Comparison of vildagliptin and pioglitazone in patients with type 2 diabetes inadequately controlled with metformin

Aim: To compare the tolerability and efficacy of vildagliptin to pioglitazone as add‐on therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy over 1‐year duration. Methods: This 52‐week, multicentre, randomized, active‐controlled study compared vildagliptin (50 mg b.i.d., n = 295) and pioglitazone (30 mg daily, n = 281) in patients with inadequate glycaemic control [haemoglobin A1c (HbA_1c) 7.5–11%] receiving a stable dose of metformin (≥1500 mg). The primary objective was to demonstrate non‐inferiority of vildagliptin at 24 weeks in the change in HbA_1c from baseline. The objective of the additional 28 weeks of the study was to assess long‐term safety, while also assessing mean change from baseline to study end in HbA_1c, fasting plasma glucose and body weight. Results: When added to a stable dose of metformin (mean baseline dose approximately 2 g/day), the non‐inferiority of HbA_1c lowering of vildagliptin to pioglitazone over 24 weeks was established at the non‐inferiority margin of 0.3% (between‐group difference = 0.1%). During the remaining 28 weeks, comparable HbA_1c decreases were recorded in both groups. Overall adverse event (AE) rates were similar in both groups, as was the occurrence of peripheral oedema. Hypoglycaemia occurred rarely in both groups. Serious AEs occurred more frequently with pioglitazone group. While mean body weight increased significantly in the pioglitazone group (+2.6 kg) from baseline, there was no significant weight gain with vildagliptin (+0.2 kg). Conclusions: When added to metformin, vildagliptin demonstrates favourable safety and tolerability over 1 year. Vildagliptin provided additional HbA_1c lowering to that achieved with metformin alone and comparable to that achieved with pioglitazone, with only pioglitazone causing weight gain.     

Long-term effects of pioglitazone and metformin on insulin sensitivity in patients with Type 2 diabetes mellitus.

AIM: Despite their comparable glycaemic effects in patients with Type 2 diabetes mellitus (T2DM), pioglitazone and metformin may have different effects on insulin sensitivity because they have different mechanisms of action. We studied the changes in insulin sensitivity, as assessed by the Quantitative Insulin Sensitivity Check Index (QUICKI), in patients with T2DM who used metformin or pioglitazone as monotherapy or in combination therapy with sulphonylurea. METHODS: Data in this report are from two multicentre, randomized, double-blind, double-dummy studies conducted in Europe (monotherapy) or in Europe and Canada (combination therapy study). Patients were randomized to 52 weeks of treatment consisting of a 12-week forced titration period and a 40-week maintenance period. HbA(1c), fasting plasma glucose (FPG) and fasting serum insulin (FSI) were quantified from a single blood sample at weeks 0, 8, 16, 24, 32, 42 and 52. Insulin sensitivity was assessed with QUICKI, which is calculated from FSI and fasting blood glucose (FBG) concentrations using the formula 1/(log(10) FSI + log(10) FBG). Time course effects of the treatments were compared by repeated measures analysis of covariance. RESULTS: As monotherapy, pioglitazone and metformin increased QUICKI compared with baseline (baseline vs. end point [mean +/- sem]; pioglitazone [0.303 +/- 0.001 vs. 0.321 +/- 0.001; P < 0.001] and metformin [0.304 +/- 0.001 vs. 0.315 +/- 0.001; P < 0.001]). Pioglitazone increased insulin sensitivity more than metformin from week 4 through week 52. There were significant increases in QUICKI from baseline in both combination therapy groups (baseline vs. end point; pioglitazone + sulphonylurea [0.305 +/- 0.001 vs. 0.319 +/- 0.001; P < 0.001] and metformin + sulphonylurea [0.306 +/- 0.001 vs. 0.317 +/- 0.001; P < 0.001]). Overall, pioglitazone + sulphonylurea significantly increased insulin sensitivity more than metformin + sulphonylurea. CONCLUSION: Pioglitazone differed from metformin in its effects on insulin sensitivity despite both drugs having comparable glycaemic effects.     

Comparison of metabolic effects of pioglitazone, metformin, and glimepiride over 1 year in Japanese patients with newly diagnosed Type 2 diabetes.

