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Peer-reviewedCC BYJournal of Gastroenterology and Hepatology

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
  • Ziyad M. AlSughayyir2
  • Rayan Saleh Alsaud2
  • Mohammed Aljabr2
  • Ahmad K. Alanazi2
  • Ahmad A. Alosaily2
  • Abdulrhman Khaled Al Abdulqader4
  • Hamza Ali Almusabeh5
  • Rayyan Fahad H. Altemani6
  • Ahmed Y. Azzam7,8
8 affiliations
  1. 1College of Medicine Imam Abdulrahman Bin Faisal University Dammam Saudi Arabia
  2. 2College of Medicine Qassim University Qassim Saudi Arabia
  3. 3College of Medicine Al‐Rayan Colleges Medinah Saudi Arabia
  4. 4Department of Internal Medicine, College of Medicine King Faisal University Al‐Ahsa Saudi Arabia
  5. 5Department of Internal Medicine West Virginia University School of Medicine Morgantown West Virginia USA
  6. 6Department of Internal Medicine University of Utah Salt Lake City Utah USA
  7. 7Clinical Research and Clinical Artificial Intelligence ASIDE Healthcare Lewes Delaware USA
  8. 8Division of Global Health and Public Health, School of Nursing, Midwifery and Public Health University of Suffolk Ipswich UK
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Abstract

INTRODUCTION: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) have demonstrated cardiovascular and metabolic benefits individually; however, the comparative effectiveness of combination therapy versus monotherapy in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes mellitus (T2DM) remains incompletely characterized. METHODS: We conducted three pairwise target trial emulations using the TriNetX Research Network. Adults with MASLD and T2DM initiating GLP-1 RA plus SGLT2i combination therapy, GLP-1 RA monotherapy, or SGLT2i monotherapy were identified. Primary outcomes were all-cause mortality, major adverse cardiovascular events (MACE), and composite liver outcomes. Propensity score matching (PSM) (1:1) was performed for each pairwise comparison. Cox proportional hazards regression with Bayesian hierarchical bias-effect (BHBE) correction was utilized to address residual confounding. RESULTS: Following PSM, 42423 combination versus 42 423 GLP-1 RA, 40349 combination versus 40 349 SGLT2i, and 51 826 GLP-1 RA versus 51 826 SGLT2i patients were analyzed. Combination therapy significantly reduced all-cause mortality versus SGLT2i monotherapy (hazard ratio [HR] 0.522, 95% confidence interval [CI] 0.488-0.559), with probable benefit after bias correction (corrected HR 0.655, posterior probability 92.4%; credible interval includes the null). Combination therapy demonstrated increased MACE risk versus GLP-1 RA (HR 1.106, 95% CI 1.045-1.170), remaining significant after correction (corrected HR 1.111). Composite liver outcomes favored combination therapy versus SGLT2i (corrected HR 0.907, probability of benefit 81.9%). CONCLUSIONS: GLP-1 RA and SGLT2i combination therapy significantly reduced mortality and liver outcomes versus SGLT2i monotherapy in MASLD with T2DM; however, increased MACE risk versus GLP-1 RA monotherapy warrants consideration in management decisions.

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Cite

BibTeXRIS
BibTeX
@article{alkuwaiti2026glp1,
  title = {{GLP‐1 RA Plus SGLT2i Versus Monotherapy in MASLD and Type 2 Diabetes: Three Pairwise Target Trial Emulations}},
  author = {Mohanad A. Alkuwaiti and Faisal A. Al-Harbi and Ahmed K. Alsaif and Ziyad M. AlSughayyir and Rayan Saleh Alsaud and Mohammed Aljabr and Ahmad K. Alanazi and Ahmad A. Alosaily and Abdulrhman Khaled Al Abdulqader and Hamza Ali Almusabeh and Rayyan Fahad H. Altemani and Ahmed Y. Azzam},
  journal = {Journal of Gastroenterology and Hepatology},
  year = {2026},
  month = jul,
  doi = {10.1111/jgh.70589},
  url = {https://doi.org/10.1111/jgh.70589},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - GLP‐1 RA Plus SGLT2i Versus Monotherapy in MASLD and Type 2 Diabetes: Three Pairwise Target Trial Emulations
AU  - Mohanad A. Alkuwaiti
AU  - Faisal A. Al-Harbi
AU  - Ahmed K. Alsaif
AU  - Ziyad M. AlSughayyir
AU  - Rayan Saleh Alsaud
AU  - Mohammed Aljabr
AU  - Ahmad K. Alanazi
AU  - Ahmad A. Alosaily
AU  - Abdulrhman Khaled Al Abdulqader
AU  - Hamza Ali Almusabeh
AU  - Rayyan Fahad H. Altemani
AU  - Ahmed Y. Azzam
PY  - 2026
DA  - 2026/07/13
JO  - Journal of Gastroenterology and Hepatology
DO  - 10.1111/jgh.70589
UR  - https://doi.org/10.1111/jgh.70589
AB  - INTRODUCTION: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) have demonstrated cardiovascular and metabolic benefits individually; however, the comparative effectiveness of combination therapy versus monotherapy in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes mellitus (T2DM) remains incompletely characterized. METHODS: We conducted three pairwise target trial emulations using the TriNetX Research Network. Adults with MASLD and T2DM initiating GLP-1 RA plus SGLT2i combination therapy, GLP-1 RA monotherapy, or SGLT2i monotherapy were identified. Primary outcomes were all-cause mortality, major adverse cardiovascular events (MACE), and composite liver outcomes. Propensity score matching (PSM) (1:1) was performed for each pairwise comparison. Cox proportional hazards regression with Bayesian hierarchical bias-effect (BHBE) correction was utilized to address residual confounding. RESULTS: Following PSM, 42423 combination versus 42 423 GLP-1 RA, 40349 combination versus 40 349 SGLT2i, and 51 826 GLP-1 RA versus 51 826 SGLT2i patients were analyzed. Combination therapy significantly reduced all-cause mortality versus SGLT2i monotherapy (hazard ratio [HR] 0.522, 95% confidence interval [CI] 0.488-0.559), with probable benefit after bias correction (corrected HR 0.655, posterior probability 92.4%; credible interval includes the null). Combination therapy demonstrated increased MACE risk versus GLP-1 RA (HR 1.106, 95% CI 1.045-1.170), remaining significant after correction (corrected HR 1.111). Composite liver outcomes favored combination therapy versus SGLT2i (corrected HR 0.907, probability of benefit 81.9%). CONCLUSIONS: GLP-1 RA and SGLT2i combination therapy significantly reduced mortality and liver outcomes versus SGLT2i monotherapy in MASLD with T2DM; however, increased MACE risk versus GLP-1 RA monotherapy warrants consideration in management decisions.
SN  - 0815-9319
SN  - 1440-1746
ER  -