In Silico Examination of Initiation of Long-Acting Insulin Analogs Toujeo Compared to Lantus Under 3 Dosing Titration Rules in Virtual Type 2 Diabetes Subjects.

BACKGROUND: Despite the benefits and clinical necessity of insulin treatment in type 2 diabetes (T2D), healthcare providers are reluctant to initiate insulin, and patients are reluctant to start it for several reasons, one of these being the complexity of insulin treatment. Patients and their healthcare providers can benefit from titration algorithms (TAs) or rules that assist with the initiation and titration of insulin, performing the calculations that are needed to safely initiate and conservatively adjust. METHODS: The primary objective for this in silico study was to examine the effectiveness of 3 dose TAs (1-3) for optimization of basal insulin glargine (Gla-100 and Gla-300). In the simulations, 100 virtual subjects with T2D were included (50% men, age 62 ± 3 years, HbA1c 8.1% ± 2.9%, body weight 94 ± 16 kg). Subjects were studied under each TA (TA1 and TA2 fasting blood glucose [FBG] targets 90-130 mg/dL, TA3 FBG target 110-150 mg/dL). Initial dose of both insulins was based on 0.2 U/kg body weight. During 3 months, subjects reported their FBG to the LTHome web-based dose guidance system with a rules engine to safely guide long-acting insulin titration and maintenance. Subjects followed dose recommendations to reach designated FBG target ranges. RESULTS: All subjects reached stable doses under all TAs with both Gla-100 and Gla-300 insulin, and 93 or more of the 100 subjects, depending on the assigned TA, achieved the target FBG range within the 3-month simulation for all TAs. Mean FBG was lowered (Gla-100: 155 ± 40 to 118 ± 11 mg/dL with TA1 and TA2 and 132 ± 12 mg/dL for TA3; Gla-300: 125 ± 14 with TA1 and TA2 and 134 ± 15 mg/dL with TA3). Calculated HbA1c improved from 8.1% ± 2.9% to 7.1% ± 2.5% for TA1 and TA2 and 7.5% ± 2.5% for TA3, a reduction of 0.9% and 0.6% over 3 months for both insulins. Three subjects on Gla-100 and one subject on Gla-300 experienced mild hypoglycemia. CONCLUSION: All TAs delivered safe dose recommendations with minimal hypoglycemia, leading to a stable glucose control in the majority of subjects.

A Randomized Controlled, Treat-to-Target Study Evaluating the Efficacy and Safety of Insulin Glargine 300 U/mL (Gla-300) Administered Using Either Device-Supported or Routine Titration in People With Type 2 Diabetes.

BACKGROUND: The efficacy/safety of device-supported versus routine titration with Gla-300 in type 2 diabetes (T2DM) was evaluated. METHOD: AUTOMATIX was a 16-week, randomized, open-label, parallel-group, multicenter, noninferiority trial in insulin-treated or insulin-naïve people with T2DM. The fasting self-monitored plasma glucose (FSMPG) target was 90-130 mg/dL (5.0-7.2 mmol/L). Primary endpoint: proportion of participants achieving target FSMPG at week 16 without severe hypoglycemia. Secondary endpoints included: proportion reaching FSMPG target without confirmed (≤70 mg/dL [≤3.9 mmol/L]) or severe hypoglycemia; time to first achieve FSMPG target; mean FSMPG and HbA1c change (baseline to week 16). Safety endpoints included hypoglycemia and adverse events. Patient-reported outcomes (PROs) were also assessed. RESULTS: Participants were randomized to device-supported (n = 75) or routine titration (n = 76); 17 participants in the device-supported group discontinued device use. Noninferiority was achieved for the primary endpoint (device-supported: 45.9%, routine: 36.8%; weighted difference: 9.04 [95% CI: -6.75, 24.83]), but not superiority (P = .262). The proportion reaching FSMPG target range without confirmed (≤70 mg/dL [≤3.9 mmol/L]) or severe hypoglycemia was 34.3% vs 14.5%, respectively. The time at which 50% of the participants achieved the FSMPG target was less in the device-supported than routine titration arm (10 vs 13 weeks). Least squares mean HbA1c reduction, safety profiles, and PROs were similar in both arms. Mean "ease of use" score for the device, assessed by healthcare professionals and participants on a scale of 1-7, was ≥6. CONCLUSIONS: Device-supported self-titration had a good safety/efficacy profile, and was noninferior to routine titration and well accepted by diabetes specialists and patients.

