Time-action profile and patient assessment of inhaled insulin via the Exubera device in comparison with subcutaneously injected insulin aspart via the FlexPen device.

BACKGROUND: The goal of our investigation was to compare the pharmacokinetics/pharmacodynamics properties of and patient preference for insulin aspart applied with the FlexPen (Novo Nordisk, Bagsvaerd, Denmark) (IAFP) with pulmonary human insulin applied with the Exubera (Pfizer, New York, NY) device (HIEX). METHODS: Twelve patients with diabetes (six with type 1 and six with type 2; eight men, four women; age, 54.5 +/- 11.0 years; duration of diabetes, 16.5 +/- 10.6 years; hemoglobin A1c, 7.5 +/- 0.7%; body mass index, 29.5 +/- 7.2 kg/m(2); mean +/- SD) participated in an open-label, randomized, euglycemic clamp study. The patients received 11 units of IAFP or a dose-equivalent of (3 + 1 mg) insulin from HIEX in a randomized sequence on two different study days. Insulin plasma levels and the required glucose infusion rate (GIR) were monitored for a time period of 6 h. In addition, the patients' individual ratings from 1 (excellent) to 5 (poor) regarding several different handling items were assessed using a questionnaire. RESULTS: No significant difference in the pharmacokinetics/pharmacodynamics parameters could be observed between IAFP and HIEX within the first 120 min. In the second part of the clamp procedure, plasma insulin levels (area under the curve versus time [AUC]) and the GIR was significantly higher after HIEX compared with IAFP (insulin AUC(120-360), 66,232 +/- 4,521 vs. 48,852 +/- 2,999 pmol/L, P < 0.05; GIR AUC(120-360), 8,928 +/- 1,334 vs. 6,805 +/- 1,655 mg/kg/min). A superior patient judgment was obtained for the FlexPen with regard to trust in insulin delivery (2.3 +/- 1.1 vs. 2.8 +/- 1.0), trust in correct insulin dosing (1.8 +/- 1.1 vs. 2.6 +/- 0.9), size (2.3 +/- 1.1 vs. 3.6 +/- 0.9), and appearance of the device (2.4 +/- 1.0 vs. 3.8 +/- 0.9) (P < 0.05, respectively). CONCLUSIONS: Insulin treatment with HIEX was found to have pharmacokinetics/pharmacodynamics properties comparable to IAFP. Both insulin administration technologies were overall evaluated positive, but most patients preferred IAFP.

The IRIS V study: pioglitazone improves systemic chronic inflammation in patients with type 2 diabetes under daily routine conditions.

BACKGROUND: The peroxisome proliferator-activated receptor-gamma agonist pioglitazone is established as a drug to treat patients with type 2 diabetes mellitus. In addition to lowering blood glucose levels, one of the favorable effects of pioglitazone is improvement of systemic chronic inflammation particularly affecting vessel walls. The effect can be monitored by the measurement of the biomarker C-reactive protein in the range of 0-10 mg/L (high-sensitivity C-reactive protein [hsCRP]). This observational trial was performed to evaluate the effects of pioglitazone on hsCRP values in a large population under daily life conditions. METHODS: A total of 1,170 subjects could be included into the final analysis (633 men, 537 women; age [mean +/- SD], 63.5 +/- 10.4 years, body mass index, 31.0 +/- 5.5 kg/m2; duration of diabetes, 6.9 +/- 8.1 years; glycosylated hemoglobin [HbA1c], 7.5 +/- 1.1%). All patients were glitazone-naive prior to study entry. The patients received pioglitazone alone or in combination with their previous treatment (acarbose, sulfonylurea drugs, and/or metformin). Patients were evaluated at baseline and after 10 +/- 2 weeks and 20 +/- 2 weeks of treatment. Observation parameters were fasting blood glucose, lipids, and blood pressure. The level of hsCRP was determined in a central laboratory at baseline and at end point. RESULTS: All markers showed a significant improvement at trial end point. A decrease of hsCRP (baseline 3.3 +/- 1.0 mg/L vs. end point 2.8 +/- 2.3 mg/L, P < 0.01), HbA1c (7.5 +/- 1.1% vs. 6.8 +/- 0.9%, P < 0.001), fasting blood glucose (8.7 +/- 2.6 mM vs. 7.2 +/- 2.1 mM, P < 0.001), low-density lipoproteins (3.3 +/- 1.0 mM vs. 3.2 +/- 0.9 mM, P < 0.001), and triglycerides (2.4 +/- 2.0 mM vs. 2.2 +/- 2.5 mM, P < 0.001) and an increase in high-density lipoproteins (1.3 +/- 0.4 mM vs. 1.4 +/- 0.4 mM, P < 0.001) was observed. Parallel to the metabolic improvement, both systolic and diastolic blood pressure values were reduced (141 +/- 17 mm Hg vs. 137 +/- 15 mm Hg and 83 +/- 9 mm Hg vs. 80 +/- 9 mm Hg, respectively; P < 0.001 in both cases). CONCLUSIONS: These observational results, obtained from a nonselected patient population under daily routine conditions, confirm the benefits of pioglitazone treatment on blood glucose, lipid metabolism, and blood pressure. The results show that pioglitazone treatment improves chronic vascular inflammation, which may be associated with reduced cardiovascular risk.

Relaxin expression correlates significantly with serum changes in VEGF in response to antidiabetic treatment in male patients with type 2 diabetes mellitus.

