Triglyceride-glucose index, genetic susceptibility, and trajectory of microvascular multimorbidity in type 2 diabetes

The role of the triglyceride-glucose (TyG) index in the progression of diabetic microvascular complication (DMC) multimorbidity remains unclear. Moreover, its interaction with genetic susceptibility to type 2 diabetes (T2D) has not been fully elucidated. This study included T2D patients from the UK Biobank. Primary outcomes were the incidence of first DMC and DMC multimorbidity (including retinopathy, neuropathy, and nephropathy). Multivariable Cox regression and multistate models were used to assess associations between the TyG index and DMC progression. Interaction analyses examined the joint association of the TyG index and T2D genetic risk. A total of 19,512 T2D patients were included, with a median follow-up of 12.9 years. Among them, 5,875 (30.11%) developed a first DMC, and 1,314 (22.37%) progressed to multimorbidity. Each 1-SD increase in TyG was associated with a 19% increased risk of first DMC and a 38% higher risk of multimorbidity. Multistate models showed TyG was a significant predictor of progression from first DMC to multimorbidity (HR = 1.25; 95% CI: 1.15–1.37; P < 0.001), particularly among those with retinopathy (HR = 1.39) or nephropathy (HR = 1.14). A combined association was observed between high TyG index and elevated genetic risk, demonstrating a stepwise increase in risk for DMC onset and progression. In this large, population-based cohort of T2D patients, an elevated TyG index independently predicted both the onset and progression of DMC multimorbidity. This association was particularly evident in patients with retinopathy or nephropathy, with the highest risk observed among individuals with higher genetic risk, highlighting the potential utility of TyG for risk stratification and precision prevention strategies.