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
Griffin, Simon J.; Rutten, Guy E.H.M.; Khunti, Kamlesh; Witte, Daniel R.; Lauritzen, Torsten; Sharp, Stephen J.; Dalsgaard, Else Marie; Davies, Melanie J.; Irving, Greg J.; Vos, Rimke C.; Webb, David R.; Wareham, Nicholas J.; Sandbæk, Annelli
(2019) The Lancet Diabetes and Endocrinology, volume 7, issue 12, pp. 925 - 937
(Article)
Abstract
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
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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, HbA1c, 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.
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Keywords: Endocrinology, Internal Medicine, Endocrinology, Diabetes and Metabolism, Journal Article
ISSN: 2213-8587
Publisher: Elsevier BV
Note: Funding Information: We gratefully acknowledge the contributions of all participants, practice nurses, and general practitioners involved in the ADDITION-Europe study. We are grateful to the independent endpoint committee in Denmark (Kristian Thygesen, Hans Ibsen, Ole Færgeman, and Birger Thorsteinsson), the UK (Jane Armitage and Louise Bowman), and the Netherlands (Cees Tack and Jaap Kappelle), and the independent data monitoring and safety committee (Christian Gluud, Per Winkel, and Jørn Wetterslev). We thank Knut Borch-Johnsen, Ronald P Stolk, and Bruce H R Wolffenbuttel for their participation on the committee that oversaw the design of the study; Knut Borch-Johnsen was a also principal investigator in the original trial. We also thank Rebecca Simmons and Maureen van den Donk for their contribution to data acquisition and Daniel Barnes for contribution to data cleaning. SJG, NJW, MJD, and KK are UK National Institute for Health Research (NIHR) Senior Investigators. The University of Cambridge has received salary support for SJG from the UK National Health Service (NHS) in the East of England through the Clinical Academic Reserve. MJD and KK receive support from the UK Department of Health NIHR Programme Grant funding scheme (grant RP-PG-0606–1272). The views expressed in this publication are those of the authors and not necessarily those of the UK Department of Health. ADDITION-Cambridge was supported by the Wellcome Trust (grant G061895), the UK Medical Research Council (MRC; grant G0001164 and Epidemiology Unit Programme MC_UU_12015/4 and MC_UU_12015/1), the UK NIHR Technology Assessment Programme (grant 08/116/300), the NIHR Programme Grants for Applied Research (grant RP-PG-0606–1259), and NHS R&D support funding (including the Primary Care Research Network and Diabetes Research Network). Bio-Rad provided equipment for HbA1c testing during the screening phase. We are grateful to the ADDITION-Cambridge independent trial steering committee: Nigel Stott, John Weinman, Richard Himsworth, and Paul Little. We thank the Cambridge University Hospitals NHS Foundation Trust Department of Clinical Biochemistry and the NIHR Cambridge Biomedical Research Centre Core Biochemical Assay Laboratory for doing the biochemical assays, and the following groups within the MRC Epidemiology Unit: Data Management (Clare Boothby and Adam Dickinson), Information Technology (Iain Morrison and Rich Hutchinson), Technical (Matt Sims), and Field Epidemiology (James Sylvester, Gwen Brierley, Richard Salisbury, and Kit Coutts). 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, ASTRA 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. We thank the Biochemistry department at Steno Diabetes Centre for doing the biochemical assays and the following hospital departments for doing the clinical measurements: Steno Diabetes Centre Research Laboratory, Esbjerg Hospital Diabetes Clinic, Holstebro Hospital Research Department, Aabenraa Hospital Outpatient Clinic, and Aarhus University Hospital Eye Department. 