Human Insulin Formulations Research Articles

Equivalent Recombinant Human Insulin Preparations and their Place in Therapy.

Recombinant human insulin was one of the first products of biotechnology. It was developed in response to the need for a consistent and sufficient worldwide supply. Recombinant human insulin replaced the animal insulins and semisynthetic insulins obtained by modification of animal insulins. Bioequivalence studies were required for regulatory approval. Three reference products were independently established during these procedures: Humulin® (Eli Lilly and Co), Novolin® (NovoNordisk) and Insuman® (Sanofi). Numerous brand names have been used during the commercial development of recombinant human insulin formulations. In this review, three current brand names are used for consistent identification. Human insulin for Humulin and Insuman are produced by fermentation in bacteria (Escherichia coli) and for Novolin in yeast (Saccharomyces cerevisiae). The bioequivalence of recombinant human insulin products was investigated in euglycaemic clamp studies. An overview of such bioequivalence studies is provided here. This paper will consider the relevance of human insulin formulations today and their place in therapy.

Effect of protease inhibitors on pulmonary bioavailability of therapeutic proteins and peptides in the rat

The objective of the present study was to evaluate the effect of protease inhibitors on the pulmonary absorption of therapeutic peptides and proteins with varying molecular weights. Dry powder formulations of leuprolide (1.2kD), salmon calcitonin (3.4kD), human insulin (5.8kD), human leptin (16.0kD), and human chorionic gonadotropin (HCG) (36.5kD) were prepared with or without protease inhibitors; aprotinin and bestatin. The formulations were administered intrapulmonary to anesthetized rats. The pharmacokinetics of these proteins were assessed by measuring serum drug concentrations. In addition, in vitro stability of these proteins in rat lung homogenate was assessed using the trifluoroacetic acid method. Bioavailability of leuprolide following pulmonary administration was 75% higher compared to subcutaneously administered leuprolide. Protease inhibitors had little or no effect on the pulmonary bioavailability of leuprolide. However, protease inhibitors (1mg/kg) increased the bioavailability of calcitonin by more than 50%. Similarly, the bioavailabilities of leptin and HCG in the presence of bestatin were increased by 1.9 and 2.1-fold, respectively. Leuprolide was stable both in the lung cytosol and subcellular pellets with about 10% degradation at the end of the study period (4h). In contrast, calcitonin, insulin, leptin and HCG were significantly degraded in the lung cytosol and subcellular pellets. Presence of protease inhibitors in formulation could improve the stability of protein drugs. The results of this study demonstrate that the pulmonary absorption of proteins may be enhanced by the selection of optimal concentration and type of protease inhibitor.

Development of a Transgenic Mouse Model to Study the Immunogenicity of Recombinant Human Insulin

Mouse models are commonly used to assess the immunogenicity of therapeutic proteins and to investigate the immunological processes leading to antidrug antibodies. The aim of this work was to develop a transgenic (TG) Balb/c mouse model for evaluating the immunogenicity of recombinant human insulin (insulin) formulations. Validation of the model was performed by measuring the antibody response against plain and particulate insulin in TG and nontransgenic (NTG) mice. Intraperitoneal administration of insulin (20 μg/dose, 12 doses over a period of 4 weeks) did not break the immune tolerance of the TG mice, whereas it did elicit antibodies in NTG mice. The immune tolerance of TG mice could be circumvented, albeit at low titers, by administering insulin covalently bound to 50-nm polystyrene nanoparticles. The TG mouse model was employed to compare the immunogenicity of oxidized aggregated insulin, oxidized nonaggregated insulin, and three commercially available formulations of insulin variants (i.e., Levemir®, Insulatard®, and Actrapid®). Oxidized insulin, aggregated or nonaggregated, was moderately immunogenic in TG mice (50% and 33% responders, respectively), whereas the immunogenicity of the commercial formulations was low. This model can be used to compare the immunogenicity of insulin formulations and to study immune mechanisms of antibody formation against insulin.

