Bridging lipidic and endocrine insulin resistance pathways: association of an integrated insulin resistance index with long-term mortality in a coronary angiography cohort

Background Insulin resistance (IR) is associated with lipid metabolism disorders, glucose intolerance, and cardiovascular disease. The triglyceride glucose (TyG) index and homeostasis model assessment of insulin resistance (HOMA2-IR) reflect distinct metabolic and endocrine dimensions of IR. However, these indices capture only single components of a complex metabolic phenotype. Whether integrating complementary pathways of IR improves prognostic discrimination in patients at cardiovascular risk remains unclear. Purpose To evaluate the associations of TyG, HOMA2-IR, and a novel integrated insulin resistance index (iIR), combining fasting glucose, triglycerides, and insulin, with long-term all-cause and cardiovascular mortality. Methods We analysed 3,245 individuals (mean age 62.7±10.6 years; 69.7% men) undergoing coronary angiography with a median follow-up of 10 years. The iIR was constructed as a standardised composite of fasting glucose, triglycerides, and insulin. Cox proportional hazards models estimated hazard ratios (HRs) for a 1-standard-deviation increase, adjusted for age, sex, BMI, renal function, diabetes, hypertension, smoking, LDL cholesterol, and coronary artery disease status. Results In fully adjusted models, iIR was independently associated with all-cause mortality (HR 1.11, 95% CI 1.03–1.19; p=0.0047) and cardiovascular mortality (HR 1.10, 95% CI 1.01–1.21; p=0.028). TyG remained associated with all-cause mortality only (HR 1.08, 95% CI 1.01–1.16; p=0.021), whereas HOMA2-IR was not independently associated with either endpoint (all-cause HR 1.04, 95% CI 0.98–1.10; cardiovascular HR 1.01, 95% CI 0.93–1.09). Conclusions An integrated assessment of insulin resistance combining lipidic and endocrine components provides more consistent prognostic information than established single-pathway indices. Integrative characterisation of insulin resistance may enhance cardiometabolic risk stratification beyond conventional single-pathway markers.