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

Robert G Moses


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

In This Article

Pharmacokinetics & Metabolism

Repaglinide is rapidly and almost completely absorbed after oral administration, with peak plasma concentrations achieved in about 1 h.[52] When taken 15 min before a meal, repaglinide produces a rapid insulin-releasing effect that lasts for 3 h, coinciding with the duration of meal digestion. Repaglinide is cleared rapidly from the circulation. Total body clearance of a 2-mg intravenous dose over 15 min was 33 l/h.[52] Repaglinide clearance depends predominantly on liver blood flow, but also on protein binding and liver enzyme activity. Following an oral dose, repaglinide concentrations fall rapidly, reaching predose concentrations within 4–5 h after oral administration. Repaglinide is mainly metabolized via oxidative biotransformation involving the hepatic microsomal cytochrome P450 (CYP450) system. In patients with reduced renal function, repaglinide may be advantageous considering that excretion of repaglinide is principally by the biliary route. The rapid elimination half-life of repaglinide and lack of accumulation upon repeated dosing reduce the risk of hypoglycemia.[53] Repaglinide has been safe and well tolerated in patients with varying degrees of renal impairment.[54–56] Glycemic control was maintained in a similar manner in patients with and without renal impairment. Rates of minor hypoglycemic episodes were similar in patients with varying degrees of renal impairment, and no major hypoglycemic episodes were reported in these studies. In patients with severe renal impairment, a longer half-life was observed with repaglinide following multiple dosing[55] and the final repaglinide dose was lower in patients with severe renal impairment when compared with patients with mild-to-moderate impairment.[54]

Metformin is a stable hydrophilic biguanide that is quickly absorbed and eliminated unchanged in urine.[24] Peak plasma concentration of metformin is short lived, with a plasma half-life of 2–5 h. Almost 90% of the absorbed dose is eliminated within 12 h.[22] Metformin is eliminated by tubular secretion rather than glomerular filtration and there is little binding to plasma proteins. Compromise in renal function increases the risk for development of metformin-associated lactic acidosis and thus it is important that patients using metformin have renal function that is sufficient to avoid accumulation of the drug. Considering that metformin is not metabolized, it does not interfere with the metabolism of coadministered medications. Metformin is widely distributed and is retained in the walls of the gastrointestinal tract, which can act as a reservoir from which plasma concentration of the drug is maintained.

A study that investigated the bioequivalence of a fixed-dose combination (FDC) tablet of repaglinide/metformin 2 mg/500 mg versus repaglinide 2 mg and metformin 500 mg coadministered as separate formulations, demonstrated that the combination tablet was bioequivalent to the individual tablets of repaglinide and metformin.[57] Additionally, a FDC tablet of repaglinide/metformin 2 mg/500 mg was determined to be dose proportional to a FDC of repaglinide/metformin 1 mg/500 mg.


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