WILLINGNESS-TO-PAY FOR INSULIN IN DIABETES TREATMENT: A SYSTEMATIC REVIEW AND META-ANALYSIS

Background: Insulin treatment is necessary for all patients with type 1 diabetes and a subset of patients with type 2 diabetes. However, lifetime insulin treatment is relatively costly that has put a heavy financial burden on insulin-dependent diabetics. Several studies thus have been conducted widely to estimate diabetes patients' willingness to pay (WTP) for insulin therapies worldwide. This study aimed to derive the diabetes patients' WTP for insulin therapy from the results of previous research studies. Methods: A systematic review and meta-analysis of diabetes patients’ WTP for insulin was conducted. All studies were searched and derived from PubMed combined with MeSH, Cochrane library combined with MeSH, ScienceDirect, and Springer Nature. The WTP values were estimated for three different types of insulin, including short-acting, rapid-acting insulin; long-acting, slow-acting insulin, and mixed insulin. Review Manager 5.1.4 software was used to conduct the meta-analysis. Results: Twelve studies were identified by the systematic review, in which eight studies were eligible for a meta-analysis. Most studies were conducted in high-income countries (83.3%), mainly in America (41.7%) and Europe (33.3%). The insulin formulation with the highest mean WTP value was Humalog Mix25 insulin, which was recorded at 410.42 USD per month in the UK and more than 120 USD per month in France, Italy, Spain, and Germany; while most of the other insulin formulations had mean WTP values less than 120 USD per month. Compared to diabetes patients, general populations were willing to pay less for insulin, which was observed in the case of Humalog Mix25 insulin (mean 95.77 USD per month vs 205.89 USD per month) and inhaled insulin (mean 50.43 USD per month compared to more than 120 USD per month). The meta-analysis showed the WTP value for insulin was 74.15 USD per month (95% CI; 55.82 - 92.48). Conclusion: This study showed a comparison of WTP values for different insulin formulations worldwide. The mean WTP value for insulin derived from all previous research may provide an initial understanding of the individuals' preference and WTP. This information could contribute to the effort of managing diabetes and reducing the financial burden of this chronic disease.

Medicsen Smartpatch: A New Approach to Diabetes Management

Introduction: Diabetes is a metabolic disorder characterized by a dysregulation of the glucose levels. With insulin being the main drug to be administrated for glucose levels modulation, it needs to be injected subcutaneously with daily injections, which can lead to poor patient compliance, apart from several side-effects. Although other administration methodologies have been investigated (oral or inhaled insulin), they show enough drawbacks to not to be consider as feasible alternatives for diabetes therapy. That′s why Medicsen has developed a Smartpatch that integrates a wide range of technologies, with the purpose of ensuring the correct insulin delivery from the skin′s surface to the bloodstream using a non-invasive and painless drug delivery method through a phenomenon induced by sonophoresis. Materials and Methods: Several in vitro and in vivo tests have been performed to prove the efficacy and safety of the technology, allowing us to collect experimental evidence through different methodologies that demonstrate the therapeutic potential of the device. Among these methodologies, permeability studies using Franz diffusion Cell and swine models (that prove efficacy of the technology) as well as safety studies, for both the insulin and the skin are highlighted. Results: In voltage experiments, the mean time for the disappearance of the membrane potential between the compartments separated by skin was: 334.7 (SD+/-103.6) seconds. Regarding the slope of the voltage line, as an approximation to the transfer speed, an arithmetic mean of (μ)= 0.0164 Mvolts/sec (+/- SD(σ): 0.006) was obtained. No significant differences were found between the circular dichroism spectra of samples (minimum peak at 219nm (sd+/-8.31) and that of the standard, which suggests that the molecular structure of insulin maintains stability. In the same way, HPLC studies shows no variability between the standard and all groups tested. Regardin skin safety, SEM images shows no significant damage to the skin, and ELISA test for TNF α and IL-2, as well as other biochemical tests, show no differences between control and samples. On In vivo experiments with our technology, glucose changes are comparable to those evoked through direct drug injection using conventional syringes. Lastly, the technology proved to be effective in the delivery of insulin through the skin in a non-invasive way, as observed in a Franz Diffusion Cell system and in the in vivo model of blood glucose reduction. Conclusions: Results observed during in vitro and in vivo studies indicate that the technology developed by Medicsen is effective and safe for the patient and the insulin. Following steps, including human trials, will be critical to fully demonstrate its potential in the treatment of diabetes.