AIMS: To compare the metabolic effects of pioglitazone, metformin, and glimepiride in the treatment of Japanese patients with newly diagnosed Type 2 diabetes. METHODS: A total of 114 patients with Type 2 diabetes who had never used oral hypoglycaemic drugs were studied for 12 months. Patients were randomly assigned to pioglitazone (30-45 mg/day, n = 38), metformin (750 mg/day, n = 39), or glimepiride (1.0-2.0 mg/day, n = 37). The effect of treatment on fasting plasma glucose (FPG), glycated haemoglobin (HbA(1c)), 1,5-anhydroglucitol (1,5AG), total cholesterol, high-density lipoprotein (HDL)-cholesterol, triglycerides, free fatty acids (FFA), and fasting plasma insulin levels was monitored monthly. Body weight and safety data were also collected. RESULTS: Eight patients withdrew from the study (three in the pioglitazone group, two in the metformin group, and three in the glimepiride group). The rate of reduction of HbA(1c) was fastest in patients receiving glimepiride and slowest in patients receiving pioglitazone. Although there were no significant differences among the three groups in HbA(1c) levels at the end of the study, patients taking pioglitazone had relatively lower FPG and 1,5AG levels than patients taking the other two drugs. These results suggest that pioglitazone acts predominantly on nocturnal metabolism rather than at mealtimes. FFA were reduced significantly in those taking pioglitazone (542.2 microEq/l vs. 237.3 microEq/l; P < 0.01) before a decrease in HbA(1c) was apparent. The change in FFA levels correlated with the change in HbA(1c) (r = 0.409, P < 0.01). There were no significant differences in other lipid parameters among the groups. CONCLUSIONS: Pioglitazone, metformin, and glimepiride are equally effective in reducing blood glucose in patients with newly diagnosed Type 2 diabetes. However, their specific characteristics, such as the rapid action on blood glucose levels of glimepiride and the favourable action on FPG and FFA of pioglitazone, should be considered when choosing an appropriate agent.     

Effects of pioglitazone and rosiglitazone combined with metformin on body weight in people with diabetes

Currently, pioglitazone and rosiglitazone are the thiazolidinediones available for clinical use. In the literature, there are different studies concerning the efficacy, safety and tolerability of thiazolidinediones as add-on therapy to metformin in patients with type 2 diabetes inadequately controlled with metformin alone. Metformin and thiazolidinediones are both antihyperglycaemic drugs, both lower blood glucose concentrations in type 2 diabetes without causing overt hypoglycaemia and both require the presence of insulin to generate their therapeutic effects, but act without stimulating insulin secretion. Some authors reported that the improved glycaemic control obtained with thiazolidinediones is associated with an increase in body weight with an estimated 2–3 kg weight gain for every 1% decrease in HbA_1c which could negate some of the benefits of the improved metabolic control. Some other authors, instead, reported that thiazolidinediones give a better improvement in the glycaemic control compared with metformin alone without giving weight gain. The emerging discrepancies from these studies could be because of the study design, the patient selection, the degree of glycaemic control and/or the methods to measure body weight. We have undertaken a thorough literature search on Medline and Embase to evaluate the effects of thiazolidinediones plus metformin combination in people with diabetes on the body weight.     

Changes in liver tests during 1-year treatment of patients with Type 2 diabetes with pioglitazone, metformin or gliclazide.

AIMS: Patients with Type 2 diabetes are at increased risk of liver damage. Therefore, it is of particular importance to investigate the hepatic effects of drugs used to treat such patients. METHODS: Liver testing results performed in four 1-year, randomized, double-blind studies comparing effects of pioglitazone, metformin or a sulphonylurea, gliclazide, in the treatment of over 3700 patients with Type 2 diabetes have been analysed. RESULTS: Pioglitazone caused reductions in mean levels of hepatic enzymes of between 3 and 18%, whilst gliclazide caused small increases of between 3 and 13%. Metformin treatment showed either small mean increases or decreases. More patients receiving pioglitazone had liver tests within the normal range at the end of treatment (> or = 87%) compared with patients receiving metformin (> or= 80%) or gliclazide (> or = 75%). Slightly fewer patients with pioglitazone than with comparators showed a large increase (> 3 upper limit of normal) in alanine aminotransferase levels at any time during treatment (pioglitazone 0.9%, metformin 1.9%, gliclazide 1.9%). CONCLUSIONS: During pioglitazone treatment there is a reduction in liver enzyme levels. Although the mechanism of this effect is not clear, the results demonstrate potential beneficial effects on the liver during treatment of patients with Type 2 diabetes with pioglitazone.     

