Combination Of Mitiglinide Research Articles

Comparison of the Efficacy of Repaglinide Versus the Combination of Mitiglinide and Voglibose on Glycemic Variability in Japanese Patients with Type 2 Diabetes

Glycemic variability is a risk factor for total death and cardiovascular events. There are no obvious guidelines for the direct treatment of glycemic variability, but it can be improved with the treatment of postprandial hyperglycemia. We compared the effect of repaglinide versus the combination of mitiglinide and voglibose, used to improve postprandial hyperglycemia, on glycemic variability in Japanese patients with type 2 diabetes. We performed an open-label randomized cross-over trial between April 2016 and April 2018. Patients with type 2 diabetes who were admitted to our hospital were enrolled in our study (n = 12). Glycemic variability. was assessed using a continuous glucose monitoring system. The average glucose level of the repaglinide phase (146.1 ± 20.7 mg/dl) and the combination of mitiglinide and voglibose phase (132.3 ± 19.8 mg/dl) were similar (P = 0.10). The standard division (P = 0.0005), coefficient of variation (P = 0.006), and mean amplitude of glycemic excursion (P = 0.002) of glucose were lower in the combination of mitiglinide and voglibose phase than in the repaglinide phase. Treatment with the combination of mitiglinide and voglibose might be more effective than repaglinide for the improvement of glycemic variability.

Effects of combination of mitiglinide with various oral antidiabetic drugs in streptozotocin‐nicotinamide‐induced type 2 diabetic rats and Zucker fatty rats

We examined the effects of combining the rapid insulin secretagogue, mitiglinide, with various oral hypoglycaemic drugs including biguanides, pioglitazone, α-glucosidase inhibitors, and sodium-glucose co-transporter 2 inhibitors in a rat model of type 2 diabetes. The oral glucose tolerance test (OGTT) using glucose, sucrose, or a liquid meal was used to compare the effects of mitiglinide with those of the four oral hypoglycaemic drugs and examine their combined effects on blood glucose levels and insulin secretion in the rat model. The combination of mitiglinide with other oral hypoglycaemic drugs suppressed the plasma glucose levels more than either agent did alone. Furthermore, the combination of these agents decreased insulin secretion more than mitiglinide did alone. These results indicate that mitiglinide is suitable for use in combination with other hypoglycaemic drugs because it inhibits postprandial hyperglycaemia by rapidly stimulating insulin secretion.

Comparison of the Effects of Mitiglinide and Glibenclamide Administered in Combination with the Dipeptidyl Peptidase-IV Inhibitor Sitagliptin in Rats with Streptozotocin-Nicotinamide-Induced Type 2 Diabetes

We compared the individual effects of mitiglinide and glibenclamide administered in combination with the dipeptidyl peptidase-IV (DPP-IV) inhibitor sitagliptin on plasma DPP-IV activity and blood glucose levels in rats with streptozotocin-nicotinamide-induced type 2 diabetes (STZ-NA rats). We examined the inhibitory activity of mitiglinide and glibenclamide as well as their combination with sitagliptin on plasma DPP-IV activity in STZ-NA rats. The oral glucose tolerance test (OGTT) was used to compare effects of mitiglinide, glibenclamide, and their combination with sitagliptin on blood glucose levels in STZ-NA rats. Mitiglinide and glibenclamide did not inhibit rat DPP-IV and did not influence the inhibitory effect of sitagliptin on rat plasma DPP-IV activity. In STZ-NA rats, plasma glucose levels were stronger suppressed by a combination of mitiglinide and sitagliptin than by either drug used alone. However, no clear effect of the combination of glibenclamide and sitagliptin was observed. These results indicate that the combination of mitiglinide and sitagliptin has a lower risk of hypoglycemia in the rats with induced type 2 diabetes compared with the combination of glibenclamide and sitagliptin. The combination of mitiglinide and sitagliptin can be a promising combination for the treatment of diabetic patients.

Cross-Over Study Comparing Postprandial Glycemic Increase After Addition of a Fixed-Dose Mitiglinide/Voglibose Combination or a Dipeptidyl Peptidase-4 Inhibitor to Basal Insulin Therapy in Patients with Type 2 Diabetes Mellitus.

