Drug Interactions of Clinical Importance with Antihyperglycaemic Agents

Because management of type 2 diabetes mellitus usually involves combined pharmacological therapy to obtain adequate glucose control and treatment of concurrent pathologies (especially dyslipidaemia and arterial hypertension), drugdrug interactions must be carefully considered with antihyperglycaemic drugs. Additive glucose-lowering effects have been extensively reported when combining sulphonylureas (or the new insulin secretagogues, meglitinide derivatives, i.e. nateglinide and repaglinide) with metformin, sulphonylureas (or meglitinide derivatives) with thiazolidinediones (also called glitazones) and the biguanide compound metformin with thiazolidinediones. Interest in combining α-glucosidase inhibitors with either sulphonylureas (or meglitinide derivatives), metformin or thiazolidinediones has also been demonstrated. These combinations result in lower glycosylated haemoglobin (HbA_1c), fasting glucose and postprandial glucose levels than with either monotherapy. Even if modest pharmacokinetic interferences have been reported with some combinations, they do not appear to have important clinical consequences. No significant adverse effects, except a higher risk of hypoglycaemic episodes that may be attributed to better glycaemic control, occur with any combination. Challenging the classical dual therapy with sulphonylurea plus metformin, there is a recent trend to use alternative dual combinations (sulphonylurea plus thiazolidinedione or metformin plus thiazolidinedione). In addition, triple therapy with the addition of a thiazolidinedione to the metformin-sulphonylurea combination has been recently evaluated and allows glucose targets to be reached before insulin therapy is considered. This triple therapy appears to be safe, with no deleterious drug-drug interactions being reported so far.

Potential interferences may also occur between glucose-lowering agents and other drugs, and such drug-drug interactions may have important clinical implications. Relevant pharmacological agents are those that are widely coadministered in diabetic patients (e.g. lipid-lowering agents, antihypertensive agents); those that have a narrow efficacy/toxicity ratio (e.g. digoxin, warfarin); or those that are known to induce (rifampicin [rifampin]) or inhibit (fluconazole) the cytochrome P450 (CYP) system. Metformin is currently a key compound in the pharmacological management of type 2 diabetes, used either alone or in combination with other antihyperglycaemics. There are no clinically relevant metabolic interactions with metformin, because this compound is not metabolised and does not inhibit the metabolism of other drugs. In contrast, sulphonylureas, meglitinide derivatives and thiazolidinediones are extensively metabolised in the liver via the CYP system and thus, may be subject to drug-drug metabolic interactions. Many HMGCoA reductase inhibitors (statins) are also metabolised via the CYP system. Even if modest pharmacokinetic interactions may occur, it is not clear whether drugdrug interactions between oral antihyperglycaemic agents and statins may have clinical consequences regarding both efficacy and safety. In contrast, a marked pharmacokinetic interference has been reported between gemfibrozil and repaglinide and, to a lesser extent, between gemfibrozil and rosiglitazone. This leads to a drastic increase in plasma concentrations of each antihyperglycaemic agent when they are coadministered with the fibric acid derivative, and an increased risk of adverse effects.

Some antihypertensive agents may favour hypoglycaemic episodes when coprescribed with sulphonylureas or meglitinide derivatives, especially ACE inhibitors, but this effect seems to result from a pharmacodynamic drug-drug interaction rather than from a pharmacokinetic drug-drug interaction. No, or only modest, interferences have been described with glucose-lowering agents and other pharmacological compounds such as digoxin or warfarin. The effects of inducers or inhibitors of CYP isoenzymes on the metabolism and pharmacokinetics of the glucose-lowering agents of each pharmacological class has been tested. Significantly increased (with CYP inhibitors) or decreased (with CYP inducers) plasma levels of sulphonylureas, meglitinide derivatives and thiazolidinediones have been reported in healthy volunteers, and these pharmacokinetic changes may lead to enhanced or reduced glucose-lowering action, and thus hypoglycaemia or worsening of metabolic control, respectively. In addition, some case reports have evidenced potential drug-drug interactions with various antihyperglycaemic agents that are usually associated with a higher risk of hypoglycaemia.