Virtual Private Network (VPN) connection. In accordance with the Danish Act of processing of personal data, future interested researchers must perform the steps mentioned above to obtain access to the data.

Funding

ADDITION-Denmark was supported by the national health services in the counties of Copenhagen, Aarhus, Ringkøbing, Ribe and South Jutland in Denmark, the Danish Council for Strategic Research, the Danish Research Foundation for General Practice, Novo Nordisk Foundation, the Danish Centre for Evaluation and Health Technology Assessment, the diabetes fund of the National Board of Health, the Danish Medical Research Council and the Aarhus University Research Foundation. The trial has been supported by unrestricted grants from Novo Nordisk A/S, Novo Nordisk Scandinavia AB, Novo Nordisk UK, ASTRA Denmark, Pfizer Denmark, GlaxoSmithKline Pharma Denmark, Servier Denmark AS and HemoCue Denmark AS. The study sponsor was not involved in the design of the study; the collection, analysis and interpretation of data; writing the report; or the decision to submit the report for publication.

Duality of interest

DRW and RKS are supported by the Danish Diabetes Academy, which is funded by the Novo Nordisk Foundation. RKS is further supported by the Aarhus Institute of Advanced Studies. DRW reports receiving lecture fees from Novo Nordisk A/S and Steno Diabetes Center. DRW, MEJ and TL hold shares in Novo Nordisk A/S. TL reports receiving a travel reimbursement for attending meetings on early detection and treatment of diabetes in 2015 and 2016. These meetings were held by the International Diabetes Federation (IDF) and Primary Care Diabetes Europe, and were sponsored by Astra Zeneca. AS reports receiving lecture fees for providing continuing medical education to general practitioners. MEJ is the principal investigator of an investigator initiated trial sponsored by Astra Zeneca and reports receiving lecture fees from Astra Zeneca. All other authors declare that there is no duality of interest associated with their contribution to this manuscript.

Contribution statement

NHB and TL had full access to all of the data in the study and take responsibility for the accuracy of the data analysis. TL acts as guarantor for this paper. AS, TL and KB-J designed the ADDITION-Denmark study and are principal investigators for the trial. DRW, MEJ, AS and TL developed the study proposal. NHB, DRW and TL participated in the acquisition of the data from Statistics Denmark. NHB analysed the data. RKS drafted the report. DRW, RKS, KB-J, MEJ, AS and TL participated in the interpretation of the data and critical revision of the report for important intellectual content. All co-authors gave final permission for this version of the manuscript to be published.

Figures

Fig. 1

Cumulative incidence of (a) CVD and (b) all-cause mortality among individuals with normal glucose tolerance in the ADDITION-Denmark intensive treatment and routine care groups (2001–2011). This figure is unadjusted. Routine care group, blue; intensive treatment group, red. Heart SCORE ≥ 0 to <5, dashed line; heart SCORE ≥ 5 to <10, dot/dash line; heart SCORE ≥10, solid line