Evaluation of Four Blood Glucose Monitoring Systems for Self-Testing with Built-in Insulin Dose Advisor Based on ISO 15197:2013: System Accuracy and Hematocrit Influence.

BACKGROUND: Self-monitoring of blood glucose (SMBG) is important in diabetes therapy; however, not all SMBG systems are sufficiently accurate. In addition, some SMBG systems are influenced by the user's hematocrit value. METHODS: System accuracy and hematocrit influence was evaluated for four SMBG systems with built-in insulin dose advisors (Accu-Chek® Aviva Expert [1], FreeStyle InsuLinx [2], FreeStyle Precision Neo [3], MyStar DoseCoach® [4]) based on International Organization for Standardization (ISO) 15197:2013 section 6.3 (system accuracy) and 6.4.3 (packed cell volume [hematocrit]) with three test strip lots for each system. Two different established comparison methods were used to investigate a possible impact of the comparison method on analytical performance data. RESULTS: Two systems (2, 4) fulfilled ISO 15197:2013 accuracy criteria when the manufacturer's comparison measurement method was applied and showed with all three tested lots 97% to 99.5% of results within ±15 mg/dL and ±15% of the comparison measurement results at blood glucose (BG) concentrations <100 and ≥100 mg/dL, respectively, and 100% of results within consensus error grid zones A and B. Regarding hematocrit influences, two systems (3, 4) showed with all three tested lots ≤10 mg/dL and ≤10% difference between the test sample and the respective control sample for BG concentrations <100 and ≥100 mg/dL, respectively, when using the manufacturer's comparison measurement method. CONCLUSIONS: When using the manufacturer's comparison measurement method, two out of four SMBG systems fulfilled the minimum system accuracy requirements of ISO 15197:2013. In addition, varying hematocrit levels can affect measurement results with some SMBG systems with built-in insulin dose advisors.

Improved Glycemic Control in a Patient Group Performing 7-Point Profile Self-Monitoring of Blood Glucose and Intensive Data Documentation: An Open-Label, Multicenter, Observational Study.

INTRODUCTION: Regular self-monitoring of blood glucose (SMBG) is recommended as an integral part of therapy for all patients with diabetes treated with insulin. In the current study, the effects on glycemic control of taking 7-point SMBG profiles and using a diabetes management system (DMA) on a smartphone were investigated. METHODS: In a 12-week, open-label, multicenter, observational study, 51 patients [26 with type 1 diabetes mellitus (T1DM) and 25 with type 2 diabetes mellitus (T2DM)] were instructed to perform SMBG at least seven times a day using DMA combined with the iBGStar ® SMBG system. HbA1c was measured at regular visits to the study sites. Patients reviewed and managed their data as well as their treatment on their own and there were no further assistance or treatment recommendations. Adverse events (AEs) were recorded throughout. RESULTS: Overall, mean (SD) change from baseline in HbA1c at week 12 was -0.46 (0.57)% [-5 (6) mmol/mol (p < 0.0001)]. The change in HbA1c was observed in patients with T1DM [-0.27 (0.45)% (-3 [5] mmol/mol; p = 0.0063)] and T2DM [-0.65 (0.62)% (-7 [7] mmol/mol; p < 0.0001)]. The change in HbA1c was not correlated with an increased number of hypoglycemic events (blood glucose less than 55 mg/dL). The majority of AEs were symptomatic hypoglycemic events (42 events; nine patients). CONCLUSIONS: Glycemic control can be improved, without receiving any recommendations or advice on insulin dose, by performing daily 7-point SMBG profiles and using electronic documentation with a smartphone app. These results must be confirmed in a larger controlled trial, but they already strengthen the importance of structured SMBG in diabetes therapy. FUNDING: Sanofi.

Strengths and Limitations of New Approaches for Graphical Presentation of Blood Glucose Monitoring System Accuracy Data.

