Oral combination therapy: repaglinide plus metformin for treatment of type 2 diabetes

Type 2 diabetes is characterized by decreases in insulin secretion and insulin sensitivity. Several classes of oral antidiabetic medications are currently approved for the treatment of type 2 diabetes. A stepwise treatment approach from monotherapy to combination therapy is traditionally used; however, the frequency of treatment failure with monotherapy has resulted in a move towards earlier treatment with combination therapies that target the two principal defects in glycaemic control. One such combination regimen is repaglinide (a prandial glucose regulator that increases insulin release) plus metformin (an insulin sensitizer that inhibits hepatic glucose output, increases peripheral glucose uptake and utilization and minimizes weight gain). Findings from several clinical trials have shown that combination therapy with repaglinide plus metformin is well tolerated and results in greater reductions of haemoglobin A(1c) and fasting plasma glucose values compared with either monotherapy. Repaglinide may also provide a more suitable alternative to combination therapy with sulphonylureas and metformin because of its reduced propensity for hypoglycaemia. The combination regimen of repaglinide plus metformin should therefore be considered as a valuable option in the management of patients with type 2 diabetes when monotherapy is no longer adequate.     

Combination therapy for type 2 diabetes: repaglinide plus rosiglitazone.

AIMS: This 24-week, randomized, multicentre, open-label, parallel-group clinical trial compared efficacy and safety of repaglinide monotherapy, rosiglitazone monotherapy, and combination therapy (repaglinide plus rosiglitazone) in Type 2 diabetes after unsatisfactory response to sulphonylurea or metformin monotherapy. METHODS: Enrolled patients (n = 252) were adults having Type 2 diabetes for at least 1 year, with HbA(1c) values > 7.0% after previous monotherapy (sulphonylurea or metformin, >/= 50% maximal dose). Prior therapy was withdrawn for 2 weeks, followed by randomization to repaglinide, rosiglitazone, or repaglinide/rosiglitazone. Study treatments were initiated with a 12-week dose optimization period (doses optimized according to labelling), followed by a 12-week maintenance period. Efficacy endpoints were changes in HbA(1c) values (primary) or fasting plasma glucose values (secondary). RESULTS: Baseline HbA(1c) values were comparable (9.3% for repaglinide, 9.0% for rosiglitazone, 9.1% for combination). Mean changes in HbA(1c) values at the end of treatment were greater for repaglinide/rosiglitazone therapy (-1.43%) than for repaglinide (-0.17%) or rosiglitazone (-0.56%) monotherapy. Reductions of fasting plasma glucose values were also greater for combination therapy (-5.2 mmol/l, -94 mg/dl) than for repaglinide monotherapy (-3.0 mmol/l, -54 mg/dl) or rosiglitazone monotherapy (-3.7 mmol/l, -67 mg/dl). Minor hypoglycaemic events occurred in 9% of combination therapy patients, vs. 6% for repaglinide and 2% for rosiglitazone. Individual weight gains for combination therapy were correlated to HbA(1c) response. CONCLUSIONS: The combination therapy regimen was well tolerated. In patients previously showing unsatisfactory response to oral monotherapy, glycaemic reductions were greater for the repaglinide/rosiglitazone combination regimen than for use of either repaglinide or rosiglitazone alone.     

Combination therapy with pioglitazone plus metformin or sulfonylurea in patients with Type 2 diabetes: influence of prior antidiabetic drug regimen

