Impact of newer antihyperglycemic agents on hepatic complications: A systematic review and meta-analysis of data from 5.3 million patients with type 2 diabetes mellitus

Background & Aims: Type 2 diabetes mellitus (T2DM) is a recognized modifiable risk factor for hepatocellular carcinoma (HCC) and liver-related mortality. The effects of newer antidiabetic agents—including glucagon-like peptide-1 receptor agonists (GLP-1 RAs), sodium-glucose cotransporter-2 (SGLT-2) inhibitors, and dipeptidyl peptidase-4 (DPP-4) inhibitors—on hepatic outcomes remain uncertain. We aimed to evaluate whether these therapies reduce the risk of HCC and non-HCC liver-related events (LREs) in patients with T2DM. Approach and Results: A systematic literature search was performed to identify studies reporting hepatic complications among patients with T2DM prescribed GLP-1 RAs, SGLT-2 inhibitors, or DPP-4 inhibitors. Comparisons were made against patients receiving various glucose-lowering therapies other than the drug of interest. Subgroup analyses were conducted in patients with chronic liver disease. Random-effects meta-analyses were used to estimate pooled hazard ratios (HRs). Of 2,228 records screened, 36 cohort studies comprising 5,363,858 patients were included. Compared with other glucose-lowering therapies, GLP-1 RAs were associated with significantly reduced risks of HCC (pooled HR 0.77, 95% CI 0.66–0.90) and LREs (0.79 0.65–0.95). SGLT-2 inhibitors similarly conferred protection against HCC (0.76 0.67–0.86) and LREs (0.82 0.73–0.92). By contrast, DPP-4 inhibitors were not associated with hepatoprotection, showing neutral effects on HCC (1.12 0.91–1.39) and increased risk of LREs (1.24 1.15–1.34). In patients with chronic liver disease, GLP-1 RAs were uniquely associated with reduced hepatic decompensation (0.79 0.71–0.88). Conclusions: GLP-1 RAs and SGLT-2 inhibitors were associated with hepatoprotective effects compared with other glucose-lowering therapies in patients with T2DM, with GLP-1 RAs showing additional benefits in chronic liver disease. These findings provide evidence on the relationships between antidiabetic drug classes and liver-related outcomes in patients with T2DM and may inform clinical decision-making.