Zahir H Alshehry1, Piyushkumar A Mundra1, Christopher K Barlow1, Natalie A Mellett1, Gerard Wong1, Malcolm J McConville1, John Simes1, Andrew M Tonkin1, David R Sullivan1, Elizabeth H Barnes1, Paul J Nestel1, Bronwyn A Kingwell1, Michel Marre1, Bruce Neal1, Neil R Poulter1, Anthony Rodgers1, Bryan Williams1, Sophia Zoungas1, Graham S Hillis1, John Chalmers1, Mark Woodward1, Peter J Meikle2. 1. From Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia (Z.H.A., P.A.M., C.K.B., N.A.M., G.W., P.J.N., B.A.K., P.J.M.); King Fahad Medical City, Riyadh, Saudi Arabia (Z.H.A.); Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, VIC, Australia (Z.H.A., M.J.M., P.J.M.); NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia (J.S., E.H.B.); School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia (A.M.T., S.Z.); Royal Prince Alfred Hospital, Sydney, NSW, Australia (D.R.S.); Hópital Bichat-Claude Bernard and Université Paris 7, Paris, France (M.M.); George Institute for Global Health, Sydney, NSW, Australia (B.N., N.R.P., S.Z., G.S.H., J.C., M.W.); University College London and National Institute for Health Research, University College London Hospitals, Biomedical Research Centre, London, UK (B.W.); Department of Cardiology, Royal Perth Hospital/University of Western Australia, Perth, WA, Australia (G.S.H.); George Institute for Global Health, University of Oxford, Oxford, UK (M.W.); and Department of Epidemiology, Johns Hopkins University, Baltimore, MD (M.W.). 2. From Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia (Z.H.A., P.A.M., C.K.B., N.A.M., G.W., P.J.N., B.A.K., P.J.M.); King Fahad Medical City, Riyadh, Saudi Arabia (Z.H.A.); Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, VIC, Australia (Z.H.A., M.J.M., P.J.M.); NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia (J.S., E.H.B.); School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia (A.M.T., S.Z.); Royal Prince Alfred Hospital, Sydney, NSW, Australia (D.R.S.); Hópital Bichat-Claude Bernard and Université Paris 7, Paris, France (M.M.); George Institute for Global Health, Sydney, NSW, Australia (B.N., N.R.P., S.Z., G.S.H., J.C., M.W.); University College London and National Institute for Health Research, University College London Hospitals, Biomedical Research Centre, London, UK (B.W.); Department of Cardiology, Royal Perth Hospital/University of Western Australia, Perth, WA, Australia (G.S.H.); George Institute for Global Health, University of Oxford, Oxford, UK (M.W.); and Department of Epidemiology, Johns Hopkins University, Baltimore, MD (M.W.). peter.meikle@bakeridi.edu.au.
Abstract
BACKGROUND: Clinical lipid measurements do not show the full complexity of the altered lipid metabolism associated with diabetes mellitus or cardiovascular disease. Lipidomics enables the assessment of hundreds of lipid species as potential markers for disease risk. METHODS: Plasma lipid species (310) were measured by a targeted lipidomic analysis with liquid chromatography electrospray ionization-tandem mass spectrometry on a case-cohort (n=3779) subset from the ADVANCE trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation). The case-cohort was 61% male with a mean age of 67 years. All participants had type 2 diabetes mellitus with ≥1 additional cardiovascular risk factors, and 35% had a history of macrovascular disease. Weighted Cox regression was used to identify lipid species associated with future cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death) and cardiovascular death during a 5-year follow-up period. Multivariable models combining traditional risk factors with lipid species were optimized with the Akaike information criteria. C statistics and NRIs were calculated within a 5-fold cross-validation framework. RESULTS: Sphingolipids, phospholipids (including lyso- and ether- species), cholesteryl esters, and glycerolipids were associated with future cardiovascular events and cardiovascular death. The addition of 7 lipid species to a base model (14 traditional risk factors and medications) to predict cardiovascular events increased the C statistic from 0.680 (95% confidence interval [CI], 0.678-0.682) to 0.700 (95% CI, 0.698-0.702; P<0.0001) with a corresponding continuous NRI of 0.227 (95% CI, 0.219-0.235). The prediction of cardiovascular death was improved with the incorporation of 4 lipid species into the base model, showing an increase in the C statistic from 0.740 (95% CI, 0.738-0.742) to 0.760 (95% CI, 0.757-0.762; P<0.0001) and a continuous net reclassification index of 0.328 (95% CI, 0.317-0.339). The results were validated in a subcohort with type 2 diabetes mellitus (n=511) from the LIPID trial (Long-Term Intervention With Pravastatin in Ischemic Disease). CONCLUSIONS: The improvement in the prediction of cardiovascular events, above traditional risk factors, demonstrates the potential of plasma lipid species as biomarkers for cardiovascular risk stratification in diabetes mellitus. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov. Unique identifier: NCT00145925.
RCT Entities:
BACKGROUND: Clinical lipid measurements do not show the full complexity of the altered lipid metabolism associated with diabetes mellitus or cardiovascular disease. Lipidomics enables the assessment of hundreds of lipid species as potential markers for disease risk. METHODS: Plasma lipid species (310) were measured by a targeted lipidomic analysis with liquid chromatography electrospray ionization-tandem mass spectrometry on a case-cohort (n=3779) subset from the ADVANCE trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation). The case-cohort was 61% male with a mean age of 67 years. All participants had type 2 diabetes mellitus with ≥1 additional cardiovascular risk factors, and 35% had a history of macrovascular disease. Weighted Cox regression was used to identify lipid species associated with future cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death) and cardiovascular death during a 5-year follow-up period. Multivariable models combining traditional risk factors with lipid species were optimized with the Akaike information criteria. C statistics and NRIs were calculated within a 5-fold cross-validation framework. RESULTS:Sphingolipids, phospholipids (including lyso- and ether- species), cholesteryl esters, and glycerolipids were associated with future cardiovascular events and cardiovascular death. The addition of 7 lipid species to a base model (14 traditional risk factors and medications) to predict cardiovascular events increased the C statistic from 0.680 (95% confidence interval [CI], 0.678-0.682) to 0.700 (95% CI, 0.698-0.702; P<0.0001) with a corresponding continuous NRI of 0.227 (95% CI, 0.219-0.235). The prediction of cardiovascular death was improved with the incorporation of 4 lipid species into the base model, showing an increase in the C statistic from 0.740 (95% CI, 0.738-0.742) to 0.760 (95% CI, 0.757-0.762; P<0.0001) and a continuous net reclassification index of 0.328 (95% CI, 0.317-0.339). The results were validated in a subcohort with type 2 diabetes mellitus (n=511) from the LIPID trial (Long-Term Intervention With Pravastatin in Ischemic Disease). CONCLUSIONS: The improvement in the prediction of cardiovascular events, above traditional risk factors, demonstrates the potential of plasma lipid species as biomarkers for cardiovascular risk stratification in diabetes mellitus. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov. Unique identifier: NCT00145925.
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