Old and new basal insulin formulations: understanding pharmacodynamics is still relevant in clinical practice

Long-acting insulin analogues have been developed to mimic the physiology of basal insulin secretion more closely than human insulin formulations (Neutral Protamine Hagedorn, NPH). However, the clinical evidence in favour of analogues is still controversial. Although their major benefit as compared with NPH is a reduction in the hypoglycaemia risk, some cost/effectiveness analyses have not been favourable to analogues, largely because of their higher price. Nevertheless, these new formulations have conquered the insulin market. Human insulin represents currently no more than 20% of market share. Despite (in fact because of) the widespread use of insulin analogues it remains critical to analyse the pharmacodynamics (PD) of basal insulin formulations appropriately to interpret the results of clinical trials correctly. Importantly, these data may help physicians in tailoring insulin therapy to patients' individual needs and, additionally, when clinical evidence is not available, to optimize insulin treatment. For patients at low risk for/from hypoglycaemia, it might be acceptable and also cost-effective not to use long-acting insulin analogues as basal insulin replacement. Conversely, in patients with a higher degree of insulin deficiency and increased risk for hypoglycaemia, analogues are the best option due to their more physiological profile, as has been shown in PD and clinical studies. From this perspective optimizing basal insulin treatment, especially in type 2 diabetes patients who are less prone to hypoglycaemia, would be suitable making significant resources available for other relevant aspects of diabetes care.

New Insulins and Insulin Therapy

While the pharmacokinetic properties of the long-acting insulin analogues, insulin glargine and insulin detemir, clearly demonstrate clinical benefits over NPH insulin in terms of reduced frequency of overall and nocturnal hypoglycaemic events and lowered glycaemic variability, several new insulin analogues with even longer and smoother time-action profiles are being developed and explored. Among these, insulin degludec is the first to enter the market. The ultra-long action profile of this insulin analogue is mainly the result of a slow and stable release of insulin degludec monomers from soluble multihexamers that form after subcutaneous administration. In the last year, the results of the first phase II trials with insulin degludec have been published, where the efficacy and safety of this basal insulin analogue have been compared with insulin glargine in patients with type 1 (T1D) and type 2 (T2D) diabetes. With regard to short-acting insulins for mealtime insulin supplementation, there is also a search for new insulins with a more rapid onset of action, and hence improved postprandial glucose control. Linjeta (formerly named VIAject) is a human insulin formulation with faster insulin absorption and action than insulin lispro and regular human insulin. A new drug application to market Linjeta as a treatment for diabetes was submitted to the US Food and Drug Administration (FDA) by the manufacturer at the beginning of 2010. However, the FDA’s review cycle, which was announced late in 2010, concluded that the application could not be approved in its present form. The FDA’s complete response letter included comments related to clinical trials, statistical analysis and chemistry, manufacturing and controls. The FDA requested that the company should conduct two new phase III clinical trials using the commercial formulation, one in patients with T1D and the other in patients with T2D, to establish efficacy and safety with regard to hypoglycaemia and toleration. Co-administration of hyaluronidase together with insulin is another novel concept which has been proven to accelerate the absorption of both insulin lispro and regular human insulin in healthy subjects. In this review, we comment on two recent publications in which the pharmacokinetic and pharmacodynamic characteristics of Linjeta and co-formulations of prandial insulins with recombinant human hyaluronidase were investigated in patients with T1D. Lastly, a recent review on the ongoing discussion regarding insulin treatment and cancer risk is included.

A Review of a Family of Ultra-Rapid-Acting Insulins: Formulation Development

This review summarizes the clinical development of a family of ultra-rapid-acting recombinant human insulin formulations. These formulations use ethylenediaminetetraacetic acid (EDTA) to chelate zinc and thereby destabilize insulin hexamers. In addition, insulin monomer surface charges are chemically masked with citrate to prevent reaggregation. The first phase 1 trials were performed using BIOD-090, an acidic 25 unit U/ml insulin formulation, which contained disodium-EDTA (NaEDTA). When compared with regular human insulin (RHI) and/or insulin lispro in multiple phase 1 studies, BIOD-090 consistently showed more rapid absorption and/or onset of action. A standard meal challenge study also demonstrated improved postprandial glucose profiles associated with BIOD-090. However, increased patient exposure in larger phase 3 trials showed that this formulation was associated with an increased incidence of local injection site reactions, most commonly pain. A next generation formulation, BIOD-100, contained the same excipients as a standard insulin concentration of 100 U/ml. BIOD-100 maintained an ultra-rapid action profile and was associated with modest but significantly improved toleration when compared with BIOD-090. In order to further improve toleration, the hypothesis that NaEDTA contributed to discomfort by chelating endogenous calcium was tested by either substituting calcium-EDTA for NaEDTA or by adding calcium chloride to the NaEDTA formulation. These calcium formulations essentially eliminated the excess discomfort associated with BIOD-090 but were associated with less optimal pharmacokinetic profiles in humans. Recent efforts have succeeded in developing ultra-rapid-acting human insulin formulations with acceptable injection site toleration by optimizing concentrations of calcium (BIOD-125) and with the use of magnesium sulfate to mitigate discomfort (BIOD-123). Similar formulation technology has also been shown to accelerate absorption of insulin analogs in animal models.

