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Heart failure & cardiomyopathiesResearch article

Genetic evidence for GLP1R agonists in non-ischaemic heart failure

ESC Heart FailPublished

  • drug-target Mendelian randomization (MR)
  • inverse-variance weighted analysis adjusted for multiple testing
  • weighted median and MR-Egger sensitivity analyses
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Authors' conclusion

This study provides genetic support for a protective association between GLP1R activation and HF, particularly ni-HFpEF, with effects beyond glycaemia. The magnitude and subtype specificity are consistent with contemporary trial evidence and support further evaluation of GLP1R agonism in cardio-metabolic HFpEF.

Study context

Population
Summary statistics from the largest available GWAS of HF, non-ischaemic HF (ni-HF), ni-HFpEF, ni-HFrEF, and atrial fibrillation (AF)
Comparison
MR estimates for GLP1R agonism were scaled to per 0.1 log-odds lower liability to type 2 diabetes (T2DM) and compared with general type 2 diabetes (T2DM) or body mass index (BMI) lowering effects

Main finding

Overall HF

Odds ratio

0.96 per 0.1 log-odds lower T2DM liability

95% CI 0.95–0.98

P & .0002

GLP1R activation
OR 0.96 per 0.1 log-odds lower T2DM liability (95% CI 0.95–0.98); P & .0002

Per 0.1 log-odds lower T2DM liability, as printed

As reported in the abstract

Further findings

OutcomeOR (per 0.1 log-odds lower T2DM liability) (CI)P value
ni-HF · lower risk0.94 (0.91–0.96)P & .0001
ni-HFpEF · lower risk0.82 (0.74–0.90)P & .0001

Comparison with glycaemic and BMI lowering

GLP1R-proxied effects greater than those expected from glycaemic lowering alone and of comparable magnitude to those from BMI reduction

ni-HFrEF

Directionally adverse but not significant

AF

Nominal association consistent with BMI lowering, driven by a single cis-BMI variant
  • exploratory

Original publication

Genetic evidence for GLP1R agonists in non-ischaemic heart failure. ESC Heart Fail. Published 14 March 2026. doi:10.1093/eschf/xvag077
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Summarised from the published abstract; every number is checked against it