GLP-1 receptor agonist discontinuation and cardiovascular events and all-cause mortality in people with type 2 diabetes: a retrospective cohort study

Background: Discontinuation of Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RA) has been associated with the deterioration of multiple cardiovascular risk factors, especially body weight regain. However, whether the interruption of such medication, compared with their continued use, is associated with an increased risk of cardiovascular events or mortality is unclear. Methods: Leveraging data collected between 2004 and 2024 from 301 diabetes clinics in Italy, we conducted a retrospective cohort study in which people with type 2 diabetes (T2D), without cardiovascular diseases, and initiating a GLP-1RA were categorized as persistent users or as discontinuation group. The primary end point was a composite of myocardial infarction, stroke, or death from any cause among patients discontinuing the medication as compared with persistent users, accounting for immortal time bias through the treatment-exposed person-time approach and adjusting the analyses for unbalanced variables. We also examined the associated trends of risk factors levels. Findings: Of the 80,302 subjects initiating a therapy with a GLP-1RA, 31,687 (39.5%) were still on therapy at the last visit, while 48,615 (60.5%) had discontinued treatment. Mean exposure was 2.97 ± 2.93 years among persistent users and 1.21 ± 2.13 years in the discontinuation group. Follow-up was 3.65 ± 3.03 and 4.25 ± 3.41 years, respectively. During this period, 3,240 primary end point events occurred in the persistent users group and 4,038 events in the discontinuation group. The resulting incidence rate ratio (IRR) was 1.66 (95% confidence interval [CI] 1.49–1.85) while the relative hazard ratio (HR) was 1.68 (95% CI 1.60-1.77). The IRR for death from any cause was 2.82 (95% CI 2.49-3.20) and the corresponding HR 2.94 (95% CI 2.72-3.18). Interpretation: In people with T2D and without previous cardiovascular disease, interrupting a therapy with GLP-1RA had a higher risk of a composite of myocardial infarction, stroke, or death from any cause compared to those continuing the treatment. Continuous treatment with these medications may be required to maintain their long-term benefit on cardiovascular diseases and reduced mortality.