Ultra-Rapid Absorption of Recombinant Human Insulin Induced by Zinc Chelation and Surface Charge Masking

In order to enhance the absorption of insulin following subcutaneous injection, excipients were selected to hasten the dissociation rate of insulin hexamers and reduce their tendency to reassociate postinjection. A novel formulation of recombinant human insulin containing citrate and disodium ethylenediaminetetraacetic acid (EDTA) has been tested in clinic and has a very rapid onset of action in patients with diabetes. In order to understand the basis for the rapid insulin absorption, in vitro experiments using analytical ultracentrifugation, protein charge assessment, and light scattering have been performed with this novel human insulin formulation and compared with a commercially available insulin formulation [regular human insulin (RHI)]. Analytical ultracentrifugation and dynamic light scattering were used to infer the relative distributions of insulin monomers, dimers, and hexamers in the formulations. Electrical resistance of the insulin solutions characterized the overall net surface charge on the insulin complexes in solution. The results of these experiments demonstrate that the zinc chelating (disodium EDTA) and charge-masking (citrate) excipients used in the formulation changed the properties of RHI in solution, making it dissociate more rapidly into smaller, charge-masked monomer/dimer units, which are twice as rapidly absorbed following subcutaneous injection than RHI (Tmax 60 ± 43 versus 120 ± 70 min). The combination of rapid dissociation of insulin hexamers upon dilution due to the zinc chelating effects of disodium EDTA followed by the inhibition of insulin monomer/dimer reassociation due to the charge-masking effects of citrate provides the basis for the ultra-rapid absorption of this novel insulin formulation.

New insulins and insulin therapy

New insulins and insulin therapy

Insulin detemir for the treatment of obese patients with type 2 diabetes.

The risk for developing type 2 diabetes (T2DM) is greater among obese individuals. Following onset of the disease, patients with T2DM become more likely to be afflicted with diabetic micro- and macrovascular complications. Decreasing body weight has been shown to lower glycosylated hemoglobin and improve other metabolic parameters in patients with T2DM. Medications used to lower blood glucose may increase body weight in patients with T2DM and this has been repeatedly shown to be the case for conventional, human insulin formulations. Insulin detemir is a neutral, soluble, long-acting insulin analog in which threonine-30 of the insulin B-chain is deleted, and the C-terminal lysine is acetylated with myristic acid, a C14 fatty acid chain. Insulin detemir binds to albumin, a property that enhances its pharmacokinetic/pharmacodynamic profile. Results from clinical trials have demonstrated that treatment with insulin detemir is associated with less weight gain than either insulin glargine or neutral protamine Hagedorn insulin. There are many potential reasons for the lower weight gain observed among patients treated with insulin detemir, including lower risk for hypoglycemia and therefore decreased defensive eating due to concern about this adverse event, along with other effects that may be related to the albumin binding of this insulin that may account for lower within-patient variability and consistent action. These might include faster transport across the blood–brain barrier, induction of satiety signaling in the brain, and preferential inhibition of hepatic glucose production versus peripheral glucose uptake. Experiments in diabetic rats have also indicated that insulin detemir increases adiponectin levels, which is associated with both weight loss and decreased eating.

