Inhaled insulin for the treatment of Type 2 diabetes in Adults, in comparison with subcutaneous Insulin
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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 insignificant and easily reserved after discontinuation of Exubera as seen in the washout phase. It could be seen that lung function changes did not cause an augmented effect during the discontinuation and readminstration of inhaled Exubera. Thus, this study demonstrated that no irreversible lung injury occurred during the 2 years of continuous inhaled Exubera thus confirming it to be safe and comparable with the subcutaneous injections of insulin group (Skyler et al., 2008).
Determining the efficacy of inhaled Exubera insulin was the secondary endpoint of this study, from the result it was found that patients in the Exubera group had significantly lower weight gain those in subcutaneous insulin group during the comparative phase (Mean adjusted treatment difference of -1.24kg). The pharmacokinetic properties of inhaled insulin resulted in hyperinsulinemia which cause less weight gain (Rave et al., 2005). The incidence of hypoglycaemic event during the comparative and readminstration phase was 4.3 and 3.7 and 4.1 and 3.2 events/subject-month for Exubera and subcutaneous insulin treated patients respectively. The incident of severe hypoglycaemia was significantly lower in the inhaled Exubera group than the subcutaneous insulin group, 20.9% and 31.2% patients affected respectively (Skyler et al., 2008). figure, shows the glycaemic control during comparative, washout and readminstration period in both inhaled and subcutaneous insulin group.
It can be seen that glyacemic control during the 3 phases was maintained in both Exubera and subcutaneous group. The adjusted mean treatment difference in A1C in both Exubera and subcutaneous insulin at the end of 6months readminstration period was found to be 0.338, thus the difference in glycaemic level was small and clinically insignificant. The mean baseline of glycaemic level was found to be 7.37% and 7.41% in inhaled and subcutaneous insulin groups respectively (Skyler et al., 2008).
Thus in conclusion, it could be seen that the incidence of mild hypoglycaemic event in inhaled insulin was as effective as with the subcutaneous insulin group. On the other hand, the incidence of severe hypoglycaemia and weight gain was less with in inhaled group in comparison to the subcutaneous insulin group. From figure above, it was shown that glycaemic control was equally maintained in the Exubera and subcutaneous insulin group throughout the washout and readminstration phases. This indicates that cessation and resumption of inhaled Exubera therapy does have any detrimental impacton glycaemic control. The result presented from this study (Skyler et al., 2008) concludes that inhaled insulin therapy was as safe and effective as subcutaneous insulin and this is consistent with other studies performed (Jay et al., 2007). Similar results have been obtained in subjects with type 2 diabetes; data from ongoing investigations also suggest that that glycaemic control is maintained during 24 months of inhaled insulin therapy. In the study by Skyler et al, inhaled insulin had a comparable incidence of hypoglycaemia to subcutaneous insulin In addition, in a long term extension study of Exubera 111 program conducted by Quattrin et al., (2004) changes in lung function initially observed remained small and non-progressive.
Critical Analysis 2:
A randomised controlled study was conducted by Royle et al., in 2008 to assess the patient acceptability of a combination of short acting inhaled insulin and long acting inhaled insulin in comparison with a combination of short acting injected and long acting injected insulin. People with either type 1 or 2 diabetes were considered for this study and only randomised controlled trials with parallel groups and controlled cross over trials were considered eligible for this study. Around 1191 participants were in six trials; 735 had type 1 and 456 had type 2 diabetes. The mean age of people with type 1 diabetes was 34years, and mean age of those with type 2 diabetes were 56years old. It is difficult to comment on generalisation because several of the studies gave little or no details of patients recruited. The average ages of the type 2 patient in the study was 56, which may be representative of type 2 patients treated with insulin (Royle et al., 2008).
