Nonalcoholic fatty liver disease without overlapping metabolic-associated fatty liver disease and the risk of incident type 2 diabetes

Background and Aims: Re-classifying NAFLD as metabolic-associated fatty liver (MAFLD) has been proposed. While some people fulfil criteria for NAFLD, they do not have MAFLD; and whether NAFLD-only subjects have increased the risk of type 2 diabetes remains unknown. We compared risk of incident T2D in individuals with: (a) NAFLD-only; and (b) MAFLD, to individuals without fatty liver, considering effect modification by sex. Methods: 246 424 Koreans without diabetes or a secondary cause of ultrasound-diagnosed hepatic steatosis were studied. Subjects were stratified into: (a) NAFLD-only status and (b) NAFLD that overlapped with MAFLD (MAFLD). Cox proportional hazards models with incident T2D as the outcome were used to estimate hazard ratios (HRs) for: (a) and (b). Models were adjusted for time-dependent covariates, and effect modification by sex was analysed in subgroups. Results: A total of 5439 participants had NAFLD-only status and 56 839 met MAFLD criteria. During a median follow-up of 5.5 years, 8402 incident cases of T2D occurred. Multivariable-adjusted HRs (95% CI) for incident T2D comparing NAFLD-only and MAFLD to the reference (neither condition) were 2.39 (1.63–3.51) and 5.75 (5.17–6.36) (women), and 1.53 (1.25–1.88) and 2.60 (2.44–2.76) (men), respectively. The increased risk of T2D in the NAFLD-only group was higher in women than in men (p for interaction by sex <0.001) and consistently observed across all subgroups. Risk of T2D was increased in lean participants regardless of metabolic dysregulation (including prediabetes). Conclusions: NAFLD-only participants without metabolic dysregulation and the criteria for MAFLD are at increased risk of developing T2D. This association was consistently stronger in women than in men.