Comparison of the Effects of Pioglitazone versus Placebo when Given in Addition to Standard Insulin Treatment in Patients with Type 2 Diabetes Mellitus Requiring Hemodialysis: Results from the PIOren Study.

BACKGROUND: Patients with type 2 diabetes mellitus and advanced kidney disease are usually treated with insulin. However, the prolonged pharmacokinetic insulin profile in patients with delayed renal insulin elimination impairs a successful therapy. Due to its hepatic metabolism, pioglitazone is a potential candidate for additional administration. The aim of this study was to investigate the effect of pioglitazone versus placebo on total daily insulin requirements and several pleiotropic factors in type 2 diabetes patients requiring hemodialysis. METHODS: The effect of pioglitazone (30 mg) versus placebo was explored in this prospective, randomized, double-blind parallel multicenter phase II study analyzing data from 36 patients with type 2 diabetes mellitus currently under hemodialysis (25 male, 11 female, aged 69.2 ± 7.9 years, baseline HbA1c 7.6 ± 0.9%). The most important efficacy parameters collected before dialysis and after an overnight fast at baseline and after 6 months were: total daily insulin dose, HbA1c, fasting blood glucose, adiponectin, HDL, LDL, triglycerides, NT-proBNP, and ultrafiltrate volume. RESULTS: Application of pioglitazone resulted in a significant decrease of the daily insulin dose by 35% versus baseline (placebo: -10%, n.s.), improvement in HbA1c (-0.60 ± 0.87%, p = 0.015; placebo: 0.21 ± 1.1%, n.s.) and adiponectin (7.33 ± 4.80 mg/l, p < 0.001; placebo: -1.37 ± 2.56 mg/l, n.s.). Slight improvements or no changes were seen with fasting glucose, triglycerides, HDL, LDL and NT-proBNP. There was no indication of increased hypoglycemia risk and volume overload by the addition of pioglitazone. CONCLUSIONS: Addition of pioglitazone to insulin in patients with late-stage kidney failure requiring hemodialysis is a well-tolerated treatment option that improves glycemic control with simultaneous insulin-sparing potential.

Effect of pioglitazone and ramipril on biomarkers of low-grade inflammation and vascular function in nondiabetic patients with increased cardiovascular risk and an activated inflammation: results from the PIOace study.

AIMS: This study investigated the effects of pioglitazone (PIO), ramipril (RAM), or their combination (PIRA) on low-grade inflammation in nondiabetic hypertensive patients with increased cardiovascular risk. METHODS AND RESULTS: Patients enrolled in this placebo-controlled, double-blind, randomized, parallel trial (72 male, 77 female, aged 60 ± 9 years, body mass index 30.4 ± 4.7 kg/m(2), duration of hypertension 9 ± 8 years) were treated with either 30/45 mg PIO (dose titration), 2.5/5 mg RAM, or their combination for 12 weeks. A reduction in high-sensitivity C-reactive protein was observed with PIO (-0.89 ± 1.98 mg/liter; -25%) and PIRA (-0.49 ± 2.11 mg/liter; -16%), while an increase was seen with RAM (0.58 ± 2.13 mg/liter; +20%, p < .05 vs PIO and PIRA). The 24-hour blood pressure profile showed a small increase with both monotherapies but a decrease with PIRA (p < .05 vs PIO). Improvements in biomarkers of chronic systemic inflammation and insulin resistance (IR) were observed in the PIO and PIRA arms only [PIO/RAM/PIRA: homeostasis model of assessment of IR: -0.78 ± 1.39 (-29%)/0.15 ± 1.03 (+5%)/ -1.44 ± 2.83 (-40%); adiponectin: 8.51 ± 5.91 (+104%)/ 0.09 ± 2.63 (+1%)/ 8.86 ± 6.37 mg/liter (+107%); matrix metallo-proteinase-9: -48 ± 127 (-12%)/-1 ± 224 (0%)/-60 ± 210 ng/ml (-13%), p < .05 for RAM vs PIO or PIRA in all cases]. CONCLUSIONS: Our 3-month study in nondiabetic hypertensive patients showed a decrease in biomarkers of IR and chronic systemic inflammation with the PIO monotherapy and the PIRA combination only, which may help to explain some findings in other cardiovascular outcome trials.

