Unexpected cardiovascular risks of glucagon‐like peptide‐1 receptor agonist and aspirin co‐administration in individuals with obesity, with and without type 2 diabetes: A propensity score matched cohort study

Figures

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  FIGURE 1. Flow chart of cohort selection. From an initial population of 2 946 579 individuals with obesity in the TriNetX database between January 2016 and April 2024, we identified 102 864 individuals who received GLP‐1 receptor agonist (GLP‐1 RA) treatment after applying exclusion criteria, such as removing individuals with type 1 diabetes, bariatric surgery history or organ transplants. These individuals were then stratified by type 2 diabetes (T2D) status and aspirin use. Using propensity score matching, we created balanced cohorts of individuals receiving either GLP‐1 RA plus aspirin or GLP‐1 RA alone. For individuals with T2D, we matched 2033 individuals in each treatment group. Similarly, for those without T2D, we matched 7478 individuals per group. The final analysis included these four matched cohorts, with treatment effects evaluated over a 5‐year follow‐up period. aIndividuals could have met multiple exclusion criteria. bIncluding pramlintide, tirzepatide, guar gum, nateglinide and repaglinide.

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  FIGURE 2. Cardiovascular risks and adverse events associated with GLP‐1 RA plus aspirin therapy compared to GLP‐1 RA alone in individuals with obesity, with and without T2D. Hazard ratios (HR) and 95% confidence intervals (CI) for cardiovascular events during 5‐year follow‐up. Results are shown for individuals with obesity and T2D (A) and individuals with obesity without T2D (B). Conditions shown include hypertensive heart disease (HHD), heart disease (HD), ischaemic heart disease (IHD), cerebrovascular disease (CBVD), vascular disease (VD), diseases of arteries, arterioles and capillaries (DAAC), pulmonary heart disease (PHD), hypertension, heart failure (HF), cardiac arrhythmias (CAR), atrial fibrillation (AF) and chronic rheumatic heart disease (CRHD). HRs and 95%CI for adverse drug events (ADEs). Results are shown for individuals with obesity and T2D (A) and individuals with obesity without T2D (B). ADEs include vomiting, abdominal pain, functional dyspepsia, volume depletion, headache, angina pectoris, stroke and pulmonary embolism. All reported HRs are statistically significant with p‐values <0.05. Exact p‐values are provided in the main text.

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  FIGURE 3. Stratified analysis of cardiovascular risks associated with GLP‐1 receptor agonist plus aspirin combination therapy versus GLP‐1 receptor agonist monotherapy. Data shown are hazard ratios (HRs) and 95% confidence intervals (CIs) from Cox proportional hazards models comparing cardiovascular outcomes in four individual subgroups: besity without type 2 diabetes (T2D) or cardiovascular disease (CVD), obesity with T2D only, obesity with CVD only and obesity with both T2D and CVD. Results show a progressive increase in cardiovascular risk from individuals with obesity alone to those with multiple comorbidities. Negative control outcomes showed no significant differences between treatment groups, supporting the specificity of cardiovascular findings. Values greater than 1.0 indicate increased risk with combination therapy. All HRs are adjusted for baseline characteristics through propensity score matching.