The time‐varying cardiovascular benefits of glucagon‐like peptide‐1 receptor agonist therapy in patients with type 2 diabetes mellitus: Evidence from large multinational trials

AIMS: To evaluate the time‐varying cardio‐protective effect of glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) using pooled data from eight contemporary cardiovascular outcome trials using the difference in the restricted mean survival time (ΔRMST) as the effect estimate. MATERIAL AND METHODS: Data from eight multinational cardiovascular outcome randomized controlled trials of GLP‐1RAs for type 2 diabetes mellitus were pooled. Flexible parametric survival models were fit from published Kaplan‐Meier plots. The differences between arms in RMST (ΔRMST) were calculated at 12, 24, 36 and 48 months. ΔRMST values were pooled using an inverse variance‐weighted random‐effects model; heterogeneity was tested with Cochran's Q statistic. The endpoints studied were: three‐point major adverse cardiovascular events (MACE), all‐cause mortality, stroke, cardiovascular mortality and myocardial infarction. RESULTS: We included eight large (3183‐14 752 participants, total = 60 080; median follow‐up range: 1.5 to 5.4 years) GLP‐1RA trials. Among GLP‐1RA recipients, we observed an average delay in three‐point MACE of 0.03, 0.15, 0.37 and 0.63 months at 12, 24, 36 and 48 months, respectively. At 48 months, while cardiovascular mortality was comparable in both arms (pooled ΔRMST 0.163 [−0.112, 0.437]; P = 0.24), overall survival was higher (ΔRMST = 0.261 [0.08‐0.43] months) and stroke was delayed (ΔRMST 0.22 [0.15‐0.33]) in patients receiving GLP‐1RAs. CONCLUSIONS: Glucagon‐like peptide‐1 receptor agonists may delay the occurrence of MACE by an average of 0.6 months at 48 months, with meaningfully larger gains in patients with cardiovascular disease. This metric may be easier for clinicians and patients to interpret than hazard ratios, which assume a knowledge of absolute risk in the absence of treatment.