Pioglitazone,but not metformin,reduces liver fat in Type-2 diabetes mellitus independent of weight changes

BackgroundPioglitazone (Pio) treatment induces weight gain in Type 2 diabetes mellitus (T2DM), which could worsen hepatic lipid accumulation, and alter adiponectin and high-sensitivity C-reactive protein (hs-CRP).ObjectiveTo compare changes in hepatic lipid, serum adiponectin and hs-CRP in diabetics treated with Pio (with and without weight gain) against metformin (Met) treatment, which produces weight loss.DesignFifty-one men and women with T2DM, naive to thiazolidinediones, entered a 16-week, open-label, parallel arm study, where participants were randomized to one of three groups: (1) Pio plus the American Diabetes Association diet (Pio+ADA); (2) Pio plus a portion control weight loss diet (Pio+PC), or (3) metformin plus ADA diet (Met+ADA).MethodsHepatic lipid was assessed with abdominal computed tomography (CT) and the serum adiponectin and hs-CRP by enzyme-linked immunosorbent assay at baseline and study end.ResultsForty-eight subjects completed the study. The Pio+ADA group gained (mean±S.E.M.) 2.15±1.09 kg, while Pio+PC and Met+ADA group lost ?2.59±1.25 and ?3.21±0.7 kg, respectively. Pio-treated groups (Pio+ADA and Pio+PC) significantly decreased hepatic fat as indicated by increased liver density on CT scan [10.1±2.4: 11.4±1.0 Hounsfield units (HU)], compared with Met+ADA group (?2.4±3.1 HU). The Pio groups demonstrated significantly increased serum adiponectin, (8.6±1.5; 7.4±1.6 μg/ml) independent of weight change, compared to Met+ADA (?0.14±0.6 μgm/ml) group which lost weight. Serum hs-CRP decreased in groups showing weight loss (Pio+PC, ?3.1±1.7 mg/l; Met+ADA, ?1.5±1.2 mg/l) compared to Pio+ADA (1.8±3.0 mg/l) group that gained weight.ConclusionsPio treatment in T2DM significantly reduced hepatic lipid and increased adiponectin independent of weight change, while decreasing hs-CRP with weight loss.     

Alogliptin as a third oral antidiabetic drug in patients with type 2 diabetes and inadequate glycaemic control on metformin and pioglitazone: a 52-week, randomized, double-blind, active-controlled, parallel-group study

Aim: To assess the efficacy and safety of adding alogliptin versus uptitrating pioglitazone in patients with type 2 diabetes and inadequate glycaemic control on metformin and pioglitazone. Methods: In this randomized, double‐blind, active‐controlled, parallel‐group study, patients with type 2 diabetes and A1c ≥7.0 and ≤10.0% on metformin (≥1500 mg or maximum tolerated dose; Met) and pioglitazone 30 mg (Pio30) received alogliptin 25 mg (Alo25; n = 404) or pioglitazone 15 mg (n = 399) added to Met+Pio30 for 52 weeks. The primary endpoint was change from baseline (CFB) in A1c at weeks 26 and 52, with sequential testing for non‐inferiority of Met+Pio30+Alo25 at weeks 26 and 52 and then for superiority at week 52. Results: Met+Pio30+Alo25 showed superior glycaemic control versus Met+Pio45 at week 52 [least squares (LS) mean CFB in A1c, ?0.70 vs. ?0.29%; p < 0.001]. At week 52, Met+Pio30+Alo25 resulted in greater CFB in A1c regardless of baseline A1c (p < 0.001); higher proportions of patients achieving A1c ≤7.0 (33.2 vs. 21.3%) and ≤6.5% (8.7 vs. 4.3%; p < 0.001); greater CFB in fasting plasma glucose (FPG; LS mean CFB, ?0.8 vs. ?0.2 mmol/L; p < 0.001); and greater improvements in measures of β‐cell function (p < 0.001). Hypoglycaemia incidence was low (Met+Pio30+Alo25, 4.5%; Met+Pio45, 1.5%), mostly mild to moderate, but with two severe events in the Met+Pio30+Alo25 group. No meaningful differences in incidences of individual adverse events were observed between treatments. Conclusions: Adding alogliptin to an existing metformin–pioglitazone regimen provided superior glycaemic control and potentially improved β‐cell function versus uptitrating pioglitazone in patients with type 2 diabetes, with no clinically important differences in safety.     

