Glucagon-Like Peptide 1 (GLP-1) Receptor Variants and Glycemic Response to Liraglutide: A Pharmacogenetics Study in Iranian People with Type 2 Diabetes Mellitus

• Published in: Advances in therapy Vol. 41; no. 2; pp. 826 - 836
• Main Authors: Eghbali, Maryam, Alaei-Shahmiri, Fariba, Hashemi-Madani, Nahid, Emami, Zahra, Mostafavi, Ladan, Malek, Mojtaba, Khamseh, Mohammad E.
• Format: Journal Article
• Language: English
• Published: Cheshire Springer Healthcare 01-02-2024
• Subjects: Cardiology; Endocrinology; Internal Medicine; Medicine; Medicine & Public Health; Oncology; Original Research; Pharmacology/Toxicology; Rheumatology; GLP-1 receptor variants; GLP-1 receptor agonists; Type 2 diabetes mellitus; Glycemic response
• ISSN: 0741-238X; 1865-8652; 1865-8652
• DOI: 10.1007/s12325-023-02761-1

Introduction
Pharmacogenetics studies suggest that genetic variants have a possible influence on the inter-individual differences in therapeutic response to glucagon-like peptide 1 receptor agonists (GLP-1 RAs). We aimed to examine the potential role of genetic variability of glucagon-like peptide 1 receptor (GLP-1R) on glycemic response to GLP-1 RAs in a population of Iranian people with type 2 diabetes mellitus (T2DM).
Methods
In this study, we analyzed the data from participants in a non-inferiority randomized clinical trial between 2019 and 2020. Patients received liraglutide 1.8 mg/day subcutaneously for 24 weeks. They were stratified by the baseline hemoglobin A1c (HbA1c) into four categories: 7–7.99, 8–8.99, 9–9.99, and ≥ 10%. In each category, subjects with HbA1c reduction greater than the median ΔHbA1c value for that group were defined as optimal responders. The pooled number of optimal/suboptimal responders in the four groups was used for the comparison. We evaluated two genetic variants of GLP-1R, rs6923761 and rs10305420, using Sanger sequencing. Logistic regression analyses were performed to examine the associations of the GLP-1R variants with the glycemic response in different genetic models.
Results
Out of 233 participants, 120 individuals were optimal responders. Median HbA1c reduction was − 2.5% in the optimal responder group compared with − 1.0% in the suboptimal responder group (
P
 < 0.001). In genetic models, rs10305420 T allele homozygosity was associated with optimal glycemic response to liraglutide compared with heterozygous and wild-type homozygous states (recessive model: OR 3.28, 95% CI 1.41–7.65,
P
 = 0.006; codominant model: OR 2.52, 95% CI 1.03–6.13,
P
 = 0.04). No significant association was found between rs6923761 variant and HbA1c reduction.
Conclusion
GLP-1R rs10305420 polymorphism can explain some of the inter-individual differences in glycemic response to liraglutide in a population of Iranian people with T2DM.