Novel biomarkers in cardiovascular disease and dysglycaemia

<p dir="ltr"><b>Background</b><b>.</b> Cardiovascular disease (CVD) and dysglycaemia are closely interconnected. Dysglycaemia, defined as impaired glucose tolerance (IGT) or type 2 diabetes (T2DM), increases the risk of adverse cardiovascular events. Traditional glycaemic markers may not fully capture cardiometabolic risk and novel biomarkers reflecting early glucometabolic perturbations and their prognostic importance may improve risk stratification and management. Plasma mannose, a marker of insulin resistance (IR), and copeptin, a surrogate for vasopressin (AVP) activity, have emerged as potential candidates.</p><p dir="ltr"><b>Aims. </b>The overall aim was to investigate novel biomarkers in the context of CVD and dysglycaemia, focusing on their associations with myocardial infarction (MI), glucometabolic profiles, and long-term outcomes, as well as their response to a cardioprotective glucose-lowering treatment such as empagliflozin, a sodium- glucose cotransporter 2 (SGLT2) inhibitors. Specifically, the four studies explored:</p><ul><li>The relationship between plasma mannose levels and risk of a first MI across glycaemic states (<b>Study I</b>).</li><li>The association between mannose, IR indexes, and major adverse cardiovascular events (MACE) (<b>Study II</b>).</li><li>The effects of the SGLT2-inhibitors empagliflozin on IR, B-cell function, and relevant biomarkers, including mannose (<b>Study III</b>).</li><li>The effect of empagliflozin on copeptin levels, evaluating AVP signalling as a potential mediator of cardioprotection (<b>Study IV</b>).</li></ul><p dir="ltr"><b>Methods. Study I and II</b> were based on the population from the PAROKRANK Study, a cohort of 1,547 individuals, including patients with a first myocardial infarction (MI) and age and gender matched controls. Study participants were categorized by an oral glucose tolerance test (OGTT) as having normal glucose tolerance, IGT, or newly detected T2DM. The association between mannose, measured by high- performance liquid chromatography coupled with mass spectrometry, and MI was investigated across the glycaemic states by logistic regression. Multivariate regression models were used to explore mannose independent relationship with indexes of IR and insulin secretion derived during an OGTT. Multivariate Cox regression models were applied to assess the association between elevated (top quartile) and lower (lower three quartiles) mannose levels and the occurrence of MACE over a 10-year follow-up period.<b> Study III </b>and<b> IV</b> were based on the SOCOGAMI Trial, a randomized double-blind placebo-controlled study which enrolled 42 patients with IGT or T2DM detected in connection to a previous recent acute coronary syndrome (ACS). Study participants were randomized to receive 25 mg empagliflozin or placebo for 10 months in total, 7 on treatment and the last 3 off treatment. IR/insulin secretion, mannose (<b>Study III</b>) and copeptin, measured using an automated immunofluorescence assay (<b>Study IV</b>), were assessed before, during, and 3 months off treatment. The effects were primarily evaluated by repeated measures ANOVA and regression models.</p><p dir="ltr"><b>Results.</b></p><p dir="ltr">Plasma mannose as a biomarker of cardiovascular risk. <b>Study I</b> found that plasma mannose levels increased with worsening glucose intolerance and were independently associated with a first MI, particularly in individuals with normal glucose tolerance (odds ratio - OR: 2.0; 95% confidence interval - CI: 1.2-3.6). <b>Study II</b> confirmed that mannose was associated with IR indexes and independently predicted MACE over 10 years (hazard ratio - HR: 1.54; 95% CI: 1.1-2.2), suggesting that mannose may serve as a marker of cardiometabolic risk.</p><p dir="ltr">Biomarker responses to the SGLT2i empagliflozin in patients with ACS and dysglycaemia. <b>Study III</b> found that empagliflozin improved OGTT-based surrogate markers of IR but did not impact B-cell function, traditional IR indexes, or levels of mannose. The glucose-lowering effects were reversible after treatment discontinuation. In <b>Study IV</b>, copeptin correlated positively with arterial stiffness but empagliflozin did not significantly affect copeptin levels compared with placebo. Copeptin levels did not predict the glycaemic response to treatment.</p><p dir="ltr"><b>Conclusions.</b> These studies suggest that: 1) plasma mannose is a potential biomarker for early identification of cardiovascular risk independently of glycaemic state and 2) while SGLT2-inhibitors offer metabolic benefits in patients with newly detected dysglycaemia post-ACS, their effects may not be mediated through changes in AVP activity.</p><h3>List of scientific papers</h3><p dir="ltr">I. <b>Fortin E,</b> Ferrannini G, Campi B, Mellbin L, Norhammar A, Näsman P, Saba A, Ferrannini E and Rydén L. Plasma mannose as a novel marker of myocardial infarction across different glycaemic states: a case control study. Cardiovascular Diabetology (2022) 21:195 <a href="https://doi.org/10.1186/s12933-022-01630-5" rel="noreferrer" target="_blank">https://doi.org/10.1186/s12933-022-01630-5</a></p><p dir="ltr">I. <b>Fortin E,</b> Campi B, Ferrannini E, Mari A, Mellbin L, Norhammar A, Näsman P, Rydén L, Saba A, Ferrannini G. High Mannose Correlates with Surrogate Indexes of Insulin Resistance and Is Associated with an Increased Risk of Cardiovascular Events Independently of Glycemic Status and Traditional Risk Factors. Diabetes Care 2024;47(2):246-251 <a href="https://doi.org/10.2337/dc23-0870" rel="noreferrer" target="_blank">https://doi.org/10.2337/dc23-0870</a></p><p dir="ltr">III. <b>Fortin E,</b> Lundin M, Mellbin L, Norhammar A, Näsman Per, Smetana S, Sörensson P, Ferrannini E, Rydén, Ferrannini G. Empagliflozin improves insulin sensitivity in patients with recent acute coronary syndrome and newly detected dysglycaemia Cardiovascular Diabetology (2023) 22:208 <a href="https://doi.org/10.1186/s12933-023-01950-0" rel="noreferrer" target="_blank">https://doi.org/10.1186/s12933-023-01950-0</a></p><p dir="ltr">IV. <b>Fortin E,</b> Melander O, Ferrannini G, Näsman P, Norhammar A, Rydén L, Smetana S, Svensson M, Mellbin L. Response of Copeptin Levels to Empagliflozin in Patients with Recent Acute Coronary Syndrome and Newly Detected Dysglycaemia [Manuscript]</p>