GLP-1 RAs Provide Greater Hepatic Benefit Than SGLT2is For MASLD, Type 2 Diabetes

Treatment with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) is associated with better long-term liver outcomes than sodium-glucose cotransporter-2 inhibitors (SGLT2is) in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes (T2D), according to findings from a recent study.1

Leveraging data for more than 150,000 patients from the TriNetX Research Network database, the retrospective cohort study found GLP-1 RA use was linked to a 16% relative risk reduction in major adverse liver outcomes (MALOs) compared with SGLT2i use in patients with MASLD and T2D, primarily driven by a decrease in decompensated cirrhosis events.1

MASLD is the most common chronic liver disease around the world, affecting more than 30% of the global population. Despite its prevalence and high clinical burden, resmetirom (Rezdiffra) is the only US Food and Drug Administration-approved pharmacologic treatment option.2,3

MASLD is especially common among individuals with T2D and metabolic syndrome, underscoring the role insulin resistance plays in disease development and progression. As a result, GLP-1 RAs and SGLT2is have emerged as promising candidates for MASLD drug development.1

“While large retrospective cohort studies have suggested that GLP-1 RAs and SGLT-2is may provide liver-related benefits over other glucose-lowering agents no direct comparisons between these two drug classes have been conducted,” Chia-Chih Kuo, APN, of the department of nursing at Chi-Mei Medical Center in Taiwan, and colleagues wrote.1

To address this gap in research, investigators conducted a retrospective cohort study using data from the TriNetX Research Network for adult patients ≥ 18 years of age with T2D and MASLD who were prescribed either a GLP-1 RA or an SGLT2i between January 1, 2010, and June 1, 2023.1

Investigators categorized eligible patients into GLP-1 RA and the SGLT2i groups, excluding those who had previously received medications from the opposing group within 6 months before or at any time after the index prescription. Groups were balanced using propensity score matching (PSM) in a 1:1 ratio with a matching process involving 51 variables, including demographics, comorbidities, medications, and laboratory results.1

​​Patients were followed for ≥ 1 month after cohort entry, with follow-up continuing for up to 8 years or until the end of the study period on August 12, 2024. The primary outcome was the risk of MALOs, including decompensated cirrhosis events, hepatocellular carcinoma (HCC), and liver transplantation. Secondary outcomes included all-cause mortality and individual components of the primary outcome.1

In total, investigators identified 28,912 new GLP-1 RA users and 17,707 new SGLT2i users during the study period. After PSM, 15,176 individuals remained in each group for outcome analyses.1

During a median follow-up of 31.2 months, MALOs developed in 347 patients in the GLP-1 RA group (adjusted incidence rate, 88.9 events per 10,000 person-years) and 398 patients in the SGLT2i group (adjusted incidence rate, 105.3 events per 10,000 person-years). Investigators noted the GLP-1 RA group demonstrated a lower adjusted hazard ratio (aHR) for MALO compared with the SGLT2i group (0.84; 95% CI, 0.73 to 0.97; P = .019).1

Additionally, the GLP-1 RA group had a lower risk of total decompensated events (aHR, 0.83; 95% CI, 0.71 to 0.96; P = .013) and all-cause mortality (aHR, 0.84; 95% CI, 0.75 to 0.94; P = .003) than the SGLT2i group. However, investigators did not observe any significant differences for HCC (aHR, 0.94; 95% CI, 0.63 to 1.42; P = .78) and liver transplantation (aHR, 1.21; 95% CI, 0.63 to 2.34; P = .57).1

For metabolic outcomes, GLP-1 RA use was associated with consistently greater reductions in HbA1c levels (treatment difference, −0.20; 95% CI, −0.23 to −0.16) and improvements in lipid profiles, including TC (treatment difference, −3.48; 95% CI, −6.77 to −0.19), LDL (treatment difference, −2.52; 95% CI, −5.00 to −0.04), and TG (treatment difference, −13.99; 95% CI, −27.90 to −0.08) over the first 6 years of follow-up. Although similar findings were observed at 8 years of follow-up, investigators called attention to wider confidence intervals for lipid measures, suggesting greater variability in long-term outcomes.1

They acknowledged multiple limitations to these findings, including the potential for underrepresentation of mild cases and misclassification due to diagnostic codes; the inability to eliminate residual confounding; and the limited ability to accurately assess baseline fibrosis severity.1

“Our study demonstrates that GLP-1 RA treatment is associated with a lower risk of MALOs compared to SGLT2i, primarily due to a reduction in decompensated liver events, through a direct head-to-head comparison in patients with MASLD and T2D,” investigators concluded.1

References

1. Kuo CC, Chuang MH, Li CH, et al. Glucagon-Like Peptide-1 Receptor Agonists and Liver Outcomes in Patients With MASLD and Type 2 Diabetes. Aliment Pharmacol Ther. doi:10.1111/apt.18502
2. American Association for the Study of Liver Diseases. New MASLD Nomenclature. Accessed January 13, 2025. https://www.aasld.org/new-masld-nomenclature
3. Brooks A. Resmetirom (Rezdiffra) Receives Historic FDA Approval for Noncirrhotic NASH. HCPLive. March 14, 2024. Accessed January 13, 2025. https://www.hcplive.com/view/resmetirom-rezdiffra-receives-historic-fda-approval-for-noncirrhotic-nash