Effects of intensive insulin therapy alone and in combination with pioglitazone on body weight, composition, distribution and liver fat content in patients with type 2 diabetes

Aim: To evaluate the effects of intensive insulin therapy alone and with added pioglitazone on body weight, fat distribution, lean body mass (LBM) and liver fat in type 2 diabetic patients. Methods: Twenty‐five insulin‐treated, obese patients with type 2 diabetes were randomized to addition of pioglitazone 45 mg (n = 12) or placebo (n = 13) and treated intensively for 12–16 weeks. Dual‐energy X‐ray absorptiometry/abdominal computed tomography scans were performed before/after treatment. LBM, visceral/subcutaneous adipose tissue (VAT/SAT) and liver/spleen (L/S) attenuation ratios were measured pre‐/posttreatment (a ratio <1 represents fatty liver). Results: Intensive insulin alone and insulin + pioglitazone significantly improved glycaemic control (7.8 ± 0.3 to 7.2 ± 0.3% and 7.6 ± 0.3 to 7.1 ± 0.4%, respectively). Body weight gain was greater with insulin + pioglitazone (4.9 ± 4.5 kg) versus insulin therapy alone (1.7 ± 0.7 kg). SAT increased significantly with pioglitazone + insulin therapy (393.9 ± 48.5 to 443.2 ± 56.7 cm², p < 0.01) compared to a non‐significant increase with insulin therapy alone (412.9 ± 42.5 to 420.8 ± 43.8 cm²). VAT decreased non‐significantly in both groups (240.3 ± 41.7 to 223.8 ± 38.1 cm² with insulin + pioglitazone and 266.6 ± 27.4 to 250.5 ± 22.2 cm² with insulin therapy). LBM increased significantly by 1.92 ± 0.74 kg with insulin + pioglitazone treatment. The L/S attenuation ratio in the placebo + insulin group decreased from 1.08 ± 0.1 to 1.04 ± 0.1 (p = ns) and increased from 1.00 ± 0.1 to 1.08 ± 0.05 (p = 0.06) in the pioglitazone + insulin group. Conclusions: Intensification of insulin therapy in type 2 diabetic patients causes modest weight gain and no change in body fat distribution, LBM or liver fat. In contrast, the addition of pioglitazone, at equivalent glycaemia, increases weight gain, fat mass and SAT; increases LBM and tends to decrease liver fat. These changes in fat distribution may contribute to the beneficial effects of pioglitazone, despite greater weight gain.     

Efficacy and tolerability of vildagliptin vs. pioglitazone when added to metformin: a 24-week, randomized, double-blind study

Aim: The aim of this study was to compare the efficacy and tolerability of vildagliptin vs. pioglitazone as add‐on therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy. Methods: This 24‐week, multicentre, double‐blind, randomized, active‐controlled study compared vildagliptin (100 mg daily, given as equally divided doses, n = 295) and pioglitazone (30 mg daily, given as a single q.d. dose, n = 281) in patients with inadequate glycaemic control (A1C 7.5–11%) while receiving a stable metformin dose (≥1500 mg daily). The adjusted mean changes from baseline to study endpoint (AMΔ) in A1C, fasting plasma glucose (FPG), fasting lipids and body weight were compared by analysis of covariance. Results: When added to a stable dose of metformin (mean dose at baseline >2000 mg/day), both vildagliptin and pioglitazone decreased A1C (AMΔ = ?0.9 ± 0.1% and ?1.0 ± 0.1%, respectively) from identical baseline values (8.4 ± 0.1%). The between‐group difference in AMΔ A1C was 0.1 ± 0.1%, and non‐inferiority of vildagliptin to pioglitazone was established at both 0.4 and 0.3% margins for upper limit of the 95% confidence intervals. Pioglitazone decreased FPG (AMΔ = ?2.1 ± 0.1 mmol/l) to a greater extent than vildagliptin (AMΔ = ?1.4 ± 0.1 mmol/l), but only pioglitazone increased body weight (AMΔ = +1.9 ± 0.2 kg: between‐group difference = ?1.6 ± 0.3 kg, p < 0.001). Adverse events (AEs) were reported by 60% of vildagliptin‐treated patients and by 56.4% of pioglitazone‐treated patients; serious AEs were reported by 2.0 and 4.6% of patients receiving vildagliptin and pioglitazone respectively. Mild hypoglycaemia was reported by one patient (0.3%) in the vildagliptin group and by no patients receiving pioglitazone. Conclusions: When added to metformin, the efficacy of vildagliptin is non‐inferior to that of pioglitazone. The treatments were similarly well tolerated, but only pioglitazone increased body weight.     

