Beyond Compensation: Hyperinsulinemia as an Early Driver of Cardiovascular-Kidney-Metabolic Syndrome

Background. Cardiovascular-kidney-metabolic (CKM) syndrome encompasses obesity, type 2 diabetes, cardiovascular disease, and chronic kidney disease. Insulin resistance has traditionally been considered the primary driver, with hyperinsulinemia viewed as a compensatory response. However, emerging evidence suggests that hyperinsulinemia may precede insulin resistance in specific phenotypes and contribute to early disease mechanisms. Methods. We conducted a narrative review of the role of hyperinsulinemia in CKM syndrome. Literature searches were performed in PubMed/MEDLINE, Embase, and Scopus through December 2025. We prioritised prospective cohort studies, meta-analyses, Mendelian randomisation studies, and randomised controlled trials, and synthesised evidence across cardiovascular, renal, and metabolic domains. Results. Sustained hyperinsulinemia is associated with myocardial hypertrophy and fibrosis through selective preservation of mitogenic signalling, contributing to heart failure phenotypes. In the kidney, it enhances sodium and glucose reabsorption, increases intraglomerular pressure, and promotes podocyte dysfunction, potentially accelerating CKD progression. Epidemiological evidence consistently shows associations between elevated fasting insulin levels and cardiovascular events, renal outcomes, and mortality across diverse populations, with meta-analytic estimates reporting a pooled relative risk of 1.46 (95% CI 1.16-1.84) for incident cardiovascular events. However, available data are largely observational and heterogeneous in exposure definitions and adjustment models. Conclusions. Hyperinsulinemia represents a clinically relevant and potentially modifiable component of CKM syndrome, with effects extending beyond glucose homeostasis. While causality is biologically plausible and supported by genetic and epidemiological evidence, it remains to be established through interventional studies. Recognition of hyperinsulinemia may support earlier risk stratification and mechanism-based interventions, although prospective validation is required before routine clinical implementation.