rs6923761 — GLP1R Gly168Ser

GLP-1 Receptor Gly168Ser — Your Response to Weight-Loss Medications

The GLP-1 receptor (GLP1R) is the target of some of the most widely prescribed medications for weight loss and type 2 diabetes, including semaglutide (Ozempic, Wegovy), liraglutide (Saxenda, Victoza), and tirzepatide (Mounjaro). The rs6923761 variant causes a glycine-to-serine substitution at position 168 of the receptor protein, which sits in the extracellular domain¹¹ extracellular domain
the part of the receptor that protrudes outside the cell and binds the drug where GLP-1 and its pharmaceutical analogs dock.

The Mechanism

The Gly168Ser substitution reduces GLP-1 receptor binding affinity by approximately 30%²² reduces GLP-1 receptor binding affinity by approximately 30%
Integrated pharmacogenomic analysis, p=3.2x10^-5 and decreases receptor expression in adipose tissue. Paradoxically, carriers of the A allele (serine) appear to have higher basal GLP-1 levels and better baseline metabolic profiles, suggesting the variant may cause constitutive activation³³ constitutive activation
a state where the receptor is partially "on" even without a drug binding to it of the receptor. This means carriers get some GLP-1 signaling benefit at baseline but respond less strongly when pharmacologic agonists are added.

This constitutive activation hypothesis explains a striking dual pattern: carriers lose more weight on GLP-1 agonists but get less improvement in blood sugar control. The weight loss likely comes from enhanced gastric emptying delay⁴⁴ gastric emptying delay
slowed stomach emptying, which increases fullness and reduces caloric intake, while the blunted metabolic response reflects diminished beta-cell stimulation by the drug.

The Evidence

The largest pharmacogenomic study to date, a GWAS of 4,571 adults with type 2 diabetes⁵⁵ GWAS of 4,571 adults with type 2 diabetes
Dawed AY et al. Pharmacogenomics of GLP-1 receptor agonists. Lancet Diabetes Endocrinol, 2023, found that each copy of the A allele was associated with 0.9 mmol/mol (0.08%) less HbA1c reduction on GLP-1 receptor agonist therapy (p=6.0x10^-5). While modest per allele, this translates to meaningful differences: the 4% of the population with the least favorable genotype combination (including ARRB1 variants) had 30% less HbA1c reduction than the 9% with the best response.

A randomized controlled trial of 83 obese adults with prediabetes⁶⁶ randomized controlled trial of 83 obese adults with prediabetes
Mashayekhi M et al. Effects of a GLP-1 receptor polymorphism on responses to liraglutide. J Endocrinol, 2025 demonstrated a dose-dependent weight loss effect with liraglutide: GG carriers lost 2.05 kg, AG carriers lost 2.89 kg, and AA carriers lost 4.80 kg. However, only GG carriers showed significant improvements in fasting insulin, HOMA-IR, and glucagon levels. Variant carriers did show significant reductions in PAI-1⁷⁷ PAI-1
plasminogen activator inhibitor-1, a marker of cardiovascular and thrombotic risk prior to any weight change, suggesting a weight-independent cardiovascular benefit.

A pilot pharmacogenetics study of 60 obese individuals⁸⁸ pilot pharmacogenetics study of 60 obese individuals
Chedid V et al. Allelic variant in GLP1R associated with greater effect on gastric emptying. Neurogastroenterol Motil, 2018 showed that A allele carriers had approximately 50% greater gastric emptying delay with liraglutide (129 vs 61 minutes) and exenatide (118 vs 96 minutes), providing a mechanistic explanation for the enhanced weight loss.

An oral semaglutide study of 210 T2D patients⁹⁹ oral semaglutide study of 210 T2D patients
Acta Diabetologica, 2025 found no significant association between rs6923761 and HbA1c or BMI response, though the cohort had lower baseline HbA1c (<7.5%), which may have limited the ability to detect differences.

Practical Implications

This variant creates a pharmacogenomic paradox: if your primary goal is weight loss, carrying the A allele may actually be advantageous on GLP-1 agonists. If your primary goal is blood sugar control, your response may be somewhat blunted. This distinction is clinically relevant as GLP-1 agonists are increasingly prescribed for weight management in people without diabetes.

The DPP-4 inhibitor sitagliptin also shows reduced glucose-lowering efficacy in A allele carriers¹⁰¹⁰ reduced glucose-lowering efficacy in A allele carriers
Mashayekhi M et al. Diabetes Obes Metab, 2021, suggesting the effect extends beyond injectable GLP-1 agonists to the broader incretin drug class.

Interactions

The Lancet GWAS identified an interaction between GLP1R rs6923761 and ARRB1 rs140226575 (beta-arrestin 1). Beta-arrestin mediates GLP-1 receptor internalization and biased signaling. Carriers of both variants had the smallest HbA1c reduction on GLP-1 agonist therapy. The combination of reduced receptor binding (GLP1R) and altered receptor trafficking (ARRB1) may compound the blunted metabolic response. Another GLP1R variant, rs2268641, has been associated with obesity parameters in the same Polish cohort study and may have additive effects on GLP-1 receptor function.