Glucagon-like peptide 1 receptor agonist discontinuation and risks of major adverse cardiovascular events in adults with type 2 diabetes: target trial emulation.

Objectives: To characterise patterns of use of glucagon-like peptide 1 receptor agonists (GLP-1RAs) and assess the associations between various GLP-1RA treatment scenarios and the risk of major adverse cardiovascular events. Design: Target trial emulation. Setting: Electronic healthcare databases of US Department of Veterans Affairs, 1 January 2017 to 31 December 2023. Data obtained from domains in the Veterans Affairs Corporate Data Warehouse. Participants: Veterans Affairs users with type 2 diabetes who started treatment with GLP-1RAs (n=132 551) or sulfonylureas (n=201 136), followed up for three years. Veterans Affairs users were defined as having at least two visits to Veterans Affairs and having used the Veterans Affairs outpatient pharmacy within a year before receiving treatment with GLP-1RAs or sulfonylureas. Interventions: GLP-1RAs or sulfonylureas. In the GLP-1RA arm, treatment status was reassigned every six months, generating 16 prespecified treatment strategies that varied in length of continued use, discontinuation, or interruption. Main outcome measures: Three year cumulative incidence of major adverse cardiovascular events (myocardial infarction, stroke, or all cause death). Results: The cohort included 132 551 incident users of GLP-1RAs and 201 136 incident users of sulfonylureas (defined as no prescription for GLP-1RAs or sulfonylureas within a year of the first prescription). A duration dependent association was found between the use of GLP-1RAs and the cumulative three year risk of major adverse cardiovascular events. Compared with the sulfonylurea reference group, participants who used GLP-1RAs for 0.5, 1, or 1.5 years, before discontinuing for the remainder of the three years, showed incidence risk ratios close to 1.0, with no significant reduction in the risk of major adverse cardiovascular events at three years. Compared with the sulfonylurea group, the reduction in the risk of major adverse cardiovascular events was significant in people who continued to use GLP-1RAs for 2 and 2.5 years, before discontinuing for the remainder of the three years (incidence risk ratio 0.93, 95% confidence interval (CI) 0.88 to 0.98 and 0.85, 0.81 to 0.90, respectively). Participants who continued to use GLP-1RAs for the whole three year follow-up period had the most pronounced risk reduction (incidence risk ratio 0.82, 95% CI 0.78 to 0.85) compared with the sulfonylurea group. Compared with continued use of GLP-1RA, discontinuing treatment for 0.5 years was associated with an increased risk of major adverse cardiovascular events (incidence risk ratio 1.04, 95% CI 1.01 to 1.08); the risk increased progressively with a longer duration of discontinuation, with an incidence risk ratio of 1.14 (1.09 to 1.18) and 1.22 (1.16 to 1.27) for one and two years of discontinuation, respectively. Compared with continued use of GLP-1RA, 0.5 years of interruption was associated with an increased risk of major adverse cardiovascular events; longer durations of interruption were progressively associated with a higher risk of major adverse cardiovascular events, with an incidence risk ratio of 1.12 (95% CI 1.06 to 1.19) and 1.16 (1.11 to 1.22) for one and two years of interrupted use, respectively. Conclusions: The cardiovascular benefit of GLP-1RAs accumulated with continuous use, but even brief periods of discontinuations or interruptions might progressively erode and could ultimately reverse this protection, increasing the risk of cardiovascular events.