REVIEW ARTICLE

Drugs Aging 2003; 20 (4): 303-312 1170-229X/03/0004-0303/$30.00/0 © Adis International Limited. All rights reserved.

Novel Drug Delivery Systems for Insulin Clinical Potential for Use in the Elderly Joël Belmin1 and Paul Valensi2 1 Service Hospitalo-Universitaire de Gériatrie Hôpital Charles Foix and Université Paris Nord, Ivry-sur-Seine, France 2 Service d’Endocrinologie-Diabétologie-Nutrition, Hôpital Jean Verdier and Université Paris Nord, Bondy, France

Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Use of Subcutaneous Insulin in Elderly Patients with Diabetes . . . . . . 1.1 Place in Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2 Choice of Regimen . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3 Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Alternative Routes of Insulin Delivery . . . . . . . . . . . . . . . . . . . . . 2.1 Oral or Rectal Insulin . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 Dermal Insulin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3 Buccal or Nasal Insulin . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4 Pulmonary Insulin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4.1 Formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4.2 Absorption and Distribution . . . . . . . . . . . . . . . . . . . . 2.4.3 Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Potential Clinical Use of Inhaled Insulin In Elderly Patients with Diabetes: More Questions Than Answers . . . . . . . . . . . . . . . . . . . . . . . . 4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Abstract

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Diabetes mellitus is a very common disease in the elderly and its complications are responsible for excess morbidity/mortality, loss of independence and impaired quality of life. Recent studies, while not performed in the elderly, have outlined the importance of achieving tight glycaemic control in order to prevent complications. Eighty years after its discovery, subcutaneous insulin remains a major treatment for diabetes. It is used as a first-line agent in type 1 diabetes, and in type 2 diabetes when oral antihyperglycaemic agents combined with diet and exercise fail to achieve an appropriate metabolic control. To avoid injections, other routes of insulin administration have been studied, including oral, dermal and rectal routes but they were not found to be appropriate for clinical use. Buccal or nasal insulin combined with absorption enhancers proved to have interesting properties. Inhaled insulin appears to be suitable for use in patients with diabetes because

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of its better bioavailability and a pharmacokinetic profile that mimics the time kinetics of insulin secretion after a meal. Clinical studies were conducted among small numbers of patients with type 1 or type 2 diabetes who had been treated with subcutaneous insulin. Inhaled insulin was given three times daily, just before meals, and was combined with a bedtime subcutaneous injection of long-acting insulin. In patients with type 1 or type 2 diabetes the metabolic control achieved with inhaled insulin was similar to that obtained with a subcutaneous insulin regimen. Tolerance of inhaled insulin was good and treatment satisfaction was better than that with the subcutaneous regimen. Insulin inhalation appears to be an interesting way of insulin delivery for elderly patients with diabetes. However, no studies have been conducted in elderly patients with diabetes to assess this route’s acceptability, convenience and ease of use in this particular population. In addition, it is necessary to conduct pharmacokinetic studies in the elderly because lung aging might reduce the bioavailability of inhaled insulin.

Diabetes mellitus is a disease characterised by an impaired carbohydrate metabolism resulting from an absolute or relative deficiency of insulin. Diabetes is responsible for increased mortality and morbidity and for an altered functional status and quality of life because of its numerous complications. These include myocardial infarction, heart failure, stroke, renal failure, loss of vision, amputation, peripheral and autonomic neuropathies, and vulnerability to infections. Diabetes is very common in the elderly, and up to 20% of patients aged 65 years and over were found to have diabetes in the US in the 1990s.[1,2] In France and the UK in the 1990s, the prevalence of diagnosed diabetes in patients over 65 years of age was estimated to be about 10%.[3-5] In the next decade the number of elderly patients with diabetes will continue to grow because of the increasing life expectancy in both the general and diabetic populations, a more sedentary lifestyle and increased prevalence of obesity, and the arrival of the babyboomers in the over 65-year-old age group.[1] Most elderly patients with diabetes have type 2 diabetes. A recent French survey carried out during the first quarter of 1999 showed that the prevalence of type 2 diabetes had grown by 5.7% annually between 1994–99.[6,7] Moreover, as the prevalence of undiagnosed diabetes increases with age,[2] bet© Adis International Limited. All rights reserved.

