Personal Report on the place of inhaled insulin in the NHS. Submitted to the Appraisal Committee of the HTA. 3 rd March 2006

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1 Personal Report on the place of inhaled insulin in the NHS Submitted to the Appraisal Committee of the HTA 3 rd March 2006 Stephanie A Amiel, BSc, MD, FRCP RD Lawrence Professor of Diabetic Medicine King s College London School of Medicine I am basing this report on the following experience: I am the lead clinician for the Diabetes Service at King s College Hospital, London, a very large secondary care diabetes service with a significant tertiary practice, serving an urban community and south London. We have approximately 8,000 patients on our lists, excluding the eye screening service. Our local population has a high proportion of people of African-Caribbean origin, increasing its prevalence of Type 2 diabetes. Within the general service, I have specialist clinical expertise in intensified insulin therapy, including DAFNE and insulin pump therapy; the management of diabetic pregnancy and diabetes in adolescents and young adults. I am also an active clinical researcher in diabetes, with particular interests in the causes and management of problematic hypoglycaemia in diabetes; brain function in diabetes and the pathogenesis of insulin resistance. I have also served on advisory panels to industry including for Pfizer and Sanofi Aventis during the development of inhaled insulin; and have spoken on inhaled insulin at an industry sponsored educational symposium. I have reported on behalf of the Association of British Clinical Diabetologists on the HTA for inhaled insulin, discussed the attraction of an inhaled insulin with patients and colleagues, and have consulted the literature on the topic of inhaled insulin and related issues. I broadly support the conclusions reached in the HTA systematic review and economic evaluation, which I interpret as saying that: Inhaled insulin in the form of Exubera has demonstrated comparable efficacy to conventional soluble (short acting) insulins but that it has shown no biomedical advantages and has not been compared to current optimised multiple daily insulin injection therapy with analogue insulins. Exubera as meal-time insulin replacement may or may not be able to perform as well as these state-of-the-art but now commonly used therapies. The only but potentially significant advantage of Exubera is therefore the freedom from injections. Potential disadvantages include an unknown, but probably minor, effect on the lung over time; lack of flexibility in dosing changes will be no less than 3 units at a time and large doses will require multiple inhalations, each with a new capsule insertion; the unfamiliar dosing schedule occasioned by the low bioavailability of the preparation (Exubera doses will be in mgs not units, 1 mg approximately equivalent to 3 units and with slightly different doses occurring depending on how the total dose is arrived at); the increased anti-insulin antibody formation seen with inhaled compared to injected highly purified insulins, particularly in Type 1 patients and the exclusion of smokers and people with significant lung disease from its use. There is also the issue of cost, which is likely to be significantly more than even the expensive analogue injected insulins (and considerably more than conventional highly purified animal and human insulins) and will be further inflated by the need to train Health Care Professionals as well as patients in its proper use and the need for lung function testing initially and perhaps during therapy. These disadvantages might be outweighed by the relief of patients from the need to inject, but it should be stressed that there are no data to show that patients outside the study setting will be more willing to take multiple daily insulin inhalations than injections there is evidence from the asthma literature to suggest that full compliance with inhaled drug should not be taken for granted. Using inhaled rather than injected insulin will not alter the need for home blood glucose monitoring, nor the need to consider each insulin dose injected or meal eaten in the light of its possible effect on the blood glucose. Inhaled insulin will not remove fears of high or low blood glucose concentrations. In my opinion, the potential usefulness of Exubera needs to be considered separately for Type 1 and Type 2 patients.

