Genetically proxied glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptor pathway modulation is associated with favorable aging phenotypes: a drug-target Mendelian randomization study
Authors' conclusion
Genetically proxied HbA1c- and BMI-lowering effects through GLP1R- and GIPR-related pathways were favorably associated with aging phenotypes, with broader associations observed for HbA1c lowering.
Study context
- Comparison
- Genetically proxied modulation of GLP1R, GIPR and dual GIPR/GLP1R pathways
- Outcome
- Four aging phenotypes: frailty index, PhenoAge acceleration, telomere length and longevity
Methodological detailsprimary and replication datasets
- Primary and replication datasets
Main finding
As reported in the abstract
Aging phenotypes
- HbA1c lowering via GIPR: frailty index, β (95% CI), primary
- - 0.10 [- 0.18, - 0.02]
- HbA1c lowering via GIPR: frailty index, replication
- - 0.14 [- 0.27, - 0.01]
- HbA1c lowering via GIPR: Phenotypic age (PhenoAge) acceleration, primary
- - 0.82 [- 1.17, - 0.48]
- HbA1c lowering via GIPR: PhenoAge acceleration, replication
- - 1.04 [- 1.81, - 0.27]
- HbA1c lowering via GIPR: telomere length, primary
- 0.06 [0.003, 0.11]
- HbA1c lowering via GIPR: telomere length, replication
- 0.09 [0.002, 0.19]
- HbA1c lowering via GIPR: longevity, OR (95% CI), primary
- 2.90 [1.93, 4.36]
- HbA1c lowering via GIPR: longevity, OR, replication
- 6.54 [2.92, 14.65]
- Body mass index (BMI) lowering via GIPR: frailty index, primary
- - 0.07 [- 0.13, - 0.01]
- BMI lowering via GIPR: frailty index, replication
- - 0.19 [- 0.35, - 0.04]
- BMI lowering via GIPR: longevity, primary
- 2.11 [1.22, 3.66]
- HbA1c lowering via GLP1R: longevity, OR, primary
- 3.72 [2.25, 6.18]
- HbA1c lowering via GLP1R: longevity, OR, replication
- 16.53 [4.28, 63.80]
Original publication
Genetically proxied glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptor pathway modulation is associated with favorable aging phenotypes: a drug-target Mendelian randomization study. Cardiovasc Diabetol. Published 22 July 2026. doi:10.
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