Andreas Pfützner

Biological activity of C-peptide on the skin microcirculation in patients with insulin-dependent diabetes mellitus.

19 insulin-dependent diabetes mellitus (IDDM) patients participated in a randomized double-blind crossover investigation to investigate the impact of human C-peptide on skin microvascular blood flow. The investigation was also carried out with 10 healthy volunteers. Blood pressure, heart rate, blood sugar, and C-peptide levels were monitored during a 60-min intravenous infusion period of C-peptide (8 pmol kg-1 min-1) or saline solution (154 mmol liter-1 NaCl), and 30 min after stopping the infusion. During the same time period, capillary blood cell velocity (CBV), laser Doppler flux (LDF), and skin temperature were assessed in the feet. In the verum arm, C-peptide levels increased after starting infusion to reach a maximum of 2.3+/-0.2 nmol liter-1 after 45 min, but remained below 0. 15 nmol liter-1 during the saline treatment. Baseline CBV was lower in diabetic patients compared with healthy subjects (147+/-3.6 vs. 162+/-4.2 micron s-1; P < 0.01). During C-peptide administration, CBV in IDDM patients increased progressively from 147+/-3.6 to 167+/-3.7 micron s-1; P < 0.001), whereas no significant change occurred during saline infusion or in healthy subjects. In contrast to the CBV measurements, the investigation of LDF, skin temperature, blood pressure, heart rate, or blood sugar did not demonstrate any significant change during the study. Replacement of human C-peptide in IDDM patients leads to a redistribution in skin microvascular blood flow levels comparable to levels in healthy subjects by increasing the nutritive CBV relative to subpapillary arteriovenous shunt flow.

Technosphere™/Insulin—A New Approach for Effective Delivery of Human Insulin Via the Pulmonary Route

The development of pulmonary insulin formulation offers an attractive alternative to the current requirement of repeated subcutaneous (s.c.) injections for insulin administration. Technosphere/Insulin is a formulation of regular human insulin that was designed to produce an efficient transport of insulin across the respiratory epithelium into the systemic circulation. Several studies using the euglycemic clamp technique were performed in healthy volunteers and patients with Type 2 diabetes to assess the pharmacokinetic and pharmacodynamic properties of Technosphere/Insulin. The investigations revealed a very rapid systemic insulin uptake (insulin T(max) approximately 12-14 min), a fast onset of action (maximum activity approximately 20-30 min), and a short duration of action (approximately 2-3 h) in healthy volunteers and in patients with Type 2 diabetes. In the first study, employing a commercially available inhaler, the relative bioavailability (compared with s.c. injections) was initially reported to be 26% for the first 3 h and 16% for the entire observation period of 6 h. With the development of a specific inhaler adapted to the physical properties of Technosphere/Insulin, the MedTone Inhaler, relative bioavailability was 50% for the first 3 h and 30% over the entire 6-h period. A clear linearity of systemic insulin uptake was observed in a study employing 12 healthy volunteers inhaling doses of 25, 50, and 100 IU. Repeated inhalation of 100 IU of Technosphere/Insulin by 12 patients with Type 2 diabetes revealed a lower variability in comparison with published s.c. injection data from healthy volunteers. This new Technosphere/Insulin formulation was well tolerated, and no serious adverse events were reported in any of the investigations. Given its attractive time-action profile, Technosphere/Insulin may become a suitable alternative to s.c. injection for prandial insulin delivery, especially in patients with Type 2 diabetes, if the long-term safety, tolerability, and efficacy of this pulmonary insulin are established and confirmed in future studies.