Metabolic effects of pioglitazone and rosiglitazone in patients with diabetes and metabolic syndrome treated with metformin

Background: Metformin is considered the gold standard for type 2 diabetes treatment as monotherapy and in combination with sulphonylureas and insulin, whereas the combination of metformin with thiazolidinediones is relatively less studied. The aim of the present study was to assess the differential effect on glycaemic metabolism and lipid variables of the combination of metformin plus pioglitazone or metformin plus rosiglitazone in diabetic patients with metabolic syndrome. Methods: All patients began metformin and were randomized to receive pioglitazone or rosiglitazone for 12 months. We assessed body mass index, glycated haemoglobin, fasting plasma glucose, postprandial plasma glucose, fasting plasma insulin, postprandial plasma insulin, homeostasis model assessment index, total cholesterol, low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol, triglycerides, apolipoprotein A‐I, and apolipoprotein B. Results: Significant decreases in glycated haemoglobin, fasting plasma glucose, postprandial plasma glucose, fasting plasma insulin, and postprandial plasma insulin were seen after 9 and 12 months in both groups. Homeostasis model assessment index improved at 12 months in both groups. Significant total cholesterol, low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol, triglycerides, apolipoprotein A‐I, and apolipoprotein B improvement was observed in pioglitazone group after 12 months, but not in the rosiglitazone group. These variations were significant between groups. Conclusion: The combination of metformin plus thiazolidinediones was able to improve glycaemic control compared with previous therapy. Pioglitazone was associated with a significant improvement in lipid and lipoprotein variables.     

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. Materials and Methods: 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 (HbA_1c) >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). Results: Compared with the Met + Pcb group, the Met + Mit group showed a greater reduction in HbA_1c (?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 HbA_1c 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. Conclusions: 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)     

Effect of pioglitazone in combination with insulin therapy on glycaemic control, insulin dose requirement and lipid profile in patients with type 2 diabetes previously poorly controlled with combination therapy

