Glucagon-Like Peptide-1 Receptor Agonists and Hepatic Decompensation Events in Patients With Cirrhosis and Diabetes

Abstract

Background & aims: The study sought to compare the effectiveness of glucagon-like peptide-1 receptor agonists (GLP-1RAs) with dipeptidyl peptidase-4 (DPP-4) inhibitors, sulfonylureas, or sodium-glucose cotransporter-2 (SGLT-2) inhibitors in reducing decompensation events, among patients with cirrhosis and type 2 diabetes.

Methods: This population-based, retrospective cohort study included patients with type 2 diabetes and cirrhosis, in a commercial healthcare database (IBM MarketScan). We constructed 3 pairwise, 1:1 propensity score (PS)-matched cohorts of adults initiating GLP-1RAs or a comparator medication (ie, DPP-4 inhibitors [2006-2020], sulfonylurea [2005-2020], or SGLT-2 inhibitors [2013-2020]). Patients were followed in an as-treated approach for decompensation events (ie, ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, hepatic encephalopathy, or esophageal variceal hemorrhage). Within each PS-matched cohort, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs), controlling for >90 baseline characteristics.

Results: Over 132 days of median follow-up (interquartile range, 73-290 days), PS-matched rates of any decompensation were significantly lower among GLP-1RA initiators, versus DPP-4 inhibitor initiators (105.2 vs 144.0 per 1000 person-years [PY]; HR, 0.68; 95% CI, 0.53-0.88; n = 1431 pairs), and versus sulfonylureas (97.3 vs 144.0 per 1000 PY; HR, 0.64; 95% CI, 0.48-0.84; n = 1246 pairs). Similar, inverse associations were found for individual decompensation events, including ascites, spontaneous bacterial peritonitis, or hepatorenal syndrome (HR, 0.66; 95% CI, 0.45-0.97; and HR, 0.66; 95% CI, 0.46-0.94, respectively); esophageal variceal hemorrhage (HR, 0.62 [95% CI, 0.41-0.92; and HR, 0.59; 95% CI, 0.37-0.92, respectively); and hepatic encephalopathy (HR, 0.76; 95% CI, 0.55-1.06; and HR, 0.60; 95% CI, 0.39-0.92, respectively). Results persisted in subgroups of patients with and without previously decompensated cirrhosis. In contrast, decompensation rates were similar when GLP-1RAs and SGLT-2 inhibitors were directly compared (103.5 vs 112.8 per 1000 PY; HR, 0.89; 95% CI, 0.62-1.28).

Conclusions: Among cirrhotic patients with type 2 diabetes, we find high rates of decompensation, consistent with previous reports; these rates were substantially lower among GLP-1RA initiators compared with DPP-4 inhibitors or sulfonylureas.

Keywords: Antidiabetic Therapy; Comparative Effectiveness; Decompensated Cirrhosis; Pharmacoepidemiology.

Figure 1.

Cohort Construction Abbreviations: GLP-1 RA, glucagon-like peptide receptor agonist; DPP-4, Dipeptidyl Peptidase-4; SGLT-2, sodium-glucose cotransporter-2; GDM, gestational diabetes *included patients were adults over age 18 years with diagnoses of both type 2 diabetes and cirrhosis, as outlined in the Methods. Cohort 1 included new initiators of either GLP-1RA or DPP-4i starting on October 19, 2006 (consistent with the marketing of sitagliptin, the first approved DPP-4i); Cohort 2 included new initiators of either GLP-1RA or sulfonylureas, starting on April 28, 2005 (consistent with the marketing of exenatide, the first approved GLP-1RA); Cohort 3 included new initiators of either GLP-1RA or SGLT-2i, starting on March 29, 2013 (consistent with the marketing of canagliflozin, the first approved SGLT-2i). For details, see Methods.

Figure 2.

Cumulative Incidence of Hepatic Decompensation* among Propensity Score-Matched Patients with Cirrhosis Initiating GLP-1 RA Therapy or Alternative Antidiabetic Medications Abbreviations: GLP-1 RA, glucagon-like peptide receptor agonist; DPP-4, Dipeptidyl Peptidase-4; SGLT-2, sodium-glucose cotransporter-2; No., number *Hepatic decompensation was defined as the first hospitalization for ascites, spontaneous bacterial peritonitis (SBP), hepatorenal syndrome, bleeding esophageal varices or hepatic encephalopathy after the cohort entry date (i.e. date of drug initiation). For details, see Methods. **P-values were obtained using Gray’s test for equality of the cumulative incidence functions between each exposure group after propensity score-matching, accounting for the competing risk of all-cause mortality.