Double-blind, randomized, multicentre, and active comparator controlled investigation of the effect of pioglitazone, metformin, and the combination of both on cardiovascular risk in patients with type 2 diabetes receiving stable basal insulin therapy: the PIOCOMB study.

BACKGROUND: We analyzed specific effects of an add-on therapy with pioglitazone compared to metformin and their combination in patients with basal insulin treatment on biomarkers of CV risk. METHODS: In this double-blind, randomized, multicentre, active comparator controlled trial, 121 patients with type 2 diabetes were enrolled. Inclusions: treatment with basal insulin, HbA(1C) 6.5%-8.5%, age 30-75 years. After glargine therapy over 2 weeks for titration towards FBG ≤ 7.8 mmol/L, patients received either (A) bid 850 mg metformin (n = 42), (B) bid 15 mg pioglitazone (n = 40), or (C) 30 mg pioglitazone plus 1.7 g metformin (n = 39) over 6 months. Matrix Metal Proteinase 9 (MMP-9) was primary objective, together with biomarkers of CV risk. RESULTS: Pioglitazone (B) reduced MMP-9 versus baseline by 54.1 ± 187.1 ng/mL, with metformin (A) it was increased by 49.6 ± 336.2 ng/mL (p = 0.0345; B vs. A), and with the combination of both (C) it was decreased by 67.8 ± 231.4 ng/mL (A vs. C: p = 0.0416; B vs. C: p = 0.8695). After logarithmic transformation due to high variances the exploratory results showed significance for A vs. B (p = 0.0043) and for A vs. C (p = 0.0289).Insulin dosage was reduced by 7.3 units in group B (p < 0.0001), by 6.0 units in C (p = 0.0004), but was increased by 2.5 units (p = 0.1539) in A at follow up. Reduction in hs-CRP was significant within treatment groups for B (p = 0.0098) and C (p < 0.0001), and between the groups for A vs. C (p = 0.0124). All three single regimens reduced PAI-1. Adiponectin was significantly elevated in B and C (p < 0.0001) and between-groups. HbA(1C) was only significantly decreased in the combination group. No significant effects were observed for NFkB and PGFα. peripheral edema were seen in 11.9% vs. 40.0% vs. 20.5%, and weight change was -0.7 kg vs. +4.3 kg vs. +2.7 kg (A vs. B vs. C). CONCLUSIONS: Addition of pioglitazone but not of metformin reduces MMP-9, hs-CRP and increased insulin sensitivity and adiponectin in this study. The combination of both had no additional effect on inflammation. Pioglitazone is suggested to be a rational add-on therapy to basal insulin in patients with high CV risk.

PIOfix-study: effects of pioglitazone/metformin fixed combination in comparison with a combination of metformin with glimepiride on diabetic dyslipidemia.

