Both glimepiride and high-dose metformin are important for sustained glucose lowering in Japanese type 2 diabetes patients on glimepiride-sitagliptin-metformin therapy: subanalysis of a single-center, open-label, randomized study.

BACKGROUND: In a previous single-center, open-label randomized 3-month study of triple oral antidiabetes drug (OAD) therapy, we investigated factors affecting the glycemic control afforded by sitagliptin, high-dose metformin, and low-dose glimepiride. Patients were prospectively assigned to either Group 1 (50% reduction in metformin) or Group 2 (discontinuation of glimepiride) and compared. The results showed that the glycated hemoglobin (HbA1c) levels of patients in Group 2 deteriorated more than those in Group 1, whereas HbA1c levels were maintained in some patients in both groups. MATERIALS AND METHODS: To determine the factors associated with maintenance of HbA1c under this triple OAD regimen, data from the prospective study were further analyzed. RESULTS: In both Groups 1 and 2, the baseline HbA1c level was higher in patients with HbA1c ≥7.0% after 3 months of treatment than those with an HbA1c level of <7.0%. A generalized linear model revealed that high-dose metformin was associated with a deterioration of HbA1c levels in Group 2. CONCLUSIONS: Together, the findings indicate that glimepiride and high-dose metformin are important for sustained glycemic control in triple OAD therapy with sitagliptin, metformin, and sulfonylurea.

Glimepiride strongly enhances the glucose-lowering effect in triple oral antidiabetes therapy with sitagliptin and metformin for Japanese patients with type 2 diabetes mellitus.

BACKGROUND: After approval of sitagliptin and >750 mg of metformin in Japan, a triple oral antidiabetes drug (OAD) regimen including sulfonylurea, metformin, and sitagliptin was sometimes described. However, in the real world of clinical practice, the daily dose of sulfonylurea tended to be decreased according to the warning from the Japan Diabetes Society for avoiding hypoglycemia, instead of increasing the dose of metformin for maintaining hemoglobin A1c (HbA1c) levels with this regimen. This study examined the impact of either a small dose of glimepiride or a high dose of metformin on HbA1c in triple OAD therapy with sitagliptin in a 3-month, single-center, open-label, randomized controlled study. SUBJECTS AND METHODS: Fifty-six type 2 diabetes mellitus patients who had been treated with 50 mg of sitagliptin, ≥ 1,000 mg of metformin, and ≤ 1 mg of glimepiride with an HbA1c level of <7.4% during at least 3 months were enrolled in the study. The patients were randomly assigned to two treatment groups who either received a 50% reduced dose of metformin (n = 27) or discontinued glimepiride (n = 29), while sitagliptin administration continued in both groups. Twenty-six patients from the reduced metformin group and 27 patients from the discontinued glimepiride group completed the study. RESULTS: Significantly greater changes were observed in HbA1c and glycated albumin levels in patients who discontinued glimepiride than in patients with a 50% reduced metformin dose, during the 2-3-month period than in the 1-3-month period. CONCLUSIONS: Glimepiride is important for good glycemic control in triple OAD therapy with sitaglitpin and metformin. This regimen may be useful for those patients who do not achieve satisfactory glycemic control with dual combination therapy.

Combination Therapy with a Dipeptidyl Peptidase-4 Inhibitor, Sulfonylurea, and Metformin Markedly Improves HbA1c Levels in Japanese Patients with Type 2 Diabetes Mellitus.

Combination therapy with a dipeptidyl peptidase (DPP)-4 inhibitor and metformin or sulfonylurea results in substantial and additive glucose-lowering effects in patients with type 2 diabetes mellitus (T2DM). However, it is not known whether triple combination therapy with a DPP-4 inhibitor, metformin, and sulfonylurea has greater additive effects or synergic effects. In the present report, we investigated the effect of addition of sitagliptin, the first-in-class DPP-4 inhibitor, to ongoing metformin and sulfonylurea therapy in three female Japanese patients with T2DM who refused insulin therapy. Combined treatment with all three drugs resulted in marked improvements in HbA1c. In the first patient, HbA1c levels decreased from 11.1% to 6.1% after the addition of sitagliptin to metformin 1000 mg, glibenclamide, and miglitol, even though the dose of glibenclamide was decreased. HbA1c levels decreased similarly in the second patient, who was being treated with metformin and glibenclamide, from 7.9% to 6.0% after addition of sitagliptin and an increase in metformin to 2250 mg; this patient ceased glibenclamide because of hypoglycemia and instead was started on low-dose glimepiride. In the third patient, HbA1c levels decreased from 8.6% to 7.1% after addition of glimepiride to ongoing sitagliptin and metformin therapy. All three patients had refused insulin therapy, despite the fact that ongoing combination therapy had failed to achieve satisfactory glycemic control. Based on these results, it is likely that the addition of sitagliptin to metformin and at least a small dose of sulfonylurea may be effective in reducing HbA1c levels without weight gain. This triple combination therapy may prove useful in at least some patients who need initiation of insulin therapy.

