Background: Few preclinical studies have shown that sodium-glucose cotransporter-2 (SGLT2) inhibitors may prevent or delay hepatocarcinogenesis by suppressing β-catenin signaling or inducing apoptosis of tumor cells. One recent population-based cohort study also reported that use of SGLT2 inhibitors was significantly associated with a lower risk of major hepatic events. However, the risk of hepatocellular carcinoma (HCC) with SGLT2 inhibitors remain unknown.
Objectives: To assess whether the use of SGLT2 inhibitors is associated with a lower risk of HCC compared with dipeptidyl peptidase-4 (DPP4) inhibitors.
Methods: We conducted a population-based cohort study using an active comparator, new-user design and nationwide healthcare data from Korea between 2014 and 2020. Patients newly prescribed SGLT2 inhibitors or DPP4 inhibitors were included in the study cohort. Patients were followed from 365 days after cohort entry until an incident diagnosis of HCC, switch to a comparator drug, death, or end of the study period (31 Dec 2020), whichever occurred first; analogous to a modified intention-to-treat approach. Within the propensity score fine stratification weighted cohort of 873,320 new users of SGLT2 inhibitors and DPP4 inhibitors, we used weighted Cox proportional hazards models to estimate weighted hazard ratios (HRs) with 95% CIs for the risk of HCC associated with SGLT2 inhibitor use versus DPP4 inhibitor use. Secondary analyses examined the ingredient specific effects of SGLT2 inhibitors and stratified on age, sex, and history of liver-related comorbidities including non-alcoholic fatty liver disease. Various sensitivity analyses were done to assess the robustness of the main findings.
Results: Over a median follow-up of 2.5 and 3.6 years for the SGLT2 inhibitor and DPP4 inhibitor groups, respectively, the incidence rate of HCC was lower with SGLT2 inhibitors than DPP4 inhibitors (weighted incidence rate 76.2 versus 95.0 per 100,000 person-years), corresponding to a weighted HR of 0.81 (95% CI, 0.67-0.98). Results of secondary analyses showed significantly lower HCC risks with SGLT2 inhibitors among those aged < 50 years (0.58 [0.35-0.99]), females (0.65 [0.42-0.99]), no history of liver cirrhosis (0.77 [0.62-0.95]) or viral hepatitis (0.71 [0.56-0.89]), and fatty liver index ≥60 (0.71 [0.53-0.96]). Consistent point estimates were found across sensitivity analyses.
Conclusions: These findings suggest that initiating SGLT2 inhibitors, as compared with DPP4 inhibitors, is associated with a lower risk of HCC in routine clinical practice, with particular benefits possible among patients with type 2 diabetes aged < 50 years, female, or with non-alcoholic fatty liver disease.
