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Inhaled Insulin as an Alternative Treatment Method for Diabetes
October 24, 2008
Diabetes is a chronic and incurable disease which currently plagues over 246 million individuals worldwide (http://www.idf.org/home/index.cfm?node=37). A diagnosis of diabetes is often devastating to both the patient and his family. The day-to-day struggle to control it through continual monitoring and treatment not only impacts on the physical well-being of the patient, but results in social, emotional and psychological consequences. However, these ramifications may be minimized by effectively integrating diabetes management into a patient’s daily routine, rather than permitting the disease to dictate his life (Roemer). And, inhaled insulin, an innovative therapy, may bridge the gap between effective treatment and patient satisfaction, leading to a more rewarding quality of life.
Diabetes: An Overview
In 2007, the National Center for Disease Control estimated that 23.6 million Americans, comprising 7.8% of the population, had diabetes. The incidence of this disease is steadily growing, with 1.6 million new cases diagnosed in the U.S. that year ("National" 5, 7). Insulin dependent diabetes mellitus (IDDM), commonly referred to as type 1 diabetes, is generally onset at an early age and involves a lack of insulin production by the pancreas, leading to increased blood glucose levels in the blood. Non-insulin dependent diabetes mellitus (NIDDM), or type 2 diabetes, is the most common form of diabetes and is characterized by a decreased sensitivity of target tissues to the metabolic effect of insulin (http://www.diabetes.org/about-diabetes.jsp).
The development of type 2 diabetes is signified by increasing blood glucose levels causing a disorder called hyperglycemia. When insulin resistance occurs, there are inadequate levels of insulin within the blood, causing limited uptake and storage of glucose in the cells. Thus, by the cells’ inability to be receptive to insulin, they are not able to use glucose, the basic building blocks for energy, for necessary metabolic and biological processes. As a result of this chemical imbalance, major complications such as cardiovascular disease, retinopathy, neuropathy, and kidney failure can occur if one’s glycemic level in the blood is not properly monitored and controlled (http://www.diabetes.org/about-diabetes.jsp). If not continually assessed, these complications will inevitably deteriorate and can eventually result in death, which is why treating this disease effectively and urgently must be underlined.
What are the Current Methods of Treatment?
To control type 2 diabetes and various forms of type 1 diabetes, common treatments are implemented, with each having its own distinguishable characteristics. Although oral diabetes pills are often utilized by patients with type 2 diabetes, they are essentially ineffective in patients with type 1 diabetes, since the pills are not insulin formatted and act to lower blood glucose through other means (http://www.fda.gov/DIABETES/pills.html). (http://www.cdc.gov/diabetes/pubs/tcyd/ktrack.htm)
Consequently, most diabetes patients use either syringes or pens that satisfy the same purpose of insulin delivery: through use of a sharp needle, insulin is injected through the outer layer of skin and into the fatty subcutaneous layer, allowing it to be transferred to the bloodstream. In order to ensure that the proper amount of insulin is administered, a patient is required to check his blood glucose level. Although many of the newer machines boast that their blood testing procedure is painless, a prick on the test site is still necessary for an accurate reading. Following the reading and recording it in a logbook, the syringe or pen is adjusted to the proper amount of insulin needed, and the delineated amount is accordingly administered to the patient (http://www.diabetes.org/about-diabetes.jsp). Further, it must be emphasized that diabetes is an incurable disease, and therefore these treatment approaches depend on underlying therapy that focuses on managing a patient’s diabetes to a safe, stable level.
What is Inhaled Insulin?
Although it is evident that effective management of blood glucose concentrations in type 1 and type 2 diabetes has long-term benefits, insulin therapy is often sub-optimally executed, resulting in an alarming number of patients who have poorly managed glycemic levels. It was not until January 2006, that the insulin inhalant Exubera became the “first new insulin delivery option to be approved by the FDA since insulin was approved in the 1920’s,” and was believed to be a revolutionary breakthrough in diabetes therapy (Ansorge 1). Administered 10 minutes before every meal, Exubera functioned as an insulin inhalant that used dry-powder to control glycemic levels. By inhaling this dry insulin powder, the insulin air was transported to the respiratory cavity, where the lungs enabled it to be absorbed into the bloodstream. Thus, this insulin powder was used in congruence with a pulmonary inhaler which, similar to an asthmatic inhaler, “was designed to deliver the aerosolized powder to the small airways and alveoli to enable systemic insulin absorption” (Rosenstock, “Inhaled” 551). Through this technique, which was commonplace and socially acceptable for asthma treatment, Exubera presented an innovative alternative to administer insulin to those diabetic patients who could not tolerate the previously mentioned treatment forms.