Graphical presentation of blood glucose monitoring systems' (BGMSs) accuracy typically includes difference plots (DPs). Recently, 3 new approaches were presented: radar plots (RPs), rectangle target plots (RTPs), and surveillance error grids (SEGs). BGMS data were modeled based on 3 scenarios that can be encountered in real life to highlight strengths and limitations of these approaches. Detailed assessment of BGMS data may be easier in plots with individual data points (DPs, RPs, SEGs), whereas RTPs may facilitate display of large amounts of data or comparison of BGMS. SEGs have the advantage of assessing clinical risk. The selection of a specific type depends mostly on the kind of information sought (eg, accuracy in specific concentration intervals, lot-to-lot variability, clinical risk) as there is no "absolute best" approach.

Real-World Data Collection Regarding Titration Algorithms for Insulin Glargine in Patients With Type 2 Diabetes Mellitus.

The primary objective of this study was to collect data regarding the effectiveness of different dose titration algorithms (TAs) for optimization or initiation of basal insulin supported oral therapy (BOT) in patients with type 2 diabetes. A total of 50 patients were enrolled in this trial (17 women, 33 men, age 63 ± 8 years, HbA1c 7.9 ± 0.8%). The investigator decided on an individual basis to apply any of 4 standard TAs: standard (S: fasting glucose target 90-130 mg/dL, n = 39), standard-fast titration (S-FT: 90-130 mg/dL, larger dose increments at FBG < 180 mg/dl, n = 1), less tight (LT: 110-150 mg/dL, n = 5), and tight (T: 70-100 mg/dL, n = 5). During the next 30 days daily contacts were used to adapt the insulin dose. The majority of all patients (70%) achieved a stable insulin glargine dose within 5 ± 6 days after initiation of the dose titration. HbA1c improved from 7.9 ± 0.8% to 7.5 ± 0.7% (P < .001). In total, 1300 dose decisions were made (1192 according to the TA and 108 by the physicians independently from the TA in 29 patients [58% of study population]). Reasons for TA-overruling dosing decisions were hypoglycemic events (14 mild/4 moderate) in 9 patients. In the majority of these cases (89.8%), the physician recommended continuation of the previous dose or a higher dose. The majority of FBG values were within the respective target range after 4 weeks. In conclusion, the insulin glargine TAs delivered safe dose recommendations with a low risk of hypoglycemia, which successfully led to a stable dose in the vast majority of patients.

Evaluation of a Methodology for Estimating HbA1c Value by a New Glucose Meter.

BACKGROUND: Accuracy/robustness of HbA1c estimation (eA1c) with an algorithm built into the MyStar Extra blood glucose (BG) meter has been demonstrated by in silico testing. We evaluated the performance and use of eA1c in a clinical setting. METHODS: Subjects took the BG meter home for 4 months to obtain eA1c in this open-label, single-center study. Laboratory HbA1c values were obtained approximately every 2 weeks and the corresponding eA1c documented. Subjects completed a questionnaire at study end (NCT01885546). RESULTS: There were 133 enrolled subjects (mean [SD] age 60.0 [15.0] years, 69 males, 104 with diabetes, HbA1c 7.0% [1.4]). A total of 1008 pairs of eA1c and laboratory HbA1c values were available. In subjects with diabetes, 97.5% of the eA1c results fell within ± 20% of the laboratory HbA1c, 95.0% within ± 18%, and 90.7% within ± 15%. When results were limited to the reportable HbA1c range of ≥ 6 to ≤ 10%, 99.3% of eA1c values fell within ± 20% of the laboratory HbA1c, 98.5% within ± 18%, and 96.2% within ± 15% Most subjects agreed/strongly agreed that the eA1c section in the user guide and flash cards was easy to follow (72%), they would use the system to track their eA1c (70%), they found the eA1c tool helpful (79%), and the tool may motivate them to manage their diabetes better (83%). CONCLUSIONS: Accuracy of the eA1c feature in this clinical setting was similar to the performance in silico. The majority of subjects found this tool helpful and agreed it may motivate to manage their diabetes better.

Initial experience and evaluation of reusable insulin pen devices among patients with diabetes in emerging countries.

