ORIGINAL RESEARCH article
Front. Endocrinol.
Sec. Clinical Diabetes
Volume 16 - 2025 | doi: 10.3389/fendo.2025.1547920
This article is part of the Research TopicIncretin-based Therapies in the Treatment of Metabolic Syndrome: Expanding Roles Beyond Weight ManagementView all 3 articles
Genetic variability in sodium-glucose cotransporter 2 and glucagonlike 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
Provisionally accepted
- 1Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
- 2Faculty of Arts, University of Ljubljana, Ljubljana, Slovenia
- 3Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
- 4Department of Internal Medicine, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
- 5Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia
- 6Department of Abdominal Surgery, University Medical Centre Ljubljana, Ljubljana, Slovenia
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We investigated the impact of genetic polymorphisms in the GLP1R and SLC5A2 genes on the response to treatment with glucagon-like peptide-1 receptor (GLP-1R) agonists and sodium-glucose co-transporter-2 (SLGT2) inhibitors in patients with type 2 diabetes mellitus (T2DM) in everyday clinical practice.In our prospective interventional cohort open-label real-world genetic association study (DRKS-ID: DRKS00034478, https://drks.de/search/en/trial/DRKS00034478), we enrolled 161 clinically well-defined T2DM patients who received SGLT2 inhibitors and/or GLP-1R agonists alongside other medications for 3-6 months. The study's primary outcomes (HbA1c, body mass, and blood pressure) were measured before the treatment and at the follow-up at 3-6 months. GLP1R rs6923761, rs10305420, and SLC5A2 rs9934336 genotypes were determined by competitive allelespecific polymerase chain reaction. In patients receiving GLP-1R agonists, we analyzed the effect of GLP1R polymorphisms on the patients' response to treatment, while in patients receiving SGLT2 inhibitors, we analyzed the impact of the SLC5A2 polymorphism on the treatment effect.Treatment with prescribed antihyperglycemic drugs improved all primary outcomes (p < 0.050). The normal GLP1R rs6923761 G allele was associated with a greater reduction in HbA1c with GLP-1R agonists treatment than the polymorphic A allele in the dominant model (p = 0.029).The prevalent polymorphic A allele of GLP1R rs6923761 polymorphism was associated with the clinically relevant lower glycemic response to GLP-1R agonists. The described impact extends to everyday clinical practice, indicating that knowledge of these genetic polymorphisms could facilitate the development of targeted and personalized therapy in managing T2DM.
Keywords: polymorphism, SLC5A2, GLP1R, treatment response, type 2 diabetes mellitus, SGLT2, GLP-1RA, Everyday clinical practice
Received: 18 Dec 2024; Accepted: 20 Jun 2025.
Copyright: © 2025 Tonin, Goričar, Blagus, Janez, Dolzan and Klen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Jasna Klen, Department of Internal Medicine, Faculty of Medicine, University of Ljubljana, Ljubljana, SI-1000, Slovenia
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