Pharmacogenetics of novel glucose-lowering drugs

Abstract

The aim of this work was to review studies in which genetic variants were assessed with respect to metabolic response to treatment with novel glucose-lowering drugs: dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium–glucose cotransporter 2 inhibitors (SGLT2i). In total, 22 studies were retrieved from the literature (MEDLINE). Variants of the GLP-1 receptor gene (GLP1R) were associated with a smaller reduction in HbA1c in response to DPP-4i. Variants of a number of other genes (KCNQ1, KCNJ11, CTRB1/2, PRKD1, CDKAL1, IL6 promoter region, TCF7L2, DPP4, PNPLA3) have also been related to DPP-4i response, although replication studies are lacking. The GLP1R gene was also reported to play a role in the response to GLP-1 RA, with larger weight reductions being reported in carriers of GLP1R variant alleles. There were variants of a few other genes (CNR1, TCF7L2, SORCS1) described to be related to GLP-1 RA. For SGLT2i, studies have focused on genes affecting renal glucose reabsorption (e.g. SLC5A2) but no relationship between SLC5A2 variants and response to empagliflozin has been found. The relevance of the included studies is limited due to small genetic effects, low sample sizes, limited statistical power, inadequate statistics (lack of gene–drug interactions), inadequate accounting for confounders and effects modifiers, and a lack of replication studies. Most studies have been based on candidate genes. Genome-wide association studies, in that respect, may be a more promising approach to providing novel insights. However, the identification of distinct subgroups of type 2 diabetes might also be necessary before pharmacogenetic studies can be successfully used for a stratified prescription of novel glucose-lowering drugs. Graphical abstract

Circulating microRNAs Signature for Predicting Response to GLP1-RA Therapy in Type 2 Diabetic Patients: A Pilot Study

“…In recent years, significant progress was made in this field, prompting researchers to suggest the use of pharmacogenetics to guide drug selection. For example, single nucleotide polymorphisms (SNPs) in SLC22A1 and SLC2A2 genes have been related to better efficacy of metformin treatment [9][10][11], whereas other genetic variants, such as a reducedfunction alleles of the OCT1 gene, may be associated to gastrointestinal side effects of metformin [9,12,13]. Similar data also highlighted the influence of genetic variants on treatment response to thiazolidinediones (TZDs) [14], sulphonylureas and metaglinides [10].…”

“…For example, single nucleotide polymorphisms (SNPs) in SLC22A1 and SLC2A2 genes have been related to better efficacy of metformin treatment [9][10][11], whereas other genetic variants, such as a reducedfunction alleles of the OCT1 gene, may be associated to gastrointestinal side effects of metformin [9,12,13]. Similar data also highlighted the influence of genetic variants on treatment response to thiazolidinediones (TZDs) [14], sulphonylureas and metaglinides [10]. Available evidence also suggests that gene polymorphisms may mediate the response to novel glucose-lowering drugs.…”

“…Available evidence also suggests that gene polymorphisms may mediate the response to novel glucose-lowering drugs. In a recent review, Rathmann and colleagues summarized available findings regarding the role of pharmacogenetics in the response to dipeptidyl peptidase 4-inhibitors (DPP4i), glucagon-like peptide-1 receptor agonists (GLP1-RA) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) treatments [10]. As an example, genetic polymorphisms in GLP-1 receptor gene seem to influence the interindividual differences in response to both DPP4i and GLP1-RA treatment [10,15,16], with some variants associated with poorer glycemic response and others associated with higher HbA1c reduction.…”

“…In a recent review, Rathmann and colleagues summarized available findings regarding the role of pharmacogenetics in the response to dipeptidyl peptidase 4-inhibitors (DPP4i), glucagon-like peptide-1 receptor agonists (GLP1-RA) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) treatments [10]. As an example, genetic polymorphisms in GLP-1 receptor gene seem to influence the interindividual differences in response to both DPP4i and GLP1-RA treatment [10,15,16], with some variants associated with poorer glycemic response and others associated with higher HbA1c reduction. In particular, the GLP1R rs6923761 A allele has been related to better HbA1c reduction and weight loss after liraglutide therapy, while the T allele of GLP1R rs10305420 was associated with lower HbA1c and weight reduction in exenatide-treated patients [10].…”

“…As an example, genetic polymorphisms in GLP-1 receptor gene seem to influence the interindividual differences in response to both DPP4i and GLP1-RA treatment [10,15,16], with some variants associated with poorer glycemic response and others associated with higher HbA1c reduction. In particular, the GLP1R rs6923761 A allele has been related to better HbA1c reduction and weight loss after liraglutide therapy, while the T allele of GLP1R rs10305420 was associated with lower HbA1c and weight reduction in exenatide-treated patients [10]. CNR1, TCF7L2 and SORCS1 variants are also reported to influence GLP1-R response [10,16].…”