PURPOSE: To evaluate two trials of combination therapy, pioglitazone together with metformin or sulfonylurea, for Type 2 diabetes mellitus and to examine how pretrial antidiabetic therapies may have influenced the results. SUBJECTS AND METHODS: The results of two published trials that examine combination therapy, pioglitazone plus metformin or pioglitazone plus sulfonylurea were analyzed. A post hoc analysis was performed in which patients from both of these trials were subdivided on the basis of their oral antidiabetic therapy before enrollment into the trials. Those subsets receiving pretrial therapy with a sulfonylurea plus metformin - and discontinuing one of the agents before randomization - were compared to those receiving only one of the agents before enrollment. RESULTS: Patients in the combination pioglitazone (30 mg/day) plus metformin therapy arm of one trial, who entered with stable metformin monotherapy, experienced a significant decrease in glycosylated hemoglobin (HbA(1C)) levels during the 16-week course of the trial (-1.0+/-0.1 [mean+/-S.E.] percentage points; P<.05). In contrast, those in the same arm of the trial whose pretrial therapy included metformin plus a sulfonylurea - and who discontinued the sulfonylurea before enrollment - experienced no significant change in HbA(1C) levels (0.2+/-0.2 percentage points; P>.05). The difference between groups was significant (P<.001). Patients in the combination pioglitazone (15 or 30 mg/day) plus sulfonylurea therapy arm of the other trial, who entered the trial on stable sulfonylurea monotherapy, experienced significant decreases in HbA(1C) levels (-1.0+/-0.1 and -1.4+/-0.1 percentage points, respectively, for the 15- and 30-mg pioglitazone arms; P<.05). Those in the same arm whose pretrial therapy included sulfonylurea plus metformin - and who discontinued the metformin before enrollment - experienced no significant change in HbA(1C) levels. Differences between the groups separated on the basis of pretrial antidiabetic regimen were significant (P<.001). CONCLUSIONS: The efficacy of pioglitazone as an add-on in combination therapy (with metformin or a sulfonylurea) is likely to be greater than in previous reports, because those trial results were influenced by treatment regimens used by a portion of the patients before enrollment. Trials of oral hypoglycemic agents must be carefully constructed to consider the effects of agents given prior to the trial.     

Efficacy and safety of teneligliptin in combination with pioglitazone in Japanese patients with type 2 diabetes mellitus

Aim

To confirm the efficacy and safety of teneligliptin in combination with pioglitazone in Japanese patients with type 2 diabetes mellitus inadequately controlled with pioglitazone monotherapy.

Materials and Methods

In an initial 12‐week, double‐blind, placebo controlled, parallel‐group study, patients (n = 204) were randomized to teneligliptin 20 mg or placebo once daily added to their stable pioglitazone therapy. This was followed by a 40‐week, open‐label period during which all patients received teneligliptin once daily. The primary end‐point was the change in hemoglobin A1c (HbA_1c) from baseline to week 12.

Results

Patients in the teneligliptin group showed significantly greater reductions in HbA_1c compared with the placebo group at week 12 (P < 0.001). The changes in HbA_1c from baseline to week 12 were −0.9 ± 0.0% (least‐squares mean ± standard error) in the teneligliptin group and −0.2 ± 0.0% in the placebo group. The change in fasting plasma glucose from baseline to week 12 was greater in the teneligliptin group than in the placebo group (P < 0.001). The blood glucose lowering effects of teneligliptin were sustained throughout the 40‐week open‐label period. Adverse events and adverse drug reactions occurred slightly more frequently in the teneligliptin group than in the placebo group, although the incidence of hypoglycemia was low. Bodyweight was unchanged in the double‐blind period, but was slightly increased in the open‐label period.

Conclusions

Add‐on therapy with teneligliptin was effective and generally well tolerated throughout the study period in Japanese patients with type 2 diabetes mellitus inadequately controlled with pioglitazone monotherapy. This trial was registered with ClinicalTrials.gov (no. NCT01026194).     

