Associations of different insulin resistance-related indices with the incidence and progression trajectory of cardiometabolic multimorbidity: a prospective cohort study from UK biobank

Abstract

Background: Despite established associations between insulin resistance (IR)-related indices and cardiometabolic diseases (CMDs), most studies are limited to single CMD outcomes. The study aimed to examine the influence of IR-related indices on the incidence, predictive value, and progression trajectory of cardiometabolic multimorbidity (CMM), as well as potential biological mechanisms.

Methods: This prospective study included 374,274 individuals from the UK Biobank who were free of CMDs at baseline. CMM was defined as the presence of two or more CMDs, including type 2 diabetes (T2D), coronary heart disease (CHD), and stroke. Five indices were developed to assess IR levels: triglyceride-glucose (TyG) index, TyG-body mass index (TyG-BMI), TyG-waist circumference (TyG-WC), TyG-waist-height ratio (TyG-WHtR), and triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio. Cox proportional hazards and multi-state models were utilized to examine the associations between IR-related indices and CMM incidence and transition, respectively, with results expressed as hazard ratios (HRs) and 95% confidence intervals (CIs). The predictive utility of these indices was assessed using the net reclassification index (NRI) and integrated discrimination improvement index (IDI). Mediation analyses were conducted to quantify the potential mediating roles of biomarkers.

Results: During a mean follow-up period of 13.7 years, 5048 (1.3%) individuals developed CMM. Elevated baseline IR-related indices were associated with higher risks of incident CMM. The HRs (95% CIs) for each 1-standard deviation increase were as follows: 1.30 (1.26-1.34) for the TyG index, 1.42 (1.39-1.46) for the TyG-BMI, 1.54 (1.49-1.59) for the TyG-WC, 1.52 (1.48-1.57) for the TyG-WHtR, and 1.19 (1.17-1.21) for the TG/HDL-C ratio. Besides, TyG-WHtR and TyG-WC exhibited significantly higher NRI and IDI, indicating superior predictive performance for CMM risk. These indices played critical yet distinct roles in the progression of CMM. For transitions from being free of CMDs to single CMDs, these indices had the strongest impact on T2D (all P < 0.001). Participants initially diagnosed with CHD were more likely to progress to CMM when exposed to higher IR-related indices (all P < 0.001). The effect sizes for TyG-WC and TyG-WHtR were greater than those of other indices across all transitions. Mediation analyses revealed that biomarkers associated with liver function, renal function, and inflammation collectively mediated approximately one-third of the associations of the TyG-WHtR and TyG-WC indices with incident CMM.

Conclusions: Our findings highlight the critical role of IR-related indices, particularly TyG-WHtR and TyG-WC, in the incidence, progression, and prevention of CMM. The mediation effects of biomarkers indicate the potential for targeted interventions to reduce CMM risk in high-IR individuals.

Keywords: Cardiometabolic multimorbidity; Disease trajectory; Insulin resistance; Mediation; Triglyceride-glucose index.

Fig. 1

Flowchart of selecting study population in the UK Biobank

Fig. 2

Transitions from baseline to single cardiometabolic diseases, and subsequently to cardiometabolic multimorbidity. Note Transition A represents the progression from baseline “healthy” to T2D; Transition B represents the progression from baseline “healthy” to stroke; Transition C represents the progression from baseline “healthy” to CHD; Transition D represents the progression from T2D to CMM; Transition E represents the progression from stroke to CMM; and Transition F represents the progression from CHD to CMM. T2D type 2 diabetes, CHD coronary heart disease, CMM cardiometabolic multimorbidity

Fig. 3

Kaplan–Meier curves of incident cardiometabolic multimorbidity stratified by the quartiles of IR-related indices. IR insulin resistance, TyG triglyceride-glucose index, BMI body mass index, WC waist circumference, WHtR weight-to-height ratio, TG triglyceride, HDL-C high-density lipoprotein cholesterol

Fig. 4

Dose–response relationship of insulin resistance-related indices with the risk of cardiometabolic multimorbidity. Note: Models were adjusted for age, sex, ethnicity, employment status, Townsend deprivation index, educational levels, family income, physical activity, smoking status, drinking, sleep, healthy diet scores, family history of cardiometabolic disease, SBP, DBP, and HbA1c. HR hazard ratio, CI confidence interval, TyG triglyceride-glucose index, BMI body mass index, WC waist circumference, WHtR weight-to-height ratio, TG triglyceride, HDL-C high-density lipoprotein cholesterol, SBP systolic blood pressure, DBP diastolic blood pressure, HbA1c glycated hemoglobin

Fig. 5

Mediated proportion of selected biomarkers in the associations of TyG-WC and TyG-WHtR indices with cardiometabolic multimorbidity. ^aBeta for associations between the TyG-WC index and selected mediators, ^bbeta for associations between the TyG-WHtR index and selected mediators, which were estimated using linear regression models, ^cbeta for associations between selected mediators and risk of CMM, ^dmediated proportion by selected mediators in associations between TyG-WC and CMM, ^emediated proportion by selected mediators in associations between TyG-WHtR and CMM. Models were adjusted for age, sex, ethnicity, employment status, Townsend deprivation index, educational levels, family income, physical activity, smoking status, drinking, sleep, healthy diet scores, family history of cardiometabolic disease, SBP, DBP, and HbA1c. CMM cardiometabolic multimorbidity, TyG triglyceride-glucose index, WC waist circumference, WHtR weight-to-height ratio, SBP systolic blood pressure, DBP diastolic blood pressure, HbA1c glycated hemoglobin