2 In Type 1, there is evidence to show that multiple daily injection therapy, using one or two daily injections of intermediate acting insulin for basal (background) replacement (for the control of the body s own tendency to make glucose) and fast acting insulins at every significant food intake, can be associated with better glycaemic control and less nocturnal hypoglycaemia. Inhaled insulin might be worthwhile in Type 1 patients if its availability encouraged people to convert to such multiple daily injections regimens from less physiological regimens such as twice daily mixtures of insulin IF this conversion was demonstrated in clinical practice to be associated with clinically significant improvements in glucose control. There are no data to support or refute this hypothesis. An increasing number of Type 1 patients are now using flexible insulin therapy. In this, meal insulin injections are adjusted in time and dose according to the food about to be eaten and the measured blood glucose. Such regimens have been shown to improve both glycaemic control and quality of life. DAFNE is one example of such a regimen, For these patients, and perhaps for many others with well-controlled Type 1 diabetes, the injections themselves are not the most important problem. In conversations with patients on our DAFNE course, the views were uniformly expressed that it is the need for blood testing and constant vigilance that are the main problems, not the injections themselves. The relative inflexibility of dosing with Exubera and the need for multiple inhalations for larger doses are real problems in regimens where doses are adjusted one unit or even 2 - units at a time, so that an insulin that is altered in 3 unit doses will be a problem. This problem will apply to any Type 1 patient who is very insulin sensitive, and thus using small doses. Furthermore, the tendency to form anti-insulin antibodies in Type 1 patients should not be dismissed. We have spent the last 30 years making insulins cleaner in order to reduce antibody formation. This has been deemed useful because antibodies can retard and render unpredictable the action of an insulin. High levels of anti-insulin antibodies have also in the past been implicated strongly in increased hypoglycaemia risk; associated with a greater tendency to lipohypertrophy and suspected of contributing to the risk of microvascular disease in the form of albuminuria. Antibodies can also carry insulin across the placenta in pregnancy. There is a small but important subgroup where needle phobia and/or cultural issues may make injection therapy particularly difficult. There are some cultures where injection therapy seems to be particularly feared and there are some patients with chronically poor control where it is clear that insulin avoidance is a major contributor. This will be associated with high HbA1c (usually > 10%) reflecting poor glycaemic control. Exubera could be very useful in improving glycaemic control in these selected patients, although background insulin injections will remain necessary in Type 1 patients and the inflexibility of dosing may be a barrier. I would welcome studies to show that the availability of inhaled insulin did achieve significantly better HbA1c levels in such cases. Meanwhile, in a clinical setting, use of inhaled insulin may be beneficial for these patients. Were one to prescribe inhaled insulin clinically for such a patient it would be important to monitor the HbA1c and only continue the prescription if a significant fall (e.g. < 8.5% or by at least 1.5%, whichever is greater) was achieved and sustained, implying obvious clinical benefit in terms of reduced risk of long term complications, which might be expected to outweigh any potential long term risk associated with the inhaled insulin and the added cost. Antibody levels might need to be monitored and if present, the inhaled doses replaced by injected if pregnancy was required. Patients with Type 2, who lose insulin secretory capacity over time, can delay insulin initiation by choice and often do so for prolonged periods, while they and their health care professionals hesitate over injection therapy. In theory this could be the group really helped by availability of inhaled insulin, if, in overcoming fear of injection, it allowed for the introduction of insulin several years earlier, preventing prolonged exposure to HbA1c > 6.5%. Furthermore, there is much less antibody formation and perhaps less pulmonary change with Exubera in Type 2. It should be noted that the trials of Exubera did not achieve such good HbA1c levels universally and performed no less well than conventional therapy. Furthermore, it is not just injection therapy that diminishes enthusiasm for early insulin initiation fears of insulin resistance and lack of efficacy and fears of insulin-driven weight gain from the Health Care Professionals and feelings of failure and memories of insulin treatment being started in