Pharmacokinetic profiles of repaglinide in elderly subjects with type 2 diabetes

Pharmacokinetic profiles of single- and multiple-dose regimens of repaglinide were evaluated in 12 elderly subjects with type 2 diabetes. On day 1, following a 10-hour fast, subjects received a single 2-mg dose of repaglinide. Starting on day 2 and continuing for 7 days, each subject received a 2-mg dose of repaglinide 15 minutes before each of the three main meals. On day 9, subjects received a single 2-mg dose of repaglinide. Pharmacokinetic profiles, including area under the curve (AUC), log(AUC), maximal concentration (Cmax), log(Cmax), time to maximal concentration (Tmax), and half-life (T(1/2)), were determined at completion of the single- and multiple-dose regimens (days 1 and 9, respectively). Trough repaglinide values were collected on days 2 through 7. The mean log(AUC) values after multiple dosing were significantly higher than the values obtained after a single dose. The mean values for log(Cmax), and Tmax were comparable after each dosing regimen. The T(1/2) of repaglinide after multiple dosing was 1.7 hours. The trough values for repaglinide were low. No hypoglycemic events were reported. The pharmacokinetic profiles of repaglinide after single- and multiple-dose regimens were similar, and repaglinide was well tolerated by elderly subjects with type 2 diabetes.     

Earlier triple therapy with pioglitazone in patients with type 2 diabetes

Aims: This study assessed the efficacy of add‐on pioglitazone vs. placebo in patients with type 2 diabetes uncontrolled by metformin and a sulphonylurea or a glinide. Methods: This multicentre, double‐blind, parallel‐group study randomized 299 patients with type 2 diabetes to receive 30 mg/day pioglitazone or placebo for 3 months. After this time, patients continued with pioglitazone, either 30 mg [if glycated haemoglobin A1c (HbA_1c) ≤6.5%] or titrated up to 45 mg (if HbA_1c >6.5%), or placebo for a further 4 months. The primary efficacy end‐point was improvement in HbA_1c (per cent change). Secondary end‐points included changes in fasting plasma glucose (FPG), insulin, C‐peptide, proinsulin and lipids. The proinsulin/insulin ratio and homeostasis model assessment of insulin resistance (HOMA‐IR) and homeostasis model assessment of β‐cell function (HOMA‐B) were calculated. Results: Pioglitazone add‐on therapy to failing metformin and sulphonylurea or glinide combination therapy showed statistically more significant glycaemic control than placebo addition. The between‐group difference after 7 months of triple therapy was 1.18% in HbA_1c and ?2.56 mmol/l for FPG (p < 0.001). Almost half (44.4%) of the patients in the pioglitazone group who had a baseline HbA_1c level of <8.5% achieved the HbA_1c target of < 7.0% by final visit compared with 4.9% in the placebo group. When the baseline HbA_1c level was ≥ 8.5%, 13% achieved the HbA_1c target of < 7.0% in the pioglitazone group and none in the placebo group. HOMA‐IR, insulin, proinsulin and C‐peptide decreased and HOMA‐B increased in the pioglitazone group relative to the placebo group. Conclusions: In patients who were not well controlled with dual combination therapy, the early addition of pioglitazone improved HbA_1c, FPG and surrogate measures of β‐cell function. Patients were more likely to reach target HbA_1c levels (< 7.0%) with pioglitazone treatment if their baseline HbA_1c levels were < 8.5%, highlighting the importance of early triple therapy.     

Dose titration of repaglinide in patients with inadequately controlled type 2 diabetes

A total of 385 drug-therapy na?ve patients, with inadequately controlled type 2 diabetes, were randomised into a multinational, parallel-group study to compare two strategies for dose titration of the oral hypoglycaemic agent repaglinide. Patients were allocated to either a fasting blood glucose (FBG) monitoring group with titration target 4.4-6.1 mmol/l or to a post-prandial blood glucose (PPBG) monitoring group with titration target 4.4-8.0 mmol/l. An initial titration period of up to 8 weeks was followed by a 12-week treatment period. Glycaemic control and hypoglycaemic outcomes were compared for the respective groups. HbA(1c) decreased significantly more in the FBG monitoring group by a mean of 1.38% compared to the PPBG group by a mean of 1.22% (P=0.03). The glycaemic control targets were met by fewer patients in the FBG group than in the PPBG group (57% versus 86% (P<0.001)) despite a higher mean dose of repaglinide in the FBG group. The within-patient blood glucose variability was significantly lower in the FBG group than in the PPBG group (P<0.001). In conclusion, repaglinide lowered the HbA(1c) effectively and safely in both groups and self-monitored FBG is a suitable parameter for titration of repaglinide. Whether a lower PPBG target might be as good a guide as FBG for titration of repaglinide should be addressed in a future study.     