ter detection of diabetes in the elderly might also increase the number to be treated. 1. Use of Subcutaneous Insulin in Elderly Patients with Diabetes Exogenous insulin improves hyperglycaemia in patients with diabetes by inhibiting hepatic glucose production and enhancing glucose uptake in skeletal muscle. Insulin therapy is commonly used in elderly patients with diabetes. In the US, up to 25% of elderly patients with type 2 diabetes receive insulin.[8] In Europe, insulin is less often prescribed for elderly patients with type 2 diabetes, and in France insulin was found to be used by 6.5% of patients with diabetes in a population-based cohort of persons aged 65 years or more.[4] In UK nursing homes, insulin is used in 25–47% of elderly subjects with type 2 diabetes.[9-11] 1.1 Place in Therapy

There is no alternative for insulin in the treatment of patients with type 1 diabetes, who represent a significant fraction of all elderly patients with diabetes. Type 1 diabetes is characterised by an absolute deficiency of endogenous insulin secretion and the treatment with exogenous insulin is vital. Improved survival of patients with early-onset type 1 diabetes results in an increased prevalence Drugs Aging 2003; 20 (4)

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of type 1 diabetes in advanced age. Moreover, type 1 diabetes is described in very old persons,[12] and 5–10% of elderly patients with newly diagnosed diabetes have type 1 disease.[13] Type 2 diabetes, the commonest form of diabetes in the elderly, is mainly characterised by insulin resistance.[1,9,14] Therefore, administration of exogenous insulin is not logical, especially in overweight patients, and other therapies including diet, exercise and oral antihyperglycaemic agents should be tried first.[8,15-17] However, as the disease progresses, glycaemic control gradually deteriorates in many patients and the relative insulin deficit becomes more apparent. Insulin can then be considered for type 2 diabetics with uncontrolled hyperglycaemia and/or high glycated haemoglobin levels, despite adequate therapy including diet, physical activity and appropriate oral antihyperglycaemic drugs.[16,18,19] This strategy is supported by the results of the United Kingdom Prospective Diabetes Study (UKPDS) which showed that in adults with recentonset type 2 diabetes, the improvement of glycaemia by intensive therapy with a sulphonylurea or insulin is associated with a significant reduction in the risk of microvascular endpoints and the need for cataract extraction compared with conventional treatment with diet only.[20] Although the adults included in this study were younger than 65 years at entry, about half of them were older than 65 years by the end of the study; therefore, the UKPDS conclusions can be extrapolated to otherwise healthy elderly patients with diabetes and physicians should be encouraged to use insulin therapy for such patients if other therapies fail to achieve appropriate glycaemic control.[17,19] Exogenous insulin is temporarily used in patients with type 2 diabetes during surgery and the postoperative phase, and during intercurrent illnesses where severe hyperglycaemia may be a problem.[8,9,17] Some patients with type 2 diabetes require insulin after a life-threatening complication such as ketocetosis or hyperosmolar coma. In most cases, long-term insulin therapy is used after these complications to prevent their recur© Adis International Limited. All rights reserved.

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rence.[9,16,17] The use of insulin may also be justified by the age-limitations of certain oral hypoglycaemic agents[21] and has been made easier by the use of pre-filled insulin pens.[22] 1.2 Choice of Regimen

All the available types of subcutaneous insulin regimens can be used in elderly patients.[9,17] Short-, intermediate- or long-acting insulin preparations may be variously combined and the choice depends on the goal of the therapy. Insulin analogues such as subcutaneous insulinlispro can also be used in elderly patients with diabetes.[23] The rapid onset and short duration of action of insulin-lispro mimic the physiological secretion of insulin in response to a meal and allow better control of post-prandial glucose levels whilst limiting hypoglycaemic episodes.[23] Other short-acting insulin analogues, or a long-acting analogue such as glargine,[24] could in the future be considered for elderly patients with diabetes. Postprandial glycaemic levels could be controlled with the former and nocturnal hypoglycaemic levels managed with the latter. Therefore, a combination of these two types of analogue is expected to be beneficial. In type 2 elderly patients, a short-acting analogue may be combined with a sulphonylurea.[9] The goals of diabetes therapy, recently summarised by the American Diabetes Association,[18] determine the appropriate type of insulin regimen. In otherwise healthy elderly diabetic patients with no life-threatening condition, the goal of therapy should be similar to that for a younger adult with diabetes, i.e. to achieve a tight metabolic control via multiple insulin injections. Standard protocols are based on two daily injections, often comprising a mixture of regular and intermediate-acting insulin. The treatment regimen could even comprise three daily injections of short-acting insulin analogue before each meal and one daily injection of intermediate-acting insulin at bedtime. This type of protocol minimises the risk of hypoglycaemia occurring soon after the post-prandial period or late in the evening. In frail elderly subjects with Drugs Aging 2003; 20 (4)

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significant comorbidities and/or limited life expectancy, less strict glycaemic control is more appropriate, and the goal is to avoid hyperosmolar or ketocetosis coma and excessive hyperglycaemia. This can be achieved by a single daily injection of intermediate- or long-acting insulin.

