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Inhaled insulin for the treatment of Type 2 diabetes in Adults, in comparison with subcutaneous Insulin

Shahdin Ali

Word count: 3259.

Inhaled insulin for the treatment of Type 2 diabetes in Adults, in comparison with subcutaneous Insulin


Diabetes is a common disorder which affects around 180 million people and results in 2.9 million deaths per annum. It has been suggested that mortality rate is likely to rise by 50% in the next decade (Yadav et al., 2009). In the year 2004, around 33,000 deaths were caused by diabetes alone in UK (Carlsson et al., 2004).  In addition, WHO projects that diabetes death will double between 2005 and 2030.

Management of type 2 diabetes typically commences with diet and lifestyle interventions, eventually followed by the addition of a single oral anti-diabetic drug and then a combination of oral drugs. However, oral therapy is often not sufficient to achieve appropriate glycaemic control of less than 7% (Tarnow et al., 2008). Current guidelines recommend that treatment should aim to achieve a blood level of glycated haemoglobin (HbA1c) of between 6.5% and 7.5%, although it is acknowledged that such targets may not be achieved in all patients. Data from the Kaiser Permanente databases suggested that only half the patients achieve targeted glycemic control when using the combination of sulphonylurea and metformin. Furthermore, even when successful, these patients maintained target control for less than one year (Brown et al., 2010). The prevalence of diabetes is reaching epidemic proportions with an increasing need for new therapies. It is imperative that diabetic patients who fail to achieve satisfactory glycaemic control are treated more effectively. Data from UK prospective diabetes study and the diabetes intervention study have revealed an association between good glycaemic control and reduction in micro-vascular and macro-vascular complications on type 2 diabetes (UKPDS, 1988)

Several new therapies are in development and amongst these is inhaled Insulin. Inhaled insulin (INH) could prove to be an ideal non-invasive alternative to subcutaneous injections of insulin. It is believed that increased satisfaction would result in better adherence to medication which would in turn lead to a better glycaemic control (Royle P et al., 2009). The pulmonary route exploits a large vascular bed and permeability of the alveoli to deliver insulin directly into the bloodstream (Paton et al., 2004). Inhaled insulin is under investigation for the preprandial administration of rapid onset in type 1 and type 2 diabetes and has been shown in preliminary short term clinical studies to provide a safe and effective control of meal related glycaemia.

This assignment will analyse randomised controlled trials to compare inhaled insulin with subcutaneous insulin.


Critical analysis 1:

Study was conducted by Hauber and colleagues in which he demonstrated that difficulty with administration, and concerns about side effects, complications and disease progression contributed to the barriers to treatment acceptance. This is further supported by various other authors Such as Freemantle et al., (2005) who suggested even physicians resist initiating insulin therapy for several reasons, including fear of injections.  In addition, the NICE guidelines recommend that inhaled insulin may be used as a treatment option for people with type 1 or type 2 diabetes who show evidence of poor glycaemic control and are unable to adequately control it with other therapeutic interventions such as diet, oral hypoglycaemic agents OHAS and subcutaneous insulin (NICE, 2008).  The pulmonary route is the most widely researched non-invasive alternative to subcutaneous administration and offers the greatest potential for systemic insulin delivery. Its advantages include a large absorptive surface and high permeability (Paton et al., 2004). Inhaled Insulin (Exubera, Pfizer Ltd) is an inhaled, rapid-acting, dry power, human insulin produced by recombinant DNA technology. It has a UK marketing authorisation for the treatment of adults with type 1 and type 2 diabetes not adequately controlled with OHAs and requiring insulin therapy (NICE, 2008).

A randomized three year study was conducted to assess the pulmonary safety during discontinuation and readminstration of inhaled insulin, Exubera in type 1 diabetic patients. Previously, this study was designed only for two years to compare the respiratory safety of both inhaled and subcutaneous insulin (Skyler et al., 2007). However it was extended to allow 6months of washout period, where inhaled Exubera therapy was discontinued and all the patients received only subcutaneous insulin and then, readminstration of inhaled Exubera again for 6 months. The study used patients within the 18-65 age groups who had received regular insulin treatment for at least 2months. Individuals with pulmonary or respiratory disease or who were smokers in the past 6 months were excluded from this study (Skyler et al., 2008).

 At screening, all eligible patients received subcutaneous insulin for 4 weeks, and were then randomized to receive either multiple short acting subcutaneous injections of insulin, or pre-meal inhaled Exubera combined with a single glargine or  Ultralente® insulin injections.  Exubera was administrated 10mins prior to meal and the dose of Exubera was adjusted according to the body weight. Pulmonary function tests (PFT) were performed during the comparative phase and washout months 1, 3, 6 and at readminstration months 1, 3 and 6 and assessment of safety was done by monitoring adverse events. These pulmonary function tests can diagnose lung disease and measures the severity of lung problems (Mason et al.,2005). Efficacy was assessed during the comparative phase by measuring glycaemic levels, incidence of hypoglycaemic events and body weight during the washout and readminstration months.  A total of 582 patients participated in this study: 222 participants in Exubera group and 229 participants in the subcutaneous insulin group respectively.

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The pulmonary lung function tests were found to be well tolerated during all three phases of the study. Overall it was found that 5.2% of patients in Exubera group and 1.5% patients in subcutaneous group discontinued their insulin therapy during either the comparative or readminstration phase because of adverse effects.   Thus, the incidence of adverse effect was comparable between Exubera and subcutaneous groups. Small  treatment differences were observed in lung function between Exubera and subcutaneous insulin group in type 1 diabetic patients during the first two years of the study.  However, these treatment differences were small, non progressive, clinically ...

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