BackgroundAlthough the efficacy of combination therapy consisting of basal insulin and oral hypoglycemic agents (OHAs) has been shown, which OHAs are the most efficient remains unclear.Material/MethodsFive patients with type 2 diabetes were enrolled and treated with insulin degludec and metformin as a basal therapy. The patients were randomized in a cross-over fashion to receive a combination of mitiglinide (10 mg) and voglibose (0.2 mg) (M+V) 3 times daily or linagliptin (5 mg) (L) once daily for 8 weeks. After 8 weeks, 2 kinds of meal tolerance tests were performed as breakfast on 2 consecutive days. The first breakfast contained 460 kcal (carbohydrates, 49.1%; protein, 15.7%; fat, 35.2%), while the second contained 462 kcal (carbohydrates, 37.2%; protein, 19.6%; fat, 43.2%). Self-monitoring blood glucose levels were measured at 0, 30, 60, and 120 min after the meal tests, and the increase in the postprandial area under the curve (AUC)0–120 min was determined. The HbA1c, glycated albumin, and 1,5-anhydroglucitol (AG) levels were measured, and continuous glucose monitoring was performed.ResultsThe increase in the postprandial AUC0–120 min was significantly smaller in the M+V group than in the L group after both meals. The 24-h average, 24-h standard deviations, 24-h AUC, and mean amplitude of glycemic excursion (MAGE) were similar for both groups and after both meals. The change in 1,5-AG was higher in the M+V group than in the L group.ConclusionsThe combination of M+V with basal therapy improved postprandial glucose excursion more effectively than L in T2DM patients.

Differences between Mitiglinide/Voglibose Fixed-dose Combination and Glimepiride in Modifying Low-density Lipoprotein Heterogeneity in Japanese Type-2 Diabetic Patients: A Pilot Study

The purpose of this study was to compare the effects of mitiglinide/voglibose fixed-dose combination and glimepiride on low-density lipoprotein (LDL)-heterogeneity in type-2 diabetic patients with unstable glycemic control after treatment with dipeptidyl peptidase-4 (DPP-4) inhibitors. This was an open-label pilot study in which type-2 diabetic patients were randomly assigned to the mitiglinide/voglibose (fixed-dose combination of mitiglinide 10 mg and voglibose 0.2 mg, n=14) or glimepiride (0.5 mg, n=16). In the glimepiride group, serum LDL cholesterol (LDL-C) and small-dense (sd) LDL levels decreased significantly (-8.5% and -9.0%), while sd-LDL/LDL-C and an indicator of LDL-particle size, LDL-C/apoB, did not change significantly. In the mitiglinide/voglibose group, serum LDL-C levels did not change, while sd-LDL levels and sd-LDL/LDL-C decreased significantly (-8.6% and -7.9%) and LDL-C/apoB increased significantly (5.8%). Fasting blood glucose levels tended to be reduced to a greater extent in the glimepiride group than in the mitiglinide/voglibose group (-13.9% vs. -8.4%, p=0.08), while the rate of reduction of HbA1c levels tended to be higher in the mitiglinide/voglibose group than in the glimepiride group (-6.9% vs. -3.4%, p=0.09), suggesting differences in fluctuating blood glucose levels between the 2 groups. There were differences in the effects of mitiglinide/voglibose fixed-dose combination and glimepiride in addition to DPP-4 inhibitors on LDL-metabolism, and this may be related to fluctuations in blood glucose levels after treatment with these agents.

Efficacy of Mitiglinide Combined with Dapagliflozin in Streptozotocin-nicotinamide-induced Type 2 Diabetic Rats and in Zucker Fatty Rats.

The efficacy of the combination of the rapid-acting insulin secretagogue mitiglinide and the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin was explored in streptozotocin-nicotinamide-induced type 2 diabetic (STZ-NA) rats and in Zucker fatty (ZF) rats. The STZ-NA rats were prepared at 8 weeks of age. At 9 weeks of age, the combination study was conducted by oral glucose tolerance test (OGTT). At 13 weeks of age, ZF rats were dosed orally with dapagliflozin once daily up to the 22(nd) day. At days 15 and 22, the combination study was conducted by OGTT. In 2 different animal models, plasma glucose levels were strongly suppressed by the combination of mitiglinide and dapagliflozin as compared with either drug alone. The urinary glucose excretion was drastically elevated in the dapagliflozin group, but the combination with mitiglinide suppressed it about 50%. In STZ-NA rats, the plasma insulin secretion by the combination of both drugs was about at the same level as in the mitiglinide group. In ZF rats, the plasma insulin secretion by the combination of both drugs was less than mitiglinide group. Thus, in 2 different animal models, the combination of mitiglinide and dapagliflozin showed stronger antihyperglycemic action accompanied by less insulin secretion than mitiglinide alone, and reduced the urinary glucose excretion as compared with dapagliflozin used alone. These results indicate that the combination of mitiglinide and dapagliflozin can be a promising combination for the treatment of diabetic patients.