The accuracy of the result is reduced by the large number of exclusion criteria, it should be noted that one of the main reasons for exclusion is asthma, which has been reported in Europe to be less common in people with type 1 diabetes than the general population (EURODIAB, 2000). There does not appear to be any evidence of increased risk of harm in people with both diabetes and asthma, and their exclusion is presumably only on the grounds of caution. However the bioavailability of inhaled insulin might well be affected if asthma led to bronchoconstriction, and this would need to be assessed. Smokers have also been excluded; A study conducted determined that smoking had a significant impact on the absorption of inhaled Insulin. Pharmacokinetic analysis indicates that the absorption of inhaled insulin in smokers is increased in comparison to the ones that don’t smoke. Although this effect can be partly reversed after just a week of non-smoking but it reverts back to absorption level typical of chronic smokers within a few days when smoking starts (Becker et al., 2006). This puts the diabetic smokers at a higher risk of hypoglycaemia due to consequences of short term changes in insulin availability. Some authors however have argued that there is not enough research carried out, to validate the connection between developing lung cancers for patients smoke whilst on treatment with INH (Heinemann et al., 2008 and Alabrada et al., 2009).
Blinding was not carried out for the different groups, and this could introduce a bias in favour of inhaled insulin for patient’s satisfaction, which was one of the key outcomes. Patient satisfaction was greater in the inhaled insulin group ( Royle et al., 2008), and it should be noted that satisfaction also increases in some control patients, presumably due to the effects of being in a trial. Patient’s views on injections will influence their satisfaction. Inhaled insulin may be particularly useful in the very small proportion of insulin treated patients with injection phobia. However, as reported by Siekmier 2008, that 42% of a group of 116 patients had some anxiety about increasing the number of injections. Whether and how much inhaled insulin would help this group is not known, since anxiety about intensification of insulin regimens could be due to other factors such as fear of hypoglycaemia or reluctant to increase blood glucose self monitoring, rather than the injections themselves. All trials, apart from (Hermansen, 2002) reported on patient satisfaction and all five showed significantly greater satisfaction with the inhaled insulin because of the reduced number of injections. Three trials ( Belanger 2002; Cefalu 2001; Quattrin 2002) also reported significant improvements in all the subscales of treatment satisfaction measured. In addition, results also showed that patient preferred to continue with inhaled insulin over subcutaneous insulin and Cefalu ( 2001) reported that patients in the inhaled insulin group, all with type 2 diabetes were 71% more likely to continue their assigned regimen than patients who had inject short acting subcutaneous insulin. This is statistically significant and the p value was found to be less than 0.05. To support this, Gerber in 2002 reported results of a multicentre extension study of 70 patients with type 1 diabetes who completed a three month randomised trial and were offered a one year treatment extension. Subjects could choose their insulin regimen (INH or SC) for the 1 year extension. Of those on INH in the 3 month trial, 81% chose to stay on INH; of those on SC in the parent study, 79% switched to INH. Subjects switching from SC to INH had significant improvements in overall satisfaction. By contrast, subjects switching from INH to SC showed a trend toward deteriorating satisfaction. However, these results should be treated with caution as the patients were not randomised to their respective groups, and hence the results are potentially subject to being bias.
