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

Sep 10, 2025Diabetes, obesity & metabolism

Heart risk reduction from GLP-1 drugs is linked to blood sugar lowering in type 2 diabetes

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Abstract

A total of 73,263 individuals were included from 10 trials evaluating the effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs).

GLP-1RAs reduced major adverse cardiovascular events () by 14%.
Hospitalization for heart failure and composite kidney outcomes also decreased significantly with GLP-1RAs.
Every 1% reduction in HbA1c was associated with a 27% lower hazard ratio for MACE.
Reduction in HbA1c was not significantly linked to secondary outcomes, though trends were similar to MACE.
Bodyweight change did not show a significant association with MACE or other analyzed endpoints.

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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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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

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