GLP-1 Analogues and cardiovascular risk reduction in adults with obesity and elevated CRP: a real-world matched cohort study

Adults with obesity and systemic inflammation (elevated C-reactive protein [CRP]) are at increased cardiometabolic risk. Glucagon-like peptide-1 receptor agonists (GLP-1 RA) improve weight and metabolic profiles, but their association with long-term cardiovascular outcomes in obese adults with elevated CRP remains incompletely characterised in real-world practice. To evaluate the association between GLP-1 RA exposure and long-term clinical outcomes in adults with obesity and elevated CRP. We performed a cohort study using the TriNetX Global Collaborative Network. Adults (≥18 years) with obesity defined by BMI ≥30 kg/m² (TNX:9083) and elevated C-reactive protein 3–10 mg/L (TNX:9063) were identified. The exposure cohort had GLP-1 analogue use; the comparator cohort had no GLP-1 RA use. Propensity score matching (1:1) was performed across 18 covariates (including age, sex, BMI, and comorbidities). Follow-up began 1 day after cohort entry and continued up to 5,475 days (~15 years). The primary outcome was a composite of all-cause mortality, acute myocardial infarction, and ischaemic stroke. Secondary outcomes were acute heart failure hospitalisation (systolic and/or diastolic) and arrhythmias (atrial fibrillation/flutter, ventricular tachycardia, ventricular fibrillation/flutter). Before matching, cohort sizes were 6,021 (GLP-1 RA) and 84,790 (no GLP-1 RA); after matching, 5,208 patients were included in each cohort. For the primary composite outcome (excluding prior outcome), event risk was 6.5% in the GLP-1 RA group vs 12.8% in the no GLP-1 RA group (odds ratio [OR] 0.47; 95% CI 0.41–0.54; p<0.0001). Similarly, in the GLP-1 RA group, in time-to-event analysis, the hazard ratio (HR) was 0.41 (95% CI 0.35–0.46; log-rank p<0.0001), with survival at 5,475 days of 71.3% vs 43.5% in the non GLP-1 RA group. For acute heart failure hospitalisation, risk was 1.6% vs 1.8% (OR 0.87; 95% CI 0.65–1.18; p=0.373) in the 2 groups, respectively. Time-to-event analysis showed HR 0.70 (95% CI 0.52–0.95; log-rank p=0.021) in favour of GLP-1 RA group. Similarly, for arrhythmias, risk was 5.1% vs 7.3% (OR 0.69; 95% CI 0.58–0.82; p<0.001) and time-to-event analysis showed HR 0.57 (95% CI 0.48–0.68; log-rank p<0.001), with survival at 5,475 days of 76.02% vs 65.74% in favour of GLP-1 RA group. In this large real-world matched cohort of adults with obesity and elevated CRP, GLP-1 RA exposure was associated with substantially lower long-term odds of death, myocardial infarction, or ischaemic stroke, and lower arrhythmia risk. Prospective studies are warranted to confirm these associations and clarify mechanisms in this inflammation-associated obesity phenotype.