Protective Effect of Nedocromil Against Insulin Induced Airway Hyper-Reactivity

Background: Use of inhalable insulin is limited because it causes airway hyper-reactivity. So present study was designed to ameliorate inhalational insulin induced airway hyper-responsiveness.Objectives: The objective of the study was to evaluate the acute effects of insulin on airway reactivity and protective effects of nedocromil against insulin induced airway hyper-reactivity on isolated tracheal tissues of guinea pigs in vitro.Material and Methods: This experimental study was carried out in Pharmacology department of Army Medical College Rawalpindi from January 2012 to July 2012. We observed acute effect of insulin (10-7- 10-3 M) and insulin pretreated with nedocromil (10-5 M) on isolated tracheal strip of guinea pig (n=6) in vitro by constructing cumulative concentration response curves. The tracheal smooth muscle contractions were recorded with Transducer on Four Channel Oscillograph.Results: Insulin significantly increased the tracheal smooth muscle contraction. The mean ± SEM of maximum amplitudes of contraction with insulin and insulin pretreated with nedocromil were 35 ± 1.13 mm and 27.8 ± 1.27 mm respectively. So nedocromil significantly antagonized insulin elicited contractile effect. Conclusion: Nedocromil significantly inhibited the insulin mediated airway hyper-reactivity in guinea pigs. So we suggest that pretreatment of inhaled insulin with nedocromil may have clinical implication in amelioration of its potential respiratory adverse effects.

Long-Term Nonclinical Pulmonary Safety Assessment of Afrezza, a Novel Insulin Inhalation Powder

Afrezza delivers inhaled insulin using the Gen2 inhaler for the treatment of patients with type 1 and type 2 Diabetes. Afrezza was evaluated in long-term nonclinical pulmonary safety studies in 2 toxicology species. Chronic inhalation toxicology studies in rat (26 weeks) and dog (39 weeks) and an inhalation carcinogenicity study in rats were conducted with Technosphere insulin (Afrezza) and with Technosphere alone as a vehicle control. Respiratory tract tissues were evaluated by histopathology and cells expressing proliferating cell nuclear antigen (PCNA) were quantified in lungs of rats. Microscopic findings in rats exposed to Afrezza were attributed to the Technosphere particle component, were confined to nasal epithelia, and consisted of eosinophilic globules and nasal epithelial degeneration. There were no Afrezza-related changes in pulmonary PCNA labeling indices in alveoli, large bronchioles, or terminal bronchioles. Microscopic findings in rats exposed to Technosphere particles included eosinophilic globules, mucus cell hyperplasia, and epithelial degeneration in the nasal cavities. PCNA labeling indices were increased in large bronchioles and terminal bronchioles but not in alveoli. There were no Technosphere particle-related findings in the dog study. Afrezza did not exhibit carcinogenic potential in the 2-year study in rats. These nonclinical inhalation studies support the use of Afrezza in humans over extended periods.

A Review: The Prospect of Inhaled Insulin Therapy via Vibrating Mesh Technology to Treat Diabetes

Background: Inhaled insulin has proven to be viable and, in some aspects, a more effective alternative to subcutaneous insulin. Past and present insulin inhaler devices have not found clinical or commercial success. Insulin inhalers create a dry powder or soft mist insulin aerosol, which does not provide the required uniform particle size or aerosol volume for deep lung deposition. Methods: The primary focus of this review is to investigate the potential treatment of diabetes with a wet insulin aerosol. Vibrating mesh nebulisers allow the passive inhalation of a fine wet mist aerosol for the administration of drugs to the pulmonary system in higher volumes than other small-volume nebulisers. Results: At present, there is a significant focus on vibrating mesh nebulisers from the pharmaceutical and biomedical industries for the systemic administration of pharmaceuticals for non-traditional applications such as vaccines or the treatment of diabetes. Systemic drug administration using vibrating mesh nebulisers leads to faster-acting pharmaceuticals with a reduction in drug latency. Conclusions: Systemic conditions such as diabetes, require the innovative development of custom vibrating mesh devices to provide the desired flow rates and droplet size for effective inhaled insulin administration.

Fumaryl Diketopiperazine Microspheres Platform Design for Protein Pulmonary Delivery in Diabetes Rats Model

The cornerstone of this study was to formulate and optimize fumaryl diketopiperazine (FDKP) microspheres of insulin-load (INS@FDKP-MPs) with the aid of Box-Behnken design (BBD) to enhance insulin bioavailability. The property characterization of INS@FDKP-MPs was studied and the stability study was confirmed by evaluating the effect on sample appearance, insulin and related protein content, hygroscopicity. At the same time, the pharmacodynamics of INS@FDKP-MPs was evaluated by testing the concentration of blood glucose of the diabetic model rats under different conditions. The optimized formulation of INS@FDKP-MPs drug loading microspheres is 2.37 h of stirring time, 4.64 of pH value and 23.11% of the drug ratio. Under this condition, the results of optimized formulation showed the average microspheres size of 1.69 nm, the drug loading rate of 10.95%. The size of microspheres is all below 3 m and the pulmonary deposition rate in stage 3 and stage 4 is more than twice that of other stages. The results of stability confirmed that INS@FDKP-MPs had good stability within three months. Futhermore, pharmacodynamics results indicated that inhaled insulin (Tmin 60 to 90 min) could rapidly be absorbed into the systemic circulation compared to subcutaneous injection (Tmin 120 min); Inhaled insulin can continuously reduce blood glucose concentration within 120 minutes, which is significantly faster than subcutaneous injection (180 minutes). That is stand for reducing the possibility of hypoglycemia. Through Pulmonary Administration, INS@FDKP-MPs can be efficiently and effectively absorbed into the systemic circulation with good pharmacodynamics and the ability to lower blood glucose levels.