Non-Alcoholic Fatty Liver Disease Increases the Risk of Incident Type 2 Diabetes with Effect Modification by Sex and Menopausal Status

Abstract

Background: We investigated effect modification by menopausal status and sex on the association between non-alcoholic fatty liver disease (NAFLD) and risk of incident type 2 diabetes (T2D), and whether a diagnosis of NAFLD improves risk prediction for incident T2D. Methods: In total, 242,436 adults without diabetes (111,991 premenopausal women; 6,464 postmenopausal women; 123,981 men) were included. Cox proportional hazard models were used to estimate hazard ratios (HRs; 95% confidence intervals [CIs]) for incident diabetes according to NAFLD status assessed by hepatic ultrasound. The incremental predictive role of NAFLD for incident T2D was assessed using the area under the receiver operating characteristic curve, net reclassification improvement, and integrated discrimination improvement. Findings: A total of 8,382 participants developed T2D (crude incidence rate/10 3 person-years: 3.0 premenopausal women; 10.2 postmenopausal women; 9.2 men) during median follow-up of 5.7 years. NAFLD was positively associated with incident T2D in all groups. After adjustment for potential confounders, the multivariable-adjusted HRs (95% CIs) for incident T2D comparing NAFLD to no NAFLD were 4.41 (3.99–4.87), 2.73 (2.13–3.49), and 2.17 (2.05–2.30) in premenopausal women, postmenopausal women and men, respectively. The addition of NAFLD to conventional risk factors improved risk prediction for incident T2D in both sexes, with a greater improvement in women than men. Interpretation: NAFLD is a stronger risk factor for incident T2D in premenopausal women than in post-menopausal women or men. The presence of NAFLD identifies individuals at high risk of T2D who may benefit from participation in diabetes prevention programs. Funding Information: This study was supported by the SKKU Excellence in Research Award Research Fund, Sungkyunkwan University, 2020. CDB is supported in part by the Southampton NIHR Biomedical Research Centre (IS-BRC-20004), UK. Declaration of Interests: The authors have no conflicts of interest to disclose. Ethics Approval Statement: This study was approved by the institutional review board of Kangbuk Samsung Hospital (IRB No. KBSMC 2021-10-043), which waived the need for informed consent owing to the use of de-identified retrospective data from routine health screening.