RISING STARS: Effects of a GLP-1 receptor polymorphism on responses to liraglutide

Area of Science:

• Pharmacogenomics
• Metabolic Disorders
• Obesity Research

Background:

• The glucagon-like peptide-1 receptor (GLP-1R) rs6923761 variant is linked to obesity and altered responses to incretin therapies.
• Understanding genetic influences on treatment efficacy is crucial for personalized medicine in obesity and pre-diabetes.

Purpose of the Study:

• To investigate the impact of the GLP-1R rs6923761 variant on outcomes in individuals with obesity and pre-diabetes treated with liraglutide, sitagliptin, or diet.
• To evaluate the gene dose effect of the rs6923761 variant on weight loss and metabolic parameters.

Main Methods:

• Pre-specified analysis of a randomized-controlled trial comparing liraglutide, sitagliptin, and hypocaloric diet.
• Genotyping for the rs6923761 variant and assessment of anthropometric and metabolic parameters, including weight, fasting glucose, insulin, C-peptide, glucagon, and HOMA-IR.

Main Results:

• Greater weight loss with liraglutide was observed with each copy of the rs6923761 variant allele, suggesting a gene dose effect.
• Individuals with the variant allele showed reduced plasminogen activator inhibitor-1 levels after liraglutide treatment.
• The rs6923761 variant was associated with decreased responsiveness to liraglutide and diet in fasting insulin, C-peptide, glucagon, and HOMA-IR, despite no effect on fasting glucose.

Conclusions:

• The GLP-1R rs6923761 variant has a dual effect on liraglutide efficacy, promoting weight loss while diminishing certain metabolic benefits.
• Observed associations may stem from constitutive GLP-1R activation with this variant, leading to reduced signaling response to pharmacologic agents.
• Further research is needed to elucidate the molecular mechanisms underlying the rs6923761 variant's impact on GLP-1R signaling and treatment outcomes.