Comparison of the pharmacokinetic and pharmacodynamic profiles of biphasic insulin aspart 50 and 30 in patients with type 2 diabetes mellitus: a single-center, randomized, double-blind, two-period, crossover trial in Japan.

BACKGROUND: To overcome the complicated mixing procedures required in the use of insulin formulations, premixed formulations consisting of rapid-acting and intermediate-type insulin in various mixing proportions have been developed. Biphasic insulin aspart 50 (BIAsp50) and 30 (BlAsp30) are 2 premixed formulations containing the active ingredient insulin aspart (IAsp) and consisting of a rapid-acting component soluble IAsp) and intermediate-acting component (protamine-crystallized protracted IAsp) in ratios of 50/50 and 30/70, respectively. These formulations are provided with the expectation that BIAsp30 and BIAsp50 will be beneficial for patients needing to improve their postprandial blood glucose control without changing their dietary habits and lifestyles. BIAsp30 has been widely used in medical practice, whereas BIAsp50 is being investigated in clinical trials. OBJECTIVE: The aim of this study was to compare the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of BIAsp50 (test) and BIAsp30 (reference) after single-dose SC injection in patients with type 2 diabetes mellitus. METHODS: This single-center, randomized, doubleblind, 2-period, crossover trial was conducted at the H.E.C. Science Clinic, Yokohama, Japan. Male and female patients aged > or = 20 years with a > or = 1 year history of type 2 diabetes were eligible. Patients were randomly assigned to 1 of 2 treatment sequences: group A received BIAsp30 in period 1 and BIAsp50 in period 2; group B received BIAsp50 in period 1 and BIAsp30 in period 2. All treatments were administered as an SC injection of a single dose (0.3 U/kg). The study periods were separated by a washout period of 4 to 21 days. For PK analysis of IAsp (maximum serum IAsp concentration [C(max,IAsp); primary end point], AUC of serum IAsp 0 to 120, 240, and 480 minutes after administration [AUC(0-120 min,IAspl), AUC(0-240 min,IAsp), and AUC(0-480 min,IAsp5) respectively], and time to (Cmax,IAsp) [T(max,IAsp)] ), blood samples were drawn immediately before (baseline) and at prespecified time points over 480 minutes after administration. The PD profiles of BIAsp50 and BIAsp30 were also examined by comparing the time course of the glucose infusion rate (GIR) using the euglycemic clamp technique. The PD end points were AUC of GIR 0 to 120 minutes after administration (AUC(0-120 min,GIR)), maximum GIR (GIR(max)), and time to GIRmax (T(max,GIR)). Tolerability was assessed using physical examination, including vital sign measurement, electrocardiography, body weight, adverse events (AEs), and clinical laboratory analysis (hematology and serum biochemistry). RESULTS: Six men and 4 women were enrolled in the study (mean age, 62.4 years; mean body weight, 58.3 kg; mean body mass index, 22.22 kg/m(2); mean duration of diabetes, 9.53 years; and mean glycosylated hemoglobin concentration, 6.07%). Mean(Cmax,IAsp) with BIAsp50 was 63% higher than that for BIAsp30 (P < 0.002). The BIAsp50/BIAsp30 ratio with AUC(0-120 min,IAsp) was 1.68 (95% CI, 1.31-2.14). The BIAsp50/BIAsp30 ratiofor AUC(0-120 min,GIR) was 1.31 (95% CI, 1.02-1.68). A total of 9 AEs were reported in 5 patients, but none of the AEs were considered related to the study drug. CONCLUSION: In this small PK/PD study in adults with type 2 diabetes in Japan, mean C(max,IAsp) was significantly higher with BIAsp50 than with BIAsp30, and AUC(0-120 min,IAsp) and AUC(0-120 min,GIR) were higher with BIAsp50 than with BIAsp30.