Accuracy evaluation of five blood glucose monitoring systems obtained from the pharmacy: a European multicenter study with 453 subjects

BACKGROUND This multicenter study was conducted to evaluate the performance of five recently introduced blood glucose (BG) monitoring (BGM) devices under daily routine conditions in comparison with the YSI (Yellow Springs, OH) 2300 Stat Plus glucose analyzer. METHODS Five hundred one diabetes patients with experience in self-monitoring of BG were randomized to use three of five different BGM devices (FreeStyle Lite® [Abbott Diabetes Care Inc., Alameda, CA], FreeStyle Freedom Lite [Abbott Diabetes Care], OneTouch® UltraEasy® [LifeScan Inc., Milpitas, CA], Accu-Chek® Aviva [Roche Diagnostics, Mannheim, Germany], and Contour® [Bayer Vital GmbH, Leverkusen, Germany]) in a daily routine setting. All devices and strips were purchased from local regular distribution sources (pharmacies, four strip lots per device). The patients performed the finger prick and the glucose measurement on their own. In parallel, a healthcare professional performed the glucose assessment with the reference method (YSI 2300 Stat Plus). The primary objective was the comparison of the mean absolute relative differences (MARD). Secondary objectives were compliance with the International Organization for Standardization (ISO) accuracy criteria under these routine conditions and Clarke and Parkes Error Grid analyses. RESULTS MARD ranged from 4.9% (FreeStyle Lite) to 9.7% (OneTouch UltraEasy). The ISO 15197:2003 requirements were fulfilled by the FreeStyle Lite (98.8%), FreeStyle Freedom Lite (97.5%), and Accu-Chek Aviva (97.0%), but not by the Contour (92.4%) and OneTouch UltraEasy (91.1%). The number of values in Zone A of the Clarke Error Grid analysis was highest for the FreeStyle Lite (98.8%) and lowest for the OneTouch Ultra Easy (90.4%). CONCLUSIONS FreeStyle Lite, FreeStyle Freedom Lite, and Accu-Chek Aviva performed very well in this study with devices and strips purchased through regular distribution channels, with the FreeStyle Lite achieving the lowest MARD in this investigation.

Association of sulphonylurea treatment with all-cause and cardiovascular mortality: A systematic review and meta-analysis of observational studies

We conducted a meta-analysis of cohort and case-control studies to evaluate all-cause and cardiovascular (CV) mortality of patients with type 2 diabetes mellitus (T2DM) who received sulphonylurea (SU) treatment, when compared to any other diabetes treatment. Only studies reporting raw data on mortality during SU treatment were included. Data were combined using random-effects (RE) models. Unadjusted odds ratios (ORs) are presented. Of 4991 publication titles and abstracts reviewed, 20 studies (n = 551,912 patients) were included. For cohort studies (n = 276,050), patients receiving SU monotherapy or combination treatment had significantly higher all-cause and CV mortality risks compared to any non-SU treatment [all-cause, 13 studies: OR = 1.92, 95% confidence interval (CI) = 1.48–2.49; CV, 5 studies: OR = 2.72, 95% CI = 1.95–3.79]. Validity was limited by the high treatment group heterogeneity (I 2 > 90%) and study-inherent biases/design differences. In conclusion, patients receiving SU treatment had increased all-cause and CV mortality risks. However, the meta-analysis was limited by the high heterogeneity of non-randomized studies.

Pulmonary insulin delivery by means of the Technosphere™ drug carrier mechanism

Technosphere™/Insulin (TI) is a formulation of regular human insulin designed for efficient transport across the respiratory epithelium into the circulation. The drug carrier mechanism achieves a fast systemic insulin uptake (maximum time ∼ 15 – 20 min), a fast onset of action (maximum activity ∼ 25 – 30 min) and a short duration of action (∼ 2 h). Bioavailability, relative to subcutaneous injection, was established to be between 30 and 50% with a linear dose–response relationship and low variability. In all published short-term studies, TI was well tolerated. Provided a reliable long-term safety profile, TI may become a suitable alternative to subcutaneous injection for prandial insulin delivery. TI offers the possibility of new treatment regimens, especially in patients with Type 2 diabetes.

Influence of Glucose Control and Improvement of Insulin Resistance on Microvascular Blood Flow and Endothelial Function in Patients with Diabetes Mellitus Type 2

Objective: The study was performed to investigate the effect of improving metabolic control with pioglitazone in comparison to glimepiride on microvascular function in patients with diabetes mellitus type 2.

