Genetic Evidence for Repurposing of GLP1R (Glucagon-Like Peptide-1 Receptor) Agonists to Prevent Heart Failure

J Am Heart Assoc. 2021 Jul 6;10(13):e020331. doi: 10.1161/JAHA.120.020331. Epub 2021 Jun 29.


Background This study was designed to investigate the genetic evidence for repurposing of GLP1R (glucagon-like peptide-1 receptor) agonists to prevent heart failure (HF) and whether the potential benefit exceeds the benefit conferred by more general glycemic control. Methods and Results We applied 2-sample Mendelian randomization of genetically proxied GLP1R agonism on HF as the main outcome and left ventricular ejection fraction as the secondary outcome. The associations were compared with those of general glycemic control on the same outcomes. Genetic associations were obtained from genome-wide association study summary statistics of type 2 diabetes mellitus (228 499 cases and 1 178 783 controls), glycated hemoglobin (n=344 182), HF (47,309 cases and 930 014 controls), and left ventricular ejection fraction (n=16 923). Genetic proxies for GLP1R agonism associated with reduced risk of HF (odds ratio per 1 mmol/mol decrease in glycated hemoglobin 0.75; 95% CI, 0.64-0.87; P=1.69×10-4), and higher left ventricular ejection fraction (SD change in left ventricular ejection fraction per 1 mmol/mol decrease in glycated hemoglobin 0.22%; 95% CI, 0.03-0.42; P=0.03). The magnitude of these benefits exceeded those expected from improved glycemic control more generally. The results were similar in sensitivity analyses, and we did not find evidence to suggest that these associations were mediated by reduced coronary artery disease risk. Conclusions This genetic evidence supports the repurposing of GLP1R agonists for preventing HF.

Keywords: GLP1R; Mendelian randomization; diabetes mellitus; ejection fraction; heart failure.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Biomarkers / blood
  • Blood Glucose / drug effects
  • Blood Glucose / metabolism
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / diagnosis
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / genetics
  • Drug Repositioning*
  • Genetic Variation*
  • Genome-Wide Association Study
  • Glucagon-Like Peptide-1 Receptor / agonists*
  • Glucagon-Like Peptide-1 Receptor / genetics*
  • Glycated Hemoglobin / metabolism
  • Heart Failure / diagnosis
  • Heart Failure / genetics
  • Heart Failure / physiopathology
  • Heart Failure / prevention & control*
  • Humans
  • Hypoglycemic Agents / therapeutic use*
  • Incretins / therapeutic use*
  • Mendelian Randomization Analysis
  • Risk Assessment
  • Risk Factors
  • Stroke Volume / drug effects
  • Treatment Outcome
  • Ventricular Function, Left / drug effects


  • Biomarkers
  • Blood Glucose
  • GLP1R protein, human
  • Glucagon-Like Peptide-1 Receptor
  • Glycated Hemoglobin A
  • Hypoglycemic Agents
  • Incretins
  • hemoglobin A1c protein, human