Elena Fortin

Background: Patients with dysglycaemia have 2-to-4 fold risk of developing cardiovascular disease. Insulin resistance, as well as stress and inflammation are suggested to explain a significant part of the cardiovascular risk. High mannose has emerged as a new marker of insulin resistance. Moreover, copeptin, a marker for vasopressin has also been associated to abnormalities in insulin metabolism. Downstream effects of the activation of the complement system, i.e a part of the inflammatory pathways, may contribute to the pathogenesis of complications of dysglycaemia. Aims: 1) to investigate if mannose levels differ among different glycaemic states in patients with and without a first myocardial infarction and explore its association with surrogate indexes of insulin resistance and long-term cardiovascular outcomes. 2) to study whether the SGLT2 inhibitor empagliflozin influences insulin resistance, mannose and copeptin levels in patients with a recent acute coronary event and dysglycaemia. 3) to evaluate the effect of early long-term insulin compared to standard glucose-lowering treatment on components of the complement system (MBL and MAC) in people with dysglycaemia and high cardiovascular risk. Workplan: The PhD project comprises five studies whereof three are published (Study I, II and III). The biomarker analyses are based on collected material from three clinical studies: PAROKRANK (Periodontitis and Its Relation to Coronary Artery Disease

n= 1547

study I and II), SOCOGAMI (SOdium-glucose CO-transporter inhibition in patients with newly detected Glucose Abnormalities and a recent Myocardial Infarction

n=42

study

study III and IV) and a Swedish biomarker substudy substudie (n=133) in the international ORIGIN (Outcome Reduction with an Initial Glargine Intervention) Trial (study V.) In study IV copeptin will be studied during oral glucose tolerance tests before and after treatment with empagliflozin/placebo. Study V will investigate the effect of insulin treatment on MBL and MAC. Significance: This project examines the role of different biomarkers in cardiovascular disease combining a laboratory and epidemiological approach. The studies will expand existing knowledge by investigating the listed biomarkers in carefully characterized cohorts and by studying the effects of a pharmacological intervention. The results may be used to optimize risk stratification and glucose-lowering treatment in clinical practice.