Effect of Repaglinide Addition to NPH Insulin Monotherapy on Glycemic Control in Patients With Type 2 Diabetes

Repaglinide is a new type of oral hypoglycemic agent. Its rapid absorption, short metabolic half-time (1 h), and novel insulin release profile are all characteristics desired for treating elderly people with type 2 diabetes. The aim of this study was to investigate the efficacy and safety of repaglinide in combination with NPH insulin in subjects with type 2 diabetes on insulin monotherapy with suboptimal glycemic control.

The prospective, no-blind study was performed in our clinical research unit. We selected 27 (7 men and 20 women) type 2 diabetic patients who were nonsmokers and whose glycemic control was unsatisfactory (HbA_1c >7.1%) with two doses of NPH insulin for >6 months. Additional inclusion criteria were age 45–75 years (mean 65 ± 9.6) and BMI >21 kg/m² (mean 27.2 ± 3.9). For the purpose of this study, we followed the American Diabetes Association’s standards for medical care, which considers an HbA_1c level <1% above the upper reference range for a nondiabetic population as a goal for good glycemic control and an HbA_1c level >7.1% as unsatisfactory glycemic control. All subjects were required to be able to comply with the protocol and to carry out home blood glucose monitoring. The initial exclusion criteria included any clinically significant elevation of liver transaminases, previous rapid insulin treatment, alcohol or drug abuse, and unawareness of hypoglycemia. All subjects gave informed consent to participate in the study. The study was conducted in accordance with the 1964 Declaration of Helsinki and Guidelines for Good Clinical Research Practice in Spain.

After recruitment, prestudy insulin doses for each patient were maintained during a 4-week baseline period. Subjects who still were not under optimal control after that period were maintainted on their prestudy insulin doses, and a fixed dose of repaglinide (2 mg three times a day) was added to the treatment until the end of the study. Insulin doses were adjusted only during the first 4 weeks and were then kept constant for 3 months. Blood pressure, HbA_1c, number of ambulatory hypoglycemic events, mean of premeal and 2-h postprandial glucose profiles, and total, LDL, and HDL cholesterol and triglycerides were measured at the start of the study and after 3 months of treatment with repaglinide. Changes in insulin dosage from the initial treatment as well as hypoglycemic events compared with the previous 3 months of the study were also assessed. During treatment, patients followed the same dietary intake (1,500 calories/day) and physical activity regimen that they followed before the study. If antihypertensive and antilipid agents were being taken at recruitment, administration was continued during treatment. Blood pressure was measured twice after a 10-min rest with a random zero mercury sphygmomanometer, and the two measurements were averaged.

Demographic and baseline characteristics were mean age 65 ± 9.6, duration of diabetes 12.2 ± 8.4 years, and BMI 27.2 ± 3.9 kg/m². HbA_1c decreased significantly from 8.2 to 7.0% (P = 0.0001) (14.7% decrease from baseline), and 2-h postprandial glucose decreased significantly by 3.61 mmol/l (from 11.4 ± 2.5 to 7.8 ± 2.7 mmol/l, [P = 0.01]). No significant decrease was detected in preprandial glucose levels (9.44 ± 3.2 to 9.17 ± 3.2 mmol/l, P = NS). No significant changes were observed in other cardiovascular functions, BMI, or blood pressure. Taken together, the patients’ insulin dose did not change significantly (33.1 ± 17.5 to 29 ± 27 units/day, P = NS); although 66.7% of our patients needed less insulin while on repaglinide than before, 29.6% maintained the same dose, and 3.7% increased their dosage. The number of hypoglycemic events during 3 months of treatment with repaglinide was similar to that before treatment (2.7 ± 2.4 to 1.45 ± 2.6 events, P = NS). None of the subjects were in optimal glycemic control at entry. By the end of our study, 37.5% of subjects were in optimal control (HbA_1c <7.1%).

In short-term placebo-controlled trials, HbA_1c was reduced from 8.5% at baseline to 7.8% after only 12 weeks with repaglinide monotherapy (1). In diabetic patients not previously treated with other drugs, repaglinide resulted in a 30% decrease in HbA_1c, from 6.98 to 4.87%, with fasting and postprandial blood glucose levels decreased by 70 and 112 mg/dl, respectively (2). A long-term trial (3) compared repaglinide with glipizide at doses of 5–15 mg twice a day. This study (3) demonstrated the significant superiority of repaglinide in lowering HbA_1c (0.6%, P < 0.05) and fasting glucose (16 mg/dl, P < 0.05) over a period of 1 year. In two direct comparison studies with glyburide, the degree of glycemic control was similar between repaglinide and glyburide after 14 months. In patients naive to oral treatment, repaglinide resulted in a decrease in HbA_1c from 9.4 to 7.6% within the first 3 months, and the effect was maintained for 1 year (4,5). In another study (6), repaglinide and glibenclamide were compared, and the decrease in blood glucose levels and HbA_1c values were similar in both groups (0.3% of HbA_1c). When repaglinide was used in combination with metformin for the treatment of type 2 diabetes, more improvements in glycemic control were observed than with metformin therapy alone (HbA_1c 6.9 vs. 8.3%, respectively) (7). With the combination of repaglinide and troglitazone, Raskin et al. (8) showed a significant reduction in mean HbA_1c values (−1.7%) that was greater than that with either therapy alone.

Our study is the first prospective evaluation specifically designed to examine the efficacy of administering repaglinide to patients on insulin monotherapy with inadequate glycemic control. In conclusion, insulin therapy combined with repaglinide resulted in a decrease in HbA_1c and postprandial glucose levels, with no increase in the number of hypoglycemic episodes.