BACKGROUND: Many individuals with type 2 diabetes in emerging countries are transitioning from vial-and-syringe insulin delivery to that of insulin pens (disposable or reusable). As with all insulin delivery methods, patient preferences and comfort are of utmost importance to optimize adherence to treatment. Patient-preferred characteristics for reusable insulin pens and barriers to appropriate injection, particularly in these regions, have not been widely reported in the clinical literature, highlighting a key information gap for clinicians considering these methods as part of a comprehensive diabetes management approach. METHODS: Face-to-face interviews were conducted with people with type 1/2 diabetes, including insulin-naïve and established insulin users. After moderator demonstration, participants were evaluated on their ability to perform a six-step process to inject a 10-unit dose into a pad with the AllStar(®) (AS; Sanofi, Mumbai, India), HumaPen Ergo II(®) (HE2; Eli Lilly, Indianapolis, USA), and NovoPen 4(®) (NP4; Novo Nordisk, Bagsværd, Denmark) pens. Local pens were also tested in India, China and Brazil. RESULTS: A total of 503 people from India, Malaysia, Brazil, Egypt, and China participated. Participants completed the six-step process in an average, 2-3 min per pen. Participants ranked ease of overall use and ease of self-injection and dialing/reading dose as most important features for new insulin pens. When using the pens, the most difficult step was priming/safety testing, with 7-12% failing and 28-40% having difficulty; 6%, 18%, and 22% failed to hold the injection button down for the required period of time using AS, NP4, and HE2, respectively. Participants ranked AS significantly higher for nine of 12 ease-of-use features including three of the top four features considered the most important for reusable pens, while HE2 was ranked higher for two features. Local pens were ranked lowest. CONCLUSIONS: Priming the pen and injecting the dose imparted most difficulty for people with diabetes in emerging countries. Most participants found AS easiest to use overall, with differences noted between pens for individual steps of dose delivery. Identifying characteristics most preferred by patients may assist in improving adherence to insulin therapy.

Accuracy and robustness of dynamical tracking of average glycemia (A1c) to provide real-time estimation of hemoglobin A1c using routine self-monitored blood glucose data.

BACKGROUND: Laboratory hemoglobin A1c (HbA1c) assays are typically done only every few months. However, self-monitored blood glucose (SMBG) readings offer the possibility for real-time estimation of HbA1c. We present a new dynamical method tracking changes in average glycemia to provide real-time estimation of A1c (eA1c). MATERIALS AND METHODS: A new two-step algorithm was constructed that includes: (1) tracking fasting glycemia to compute base eA1c updated with every fasting SMBG data point and (2) calibration of the base eA1c trace with monthly seven-point SMBG profiles to capture the principal components of blood glucose variability and produce eA1c. A training data set (n=379 subjects) was used to estimate model parameters. The model was then fixed and applied to an independent test data set (n=375 subjects). Accuracy was evaluated in the test data set by computing mean absolute deviation (MAD) and mean absolute relative deviation (MARD) of eA1c from reference HbA1c, as well as eA1c-HbA1c correlation. RESULTS: MAD was 0.50, MARD was 6.7%, and correlation between eA1c and reference HbA1c was r=0.76. Using an HbA1c error grid plot, 77.5% of all eA1c fell within 10% from reference HbA1c, and 97.9% fell within 20% from reference. CONCLUSIONS: A dynamical estimation model was developed that achieved accurate tracking of average glycemia over time. The model is capable of working with infrequent SMBG data typical for type 2 diabetes, thereby providing a new tool for HbA1c estimation at the patient level. The computational demands of the procedure are low; thus it is readily implementable into home SMBG meters. Real-time HbA1c estimation could increase patients' motivation to improve diabetes control.

Evaluation of the effects of insufficient blood volume samples on the performance of blood glucose self-test meters.