OBJECTIVE: Dyslipidemia in patients with type 2 diabetes is characterized by elevated triglyceride levels, decreased high-density lipoprotein (HDL) cholesterol, and a predominance of small dense low-density lipoprotein (LDL) particles. Also, patients suffer from ß-cell dysfunction, chronic systemic inflammation, increased hormonal visceral adipose tissue activity, and an increased risk of cardiovascular events. The aim of our study was to investigate the effect of a fixed pioglitazone + metformin (PM) combination (vs. glimepiride + metformin [GM]) on diabetic dyslipidemia. RESEARCH DESIGN AND METHODS: A total of 288 type 2 diabetes patients completed this double-blind parallel study (187 men, 101 women; age [mean ± SD], 59 ± 10 years; body mass index, 32.6 ± 5.1 kg/m(2); hemoglobin A1c [HbA1c], 7.3 ± 0.8%). They were randomized to PM or GM for 6 months. Observation parameters at baseline and end point included HDL, LDL, triglycerides, fasting insulin, fasting glucose, total adiponectin, intact proinsulin, and high-sensitivity C-reactive peptide (hsCRP). RESULTS: HDL increased in the PM group by 0.08 ± 0.25 mmol/L (GM, -0.01 ± 0.2.8 mmol/L; P < 0.001 vs. PM), whereas LDL increased in both groups (GM, 0.25 ± 0.90 mmol/L; PM, 0.29 ± 0.66 mmol/L; difference not significant between groups). Improvements were seen for triglycerides (PM, -0.47 ± 1.30; GM, -0.19 ± 1.39 mmol/L), HbA1c (PM, -0.8 ± 0.9%; GM, -1.0 ± 0.9%), and glucose (PM, -1.2 ± 2.1; GM, -1.2 ± 2.2 mmol/L). Decreases in fasting insulin (PM, -5.2 ± 11.9; GM, -0.1 ± 9.8 µU/mL; P < 0.001 between groups), hsCRP (PM, -0.9 ± 1.9; GM, 0.0 ± 1.8 mg/L; P < 0.001), and fasting intact proinsulin (PM, -5.5 ± 11.1; GM, -0.1 ± 10.0 pmol/L; P < 0.001) and an increase in adiponectin (PM, +6.8 ± 6.4 mg/L; GM, +0.7 ± 2.7 mg/L; P < 0.001) were seen in the PM arm, only. CONCLUSIONS: With comparable glycemic control, the fixed PM combination was more efficacious on HDL cholesterol improvement than the GM combination. Additional positive effects were observed for biomarkers of lipid metabolism, ß-cell function, activity of the visceral adipose tissue, and chronic systemic inflammation.

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/m(2)). 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.

Limitations of the HOMA-B score for assessment of beta-cell functionality in interventional trials-results from the PIOglim study.

BACKGROUND: Drugs with unspecific stimulating effects on beta-cell secretion increase the homeostasis model assessment (HOMA)-B score, indicating improved beta-cell "function." We investigated whether the beta-cell protection provided by adding pioglitazone (PIO) to glimepiride (GLIM) in comparison to up-titrating the GLIM dose alone is reflected by appropriate changes in several measures of beta-cell function, including HOMA-B score. METHODS: This double-blind, parallel prospective 6-month study was performed with 82 patients (47 men, 35 women; age, 61 +/- 9 years; duration of disease, 5.3 +/- 4.4 years; body mass index, 32.6 +/- 6.0 kg/m(2); hemoglobin A1c [HbA1c], 7.3 +/- 0.7%) with GLIM monotherapy (1-3 mg). They were randomized to receive a GLIM + PIO combination with up-titration (2 mg + 30 mg/4 mg + 30 mg/4 mg + 4 mg) or to remain on GLIM (up-titration 4/5/6 mg). Observation parameters determined at baseline and end point included HOMA-B, HOMA-IR, HbA1c, glucose, insulin, and intact proinsulin. RESULTS: There was a slight increase in the HOMA-B score in the GLIM group but not in the GLIM + PIO arm (baseline/end point: for GLIM, 71 +/- 48/88 +/- 64; for PIO + GLIM, 74 +/- 56/69 +/- 52). Improvements in the other observation parameters were predominantly detected in the PIO + GLIM group (HbA1c, 7.20 +/- 0.61%/6.36 +/- 0.90%; HOMA-IR, 7.0 +/- 4.5/4.1 +/- 2.1; intact proinsulin, 12.4 +/- 10.3/7.6 +/- 4.8 pmol/L [all P < 0.05 vs. baseline]) compared with the GLIM group (HbA1c, 7.45 +/- 0.69%/7.15 +/- 0.97% [P < 0.05]; HOMA-IR, 7.4 +/- 4.5/7.5 +/- 4.3 [not significant]; intact proinsulin, 17.3 +/- 21.6/16.3 +/- 15.5 pmol/L [not significant]). CONCLUSIONS: The PIO + GLIM combination led to overall improvement of laboratory biomarkers for beta-cell function, except for HOMA-B. Glimepiride up-titration had no such effects but increased the HOMA-B score. HOMA-B seems to provide misleading results when used as a diagnostic tool in patients treated with sulfonylurea drugs. A corrective term for consideration of proinsulin in the HOMA-B equation may address this limitation.