AIM: The aim of this randomized placebo-controlled study was to evaluate the safety and efficacy of pioglitazone administered alone or in combination with metformin in reducing insulin dosage requirements for improved glycaemic control in patients with type 2 diabetes previously poorly controlled with combination therapy. METHODS: In this multicentre, double-blind study, 222 patients with haemoglobin A1c (HbA(1c))>8.0% at screening treated with combination therapy initially were given titrated insulin therapy (to fasting plasma glucose <140 mg/dl) and then were randomly assigned to 20-week treatment with pioglitazone or placebo in combination with insulin, with or without concurrent metformin therapy. More than 98% of patients were taking metformin prior to and during the study. RESULTS: Pioglitazone significantly reduced (p < 0.05) insulin dose requirements 2 weeks after treatment initiation. At study end relative to baseline, pioglitazone reduced daily insulin dosages by 12.0 units (p < 0.001), a 21.5% (12.0/55.8 units at baseline) group mean average reduction. Relative to placebo, pioglitazone reduced daily insulin dosages by 12.7 units [95% confidence interval [CI]: -17.5, -8.0], while improving mean HbA(1c) levels [adjusted mean HbA(1c) change: pioglitazone, -1.6% vs. placebo, -1.4% (not statistically different)]. Pioglitazone also significantly increased high-density lipoprotein cholesterol levels [adjusted mean difference: +4.5 (95% CI: 2.6-6.5) mg/dl], decreased triglyceride levels [-43.9 (-69.2, -18.6) mg/dl], shifted low-density lipoprotein (LDL) particle concentrations from small [pattern B, -13.6% (-17.7%, -9.5%)] to large [pattern A, +15.1% (10.8%, 19.5%)] and increased mean LDL particle size [+3.8 (2.6, 4.9) A]. More pioglitazone-treated patients experienced oedema (9.0 vs. 4.5%) and weight gain (9.1 vs. 2.7%) than placebo patients. CONCLUSIONS: Pioglitazone in combination with insulin therapy improved glycaemic control, reduced insulin dose requirements and improved lipid profiles in patients with type 2 diabetes previously poorly controlled with combination therapy.     

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.     

Effects of pioglitazone on serum fetuin-A levels in patients with type 2 diabetes mellitus

Fetuin-A (α2-Heremans-Schmid glycoprotein), a circulating glycoprotein, can inhibit insulin signaling both in vivo and in vitro. Recently, we and another independent group have shown that fetuin-A is positively associated with insulin resistance in humans. Furthermore, it has been reported that higher fetuin-A levels are associated with metabolic syndrome and atherogenic lipid profiles. These data suggest that fetuin-A might be a regulator of insulin resistance and/or metabolic syndrome. However, it is not clear how fetuin-A levels are regulated. To address this, we investigated the effects of representative insulin-sensitizing therapies such as pioglitazone, metformin, and aerobic exercise on fetuin-A levels. Twenty-seven patients with type 2 diabetes mellitus were divided into pioglitazone-treated (Pio), metformin-treated (Met), and exercise-treated (Ex) groups. Ten patients in the Pio group and 9 patients in the Met group took 15 or 30 mg/d pioglitazone or 500 or 750 mg/d metformin, respectively, for 6 months. Eight patients in the Ex group underwent a 3-month aerobic exercise program. Serum fetuin-A levels were measured before and after each intervention. Intervention significantly decreased hemoglobin A_1c in all groups. After treatment, serum fetuin-A levels significantly decreased in the Pio group (291.2 ± 57.7 to 253.1 ± 43.9 μg/mL, P = .006), whereas there were no changes in serum fetuin-A after intervention in either the Met or the Ex groups. We hypothesize that pioglitazone could partially ameliorate insulin resistance via modulating fetuin-A levels.     

