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GLP-1 RA Plus SGLT2i Versus Monotherapy in MASLD and Type 2 Diabetes: Three Pairwise Target Trial Emulations

Mohanad A Alkuwaiti1, Faisal A Al-Harbi2, Ahmed K Alsaif3

  • 1College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia.

Journal of Gastroenterology and Hepatology
|July 13, 2026
PubMed
Abstract

Insights

Combination therapy with GLP-1 RAs and SGLT2is reduced mortality and liver issues in patients with metabolic dysfunction-associated steatotic liver disease and type 2 diabetes. However, it increased major adverse cardiovascular events risk compared to GLP-1 RA monotherapy.

Area of Science:

  • Cardiology
  • Endocrinology
  • Hepatology

Background:

  • Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) offer individual cardiovascular and metabolic benefits.
  • Comparative effectiveness of combined GLP-1 RA and SGLT2i therapy versus monotherapy in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes mellitus (T2DM) is not well-defined.

Purpose of the Study:

  • To compare the effectiveness of combination therapy (GLP-1 RA + SGLT2i) against monotherapy (GLP-1 RA or SGLT2i) in patients with MASLD and T2DM.
  • To evaluate the impact on all-cause mortality, major adverse cardiovascular events (MACE), and composite liver outcomes.

Main Methods:

  • Three pairwise target trial emulations were conducted using the TriNetX Research Network.
  • Propensity score matching (1:1) and Cox proportional hazards regression with Bayesian hierarchical bias-effect (BHBE) correction were employed to analyze outcomes.
  • Adult patients with MASLD and T2DM initiating combination therapy, GLP-1 RA monotherapy, or SGLT2i monotherapy were identified.

Main Results:

  • Combination therapy significantly reduced all-cause mortality compared to SGLT2i monotherapy (corrected HR 0.655).
  • A significant increase in MACE risk was observed with combination therapy versus GLP-1 RA monotherapy (corrected HR 1.111).
  • Composite liver outcomes favored combination therapy over SGLT2i monotherapy (corrected HR 0.907).

Conclusions:

  • GLP-1 RA and SGLT2i combination therapy significantly lowers mortality and improves liver outcomes in MASLD patients with T2DM when compared to SGLT2i monotherapy.
  • The increased risk of MACE with combination therapy compared to GLP-1 RA monotherapy requires careful consideration in clinical decision-making.
Keywords:
GLP‐1 RAMASLDSGLT2 inhibitorscardiometabolic outcomesdiabetes

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