Glycemic/metabolic responses to identical meal tolerance tests at breakfast, lunch and dinner in Japanese patients with type 2 diabetes mellitus treated with a dipeptidyl peptidase-4 inhibitor and the effects of adding a mitiglinide/voglibose fixed-dose combination

Background: The effects of the mitiglinide/voglibose fixed-dose combination on postprandial glycemic/metabolic responses in patients with type 2 diabetes mellitus (T2DM) treated with dipeptidyl peptidase-4 (DPP-4) inhibitors are unknown.Methods: Twelve T2DM patients treated with a DPP-4 inhibitor underwent identical meal tolerance tests (MTTs) at breakfast, lunch and dinner, before and 2 – 3 weeks after treatment with a fixed-dose combination of mitiglinide 10 mg and voglibose 0.2 mg (combination). Patients were randomized in a cross-over fashion to administer the combination either three-times-daily before each meal or twice-daily before breakfast and dinner. Glycemic/metabolic responses were evaluated at 0, 30, 60 and 120 min in each MTT.Results: Three-times-daily administration of the combination significantly suppressed postprandial hyperglycemia after each meal, particularly after lunch and dinner. Active glucagon-like peptide-1 levels increased significantly after each meal, as did early-phase insulin secretion without excessive insulin secretion. Postprandial hyperglycemia after lunch was significantly greater after twice-daily than three-times-daily administration, but there were no clinically relevant differences in other metabolic responses.Conclusion: This study revealed that adding the mitiglinide/voglibose combination to a DPP-4 inhibitor elicited additive improvements in postprandial glycemic/metabolic responses assessed using MTTs at breakfast, lunch and dinner with identical meal compositions.

Additive Postprandial Glucose-Lowering Effects of Mitiglinide and Sitagliptin in Patients with Type 2 Diabetes Mellitus

The aim of this research was to compare the pharmacodynamics of the combination of mitiglinide and sitagliptin to that of each agent alone in Korean patients with type 2 diabetes mellitus (T2DM). Patients with T2DM received mitiglinide alone, sitagliptin alone, or both drugs together in randomized sequence. A meal tolerance test (MTT) was conducted for each group, and plasma concentrations of glucose, insulin, C-peptide, glucagon, and intact glucagon-like peptide-1, and dipeptidyl peptidase-4 activity were measured from 2 h before breakfast through 4 h after breakfast on day 0 (pretreatment) and day 1 (posttreatment) of each treatment period. Integrated values of these pharmacodynamic variables were analyzed for changes from pretreatment to posttreatment and for differences between the three treatment groups. Twenty-six patients with glycated hemoglobin A1c level of 7.4% ± 0.6%, fasting plasma glucose concentration of 141 ± 22 mg/dL, postprandial plasma glucose (PPG) concentration of 264 ± 48 mg/dL 1 h after the MTT, and diabetes duration of 3.0 ± 3.1 years (mean ± SD) were included in the study. Compared with mitiglinide or sitagliptin alone, the combination treatment lowered PPG additively (P < 0.001 vs. mitiglinide or sitagliptin alone) and the insulin secretory response (P = 0.03 vs. mitiglinide or sitagliptin alone). The integrated insulin concentrations changed significantly from before to after treatment (P < 0.01), but the change did not differ between the combination and mitiglinide groups. The insulinogenic index increased significantly after the combination treatment (P < 0.001 vs. mitiglinide or sitagliptin alone). The combination of mitiglinide and sitagliptin was generally well tolerated, with no hypoglycemic events. The combination of mitiglinide and sitagliptin did not trigger hypoglycemia and controlled postprandial glucose excursion more effectively compared with either drug alone.