However, after suffering major short-term economic blows when the drug was released into the market, Pfizer made the decision to pull this revolutionary drug off the market, in an attempt to cut its losses and regain its economic viability (“Inhaled”). Nevertheless, other companies such as MannKind Corporation, Aradigm and other boutique pharmaceutical companies, believing in the long-term financial and humane benefits of inhaled insulin, are continuing the research and development of their versions of inhaled insulin products (Hite; Cefalu).
The Scientific Evidence:
Research studies consistently confirm the efficacy of inhaled insulin treatments. A controlled study suggests that as compared with the normalized insulin injections, the insulin inhalant is absorbed by the body at an exponentially quicker rate, and stimulates a hasty decrease in blood glucose levels (Rosenstock, “Inhaled” 549). This can be explained by the fact the inhaled insulin is directly transferred to the lungs, allowing diffusion to exchange the insulin from high to low concentration into the bloodstream. The argument is additionally supported by the FDA when Exubera was released, which stated that “peak insulin levels were achieved at 49 minutes (range 30 to 90 minutes) with Exubera inhaled insulin, compared to 105 minutes (range 60 to 240 minutes) with regular insulin, respectively” (http://www.fda.gov/bbs/topics/news/2006/new01304.html). A later scientific study evaluated the time-action profile of MannKind’s inhaled insulin product Technosphere. Thirteen adult subjects with type 2 diabetes randomly received single doses of either this inhaled insulin or subcutaneous insulin on three separate days. While the sample size was small, the study conformed to the prior findings that the inhalant had a more rapid onset than subcutaneous insulin (Rave). Further, according to clinical studies conducted by MannKind, it claims that the fast and concentrated delivery of insulin by Technosphere goes beyond the other inhalants and replicates normal insulin production by non-diabetics at the commencement of a meal, as summarized in the graph below:
It is this rapidly-acting consequence of inhaled insulin systems that is crucial, as all share time-action profiles that are better than or equivalent to injectable insulin. Inhalants diminish the time lag that is characteristic of other insulin therapies, and give patients a sense of hope in obtaining a more consistent stabilization of their blood glucose levels.
In addition to its efficacy at the onset of action, other clinical studies demonstrate the efficacy of inhaled insulin over a two-year period. One study focused on adults with type 1 diabetes, while a parallel study focused on those with type 2 diabetes, each comparing an Exubera group with a subcutaneous insulin control group. Among other findings, the first study concluded that both groups with type 1 diabetes maintained glycemic control over this extended time period (Skyler). As well, those with type 2 diabetes, both in the inhaled insulin group and the subcutaneous insulin group, yielded comparable glycemic control over two years (Rosenstock, “Two-Year”).
While effective in the treatment of diabetes, is inhaled insulin safe? It was this concern that Pfizer claims prompted it to remove Exubera from the market. Since inhaled insulin triggers lung absorption, Pfizer argued that there was a potential risk of long term pulmonary complications, including lung cancer (Krauskopf 1). However, the scientific evidence belies this assertion. The two-year studies by Skyler (2007) and Rosenstock (2008) discussed above also compared the long-term effects of inhaled insulin on pulmonary function of type 1 and type 2 diabetes patients with their respective subcutaneous control groups. Both clinical trials used standardized pulmonary function tests (forced expiratory volume and carbon monoxide diffusing capacity) in their assessments. The studies concluded that during the first 3 months, there were statistically insignificant differences between the comparison groups with regard to pulmonary function and incidence of cough, but these differences did not progress for the remainder of the studies. Significantly, the annual rate of decline of lung function between the type 1 and type 2 treatment groups were comparable between Exubera and the subcutaneous insulin groups (Skyler; Rosenstock, “Two-Year”). These results were also confirmed in another 2-year study which evaluated the pulmonary safety of Exubera for type 2 diabetes patients (Barnett). In addition, Pfizer’s claim that it was removing Exubera from the market due to its concern about the potential risk of lung cancer proved to be unsubstantiated. It was later revealed that “all patients who developed lung cancer had a history of cigarette smoking, and that too few cases existed” (Krauskopf 1). Additionally, smoking has always been a contraindication for initiating insulin inhalant therapy, suggesting that these individuals should have been informed by their physicians about the warnings and never put on this regimen in the first place (McMahon 498-499). Thus, it is not that Exubera was unsafe, but rather, Pfizer’s decision to pull this revolutionary drug off the market seems to have been economically motivated.
What are the Benefits and Social Implications of Inhaled Insulin Treatment?
While the clinical studies have established the efficacy and safety of inhaled insulin, the social, psychological and emotional components of utilizing this alternative treatment method cannot be minimized. A study of the impact of these factors, which focused on children but which is equally applicable to adults, confirms the burden that is experienced by diabetes patients on a daily basis. The stigma of feeling different often leads to low self-esteem, anxiety and depression (Roemer). It is often these factors that present an insurmountable barrier to patient compliance, which in turn leads to ineffective glycemic control and further medical complications.