Flexible prandial glucose regulation with repaglinide in patients with type 2 diabetes.

Repaglinide is a novel, rapid-acting prandial glucose regulator. To investigate the effect of repaglinide, 1 mg before each meal, in maintaining glycaemic control in Type 2 diabetic patients who either miss a meal or have an extra meal, 25 patients were randomized to either a fixed-meal regimen of three meals/day or one of two mixed-meal regimens consisting of repeating patterns of two, three or four meals/day over a 20-day period. On the 21st day each patient received three meals. Overall glycaemic control was assessed by weekly serum fructosamine concentrations and 13-point and 37-point serum glucose profiles. Mean fructosamine concentrations decreased significantly to normal values during the treatment period (from 3.10 to 2.68 mg/dl on the fixed-meal regimen and from 3.37 to 2.85 mg/dl on the mixed-meal regimens; P < 0.05), with no statistically significant difference in glucose control between the fixed-meal and mixed-meal regimen groups. Fasting serum glucose levels decreased slightly in both groups, but were not altered by the number of meals consumed. Similarly, serum glucose profiles were not altered significantly by the number of meals consumed. Repaglinide was well tolerated, and no hypoglycaemic events were reported. Serum cholesterol levels were significantly reduced (P < 0.05) in both the fixed-meal and mixed-meal groups, as were triglyceride levels in the mixed-meal group (P < 0.05). It was concluded that meal-associated treatment with repaglinide was well tolerated irrespective of the number of meals consumed/day. Thus, since missing or postponing a meal is a realistic scenario for many individuals, repaglinide offers an oral anti-diabetic treatment which can be adjusted to suit each individual's lifestyle.     

Efficacy and safety of initial combination therapy with sitagliptin and pioglitazone in patients with type 2 diabetes: a 54-week study

Aim: To assess the 54‐week efficacy of initial combination therapy with sitagliptin and pioglitazone, compared with pioglitazone monotherapy, and to assess safety in these groups during the 30 weeks after the dosage of pioglitazone was increased from 30 to 45 mg/day, in drug‐naÏve patients with type 2 diabetes mellitus and inadequate glycaemic control [haemoglobin A1c (HbA1c) 8–12%]. Methods: Following a 24‐week, randomized, double‐blind, parallel‐group study (Sitagliptin Protocol 064, Clinicaltrials.gov: NCT00397631; Yoon KH, Shockey GR, Teng R et al. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase‐4 inhibitor, and pioglitazone on glycaemic control and measures of beta‐cell function in patients with type 2 diabetes. Int J Clin Pract 2011; 65: 154–164) in which patients were treated with the combination of sitagliptin 100 mg/day and pioglitazone 30 mg/day or monotherapy with pioglitazone 30 mg/day, patients entered a 30‐week extension study. In the extension study, the pioglitazone dose was increased from 30 to 45 mg/day in both groups. Depending upon treatment allocation, patients took one tablet of sitagliptin 100 mg or matching placebo daily. Pioglitazone was administered in an open‐label fashion as a single 45‐mg tablet taken once daily. Patients not meeting specific glycaemic goals in the extension study were rescued with metformin therapy. Efficacy and safety results for the extension study excluded data after initiation of rescue therapy. Results: Of the 520 patients initially randomized, 446 completed the base study and, of these, 317 entered the extension. In this extension study cohort, the mean reductions from baseline in HbA1c and fasting plasma glucose (FPG) at the end of the base study (week 24) were ?2.5% and ?62.1 mg/dl with the combination of sitagliptin 100 mg and pioglitazone 30 mg versus ?1.9% and ?48.7 mg/dl with pioglitazone monotherapy. At the end of the extension study (week 54), the mean reduction in haemoglobin A1c (HbA1c) was ?2.4% with the combination of sitagliptin 100 mg and pioglitazone 45 mg versus ?1.9% with pioglitazone monotherapy [between‐group difference (95% CI) = ?0.5% (?0.8, ?0.3)] and the mean reduction in FPG was ?61.3 mg/dl versus ?52.8 mg/dl, respectively [between‐group difference (95% CI) = ?8.5 mg/dl (?16.3, ?0.7)]. Safety and tolerability of initial treatment with the combination of sitagliptin and pioglitazone and pioglitazone monotherapy were similar. As expected, increases in body weight from baseline were observed in both treatment groups at week 54: 4.8 and 4.1 kg in the combination and monotherapy groups, respectively [between‐group difference (95% CI) = 0.7 kg (?0.7, 2.1)]. Conclusion: In this study, initial combination therapy with sitagliptin 100 mg and pioglitazone 30 mg increased to 45 mg after 24 weeks led to a substantial and durable incremental improvement in glycaemic control compared with initial treatment with pioglitazone monotherapy during a 54‐week treatment period. Both initial combination therapy with sitagliptin and pioglitazone and pioglitazone monotherapy were generally well tolerated (Clinicaltrials.gov: NCT01028391).     

