Single-point insulin sensitivity estimator and incident cardiometabolic multimorbidity: a prospective cohort study of middle-aged and older Chinese adults

Insulin resistance is closely involved in the development of diabetes, dyslipidemia, adiposity-related metabolic dysfunction, and cardiovascular disease. The single-point insulin sensitivity estimator (SPISE), derived from triglycerides, HDL-C, and body mass index, may provide a simple marker of insulin sensitivity-related metabolic status. We examined the association between SPISE and incident cardiometabolic multimorbidity (CMM) among middle-aged and older Chinese adults. This prospective cohort study included 7,628 participants aged 45 years or older from the China Health and Retirement Longitudinal Study who were free of CMM at baseline. Baseline SPISE was calculated from triglycerides, HDL-C, and body mass index. Incident CMM was defined as the occurrence of at least two cardiometabolic conditions, including diabetes, heart disease, and stroke. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Restricted cubic splines, subgroup analyses, sensitivity analyses, mediation analyses, and complementary two-sample Mendelian randomization analyses of SPISE-related metabolic components were performed. During 7 years of follow-up, 592 participants developed incident CMM. In the fully adjusted model, each 1-SD increase in SPISE was associated with a 39% lower risk of incident CMM (HR 0.61, 95% CI 0.56–0.67). The association was approximately linear and remained consistent across multiple sensitivity analyses. Participants in the highest SPISE tertile had a lower risk of CMM than those in the lowest tertile. The inverse association was stronger among participants without hypertension than among those with hypertension (HR 0.53, 95% CI 0.47–0.60 vs. HR 0.76, 95% CI 0.66–0.87; P for interaction < 0.001). In complementary two-sample Mendelian randomization analyses, genetically predicted higher BMI and lower HDL-C, but not triglycerides, were associated with increased CMM risk. Higher SPISE was associated with a lower risk of incident CMM in middle-aged and older Chinese adults. As an index derived from routine lipid and anthropometric measures, SPISE may help describe insulin sensitivity-related metabolic risk in population-based studies. However, it should not be interpreted as a standalone clinical prediction tool. Further validation in independent cohorts is warranted.