SUN-158 - Comparative Risk of NAFLD and NASH in Patients with PCOS Treated with Metformin Versus GLP-1 Receptor Agonists: A Multicenter Retrospective Analysis

Introduction: Current literature indicates a strong link between polycystic ovarian syndrome (PCOS) and an increased risk of developing non-alcoholic fatty liver disease (NAFLD) and progression to non-alcoholic steatohepatitis (NASH). Proposed mechanisms include insulin resistance and hyperandrogenism as independent mediators of intrahepatic lipid accumulation and hepatic inflammation. Emerging research demonstrates that glucagon-like peptide-1 receptor agonists (GLP-1RAs) possess potent anti-inflammatory effects and improve insulin sensitivity. The objective of our study is to compare the risk of NAFLD and NASH in patients treated with Metformin - the current standard therapy for patients with PCOS and metabolic syndrome - versus GLP-1RAs.

Methods: We conducted a multicenter retrospective cohort analysis using the Global Collaborative Network on the TrinetX platform, which contains deidentified healthcare data from over 200 million patients across more than 150 healthcare organizations. Cohorts were defined as female patients over 18 years old with a diagnosis of PCOS who received either Metformin (Cohort 1: n=133,362) or GLP-1RAs (Cohort 2: n=28,320). Propensity score matching was applied to minimize bias and confounding. Variables included in the matching process included demographic factors (such as age, race, and ethnicity), markers of metabolic syndrome (such as body mass index, lipid profile, blood pressure, and Hemoglobin A1c), and indicators of progressive liver disease (such as INR and hepatic function panel). This resulted in balanced cohorts of 22,169 patients each. Outcomes assessed were NAFLD (ICD-10 code K76.0) and NASH (ICD-10 code K75.81), occurring at least six months after the index event. Risk differences (RDs) and 95% confidence intervals (95% CIs) were calculated to assess the outcomes within a 5-year observation window. Those with the outcomes prior to the index event were excluded from analysis.

Results: Compared to the GLP-1RA cohort, the Metformin cohort demonstrated a small but statistically significant reduction in absolute risk of NAFLD (RD: -0.004, 95% CI: -0.008 to -0.001, p-value=0.023) and NASH (RD: -0.002, 95% CI: -0.003 to -0.000, p-value=0.007).

Conclusion: This study suggests that Metformin use may be associated with a lower absolute risk of NAFLD and NASH compared to GLP-1RA use in patients with PCOS. This effect may be due to differences in prescribing patterns, or from Metformin’s ability to directly suppress hepatic gluconeogenesis and lipogenesis. Our findings contribute to the limited comparative research on these medications and their impact on metabolically driven liver disease. However, due to the small effect size and retrospective design, further prospective research is encouraged to validate these results.

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