利用Botnia钳夹试验评估新HOMA稳态模型

目的 研究新HOMA稳态模型(HOMA2)的胰岛素敏感性指数(HOMA2-%S)和分泌功能指数(HOMA2-%B)在临床中的应用价值.方法 利用80例重庆地区多囊卵巢综合征妇女[正常糖耐量(NGT)组50人,糖调节受损(IGR)组30人]的口服葡萄糖耐量试验和Botnia钳夹试验资料,应用传统HOMA稳态模型(HOMA1)计算胰岛素敏感性指数HOMAl-ISI、分泌功能指数HOMA1-β和葡萄糖处置指数DI-HOMA1,借助新HOMA稳态模型计算胰岛素敏感性指数HOMA2-%S、分泌功能指数HOMA2-%B和葡萄糖处置指数DI-HOMA2,分别研究两种敏感性指数(HOMAl-ISI和HOMA2-%S)与Botnia钳夹试验稳态葡萄糖输注速率(GIR)的相关性,以及两种分泌功能指数(HOMA1-β和HOMA2-%B)与第一时相胰岛素分泌(AIR)的相关性.结果 HOMA2-%S与GIR的Pearson线性相关系数为0.503(P相似文献   

Long-term therapy with addition of pioglitazone to metformin compared with the addition of gliclazide to metformin in patients with type 2 diabetes: a randomized, comparative study

BACKGROUND: This 52-week, randomized, double-blind study compared the efficacy and safety of metformin plus pioglitazone with the established combination of metformin plus gliclazide in type 2 diabetes mellitus. METHODS: Patients with poorly controlled type 2 diabetes (HbA1c > or = 7.5% to < or =11.0%) received either pioglitazone 15 mg o.d. (titrated up to 45 mg; n = 317) or gliclazide 80 mg o.d. (titrated up to 320 mg; n = 313) and metformin at the pre-study dose. HbA1c, fasting plasma glucose (FPG), insulin, lipids and the urinary albumin/creatinine ratio were measured. RESULTS: There were no significant differences in HbA1c (1% decrease in both groups) and FPG between groups. There was a decrease in fasting insulin in the pioglitazone group compared to an increase in the gliclazide group (p < 0.001). There were significantly greater improvements in triglycerides and HDL-cholesterol in the metformin plus pioglitazone group compared to the metformin plus gliclazide group (p < 0.001). Mean LDL-cholesterol decreased with metformin plus gliclazide and increased with metformin plus pioglitazone (p < 0.001); however, this increase was considerably less marked than that in HDL-cholesterol. The mean urinary albumin/creatinine ratio was reduced by 10% in the metformin plus pioglitazone group compared to an increase of 6% in the metformin plus gliclazide group (p = 0.027). The incidence of adverse events was comparable between groups and both combinations were well tolerated. CONCLUSIONS: Compared to the established combination of metformin plus gliclazide, this study indicates potential benefits of addition of pioglitazone to metformin in terms of improvements in microalbuminuria and specific abnormalities associated with diabetic dyslipidemia.     

Effects of pioglitazone versus metformin on circulating endothelial microparticles and progenitor cells in patients with newly diagnosed type 2 diabetes--a randomized controlled trial