瑞格列奈与甘精胰岛素联合治疗新诊断2型糖尿病的疗效观察

目的：比较新诊断2型糖尿病患者应用胰岛素促泌剂瑞格列奈单一治疗及联合长效胰岛素甘精胰岛素治疗12周后血糖水平的差异。方法纳入2012年1月~2013年1月北京军区总医院新诊断2型糖尿病患者48例,随机分为单药治疗组（n=24）及联合治疗组（n=24）,单药治疗组仅餐前口服瑞格列奈（初始计量0.5 mg）,联合治疗组除餐前服用瑞格列奈外,每晚8 pm皮下注射甘精胰岛素（初始计量6 u）。根据血糖水平调整用药剂量,治疗12周后观察两组空腹静脉血糖（FBG）水平、餐后2小时血糖（2 hPBG）水平、糖化血红蛋白（HbA1c）水平及血糖达标时间。结果与单药治疗组相比,联合治疗组FBG[（5.9±1.6）mmol/L vs.（6.8±1.5）mmol/L]、2 hPBG[（8.8±0.9）mmol/L vs.（9.2±0.8）mmol/L]、HBA1c[（7.4±0.5）% vs.（7.8±1.3）%]均更低,且血糖达标时间明显缩短[（6.1±1.3）d vs.（8.9±2.5）d]。结论胰岛素促泌剂与长效胰岛素联合治疗2型糖尿病初始治疗较单独应用胰岛素促泌剂效果更好,并能促使血糖尽快达标。     

盐酸吡格列酮治疗2型糖尿病患者的临床研究

目的研究胰岛素增敏剂盐酸吡格列酮对2型糖尿病(T2DM)患者的胰岛素抵抗、血压、血脂的影响.方法对102例体质指数(BMI)≥25 kg/m2且使用磺脲类+双胍类药物后糖化血红蛋白(HbA1c)>7.0%的T2DM患者,在重新制定合理的饮食和运动的基础上,随机分为两组:治疗组使用盐酸吡格列酮15 mg/d连用12周,对照组使用原药物,观察两组患者治疗前后空腹血糖(FBG)、餐后两小时血糖(2hPG)、空腹胰岛素(FIns)、餐后2小时胰岛素(2hIns)HbA1c、甘油三酯(TG)、胆固醇(TC)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)、血压(BP)、胰岛素抵抗指数(HOMA-IR)等指标的变化.结果治疗12周后,治疗组FBG、HbA1c、Ins、BP、TG、LDL-C及HOMA-IR较较对照组均下降.结论盐酸吡格列酮能减轻胰岛素抵抗,降低血糖,改善脂代谢.     

