Current Progress in Pharmacogenetics of Second-Line Antidiabetic Medications: Towards Precision Medicine for Type 2 Diabetes

Abstract

Precision medicine is a scientific and medical practice for personalized therapy based on patients’ individual genetic, environmental, and lifestyle characteristics. Pharmacogenetics and pharmacogenomics are also rapidly developing and expanding as a key element of precision medicine, in which the association between individual genetic variabilities and drug disposition and therapeutic responses are investigated. Type 2 diabetes (T2D) is a chronic metabolic disorder characterized by hyperglycemia mainly associated with insulin resistance, with the risk of clinically important cardiovascular, neurological, and renal complications. The latest consensus report from the American Diabetes Association and European Association for the Study of Diabetes (ADA-EASD) on the management of T2D recommends preferential use of glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose cotransporter-2 (SGLT2) inhibitors, and some dipeptidyl peptidase-4 (DPP-4) inhibitors after initial metformin monotherapy for diabetic patients with established atherosclerotic cardiovascular or chronic kidney disease, and with risk of hypoglycemia or body weight-related problems. In this review article, we summarized current progress on pharmacogenetics of newer second-line antidiabetic medications in clinical practices and discussed their therapeutic implications for precision medicine in T2D management. Several biomarkers associated with drug responses have been identified from extensive clinical pharmacogenetic studies, and functional variations in these genes have been shown to significantly affect drug-related glycemic control, adverse reactions, and risk of diabetic complications. More comprehensive pharmacogenetic research in various clinical settings will clarify the therapeutic implications of these genes, which may be useful tools for precision medicine in the treatment and prevention of T2D and its complications.

Pleiotropic Effects of Sodium-Glucose Cotransporter-2 Inhibitors: Renoprotective Mechanisms beyond Glycemic Control

“…Persistent hyperglycemia causes inflammation, endothelial dysfunction, and oxidative stress in the kidneys and, thus, is partly associated with DKD progression [ 8 , 9 , 10 ]. In addition to traditional hypoglycemic agents and insulin, several agents targeting peptidyl hormones, such as dipeptidyl peptide IV and glucagon-like peptide-1, have recently been introduced for the treatment of hyperglycemia [ 11 ]. These therapeutic options have improved the management of hyperglycemia in patients with diabetes mellitus.…”

New Insights into Beta-Cell GLP-1 Receptor and cAMP Signaling

“…An increasing number of genetic variants for gastrointestinal hormones and their cognate receptors are currently being associated with obesity phenotypes, appetite regulation, and metabolic disturbances. The field of pharmacogenetics is rapidly expanding as a key element of precision medicine, with current research also focusing on responses to GLP-1RAs and other second-line antidiabetic medications [55,56]. For the GLP-1R, a pilot study in nondiabetic subjects assessed the effect of receptor polymorphisms on insulin secretion in response to infused GLP-1, with two single nucleotide polymorphisms (SNPs), rs6923761 and rs3765467, associated with changes in responsivity to GLP-1 [57].…”

Pharmacogenomic Studies of Current Antidiabetic Agents and Potential New Drug Targets for Precision Medicine of Diabetes

“…Pharmacogenomics considers genetic factors of individuals, and guides medication selection and more efficient use of medication according to genomic and other ''omic'' information, which can improve the efficacy of pharmacotherapy and reduce risks of adverse effects [15]. Thus, precision medicine is the practice of providing tailored treatments for patients on the basis of individual characteristics, including genetic, environmental, and lifestyle factors, and it is beneficial for overcoming existing limitations of therapeutic interventions [14,16]. Pharmacogenomics, which studies almost all current antidiabetic agents, is becoming a more effective approach to prevent, classify, manage, and treat diabetes [11].…”