Summary:
This prospective cohort study aimed to investigate how insulin-resistance (IR) related indices and genetic risk jointly influence the incidence of cardiovascular disease (CVD) among individuals with either preclinical or clinical obesity. The study utilised data from 112,866 participants in the UK Biobank who were classified as having excess adiposity (obesity) but not necessarily overt organ dysfunction, and followed them for a median of 13.45 years. Key IR related indices under investigation included the triglyceride-glucose index (TyG), TyG in combination with body mass index (TyG-BMI), TyG combined with waist circumference (TyG-WC), and TyG combined with waist-to-height ratio (TyG-WHtR). A polygenic risk score (PRS) was also derived to quantify each participant’s genetic predisposition to cardiovascular disease.

At baseline, characteristics differed across quartiles of TyG-related indices: participants in the highest quartiles tended to be older, more likely male, of lower socioeconomic status, more likely to smoke, to have hypertension or diabetes, and to be on antihypertensive/antidiabetic/lipid-lowering medications. The authors then used Cox proportional-hazards models to test associations between each IR-index quartile and incident total CVD, coronary artery disease (CAD), and stroke over follow-up. They found that, compared with the lowest quartile of TyG-related indices, those in the highest quartile had significantly increased risk of total CVD and CAD. For example, the hazard ratio (HR) for TyG-WC (highest vs lowest quartile) for total CVD was 1.41 (95 % CI 1.34–1.48) and for CAD was similarly elevated. TyG-BMI had HR around 1.33 for total CVD (95 % CI 1.28–1.39). Stroke associations were more modest and in some cases borderline.

Importantly, the study also evaluated incremental predictive value of adding these IR-indices to traditional risk models. They showed that the addition of TyG-WC, TyG-BMI and TyG-WHtR significantly improved discrimination (via integrated discrimination improvement (IDI) and net reclassification improvement (NRI)) beyond conventional risk factors; among these indices TyG-WC showed the strongest performance (for total CVD: NRI ~6.51 %, IDI ~0.309) according to the published data. The authors further considered joint effects of IR-indices and genetic risk: participants who had both high IR index (e.g., highest quartile TyG-WC) and high genetic risk (top PRS tertile) had the greatest risk of CVD (HR ~1.88 for TyG-WC + high genetic risk vs lowest IR + low genetic risk). Additive interaction metrics indicated a positive additive interaction for TyG-WC and genetic risk (relative excess risk due to interaction (RERI) ~0.101).

Mediation analyses were also performed to explore possible mechanisms: biomarkers of systemic inflammation (e.g., CRP), hepatic dysfunction (ALT, GGT, etc) and renal biomarkers (cystatin C, creatinine) together explained portions of the association between elevated IR indices and incident CVD. For instance, cystatin C (renal biomarker) mediated ~16.33% of the TyG-WC → CVD association. The authors interpret this as supporting the idea that insulin resistance in obesity may drive cardiovascular risk partly via metabolic organ dysfunction (liver, kidney) and inflammatory pathways.

In their discussion, the authors emphasise that among people with obesity (even without overt organ dysfunction), IR-related indices – particularly TyG-WC – can identify higher risk of CVD, and that the combination of IR index + genetic risk enhances stratification. They suggest that these indices could help clinicians identify high-risk obese patients who might benefit from more intensive monitoring or interventions. The strengths include large sample size, long follow-up, and well-adjusted models; limitations include the “healthy volunteer” bias in UK Biobank, predominantly White population, and reliance on baseline indices (no repeated measures).

This article highlights how obesity is more than just excess weight: it’s the metabolic dysfunction and insulin resistance that matter for cardiovascular risk.

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