XML Template (2013) [25.11.2013–2:50pm] //blrnas3/cenpro/ApplicationFiles/Journals/SAGE/3B2/CPRJ/Vol00000/130307/APPFile/SG-CPRJ130307.3d
(CPR)
[1–8] [PREPRINTER stage]
EURO PEAN SO CIETY O F CARDIOLOGY ®
Original scientific paper
Adiponectin, type 2 diabetes and cardiovascular risk Søren Lindberg1,2, Jan Skov Jensen1,2,3, Mette Bjerre4,5, Sune H Pedersen2, Jan Frystyk4,5, Allan Flyvbjerg4,5, Søren Galatius2, Jørgen Jeppesen3,6 and Rasmus Mogelvang1,2
European Journal of Preventive Cardiology 0(00) 1–8 ! The European Society of Cardiology 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/2047487313514894 ejpc.sagepub.com
Abstract Background: Adiponectin is viewed as an insulin-sensitizing hormone with anti-inflammatory effects. In accordance, plasma adiponectin is decreased in metabolic disorders including type 2 diabetes mellitus (T2DM). However, in spite of the apparently beneficially effects, recent data from large prospective studies have consistently linked high adiponectin levels with increased cardiovascular (CV) disease and mortality, thus questioning the positive view on adiponectin. Accordingly, we investigated the relationship between adiponectin, incident T2DM and subsequently CV events. Methods: We prospectively followed 5349 randomly selected men and women from the community, without T2DM or CV disease. Plasma adiponectin was measured at study entry. Median follow-up time was 8.5 years (IQR 8.0–9.1 years). During follow up, 136 participants developed T2DM. Following their diagnosis, 36 of the 136 participants experienced a CV event (myocardial infarction, ischaemic stroke, or CV death). Results: Participants with increasing adiponectin had reduced risk of developing T2DM (p < 0.001). After adjustment for confounding risk factors (including age, gender, body mass index, physical activity, alcohol consumption, blood glucose, HbA1c, blood pressure, lipids, high-sensitivity C-reactive protein, estimated glomerular filtration rate, and plasma N-terminal pro-brain natriuretic peptide, competing risk Cox-regression analysis identified adiponectin as an independent predictor of T2DM: hazard ratio (HR) for each doubling of adiponectin 0.55 (95% CI 0.41–0.74; p < 0.001). After development of T2DM, the risk of a CV event more than doubled. Increasing adiponectin (adjusted for the confounding risk factors mentioned) was associated with reduced risk of CV events: HR 0.34 (95% CI 0.16–0.72; p ¼ 0.005) for each doubling in plasma adiponectin. Conclusions: In conclusion, increasing plasma adiponectin is associated with decreased risk of T2DM and subsequently reduced risk of CV events.
Keywords Adiponectin, cardiovascular disease, type 2 diabetes, T2DM Received 25 July 2013; accepted 9 November 2013
Introduction
1
Bispebjerg University Hospital, Copenhagen, Denmark Gentofte University Hospital, Copenhagen, Denmark 3 University of Copenhagen, Copenhagen, Denmark 4 Aarhus University, Aarhus, Denmark 5 Aarhus University Hospital, Aarhus, Denmark 6 Glostrup Hospital, Copenhagen, Denmark 2
Adiponectin is almost exclusively secreted by adipocytes and appears to acts as a hormone with believed anti-inflammatory and insulin-sensitizing properties.1 Plasma levels are decreased in cardiovascular disease (CVD) and several metabolic disorders including obesity, inflammatory states, insulin resistance, and type 2 diabetes mellitus (T2DM);2 however, the effect in humans are still not fully elucidated.
Corresponding author: Søren Lindberg, Department of Cardiology, Gentofte University Hospital, Niels Andersens Vej 65, DK-2900 Hellerup, Denmark. Email: [email protected]
Downloaded from cpr.sagepub.com at UNIV OF MEMPHIS on May 17, 2015
XML Template (2013) [25.11.2013–2:50pm] //blrnas3/cenpro/ApplicationFiles/Journals/SAGE/3B2/CPRJ/Vol00000/130307/APPFile/SG-CPRJ130307.3d
(CPR)
[1–8] [PREPRINTER stage]
2
European Journal of Preventive Cardiology 0(00)
Over the past decade, several studies have documented an inverse relationship between plasma adiponectin and incident T2DM.3–7 Contradictory, recent studies have consistently documented a positive relationship between high adiponectin levels and mortality and CVD,8 thus questioning the perceived beneficial effects of adiponectin. There are several possible explanations for this apparent paradox: in several of the prospective studies investigating adiponectin and incident T2DM, the beneficial association vanished after adjustment for confounders including lipids or markers of inflammation.3,4,7 Moreover, natriuretic peptides (including plasma N-terminal pro-brain natriuretic peptide, proBNP) have emerged as a very strong confounder for the relationship between adiponectin and outcome, as they stimulate adiponectin synthesis, increase lipid metabolism, and appear to be highly correlated.9,10 Finally, in none of the previous studies, the competing risk of death were taken into account, which may have biased the data when evaluating an endpoint like T2DM.11 These observations raise the possibility that the previously described beneficial relationship between high adiponectin and lower incidence of T2DM, may be caused by these factors. Accordingly, we investigated the relationship between plasma adiponectin and incident T2DM and subsequent cardiovascular (CV) events in a large population-based cohort, including an evaluation of these highly important confounders.
