Target Trial Emulations of GLP-1 and Dual GLP-1/GIP Agonists to Reduce Major Adverse Liver Outcomes in Type 2 Diabetes.

BACKGROUND: Clinical trials suggest GLP-1 receptor agonists (RAs) and dual glucagon-like peptide-1 (GLP-1)/glucose-dependent insulinotropic polypeptide (GIP) RAs improve metabolic dysfunction associated with steatohepatitis (MASH) in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to compare the estimate of the relative effect of tirzepatide, semaglutide, and liraglutide in reducing the risk of major adverse liver outcomes (MALOs) in patients with type 2 diabetes (T2D). DESIGN, SETTING AND PARTICIPANTS: We emulated target trials based on a real-world network of electronic health records (EHRs) from over 150 million patients. Three target trials were emulated, among eligible patients with T2D who had no prior MALO diagnosis, by comparing therapy involving tirzepatide, semaglutide, and liraglutide versus DPP4 inhibitor (DPP4i) therapy. We identified the first-ever diagnosis of MALO occurring within a 2-year follow-up period and compared across the treatment groups using Kaplan-Meier survival analyses. Cohorts underwent propensity score matching 1:1 for confounders. We performed sensitivity analyses relating to geographical location, combination with metformin, and by treatment adherence. We also performed head-to-head analyses of the incretin-based therapies. RESULTS: After matching, we identified three target trials comprised of 10 165, 56 702, and 8 301 patients treated with tirzepatide, semaglutide, and liraglutide, respectively (1:1 with reference patients) for a 2-year period. Tirzepatide (HR 0.53 [95% CI 0.40, 0.71]) and semaglutide (HR 0.81 [0.72, 0.90]) were associated with a significant reduction in the risk of incident MALO compared with DPP4i, whereas liraglutide was not (HR 1.04 [95% CI 0.79, 1.36]). In head-to-head comparisons, tirzepatide was associated with a significantly lower risk of incident MALO compared with liraglutide (HR 0.56 [95% CI 0.39, 0.79]), but not semaglutide (HR 0.83 [95% CI 0.63, 1.09]). Semaglutide was not associated with a reduced risk compared with liraglutide (HR 0.77 [95% CI 0.57, 1.05]). CONCLUSION: Treatment with tirzepatide and, to a lesser extent, semaglutide, in patients with T2D, was associated with a lower incidence of MALO compared with DPP4i after 2 years; largely driven by a reduction in the rates of compensated and decompensated cirrhosis. A reduction in MALO was not demonstrated with the use of liraglutide. These findings highlight a comparative benefit of tirzepatide (and semaglutide) versus DPP4i and should prompt more robust, longer-term randomised controlled studies to evaluate their role in preventing MALO in this increasingly prevalent patient population with co-existing T2D and MASLD.