Association between variants in TCF7L2, CTRB1/2, and GLP-1R genes and response to therapy with glucagon-like peptide-1 receptor agonists

ABSTRACT

Objectives

The factors determining the response to treatment with glucagon-like peptide-1 receptor agonists (GLP-1- RAs) have not been clarified. The present study investigated the association between polymorphisms in TCF7L2, CTRB1/2, and GLP-1 R genes and response to GLP-1 RAs regarding glycemic control and weight loss among Greek patients with type 2 diabetes mellitus (T2DM).

Methods

Patients (n = 191) treated with GLP-1 RAs for at least 6 months were included. Participants were genotyped for TCF7L2 rs7903146 (C>T), CTRB1/2 rs7202877 (T>G) and GLP-1 R rs367543060 (C>T) polymorphisms. Clinical and laboratory parameters were measured before, 3, and 6 months after treatment initiation. The patients were classified into responders and non-responders according to specific criteria.

Results

Carriers of at least one rs7903146 ‘T’ allele and rs7202877 ‘G’ allele presented similar glucose control and weight loss response to GLP-1 RAs with the respective homozygous wild-type genotypes [odds ratio (OR): 1.08, 95% confidence interval (CI): 0.5, 2.31, p = 0.85 and OR: 1.35, 95% CI: 0.66, 2.76, p = 0.42; OR: 1.4, 95% CI: 0.56, 3.47, p = 0.47 and OR: 1.28, 95% CI: 0.55, 2.98, p = 0.57, respectively]. Regarding the GLP-1 R polymorphism, all participants were homozygous for the wild-type allele; thus, no comparisons were feasible. Female sex (p = 0.03) and lower baseline weight (p = 0.024) were associated with an improved glycemic and weight loss response, respectively.

Conclusion

There is no evidence suggesting a role for the variants studied in response to GLP-1 RA therapy in people with T2DM. However, specific demographic and clinical factors may be related to a better response to treatment with these agents.

KEYWORDS:

• Type 2 diabetes mellitus
• gene polymorphisms
• personalized medicine
• pharmacogenetics
• GLP-1 RA

Declaration of financial/other relationships

T Koufakis has received honoraria as a speaker from and has participated in sponsored studies by Eli-Lilly, AstraZeneca, Boehringer Ingelheim, and Novo Nordisk; K Kotsa has received honoraria for lectures/advisory boards and research support from Astra Zeneca, Boehringer Ingelheim, Pharmaserve Lilly, Sanofi-Aventis, ELPEN, MSD, and Novo Nordisk. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

The present data were presented as a short oral discussion at the 58^th Annual Meeting of the European Association for the Study of Diabetes. The title of the abstract was “Association between variants in TCF7L2, CTRB1/2 and GLP-1 R genes and response to therapy with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes”.

Author contributions

A Kyriakidou and AV Kyriazou collected and analyzed the data. I Avramidis and S Baltagiannis contributed to the collection of the data. Y Vasilopoulos performed the genetic analysis. A Kyriakidou and T Koufakis reviewed the literature, analyzed the data and drafted the manuscript. DG Goulis and K Kotsa supervised the research procedure and interpreted the data. All authors have read and critically reviewed the manuscript and approved the final version.

Ethics statement

The research protocol was approved by the Ethics Committee of Aristotle University of Thessaloniki (approval number 227/23 March 2016). Written informed consent was obtained from all participants.

Data availability statement

The data presented in the study are available on reasonable request from the corresponding author.

Additional information

Funding

This research was funded by Novo Nordisk (grant number 133935/2014). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.