3 association with major complications in family members are probably more important. These fears will not logically be reduced by elimination of the injections. It is also important not to equate inhaled insulin with easy insulin risks of hypoglycaemia are not going to be less and the need to monitor glucose control and adjust doses around life style changes will not be affected by route of administration. Another important consideration is the changes in practice that are occurring across the UK for insulin initiation in Type 2 diabetes. Healthcare professionals across primary and secondary care are increasingly adopting a regimen for the initiation of insulin in type 2 diabetes in which a single injection of a background insulin is added to oral hypoglycaemic agents. This is associated with mimimised weight gain and hypoglycaemia risk and has been demonstrated to be effective in improving HbA1c. Doses are adjusted against the prebreakfast blood glucose. Powerful marketing of the newer peakless background insulins in which an apparent reduction in night time hypoglycaemia is stressed has given nonspecialists more confidence in starting insulin earlier and compliance with new contracts in primary care which offer financial incentive for achieving better HbA1c in diabetic patients is having a major impact on the willingness of HCPs to encourage early insulinisation. Greater confidence with insulin therapy among HCPs will reduce fear in patients. Until current studies comparing the efficacy of different insulin start regimens is completed, we have no data to show that meal related insulin administration is better than background insulin only and the simplicity of one bedtime insulin injection with its limited exposure to injection and its relative freedom from weight gain, hypoglycaemia and multiple daily blood testing, plus the extensive long term safety data of injected insulin makes it hard to see that three or more administrations of inhaled insulin will be more attractive to patients in general or result in better compliance or glycaemic control. Educational and psychological approaches can reduce fear of insulin therapy in Type 2 and can be very successful with conventional therapy. It would however be useful to have inhaled insulin as an option to offer when patients failing on bedtime insulin and oral agents alone need to intensify treatment by adding meal time insulin for those patients who remain fearful of injections and for those whose fear is such that they cannot start insulin by injection at all. The number of patients that might fall into these categories is not known. Again, continued prescription should be around sustained demonstrable improvement in metabolic control. In conclusion, I have never believed in replacing tried and tested familiar drugs with newer versions without long term safety data except in specific circumstances where a new property of the new agent can reasonably be expected to benefit the individual patient and his/her problem. For patients where fear of injection is deemed to be a major barrier to improving diabetic control, there is potential for major benefit from a non injectable insulin and its development should be welcomed for such patients. However, the size of this benefit and most especially the number of patients who might start or intensify insulin therapy - is not clear from current data. Importantly, the dangers inherent in any insulin therapy will not be avoided by the use of the pulmonary route and long term consequences of the inhaled route and the recurrence of high levels of insulin antibodies (in Type 1s) remain to be assessed. A guideline allowing use of Exubera in patients where fear of injection therapy is deemed by the patient and HCP to be the major barrier would be welcome but it is in the interests of the NHS budget that restrictions related to demonstrable and significant falls in HbA1c should be placed on long term prescribing for any individual. Stephanie A Amiel March 2006

4 Dear David, Thank you for sending me Tony Barnett s reports for the HTA on inhaled insulin. I do not think we disagree in fundamentals but we do indeed seem to have quite different emphases. I am afraid I have not had a chance to discuss these with him. Tony almost certainly has had more patients using Exubera in trials than I and it is possible those patients have liked it so much that he feels the case for patient preference is robustly made. Without that experience, I cannot agree. I do accept that if the availability of a non-injectable insulin made insulin use much more readily acceptable to patients, inhaled insulin may have enormous impact on the health of the Type 2 diabetic population. However, there are points that I do not think Tony has necessarily considered in the same light as I. I have pointed out that the introduction of insulin to Type 2 patients is not a stable playing field. There is a rapidly growing confidence in primary care to start insulin I assume because of the ease and safety of starting insulin as a single bedtime injection of a long acting insulin; the well-publicised (if less well justified!) reduction in nocturnal hypoglycaemia rates with peakless insulin analogues such as glargine (Lantus) and detemir (Levemir) and the GP contract increasing enthusiasm for more aggressive glycaemic control. Exubera has not been compared for efficacy and acceptability against these simple once daily regimens in Type 2 patients failing on oral agents. And we do not yet know if meal insulin replacement as a first line insulin therapy in Type 2 has any benefit (or disadvantage) compared to basal insulin replacement until we do, a confidentlyrecommended once daily injection may well be as saleable to patients as multiple inhalations. Going one step further in the Type 2 patients need for insulin, we do not have many data on the problems patients experience if, having started basal insulin replacement and grown accustomed to modern injection therapy, they are asked to add in meal injections. I am also more cautious than Tony about the public health benefits of inhaled insulin because of the literature on compliance with inhaled drugs in chest patients. I also accept the HTA report s suggestion that HCP reasons for avoiding insulin are not just about injections weight gain is a major issue, as are