Pharmacogenomics in type 2 diabetes: oral antidiabetic drugs

Abstract

Type 2 diabetes mellitus (T2DM) is a fast progressing disease reaching pandemic proportions. T2DM is specifically harmful because of its severe secondary complications. In the course of the disease, most patients require treatment with oral antidiabetic drugs (OADs), for which a relatively large number of different options are available. The growing number of individuals affected by T2DM as well as marked interindividual differences in the response to treatment call for individualized therapeutic regimens that can maximize treatment efficacy and thus reduce side effects and costs. A large number of genetic polymorphisms have been described affecting the response to treatment with OADs; in this review, we summarize the most recent advances in this area of research. Extensive evidence exists for polymorphisms affecting pharmacokinetics and pharmacodynamics of biguanides and sulfonylureas. Data on incretin-based medications as well as the new class of sodium/glucose cotransporter 2 (SGLT2) inhibitors are just starting to emerge. With diabetes being a known comorbidity of several psychiatric disorders, we also review genetic polymorphisms possibly responsible for a common treatment response in both conditions. For all drug classes reviewed here, large prospective trials are necessary in order to consolidate the existing evidence and derive treatment schemes based on individual genetic traits.

Levels of chemerin and asymmetric dimethylarginine (ADMA) in obese type 2 diabetic patients.

“…Pioglitazone, a full agonist of peroxisome proliferator-activated receptor-gamma (PPARγ) is a widely used drug for the treatment of T2DM. It decreases plasma glucose as well as HbA1c values in patients with T2DM by improving insulin sensitivity (Daniels et al, 2016). Pioglitazone depends on the presence of insulin for its mechanism of action.…”

Docking-based virtual screening in search for natural PTP1B inhibitors in treating type-2 diabetes mellitus and obesity

“…Throughout these recent decades, many therapeutic approaches have become available as the traditional insulin therapy, on its own, have not been sufficient to enhance insulin sensitivity. Injectable insulin and oral anti-diabetic agents (OAD), such as metformin, sulfonylureas (or the structurally similar meglitinides), gliflozins, dipeptidyl peptidase-IV inhibitors, new insulin analogues (lispro, aspart and glargine), inhalational insulin drug, bromocriptine, thiazolidinediones (pioglitazone is the only one currently available), incretin mimetics and α-glucosidase inhibitors, are among the few current treatments [8][9][10][11][12] . There are several limitations, however, when using these drugs either in mono-or poly-therapy.…”

“…important genes such as insulin, leptin and sodiumglucose co-transporter-2 (SGLT2) 8 . Due to the complexity and progressive nature of T2DM, it is essential to explore new and alternative therapeutic pathways and drugs.…”

Frequency of CYP2C9 (*2, *3 and IVS8‑109A>T) allelic variants, and their clinical implications, among Mexican patients with diabetes mellitus type 2 undergoing treatment with glibenclamide and metformin

“…However, a great variability in drug disposition, glycemic response tolerability and the prevalence of adverse effects to these drugs have been reported. These drawbacks have been predominantly attributed to environmental, pathological and physiological factors, in addition to gene polymorphisms (1,17).…”

“…The gene for cytochrome P450 2C9 ( CYP2C9 ) (55 kb) is situated on chromosome 10q23.33, and 60 allelic variants [single nucleotide polymorphisms (SNPs)] have been described within its exon 9-intron 8 structure (19). These variants account for ~40% of the interindividual and interethnic pharmacokinetic differences in responses to SUs (17,20-22). Nevertheless, controversy remains concerning the potential influence of CYP2C9 polymorphisms ( *2 and *3 ) on glibenclamide response variability, as the studies that have been performed were designed with different intended doses (23), pursued different objectives (hyperglycemic or hypoglycemic control) (19), analyzed different response markers (1,24) and even included cohorts of patients undergoing varied SU treatment (not glibenclamide alone) (13,24).…”