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Long-term effects of intensive multifactorial therapy in individuals with screen-detected type 2 diabetes in primary care: 10-year follow-up of the ADDITION-Europe cluster-randomised trial

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journal contribution
posted on 14.10.2019, 08:44 by Simon j Griffin, Guy E H M Rutten, Kamlesh Khunti, David R Witte, Torsten Lauritzen, Stephen J Sharp, Else-Marie Dalsgaard, Melanie J Davies, Greg J Irving, Rimke C Vos, David R Webb, Nicholas J Wareham, Annelli Sandbaek
Background
The multicentre, international ADDITION-Europe study investigated the effect of promoting intensive treatment of multiple risk factors among people with screen-detected type 2 diabetes over 5 years. Here we report the results of a post-hoc 10-year follow-up analysis of ADDITION-Europe to establish whether differences in treatment and cardiovascular risk factors have been maintained and to assess effects on cardiovascular outcomes.

Methods
As previously described, general practices from four centres (Denmark, Cambridge [UK], Leicester [UK], and the Netherlands) were randomly assigned by computer-generated list to provide screening followed by routine care of diabetes, or screening followed by intensive multifactorial treatment. Population-based stepwise screening programmes among people aged 40–69 years (50–69 years in the Netherlands), between April, 2001, and December, 2006, identified patients with type 2 diabetes. Allocation was concealed from patients. Following the 5-year follow-up, no attempts were made to maintain differences in treatment between study groups. In this report, we did a post-hoc analysis of cardiovascular and renal outcomes over 10 years following randomisation, including a 5 years post-intervention follow-up. As in the original trial, the primary endpoint was a composite of first cardiovascular event, including cardiovascular mortality, cardiovascular morbidity (non-fatal myocardial infarction and non-fatal stroke), revascularisation, and non-traumatic amputation, up to Dec 31, 2014. Analyses were based on the intention-to-treat principle. ADDITION-Europe is registered with ClinicalTrials.gov , NCT00237549 .

Findings
343 general practices were randomly assigned to routine diabetes care (n=176) or intensive multifactorial treatment (n=167). 317 of these general practices (157 in the routine care group, 161 in the intensive treatment group) included eligible patients between April, 2001, and December, 2006. Of the 3233 individuals with screen-detected diabetes, 3057 agreed to participate (1379 in the routine care group, 1678 in the intensive treatment group), but at the 10-year follow-up 14 were lost to follow-up and 12 withdrew, leaving 3031 to enter 10-year follow-up analysis. Mean duration of follow-up was 9·61 years (SD 2·99). Sustained reductions over 10 years following diagnosis were apparent for bodyweight, HbA 1c , blood pressure, and cholesterol in both study groups, but between-group differences identified at 1 and 5 years were attenuated at the 10-year follow-up. By 10 years, 443 participants had a first cardiovascular event and 465 died. There was no significant difference between groups in the incidence of the primary composite outcome (16·1 per 1000 person-years in the routine care group vs 14·3 per 1000 person-years in the intensive treatment group; hazard ratio [HR] 0·87, 95% CI 0·73–1·04; p=0·14) or all-cause mortality (15·6 vs 14·3 per 1000 person-years; HR 0·90, 0·76–1·07).

Interpretation
Sustained reductions in glycaemia and related cardiovascular risk factors over 10 years among people with screen-detected diabetes managed in primary care are achievable. The differences in prescribed treatment and cardiovascular risk factors in the 5 years following diagnosis were not maintained at 10 years, and the difference in cardiovascular events and mortality remained non-significant.

Funding

National Health Service Denmark, Danish Council for Strategic Research, Danish Research Foundation for General Practice, Novo Nordisk, Novo Nordisk Foundation, Danish Centre for Evaluation and Health Technology Assessment, Danish National Board of Health, Danish Medical Research Council, Aarhus University Research Foundation, Astra, Pfizer, GlaxoSmithKline, Servier, HemoCue, Wellcome Trust, UK Medical Research Council, UK National Institute for Health Research, UK National Health Service, Merck, Julius Center for Health Sciences and Primary Care, UK Department of Health, and Nuts-OHRA.

ADDITION-Denmark was supported by the National Health Service 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 Danish National Board of Health, the Danish Medical Research Council, and the Aarhus University Research Foundation. The trial has been given unrestricted grants from Novo Nordisk, Novo Nordisk Scandinavia, Novo Nordisk UK, Denmark, Pfizer Denmark, GlaxoSmithKline Denmark, Servier Denmark, and HemoCue Denmark. Parts of the grants from Novo Nordisk Foundation, Danish Council for Strategic Research, and Novo Nordisk were transferred to the other centres.

ADDITION-Leicester was supported by the UK Department of Health, the NIHR Health Technology Assessment Programme (grant 08/116/300), and NHS R&D support funding (including the Primary Care Research Network and Diabetes Research Network, and the NIHR Collaborations for Leadership in Applied Health Research and Care East Midlands Research Centre and NIHR Biomedical Research Centre).

ADDITION-Netherlands was supported by unrestricted grants from Novo Nordisk, Glaxo Smith Kline and Merck; and by the Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht.

History

Citation

Lancet Diabetes & Endocrinology, The, 2019-12-01, Volume 7, Issue 12, Pages 925-937

Alternative title

10-year follow-up of intensive multifactorial therapy in individuals with screen-detected type 2 diabetes in primary care: the ADDITION-Europe randomised trial (clinical trial registration number NCT00237549)

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Diabetes Research Centre

Version

AM (Accepted Manuscript)

Published in

Lancet Diabetes and Endocrinology

Volume

7

Issue

12

Pagination

925-937

Publisher

Elsevier

issn

2213-8587

Acceptance date

26/09/2019

Copyright date

2019

Available date

01/06/2020

Language

en

Publisher version

https://www.clinicalkey.com/#!/content/playContent/1-s2.0-S2213858719303493?scrollTo=#hl0000984