Insulin Resistance Indices and Cardiovascular Risk Prediction in Young Hypertensive Populations: Interpretative Challenges

Dear Editor: We read with interest the article by Chen et al. examining the prognostic value of insulin resistance indices for major adverse cardiovascular events in young and middle-aged patients with hypertension [1]. The authors should be acknowledged for addressing an underexplored population and for their long follow-up duration. Their finding that the metabolic score for insulin resistance (METS-IR) outperformed the triglyceride–glucose index and TG/HDL-C ratio in discrimination analyses is noteworthy and contributes to the growing literature on metabolic risk stratification. Nevertheless, the retrospective single-center design limits causal interpretation. Selection bias and unmeasured confounders are inherent to this approach, particularly in a cohort derived from a tertiary referral center. Prior large population-based studies have demonstrated that associations between insulin resistance surrogates and cardiovascular outcomes are highly sensitive to baseline risk distribution and population characteristics, raising concerns regarding external validity [2]. Another important consideration is residual confounding related to pharmacological treatment. Renin–angiotensin system inhibitors and certain calcium channel blockers are known to improve insulin sensitivity, whereas β-blockers and thiazide diuretics may worsen it. The absence of detailed antihypertensive treatment adjustment may therefore influence both insulin resistance indices and cardiovascular outcomes, potentially inflating observed associations [3]. In addition, although METS-IR demonstrated statistically significant improvements in the area under the curve (AUC), net reclassification improvement (NRI) and integrated discrimination improvement (IDI) the clinical relevance of these increments remains uncertain. Prior methodological work has cautioned that reclassification metrics can appear favorable even when absolute risk discrimination improves marginally, limiting their impact on clinical decision-making [4]. Whether METS-IR meaningfully alters patient management beyond established risk models is not yet clear. Finally, insulin resistance indices are surrogate measures and do not fully capture heterogeneity in adiposity distribution, inflammatory burden, or ectopic fat accumulation. Imaging-based or biomarker-integrated approaches have shown stronger mechanistic links with cardiovascular risk and may provide complementary or superior prognostic information [5]. Prospective multicenter studies incorporating such measures are required before widespread clinical adoption of METS-IR can be recommended. Sincerely, All of the authors contributed planning, writing, and revision. This work did not receive any specific funding. The authors declare no conflicts of interest. No new data was generated or analyzed in support of this letter to the editor.