Critical Analysis 3:
Study conducted to determine whether glycaemic control can be improved with the addition of inhaled insulin (INH) in type 2 diabetic patients are who inadequately are controlled with oral hyperglycaemic agents (OHA), and also to determine the tolerability and safety of INH therapy of this population. The study was randomised, open label multicenter, parallel group study comprising a four week run in phase and a 12 week treatment period. All the 68 patients recruited in this study had a primary diagnosis of type 2 diabetes with a glycosylated haemoglobin in between 8.1 to 11% inclusive, despite treatment with OHA such as metformin and or sulphonlyurea (Weiss and Landschulz, 2003)
From the results, at week 12 there was a significant greater reduction in glycosylated haemoglobin for INH+OHA cohort compared with the OHA only cohort. Eleven patients, receiving INH+ OHA achieved glycosylated haemoglobin values of less than 7% compared with none taking OHAs only. Fasting plasma glucose improved significantly more in the INHA+OHA group compared with the OHA only group and the post-prandial increase in glucose was significantly lower in those patients receiving INH+OHA. Pulmonary function was unchanged in both groups (Weiss and Landschulz, 2003). This leads to the conclusion that the addition of preprandial INH to existing OHAS improves glycaemic control without the need for injections in patients with type 2 diabetes failing to achieve satisfactory control with the OHAs alone, which is in line with other studies performed ( Skyler et al.,2001 and Cefalu, 2001) . Although, the UK prospective diabetes study and the diabetes intervention study highlighted the importance of good glycaemic control in type 2 diabetes, a large proportion of patients are not well controlled (UKPDS, 1998 and Stratton et al., 2000). The addition of insulin to existing OHA therapy improves glycaemic control and is recommended when patients fails with OHAs alone. However, the issue of treatment satisfaction, injection related anxiety and phobia are important for compliance, glycaemic control and quality of life because approximately one quarter of patients have psychological problems when injecting insulin (Bangstad et al., 2009). These limitations of injected insulin therapy contribute to poor glycaemic control in many patients with type 2 diabetes. In this regard, it is interesting to note that a questionnaire completed at the end of the study revealed high patient satisfaction with INH: 97% of those received it opted to continue in a 1 year extension of the therapy (Weiss and Landschulz, 2003). This is in line with previous studies have demonstrated that an INH treatment regiment provided glycaemic control comparable to that of a conventional SC insulin regiment in patients with type 1 or type 2 diabetes (Frost et al., 2009 ; Freemantle et al., 2006 and Freemantle et al., 2005). There are ongoing phase 3 studies in a larger patient population which aims to establish the long term glycaemic control and safety of INH.
Research is underway into new forms of insulin which do not need to be injected (Royle et al., 2009). The main disadvantage of injected insulin is that it does not mimic the natural state; short acting insulin is absorbed more slowly than ideal, with a slower rise than insulin released by the normal pancreas in response to a meal. However, although peak action is faster about 52mins compared to 145 minutes with regular soluble insulin, as reviewed by Gerich in 2002, it cannot match the 10 minute peak of pancreatic insulin.
Inhaled insulin may provide a practical, non-invasive alternative to injections, while achieving comparable glycaemic control and increased patient satisfaction and quality of life. However, it will still not completely eliminate the need for injections and the patient is required to take a once a daily injection of long acting insulin such as glargine (Henry et al., 2001). If inhaled insulin is to become a viable clinical option, longer term data on pulmonary safety and efficacy will be needed. Also, the marginal price and dosage required compared to subcutaneous insulin will be critical in determining whether it will be an economically viable alternative. In future, research could be divided into safety, efficacy and economics, for safety purposes we need long-term- follow up ( Ie years and not months) of large numbers of patients who use inhaled insulin (Royle et al., 2009). Large observational cohort studies would suffice for efficacy purposes, we need more studies which have the same basal insulin in both the inhaled and control groups, and it would be useful to use both short acting and long acting analogues in these.
Inhaled insulin is currently contraindicated in patients with asthma and other respiratory disorders, during pregnancy and in children (Becker et al., 2006). Greater caution is required in young children where the lung is still growing, and perhaps trials should be done first in the adolescent group, where many have poor control, which may cause long lasting damage needed. For economic analysis, it is important to include cost and quality of life data in future RCTs as the main gain from inhaled insulin is the quality of life. An economic analysis proposed by the manufacturers of Exubera suggests that treatment of inhaled insulin is cost effective in the long term (Black et al., 2007). The benefits are likely to be due to better adherence to treatment and reduced risk of long term complications.
The demand for inhaled insulin will place a considerable burden on the healthcare economy. NICE has recommended further research to establish the safety of inhaled insulin the long run and there are ongoing clinical trials related to this guidance include the Exubera real world classic study, which aims to assess the impact of inhaled insulin on glycaemic control in people with poorly controlled type 2 diabetes receiving two or more oral anti-diabetic agents (NICE, 2008). Once the work has been done, it won’t be long before inhaled insulin becomes reality.
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