Abstract
BACKGROUND: We investigated the risk of type 2 diabetes (T2DM) and related comorbidities including cardiovascular disease (CVD), and mortality, based on changes in metabolic dysfunction associated steatotic liver disease (MASLD). METHODS: We analyzed data from the Korean National Health Insurance Service for individuals aged ≥ 20 years. MASLD was defined as a fatty liver index (FLI), a prediction formula based on metabolic parameters, with a cutoff of ≥ 60. FLI measurements were compared within each individual over a 2 years period. Based on changes in FLI between two health checkups, individuals were classified into four categories; never MASLD (FLI consistently < 60), incident MASLD (FLI < 60 to ≥ 60), regressed MASLD (≥ 60 to < 60), and persistent MASLD (FLI consistently ≥ 60). The primary outcome was T2DM occurrence in the general population and myocardial infarction (MI), ischemic stroke, heart failure (HF) and mortality events in individuals with preexisting T2DM with adjustment for age, sex, smoking, alcohol drinking, and regular exercise. RESULTS: In 4,397,808 individuals without T2DM, 229,475 (5.2%) developed T2DM during a median follow-up period of 7.3 years. The risk of incident T2DM was the highest in individuals with persistent MASLD compared to those who never had MASLD (HR = 5.28, 95% CI = 5.22-5.34). Individuals with incident or regressed MASLD also had increased risk of developing T2DM (HR = 3.30, 95% CI = 3.25-3.35 for incident MASLD, HR = 2.87, 95% CI = 2.82-2.92 for regressed MASLD). In a cohort of 636,520 individuals with preexisting T2DM followed for a median of 6.2 years, those with persistent MASLD had a higher risk of HF (HR = 1.28, 95% CI = 1.25 to 1.32), MI (HR = 1.15, 95% CI = 1.10 to 1.20), stroke (HR = 1.14, 95% CI = 1.09 to 1.19) and all-cause mortality (HR = 1.11, 95% CI = 1.09-1.14) compared to individuals who never had MASLD. Similarly, both incident and regressed MASLD were associated with an increased risk for HF, MI, stroke and all-cause mortality. CONCLUSIONS: Persistent MASLD is associated with an increased risk of incident T2DM, and further elevates the risk of CVD, and mortality among individuals with T2DM. Even individuals with incident or regressed MASLD exhibit an increased risk of these adverse outcomes compared to those who never had MASLD. TRIAL REGISTRATION: N/A.