Methods Study population The present study included 5349 men and women (20–94 years of age) without diabetes or ischaemic heart disease (IHD) from the 4th Copenhagen City Heart Study, a longitudinal cohort study of CVD and risk factors which have been described previously.12 In total, 6035 persons were examined (participation rate 49.5%); however, we excluded individuals with prevalent diabetes (n ¼ 283), IHD (n ¼ 269), or missing data on plasma adiponectin (n ¼ 134). Patients were followed for a median of 8.5 years (IQR 8.0–9.1 years). Follow-up information was obtained from the National Person Identification Registry (death certificates) and from the highly validated Danish National Board of Health’s National Patient Registry which contains data on the entire cohort using ICD-10 codes.13 Endpoints were T2DM (E11) and subsequently CV events defined as CV mortality or hospitalization due to a myocardial infarction (I21) or ischaemic stroke (I63–64).
Health examination IHD was defined as either a history of hospital admission due to acute MI, percutaneous coronary intervention, or coronary artery bypass grafting. Diabetes was defined as self-reported disease or use of antidiabetic medicine. Physical activity was defined as moderate lenient physical activity above 4 hours a week and/or strenuous lenient physical activity above 2 hours a week. Alcohol consumption was calculated as g ethanol/week using standard ethanol concentrations in beer, wine, liquor, and spirits. All subjects gave informed consent to participate, and the study was performed in accordance with the second Helsinki Declaration and approved by the regional ethics committee. Blood samples were immediately centrifuged at 3000 rpm for 10 min and plasma was stored at –80 C until subsequent analysis. Plasma adiponectin was determined by a validated in-house time-resolved immunofluorometric assay as previously described.14 All samples were analysed in duplicate, with a detection limit of 1.5 mg/l and intra- and inter-assay coefficients of variation
(CPR)
[1–8] [PREPRINTER stage]
EURO PEAN SO CIETY O F CARDIOLOGY ®
Original scientific paper
Adiponectin, type 2 diabetes and cardiovascular risk Søren Lindberg1,2, Jan Skov Jensen1,2,3, Mette Bjerre4,5, Sune H Pedersen2, Jan Frystyk4,5, Allan Flyvbjerg4,5, Søren Galatius2, Jørgen Jeppesen3,6 and Rasmus Mogelvang1,2
European Journal of Preventive Cardiology 0(00) 1–8 ! The European Society of Cardiology 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/2047487313514894 ejpc.sagepub.com
Abstract Background: Adiponectin is viewed as an insulin-sensitizing hormone with anti-inflammatory effects. In accordance, plasma adiponectin is decreased in metabolic disorders including type 2 diabetes mellitus (T2DM). However, in spite of the apparently beneficially effects, recent data from large prospective studies have consistently linked high adiponectin levels with increased cardiovascular (CV) disease and mortality, thus questioning the positive view on adiponectin. Accordingly, we investigated the relationship between adiponectin, incident T2DM and subsequently CV events. Methods: We prospectively followed 5349 randomly selected men and women from the community, without T2DM or CV disease. Plasma adiponectin was measured at study entry. Median follow-up time was 8.5 years (IQR 8.0–9.1 years). During follow up, 136 participants developed T2DM. Following their diagnosis, 36 of the 136 participants experienced a CV event (myocardial infarction, ischaemic stroke, or CV death). Results: Participants with increasing adiponectin had reduced risk of developing T2DM (p < 0.001). After adjustment for confounding risk factors (including age, gender, body mass index, physical activity, alcohol consumption, blood glucose, HbA1c, blood pressure, lipids, high-sensitivity C-reactive protein, estimated glomerular filtration rate, and plasma N-terminal pro-brain natriuretic peptide, competing risk Cox-regression analysis identified adiponectin as an independent predictor of T2DM: hazard ratio (HR) for each doubling of adiponectin 0.55 (95% CI 0.41–0.74; p < 0.001). After development of T2DM, the risk of a CV event more than doubled. Increasing adiponectin (adjusted for the confounding risk factors mentioned) was associated with reduced risk of CV events: HR 0.34 (95% CI 0.16–0.72; p ¼ 0.005) for each doubling in plasma adiponectin. Conclusions: In conclusion, increasing plasma adiponectin is associated with decreased risk of T2DM and subsequently reduced risk of CV events.