Aim: Endothelial microparticles (EMPs) and endothelial progenitor cells (EPCs) are markers of endothelial injury and repair. We compared the effects of pioglitazone versus metformin on the circulating numbers of EMPs and EPCs in patients with newly diagnosed type 2 diabetes. Methods: This was a randomized, double‐blind, comparator‐controlled, 24‐week single‐centre trial conducted in a Teaching Hospital in Naples, Italy. One hundred and ten people with newly diagnosed type 2 diabetes who were never treated with antihyperglycaemic drugs and had haemoglobin A1c (HbA1c) levels between 7 and 10% were given pioglitazone hydrochloride (15–45 mg/day) (n = 55) or metformin (1000–2000 mg/day) (n = 55) as an active comparator. Absolute change from baseline to final visit in circulating EMPs and EPCs and their ratio were the main outcomes. Results: Baseline characteristics did not differ between the study groups. The decrease in circulating EMPs CD31+ [intergroup difference, ?32 counts/µl (95% CI ?51 to ?9)] and the increase in EPCs CD34+/KDR+ [intergroup difference, 33 cells/10⁶ events (95% CI 13 to 55)] were greater with pioglitazone versus metformin. EMPs/EPCs ratio was reduced with pioglitazone and unchanged with metformin [difference, ?1.5 (95% CI ?2.6 to ?0.5), p < 0.001]. Participants assigned to pioglitazone gained more weight and experienced greater improvements in some coronary risk measures [high‐density lipoprotein (HDL)‐cholesterol, triglycerides, adiponectin and C‐reactive protein (CRP)] than did those assigned to metformin. Conclusion: Compared with metformin, pioglitazone treatment improved the imbalance between endothelial damage and repair capacity and led to more favourable changes in coronary risk factors in patients with newly diagnosed type 2 diabetes.     

Long‐term glycaemic effects of pioglitazone compared with placebo as add‐on treatment to metformin or sulphonylurea monotherapy in PROactive (PROactive 18)

Aims To assess the long‐term glycaemic effects, concomitant changes in medications and initiation of permanent insulin use (defined as daily insulin use for a period of ≥ 90 days or ongoing use at death/final visit) with pioglitazone vs. placebo in diabetic patients receiving metformin or sulphonylurea monotherapy at baseline in the PROspective pioglitAzone Clinical Trial in macroVascular Events (PROactive). Methods In PROactive, patients with Type 2 diabetes and macrovascular disease were randomized to pioglitazone (force titrated to 45 mg/day) or placebo, in addition to other existing glucose‐lowering therapies. In a post‐hoc analysis, we categorized patients not receiving insulin at baseline and treated by oral monotherapy into two main cohorts: add‐on to metformin alone (n = 514) and sulphonylurea alone (n = 1001). The follow‐up averaged 34.5 months. Results There were significantly greater reductions in glycated haemoglobin (HbA_1c) with pioglitazone than with placebo and more pioglitazone‐treated patients achieved HbA_1c targets, irrespective of the baseline oral glucose‐lowering regimen and despite a decrease in the use of other glucose‐lowering agents. Approximately twice as many in the placebo groups progressed to permanent insulin use than in the pioglitazone groups across the two cohorts: 3.4% for pioglitazone and 6.5% for placebo when added to metformin monotherapy and 6.3% and 14.8%, respectively, when added to sulphonylurea monotherapy. The overall safety of both dual therapies was good. Conclusions Intensifying an existing oral monotherapy regimen to a dual oral regimen by adding pioglitazone resulted in sustained improvements in glycaemic control and reduced progression to insulin therapy. The efficacy and safety of adding pioglitazone to either metformin monotherapy or sulphonylurea monotherapy were good.     

非糖尿病患者ST段抬高急性心肌梗死胰岛素抵抗与临床预后关系

目的探讨非糖尿病患者急性心肌梗死时胰岛素抵抗的相关危险因素,并评估胰岛素抵抗对ST段急性心肌梗死患者住院期间预后的影响和意义。方法从2008年10月到2009年9月,连续入选初次发生ST段抬高急性心肌梗死,且在发病24小时内接受急诊经皮冠状介入治疗的患者,在入院第二天清晨测空腹血糖和胰岛素浓度,出院前均进行口服葡萄糖耐量试验,最后纳入非糖尿病患者124例,以稳态模型胰岛素抵抗指数,即HOMA-IR≥2.5认为存在胰岛素抵抗,评价胰岛素抵抗对急性心肌梗死患者预后的影响。结果 124例患者中,存在胰岛素抵抗的患者占49.2%（61/124）,病死率占12.1%（15/124）。胰岛素抵抗组较对照组有较高的入院血糖[（7.88±2.83）mmol/L比（6.93±1.60）mmol/L,P=0.025]、空腹血糖[（7.36±2.33）mmol/L比（6.43±1.81）mmol/L,P=0.014]和胰岛素浓度[（16.68±6.98）mU/L比（6.32±2.32）mU/L,P=0.000],组间比较差异具有统计学意义。多元逐步回归方程提示,体重指数[标准化回归系数（β）=0.244,P=0.021]和空腹血糖（β=0.451,P=0.000）是影响HOMA-IR严重程度的主要因素。多因素logistic回归方程提示,在调整其他因素后,胰岛素抵抗[OR=1.506,95%CI（1.062～2.134）,P=0.021]、Killip分级≥Ⅱ[OR=3.007,95%CI（1.165～7.779）,P=0.023]和心肌肌酸激酶同工酶峰值[OR=1.004,95%CI（1.000～1.008）,P=0.036]是急性心肌梗死患者住院期间死亡的独立危险因素。结论心肌梗死急性期胰岛素抵抗现象普遍存在,是急性心肌梗死患者住院期间预后不良的独立危险因素,体重指数和第二天空腹血糖水平是影响胰岛素抵抗的主要因素。     

