Cardiovascular risk reduction with glucagon‐like peptide‐1 receptor agonists is proportional to HbA1c lowering in type 2 diabetes: An updated meta‐regression analysis incorporating FLOW and SOUL trials

Abstract Aims To evaluate relationships of cardiovascular and kidney outcomes with glycemic or bodyweight reductions in randomised placebo‐controlled trials of glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs), incorporating data from FLOW and SOUL trials. Materials and Methods PubMed and EMBASE were searched up to 22 August 2025 for placebo‐controlled randomized trials of oral or bolus‐type, subcutaneous GLP‐1RAs reporting major adverse cardiovascular events (MACE; a composite of cardiovascular death, myocardial infarction, and stroke) in adults with type 2 diabetes. The primary outcome was MACE; secondary outcomes included heart failure (HF) and kidney outcomes. Random‐effects meta‐analyses were followed by meta‐regression evaluating associations with HbA1c and bodyweight reduction. Results A total of 73 263 individuals were included from 10 trials (ELIXA, LEADER, SUSTAIN‐6, EXSCEL, Harmony Outcomes, PIONEER 6, REWIND, AMPLITUDE‐O, FLOW, and SOUL). GLP‐1RAs reduced MACE by 14% (hazard ratio: 0.86; 95% CI: 0.82 to 0.91; p <0.001), as well as hospitalisation for HF and the composite kidney outcome (both p <0.001). Meta‐regression showed that every 1% extra reduction in HbA1c corresponded to a 27% lower HR for MACE ( p = 0.015; R 2 = 0.61). While HbA1c reduction was not significantly associated with secondary outcomes, the directionality was consistent with MACE. Bodyweight change was not associated with any of the analysed endpoints, including MACE ( p = 0.13; R 2 = 0.21). Conclusions HbA1c reduction, not bodyweight change, was significantly and proportionally associated with MACE risk reduction. HbA1c lowering may serve as a useful surrogate for the cardiovascular improvements associated with GLP‐1RAs in type 2 diabetes.