Clinical assessment of the accuracy of blood glucose measurement devices

Abstract Objectives: Blood glucose meters for patient self-measurement need to comply with the accuracy standards of the ISO 15197 guideline. We investigated the accuracy of the two new blood glucose meters BG*Star and iBG*Star (Sanofi-Aventis) in comparison to four other competitive devices (Accu-Chek Aviva, Roche Diagnostics; FreeStyle Freedom Lite, Abbott Medisense; Contour, Bayer; OneTouch Ultra 2, Lifescan) at different blood glucose ranges in a clinical setting with healthy subjects and patients with type 1 and type 2 diabetes. BGStar and iBGStar are employ dynamic electrochemistry, which is supposed to result in highly accurate results. Methods: The study was performed on 106 participants (53 female, 53 male, age (mean ± SD): 46 ± 16 years, type 1: 32 patients, type 2: 34 patients, and 40 healthy subjects). Two devices from each type and strips from two different production lots were used for glucose assessment (∼200 readings/meter). Spontaneous glucose assessments and glucose or insulin interventions under medical supervision were applied to perform measurements in the different glucose ranges in accordance with the ISO 15197 requirements. Sample values <50 mg/dL and >400 mg/dL were prepared by laboratory manipulations. The YSI glucose analyzer (glucose oxidase method) served as the standard reference method which may be considered to be a limitation in light of glucose hexokinase-based meters. Results: For all devices, there was a very close correlation between the glucose results compared to the YSI reference method results. The correlation coefficients were r = 0.995 for BGStar and r = 0.992 for iBGStar (Aviva: 0.995, Freedom Lite: 0.990, Contour: 0.993, Ultra 2: 0.990). Error-grid analysis according to Parkes and Clarke revealed both 100% of the readings to be within the clinically acceptable areas (Clarke: A + B with BG*Star (100 + 0), Aviva (97 + 3), and Contour (97 + 3); and 99.5% with iBG*Star (97.5 + 2), Freedom Lite (98 + 1.5), and Ultra 2 (97.5 + 2)). Conclusions: This study demonstrated the very high accuracy of BG*Star, iBG*Star, and the competitive blood glucose meters in a clinical setting.

Prefilled insulin device with reduced injection force: patient perception and accuracy.

ABSTRACT Objective: The injection force and the patient perception of the Next Generation FlexPen* (NGFP) with design modifications aimed at reducing injection force was assessed. The accuracy and precision of the NGFP was also tested under standard conditions. * FlexPen is a registered trade name of Novo Nordisk A/S, Bagsværd, Denmark Research design and methods: Dosing accuracy was tested (according to ISO 11608 requirements) at 1 IU, 30 IU and 60 IU doses (acceptable limits were 1 ± 1 IU (0–2 IU), 30 ± 1.5 IU (28.5–31.5 IU), and 60 ± 3 IU (57–63 IU)). Pens were tested at reference conditions (18–28°C and relative humidity 25–75%). Delivered doses were measured on a sensitive balance and corrected for the specific density of the insulin aspart used (according to ISO 11608-1). Precision was calculated from the variance around the mean delivered dose. The injection force of NGFP was measured, and user-preference of NGFP and FlexPen (FP) were compared in 50 patients with type 2 diabetes. Results: The mean injection force with NGFP and FP was 12.57 ± 1.81 N and 17.90 ± 1.51 N ( p < 0.001), respectively. Almost twice as many patients rated the injection force as ‘good’ or ‘very good’ with NGFP (80%, 72% and 38% when delivering 20 IU, 40 IU and 60 IU, respectively) compared with FP (48%, 32% and 20% when delivering 20 IU, 40 IU and 60 IU, respectively) and 76% of patients rated NGFP as superior, in terms of simplicity and comfort, to FP. NGFP accurately delivered the set doses (means [SD] were 0.98 [0.06] IU, 29.98 [0.18] IU, and 59.93 [0.24] IU for the 1 IU, 30 IU and 60 IU doses, respectively). Conclusions: These results show that NGFP has a 30% reduction in injection force compared with FP and was rated as ‘more simple and comfortable to use’ by patients. Furthermore, NGFP was as accurate and as precise as FP.

