GLP-1 Receptor Agonists and Cardiorenal Outcomes in Non-Obese, Non- Diabetic MASLD: A Propensity Score-Matched Study

Q: What are the key findings of this study?

Sustained GLP-1 receptor agonist use was associated with lower 5-year MACE rates (HR 0.54, 95% CI 0.33-0.87) in non-obese, non-diabetic adults with MASLD.

Q: What is the clinical evidence from this study?

Study design: Cohort. Population: Non-obese, non-diabetic metabolic dysfunction-associated steatotic liver disease (MASLD) (n=2522). Intervention: Sustained GLP-1 receptor agonist use (semaglutide, liraglutide, dulaglutide, exenatide, or tirzepatide) vs. No GLP-1 receptor agonist exposure at any time. Primary outcome: Major adverse cardiovascular events (MACE: composite of acute myocardial infarction, cerebral infarction, and nontraumatic intracerebral hemorrhage) over 5 years (HR 0.54, 95% CI 0.33-0.87, p=0.010).

Q: What does this research mean for the field?

Sustained GLP-1 receptor agonist use is associated with lower rates of major cardiovascular and renal events, but not major adverse liver outcomes, in non-obese, non-diabetic adults with MASLD. Novelty: ClaimNovelty.CONFIRMATORY. Consensus alignment: ConsensusAlignment.NEUTRAL.

Anh Thu Nguyen; Yahya Haj Hamad; Riddhi Prateek; Daanish Imam; Harish Gopalakrishna; Gurinder K. Luthra

doi:10.21203/rs.3.rs-11195753/v1

November 1, 2026Open Access

GLP-1 Receptor Agonists and Cardiorenal Outcomes in Non-Obese, Non- Diabetic MASLD: A Propensity Score-Matched Study

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Key result

GLP-1 receptor agonists linked to ~46% lower 5-year MACE in non-obese, non-diabetic MASLD.

HR 0.54
95% CI 0.33-0.87
P=0.010
NNT 70
n=2,522

Why the study?

Non-obese individuals account for up to 30% of MASLD cases yet are routinely excluded from GLP-1 RA outcome trials, leaving the association between sustained GLP-1 RA use and cardiovascular, renal, and hepatic outcomes in non-obese, non-diabetic adults with MASLD unexamined.

Does sustained GLP-1 receptor agonist use reduce cardiovascular, renal, and hepatic events in non-obese, non-diabetic adults with MASLD?

Key Points

To evaluate the association between sustained GLP-1 receptor agonist use and cardiovascular, renal, and hepatic outcomes in non-obese, non-diabetic adults with MASLD.
Retrospective propensity score-matched cohort study using the TriNetX federated health research network.
Identified non-obese (BMI ≤ 27 kg/m²), non-diabetic adults with MASLD and at least one cardiometabolic risk factor.
Matched 1,261 sustained GLP-1 RA users (≥2 prescriptions within 3 months of diagnosis) 1:1 to non-users across 38 baseline covariates, estimating 5-year hazard ratios with Cox models.
Sustained GLP-1 RA use was associated with significantly lower 5-year rates of MACE (2.14% vs 3.57%; HR 0.54, 95% CI 0.33–0.87; p=0.010) and heart failure (1.35% vs 3.65%; HR 0.34, 95% CI 0.19–0.59; p<0.001).
Lower rates were also observed for acute kidney injury (1.43% vs 2.78%; HR 0.46, 95% CI 0.26–0.81; p=0.005) and atrial fibrillation or flutter (3.01% vs 4.28%; HR 0.64, 95% CI 0.42–0.97; p=0.033).
Major adverse liver outcomes did not differ significantly between groups (1.51% vs 1.19%; HR 1.16, 95% CI 0.59–2.28; p=0.67).

Study Design

Type

Cohort (n=2,522)

Multicenter

Yes

Structured PICO

Does sustained GLP-1 receptor agonist use reduce cardiovascular, renal, and hepatic events in non-obese, non-diabetic adults with MASLD?

P

Population

2,522 propensity score-matched non-obese (BMI ≤27 kg/m²), non-diabetic adults with MASLD and at least one cardiometabolic risk factor (mean age ~52.8 years, 71.4% female) across 112 US healthcare organizations, followed for up to 5 years.

E

Exposure

Sustained GLP-1 receptor agonist exposure (semaglutide, liraglutide, dulaglutide, exenatide, or tirzepatide), defined as initiating a GLP-1 RA within 3 months of MASLD diagnosis and receiving a second prescription within 3 months of the first.

C

Comparator

1:1 propensity score-matched patients meeting all eligibility criteria with no GLP-1 receptor agonist exposure at any time (matched on 38 demographic, comorbidity, medication, and laboratory covariates).

