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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
Summary
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.
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