Repaglinide augments insulin release when it is taken with meals, an effect that may serve to complement the effects of drugs that decrease insulin resistance. Repaglinide has a short half-life and is excreted in the bile, making it particularly suitable for patients with renal impairment and for elderly patients. Moses and colleagues studied the efficacy of repaglinide as a substitute agent in patients who cannot take metformin or as a second agent in patients whose plasma glucose levels are not optimally controlled with metformin alone.
The double-blind, placebo-controlled study included 83 patients with type 2 diabetes (formerly known as non-insulin-dependent diabetes) and hemoglobin A1c (HbA1c) levels of at least 7.1 percent (mean HBA1c: 8.5 percent) despite at least six months of metformin therapy. Patients were randomized to one of three treatment groups: continuation of their current dosage of metformin (27 patients); a change to repaglinide monotherapy (29 patients); or the addition of repaglinide to their current dosage of metformin (27 patients). Seventy-four patients completed the trial: 21 in the metformin group, 26 in the repaglinide group and 27 in the combination therapy group.
The optimal dosage of repaglinide was determined by titrating the dosage upward every four to seven days until the patient had symptoms of hypoglycemia or a fasting plasma glucose of less than 140.5 mg per dL (7.8 mmol per L). The repaglinide dose was decreased if the plasma glucose level dropped to below 79.2 mg per dL (4.4 mmol per L) or if clinically significant hypoglycemia developed. Patients continued their drug regimen for three months after a four- to eight-week period of titration.
No change in the HbA1c level or fasting plasma glucose concentration occurred in patients who continued receiving metformin or changed to repaglinide. However, both the fasting plasma glucose and HbA1c levels decreased significantly in patients who took repaglinide in addition to metformin. Combination therapy was accompanied by a decrease in the HbA1c concentration from 8.3 percent to 6.9 percent. The fasting plasma glucose decreased from 183.7 mg per dL (10.2 mmol per L) to 144 mg per dL (8.0 mmol per L). Furthermore, none of the patients entered the study with optimal control of diabetes; 25 percent had HbA1c levels of greater than 9 percent. However, by the end of the study, nearly 60 percent of the subjects who received combination therapy were in optimal glycemic control (HbA1c of less than 7.1 percent). In contrast, optimal control was achieved in only 20 percent of those receiving repaglinide or metformin alone. None of the patients in the combination therapy group had an HbA1c level above 9 percent at the end of the trial.
There were 78 mild or moderate adverse events that were considered to possibly or probably relate to repaglinide or metformin. The most common adverse effects were hypoglycemia, diarrhea and headache. Of the 39 episodes of symptomatic hypoglycemia reported in the repaglinide and combination therapy groups, 44 percent (i.e., 17 of the 39 episodes) occurred during titration. Twelve of the 17 hypoglycemic episodes occurred in a single patient.
The authors conclude that the addition of repaglinide improves glycemic control in patients who have not achieved sufficient control with metformin alone. In addition, the findings show that repaglinide can be substituted for metformin without a change in glycemic control. The authors point out that combination therapy with metformin and repaglinide may be useful in patients who experience unacceptable side effects from metformin. In such a situation, repaglinide could be added and the metformin dose could be reduced without jeopardizing glycemic control. Although there were more episodes of hypoglycemia in the combination therapy group compared with the single-drug groups, such an increase in hypoglycemic episodes would be expected to occur with tighter glycemic control. The short half-life of repaglinide may explain why the mild to moderate episodes of hypoglycemia did not progress to severe episodes from prolonged hyperinsulinemia.