Alan Krasner

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 μg/ml; P < 0.05), whereas nitrotyrosine after insulin lispro was in between (insulin lispro 0.09 ± 0.07 μg/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.

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.

Development of Stable Liquid Glucagon Formulations for Use in Artificial Pancreas

Background: A promising approach to treat diabetes is the development of fully automated artificial/bionic pancreas systems that use both insulin and glucagon to maintain euglycemia. A physically and chemically stable liquid formulation of glucagon does not currently exist. Our goal is to develop a glucagon formulation that is stable as a clear and gel-free solution, free of fibrils and that has the requisite long-term shelf life for storage in the supply chain, short-term stability for at least 7 days at 37°C, and pump compatibility for use in a bihormonal pump. Methods: We report the development of two distinct families of stable liquid glucagon formulations which utilize surfactant or surfactant-like excipients (LMPC and DDM) to “immobilize” the glucagon in solution potentially through the formation of micelles and prevention of interaction between glucagon molecules. Results: Data are presented that demonstrate long-term physical and chemical stability (~2 years) at 5°C, short-term stability (up to 1 month) under accelerated 37°C testing conditions, pump compatibility for up to 9 days, and adequate glucose responses in dogs and diabetic swine. Conclusions: These stable glucagon formulations show utility and promise for further development in artificial pancreas systems.

Safety and efficacy of inhaled human insulin (Exubera®) during discontinuation and readministration of therapy in adults with type 1 diabetes: A 3-year randomized controlled trial

OBJECTIVE To assess pulmonary safety during discontinuation and readministration of inhaled human insulin (EXU; Exubera((R)) insulin human [rDNA origin]) Inhalation Powder) therapy in adults with type 1 diabetes. METHODS Patients were randomized to receive basal insulin plus either pre-meal EXU (n=290) or a short-acting subcutaneous (SC) insulin (n=290) for 2 years (comparative phase), followed by 6 months of SC insulin (washout) and 6 months of their original therapy (readministration). Highly standardized lung function tests were performed throughout. RESULTS Small treatment group differences favoring SC insulin in change from baseline forced expiratory volume in 1s (FEV(1)) and carbon monoxide diffusing capacity (DL(CO)) occurred early and were non-progressive. These differences resolved during washout and recurred at the same magnitude during readministration. Both groups maintained glycemic control, and hypoglycemic event rates were similar. In the EXU group, insulin antibody (IAb) levels plateaued at 12 months, declined to near baseline levels during washout and increased during readministration to levels observed in the comparative phase. CONCLUSIONS FEV(1) and DL(CO) changes observed during discontinuation and readministration of EXU therapy are consistent with a reversible, non-progressive and non-pathological effect on lung function. EXU readministration is not associated with an augmented IAb response.

Body Weight Changes Associated With Insulin Therapy A retrospective pooled analysis of inhaled human insulin (Exubera) versus subcutaneous insulin in five controlled Phase III trials

Weight gain is commonly seen when patients are started on subcutaneous (SC) insulin. In the UK Prospective Diabetes Study, those assigned insulin gained 4 kg more than those assigned conventional therapy at 10 years (1). Given that the majority of patients with type 2 diabetes are overweight or obese (2,3), additional weight gain is clearly a concern. Furthermore, while patients with type 1 diabetes were historically often underweight, the greater use of an intensified treatment approach to achieve the benefits of improved glycemic control is associated with greater weight gain than conventional treatment (4). Fear of weight gain, along with factors such as reluctance to self-inject and fear of hypoglycemia, is a frequent deterrent to initiating insulin therapy and has been linked to reduced treatment adherence in patients with both type 1 and type 2 diabetes (5). In type 2 diabetes, the β-cell dysfunction that leads to impaired insulin secretion is progressive, and eventually patients will require a treatment strategy that includes insulin either alone or with oral agents (6). The aim of this pooled analysis was to compare weight changes in a large population of adult patients with type 1 or type 2 diabetes receiving a regimen involving inhaled human insulin (Exubera [rDNA origin] Inhalation Powder) versus an SC insulin–only regimen. This was a retrospective analysis of pooled 6-month data from five controlled Phase III clinical trials …

Assessment of long-term immunological and pulmonary safety of inhaled human insulin with up to 24 months of continuous therapy

ABSTRACT Background: This study was performed to characterize the long-term safety and efficacy of inhaled human insulin (EXU; Exubera* (insulin human [rDNA origin]) Inhalation Powder). * Pfizer Inc, New York, NY, USA Scope: Patients with type 1 or type 2 diabetes (N = 1290) who had successfully completed one of six controlled EXU open-label trials elected to receive open-label treatment with EXU for up to 3 years, after which they were randomized to discontinue EXU or to continue therapy for 6 months, then discontinue. Immunologic safety was assessed by insulin antibody (IAb) binding, and pulmonary safety was assessed by tests for forced expiratory volume in 1 second (FEV1) and carbon monoxide diffusing capacity (DLCO). In addition, changes over time in IAbs were compared with changes in FEV1, DLCO, hypoglycemia, and efficacy. Findings: Antibody binding increased in patients with either type 1 or type 2 diabetes after initiation of EXU and plateaued within 6–12 months (increases were higher in patients with type 1 diabetes than in patients with type 2 diabetes). Decreases in FEV1 occurred primarily during the first 3–6 months of EXU therapy. Among adult patients in the All Subjects set, the mean (± SE) annualized rate of decline in FEV1 was −0.053 ± 0.007 liters/year (95% CI, −0.065, −0.040) in adult patients with type 1 diabetes, and −0.076 ± 0.005 liters/year (95% CI, −0.085, −0.067) in patients with type 2 diabetes. Changes in DLCO occurred primarily during the first 3–6 months of EXU therapy. Among adult patients, in the All Subjects set, the mean (± SE) annual decline in DLCO was −0.738 ± 0.097 mL/min/mmHg/year (95% CI, −0.927, −0.548) and −0.688 ± 0.082 mL/min/mmHg/year (95% CI, −0.849, −0.527) in patients with type 1 and type 2 diabetes, respectively. Antibody binding did not correlate with changes in glycemic control, lung function, dose, or hypoglycemia. Following discontinuation of EXU, IAbs decreased to near baseline levels. Conclusion: These results are consistent with other trials showing long-term maintenance of safety and efficacy of EXU despite insulin antibody formation and small treatment group differences in pulmonary function. A limitation of the study was the lack of a comparator therapy.

Development and Validation of a Radioligand Binding Assay to Measure Insulin Specific IgG Subclass Antibodies in Human Serum

Abstract: The objective was to develop and validate a radioligand binding assay for insulin antibodies (IABs) of the IgG1, IgG2, IgG3, and IgG4 subclasses in human serum. The validation studies focused on determining specificity, capacity, linearity, sensitivity, and precision of each assay. It was seen that our assay for IAB IgG subclasses is specific and has sufficient capacity to measure each of the subclasses in human serum. Moreover, the linear region and limits of detection and quantitation for each assay are clearly determined.