Comparison of the hypoglycemic effect of sitagliptin versus the combination of mitiglinide and voglibose in drug-naïve Japanese patients with type 2 diabetes

Objective: The postprandial glucose (PPG) level is reduced by α-GIs, glinides and DPP4Is through different pharmacological actions. The aim of this study was to compare the effect of sitagliptin (S) versus that of the combination of mitiglinide and voglibose (M+V) on markers of glycemic control.Research design and methods: A randomized cross-over trial was performed in 20 patients with drug-naïve type 2 diabetes. The patients were randomized to receive S (50 mg/day) or M+V (1 tablet 3 times daily). Treatment was continued for 8 weeks, after which they were switched to the other regimen and treated for another 8 weeks. At baseline, after the first regimen, and after the second regimen, a meal test was performed.Main outcome measures: The markers of glycemic control were examined.Results: Reduction of glucose excursion was significantly greater with M+V than with S. HbA1c did not change with either regimen. However, 1,5-anhydroglucitol showed a significant increase from baseline with both regimens (7.9 ± 4.3 μg/ml at baseline vs. 10.6 ± 5.5 with S, p < 0.05 and 15.1 ± 6.2 with M+V, p < 0.01). Compared with baseline, glycoalbumin was significantly reduced by M+V, but not S (19.6 ± 2.9% at baseline vs. 17.3 ± 3.8% with M+V, p < 0.05).Conclusion: M+V achieved better control of PPG excursion than S.

Pharmacokinetics of a Fixed-Dose Combination of Mitiglinide and Metformin versus Concurrent Administration of Individual Formulations in Healthy Subjects

In the treatment of diabetes mellitus, combined drugs with different mechanisms of action can be effective when adequate glycaemic control is difficult with monotherapy. A fixed-dose combination (FDC) tablet of mitiglinide and metformin has been developed as a second-line treatment for type 2 diabetes. The objective of this study was to compare the pharmacokinetics and safety of a FDC and a free combination of mitiglinide and metformin in healthy male subjects. A randomized, open-label, two-period, two-treatment, single-dose, crossover study was conducted in 24 healthy Korean male subjects. In one period, a FDC tablet of mitiglinide and metformin (10mg/500mg) was administered, and in the other period, corresponding doses of individual formulations were administered. Twenty-four subjects were enrolled and 19 subjects completed the study. The geometric mean ratios (90% confidence interval) of the maximum plasma concentration (C(max)) and area under the plasma concentration-time curve from time zero to the time of the last measurable concentration (AUC(last)) were 0.9694 (0.8120, 1.1573) and 0.8951 (0.8440, 0.9494) for mitiglinide, and 1.0235 (0.9373, 1.1057) and 1.0542 (0.9697, 1.1460) for metformin, which were within the bioequivalence range. Among the 23 subjects who received study drugs, 15 subjects experienced 34 adverse events (AEs). The most frequently reported AEs were feeling hot and compensatory sweating. There were no serious AEs and no significant differences in the incidence of AEs between the two treatments. A FDC tablet of mitiglinide and metformin was generally well tolerated in healthy male subjects. Administration of a FDC tablet and concomitant administration of individual formulations did not show significantly different pharmacokinetic profiles.

Effect of the combination of mitiglinide and metformin on glycemic control in patients with type 2 diabetes mellitus.

Aims/Introduction: Mitiglinide is the newest drug in the meglitinide family. It increases the early-phase insulin release through rapid association-dissociation kinetics in the pancreatic β cells. The efficacy and safety of adding meglitinide to metformin monotherapy in patients with type 2 diabetes are unknown. We carried out a prospective, randomized, multicenter trial to assess the efficacy and safety of combined treatment with mitiglinide and metformin for patients with type 2 diabetes who showed inadequate glycemic control with metformin monotherapy. Subjects with glycated hemoglobin (HbA1c) >7.0% after an 8-week metformin run-in phase were randomized to a 16-week trial phase with metformin plus mitiglinide (Met + Mit) or metformin plus placebo (Met + Pcb). Compared with the Met + Pcb group, the Met + Mit group showed a greater reduction in HbA1c (-0.7 ± 0.6%vs-0.4 ± 0.7%, P = 0.002), fasting plasma glucose (-0.77 ± 1.76 mmol/L vs-0.05 ± 1.60 mmol/L, P = 0.015) and 2-h postprandial glucose (-3.76 ± 3.57 mmol/L vs-0.84 ± 3.07 mmol/L, P < 0.0001). The proportion of the patients who achieved the target HbA1c value of <7% at the end of the study was also higher in the Met + Mit group than the Met + Pcb group (49.3%vs 28.8%, P = 0.016). There were no differences in the adverse event rates between groups. Combination therapy with metformin and mitiglinide is effective and safe for the treatment of patients with type 2 diabetes who have inadequate glycemic control with metformin monotherapy. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00023.x, 2010).