Nateglinide versus repaglinide for type 2 diabetes mellitus in China

The purpose of this study is to evaluate efficacy and safety of nateglinide tablet administration in comparison with those of repaglinide tablet as control on treating type 2 diabetes mellitus in China. Pooled-analysis with analysis of covariance (ANCOVA) method was applied to assess the efficacy and safety based on original data collected from four independent randomized clinical trials with similar research protocols. However meta-analysis was applied based on the outcomes of the four studies. The results by meta-analysis were comparable to those obtained by pooled-analysis. The means of HbA_1c, and fasting blood glucose in both the nateglinide and repaglinide groups were reduced significantly after 12 weeks duration but no statistical differences in reduction between the two groups. The adverse reaction rates were 9.89 and 6.51% in the nateglinide and repaglinide groups respectively, with the rate difference showing no statistical significance, and the Odds Ratio of adverse reaction rate (95% confidence interval) was 1.59 (0.99, 2.55). Both nateglinide and repaglinide administration have similarly significant effects on reducing HbA_1c and FBG. However, the adverse reaction rate in the nateglinide group is higher than that in the latter using repaglinide but no statistical significance difference as revealed in the four clinical trials detailed below.     

Efficacy and tolerability of initial combination therapy with vildagliptin and pioglitazone compared with component monotherapy in patients with type 2 diabetes

AIM: The aim of this study was to compare efficacy and tolerability of initial combination therapy with vildagliptin/pioglitazone to component monotherapy. METHODS: This 24-week, multicentre, randomized, double-blind, active-controlled study assessed the effects of the dipeptidyl peptidase-4 inhibitor vildagliptin (100 mg q.d.), pioglitazone (30 mg q.d.) and vildagliptin combined with pioglitazone (100/30 mg q.d. or 50/15 mg q.d.) in 607 drug-naive patients with type 2 diabetes (T2DM). The primary outcome measure was change from baseline in HbA(1c) in patients receiving initial combination therapy compared with pioglitazone monotherapy. RESULTS: After 24-week treatment, adjusted mean changes in HbA(1c) from baseline (approximately 8.7%) in patients receiving pioglitazone monotherapy, 50/15 mg combination, 100/30 mg combination and vildagliptin monotherapy were -1.4 +/- 0.1%, -1.7 +/- 0.1%, -1.9 +/- 0.1% and -1.1 +/- 0.1% respectively. Both low-dose and high-dose combinations were significantly more efficacious than pioglitazone alone (p = 0.039 and p < 0.001 respectively). Adjusted mean changes in fasting plasma glucose were -1.9 +/- 0.2, -2.4 +/- 0.2, -2.8 +/- 0.2 and -1.3 +/- 0.2 mmol/l respectively, and both combination groups were significantly more effective than pioglitazone monotherapy (p = 0.022 and p < 0.001 respectively). The overall incidence of adverse events ranged from 45.8% in the low-dose combination to 51.6% in the pioglitazone monotherapy group. The incidence of peripheral oedema was highest in patients receiving pioglitazone monotherapy (9.3%) and lowest in those receiving low-dose combination (3.5%). One mild hypoglycaemic event was reported by one patient receiving high-dose combination and one patient receiving vildagliptin monotherapy. CONCLUSIONS: First-line treatment with vildagliptin/pioglitazone combination in patients with T2DM provides better glycaemic control than either monotherapy component yet has minimal risk of hypoglycaemia and a tolerability profile comparable with component monotherapy.     

