One-year cardiovascular outcomes before and after GLP-1 ra discontinuation: a real-world retrospective cohort study

Abstract Background Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have demonstrated cardiovascular (CV) benefits, but their impact after discontinuation (DC) remains unclear. Purpose To compare CV outcomes of adults with overweight or obesity who discontinued GLP-1 RAs within one year (short-term) and those who continued treatment ≥1 year (long-term) both before and after DC. Methods This real-world retrospective cohort study used electronic health records data from 20,000+ clinics and 700 hospitals across 43 U.S. states. Between July 1, 2022, and December 31, 2024, we identified new adult users (≥18 years) of injectable semaglutide or tirzepatide with BMI ≥27, regardless of T2D history. Eligible participants had ≥2 prescriptions, were treated for ≥90 days, and had ≥1 year follow-up. DC was defined as a ≥90-day gap in treatment after completing their last prescription. Patients with 1 year follow-up or ongoing treatment at study end (uncertain DC status) were excluded. The primary outcomes were 1-year cumulative incidence of acute coronary syndromes (ACS), coronary artery disease (CAD) encounters, heart failure (HF), stroke, and all-cause mortality, both during treatment and after DC. Propensity score matching was adjusted for baseline conditions. Results Among 289,809 adults (median age: 54.6 years, 65.2% female, 69.2% with T2D), the GLP-1 RA discontinuation rate was 29.6% (95% CI: 29.4–29.8) at 1 year and 57.3% (57.0–57.5) at 2 years. Lower DC rates were associated with T2D (HR = 0.56, 0.55–0.56), male sex (HR = 0.87, 0.86–0.88), and Asian race (HR = 0.82, 0.79–0.86), while anxiety (HR = 1.13, 1.12–1.15) and depression (HR = 1.127, 1.11–1.14) increased DC risk. Final cohort included 69,047 short-term and 133,387 long-term users after excluding uncertain DC status patients (Table 1). During treatment, the 1-yearincidence was 1.29% (95% CI: 1.22–1.36) for ACS, 13.2% (13.0–13.4) for CAD, 7.32% (7.15–7.48) for HF, 1.94% (1.85–2.03) for stroke, and 0.06% (0.04–0.08) for all-cause mortality. Compared to long-term use, during treatment, short-term users had a higher risk of ACS (HR: 1.26, 1.12–1.42), CAD (HR: 1.06, 1.03–1.10), HF (HR: 1.09, 1.04–1.15), stroke (HR: 1.24, 1.13–1.36), and all-cause mortality (HR = 0.40, 0.19–0.84). After DC, CV event rates were 1.78% (1.66–1.91) for ACS, 17.1% (16.7–17.4) for CAD, 10.2% (9.93–10.4) for HF, 2.56% (2.38–2.73) for stroke, and 0.23% (0.18–0.27) for all-cause mortality. Short-term users remained at higher risk for CAD (HR: 1.09, 1.04–1.13) and HF (HR: 1.10, 1.05–1.16) post-DC, while ACS (HR: 1.14, 0.996–1.31), stroke (HR: 0.98, 0.88–1.10), and all-cause mortality (HR = 1.00, 0.68–1.47) risks were similar between groups (Figure 1). Conclusions Early GLP-1 RA discontinuation (≤1 year) increased ACS, CAD, HF, stroke, and mortality risks regardless of treatment duration, with persistently higher CAD and HF risks post-DC, while ACS, stroke, and mortality risks were similarly elevated after DC.Table 1 Figure 1