胰岛素抵抗大鼠视黄醇结合蛋白4骨骼肌磷脂酰肌醇3激酶的表达及吡格列酮的干预作用

目的 观察胰岛素抵抗(IR)大鼠体内视黄醇结合蛋白4(RBP4)、骨骼肌磷脂酰肌醇3激酶( P13K)和晚期氧化蛋白产物(AOPP)的水平,以及给予吡格列酮干预后其活性的变化,探讨RBP4与IR的关系及其可能的机制。 方法 将SPF级雄性Wistar大鼠35只随机分为2组,正常对照组（对照组）11只,饲以普通饲料;模型组24只,饲以高糖高脂饲料。模型组造模成功后再随机分为2个亚组,IR组和IR+吡格列酮干预组（干预组）,每组12只;IR组和干预组继续饲以高糖高脂饲料,干预组大鼠同时给予吡格列酮20mg·kg 1·d-1灌胃,持续8周。第16周末处死大鼠取血检测三酰甘油(TG)、高密度脂蛋白(HDL-C)、低密度脂蛋白(LDL-C)及空腹血糖(FBG)、空腹胰岛素(FINS),计算胰岛素抵抗指数(HOME-IR);酶联免疫吸附法(ELISA)检测血清RBP4水平,RT-PCR测定附睾脂肪组织RBP4表达;免疫组织化学染色检测骨骼肌PI3K水平;紫外分光光度计法测定AOPP水平;并取大鼠腹腔内肠系膜、附睾、腹膜反折处的脂肪组织称质量,计算腹部脂肪含量与体质量的比值。 结果 (1)IR组大鼠体质量16周后明显增加,TG、LDL-C、FINS以及脂体比较对照组均明显升高,而HDL-C则明显降低;吡格列酮干预后,干预组体质量、TG、LDL-C、FINS以及脂体比较IR组有明显下降,HDL-C明显升高;(2)IR组大鼠血清及附睾脂肪组织RBP4水平和血清AOPP水平明显高于对照组,干预组水平明显降低;(3)IR组大鼠骨骼肌组织PI3K表达水平明显低于对照组,吡格列酮干预其表达水平升高;(4)相关分析表明大鼠血清RBP4与FINS、脂体比、LDL-C呈正相关;与HDL-C、骨骼肌组织PI3K水平呈负相关。 结论 (1)IR大鼠RBP4、AOPP水平升高,RBP4是致IR的脂肪细胞因子,并可引起机体脂代谢紊乱及氧化应激增强;(2)RBP4降低大鼠胰岛素敏感性可能与其削弱胰岛素信号转导作用有关;(3)吡格列酮可降低IR大鼠RBP4及血清AOPP水平,增加骨骼肌PI3K表达,从而提高机体对胰岛素的敏感性。     

Effects of intensive insulin therapy alone and with added pioglitazone on renal salt/water balance and fluid compartment shifts in type 2 diabetes

Objective: To evaluate the effects of intensive insulin therapy alone or with added pioglitazone on renal salt/water balance and body fluid compartment shifts in type 2 diabetes. Methods: A total of 25 insulin‐treated, obese patients with type 2 diabetes were randomized to pioglitazone 45 mg (n = 12) or placebo (n = 13) and treated intensively for 12–16 weeks to achieve equivalent glycaemic control. We measured total body water (TBW) and extracellular/intracellular fluid by bioimpedance analysis; plasma/RBC volume with I¹³¹albumin; sodium handling by fractional excretion of sodium/lithium (FeNa/FeLi) and other renal/hormonal parameters. Results: Intensification of insulin therapy and the addition of pioglitazone significantly improved glycaemia (HbA1C 7.8–7.2% and 7.6–7.1%) and increased body weight (1.7 and 4.9 kg) respectively. TBW increased 1.7 l with insulin alone (65% intracellular) and 1.6 l with added pioglitazone (75% extracellular) (p = 0.06 and 0.09 respectively). Plasma volume increased 0.2 ± 0.1 l with insulin alone (p = 0.05) and 0.4 ± 0.1 l with added pioglitazone (p < 0.05). Extravascular, extracellular (interstitial) fluid increased significantly and more with added pioglitazone (0.8 ± 0.2 l, p < 0.01) than with insulin alone (0.4 ± 0.2 l, p = ns). At steady‐state, FeLi (marker of proximal‐tubular sodium delivery to the distal nephron) increased significantly with added pioglitazone (12.4 ± 1.3 to 18.0 ± 3.2%) vs. no significant change with insulin alone (15.4 ± 1.2 to 14.5 ± 2.3%). There were no significant changes in the other parameters. Conclusion: In intensively insulin‐treated obese type 2 diabetic patients, at equivalent glycaemic control, the addition of pioglitazone causes greater weight gain, but a similar increase in body water that is mainly extracellular and interstitial compared with intracellular increase with insulin therapy alone. Pioglitazone also increases the filtered load of sodium reabsorbed at the distal nephron with no net change in FeNa.     

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.     