Effects of pioglitazone hydrochloride on Japanese patients with type 2 diabetes mellitus

AIM: The effects of pioglitazone hydrochloride monotherapy on abnormal lipid control were evaluated in Japanese patients with type 2 diabetes mellitus, comparing with glibenclamide monotherapy. METHODS: Patients were randomly assigned to receive, once daily, pioglitazone hydrochloride, at 15 mg or 30 mg (n=46), or glibenclamide, at 1.25 mg or 2.5 mg (n=46). The 24-week study included patients with type 2 diabetes having high levels of triglyceride (TG). RESULTS: Pioglitazone hydrochloride produced beneficial effects on dyslipidemia in patients with type 2 diabetes, compared with the baseline and the glibenclamide group, as demonstrated by increases in high-density lipoprotein cholesterol (HDL-C) levels and low-density lipoprotein cholesterol (LDL) particle size, a fall in TG levels, and an increased ratio of visceral to subcutaneous fat volumes (V/S). Pioglitazone hydrochloride reduced fasting serum insulin levels, with low fasting plasma glucose (FPG) and glycohemoglobin levels, compared to the baseline, suggesting an improvement of insulin resistance. CONCLUSION: As expected, glibenclamide reduced FPG levels through increased insulin secretion. Pioglitazone hydrochloride and glibenclamide were well tolerated. Pioglitazone hydrochloride improved dyslipidemia related to insulin resistance, whereas glibenclamide enhanced insulin secretion, with only a minor effect on lipid control, in Japanese patients with type 2 diabetes.     

Plasma BNP levels in the treatment of type 2 diabetes with pioglitazone

We monitored the change in plasma ANP and BNP levels (as markers for left ventricular dysfunction (LVD)) in DM2 patients treated with pioglitazone (Pio) for 4 weeks. Thirty DM2 patients with no sign of heart failure were treated with Pio (15 mg/day), and their plasma ANP (normal levels 相似文献   

Vildagliptin in combination with pioglitazone improves glycaemic control in patients with type 2 diabetes failing thiazolidinedione monotherapy: a randomized, placebo-controlled study

AIM: The purpose of this study was to assess the efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor vildagliptin in combination with the thiazolidinedione (TZD) pioglitazone in patients with type 2 diabetes (T2DM). METHODS: This was a 24-week, multicentre, double-blind, randomized, parallel-group study comparing the effects of vildagliptin (50 or 100 mg daily) with placebo as an add-on therapy to pioglitazone (45 mg daily) in 463 patients with T2DM inadequately controlled by prior TZD monotherapy. Between-treatment comparisons of efficacy parameters were made by analysis of covariance model. RESULTS: The adjusted mean change (AM Delta) in haemoglobin A(1c) from baseline to endpoint was -0.8 +/- 0.1% (p = 0.001 vs. placebo) and -1.0 +/- 0.1% (p < 0.001 vs. placebo), respectively, in patients receiving vildagliptin 50 or 100 mg daily. Relative to baseline, vildagliptin added to pioglitazone also reduced fasting plasma glucose (FPG) (AM Delta FPG =-0.8 +/- 0.2 mmol/l and -1.1 +/- 0.2 mmol/l; not significant (NS) vs. placebo) and postprandial glucose (PPG) [AM Delta PPG =-1.9 +/- 0.6 mmol/l and -2.6 +/- 0.6 mmol/l (p = 0.008 vs. placebo)] for 50 and 100 mg daily respectively. Relative to placebo, both doses of vildagliptin significantly increased the insulin secretory rate/glucose by more than threefold. The overall incidence of adverse events (AEs) was 55.5, 50.0 and 48.7% in patients receiving vildagliptin 50 mg, 100 mg daily or placebo respectively. Serious AEs were experienced by 6.8, 1.3 and 5.7% of patients receiving vildagliptin 50 mg, 100 mg daily or placebo respectively. Mild hypoglycaemia was reported by 0, 0.6 and 1.9% of patients, respectively, receiving vildagliptin 50 mg, 100 mg daily or placebo. CONCLUSION: Vildagliptin is effective and well tolerated when added to a maximum dose of pioglitazone, without increasing the risk of hypoglycaemia.     

