Type 2 diabetes (T2D) accelerates progression of chronic liver disease to cirrhosis, yet the effects of most glucose-lowering drugs (GLDs) on cirrhosis risk in T2D are unknown. To address this gap, we compared cirrhosis risk following initiation of newer second-line GLDs vs. thiazolidinediones (TZDs), which improve histology in non-alcoholic fatty liver disease.

Using the US Medicare Fee-for-Service database (2007–2015) and an active comparator, new-user design, we estimated crude incidence rates (IRs) and propensity-score adjusted hazard ratios (aHR) for incident cirrhosis, comparing newer GLDs (dipeptidyl peptidase-4 inhibitors (DPP4i), glucagon-like peptide-1 receptor agonists (GLP1RA), and sodium-glucose co-transporter 2 inhibitors (SGLT2i)) vs. TZDs.

Among 239,549 total initiators, we observed 318, 151, and < 30 cirrhosis events when comparing DPP4i vs. TZD, GLP1RA vs. TZD, and SGLT2i vs. TZD, respectively. IRs ranged from 1.7 [95% CI, 0.8–3.6] to 3.6 [2.5–5.2] events per 1000 person-years. Point aHR estimates for cirrhosis were elevated among newer GLD initiators vs. TZD (DPP4i: 1.15 [0.89–1.50]; GLP1RA: 1.34 [0.82–2.20]; SGLT2i: 1.16, [0.44–3.08]), although estimates were imprecise due to short durations of drug exposure.

We observed mildly elevated cirrhosis risk with newer GLDs vs. TZD; however, uncertainty remains due to imprecise and statistically non-significant effect estimates.