Recent studies indicate that relaxin as well as VEGF possess cardioprotective properties. This study aimed to determine the association of relaxin with VEGF in patients with type 2 diabetes. We therefore analyzed samples from a recent study showing the benefits of anti-diabetic treatment on cardiovascular risk markers independently from glycemic control. VEGF, relaxin and markers of endothelial dysfunction, s-ICAM-1 and s-VCAM-1, were compared after 26 +/- 2 weeks of antidiabetic treatment with pioglitazone or glimepiride with their base line values. A total of 151 data sets (patients age, 62.7 +/- 8.1 years, diabetes duration, 6.8 +/- 6.6 years, 57 women, 94 men) were available for the analysis. Baseline values were in median, relaxin: 27.4 pg/mL 125% quartile 15.8; 75% quartile: 45.21, s-ICAM-1: 294 ng/mL [25% quartile: 260; 75% quartile: 331], s-VCAM-1: 677 ng/mL [25% quartile: 589; 75% quartile 871], VEGF: 350 pg/mL [25% quartile: 251; 75% quartile: 514]. Parameter variation after therapy showed a significant correlation of relaxin expression with VEGF expression (p = 0.02) in the entire study group. The correlation was seen in the subgroup of male patients (p < 0.01) but did not reach significance in the female patients (p = 0.71). No further correlation was observed analyzing the other investigated parameters. Our data suggest that relaxin may exert its cardioprotective action possibly via VEGF increase, particularly in men. In women, other pathways may superimpose this effect. In conclusion, our study supports the hypothesis of different regulating pathways and effects of relaxin in men and women also in patients with type 2 diabetes.

Pioglitazone improves metabolic markers in patients with type 2 diabetes independently from physical activities: results from the IRIS III study.

AIM: Pioglitazone is an established peroxisome proliferator-activated receptor gamma agonist for the treatment of insulin resistance in patients with type 2 diabetes mellitus. This analysis of the observational IRIS III study was performed to evaluate the effects of pioglitazone treatment in relation to the degree of physical exercise activities in a large patient population under daily life conditions. METHODS: A total of 1298 patients out of 2092 enrolled into the IRIS III study who had provided information about their exercise level could be included in the final analysis (622 female, 676 male; age: 63.1 +/- 10.4 years, diabetes duration: 6.6 +/- 5.0 years, mean +/- SD). All patients were glitazone naïve prior to study entry. They received pioglitazone in addition to their previous oral antidiabetic treatment. The patients were stratified according to their physical activity level (never, sometimes, and regularly). Data were evaluated at baseline and after 20 +/- 2 weeks of treatment. Observation parameters were fasting blood glucose, lipids, and blood pressure. Hemoglobin A1c (HbA1c) was determined in a central laboratory, and insulin sensitivity was assessed by the IRIS II score. RESULTS: Glycemic control, blood pressure, and the lipid profile improved independently from the degree of physical activity (e.g., no exercise vs frequent exercise: DeltaHbA1c: -0.89 +/- 1.2% vs -0.72 +/- 1.1%, not significant). A positive impact of exercise on insulin resistance could be observed at baseline, which, however, was further decreased by pioglitazone treatment [IRIS II score (baseline/end point): no exercise vs frequent exercise: 74.0 +/- 15.9/62.5 +/- 20.2 vs 66.7 +/- 19.0/58.0 +/- 21.8, p < 0.001/not significant]. CONCLUSIONS: These observational results, obtained from a nonselected patient population under daily routine conditions, confirm that the benefits of pioglitazone treatment on glycemic control, lipid metabolism, and blood pressure are independent from physical activity. Exercise has a positive influence on insulin sensitivity, but pioglitazone shows additional favorable effects and is, therefore, recommended for use independently from the activity level of the patients.

Relaxin expression correlates significantly with serum fibrinogen variation in response to antidiabetic treatment in women with type 2 diabetes mellitus.

AIM: Diabetes is associated with aberrant coagulation. Relaxin, an insulin-like peptide hormone, is a candidate to be involved in the underlying molecular mechanisms. Therefore, the present study investigated the correlation of relaxin expression with fibrinogen levels in diabetes patients undergoing oral antidiabetic treatment. METHOD: In total, 192 type 2 diabetes patients were enrolled into the study. The patients were randomized to receive either pioglitazone or glimepiride for 26 weeks. Blood was drawn at baseline and at the end of the study to measure the concentrations of relaxin and fibrinogen with an enzyme-linked immunosorbent assay and a turbimetric method, respectively. In addition, platelets were counted at both time points. RESULTS: Total datasets were available from 161 patients (age 62.5 +/- 8.1 years, mean +/- standard deviation; 58 women, 103 men). The median initial parameter concentrations were: relaxin, 27.4 pg/ml (range 0.4 - 380 pg/ml); fibrinogen, 3.0 g/l (range 1.1 - 7.9 g/l); platelets, 217,000/microl (range 51,000 - 547 000/microl). The data were analyzed according to the increase or decrease of each parameter after therapy compared with baseline. There was a significant correlation of relaxin variation with fibrinogen variation, seen particularly in the female subgroup (p < 0.05). The correlation was independent of the antidiabetic medication. CONCLUSION: The data suggest that there is a correlation between fibrinogen levels and relaxin expression. Relaxin may exert its cardioprotective properties after pathologic fibrinogen increase. This regulation may be affected by diabetes. As a consequence, cardiovascular risk may increase in women with aberrant relaxin functionality.