Synergistic Effects of Type 2 Diabetes and Alcohol on All‐Cause and Liver‐Related Mortality in Steatotic Liver Disease

BACKGROUND: Type 2 diabetes (T2D) and alcohol consumption are well-established risk factors for adverse clinical outcomes among individuals with steatotic liver disease (SLD). However, data about the synergistic effects of T2D and alcohol on all-cause and liver-related mortality in SLD remain scarce. METHOD: Leveraging data from UK Biobank and U.S. NHANES, we assessed risks of all-cause and liver-related mortality across 6 groups stratified by T2D status and SLD spectrum using Cox proportional hazards models: no T2D + MASLD, no T2D + MetALD, no T2D + ALD, T2D + MASLD, T2D + MetALD and T2D + ALD. The population attributable fraction (PAF) and relative excess risk due to interaction (RERI) were calculated to examine the interplay between these two factors. RESULTS: 24,052 all-cause and 953 liver-related deaths were recorded for 174,711 participants from the UK Biobank. The coexistence of T2D and elevated alcohol intake, particularly when with T2D and ALD, was associated with substantially worse outcomes, including a 1.23-1.60 fold increased risk of all-cause mortality and a markedly higher 1.65-7.45 fold risk of liver-related mortality compared with no T2D + MASLD. The combined effect of T2D and alcohol use accounted for a modest PAF of 6.74% for all-cause mortality, but they contributed to a PAF of 41.63% for liver-related mortality. Significant RERI was exclusively observed for liver-related mortality, but not for all-cause mortality. CONCLUSIONS: Co-exposure to T2D and alcohol intake substantially increased the risk of all-cause and liver-related mortality among individuals with SLD. Their interplay conferred significant disease burden, underscoring the importance of alcohol abstinence and glycemic control in this population.