BACKGROUND: Accuracy of blood glucose readings is (among other things) dependent on the test strip being completely filled with sufficient sample volume. The devices are supposed to display an error message in case of incomplete filling. This laboratory study was performed to test the performance of 31 commercially available devices in case of incomplete strip filling. METHODS: Samples with two different glucose levels (60-90 and 300-350 mg/dl) were used to generate three different sample volumes: 0.20 µl (too low volume for any device), 0.32 µl (borderline volume), and 1.20 µl (low but supposedly sufficient volume for all devices). After a point-of-care capillary reference measurement (StatStrip, NovaBiomedical), the meter strip was filled (6x) with the respective volume, and the response of the meters (two devices) was documented (72 determinations/meter type). Correct response was defined as either an error message indicating incomplete filling or a correct reading (±20% compared with reference reading). RESULTS: Only five meters showed 100% correct responses [BGStar and iBGStar (both Sanofi), ACCU-CHEK Compact+ and ACCU-CHEK Mobile (both Roche Diagnostics), OneTouch Verio (LifeScan)]. The majority of the meters (17) had up to 10% incorrect reactions [predominantly incorrect readings with sufficient volume; Precision Xceed and Xtra, FreeStyle Lite, and Freedom Lite (all Abbott); GlucoCard+ and GlucoMen GM (both Menarini); Contour, Contour USB, and Breeze2 (all Bayer); OneTouch Ultra Easy, Ultra 2, and Ultra Smart (all LifeScan); Wellion Dialog and Premium (both MedTrust); FineTouch (Terumo); ACCU-CHEK Aviva (Roche); and GlucoTalk (Axis-Shield)]. Ten percent to 20% incorrect reactions were seen with OneTouch Vita (LifeScan), ACCU-CHEK Aviva Nano (Roche), OmniTest+ (BBraun), and AlphaChek+ (Berger Med). More than 20% incorrect reactions were obtained with Pura (Ypsomed), GlucoCard Meter and GlucoMen LX (both Menarini), Elite (Bayer), and MediTouch (Medisana). CONCLUSIONS: In summary, partial and incomplete blood filling of glucose meter strips is often associated with inaccurate reading. These findings underline the importance of appropriate patient education on this aspect of blood glucose self-monitoring.

Blood glucose meters employing dynamic electrochemistry are stable against hematocrit interference in a laboratory setting.

BACKGROUND: Hematocrit (HCT) is known to be a confounding factor that interferes with many blood glucose (BG) measurement technologies, resulting in wrong readings. Dynamic electrochemistry has been identified as one possible way to correct for these potential deviations. The purpose of this laboratory investigation was to assess the HCT stability of four BG meters known to employ dynamic electrochemistry (BGStar and iBGStar, Sanofi; Wavesense Jazz, AgaMatrix; Wellion Linus, MedTrust) in comparison with three other devices (GlucoDock, Medisana; OneTouch Verio Pro, LifeScan; FreeStyle Freedom InsuLinx, Abbott-Medisense). METHODS: Venous heparinized blood was immediately aliquoted after draw and manipulated to contain three different BG concentrations (60-90, 130-160, and 280-320 mg/dl) and five different HCT levels (25%, 35%, 45%, 55%, and 60%). After careful oxygenation to normal blood oxygen pressure, each of the resulting 15 different samples was measured six times with three devices and three strip lots of each meter. The YSI Stat 2300 served as laboratory reference method. Stability to HCT influence was assumed when less than 10% difference occurred between the highest and lowest mean glucose deviations in relation to HCT concentrations [hematocrit interference factor (HIF)]. RESULTS: Five of the investigated self-test meters showed a stable performance with the different HCT levels tested in this investigation: BGStar (HIF 4.6%), iBGStar (6.6%), Wavesense Jazz (4.1%), Wellion Linus (8.5%), and OneTouch Verio Pro (6.2%). The two other meters were influenced by HCT (FreeStyle InsuLinx 17.8%; GlucoDock 46.5%). CONCLUSIONS: In this study, meters employing dynamic electrochemistry, as used in the BGStar and iBGStar devices, were shown to correct for potential HCT influence on the meter results. Dynamic electrochemistry appears to be an effective way to handle this interfering condition.

The precision study: examining the inter- and intra-assay variability of replicate measurements of BGStar, iBGStar and 12 other blood glucose monitors.

OBJECTIVE: Self-monitoring of blood glucose is a key element in diabetes management. Accurate and precise performance of blood glucose monitors (BGMs) ensures that valid values are obtained to guide treatment decisions by patients and physicians. BGStar and iBGStar are hand-held BGMs that use dynamic electrochemistry to correct for potential interferences and thereby minimize system errors. RESEARCH DESIGN AND METHODS: A single-center, in vitro diagnostic device performance evaluation with heparinized oxygenated venous blood samples (intra-assay precision) and control solutions (interassay precision) was performed in a laboratory setting, comparing BGStar and iBGStar with 12 competitors. MAIN OUTCOME MEASURES: The primary outcome was the coefficient of variation percent (CV%) of the BGMs investigated. RESULTS: In inter-assay precision analyses, all but GlucoMen LX had a CV <5%, and in intra-assay precision analyses, 10 of the 14 devices tested had CV <5%. BGStar and iBGStar had a CV <5% in both the inter- and intra-assay precision analyses. The smallest variation was found in the near-normoglycemic glucose range (5.3 - 8.0 mmol/l) for both BGStar and iBGStar in the inter-assay precision analysis. CONCLUSIONS: BGStar and iBGStar were proven to have very good inter-assay and high intra-assay precision, demonstrating low scattering of replicate measurements with both clinical samples and control solutions.

