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

Abstract

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. We analyzed data from 14,036 South Asian participants from the CArdiometabolic Risk Reduction cohort using unsupervised k-means clustering based on five variables: age, BMI, HbA1c, insulin resistance, and β-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 with normal glucose tolerance. 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 2.39-4.68), followed by MIDD (1.39; 95% CI 1.05-1.84) and SIRD (1.67; 95% CI 1.15-2.41). Among prediabetes subtypes, IDPD was associated with increased all-cause mortality (HR 1.32; 95% CI 1.03-1.68) and CVD mortality (HR 1.53; 95% CI 1.00-2.34), 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). Insulin-deficient subtypes made up a high proportion of individuals with T2D and prediabetes and were associated with higher mortality hazards and excess years of life lost.