Semaglutide for Primary Prevention of Major Adverse Cardiac and Cerebrovascular Events in Patients with Type 2 Diabetes and Comorbid Rheumatoid Arthritis: A Target-Trial Emulation

Q: What is the clinical evidence from this study?

Study design: Cohort. Population: Type 2 diabetes mellitus and comorbid rheumatoid arthritis (n=2034). Intervention: Semaglutide vs. Non-GLP-1 receptor agonist second-line glucose-lowering therapies. Primary outcome: Incident MACCE (composite of all-cause mortality, myocardial infarction, heart failure, or stroke) (HR 0.75, 95% CI 0.60-0.94, p=0.01).

Farheen Malik; Mandar Shah; Yu Chang; Ishmum Chowdhury; Sridhar Mangalesh; Ahmed Ashraf Morgan; Ezerioha Pascal; Vishakha Modak; Nachum Lebovics; Suraj Adhikari; Pei-Lun Lee; Wei-Cheng Chen; Kuan‐Yu Chi

doi:10.1093/ehjcvp/pvag044

June 20, 2026European Heart Journal - Cardiovascular PharmacotherapyOpen Access

Semaglutide for Primary Prevention of Major Adverse Cardiac and Cerebrovascular Events in Patients with Type 2 Diabetes and Comorbid Rheumatoid Arthritis: A Target-Trial Emulation

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Key result

Semaglutide linked to ~25% lower MACCE risk vs non-GLP-1RA therapies.

HR 0.75
95% CI 0.60-0.94
P=0.01
n=2,034

Why the study?

Does semaglutide reduce incident MACCE in obese adults with T2DM and comorbid rheumatoid arthritis in a primary-prevention setting?

Key Points

Assess the effectiveness of semaglutide on reducing major adverse cardiovascular events in obese adults with type 2 diabetes and rheumatoid arthritis.
Emulated a target trial using TriNetX US database, focusing on obese adults ≥18 years with type 2 diabetes and rheumatoid arthritis.
Compared patients starting semaglutide with those starting non-GLP-1 receptor agonists for glucose management.
Applied propensity-score matching to balance baseline characteristics across treatment groups.
Semaglutide users had a significantly lower risk of incident major adverse cardiovascular events (12.7% vs 16.5%; HR, 0.75; 95% CI, 0.60-0.94; P=0.01).
The lower risk was primarily due to reduced heart failure incidents (8.9% vs 12.5%; HR, 0.69; 95% CI, 0.53-0.91; P=0.007).
Semaglutide initiation correlated with lower disease-modifying antirheumatic drugs escalation (16.6% vs 21.6%; HR, 0.75; 95% CI, 0.60-0.90; P=0.003).

Study Design

Type

Cohort (n=2,034)

Multicenter

Yes

Structured PICO

Does semaglutide reduce incident MACCE in obese adults with T2DM and comorbid rheumatoid arthritis in a primary-prevention setting?

P

Population

2,034 propensity-matched obese adults with type 2 diabetes and comorbid rheumatoid arthritis, free of prior cardiovascular disease, followed for up to 2 years.

E

Exposure

Semaglutide initiation

C

Comparator

Initiation of non-GLP-1 receptor agonist (GLP-1RA) second-line glucose-lowering therapies

O

Outcome

Incident MACCE, defined as a composite of all-cause mortality, myocardial infarction (MI), heart failure (HF), or stroke over a follow-up of up to 2 yearscomposite

Main Result

Hazard Ratio: 0.75 (95% CI 0.6–0.94)

Absolute Event Rate: 12.7% vs 16.5%

p-value: p=0.01

Limitations

Observational design cannot establish causality
Observational design requiring prospective studies to confirm observations and establish causality

Implication

In obese adults with T2DM and rheumatoid arthritis, semaglutide initiation is associated with a reduced risk of incident MACCE, primarily driven by a reduction in incident heart failure.

Discussion

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Cite This Study

Malik et al. (2026) conducted a cohort in Type 2 diabetes mellitus and comorbid rheumatoid arthritis (n=2,034). Semaglutide vs. Non-GLP-1 receptor agonist second-line glucose-lowering therapies was evaluated on Incident MACCE (composite of all-cause mortality, myocardial infarction, heart failure, or stroke) (HR 0.75, 95% CI 0.60-0.94, p=0.01). Semaglutide initiation was associated with a lower risk of incident MACCE compared with non-GLP-1RA therapies (12.7% vs 16.5%; HR 0.75; 95% CI 0.60-0.94; P=0.01).

synapsesocial.com/papers/6a3c24ba9b30296b1cab752d https://doi.org/10.1093/ehjcvp/pvag044

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Semaglutide for Primary Prevention of Major Adverse Cardiac and Cerebrovascular Events in Patients with Type 2 Diabetes and Comorbid Rheumatoid Arthritis: A Target-Trial Emulation

Key Points

Study Design

Structured PICO

Main Result

Limitations

Implication

Discussion

Cite This Study

Semaglutide for Primary Prevention of Major Adverse Cardiac and Cerebrovascular Events in Patients with Type 2 Diabetes and Comorbid Rheumatoid Arthritis: A Target-Trial Emulation

Key Points

Study Design

Structured PICO

Main Result

Limitations

Implication

Discussion

Cite This Study

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