Combination Therapy for Patients with Type 2 Diabetes: Repaglinide in Combination with Metformin

Robert G Moses

Disclosures

Expert Rev Endocrinol Metab. 2010;5(3):331-342. 

In This Article

Drug Interactions

Drug–drug interactions between antidiabetic agents and other pharmacological compounds may be two-sided. For those antidiabetic drugs that are metabolized via the CYP450 isoenzymes, concomitant administration of an inhibitor of CYP isoenzymes carries the risk of potentiating hypoglycemia. This is frequently observed with insulin secretagogs, whereas only occasionally with insulin sensitizers.

Despite its inhibition of the CYP system and effect on gastric pH, cimetidine 800 mg/day had no effect on the mean serum profile of repaglinide 2 mg three-times daily, and did not change repaglinide pharmacokinetics from control levels or result in hypoglycemia.[76] Interestingly, significant improvement in blood glucose control was observed in patients with T2DM treated with a combination of repaglinide and pioglitazone (pioglitazone 30 mg once daily with repaglinide 0.25 mg once daily), indicating that the inhibition of CYP2C8 and CYP3A4 by pioglitazone in vivo is weak.[77,78] Coadministration of a combination tablet of levonorgestrel 0.15 mg and ethinylestradiol 0.03 mg once daily with repaglinide 2 mg three-times daily resulted in a 20% increase in repaglinide mean maximum concentration (Cmax), while mean area under the concentration time curve (AUC) remained unchanged.[79] Coadministration of nifedipine 10 mg with a single dose of repaglinide 2 mg resulted in nearly unchanged AUC (+11%) and Cmax (+2%) for repaglinide.[79] The magnitude and direction of these changes do not suggest safety concerns from these interactions.

Hatorp et al. investigated the effects of concomitant administration of rifampicin 600 mg or ketoconazole 200 mg (a strong CYP3A4 inhibitor) with repaglinide 4 mg.[79] Concomitant rifampicin decreased AUC for repaglinide by 32% and the Cmax by 26%. Compared with the administration of repaglinide alone, concomitant ketoconazole only modestly increased the mean AUC of repaglinide by 15% and mean Cmax by 8%. Despite the minor alterations in the pharmacokinetic profile of repaglinide, pharmacodynamics and safety profiles were not altered. In a study investigating interactions of gemfibrozil 600 mg (a CYP2C8 inhibitor) or itraconazole 100 mg (a CYP3A4 inhibitor) with a single dose of repaglinide 0.25 mg, the AUC of repaglinide showed an eightfold increase with gemfibrozil alone, a 1.4-fold increase with itraconazole alone, and a 19.4-fold increase with a gemfibrozil-itraconazole combination.[80] Cmax levels of repaglinide were also significantly increased with gemfibrozil alone (240%; p < 0.001) with itraconazole alone (147%; p < 0.001), and with gemfibrozil-itraconazole combination (275%; p < 0.001), thus considerably enhancing the blood glucose-lowering effect of repaglinide. Other drugs which have shown to increase plasma concentrations of repaglinide include clarithromycin, telithromycin, trimethoprim and cyclosporine. To overcome the risk of possible adverse events due to pharmacological interactions, Scheen et al. recommend starting patients on a low dose of repaglinide therapy, uptitrating when necessary, and encouraging patients to perform self-glucose assessment.[81]

Although many medications have been reported to interact with metformin, relatively few clinically important interactions exist mainly because metformin is not protein bound and is not metabolized hepatically. Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine by renal tubular secretion.

The addition of cimetidine 400 mg to metformin 250 mg resulted in a 50% increase in the plasma AUC of metformin and a 27% decrease in the 24-h renal excretion of metformin.[62]

Concomitant single-dose administration of metformin and furosemide resulted in an increased Cmax of metformin by 22%, and the Cmax of furosemide was decreased by 31% relative to separate administration of each drug. A single dose of nifedipine increased the Cmax of metformin by 20%, but coadministration of these agents had no effect on the Cmax of nifedipine.[106] The magnitude and direction of these changes do not suggest safety concerns from these interactions.

Because of the hepatic metabolism of repaglinide, the manufacturer recommends that a repaglinide-metformin combination tablet should be avoided in patients with hepatic impairment. On a similar note, because of renal clearance of metformin, the manufacturer recommends that a repaglinide-metformin combination tablet should be avoided in patients with renal impairment.

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