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). We thank the University Hospitals of Leicester NHS Trust Department of Clinical Biochemistry for doing the biochemical assays. ADDITION-Netherlands was supported by unrestricted grants from Novo Nordisk, GlaxoSmithKline, and Merck, and by the Julius Center for Health Sciences and Primary Care. We thank the directors of the Etten-Leur SHL Centre for Diagnostic Support in Primary Care (Wim Rutten and Paulien van Hessen) for their collaboration. Mardy Eckhardt, Erna Erdtsieck, Leandra Boonman, Annelies van der Smissen, all from the SHL, organised the screening and health assessments and did the biochemical assays. We thank the following groups within the Julius Center: Data Management (Nicole Boekema and Robert Veen), Statistics (Peter Zuithof), and Staff Recruitment (Lizeth Vendrig and Annette Bak). Funding Information: We gratefully acknowledge the contributions of all participants, practice nurses, and general practitioners involved in the ADDITION-Europe study. We are grateful to the independent endpoint committee in Denmark (Kristian Thygesen, Hans Ibsen, Ole Færgeman, and Birger Thorsteinsson), the UK (Jane Armitage and Louise Bowman), and the Netherlands (Cees Tack and Jaap Kappelle), and the independent data monitoring and safety committee (Christian Gluud, Per Winkel, and Jørn Wetterslev). We thank Knut Borch-Johnsen, Ronald P Stolk, and Bruce H R Wolffenbuttel for their participation on the committee that oversaw the design of the study; Knut Borch-Johnsen was a also principal investigator in the original trial. We also thank Rebecca Simmons and Maureen van den Donk for their contribution to data acquisition and Daniel Barnes for contribution to data cleaning. SJG, NJW, MJD, and KK are UK National Institute for Health Research (NIHR) Senior Investigators. The University of Cambridge has received salary support for SJG from the UK National Health Service (NHS) in the East of England through the Clinical Academic Reserve. MJD and KK receive support from the UK Department of Health NIHR Programme Grant funding scheme ( grant RP-PG-0606–1272 ). The views expressed in this publication are those of the authors and not necessarily those of the UK Department of Health. ADDITION-Cambridge was supported by the Wellcome Trust (grant G061895), the UK Medical Research Council (MRC; grant G0001164 and Epidemiology Unit Programme MC_UU_12015/4 and MC_UU_12015/1), the UK NIHR Technology Assessment Programme (grant 08/116/300), the NIHR Programme Grants for Applied Research (grant RP-PG-0606–1259), and NHS R&D support funding (including the Primary Care Research Network and Diabetes Research Network). Bio-Rad provided equipment for HbA 1c testing during the screening phase. We are grateful to the ADDITION-Cambridge independent trial steering committee: Nigel Stott, John Weinman, Richard Himsworth, and Paul Little. We thank the Cambridge University Hospitals NHS Foundation Trust Department of Clinical Biochemistry and the NIHR Cambridge Biomedical Research Centre Core Biochemical Assay Laboratory for doing the biochemical assays, and the following groups within the MRC Epidemiology Unit: Data Management (Clare Boothby and Adam Dickinson), Information Technology (Iain Morrison and Rich Hutchinson), Technical (Matt Sims), and Field Epidemiology (James Sylvester, Gwen Brierley, Richard Salisbury, and Kit Coutts). 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, ASTRA 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. We thank the Biochemistry department at Steno Diabetes Centre for doing the biochemical assays and the following hospital departments for doing the clinical measurements: Steno Diabetes Centre Research Laboratory, Esbjerg Hospital Diabetes Clinic, Holstebro Hospital Research Department, Aabenraa Hospital Outpatient Clinic, and Aarhus University Hospital Eye Department. 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). We thank the University Hospitals of Leicester NHS Trust Department of Clinical Biochemistry for doing the biochemical assays. ADDITION-Netherlands was supported by unrestricted grants from Novo Nordisk, GlaxoSmithKline, and Merck, and by the Julius Center for Health Sciences and Primary Care. We thank the directors of the Etten-Leur SHL Centre for Diagnostic Support in Primary Care (Wim Rutten and Paulien van Hessen) for their collaboration. Mardy Eckhardt, Erna Erdtsieck, Leandra Boonman, Annelies van der Smissen, all from the SHL, organised the screening and health assessments and did the biochemical assays. We thank the following groups within the Julius Center: Data Management (Nicole Boekema and Robert Veen), Statistics (Peter Zuithof), and Staff Recruitment (Lizeth Vendrig and Annette Bak). Publisher Copyright: © 2019 Elsevier Ltd
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