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

Rheumatoid arthritis (RA)-related physical limitations often hinder sustained physical activity and weight management, thereby amplifying cardiovascular risk through adverse metabolic profiles and chronic inflammation. We aimed to assess the effectiveness of semaglutide on the risk of incident major adverse cardiovascular and cerebrovascular events (MACCE) in obese adults with type 2 diabetes mellitus (T2DM) and RA in a primary-prevention setting.

We emulated a target trial using data from the TriNetX US database, including obese adults [aged ≥18 years; body mass index (BMI) ≥30 kg/m²] with T2DM and comorbid RA and no prior history of stroke, heart failure (HF), acute coronary syndrome, or coronary revascularization. Using a new-user design, we compared patients initiating semaglutide with those initiating non-GLP-1 receptor agonist (GLP-1RA) second-line glucose-lowering therapies. Patients with contraindications to GLP-1RAs were excluded. Propensity-score matching (PS) (1:1) was used to balance baseline covariates. The primary outcome was incident MACCE, defined as a composite of all-cause mortality, myocardial infarction (MI), HF, or stroke. Secondary outcomes included individual MACCE components, HF hospitalization, and disease-modifying anti-rheumatic drug (DMARD) escalation, with Bonferroni correction applied for multiple comparisons. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models over a follow-up of up to 2 years. Between 1 January 2014 and 1 January 2025, we identified 1200 and 2972 patients who initiated semaglutide and non-GLP-1RA therapies, respectively, within 3 months of meeting eligibility. After PS matching, 1017 semaglutide users were compared with 1017 non-GLP-1RA users (mean age 59.5 vs. 59.3 years; women 81.3% vs. 81.0%; mean BMI 38.2 vs. 38.0 kg/m²; HbA1c, 6.8% vs. 7.0%). Semaglutide initiation was associated with a significantly 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). This benefit was driven primarily by a lower risk of incident HF (8.9% vs. 12.5%; HR, 0.69, 95% CI, 0.53–0.91; P = 0·007). Semaglutide use was also associated with significantly lower DMARD escalation (16.6% vs. 21.6%; HR, 0.75; 95% CI, 0.60–0.90; P = 0.003). No significant differences were observed in all-cause mortality, MI, or stroke.

Among obese adults with T2DM and comorbid RA, initiation of semaglutide was associated with a reduced risk of incident MACCE, driven predominantly by a reduction in incident HF, in a primary-prevention setting. Prospective studies are needed to confirm these observations and establish causality.