Initial therapy with the fixed-dose combination of sitagliptin and metformin results in greater improvement in glycaemic control compared with pioglitazone monotherapy in patients with type 2 diabetes

Aims: To evaluate the efficacy and safety of initial therapy with a fixed‐dose combination (FDC) of sitagliptin and metformin compared with pioglitazone in drug‐naÏve patients with type 2 diabetes. Methods: After a 2‐week single‐blind placebo run‐in period, patients with type 2 diabetes, HbA1c of 7.5–12% and not on antihyperglycaemic agent therapy were randomized in a double‐blind manner to initial treatment with a FDC of sitagliptin/metformin 50/500 mg twice daily (N = 261) or pioglitazone 30 mg per day (N = 256). Sitagliptin/metformin and pioglitazone were up‐titrated over 4 weeks to doses of 50/1000 mg twice daily and 45 mg per day, respectively. Both treatments were then continued for an additional 28 weeks. Results: From a mean baseline HbA1c of 8.9% in both groups, least squares (LS) mean changes in HbA1c at week 32 were ?1.9 and ?1.4% for sitagliptin/metformin and pioglitazone, respectively (between‐group difference = ?0.5%; p < 0.001). A greater proportion of patients had an HbA1c of <7% at week 32 with sitagliptin/metformin vs. pioglitazone (57% vs. 43%, p < 0.001). Compared with pioglitazone, sitagliptin/metformin treatment resulted in greater LS mean reductions in fasting plasma glucose (FPG) [?56.0 mg/dl (?3.11 mmol/l) vs. ?44.0 mg/dl (?2.45 mmol/l), p < 0.001] and in 2‐h post‐meal glucose [?102.2 mg/dl (?5.68 mmol/l) vs. ?82.0 mg/dl (?4.56 mmol/l), p < 0.001] at week 32. A substantially greater reduction in FPG [?40.5 mg/dl (?2.25 mmol/l) vs. ?13.0 mg/dl (?0.72 mmol/l), p < 0.001] was observed at week 1 with sitagliptin/metformin vs. pioglitazone. A greater reduction in the fasting proinsulin/insulin ratio and a greater increase in homeostasis model assessment of β‐cell function (HOMA‐β) were observed with sitagliptin/metformin than with pioglitazone, while greater decreases in fasting insulin and HOMA of insulin resistance (HOMA‐IR), and a greater increase in quantitative insulin sensitivity check index (QUICKI) were observed with pioglitazone than with sitagliptin/metformin. Both sitagliptin/metformin and pioglitazone were generally well tolerated. Sitagliptin/metformin led to weight loss (?1.4 kg), while pioglitazone led to weight gain (3.0 kg) (p < 0.001 for the between‐group difference). Higher incidences of diarrhoea (15.3% vs. 4.3%, p < 0.001), nausea (4.6% vs. 1.2%, p = 0.02) and vomiting (1.9% vs. 0.0%, p = 0.026), and a lower incidence of oedema (1.1% vs. 7.0%, p < 0.001), were observed with sitagliptin/metformin vs. pioglitazone. The between‐group difference in the incidence of hypoglycaemia did not reach statistical significance (8.4 and 4.3% with sitagliptin/metformin and pioglitazone, respectively; p = 0.055). Conclusion: Compared with pioglitazone, initial therapy with a FDC of sitagliptin and metformin led to significantly greater improvement in glycaemic control as well as a higher incidence of prespecified gastrointestinal adverse events, a lower incidence of oedema and weight loss vs. weight gain.     

Spotlight on Pioglitazone in Type 2 Diabetes Mellitus

Pioglitazone (Actos(trade mark)) is an antihyperglycemic agent that, in the presence of insulin resistance, increases hepatic and peripheral insulin sensitivity, thereby inhibiting hepatic gluconeogenesis and increasing peripheral and splanchnic glucose uptake. Pioglitazone is generally well tolerated, weight gain and edema are the most common emergent adverse events, and there are no known drug interactions between pioglitazone and other drugs. In clinical trials in patients with type 2 diabetes mellitus, pioglitazone as monotherapy, or in combination with metformin, repaglinide, insulin, or a sulfonylurea, induced both long- and short-term improvements in glycemic control and serum lipid profiles. Pioglitazone was also effective in reducing some measures of cardiovascular risk and arteriosclerosis. Pioglitazone thus offers an effective treatment option for the management of patients with type 2 diabetes.     