Common standards of basal insulin titration in type 2 diabetes.

Type 2 diabetes mellitus has become a worldwide major health problem, and the number of people affected is steadily increasing. Thus, not all patients suffering from the disease can be treated by specialized diabetes centers or outpatient clinics, but by primary care physicians. The latter, however, might have time constraints and have to deal with many kinds of diseases or with multimorbid patients, so their focus is not so much on lowering high blood glucose values. Thus, the physicians, as well as the patients themselves, are often reluctant to initiate and adjust insulin therapy, although basal insulin therapy is considered the appropriate strategy after oral antidiabetic drug failure, according to the latest international guidelines. A substantial number of clinical studies have shown that insulin initiation and optimization can be managed successfully by using titration algorithms-even in cases where patients themselves are the drivers of insulin titration. Nevertheless, tools and strategies are needed to facilitate this process in the daily life of both primary health care professionals and patients with diabetes.

Determination of hematocrit interference in blood samples derived from patients with different blood glucose concentrations.

BACKGROUND: We performed a blood glucose meter hematocrit (HCT) interference test with lower sample manipulation requirements by using blood samples from patients with different blood glucose (BG) levels. METHODS: Blood from five patients with different BG levels (2.8, 5.6, 8.3, 13.9, 19.4 mmol/liter) was manipulated to contain five different HCT concentrations (35/40/45/50/55%). Each sample was measured three times in parallel with 14 BG testing devices (reference method: YSI 2300 STAT Plus™ Glucose Analyzer). The largest mean deviations in both directions from the reference method (normalized to 100% at 45% HCT) were added as a measure for hematocrit interference factor (HIF). A HIF >10% was considered to represent clinically relevant HCT interference. RESULTS: Few devices showed no clinically relevant HCT interference at high/low BG levels: BGStar® (7.2%, 7.3%), iBGStar® (9.0%, 8.6%), Contour® (10.0%, 4.6%), OneTouch® Verio™ 2 (10.0%, 5.2%), and GlucoMen® LX (7.2%, 5.1%). Other devices showed interference at one or both glucose ranges: ACCU-CHEK® Aviva (12.6%, 10.7%), Aviva Nano (7.2%, 10.5%), Breeze2 (3.6%, 30.2%), GlucoCard G+ (12.6%, 7.0%), OneTouch® Ultra®2 (12.6%, 25.6%), FreeStyle Freedom Lite® (9.0%, 11.0%), Precision Xceed (16.2%, 15.3%), and MediTouch® (19.8%, 28.0%). The deviations in all devices were less pronounced in the HCT range of 35-50%. CONCLUSIONS: The results of this trial with less sample manipulation (HCT only) confirmed previous examinations with HCT and glucose manipulation. The same devices showed HCT stability as previously observed. Artificial sample manipulation may be less crucial than expected when evaluating HCT interference.

Reduction of postprandial glycemic excursions in patients with type 1 diabetes: a novel human insulin formulation versus a rapid-acting insulin analog and regular human insulin.