Biphasic insulin aspart 30 plus metformin: an effective combination in type 2 diabetes

AIM: This study compared glycaemic control achieved with biphasic insulin aspart 30 (BIAsp 30) monotherapy, BIAsp 30 plus metformin and glibenclamide plus metformin in patients with type 2 diabetes not adequately controlled with metformin. METHODS: In this multinational, open-labelled, parallel group, 16-week trial, 341 patients (patients not adequately controlled with metformin for at least 1 month) with type 2 diabetes were studied. Patients were randomized to receive BIAsp 30, twice daily (n = 107 exposed to treatment), or BIAsp 30, twice daily, plus metformin (n = 108) or glibenclamide plus metformin (n = 114). The primary endpoint was HbA(1c) at end of trial; adverse events, hypoglycaemia episodes, blood lipids and weight were also monitored. RESULTS: In the total population (HbA(1c) 7.5-13.0% at screening), end-of-trial HbA(1c) levels were lower in patients receiving BIAsp 30 plus metformin compared with those receiving BIAsp 30 only [mean treatment difference (+/-s.e.m), 0.39 +/- 0.15%, p = 0.007]. In a subpopulation (HbA(1c) > or = 9.0% at baseline, n = 193), patients receiving BIAsp 30 plus metformin had significantly lower HbA(1c) levels at the end of the trial compared with those receiving glibenclamide plus metformin (treatment difference, 0.46 +/- 0.21%, p = 0.027). Mean body weight (+/-s.d) at the end of the trial was significantly lower in patients receiving glibenclamide plus metformin compared with those receiving BIAsp 30 only (84.3 +/- 13.3 kg vs. 88.9 +/- 16.9 kg, p < 0.001). No major hypoglycaemic episodes were recorded during the trial, and incidence rates for minor and symptoms-only hypoglycaemia were low and similar between treatment groups (0.03-0.04 events/patient/week). CONCLUSION: BIAsp 30 added to metformin could be an appropriate therapeutic option for achieving good glycaemic control, compared with the addition of a second oral agent, particularly where HbA(1c) > or = 9%.     

Effect of pioglitazone on cardiac sympathovagal modulation in patients with type 2 diabetes

This study aims to examine the effect of pioglitazone on potential progression of autonomic damage in addition to changes in control of cardiovascular function in patients with type 2 diabetes (T2DM). Thirty patients with T2DM and 32 healthy subjects participated in the study. Sympathovagal activity, assessed by power spectral analysis (PSA) of R–R intervals variability, and blood pressure (BP) were studied during clinostatism and orthostatism in controls and patients. We have assessed blood pressure control by 24-hour monitoring of ambulatory blood pressure. Patients were treated with pioglitazone (30 mg/day) for 6 months, and then re-evaluated by PSA for heart rate variability (HRV). Reduced levels of HbA1c (P < 0.0001) and urinary albumin (P = 0.008) were observed in pioglitazone-treated patients compared to untreated baseline levels. Arterial BP remained unchanged following pioglitazone treatment. T2DM patients had reduced HRV (low-frequency power; LF; P < 0.0001 and LF/HF; LF/HF; P < 0.0001) at baseline (clinostatism) compared to controls. Baseline clinostatic differences between groups persisted after pioglitazone treatment and no effect of treatment on basal HRV variables was observed. In controls, HF decreased and LF and LF/HF ratio increased in the orthostatic position. A similar effect for HF was observed in patients, but LF and LF/HF did not increase. The normal difference between HF-power in clinostatism versus orthostatism observed for controls (P < 0.0001) was restored in patients following pioglitazone treatment (P = 0.028). A significant decrease from lying to standing position in orthostatic LF-power (P < 0.0001) and LF/HF (P < 0.0001) was also observed between patients and controls. Although no differences in autonomic control of HRV were observed between controls and patients with T2DM, significant differences were observed in sympathovagal balance following either clinostatic or orthostatic challenge. These findings provide initial evidence of a potential additional benefit afforded by pioglitazone for the improvement of cardiac sympathovagal balance in T2DM.