The fixed combination of pioglitazone and metformin improves biomarkers of platelet function and chronic inflammation in type 2 diabetes patients: results from the PIOfix study

Background

Type 2 diabetes mellitus (T2DM) is characterized by a proinflammatory and procoagulant condition. This study investigates the impact of a pioglitazone plus metformin therapy on biomarkers of inflammation and platelet activation in comparison to a treatment with glimepiride plus metformin.

Methods

The study was designed as a multicenter, randomized, double-blinded two-arm trial. Patients with T2DM and dyslipidemia under metformin monotherapy with hemoglobin A1c value between 6.5% and 9.0% were eligible for trial participation. Blood was drawn at baseline and after 24 weeks of treatment from patients of five centers. Markers of inflammation and thrombocyte function (soluble CD40 ligand, thromboxane, vWillebrand factor, adhesion molecules, clotting reaction) were evaluated subsequently in a central laboratory.

Results

A total of 46 patients were included in the final analyses. Mean (± standard deviation) age was 58.5 ± 9.0 years (13 women, 33 men; disease duration 6.3 ± 5.0 years; body mass index 32.0 ± 4.8 kg/m²). A total of 25 patients were treated with pioglitazone plus metformin, and 21 patients were in the glimepiride arm. There was a significant decline of E-selectin (-3.7 ± 4.8 ng/ml, p < .001 versus baseline), vWillebrand factor (-19.5 ± 32.0%, p < .05), and high-sensitivity C-reactive protein concentrations (-1.08 ± 0.91 mg/liter, p < .05) in the metformin + pioglitazone arm only (metformin + glimepiride, -0.5 ± 3.4 ng/ml, +1.4 ± 33.2%, + 0.08 ± 0.72 mg/liter, respectively, all not significant). Also, all other surrogate markers for platelet function and inflammation showed slight improvements in the metformin + pioglitazone arm but not in the metformin + glimepiride arm.

Conclusions

The fixed metformin + pioglitazone combination treatment showed an overall improvement of laboratory surrogate markers, indicating improvement of platelet function and of chronic systemic inflammation, which was not seen with metformin + glimepiride.     

吡格列酮与二甲双胍治疗2型糖尿病的疗效比较

在4个临床中心观察吡格列酮(104例)和二甲双胍(104例)治疗12周对2型糖尿病的闻疗效并进行比较,结果显示这两种药物均使空腹和餐后血糖、HbA_(1c)明显下降(均P<0.05),两组疗效相似。两组不良事件发生率相似。     