Pioglitazone in addition to metformin improves erythrocyte deformability in patients with Type 2 diabetes mellitus.

The aim of the present study was to compare the effect of PIO (pioglitazone) or GLIM (glimepiride) on erythrocyte deformability in T2DM (Type 2 diabetes mellitus). The study covered 23 metformin-treated T2DM patients with an HbA1c (glycated haemoglobin) >6.5%. Patients were randomized to receive either PIO (15 mg, twice a day) or GLIM (1 mg, twice a day) in combination with metformin (850 mg, twice a day) for 6 months. Blood samples were taken for the measurement of fasting glucose, HbA1c, fasting insulin, intact proinsulin, adiponectin and Hct (haematocrit). In addition, the erythrocyte EI (elongation index) was measured using laser diffractoscopy. Both treatments significantly improved HbA1c levels (PIO, -0.9+/-1.1%; GLIM, -0.6+/-0.4%; both P<0.05) and resulted in comparable HbA1c levels after 6 months (PIO, 6.5+/-1.2%; GLIM, 6.2+/-0.4%) Treatment with PIO reduced fasting insulin levels (-8.7+/-15.8 milli-units/l; P=0.098), intact proinsulin levels (-11.8+/-9.5 pmol/l; P<0.05) and Hct (-1.3+/-2.3%; P=0.09), whereas adiponectin levels increased (8.2+/-4.9 microg/ml; P<0.05). No significant change in these parameters was observed during GLIM treatment. PIO improved the EI, resulting in a significant increase in EI at all physiological shear stress ranges (0.6-6.0 Pa; P<0.05). The improvement in EI correlated with the increase in adiponectin levels (r=0.74; P<0.001), and inversely with intact proinsulin levels (r=-0.47; P<0.05). This is the first study showing an improvement in EI during treatment with PIO, which was associated with an increase in adiponectin and a decrease in intact proinsulin levels, but independent of glycaemic control.

Combined pioglitazone and metformin treatment maintains the beneficial effect of short-term insulin infusion in patients with type 2 diabetes: results from a pilot study.

BACKGROUND: The aim of our study was to examine the efficacy of short-term intravenous insulin intervention followed by oral pioglitazone/metformin therapy to prevent patients from continuous insulin application. METHODS: This prospective, open-label, 4-month pilot study comprised of 14 diabetes patients (5 female, 9 male; age 60 +/- 2 years; body mass index 29 +/- 3.2 kg/m(2); hemoglobin A1c [HbA1c] 7.6 +/- 1.1%) with (1) insufficient glycemic control under a dose of metformin >or=1700 mg/day and/or metformin plus additional oral antidiabetes drugs (OADs) and (2) appropriate residual beta-cell function. Initially, an inpatient 34 h continuous intravenous insulin infusion was performed, and metformin was given (2x 850 mg/day). Insulin was stopped, and pioglitazone 30 mg/day was added at the second inpatient day. Patients were followed for four months. Efficacy parameters [change of HbA1c, fasting blood glucose [FBG], intact proinsulin, adiponectin, and high-sensitivity C-reactive protein (hsCRP)] were assessed after initial normalization of blood glucose values by intravenous insulin and at the study end point. RESULTS: During the acute insulin intervention, FBG levels were stabilized in all study subjects. In the following OAD treatment period, five patients showed an improvement of HbA1c > 0.5% [35.7%; seven patients remained stable (50.0%), two patients were nonresponders (14.3%)]. Fasting glucose values dropped after insulin infusion (-17.7%; p < .001). This effect was maintained during the consecutive OAD treatment period (glucose +0.3%, not significant (NS); HbA1c -6.0%; p < .05). The initial decrease in fasting intact proinsulin levels was also maintained during the study (end value -41%, p < .05). Improvements in hsCRP values (postinsulin value, -15%, NS; end value -37%; p < .05) and adiponectin values (postinsulin value +15%, NS; end value +128%; p < .001) were demonstrated at end point only after continued glitazone intake. CONCLUSIONS: Our pilot study demonstrated that a beneficial effect of a short-term intravenous insulin application on glycemic control was effectively maintained by pioglitazone/metformin treatment for at least 4 months. In addition, the oral therapy significantly improved cardiovascular risk parameters.