Impact of posture and fixation technique on impedance spectroscopy used for continuous and noninvasive glucose monitoring.

Impedance spectroscopy allows for the assessment of changes in the permittivity and conductivity of erythrocyte cell membranes, induced by blood glucose variations. This study was performed to evaluate the potential influence of motion-induced microvascular blood flow variations from different forearm postures on the PENDRA (Pendragon Medical AG, Zürich, Switzerland) signal. Fifteen volunteers without diabetes were included (seven female, eight male, mean +/- SD age 33.3 +/- 9.9 years, body mass index 24.8 +/- 3.0 kg/m(2)). PENDRA devices were fixed at both upper extremities with different fixation techniques (bracelet and adhesive tape). Standardized position changes of the upper extremities were performed to induce variations in cutaneous microcirculation, which were assessed by laser-Doppler-fluxmetry with different probe temperatures on the forearm. Changes in microcirculation were seen in some of the different motion procedures: supine to hanging, 61.1 +/- 29.9 arbitrary units (AU) to 46.2 +/- 24.8 AU at 37 degrees C and 15.9 +/- 13.0 AU to 13.4 +/- 10.1 at skin temperature (P < 0.01 for both probes); supine to upright, 80.5 +/- 55.4 AU to 74.9 +/- 43.8 AU (not significant) at 37 degrees C and 18.7 +/- 16.8 AU to 20.9 +/- 16.1 AU at skin temperature (P < 0.01). An initially observed subtle influence of microcirculation variations on the impedance signal was minimized when the device was fixed by both bracelet and tape. Other influencing factors (such as temperature, local anatomy, etc.) are addressed in the complex calibration procedure. Well-educated patients might be the best candidates for first using the device for continuous glucose monitoring. They may especially benefit from the trend indication and the hypoglycemia/hyperglycemia threshold and alarm functions.

Pilot Study for Assessment of Optimal Frequency for Changing Catheters in Insulin Pump Therapy—Trouble Starts on Day 3

Background: Continuous subcutaneous insulin infusion (CSII) by means of insulin pump devices is considered to be one of the most optimal therapies to achieve treatment targets in patients with diabetes mellitus. In CSII, the insulin is delivered through Teflon catheters or steel needle infusion sets, which need to be renewed on a regular basis. This pilot study was performed to investigate the optimal change frequency in daily practice and to explore potential problems that may occur when the sets are used for a more prolonged time than the recommended up to 72 hours of usage (Teflon catheters). Method: Twelve patients with type 1 diabetes participated in the trial [age (mean ± STD): 40.3 ± 12.6 years, body mass index: 26.2 ± 3.3 kg/m2, hemoglobin A1c: 6.7 ± 0.6%]. They were asked to wear their infusion set (Comfort™ or Silhouette®) for increasing periods of 1, 2, 3, 4, and 5 days. After each use, patients completed standardized questionnaires regarding technical and medical issues associated with infusion set use. A health care professional investigated the infusion sites and infusion sets and completed an “infusion set inspection” questionnaire. Blood glucose was measured and recorded to assess a potential Influence of duration of catheter use on glycemic control. Results: Infusion set and injection site problems (itching, bruising, swelling, and pain) started to occur in measurable amounts on the 3rd day of catheter use, and about 40% of patients reported significant issues when using a catheter for 5 days. In parallel, there was a consistent increase in mean daily blood glucose levels that correlated with the number of days of catheter use (e.g., day 1: 7. 5 ± 3.8 mmol/liter, day 3: 8.4 ± 4.2 mmol/liter, day 5: 9.0 ± 4.0 mmol/liter, day 7: 11.6 ± 2.2 mmol/liter, p < 0.05 vs day 1). Conclusions: Using the catheters for 2 days resulted in a safe and well-tolerated therapy. Clinically relevant adverse events started to occur during the 3rd day and their incidence increased constantly with longer use. This was associated with undesired changes in mean glycemic control. Data support the recommendation by the drug and device manufacturers that insulin pump catheters should only be used for 48–72 hours to avoid adverse events and potential metabolic deterioration.