Endocrine Abstracts

Background and Aims: Our objective was to assess the association between genetic polymorphisms in TCF7L2, CTRB1/2 and GLP-1R genes and inter-individual variability in response to treatment with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in terms of glycemic control and weight loss among Greek individuals with type 2 diabetes mellitus (T2DM) and to identify potential predictors of response to GLP-1 RA therapy.

Materials and Methods: Patients (n=191) treated with either liraglutide, exenatide, or lixisenatide for at least 6 months were enrolled in the study. Genotyping of TCF7L2 rs7903146 (C>T), CTRB1/2 rs7202877 (T>G) and GLP-1R rs367543060 (C>T) variants was conducted, using real-time PCR, while clinical and laboratory assessments were performed at baseline, 3- and 6-months post-treatment. Glycemic responders were defined as patients meeting one of the following criteria: i) HbA_1c <7% at 3 or 6 months after GLP-1 RA initiation, ii) reduction of baseline HbA_1c by ≥1% after 3 or 6 months of therapy, and iii) maintenance of HbA_1c<7% that a patient had before switching to GLP-1 RA, after 3 or 6 months of treatment. Weight loss responders were defined as individuals who achieved weight reduction ≥3% from their baseline weight after 3 or 6 months of GLP-1 RA administration.

Results: The minor allele frequencies for TCF7L2 rs7903146, CTRB1/2 rs7202877 and GLP-1R rs367543060 genetic polymorphisms were 79.1, 15.7 and 0%, respectively. 136 (71%) individuals were classified as glycemic responders and 125 (65%) as weight loss responders. Carriers of at least one rs7903146 “T” allele and rs7202877 “G” allele demonstrated a comparable glycemic 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). Weight and BMI decreased in both glycemic responders (P<0.0001) and non-responders (P<0.0001) after 6 months of treatment. Weight loss responders and non-responders exhibited a significant reduction in fasting glucose (P=0.003 and P=0.0004, respectively) and HbA_1c at 6 months (P<0.0001). Female sex (OR: 0.5, 95%, CI: 0.26, 0.94, P=0.03) and lower baseline weight (OR: 0.97, 95%, CI: 0.95, 0.99, P=0.024) were associated with improved glycemic and weight loss response to GLP-1 RA administration, respectively.

Conclusion: Our findings do not indicate a role of the studied variants in predicting response to treatment with GLP-1 RAs in Greek patients with T2DM.