Investigation of the vascular and pleiotropic effects of atorvastatin and pioglitazone in a population at high cardiovascular risk.

We investigated the effect of atorvastatin monotherapy and combined treatment with atorvastatin and pioglitazone on intima-media thickness, vascular function and the cardiovascular risk profile. In all, 148 patients (76 male, 72 female; aged 61.4+/-6.5 years; body mass index [BMI] 29.2+/-4.1 kg/m2; mean +/- SD) with increased cardiovascular (CV) risk factors were randomised. Intima-media thickness (IMT), the augmentation index (Aix@75), the microvascular response to acetylcholine (LDF), lipid status, and plasma levels of intact proinsulin, adiponectin, interleukin-6 (IL-6), monocyte chemotactic protein-1 (MCP-1), matrix metalloproteinase-9 (MMP-9), sCD40L, P-selectin, tissue plasminogen activator (t-PA) and blood lipids were monitored over six months. Atorvastatin treatment, alone and in combination with pioglitazone, revealed a significant regression in IMT (0.923+/-0.013 to 0.874+/-0.012 mm and 0.921+/-0.015 to 0.882+/-0.015 mm; mean +/- SEM; p<0.05 respectively) and Aix@75 (27.3+/-1.2 to 25.9+/-1.4; and 25.6+/-1.4 to 24.8+/-1.7%; p<0.05). The endothelial response to acetylcholine as measured by laser Doppler fluximetry (LDF) improved during combined treatment (373+/-57 to 576+/-153 AU; p<0.05). Addition of pioglitazone to atorva-statin resulted in significant further effects on high-sensitivity C-reactive protein (hsCRP), t-PA, P-selectin, adiponectin, triglycerides and high-density lipoprotein (HDL) cholesterol (p<0.05 respectively). Atorvastatin significantly improved IMT and vascular elasticity. Co-administration of pioglitazone provided additional effects on endothelial function, lipid profile and laboratory markers of inflammation.

Long-acting blood pressure reduction by candesartan cilexetil in patients with hypertension.

Candesartan cilexetil is a highly potent and long-acting angiotensin II type I (AT1) receptor antagonist. This short review summarises results of clinical studies focusing on the duration of action of candesartan cilexetil. Results of previous clinical studies indicate that candesartan has the property to maintain a sustained blood pressure reduction for up to 48 h after dosing. Since lack of compliance is a known problem in patients with hypertension, these findings could be of particular clinical relevance.

Fixed combination of candesartan with hydrochlorothiazide in patients with severe primary hypertension.

OBJECTIVE: The new guidelines for treatment of hypertension by the JNC VII in 2003 permit the initial use of a combination therapy, if blood pressure has to be lowered more than 20/10 mmHg. The aim of this investigation was to document the efficacy and safety of a combination therapy with candesartan cilexetil and hydrochlorothiazide in severe hypertension. METHODS: 116 patients freshly diagnosed as having severe primary hypertension (Grade III) and untreated for this condition were enrolled. The study was performed without a placebo control group for ethical reasons. Thus, all patients were treated for 6 weeks with 16 mg candesartan cilexetil plus 12.5mg hydrochlorothiazide daily after forced titration with 8 and 16 mg candesartan cilexetil each for