Genetic evidence for GLP1R agonists in non-ischaemic heart failure

Glucagon-like peptide-1 receptor (GLP1R) agonists reduce cardiovascular events in patients with obesity and diabetes, and recent trials demonstrate symptomatic and functional benefits in heart failure with preserved ejection fraction (HFpEF). Whether these benefits reflect glycaemic control, weight reduction, or additional mechanisms remains uncertain.

We performed drug-target Mendelian randomization (MR) using genetic variants in the GLP1R-locus to proxy GLP1R activation. 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. Summary statistics were obtained from the largest available GWAS of HF, non-ischaemic HF (ni-HF), ni-HFpEF, ni-HFrEF, and atrial fibrillation (AF). Primary inverse-variance weighted analysis was adjusted for multiple testing and validated via weighted median and MR-Egger sensitivity analyses.

Genetically proxied GLP1R activation was associated with lower risk of overall HF [OR 0.96 (95% CI 0.95-0.98), P & .0002], ni-HF [0.94 (0.91-0.96), P & .0001], and ni-HFpEF [0.82 (0.74-0.90), P & .0001] per 0.1 log-odds lower T2DM liability. The GLP1R-proxied effects were greater than those expected from glycaemic lowering alone and were of comparable magnitude to those from BMI reduction. Associations for ni-HFrEF were directionally adverse but not significant. AF showed a nominal, exploratory association consistent with BMI lowering and driven by a single cis-BMI variant.

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.