Oral antidiabetic drug metabolism: pharmacogenomics and drug interactions

Abstract

Background: Type 2 diabetes is progressive in nature and so to control cardiovascular risk, most patients need combinations of oral antidiabetic drugs (OADs) plus or minus insulin. Thus, drug–drug interactions may substantially contribute to harmful effects of intensive glucose lowering therapy. Methods: A PubMed literature search was performed to select the most recent and relevant publications examining OAD metabolism and the effects of concomitant use of OADs. Results/conclusion: Considering the individual sensitivity to OADs, pharmacogenetic factors could be of critical importance. The therapeutic range and efficacy as well as adverse effects of OADs may be significantly affected by genetic polymorphisms of cytochrome P450 drug metabolising enzymes, organic cation transporters or organic anion transporting polypeptides. Although current data suggest that modest pharmacokinetics interferences among some OAD combinations exist, they do not seem to have substantial clinical consequences. As long-term adherence to multi-drug treatment is poor in diabetic patients, the future will show a strong move towards earlier treatment with combination therapies. As metformin is cardiovascular protective and is not metabolised through the hepatic cytochrome P450 system, it is a key compound for any OAD combination. There is an overwhelming amount of small-sized in vitro studies and investigations mostly including healthy volunteers dealing with short-term effects and surrogate parameters of concomitant OAD use. Further evidence from large-scale studies including typical subjects with type 2 diabetes, in particular multimorbid and geriatric patients with polypharmacy, is needed. Postmarketing surveillance using large patients' registries could be helpful to improve the early detection of clinically relevant drug–drug interactions.

Keywords::

• acarbose
• antidiabetic drugs
• diabetes
• dipepdidyl pepdidase-IV inhibitors
• drug interactions
• glibenclamide
• glimepiride
• meglitinides
• metformin
• nateglinide
• oral antidiabetic drugs
• pharmacogenomics
• pharmacokinetics
• pioglitazone
• repaglinide
• rosiglitazone
• sitagliptin
• sulfonylureas
• thiazolidinediones
• Type 2 diabetes mellitus
• vildagliptin

Acknowledgements

This article is dedicated to E-H Egberts, the former head of the First Department of Medicine, Clinic Lippe-Detmold, who retired in September 2008.