Combination of the insulin sensitizer, pioglitazone, and the long-acting GLP-1 human analog, liraglutide, exerts potent synergistic glucose-lowering efficacy in severely diabetic ZDF rats

Objective: Severe insulin resistance and impaired pancreatic β‐cell function are pathophysiological contributors to type 2 diabetes, and ideally, antihyperglycaemic strategies should address both. Research Design and Methods: Therapeutic benefits of combining the long‐acting human glucagon‐like peptide‐1 (GLP‐1) analog, liraglutide (0.4 mg/kg/day), with insulin sensitizer, pioglitazone (10 mg/kg/day), were assessed in severely diabetic Zucker diabetic fatty rats for 42 days. Impact on glycaemic control was assessed by glycated haemoglobin (HbA_1C) at day 28 and by oral glucose tolerance test at day 42. Results: Liraglutide and pioglitazone synergistically improved glycaemic control as reflected by a marked decrease in HbA_1C (liraglutide + pioglitazone: 4.8 ± 0.3%; liraglutide: 8.8 ± 0.6%; pioglitazone: 7.9 ± 0.4%; vehicle: 9.7 ± 0.3%) and improved oral glucose tolerance at day 42 (area under the curve; liraglutide + pioglitazone: 4244 ± 445 mmol/l × min; liraglutide: 7164 ± 187 mmol/l × min; pioglitazone: 7430 ± 446 mmol/l × min; vehicle: 8093 ± 139 mmol/l × min). A 24‐h plasma glucose profile at day 38 was significantly decreased only in the liraglutide + pioglitazone group. In addition, 24‐h insulin profile was significantly elevated only in the liraglutide + pioglitazone group. Liraglutide significantly decreased food intake alone and in combination with pioglitazone, while pioglitazone alone increased cumulated food intake. As a result, rats on liraglutide alone gained significantly less weight than vehicle‐treated rats, whereas rats on pioglitazone alone gained significantly more body weight than vehicle‐treated rats. However, combination therapy with liraglutide and pioglitazone caused the largest weight gain, probably reflecting marked improvement of energy balance because of reduction of glucosuria. Conclusions: Combination therapy with insulinotropic GLP‐1 agonist liraglutide and insulin sensitizer, pioglitazone, improves glycaemic control above and beyond what would be expected from additive effects of the two antidiabetic agents.     

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.     

Effect of pioglitazone on body composition and energy expenditure: a randomized controlled trial

BACKGROUND: Several clinical studies have demonstrated that body weight increases after treatment with thiazolidinediones (TZDs). Prior studies have demonstrated an increase in insulin-stimulated lipid storage in adipose tissue. Some, but not all, studies demonstrate reductions in visceral adipose tissue. Changes in body weight are the result of changes in energy intake, energy expenditure, or both. OBJECTIVES: Based on these findings, the primary aim of this study was to evaluate the effect of TZDs on visceral, subcutaneous, and total body fat. Secondary aims were to determine the effects of pioglitazone on (a) energy expenditure, (b) hunger and satiety, (c) blood lipids, and (d) the role of insulinemia/sulfonylurea usage on weight gain in patients with type 2 diabetes. SUBJECTS AND METHODS: We performed a randomized, double-blind, placebo-controlled trial in 48 men and women with type 2 diabetes who had not previously received treatment with TZDs. Patients were treated for 24 weeks with 45 mg/d of pioglitazone or a matching placebo. Body composition was measured by dual-energy x-ray absorptiometry. Visceral and subcutaneous fat were measured by computed tomography. Resting metabolic rate and thermogenic response to a test meal were measured by indirect calorimetry before and after a standardized meal. Hunger and satiety were measured with visual analog scales before and after the same test meal. Blood was collected for the measurement of fasting glucose and insulin levels, hemoglobin A 1c levels, and lipid content. RESULTS: Pioglitazone treatment resulted in a decrease in hemoglobin A(1c) level by 0.96 +/- 1.1% vs 0.11 +/- 0.8% in the placebo group (P < .005). Body weight and fat increased steadily in the patients treated with pioglitazone during the 6 months of the study (+3.9 +/- 3.1 kg at 6 months in pioglitazone-treated patients vs -0.8 +/- 3.4 kg in the placebo-treated patients). Subcutaneous fat in the trunk, arms, and legs were all increased in the pioglitazone-treated group. Visceral fat did not change significantly in either group. Neither resting metabolic rate nor the thermogenic responses to a meal were altered by pioglitazone. Subjective measures of hunger (visual analog scale) did not change with pioglitazone treatment. Triglycerides fell in the pioglitazone-treated group (-58.5 +/- 124 mg/dL, P < .003). Neither the prior use of sulfonylureas nor the level of insulinemia before treatment was a predictor of weight or fat change. CONCLUSION: Pioglitazone increased subcutaneous body fat, but not visceral fat. There was no measurable effect on energy expenditure or hunger/satiety. In contrast to the placebo-treated patient with diabetes, weight gain occurs in the face of falling hemoglobin A(1c) and triglyceride levels.     