Insulin detemir for the treatment of obese patients with type 2 diabetes

Insulin detemir for the treatment of obese patients with type 2 diabetes Priscilla A Hollander1,21Baylor Endocrine Center, 2Baylor Medical Center, Dallas, Texas, USAAbstract: The risk for developing type 2 diabetes (T2DM) is greater among obese individuals. Following onset of the disease, patients with T2DM become more likely to be afflicted with diabetic micro- and macrovascular complications. Decreasing body weight has been shown to lower glycosylated hemoglobin and improve other metabolic parameters in patients with T2DM. Medications used to lower blood glucose may increase body weight in patients with T2DM and this has been repeatedly shown to be the case for conventional, human insulin formulations. Insulin detemir is a neutral, soluble, long-acting insulin analog in which threonine-30 of the insulin B-chain is deleted, and the C-terminal lysine is acetylated with myristic acid, a C14 fatty acid chain. Insulin detemir binds to albumin, a property that enhances its pharmacokinetic/pharmacodynamic profile. Results from clinical trials have demonstrated that treatment with insulin detemir is associated with less weight gain than either insulin glargine or neutral protamine Hagedorn insulin. There are many potential reasons for the lower weight gain observed among patients treated with insulin detemir, including lower risk for hypoglycemia and therefore decreased defensive eating due to concern about this adverse event, along with other effects that may be related to the albumin binding of this insulin that may account for lower within-patient variability and consistent action. These might include faster transport across the blood–brain barrier, induction of satiety signaling in the brain, and preferential inhibition of hepatic glucose production versus peripheral glucose uptake. Experiments in diabetic rats have also indicated that insulin detemir increases adiponectin levels, which is associated with both weight loss and decreased eating.Keywords: basal insulin, body mass index, detemir, insulin analog, satiety

Protected Graft Copolymer (PGC) Basal Formulation of Insulin as Potentially Safer Alternative to Lantus® (Insulin-Glargine): A Streptozotocin-Induced, Diabetic Sprague Dawley Rats Study

To develop a long-acting formulation of native human insulin with a similar pharmacodynamics (PD) profile as the insulin analogue insulin glargine (Lantus®, Sanofi-Aventis) with the expectation of retaining native human insulin's superior safety profile as insulin glargine is able to activate the insulin-like growth factor 1 (IGF-1) receptor and is linked to a number of malignancies at a higher rate than regular human insulin. Development of protected graft copolymer (PGC) excipients that bind native human insulin non-covalently and testing blood glucose control obtained with these formulations in streptozotocin-induced diabetic Sprague Dawley rats compared to equally dosed insulin glargine. PGC-formulations of native human insulin are able to control blood glucose to the same extent and for the same amount of time after s.c. injection as the insulin analogue insulin glargine. No biochemical changes were made to the insulin that would change receptor binding and activation with their possible negative effects on the safety of the insulin. Formulation with the PGC excipient offers a viable alternative to biochemically changing insulin or other receptor binding peptides to improve PD properties.

U‐100, pH‐Neutral formulation of VIAject®: faster onset of action than insulin lispro in patients with type 1 diabetes

VIAject® is a formulation of human insulin with a very fast onset of action. Previous studies used VIAject in a concentration of 25 U/ml and a pH of 4 [VIAject 25 (VJ25)]. Objective of this double blind, three-way crossover study was to compare the pharmacodynamic/pharmacokinetic properties of a novel formulation of VIAject with a concentration of 100 U/ml and a neutral pH [VIAject 7 (VJ7)] with VJ25 and insulin lispro (LIS). Forty-three patients with type 1 diabetes [aged 43 (21-65) years, BMI 24.1 (20-28) kg/m(2) and HbA1c 7.5 (5.7-9.5) %] participated in this study. They received subcutaneous injections of 12 U of each insulin formulation under euglycaemic glucose clamp conditions. VJ7 was bioequivalent to VJ25 [90% confidence interval (CI) of the ratios for total insulin AUCs and maximum insulin concentration (C(INS max) ) was within 0.80-1.25]. VJ7 showed a faster absorption compared to LIS [time to C(INS max) 23 vs. 60 min; difference (CI) -30 (-35 to -23)] and faster onset of action [time to early half-maximal glucose infusion rate (GIR) 25 vs. 44 min; -18 (-26 to -10)], and a higher AUC of glucose infusion rate (AUC(GIR) ) in the first 60 min after injection [176 vs. 107 mg/kg; ratio 1.65 (1.27 to 2.14)], contributing to a slightly higher value for AUC(GIR 0-480) [1263 vs. 1095 mg/kg; 1.15 (1.06 to 1.26)]. Maximum GIR was similar between VJ7 and LIS [6.1 vs.6.6 mg/kg/min; ratio 0.93 (0.86 to 1.01)], whereas the duration of action (t(GIR50%-late) ) was longer with VJ7 [274 vs. 228 min; 50 (25 to 73)]. This formulation of VIAject is bioequivalent to the previously used formulation and has a faster absorption/onset of action than LIS.