fears of lack of efficacy, potential impact on employment opportunities, association with ideas of worse disease and the need for very large doses. Large doses in Type 2s with Exubera will mean multiple inhalations per meal, which may further reduce compliance. If fear of injection is the main reason for delaying insulin, the provision of inhaled long term should produce major falls in HbA1c perhaps > 1.5 2%. In Type 1 diabetes, I remain concerned about dose inflexibility and the possible long-term effects of anti-insulin antibodies, which have not been adequately addressed. I don t think we know enough about the nature of the antibodies described in the Type 1 patients on inhaled, and I think insulin antibodies should be monitored in this group, especially in fertile females. Tony s suggestion that more Type 1 patients might move to multiple daily insulin administration regimens if they did not have to inject is possible and might be important although it is absolutely clear that multiple daily insulin dosing per se does not improve control. Only where MDI is used with robust education programmes and patient self-monitoring and dose adjustment are its benefits clearly seen. Inhalation vs injection is but a small part of this type of management. Indeed, I do not agree with Tony that inhaled insulin should be considered outside the context of structured education programmes for Type 1 diabetes with only about 16% of Type 1s in the UK with normoglycaemic HbA1c, strategies that can improve glycaemic control are essential DAFNE and its ilk can achieve this. After discussion with DAFNEtrained patients (who are by and large admittedly well motivated for self care), I really don t think there is much role for an inhaled insulin that alters in 3 unit increments here. With regard to the, to my mind, regrettable use of twice daily mixed insulins for Type 1 patients, it has to be said that there are indeed HCPs who still favour this therapy and I don t think for a moment this group of HCPs will suddenly encourage their patients to multiple daily insulin administrations just because it does not need injections. I do share with Tony surprise at the relatively small benefit the HTA document describes will be expected if Type 2 patients achieve tight glucose control earlier as a result of earlier introduction of insulin. This has to my mind always been the potential appeal of a non-injectable insulin. I do agree with Tony that the long term benefit of avoiding 4 6 years of hyperglycaemia is probably much greater than modelled in the HTA document. My concern is the lack of evidence as yet that having inhaled insulin around will achieve the improvement required. And the lack of evidence that meal-time insulin replacement is the place to start my own bias would be that one injection at night, with

5 minimal weight gain and risk of hypoglycaemia is a much better option, that I think most patients accept. If this insulin were cost-equivalent to injected insulin, would I be more positive? I suspect so for the Type 2 indication. But if it won t be, we have is a more expensive agent, naturally lacking long term safety data, that is equivalent in trial settings to non-optimised injection regimens. And there are hidden costs to be considered, with a whole new series of patients requiring pulmonary function tests and a large HCP and patient education programme required. Of course Tony is right that the availability of inhaled insulin will increase patient choice. I do therefore welcome the advent of a non-injectable option - there is no doubt that a non-injectable insulin has been sought for a long time. But patients choices are enormously influenced by the opinions of their health care professionals and I would worry about the wholesale use of inhaled insulin just because HCPs are unenthusiastic about injections, especially in the absence of any data to suggest that inhaled insulin is safer than injected. It isn t and if it is perceived by HCPs as an easier insulin to use, not requiring all the usual monitoring and safety precautions, we will not see its potential benefits realised. It is still my view that prescription should be limited to those in whom there is real evidence that fear of injections is the main barrier to their achieving good glycaemic control and that prescription should only be continued where there is evidence of on-going major improvement in diabetes control. I would still see background insulin replacement as the optimum first line therapy for Type 2 patient failing oral agents alone and I would want to be able to offer inhaled insulin then to Type 2 patients failing oral agents and background insulin where meal insulin replacement is considered impossible because it means more injections. For Type 2s not yet on insulin, I would think we should make very sure that once daily injection is impossible for that patient before trying multiple daily doses of inhaled and I would continue inhaled in either scenario if there was clear evidence of biomedical improvement. For Type 1s I would be very cautious indeed but would welcome a study in people with really poor control, where it is thought that insulin avoidance is a problem. I would wish to be able to try it in someone who had really poor glycaemic control because of avoiding injections (rather than avoiding insulin per se) especially if I had no access to effective treatment for needle phobia! Even in that setting, pump therapy has more robust long term safety data. I hope this makes sense and will be interested in further discussions. Yours sincerely Stephanie A Amiel, BSc, MD, FRCP RD Lawrence Professor of Diabetic Medicine