Combination therapy with mitiglinide and voglibose improves glycemic control in type 2 diabetic patients on hemodialysis

Objective: Mitiglinide, a rapid- and short-acting insulinotropic sulfonylurea receptor ligand, exhibits hypoglycemic action unlike other sulfonylureas. The efficacy of the combination of mitiglinide and α-glucosidase inhibitors for diabetic patients on hemodialysis (HD) has not been prospectively evaluated; therefore, we evaluated the efficacy and safety of mitiglinide in these patients.Research design and methods: We performed an open-label randomized study with 36 type 2 diabetics with poor glycemic control on HD and receiving daily doses of voglibose (0.9 mg). The patients were randomly assigned to two groups: a combination-therapy group (mitiglinide group), mitiglinide initial dose 7.5 – 15 mg titrated to 30 mg daily and constant daily dose 0.9 mg of voglibose, and a monotherapy group (control group), constant daily dose 0.9 mg of voglibose alone. The efficacy of the treatment was determined by monitoring plasma glucose, hemoglobin A1c (HbA1c), and glycated albumin (GA) levels and using homeostasis model assessment of insulin resistance (HOMA-IR). Safety and tolerance were determined by monitoring clinical and laboratory parameters.Results: The final dose of mitiglinide was 22.9 ± 8.9 (mean ± s.d.) mg (0.41 mg/kg) daily. Mitiglinide reduced fasting plasma glucose and GA levels after 4 weeks and HbA1c levels after 8 weeks. Triglyceride levels and HOMA-IR values also decreased significantly after mitiglinide treatment. No significant changes in blood pressure levels or serious adverse effects such as hypoglycemia or liver impairment were observed.Conclusions: This study suggests a combination therapy of mitiglinide and voglibose may have potential for the treatment of diabetics on HD. Due to the small sample size used, further studies should be performed, particularly to assess the safety of mitiglinide treatment.

Mitiglinide: KAD 1229, S 21403.

Mitiglinide [KAD 1229, S 21403], a derivative of benzylsuccinic acid, is a potassium channel antagonist undergoing development with Kissei for the treatment of type 2 diabetes mellitus. It has potent oral hypoglycaemic activity and is structurally different from the sulphonylureas, although it stimulates calcium influx by binding to the suphonylurea receptor on pancreatic beta-cells and closing K+ATP channels. Mitiglinide belongs to a family of meglitinide analogues that also includes repaglinide and nateglinide. Mitiglinide is licensed to Servier for Europe, where it is undergoing phase III development, and for Russia, the Commonwealth of Independent States, the Baltic Republics, the Middle East, Oceania, China (including Hong Kong) and Taiwan. Kissei exclusively licensed mitiglinide to Choongwae Pharma for South Korea in March 2003. In August 2002, Kissei and Takeda entered into a co-marketing agreement for mitiglinide in Japan. The companies will co-market the agent under a single brand name. Mitiglinide was licensed to Purdue Pharma for the US, Canada, Mexico and Central and South America. However, Kissei and Purdue Pharma terminated their agreement in February 2001 following Purdue Pharma's decision to concentrate on core areas such as oncology and analgesics. Kissei's US subsidiary, Kissei Pharma US, is currently carrying on the ongoing phase II clinical development in the US. However, in its Annual Report 2003, Kissei announced that it is considering outlicensing mitiglinide for development in marketing in North America. Mitiglinide has been recommended for approval in Japan for the management of postprandial hyperglycaemia in patients with type 2 diabetes. Kissei is also conducting phase II/III clinical trials with a combination of mitiglinide and an alpha-glucosidase inhibitor (additional indication) in patients with type 2 diabetes in Japan. In the US, the agent is being evaluated in phase II clinical trials with Kissei Pharma USA. Mitiglinide is also undergoing a phase-III, 12-month, multicentre, randomised, double-blind study in a total of 710 patients in comparison with repaglinide for the treatment of type 2 diabetes. This study will be followed by a 12-month open-label treatment with mitiglinide alone or in combination therapy. Servier (Australia) conducted a randomised, double-blind, multicentre phase III study in Australia comparing mitiglinide with metformin or a combination of the two for the treatment of type 2 diabetes.