The metabolic score for insulin resistance (METS-IR) predicts MACE and is correlated to plasma levels of leptin and sRAGE: validation and mechanistic insights from a Swedish population-based cohort

Introduction Several indices have been developed for the clinician to estimate insulin resistance (IR), an important contributor to major adverse cardiovascular events (MACE). One such novel tool taking obesity, dyslipidemia and hyperglycemia into consideration is the metabolic score of insulin resistance (METS-IR). METS-IR has shown great promise in IR estimation as well as prediction of type 2 diabetes, MACE and mortality. Nonetheless, there is a paucity of studies investigating its relation to MACE risk in European prospective cohorts. Moreover, the mechanisms underlying the association to the newly developed METS-IR have not been sufficiently investigated. Purpose To assess the relationship between METS-IR and prospective MACE in a Swedish cohort. The study also sought to explore potential mechanisms cross-sectionally using circulating biomarkers of metabolism, inflammation and extracellular matrix (ECM) turnover in a subset of the cohort. Methods Between 2012-2015, individuals from the general-population aged 40-75 years were randomly recruited from primary healthcare centers in southeast Sweden. Baseline data were obtained through clinical examinations, questionnaires and fasting venous blood sampling. METS-IR was calculated according to the original published formula. Follow-up was completed at the end of 2023 through linkage to national health registers, with ICD-10-based data on myocardial infarction, PCI, CABG, cardiovascular death and ischemic stroke comprised into a composite MACE endpoint. A dedicated subset of participants with available fasting EDTA-plasma was used for quantification of biomarkers related to metabolism (3), inflammation (3) and ECM turnover (6) using the Luminex assay. Uni- and multivariable Cox regressions, Spearman correlation analysis and multivariable linear regression were used. Results Among 6070 participants with calculated METS-IR at baseline (mean age 54±9.9 years, 43% men), 270 had developed MACE at follow-up. For biomarker analysis, the plasma of 196 MACE participants and 440 controls were available (mean age 63±7.4 years, 33% men). Following stepwise adjustment for potential confounders (Table 1), METS-IR remained a significant predictor of MACE: participants in the highest tertile had a 51% higher event risk than those in the lowest (p=0.027), with risk increasing 16% per SD (p=0.018). In correlation analysis against cardiovascular risk factors and biomarkers, METS-IR showed several significant (p<0.001) correlations (Table 2). Of these, HOMA-IR, sex, age, SBP, lipid-lowering medication, sRAGE and leptin remained significantly correlated to METS-IR. Conclusions METS-IR was independently associated with prospective MACE in the Swedish middle-aged general population. Its significant and independent correlations to leptin and sRAGE even after accounting for HOMA-IR might be suggestive of mechanisms relevant for the role of METS-IR in the context of MACE.