Across placebo-controlled GLP-1RA trials in type 2 diabetes, greater HbA1c lowering was linked to greater cardiovascular risk reduction, whereas weight loss was not.
Evidence
An updated meta-analysis and meta-regression of 10 randomized placebo-controlled GLP-1RA trials including 73,263 adults with type 2 diabetes found a 14% reduction in overall, and each 1% extra HbA1c reduction corresponded to a 27% lower hazard ratio for MACE, while bodyweight change was not associated with analysed endpoints.
Caveat
This is trial-level meta-regression, so the HbA1c finding is an association across studies and does not prove HbA1c lowering itself causes the cardiovascular benefit.
Simplified
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 (; 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 = 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 = 0.21). 2 2
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.
Key numbers
14%
Risk Reduction
Reduction in risk with across 10 trials.
27%
Reduction Impact
Relative reduction in risk per 1% decrease in .
73 263
Participants Included
Total number of individuals across 10 trials.
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