Before the storm: insulin resistance as a sentinel biomarker across the cardiometabolic continuum. A comprehensive narrative review

Insulin resistance (IR) is often seen as a curiosity associated with prediabetes and polyendocrine metabolic ovarian syndrome (PMOS, formerly PCOS). However, it is a significant early indicator of progression towards type 2 diabetes, cardiovascular disease, heart failure, chronic kidney disease, and liver disease. This review covers the pathophysiology of IR in the vascular, hepatic, renal, and cardiac systems, its epidemiological impact, and diagnostic tools, including the hyperinsulinemic-euglycemic clamp and accessible indices like HOMA-IR and the triglyceride-glucose (TyG) index. We reviewed the 2023 and 2026 American Heart Association clinical guideline framework for cardiovascular-kidney-metabolic (CKM) syndrome, which highlights insulin resistance and dysfunctional adiposity as early factors in a multi-organ continuum that precedes abnormal conventional risk factors. When assessing routine IR testing in preventive practice, it is crucial to consider diagnostic accuracy, costs, implementation feasibility, and outcomes from prevention trials. These components are essential for evaluating the effectiveness and value of testing in healthcare. While no universally validated IR index exists for population-wide screening, targeted assessment is recommended for individuals with excess adiposity, a family history of type 2 diabetes, or early metabolic risk markers. This research-oriented, risk-stratified approach is preferable to a general recommendation. It may help identify individuals who would benefit from closer monitoring and lifestyle interventions at CKM stage 0-1, pending data from outcome-driven trials. In conclusion, key research priorities include standardizing cutoffs across populations and designing outcome trials to determine whether IR-guided interventions improve the cardiometabolic continuum compared with those based solely on glycemic thresholds.