Estimated glucose disposal rate and the dynamic transitions of cardiometabolic multimorbidity and all-cause mortality in prediabetes: a multistate trajectory analysis.

AIM: To examine the association between insulin sensitivity, measured by estimated glucose disposal rate (eGDR), and the onset, progression, and prognosis of cardiometabolic multimorbidity (CMM) and all-cause mortality. METHODS: This prospective study included 50,342 UK Biobank participants with prediabetes and free of baseline cardiometabolic disease (CMD). CMM was defined as the coexistence of at least two of the following: coronary artery disease, type 2 diabetes, and stroke. eGDR was calculated according to a previously published formula based on waist circumference, HbA1c, and hypertension status.A multistate Markov model assessed associations between eGDR and sequential transitions from CMD onset to CMM and death, accounting for competing risks and nonlinearity. Nonlinear dose-response relationships were assessed using penalized splines with three degrees of freedom. RESULTS: Over a median follow-up of 13.6 years, 12,641 participants developed a first CMD (FCMD), 2,081 progressed to CMM, and 4,847 died. Higher eGDR was associated with lower risks of FCMD (HR for per unit increase: 0.88; 95% CI: 0.87-0.89), CMM (HR: 0.93; 95% CI: 0.91-0.96), and death before FCMD (HR: 0.95; 95% CI: 0.93-0.98). No significant association was observed with mortality after CMM onset. Nonlinear associations were observed between eGDR and CMM progression across multiple transition states. CONCLUSIONS: In individuals with prediabetes, higher insulin sensitivity is associated with a reduced risk of CMD, CMM, and all-cause mortality. Once the first CMD occurs, the association between eGDR and mortality becomes less pronounced, highlighting the critical importance of early intervention to improve insulin sensitivity.