Management of diabetes across the course of disease: minimizing obesity-associated complications.

Obesity increases the risk for developing type 2 diabetes mellitus (T2DM) and this in turn correlates with an elevated probability of long-term diabetes complications once diabetes is established. Interventions aimed at lowering weight via changes in diet and lifestyle have repeatedly been shown to improve glycemic control in patients with T2DM and even to reverse early disease. Weight gain, a potential side effect of treatment for patients with T2DM, is also an important concern, and it has been noted that weight increases associated with antidiabetes therapy may blunt cardiovascular risk reductions achieved by decreasing blood glucose. Among older agents, metformin and acarbose have the lowest risk for weight gain, while sulfonylureas, meglitinides, and thiazolidinediones are all associated with weight increases. Clinical trial results have also consistently demonstrated that treatment with glucagon-like peptide-1 receptor agonists and amylin lowers weight, and that dipeptidyl peptidase-4 inhibitors are weight neutral in patients with T2DM. Conventional human insulin formulations are known to increase weight in patients with T2DM. However, some insulin analogs, particularly insulin detemir, have lower liability for this adverse event. The use of both pharmacologic and surgical therapies aimed at treating obesity rather than lowering blood glucose have the potential to improve glycemic control and even resolve T2DM in some patients.

New insulins and insulin therapy

The introduction of the so-called 'designer' insulins, the insulin analogues, has offered new opportunities in the clinical management of diabetes. Two additional new entities are close to reaching clinical practice. Linjeta™ (formally called VIAject) is not an analogue but rather a different formulation of human insulin which may give it a more rapid onset of action, potentially even faster than the currently available rapid-acting insulin analogues. Degludec™, on the other hand, is an insulin analogue molecule with an ultra-long clinical profile derived from the soluble multi-hexamer formation, resulting in a continuous slow and stable release of insulin degludec monomers which may last longer than currently available long-acting analogues. As with any new type of drug, the safety of the 'designer' insulins has to be closely scrutinised. Last year the increased cancer risk in diabetes entered the spotlight and the potential role of insulin analogues led to controversial discussions. In spite of recent new in vitro and observational data no new conclusive evidence became available. The need for multiple well-conducted and appropriately designed prospective observational studies to follow up the effectiveness and safety of the new insulins and the new insulin treatment regimens remains. In this chapter it was our mission to chose articles published about "new insulins" over the last year that have the most important contribution for the on-going development of ultra-fast- and ultra-long-acting insulin analogs and preparations and their potential side-effects, particularly cancer. This has been done by means of PubMed searches as well as a review of abstracts of the recent large international diabetes meetings such as ADA, EASD and ISPAD.

Coverage of insulin delivery devices and basal insulin analogs by US managed care organizations