新HOMA稳态模型在临床中的应用

目的研究利用新HOMA稳态模型HOMA2计算的胰岛素敏感性指数（ISI）和分泌功能指数在临床的应用价值。方法选取80名志愿者，其中正常糖耐量（NGT）31人、糖调节异常（IGR）26人，2型糖尿病（T2DM）23人；抽取空腹血测定血糖、胰岛素（Ins）、真胰岛素（TI）和C肽水平，利用HOMA2计算器分别计算三种ISI（HOMA2-％S-Ins、HOMA2-％S-TI和HOMA2-％S-C）和三种胰岛素分泌功能指数（HOMA2-％B-Ins、HOMA2-％B-TI和HOMA2-％B-C），比较上述指数区分不同糖耐量组的胰岛素敏感性和分泌功能变化的能力。结果在三种ISI中，利用空腹TI计算的HOMA2-％S-TI区分三组的胰岛素敏感性的能力相对最强（F=4．888，P〈0．01），利用空腹Ins计算的HOMA2-％S-Ins次之（F=3．397，P〈0．05），利用空腹C肽计算的HOMA2-％S-C不能区分三组的胰岛素敏感性（F=1．042，P〉0．05）。利用HOMA2-％S-TI调整后，三种胰岛素分泌功能指数区分三组胰岛素分泌功能的能力非常接近（F值分别为60．323、58．203和58．179，P〈0．01），且均可很好区分IGR组和DM组的胰岛素分泌功能，其中只有HOMA2-％B-C可较好区分NGT组和IGR组的胰岛素分泌功能（t=2．2709，P〈0．05）。结论利用新HOMA稳态模型计算的HOMA2-％S-TI是一个相对较好的计算ISI的公式，HOMA2-％B-C是一个相对较好的计算胰岛素分泌功能指数的公式。     

Baseline differences in A1C explain apparent differences in efficacy of sitagliptin, rosiglitazone and pioglitazone

Aim: Published studies of patients treated with rosiglitazone or pioglitazone have reported greater reductions in HbA1c (A1C) than studies of patients treated with sitagliptin. However, studies of thiazolidinediones tended to enroll patients with higher baseline A1C levels. This meta-analysis investigates the relationship between baseline A1C and perceived efficacy of treatment.
Methods: This report describes a Bayesian random effects analysis of 23 published studies. We constructed a random effects model including a factor adjusting for between-study differences in baseline A1C levels.
Results: The random effects model correctly predicts post-treatment A1C levels from baseline A1C within a 95% confidence interval (CI) for each of the 23 studies included in the meta-analysis. After applying the model to adjust for differences in baseline A1C, we found that the difference in efficacy between rosiglitazone and sitagliptin was not significantly different from zero (0.12; 95% CI −0.09 to 0.34). Similarly, no significant differences are observed between the effects of pioglitazone and sitagliptin (0.01; 95% CI −0.21 to 0.22) or between rosiglitazone and pioglitazone (0.11; 95% CI −0.37 to 0.146). When baseline values are omitted from the Bayesian model, the findings suggest that rosiglitazone is superior to pioglitazone or sitagliptin.
Conclusions: These results illustrate the necessity for careful application of appropriate methodology when comparing results of different studies. When between-study differences in treatment effects are adjusted for baseline differences, then the findings suggest that none of the treatments has an effect that is superior to any of the other treatments.     

吡格列酮与二甲双胍治疗2型糖尿病的疗效对比观察

目的观察吡格列酮与二甲双胍分别治疗2型糖尿病的临床效果。方法将96例首次就诊诊断为2型糖尿病的患者半随机分为对照组和治疗组,各48例。对照组采用二甲双胍治疗,治疗组采用吡格列酮治疗。治疗1个月后,对两组的临床疗效、血糖水平改善情况及不良反应进行对比观察。结果对照组总有效率为87.5%（42/48）,治疗组总有效率为89.6%（43/48）,两组治疗效果差异无统计学意义（P〉0.05）;治疗组空腹血糖和餐后2 h血糖水平改善幅度略大于对照组（P〉0.05）;对照组不良反应的发生率大于治疗组,差异有统计学意义（P〈0.01）。结论二甲双胍、吡格列酮均能有效控制2型糖尿病患者的血糖值。     

Saxagliptin, a potent, selective inhibitor of DPP-4, does not alter the pharmacokinetics of three oral antidiabetic drugs (metformin, glyburide or pioglitazone) in healthy subjects

