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Background <p>Insulin resistance (IR) is thought to be a major metabolic driver of both metabolic dysfunction-associated steatotic liver disease (MASLD) and cardiometabolic diseases (CMD). Although several IR-related indices have been linked to individual CMD, their associations with cardiometabolic multimorbidity (CMM) and stage-specific disease progression in individuals with MASLD remain unclear.</p> Methods <p>A total of 109,604 UK Biobank participants with MASLD who were free of CMD at baseline were included in this study. The analysis covered nine IR-related metrics, including the triglyceride-glucose (TyG) index, TyG-body mass index (TyG-BMI), TyG-waist circumference (TyG-WC), TyG-waist-to-height ratio (TyG-WHtR), TyG-body roundness index (TyG-BRI), TyG-a body shape index (TyG-ABSI), TyG-visceral adiposity index (TyG-VAI), TyG-weight-adjusted waist index (TyG-WWI), and the triglyceride-to-high-density lipoprotein cholesterol ratio (TG/HDL-C). Associations with incident CMM were estimated using Cox models. Multi-state models were applied to evaluate stage-specific transitions. Incremental predictive performance was evaluated using time-dependent ROC analyses, C-index, net reclassification improvement (NRI), and integrated discrimination improvement (IDI). Exploratory mediation analyses were further performed to explore possible biological pathways.</p> Results <p>Over a median follow-up of 15.9&#xa0;years, 4944 participants developed CMM. Higher levels of all IR-related indices were linked to a greater risk of CMM. In the fully adjusted model, the strongest associations were observed for TyG-WHtR, TyG-BMI, and TyG-WC, with HRs (95% CIs) of 2.70 (2.45–2.97), 2.36 (2.16–2.58), and 2.33 (2.12–2.56), respectively, for the highest versus lowest quartile. Multistate analyses indicated that these indices showed stage-specific associations across the CMM trajectory. For transitions from a CMD-free state to single CMDs, the strongest associations were observed for T2D. Transitions from CHD or stroke were more likely to progress to CMM when exposed to higher IR-related indices. All indices modestly improved CMM prediction beyond conventional risk factors (all <i>P</i> &lt; 0.001), with TyG-WHtR showing the best performance. Exploratory mediation analyses suggested that inflammatory, hepatic, and renal biomarkers jointly accounted for 11–23% of the associations.</p> Conclusions <p>Among individuals with MASLD, IR-related indices were significantly associated with the incidence and progression of CMM. Indices incorporating central adiposity, especially TyG-WHtR, provided the most informative risk estimates and modest incremental predictive value.</p> Graphical Abstract <p></p>

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Associations of insulin resistance-related indices with the risk and progression of cardiometabolic multimorbidity in individuals with metabolic dysfunction-associated steatotic liver disease: a prospective cohort study

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月22日

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  • Mengtong Sun,
  • Qida He,
  • Yu Wang,
  • Jiazhen Yao,
  • Yueping Shen,
  • Zhifen Liu,
  • Qiang Han

摘要

Background

Insulin resistance (IR) is thought to be a major metabolic driver of both metabolic dysfunction-associated steatotic liver disease (MASLD) and cardiometabolic diseases (CMD). Although several IR-related indices have been linked to individual CMD, their associations with cardiometabolic multimorbidity (CMM) and stage-specific disease progression in individuals with MASLD remain unclear.

Methods

A total of 109,604 UK Biobank participants with MASLD who were free of CMD at baseline were included in this study. The analysis covered nine IR-related metrics, including the triglyceride-glucose (TyG) index, TyG-body mass index (TyG-BMI), TyG-waist circumference (TyG-WC), TyG-waist-to-height ratio (TyG-WHtR), TyG-body roundness index (TyG-BRI), TyG-a body shape index (TyG-ABSI), TyG-visceral adiposity index (TyG-VAI), TyG-weight-adjusted waist index (TyG-WWI), and the triglyceride-to-high-density lipoprotein cholesterol ratio (TG/HDL-C). Associations with incident CMM were estimated using Cox models. Multi-state models were applied to evaluate stage-specific transitions. Incremental predictive performance was evaluated using time-dependent ROC analyses, C-index, net reclassification improvement (NRI), and integrated discrimination improvement (IDI). Exploratory mediation analyses were further performed to explore possible biological pathways.

Results

Over a median follow-up of 15.9 years, 4944 participants developed CMM. Higher levels of all IR-related indices were linked to a greater risk of CMM. In the fully adjusted model, the strongest associations were observed for TyG-WHtR, TyG-BMI, and TyG-WC, with HRs (95% CIs) of 2.70 (2.45–2.97), 2.36 (2.16–2.58), and 2.33 (2.12–2.56), respectively, for the highest versus lowest quartile. Multistate analyses indicated that these indices showed stage-specific associations across the CMM trajectory. For transitions from a CMD-free state to single CMDs, the strongest associations were observed for T2D. Transitions from CHD or stroke were more likely to progress to CMM when exposed to higher IR-related indices. All indices modestly improved CMM prediction beyond conventional risk factors (all P < 0.001), with TyG-WHtR showing the best performance. Exploratory mediation analyses suggested that inflammatory, hepatic, and renal biomarkers jointly accounted for 11–23% of the associations.

Conclusions

Among individuals with MASLD, IR-related indices were significantly associated with the incidence and progression of CMM. Indices incorporating central adiposity, especially TyG-WHtR, provided the most informative risk estimates and modest incremental predictive value.

Graphical Abstract