Objective:The perception in the US is that insulin formulations prescribed for type 1 and type 2 diabetes and delivered via insulin pens are more costly to patients than the same or similar products provided in vials, and that basal insulin analogs offered either in pens or vials are likewise more costly to patients than human insulin formulations. This study compares levels of coverage and copays by private and Medicare Part D plans for insulin pens and vials containing basal insulin analogs and for NPH formulations in vials.Methods:A commercially available formulary database (Access Point, Pinsonault Associates; updated quarterly) was analyzed as of January 2010 for private insurance plans and as of March 2010 for Medicare Part D plans. Analyses were performed for Tier-level coverage and copays per prescription for basal insulin analogs in pens and vials, and NPH in vials.Results:Basal insulin analogs in pens were covered by >91% of private and Part D plans. NPH coverage was reported by >92% of private plans and 69–95% of Part D plans, depending on brand. Irrespective of delivery mode, copays in the majority of private plans for basal insulin analogs and NPH were in the >$10–35 range. Copays were higher in Part D plans, with the majority of plans and subscribers in a >$35–50 range. Prior authorization was required by <10% of insurance plans for insulin analog pen prescriptions, and <3% of plans for insulin analog or NPH prescriptions in vials.Limitations:This analysis was descriptive, copay stratification was not based on a statistical model but on copay ranges typically used by the plans, and there were no direct correlations performed on the numbers of subscribers per plan vs copay or Tier level.Conclusion:These results counter the widely held perception that insurance coverage is less extensive for insulin pens vs vials. Medicare Part D plans often had higher copay requirements than private plans for the same product at the same copay Tier.

A new C‐peptide correction model used to assess bioavailability of regular human insulin

The clinical assessment of new formulations of human insulin is problematic due to the inability to distinguish between endogenous insulin and exogenously administered insulin. The usual methods to surmount the problem of distinguishing between endogenous and exogenous human insulin include evaluation in subjects with no or little endogenous insulin, hyper-insulinemic clamp studies or the administration of somatostatin to suppress endogenous insulin secretion. All of these methods have significant drawbacks. This paper describes a method for C-Peptide correction based upon a mixed effects linear regression of multiple time point sampling of C-Peptide and insulin. This model was able to describe each individual's insulin to C-Peptide relationship using the data from four different phase I clinical trials involving both subjects with and without type 2 diabetes in which insulin and C-Peptide were measured. These studies used hyper-insulinemic euglycemic clamps or meal challenges and subjects received insulin or Glucagon-like peptide 1 (GLP-1). It was possible to determine the exogenously administered insulin concentration from the measured total insulin concentration. A simple statistical technique can be used to determine each individual's insulin to C-Peptide relationship to estimate exogenous and endogenous insulin following the administration of regular human insulin. This technique will simplify the assessment of new formulations of human insulin.

Insulin detemir improves glycemic control and reduces hypoglycemia in children with type 1 diabetes: findings from the Turkish cohort of the PREDICTIVE™ observational study

Insulin detemir is a basal insulin analog designed to produce a superior pharmacokinetic profile to basal formulations of human insulin. It has shown consistently improved tolerability in comparison to neutral protamine Hagedorn (NPH) insulin in adult cohorts, but there are relatively few publications involving pediatric cohorts. The efficacy and safety of insulin detemir in children with type 1 diabetes was assessed using data from the Turkish cohort of PREDICTIVE (a large, multinational, observational) study. The children investigated were using basal-bolus therapy involving NPH insulin or insulin glargine at baseline but were switched to insulin detemir as part of routine clinical care by their physicians. Twelve weeks of treatment with insulin detemir significantly reduced mean hemoglobin A1c (9.7-8.9%, p < 0.001) and mean fasting glucose [185-162 mg/dL (10.3-9 mmol/L), p < 0.01]. Fasting glucose variability was also lower after treatment with insulin detemir than previously (on either NPH or glargine, p < 0.05). The frequencies of total, major and nocturnal hypoglycemic events were significantly reduced with insulin detemir relative to baseline, with an estimated mean of 6.89 fewer events/patient/yr overall (p < 0.001) and 2.6 fewer nocturnal events/patient/yr (p < 0.01). Weight and insulin dose remained relatively unchanged. Twelve weeks of treatment with insulin detemir improved glycemic control and reduced hypoglycemia in children with type 1 diabetes. This improved tolerability might allow further dose titration and therefore additional improvements in glucose control.