O

Outcome

5-year incidence of major adverse cardiovascular events (MACE: composite of acute myocardial infarction, cerebral infarction, and nontraumatic intracerebral hemorrhage), heart failure, acute kidney injury (AKI), and atrial fibrillation/flutter (Afib).composite

Main Result

Hazard Ratio: 0.54 (95% CI 0.33–0.87)

Absolute Event Rate: 2.14% vs 3.57%

Absolute Risk Reduction: 1.4%

Number Needed to Treat: 70

p-value: p=0.010

Sustained GLP-1 receptor agonist therapy is associated with lower 5-year rates of MACE, heart failure, acute kidney injury, and atrial fibrillation/flutter in non-obese, non-diabetic adults with MASLD, suggesting cardiorenal benefits independent of obesity or diabetes.

Limitations

Immortal-time bias due to the sustained exposure definition requiring a second prescription within 3 months after index date.
Proportional hazards assumption was violated for MACE (p=0.003) and atrial fibrillation/flutter (p=0.043).
Residual confounding and incomplete covariate balance after matching for BMI (SMD 0.351), ALT (SMD 0.189), and AST (SMD 0.136).
Reliance on ICD-10 diagnostic coding in an observational federated database without patient-level FIB-4 calculation or verified drug indication.
Low number of hepatic outcome events (MALO) limiting statistical power, and renal evaluation limited to acute kidney injury rather than chronic kidney disease.
Immortal-time bias from requiring a second confirmatory prescription within 3 months after the index date.
Proportional hazards assumption was not satisfied for MACE (p=0.003) or atrial fibrillation/flutter (p=0.043).
Residual covariate imbalance after propensity score matching for BMI (SMD 0.351), ALT (SMD 0.189), and AST (SMD 0.136), plus potential unmeasured confounding (e.g., diet, physical activity, fibrosis stage, treatment indication).
Reliance on electronic health record ICD-10 coding and inability to compute patient-level FIB-4 scores in the federated TriNetX platform.
Low event counts for MALO and all-cause mortality (<10 events per arm), and restriction of renal outcomes to acute kidney injury rather than chronic kidney disease.

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Implication

GLP-1 RA use was associated with lower MACE in non-obese non-diabetic MASLD; hypothesis-generating and should not yet change practice pending RCTs.

Abstract

Purpose Non-obese individuals account for up to 30% of metabolic dysfunction-associated steatotic liver disease (MASLD) cases yet are routinely excluded from glucagon-like peptide-1 receptor agonist (GLP-1 RA) outcome trials. Because MASLD is increasingly recognized as the hepatic component of a systemic cardiometabolic disorder, we evaluated the association between sustained GLP-1 RA use and cardiovascular, renal and hepatic outcomes in non-obese, non-diabetic adults with MASLD. Methods Using the TriNetX federated health research network, we identified non-obese (body mass index ≤ 27 kg/m²), non-diabetic adults with MASLD and at least one cardiometabolic risk factor. Sustained GLP-1 RA users, defined by a second prescription within three months of an initial prescription started within three months of diagnosis, were matched 1:1 to non-users on 38 demographic, comorbidity, medication and laboratory covariates. Cox models estimated five-year hazard ratios (HR) for major adverse cardiovascular events (MACE), heart failure, major liver outcomes (MALO), acute kidney injury (AKI), and atrial fibrillation/flutter (Afib). Sensitivity analyses excluded baseline metformin, substance use, and tirzepatide. Results Among 1,261 matched pairs, sustained GLP-1 RA use was associated with lower rates of MACE (HR 0.54, 95% CI 0.33–0.87), heart failure (0.34, 0.19–0.59), AKI (0.46, 0.26–0.81) and Afib (0.64, 0.42–0.97). MALO did not differ (1.16, 0.59–2.28). Associations persisted after excluding baseline metformin use and were directionally consistent after excluding tirzepatide. Conclusion In non-obese, non-diabetic MASLD, sustained GLP-1 RA use was associated with lower cardiovascular and renal event rates but not with hepatic events. These findings support prospective evaluation of GLP-1 RA therapy in this understudied phenotype.

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Cite This Study

Nguyen et al. (2026) conducted a cohort in Non-obese, non-diabetic metabolic dysfunction-associated steatotic liver disease (MASLD) (n=2,522). Sustained GLP-1 receptor agonist use (semaglutide, liraglutide, dulaglutide, exenatide, or tirzepatide) vs. No GLP-1 receptor agonist exposure at any time was evaluated on Major adverse cardiovascular events (MACE: composite of acute myocardial infarction, cerebral infarction, and nontraumatic intracerebral hemorrhage) over 5 years (HR 0.54, 95% CI 0.33-0.87, p=0.010). Sustained GLP-1 receptor agonist use was associated with lower 5-year MACE rates (HR 0.54, 95% CI 0.33-0.87) in non-obese, non-diabetic adults with MASLD.

synapsesocial.com/papers/6ae92596a8a6b2adf62f5ffc https://doi.org/10.21203/rs.3.rs-11195753/v1

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GLP-1 Receptor Agonists and Cardiorenal Outcomes in Non-Obese, Non- Diabetic MASLD: A Propensity Score-Matched Study

Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

GLP-1 Receptor Agonists and Cardiorenal Outcomes in Non-Obese, Non- Diabetic MASLD: A Propensity Score-Matched Study

Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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