Keywords Adiponectin, cardiovascular disease, type 2 diabetes, T2DM Received 25 July 2013; accepted 9 November 2013
Introduction
1
Bispebjerg University Hospital, Copenhagen, Denmark Gentofte University Hospital, Copenhagen, Denmark 3 University of Copenhagen, Copenhagen, Denmark 4 Aarhus University, Aarhus, Denmark 5 Aarhus University Hospital, Aarhus, Denmark 6 Glostrup Hospital, Copenhagen, Denmark 2
Adiponectin is almost exclusively secreted by adipocytes and appears to acts as a hormone with believed anti-inflammatory and insulin-sensitizing properties.1 Plasma levels are decreased in cardiovascular disease (CVD) and several metabolic disorders including obesity, inflammatory states, insulin resistance, and type 2 diabetes mellitus (T2DM);2 however, the effect in humans are still not fully elucidated.
Corresponding author: Søren Lindberg, Department of Cardiology, Gentofte University Hospital, Niels Andersens Vej 65, DK-2900 Hellerup, Denmark. Email: [email protected]
Downloaded from cpr.sagepub.com at UNIV OF MEMPHIS on May 17, 2015
XML Template (2013) [25.11.2013–2:50pm] //blrnas3/cenpro/ApplicationFiles/Journals/SAGE/3B2/CPRJ/Vol00000/130307/APPFile/SG-CPRJ130307.3d
(CPR)
[1–8] [PREPRINTER stage]
2
European Journal of Preventive Cardiology 0(00)
Over the past decade, several studies have documented an inverse relationship between plasma adiponectin and incident T2DM.3–7 Contradictory, recent studies have consistently documented a positive relationship between high adiponectin levels and mortality and CVD,8 thus questioning the perceived beneficial effects of adiponectin. There are several possible explanations for this apparent paradox: in several of the prospective studies investigating adiponectin and incident T2DM, the beneficial association vanished after adjustment for confounders including lipids or markers of inflammation.3,4,7 Moreover, natriuretic peptides (including plasma N-terminal pro-brain natriuretic peptide, proBNP) have emerged as a very strong confounder for the relationship between adiponectin and outcome, as they stimulate adiponectin synthesis, increase lipid metabolism, and appear to be highly correlated.9,10 Finally, in none of the previous studies, the competing risk of death were taken into account, which may have biased the data when evaluating an endpoint like T2DM.11 These observations raise the possibility that the previously described beneficial relationship between high adiponectin and lower incidence of T2DM, may be caused by these factors. Accordingly, we investigated the relationship between plasma adiponectin and incident T2DM and subsequent cardiovascular (CV) events in a large population-based cohort, including an evaluation of these highly important confounders.
Methods Study population The present study included 5349 men and women (20–94 years of age) without diabetes or ischaemic heart disease (IHD) from the 4th Copenhagen City Heart Study, a longitudinal cohort study of CVD and risk factors which have been described previously.12 In total, 6035 persons were examined (participation rate 49.5%); however, we excluded individuals with prevalent diabetes (n ¼ 283), IHD (n ¼ 269), or missing data on plasma adiponectin (n ¼ 134). Patients were followed for a median of 8.5 years (IQR 8.0–9.1 years). Follow-up information was obtained from the National Person Identification Registry (death certificates) and from the highly validated Danish National Board of Health’s National Patient Registry which contains data on the entire cohort using ICD-10 codes.13 Endpoints were T2DM (E11) and subsequently CV events defined as CV mortality or hospitalization due to a myocardial infarction (I21) or ischaemic stroke (I63–64).
Health examination IHD was defined as either a history of hospital admission due to acute MI, percutaneous coronary intervention, or coronary artery bypass grafting. Diabetes was defined as self-reported disease or use of antidiabetic medicine. Physical activity was defined as moderate lenient physical activity above 4 hours a week and/or strenuous lenient physical activity above 2 hours a week. Alcohol consumption was calculated as g ethanol/week using standard ethanol concentrations in beer, wine, liquor, and spirits. All subjects gave informed consent to participate, and the study was performed in accordance with the second Helsinki Declaration and approved by the regional ethics committee. Blood samples were immediately centrifuged at 3000 rpm for 10 min and plasma was stored at –80 C until subsequent analysis. Plasma adiponectin was determined by a validated in-house time-resolved immunofluorometric assay as previously described.14 All samples were analysed in duplicate, with a detection limit of 1.5 mg/l and intra- and inter-assay coefficients of variation
