Patients with rheumatoid arthritis (RA) commonly have physical limitations that reduce sustained physical activity and weight management. These limitations can worsen metabolic risk profiles and sustain chronic inflammation, both of which increase cardiovascular risk. In people with type 2 diabetes mellitus (T2DM) and obesity, this risk is amplified. The investigators asked whether initiating the glucagon-like peptide-1 receptor agonist semaglutide reduces the risk of incident major adverse cardiovascular and cerebrovascular events (MACCE) in obese adults with T2DM and comorbid RA in a primary-prevention setting.
The study emulated a target trial using electronic health record data from the TriNetX US database. Eligible participants were adults aged ≥18 years with body mass index (BMI) ≥30 kg/m2, diagnosed T2DM, and comorbid RA. Patients were required to have no prior history of stroke, heart failure (HF), acute coronary syndrome, or coronary revascularization. Individuals with contraindications to GLP-1 receptor agonists were excluded.
A new-user design compared patients who initiated semaglutide to those who initiated non-GLP-1RA second-line glucose-lowering therapies within three months of meeting eligibility criteria. The study period spanned 1 January 2014 to 1 January 2025.
Propensity-score (PS) matching at a 1:1 ratio was used to balance baseline covariates between groups. The primary outcome was incident MACCE, defined as the composite of all-cause mortality, myocardial infarction (MI), HF, or stroke. Secondary outcomes included the individual MACCE components, HF hospitalization, and escalation of disease-modifying anti-rheumatic drugs (DMARD escalation). Bonferroni correction was applied for multiple comparisons. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox proportional hazards models, with follow-up of up to two years.
After PS matching, the incidence of the primary composite outcome, MACCE, was compared between matched cohorts. Semaglutide initiation was associated with a lower incidence of MACCE compared with initiation of non-GLP-1RA therapies (12.7% vs. 16.5%). The estimated hazard ratio was 0.75 (95% CI, 0.60–0.94; P = 0.01), indicating a 25% relative reduction in the hazard of the composite outcome over the observed follow-up period in this emulated trial.
The composite benefit observed with semaglutide appeared to be driven primarily by fewer incident heart failure events: 8.9% in the semaglutide group versus 12.5% in the non-GLP-1RA group (HR 0.69; 95% CI, 0.53–0.91; P = 0.007).
No statistically significant differences were reported between groups for all-cause mortality, myocardial infarction, or stroke. Semaglutide use was associated with lower rates of DMARD escalation (16.6% vs. 21.6%; HR 0.75; 95% CI, 0.60–0.90; P = 0.003), an outcome reflecting intensification of RA therapy.
From the study period, 1,200 patients who initiated semaglutide and 2,972 patients who initiated non-GLP-1RA therapies were identified within three months of meeting eligibility. After propensity-score matching, 1,017 semaglutide users were compared with 1,017 non-GLP-1RA users. Matched groups had similar baseline characteristics: mean age approximately 59 years (59.5 vs. 59.3), women comprised about 81% of each cohort, mean BMI approximately 38.2 vs. 38.0 kg/m2, and baseline HbA1c values around 6.8% vs. 7.0%.
Over up to two years of observation, the primary composite outcome occurred in 12.7% of semaglutide users versus 16.5% of non-GLP-1RA users (HR 0.75; 95% CI 0.60–0.94; P = 0.01). The largest driver of this difference was a reduction in incident HF (8.9% vs. 12.5%; HR 0.69; 95% CI 0.53–0.91; P = 0.007). Semaglutide initiation was also associated with reduced DMARD escalation (16.6% vs. 21.6%; HR 0.75; 95% CI 0.60–0.90; P = 0.003). There were no significant differences for all-cause mortality, MI, or stroke reported in the analysis.
In this target-trial emulation of obese adults with T2DM and RA without prior cardiovascular events, initiation of semaglutide was associated with a statistically significant reduction in incident MACCE, predominantly driven by fewer HF events. Possible explanations consistent with the study context include semaglutide’s effects on weight, glycemic control, and metabolic profiles, and potential indirect effects on systemic inflammation or functional capacity in patients with RA; however, the observational emulation design cannot establish causality.
An observed reduction in DMARD escalation among semaglutide users may reflect changes in disease activity, treatment tolerance, or healthcare utilization, but the study reports this association without mechanistic confirmation.
As an emulation using retrospective electronic health record data, the study is subject to residual confounding despite propensity-score matching, potential misclassification, and limitations inherent to observational designs. The authors state that prospective studies are required to confirm these associations and to establish causality.
For clinicians managing obese patients with T2DM and comorbid RA, these findings suggest that initiation of semaglutide may be associated with lower incidence of composite cardiovascular and cerebrovascular events, largely by reducing incident heart failure, and with less frequent escalation of RA-directed DMARD therapy over the observed follow-up. These results are hypothesis-generating and support the need for randomized or prospective studies before changing practice solely on these observational findings.