BACKGROUND: Evaluation of postprandial glycemic excursions in patients with type 1 diabetes with three prandial insulins: VIAject™ (Linjeta™), an ultra-fast insulin (UFI); insulin lispro (LIS); and regular human insulin (RHI). METHODS: After stabilization of preprandial glycemia, 18 patients received a subcutaneous injection with an individualized insulin dose prior to a meal. RESULTS: Injection of UFI resulted in a more rapid insulin absorption than with either LIS or RHI (time to half-maximal insulin levels: 13.1 ± 5.2 vs 25.4 ± 7.6 and 38.4 ± 19.5 min; p = .001 vs LIS and p < .001 vs RHI, LIS vs. RHI p < .001). Maximal postprandial glycemia was lower with UFI (0-180 min; 157 ± 30 mg/dl; p = .002 vs RHI) and LIS (170 ± 42 mg/dl; p = .668 vs RHI) than after RHI (191 ± 46 mg/dl; RHI vs LIS p = .008). The difference between maximum and minimum glycemia was smaller with UFI (70 ± 17 mg/dl) than with either RHI (91 ± 33 mg/dl; p = .007 vs UFI) or LIS (89 ± 18 mg/dl; p = .011 vs UFI). Also, the area under the blood glucose profile was lower with UFI than with RHI (0-180 min; 21.8 ± 5.8 vs 28.4 ± 7.6 g·min/dl; p < .001). CONCLUSIONS: The rapid absorption of UFI results in a reduction of postprandial glycemic excursions.

Postprandial vascular effects of VIAject compared with insulin lispro and regular human insulin in patients with type 2 diabetes.

OBJECTIVE: Recent studies suggested an impact of prandial insulin delivery on postprandial regulation of tissue blood flow. This study compared the effect of VIAject with human regular insulin and insulin lispro on postprandial oxidative stress and endothelial function in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Fourteen patients (seven men; aged 61.5 +/- 1.8 years; duration of diabetes 6.6 +/- 4.6 years; A1C 7.2 +/- 0.5% [mean +/- SEM]) received a prandial injection of VIAject, human regular insulin, and insulin lispro. At baseline and after a standardized liquid meal test (Ensure Plus), the postprandial increases in asymmetric dimethylarginine (ADMA) and nitrotyrosine levels were investigated. In addition, the postprandial effects on microvascular blood flow, skin oxygenation, and vascular elasticity were measured. RESULTS: Treatment with VIAject resulted in a significant reduction in the peak postprandial generation of ADMA compared with human insulin and insulin lispro (VIAject -27.3 +/- 22.6, human insulin 97.7 +/- 24.4, and insulin lispro 66.9 +/- 33.9 nmol/l; P < 0.05, respectively). The postprandial increases in nitrotyrosine levels were significantly less after VIAject than after human regular insulin (VIAject -0.22 +/- 0.17 vs. human insulin 0.25 +/- 0.15 microg/ml; P < 0.05), whereas nitrotyrosine after insulin lispro was in between (insulin lispro 0.09 +/- 0.07 microg/ml; NS). In parallel, earlier and more pronounced increases in microvascular blood flow and skin oxygenation were obtained after VIAject compared with those after human insulin or insulin lispro (P < 0.05, respectively). All insulin formulations resulted in comparable improvements in central arterial elasticity. CONCLUSIONS; Treatment with VIAject reduced postprandial oxidative stress and improved endothelial function compared with human regular insulin or insulin lispro.

Intra-individual variability of the metabolic effect of a novel rapid-acting insulin (VIAject) in comparison to regular human insulin.

BACKGROUND: The variability of the metabolic action of insulin after subcutaneous (sc) injection hampers optimal insulin therapy. Insulin formulations with a reduced tendency to form hexamers might exhibit a reduced variability of absorption from the sc insulin depot into the blood stream. METHODS: We investigated the within-subject variability of pharmacodynamic and pharmacokinetic properties of an ultra-fast insulin (UFI) formulation and regular human insulin (RHI) in patients with type 1 diabetes. Fourteen patients participated in six 10-hour euglycemic glucose clamp experiments. In this double-blind, crossover study, subjects were randomly assigned to a sequence of two experimental blocks: each block consisted of three doses of 0.1 IU/kg UFI or RHI, respectively, administered on separate days by abdominal sc injection. RESULTS: Ultra-fast insulin has an earlier onset of action and shorter time to maximal plasma insulin concentration when compared to RHI (tGIR(max) 99 +/- 36 min vs. 154 +/- 74 min, p = 0.002; tC(max) 33 +/- 16 min vs. 97 +/- 39 min, p = 0.00001). The within-subject variability of plasma insulin tC(max) (p = 0.027) and of tGIR(max) (p = 0.022) was less for UFI than for RHI. CONCLUSIONS: In patients with type 1 diabetes, this UFI showed reduced within-subject variability when compared with RHI.