Associations of eight insulin resistance-related indices and genetic risk with incident cardiometabolic multimorbidity among participants with hypertension: a large prospective cohort study

Background: Cardiometabolic multimorbidity (CMM) is prevalent among individuals with hypertension. Although insulin resistance (IR)-related indices have been linked to CMM, their associations with incident CMM in hypertensive populations remain unclear. This study examined the associations in this high-risk group, focusing on the roles of genetic factors and biomarkers. Methods: This observational prospective cohort analysis used data from the UK Biobank, comprising 129,853 hypertensive patients free of pre-existing coronary heart disease, stroke, or type 2 diabetes. Eight IR-related indices were computed: triglyceride-glucose (TyG) index, TyG-body mass index (TyG-BMI), TyG-waist circumference (TyG-WC), TyG-waist-to-height ratio (TyG-WHtR), TyG-a body shape index (TyG-ABSI), TyG-weight-adjusted waist index (TyG-WWI), TyG-body roundness index (TyG-BRI), and triglyceride to high-density lipoprotein cholesterol ratio (TG-HDL-C). Associations were examined using Cox proportional hazards models. Incremental predictive value was quantified using the net reclassification improvement, integrated discrimination improvement, and the C index. We also analyzed their joint and interaction effects with genetic risk and conducted exploratory biomarker analyses. Results: Over a median follow-up of 13 years, 28,455 incident CMM events were recorded. Multivariable-adjusted hazard ratios (95% CIs) the highest versus lowest tertiles were: 1.78 (1.73-1.83) for TyG index, 2.10 (2.04-2.17) for TyG-BMI, 2.29 (2.21-2.37) for TyG-WC, 2.23 (2.16-2.30) for TyG-WHtR, 2.08 (2.02-2.15) for TyG-WWI, 2.17 (2.10-2.24) for TyG-BRI, 1.90 (1.84-1.97) for TyG-ABSI, and 1.73 (1.68-1.79) for TG-HDL-C. Per standard deviation increment was associated with 18%-48% higher risks. All indices improved incremental predictive value, with TyG-WHtR showing the strongest performance. Individuals with high IR-related indices and high genetic risk exhibited the highest CMM risk, with additive interactions. High genetic risk appeared to strengthen the adverse associations between IR-related indices and CMM, with evidence of multiplicative interactions. Biomarker analyses suggested that systemic inflammation and biomarkers of liver and renal function might statistically account for part of the observed associations. Conclusion: Higher levels of IR-related indices, especially TyG-WHtR, were associated with an elevated risk of incident CMM in individuals with hypertension, particularly among those with high genetic risk. Inflammatory, hepatic, and renal biomarker abnormalities were related to the associations. IR-related indices, particularly TyG-WHtR, may provide useful information for risk stratification of CMM among individuals with hypertension.