Effects of the peroxisomal proliferator-activated receptor-gamma agonist pioglitazone on renal and hormonal responses to salt in healthy men

Glitazones are used in the treatment of type 2 diabetes as efficient insulin sensitizers. They can, however, induce peripheral edema through an unknown mechanism in up to 18% of cases. In this double-blind, randomized, placebo-controlled, four-way, cross-over study, we examined the effects of a 6-wk administration of pioglitazone (45 mg daily) or placebo on the blood pressure, hormonal, and renal hemodynamic and tubular responses to a low (LS) and a high (HS) sodium diet in healthy volunteers. Pioglitazone had no effect on the systemic and renal hemodynamic responses to salt, except for an increase in daytime heart rate. Urinary sodium excretion and lithium clearance were lower with pioglitazone, particularly with the LS diet (P < 0.05), suggesting increased sodium reabsorption at the proximal tubule. Pioglitazone significantly increased plasma renin activity with the LS (P = 0.02) and HS (P = 0.03) diets. Similar trends were observed with aldosterone. Atrial natriuretic levels did not change with pioglitazone. Body weight increased with pioglitazone in most subjects. Pioglitazone stimulates plasma renin activity and favors sodium retention and weight gain in healthy volunteers. These effects could contribute to the development of edema in some subjects treated with glitazones.     

Addition of pioglitazone or bedtime insulin to maximal doses of sulfonylurea and metformin in type 2 diabetes patients with poor glucose control: a prospective, randomized trial

PURPOSE: To compare the efficacy of adding pioglitazone or bedtime isophane (NPH) insulin to maximal doses of metformin and an insulin secretagogue in patients with poor glucose control. METHODS: We conducted a nonblinded, open-label, randomized controlled trial involving 62 patients with type 2 diabetes and glycosylated hemoglobin (HbA1C) levels >8.0%. Patients received either pioglitazone or bedtime NPH insulin in addition to their usual diabetes medication for 16 weeks. Outcome measurements of glycemic control, hypoglycemia, blood pressure, lipid levels, microalbuminuria, and quality of life were assessed at baseline and at 16 weeks. RESULTS: HbA1C levels were lowered to a similar degree in each treatment arm (pioglitazone: -1.9% +/- 1.5%; insulin: -2.3% +/- 1.5%; P = 0.32), but hypoglycemia was less common among patients who received pioglitazone than those who received insulin (37% [11/30] vs. 68% [19/28], P=0.02). Pioglitazone, but not insulin, resulted in an increase in high-density lipoprotein (HDL) cholesterol levels. Both treatments had similar effects on weight, other lipid values, blood pressure, and urine microalbumin levels. CONCLUSION: Adding pioglitazone or bedtime insulin for 16 weeks improved glycemic control in type 2 diabetic patients with secondary oral agent failure. Pioglitazone was associated with less hypoglycemia and improved HDL cholesterol levels.