Subtypes of Type 2 Diabetes and Prediabetes: Mortality and Excess Life Lost in South Asians

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Background: Current definitions of type 2 diabetes (T2D) and prediabetes do not capture their pathophysiological heterogeneity. We investigated data-driven subtypes of T2D and prediabetes and evaluated their associations with mortality. Methods: We analyzed data from 14,306 South Asian participants from the CArdiometabolic Risk Reduction cohort using unsupervised k-means clustering based on five variables: age, BMI, HbA1c, insulin resistance, and beta-cell dysfunction. For each subtype of T2D or prediabetes, we estimated Cox hazard ratios (HRs) for all-cause and cardiovascular disease (CVD) mortality and excess years of life lost compared to normal glucose tolerance. Results: Among 2,639 participants with T2D, three subtypes emerged: Severe Insulin-Deficient Diabetes (SIDD;23.0%), Mild Insulin-Deficient Diabetes (MIDD;54.5%), and Severe Insulin-Resistant Diabetes (SIRD;22.5%). Among 4,992 participants with prediabetes, two subtypes were identified: Insulin-Deficient Prediabetes (IDPD;66.0%) and Insulin-Resistant Prediabetes (IRPD;34.0%). Over a median follow-up of 10.6 years, 1,076 deaths occurred (405 due to CVD). Compared with normal glucose tolerance, SIDD had the highest all-cause mortality HR (3.34 [95%CI, 2.39 to 4.68]), followed by MIDD (1.39[95%CI, 1.05 to 1.84]) and SIRD (1.67[95%CI, 1.15 to 2.41]). Among prediabetes subtypes, IDPD was associated with increased all-cause (HR: 1.32 [95%CI, 1.03 to 1.68]) and CVD mortality (HR:1.53 [95%CI, 1.00 to 2.34]), whereas IRPD was not. Excess years of life lost were greatest for SIDD (17.7 years), followed by MIDD (12.8 years) and SIRD (12.0 years). Conclusions: Insulin-deficient subtypes made up a high proportion of T2D and prediabetes cases, harboring increased mortality hazards and excess years of life lost relative to normal glucose tolerance.

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