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 AND AIMS: Type 2 diabetes mellitus (T2DM) is a recognized modifiable risk factor for 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.