GLP1R rs6923761 genetic variant predicts worse glycemic response to GLP-1 drugs in real-world clinical practice | Research

The takeaway

In 161 T2DM patients, the GLP1R rs6923761 polymorphic A allele was associated with significantly worse HbA1c response to GLP-1 agonists versus the G allele (p=0.029), demonstrating pharmacogenomic-guided treatment selection in everyday practice.

Genetics predict GLP-1 drug response
The prevalent GLP1R rs6923761 A allele predicted significantly worse glycemic response to GLP-1 drugs in real-world practice—supporting pharmacogenomic-guided prescribing

What the researchers found

GLP1R rs6923761 A allele (prevalent): significantly worse HbA1c response to GLP-1RA vs G allele (p=0.029, dominant model). Overall: all treatments improved HbA1c, weight, BP (p significant). 161 T2DM patients. Real-world clinical practice. SLC5A2 variant: tested for SGLT2i.

Why it matters

Knowing a patient's GLP1R genotype before prescribing could guide drug selection—patients with the A allele might benefit more from tirzepatide (dual mechanism) or alternative approaches.

How the study worked

Prospective interventional open-label cohort (DRKS00034478). 161 T2DM patients. GLP1R rs6923761, rs10305420, SLC5A2 rs9934336 genotyping by competitive allele-specific PCR. 3-6 month follow-up.

What this study cannot tell us

Small sample (161). Single polymorphism significant. Open-label. 3-6 month follow-up. Single center. Clinical significance of the HbA1c difference not quantified.

How to read the evidence

Prospective registered study with genetic association. Good for pharmacogenomics but small sample.

When this study was published

Published in 2025.

The bigger picture

This is among the first prospective real-world studies demonstrating that pharmacogenomics can guide GLP-1 drug prescribing. If replicated, genetic testing before treatment selection could become routine.

Questions still open

Should GLP1R genotyping precede GLP-1 drug prescribing?
Would A allele carriers respond better to tirzepatide or other drug classes?
How large is the HbA1c difference between genotypes clinically?

Common questions

Could a genetic test predict how well GLP-1 drugs work for me?

This study found that a common genetic variant (GLP1R rs6923761 A allele) predicted significantly worse blood sugar response to GLP-1 drugs. While not yet routine clinical practice, genetic testing before prescribing could eventually help doctors choose the most effective medication for each individual patient.

What should I do if GLP-1 drugs do not work well for me?

Genetic factors may partially explain variable response. If your blood sugar improvement on GLP-1 drugs is less than expected, your doctor might consider: higher doses, switching to a dual agonist (tirzepatide), adding a second drug class (SGLT2 inhibitor), or—in the future—genetic testing to guide drug selection.

Read the original research

Genetic variability in sodium-glucose cotransporter 2 and glucagon-like peptide 1 receptor effect on glycemic and pressure control in type 2 diabetes patients treated with SGLT2 inhibitors and GLP-1RA in the everyday clinical practice.

Frontiers in endocrinology, 16, 1547920

View on PubMed ↗Publisher’s paper ↗

Citation

Tonin, Gašper; Goričar, Katja; Blagus, Tanja; Janež, Andrej; Dolžan, Vita; Klen, Jasna. (2025). Genetic variability in sodium-glucose cotransporter 2 and glucagon-like peptide 1 receptor effect on glycemic and pressure control in type 2 diabetes patients treated with SGLT2 inhibitors and GLP-1RA in the everyday clinical practice.. Frontiers in endocrinology, 16, 1547920. https://doi.org/10.3389/fendo.2025.1547920