A novel insulin formulation with a more rapid onset of action

Aims/hypothesisThis study evaluates the pharmacodynamic and pharmacokinetic properties of the novel ultra-fast insulin product VIAject, a formulation of human soluble insulin and generally recognised as safe ingredients designed to increase the rate of absorption.MethodsWe performed five euglycaemic glucose clamps (Biostator; target blood glucose 5 mmol/l) in ten healthy volunteers. Using a crossover design with a fixed treatment order, 12 IU human soluble insulin, 12 U insulin lispro and 12 IU ultra-fast insulin were injected s.c. in the abdominal region on three study days. On the other two study days, 6 and 3 IU ultra-fast insulin were injected.ResultsSubcutaneous injection of 12 IU ultra-fast insulin resulted in a time–action profile characterised by an even more rapid onset of action and maximal metabolic activity than insulin lispro: time to early half-maximal activity was 33 ± 17 min (mean ± SD) vs insulin lispro 51 ± 13 min vs human soluble insulin 66 ± 15 min (p < 0.05 ultra-fast insulin<insulin lispro<human soluble insulin); time to maximal activity was 136 ± 56 min vs insulin lispro 152 ± 30 min vs human soluble insulin 193 ± 57 min (p < 0.05 ultra-fast insulin and insulin lispro<human soluble insulin). The metabolic activity in the first 2 h after injection was higher with ultra-fast insulin and insulin lispro than with human soluble insulin (AUC glucose infusion rate [GIR] 0–120 min: 915 ± 301 and 781 ± 174 vs 580 ± 164 mg/kg; p < 0.05). A clear dose–response relationship was observed with the three doses of ultra-fast insulin: AUCGIR 0–120 min 12 IU 915 ± 301 vs 6 IU 718 ± 255 vs 3 IU 524 ± 262 mg/kg (p < 0.05). The pharmacokinetic data confirmed the pharmacodynamic results.Conclusions/interpretationThis study shows that the onset of action of VIAject is faster than that of human soluble insulin and insulin lispro.

Demonstrating strategies for initiation of insulin therapy: matching the right insulin to the right patient

To increase awareness regarding the different types of insulin available and provide discussion regarding how each type of insulin can address the needs of diverse patients in terms of their unique requirements, preferences, medical history and lifestyle concerns. New classes of antidiabetes medications, the development of insulin analogues and novel insulin delivery systems, provide more options for the management of type 2 diabetes. Given the inevitable progression of beta-cell dysfunction, along with the relatively limited glucose-lowering capacity of other agents, many patients will eventually require insulin for optimal glycaemic management. However, patients and physicians often fail to initiate insulin early enough during the progression of disease to maintain the recommended levels of glycaemic control. The inherent properties of the new insulin analogues, more physiological and user-friendly time-action profiles compared with older human insulin formulations, may partly address the barriers to insulin use. Insulin analogues include rapid acting (for prandial glycaemic control), long acting (for basal insulin coverage) and premixed insulin analogues, which combine both a rapid acting and an extended duration component in a single insulin formulation. Various case-based scenarios on initiating and intensifying therapy with insulin analogues will be presented. Development of an individualised treatment plan for initiation of insulin is a critical step in achieving target glycaemic levels in patients with type 2 diabetes.

Coverage of Postprandial Blood Glucose Excursions With Inhaled Technosphere Insulin in Comparison to Subcutaneously Injected Regular Human Insulin in Subjects With Type 2 Diabetes

Technosphere Insulin (TI) is a formulation of regular human insulin (RHI) that provides efficient pulmonary administration (1) and demonstrates unique pharmacokinetic and pharmacodynamic properties compared with subcutaneous RHI, rapid-acting insulin analogs, and other inhaled insulins (2). Administration of TI results in a time to maximum insulin concentration of ∼15 min, with almost complete absorption within 3 h (3,4). With an onset of action comparable to intravenous insulin, TI represents the first formulation that approaches the physiological early insulin release. In this study, we evaluated the efficacy and safety of TI compared with subcutaneous RHI in covering prandial insulin needs. We measured blood glucose excursions after a meal challenge after individual titration of either insulin formulation during a 7-day treatment period in subjects with type 2 diabetes. This prospective, open-label, randomized, two-period, cross-over study was conducted at one center (Profil Institute for Metabolic Research, Neuss, Germany). The study included a screening visit, 24-h in-house exposure to TI to establish initial dosing, two 7-day ambulant periods of daily mealtime TI or subcutaneous RHI separated by a 2- to 7-day washout, and a final visit. In-house meal challenges, using a standardized mixed meal with 496 kcal, were conducted at the end of each ambulant period. During treatment periods, each subject inhaled TI via a MedTone Model C Inhaler (MannKind Corporation, Valencia, CA) …