Effect of antidiabetics on the risk of hepatocellular carcinoma in patients with diabetes and metabolic dysfunction-associated steatotic liver disease

초록

Background and aims: Diabetes is a significant risk factor for the development of hepatocellular carcinoma (HCC). In this retrospective cohort study, we investigated the effects of antidiabetic drugs on the risk of HCC development in patients with diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD). Method: From 2004 to 2018, patients with diabetes and MASLD were selected from three tertiary academic institutes in South Korea. The patients were followed from the date of MASLD diagnosis until HCC diagnosis, death, or last follow-up. Independent predictors of HCC development were investigated using landmark Cox proportional hazard models. Results: In total, 4, 024 patients with diabetes and MASLD were identified. Their median age was 56.0 years, and 2, 184 (54.3%) were male. A total of 3, 370 (83.7%) patients received antidiabetics (oral antidiabetic drugs [OADs] in 2, 581 and insulin-based therapy in 789), whereas the remaining 16.3% of patients received no antidiabetics. During a median follow-up of 5.1 years, 269 (6.7%) patients developed HCC. The multivariate analysis showed that liver cirrhosis, a fibrosis-4 Index ≥1.45, male sex, older age, obesity, hypertension, dyslipidemia, lower albumin level, diabetes complications, longer duration of diabetes, and the type of antidiabetics were significantly associated with an increased risk for HCC (all p < 0.05). No treatment and OAD therapy had comparable risks for HCC, whereas insulinbased therapy was associated with an increased risk for HCC compared to no treatment (hazard ratio [HR] = 1.739, 95% confidence interval [CI] 1.047–2.888) and OAD therapy (HR = 1.717, 95% CI 1.242– 2.372) (all p < 0.05). Metformin-based therapy was associated with a reduced risk for HCC in the entire study population (HR = 0.713, 95% CI 0.522–0.973) and in a subgroup of patients receiving OAD therapy (HR = 0.362, 95% CI 0.205–0.640) (all p < 0.05). Metformin-based therapy decreased the risk for HCC in both patients who received OAD monotherapy (HR = 0.148, 95% CI 0.044–0.503) and those who received dual OAD therapy (HR = 0.448, 95% CI 0.200–0.986). However, in patients receiving insulin-based therapy, the combination of metformin treatment did not reduce the risk for HCC compared to insulin monotherapy or combined treatment of insulin and OADs other than metformin. Conclusion: Metformin use decreased the incidence of HCC in patients with diabetes and MASLD. Careful consideration regarding the choice of antidiabetic drugs is needed for HCC prevention in such patients.