Aim: To evaluate the pharmacokinetic interactions of the potent, selective, dipeptidyl peptidase‐4 inhibitor, saxagliptin, in combination with metformin, glyburide or pioglitazone. Methods: To assess the effect of co‐administration of saxagliptin with oral antidiabetic drugs (OADs) on the pharmacokinetics and tolerability of saxagliptin, 5‐hydroxy saxagliptin, metformin, glyburide, pioglitazone and hydroxy‐pioglitazone, analyses of variance were performed on maximum (peak) plasma drug concentration (C_max), area under the plasma concentration–time curve from time zero to infinity (AUC_∞) [saxagliptin + metformin (study 1) and saxagliptin + glyburide (study 2)] and area under the concentration–time curve from time 0 to time t (AUC) [saxagliptin + pioglitazone (study 3)] for each analyte in the respective studies. Studies 1 and 2 were open‐label, randomized, three‐period, three‐treatment, crossover studies, and study 3 was an open‐label, non‐randomized, sequential study in healthy subjects. Results: Co‐administration of saxagliptin with metformin, glyburide or pioglitazone did not result in clinically meaningful alterations in the pharmacokinetics of saxagliptin or its metabolite, 5‐hydroxy saxagliptin. Following co‐administration of saxagliptin, there were no clinically meaningful alterations in the pharmacokinetics of metformin, glyburide, pioglitazone or hydroxy‐pioglitazone. Saxagliptin was generally safe and well tolerated when administered alone or in combination with metformin, glyburide or pioglitazone. Conclusions: Saxagliptin can be co‐administered with metformin, glyburide or pioglitazone without a need for dose adjustment of either saxagliptin or these OADs.     

An increase in insulin sensitivity and basal beta-cell function in diabetic subjects treated with pioglitazone in a placebo-controlled randomized study.

AIMS: To investigate the effect of treatment with pioglitazone on beta-cell function and insulin sensitivity in Type 2 diabetes. METHODS: Thirty subjects with diet-controlled Type 2 diabetes were randomized to 3 months treatment with pioglitazone (n = 19) or placebo (n = 11). All subjects underwent basal sampling for homeostatic model assessment (HOMA), followed by an intravenous glucose tolerance test and hyperglycaemic clamp, followed by an euglycaemic hyperinsulinaemic clamp; at baseline and after treatment. RESULTS: All results are expressed as mean (sem). Pioglitazone increased basal insulin sensitivity by 24.7% (7.8) HOMA-%S vs. 2.1% (5.9) in the placebo group (P = 0.02). Stimulated insulin sensitivity, M/I, increased in the pioglitazone group compared with placebo: +15.1 (2.8) l kg(-1) min(-1) vs. +3.2 (2.9) l kg(-1) min(-1), respectively (P = 0.009). Pioglitazone increased adiponectin by 39.3 (6.3), ng/ml compared with a decrease of 0.8 (1.3) ng/ml with placebo (P = 0.00004). HOMA-%B increased with pioglitazone, +11.5% (4.8) vs. -2.0% (4.8) with placebo (P = 0.049), but there was no change in stimulated beta-cell function as determined by hyperglycaemic clamps. There was a significant reduction in the proinsulin/insulin ratio in the pioglitazone group, -0.057 (0.02) compared with placebo, +0.004 (0.02) (P = 0.03). There was a significant reduction in HbA(1c) of 0.6% (0.1) in the pioglitazone group compared with placebo (P = 0.003). There was no significant weight gain associated with pioglitazone therapy: +0.7 (sem 0.6) kg vs. +1.1 (sem 0.5) kg in placebo group (P = NS). CONCLUSIONS: Basal beta-cell function and insulin sensitivity improved following pioglitazone therapy. The improvement in proinsulin to insulin ratio suggests that beta-cells are under less stress.     

A case of secondary diabetes mellitus with acromegaly improved by pioglitazone.

AIM: The acromegaly patient was diagnosed with Type 2 diabetes mellitus. His HbA1c was 10.6% and fasting blood glucose (FBG) 15.3 mmol/l. We prescribed glibenclamide (10 mg/day), but his HbA1c and FBG remained high. At this stage, treatment with short-acting insulin was instigated at a dose of 20 U/day. However, the patient's blood glucose level remained unsatisfactory. We tried using pioglitazone. METHOD: Pioglitazone was prescribed at 30 mg/day in combination with the insulin. RESULTS: The FBG and HbA1c value decreased to 7.2 mmol/l and 7.3%, respectively, within 2 months and insulin was discontinued. Pioglitazone alone was able to control the FBG level. CONCLUSIONS: Pioglitazone treatment might be considered as a choice for similar cases of diabetes secondary to acromegaly.