Glucagon-like peptide-1 receptor agonists (GLP-1 RA) versus statins and the risk of hepatocellular carcinoma (HCC) and hepatic decompensation in patients with type 2 diabetes mellitus (T2DM).

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Background: Statins have been shown to reduce the risk of HCC in high-risk populations with metabolic diseases. However, emerging data suggests that GLP-1 RA’s may also offer hepatoprotection by reversing metabolic and inflammatory drivers contributing to HCC development. Patients with T2DM are at an increased risk of metabolic associated steatotic liver disease (MASLD) and HCC. To our knowledge, no real-world studies have directly compared the effectiveness of GLP-1 RA’s and statins for prevention of HCC in patients with T2DM. In this study, we aim to compare the incidence of HCC and hepatic decompensation events in patients with T2DM treated with GLP-1 RA’s vs statins. Methods: We performed a retrospective cohort study using data from TriNetX, a healthcare database of over 150 million patients in the United States. Adult patients with T2DM were identified and stratified by use of GLP-1 RA (semaglutide, dulaglutide, tirzepatide, exenatide, liraglutide, and lixisenatide) or statin (pitavastatin, simvastatin, fluvastatin, atorvastatin, rosuvastatin or lovastatin). Exposure groups were mutually exclusive with no overlap in GLP-1 RA or statin use. Propensity score matching was conducted between cohorts, matching for age, sex, race, tobacco use, alcohol use, hypertension, hyperlipidemia, obesity, MASLD, aspirin use, non-steroidal anti-inflammatory analgesic drug use, and other T2DM medications. Five-year incidence of HCC was compared between the GLP-1 RA and statin cohorts. In a subsequent analysis, hepatic decompensation events of ascites, hepatic encephalopathy (HE), spontaneous bacterial peritonitis (SBP), and esophageal varices (EV) were compared. Results: We identified 1,411,022 patients with T2DM, including 254,832 GLP-1 RA users and 1,156,190 statin users. After PSM, 219,984 patients were included in the analysis. There was no significant difference in the five-year incidence of HCC between the GLP-1 RA and statin cohorts (0.14% vs 0.15%, odds ratio (OR) 0.95, 95% confidence interval (CI)0.81-1.11, p =0.5). In the subsequent analysis, GLP-1 RA use was associated with a lower incidence of ascites (0.98% vs 1.99%, OR 0.84, 95% CI 0.46-0.51, p <0.001), HE (0.18% vs 0.22%, OR 0.84, 95% CI 0.74-0.96, p =0.01), and SBP (0.05% vs 0.1%, OR 0.52, 95% CI 0.42-0.65, p <0.001). There was no difference in incidence of EV (0.33% vs 0.35%, OR 0.94, 95% CI 0.85-1.04, p =0.25). Conclusions: In patients with T2DM at elevated risk for MASLD and HCC, we found that GLP-1 RA use was associated with significantly lower incidence of hepatic decompensation events compared to statin use. However, there was no significant difference in HCC incidence between the cohorts. Prospective studies are warranted to confirm the hepatoprotective effect of GLP-1 RA medications and evaluate long-term oncologic outcomes.