Recognizing the reluctance of patients and medical professionals to embark on or expand on a regimen of injected insulin therapy, a study was conducted to develop a questionnaire that would be utilized to measure patient satisfaction with injected and inhaled insulin delivery. The study resulted in a 15-item questionnaire that determined that there two primary factors that contribute to patient satisfaction with their diabetes regimen: convenience/ease of use and social comfort (Cappelleri).
Using this questionnaire in clinical studies, it was demonstrated that the overall satisfaction for inhaled insulin was significantly higher than other insulin delivery techniques. In addition to this overall improved satisfaction with Exubera, all satisfaction subscales including advocacy, convenience, efficacy, and flexibility showed complimentary results for this insulin inhaled approach (Hollander, "Efficacy" 2361). Moreover, it has been illustrated that the method for delivering the inhaled insulin is “well-tolerated and preferred by patients” (Rosenstock, “Inhaled” 557). In light of this evidence, increased satisfaction with inhaled insulin would likely result in an improved willingness to use insulin therapy, resulting in a better patient management of glycemic levels (DeNoon; Rosenstock, “Patient”). This tremendous satisfaction that is linked to choosing inhaled insulin enhances the patients’ well-being, thus eliciting a more fruitful quality of life.
Another aspect of this alternative therapy pertains to changes in body weight. A study was conducted that compared weight changes of type 1 and type 2 diabetes patients using inhaled versus injected insulin. The results of five clinical trials were pooled and analyzed for 1960 patients during a retrospective six-month period. The findings revealed that inhaled insulin patients gained significantly less weight than those with injected insulin treatment, and that these differences were maintained at the two-year mark. An insignificant weight gain resulted for type 1 inhaled insulin users, while type 2 inhaled insulin users gained one-half as much their injected insulin counterparts. While the study may be criticized for the short duration of the trials, the researchers cite animal studies of longer duration with similar results. Limiting weight gain has far-reaching psychological and medical ramifications, ranging from issues of self-esteem to diabetes/obesity-related complications such as cardio-vascular disease (Hollander). Even the fear of weight gain may prevent some patients from complying with their insulin regimen, leading to unsuccessful glycemic control.
Inhaled insulin treatment has significant social implications to the estimated 15 million adults who have characterized themselves as suffering from needle phobia or unyielding discomfort from injections (“Drug”). Another study found that 10% of the population is affected by this fear (Szmuk). In a drug delivery survey, it was revealed that 3.5 million of the total needle-phobic population “chose not to receive a recommended injection at some point their life” (“Drug”). This figure displays the overwhelming lack of compliance with necessary treatments that involve needle injections. Due to this refusal to conform to injected insulin therapy, these diabetic patients will not able to receive the proper medical care that will enable them to control their glycemic levels. In fact, it was reported that 25% of those that refused needle treatment suffered from complications that were “varied and serious, both from a health and economic standpoint, and directly impacted the patient’s quality of life” (“Drug”). These potential threats in the needle-phobic diabetic community are both alarming and disconcerting, spurring a sense of urgency to depend on comparable non-invasive insulin therapy, such as inhaled insulin, for this group of individuals.
Other psychological benefits of inhaled insulin arise from the fact that individuals rely on social norms to rationalize their decisions and guide their actions. Our society has cultivated a certain stigma associated with the practice of injecting oneself with a needle. This social fabrication may make diabetic patients uneasy about injecting insulin in a public environment, resulting in a decreased compliance with the regimented insulin delivery schedule. In addition, injecting insulin provides a constant painful reminder of the frailty of one’s existence. Instead, by utilizing inhaled insulin, the stigma and negative karma surrounding needle therapy will not prevail, enhancing the patients’ psychological well-being.
For the nearly quarter-billion people afflicted with diabetes worldwide, inhaled insulin holds promise as an alternative method of treatment. Research studies and clinical trials conducted on several inhaled insulin products by different pharmaceutical companies have demonstrated their short and long-term efficacy and safety for treatment of both type 1 and type 2 diabetes patients. Studies have also shown that this innovative therapy is easy to use and is preferred over subcutaneous insulin regimens, while at the same time positively impacting on the social, emotional and psychological ramifications of the disease. However, certain segments of the diabetic population, such as children, smokers and those with sub-par pulmonary function, may be at increased risk for complications. Nevertheless, the bottom line is that this alternative treatment method has the potential to provide improved glycemic control without the negative consequences associated with current therapies, thereby enhancing the quality of life of the diabetic community at large. Since inhaled insulin is not currently commercially available, it is incumbent on those patients seeking this alternative treatment method to be pro-active in their own healthcare. By enlisting the aid of their physicians to be their advocates, actively expressing their continued interest and demand for this alternative therapy, pharmaceutical companies will recognize the financial and social benefits of stepping up their efforts to deliver inhaled insulin.
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