Insulin resistance potentiates the effect of remnant cholesterol on cardiovascular mortality in individuals without diabetes
Authors: Vargas-Vázquez Arsenio , Fermín-Martínez Carlos A. , Antonio-Villa Neftali Eduardo , Fernández-Chirino Luisa , Ramírez-García Daniel , Dávila-López Gael , Díaz-Sánchez Juan Pablo , Aguilar-Salinas Carlos A. , Seiglie Jacqueline A. , Bello-Chavolla Omar Yaxmehen 
Published: April 2023

ABSTRACTBACKGROUNDRemnant cholesterol (RC) and insulin resistance (IR) have been independently associated with cardiovascular risk.OBJECTIVESWe evaluated the mediating role of IR in the risk conferred by RC on atherosclerotic cardiovascular disease (ASCVD) mortality.METHODSAnalysis of the National Health and Nutrition Examination Survey (NHANES-III/IV), including 16,201 individuals ≥20 years without diabetes and with complete mortality data. RC levels were calculated using total cholesterol, non-HDL-c, and LDL-c estimated with Sampson’s formula; IR was defined as HOMA2-IR≥2.5 and ASCVD mortality as a composite of cardiovascular and cerebrovascular mortality. Multiple linear regression was used to assess the relationship between HOMA2-IR and RC and competing-risk models to assess their joint role in ASCVD mortality. Causally ordered mediation models were used to explore the mediating role of IR in RC-associated ASCVD mortality.RESULTSWe identified an association between higher HOMA2-IR and higher RC levels. The effect of IR on ASCVD mortality was predominant (sHR 1.68, 95%CI 1.42-1.98) and decreased at older ages (sHR 0.993, 95%CI 0.991-0.995) compared to RC (sHR 0.965, 95%CI 0.826-1.126). Higher risk of ASCVD mortality was observed in individuals with IR but normal RC (sHR 1.19, 95%CI 1.01-1.41) and subjects with IR and high RC (sHR 1.27, 95%CI 1.07-1.50), but not in subjects without IR but high RC. In mediation models, HOMA2-IR accounted for 86.5% (95%CI 78.8-100.0) of the effect of RC levels on ASCVD mortality.CONCLUSIONSOur findings suggest that RC potentiates the risk of ASCVD mortality through its effect on whole-body insulin sensitivity, particularly among younger individuals.CONDENSED ABSTRACTThis study aimed to assess the role of insulin resistance (IR) in the association between remnant cholesterol (RC) and atherosclerotic cardiovascular disease (ASCVD) mortality. Using data from NHANES-III/IV, the study found that the effect of IR on ASCVD mortality was predominant compared to RC. Individuals with IR but normal RC or IR with elevated RC had higher risk of ASCVD mortality compared to subjects with elevated RC without IR. Overall, IR accounted for 86.5% of the effect of RC on ASCVD mortality. RC increases the risk of ASCVD mortality through its effect on insulin sensitivity, particularly among younger individuals.PERSPECTIVESCOMPETENCY IN PATIENT CARE AND PROCEDURAL SKILLSIn patients with elevated remnant cholesterol, insulin resistance potentiates its effect on atherosclerotic cardiovascular disease mortality.TRANSLATIONAL OUTLOOKAdditional research from randomized clinical trials is needed to evaluate whether concomitant therapies to improve insulin sensitivity in patients with residual cardiovascular risk may provide an additional benefit in reducing cardiovascular disease burden and mortality.GRAPHICAL ABSTRACT – CENTRAL IMAGE