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native routes of delivery have been extensively investigated in order to improve the pharmacokinetic profile of insulin and reduce the pain and inconvenience associated with subcutaneous injections, thus improving patients’ comfort.[28-30] To date, studies have been exploratory and conducted in young or middle-aged diabetic patients.

1.3 Tolerability

The use of insulin has limitations, especially when its aim is to achieve tight glycaemic control. Insulin therapy is associated with weight gain and hypoglycaemic episodes. In the UKPDS in middleaged patients with type 2 diabetes, the mean weight gain associated with insulin was 4kg, and the number of hypoglycaemia episodes was greater with insulin than with sulphonylureas, even though severe hypoglycaemia was rare.[20] Weight gain may amplify incapacity in elderly patients with diabetes who have associated diseases which may worsen with obesity, such as osteoarthritis, heart or respiratory failure.[25] In addition, increased body fat may worsen insulin resistance and carbohydrate metabolism. Hypoglycaemia may be more severe in elderly patients with diabetes because of impaired counter-regulatory hormone secretion and reduced awareness of hypoglycaemic warning symptoms,[26] and injuries from hypoglycaemiarelated falls may be more severe in the elderly than in other age groups. Many elderly patients experience visual impairment, low dexterity or cognitive impairment and cannot perform self-injections of insulin.[27] In these cases, insulin therapy requires the help of a visiting nurse or family caregiver. Furthermore, subcutaneous injections of insulin induce discomfort and may be inconvenient for many people. Consequently, the choice of anti-diabetic treatments and insulin regimen for elderly patients must be based on an overall evaluation, including diabetic complications, comorbidities, cognitive disorders and the familial and social environment.[14,27]

2.1 Oral or Rectal Insulin

Insulin administration via the digestive tract is an attractive route because it allows portal insulin delivery and direct distribution to the liver. However, orally administered insulin is rapidly inactivated by the proteases of the gastrointestinal tract. To avoid insulin degradation, attempts have been made to administer insulin encapsulated into liposomes,[31] but even when insulin is directly conveyed into the gut, it is poorly absorbed with unpredictable kinetics.[29] Insulin has also been administered through the rectal mucosa via suppositories containing insulin and various absorption enhancers. The extent of insulin absorption is better than the oral route but still remains low. In addition, insulin suppositories were associated with adverse effects such as discomfort or rectal urgency[28,32] and their use just before meals was not practical. 2.2 Dermal Insulin

2. Alternative Routes of Insulin Delivery

The application of insulin onto the skin results in very poor systemic penetration. Attempts to increase the transfer of insulin across the skin have consisted of applying an electrical potential (iontophoresis),[33] chemical substances or ultrasound in order to weaken the skin barrier,[34] but bioavailability remained very low.[29] The incorporation of insulin molecules into vesicles of lipid particles resembling liposomes (Transfersomes™1) improved transdermal insulin transport, but the efficacy and reproducibility of this new technique require further investigation.[35] In addition, the kinetics of insulin transport remains slow, making the dermal

Since the discovery of insulin in the 1920s, it has been used parenterally to treat diabetes. Alter-

1 Tradenames are used for product identification purposes and does not imply endorsement.

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route unsuitable for controlling post-prandial hyperglycaemia.[28,29] 2.3 Buccal or Nasal Insulin

The nasal or oropharyngeal mucosa offer other potential routes for insulin administration. A liquid formulation of insulin, using microfine membranes of mixed micelles and absorption enhancers which encapsulate insulin, was designed to be administered by buccal spray, using a simple dose inhaler.[36,37] The spray produces a fine particle aerosol and insulin appears in the systemic circulation 10 minutes after administration. Insulin via this route was found to lower blood glucose and C-peptide plasma levels and raise serum insulin levels in healthy humans. Pre-prandial administration to patients with diabetes led to a metabolic effect similar to that of subcutaneous injection. However, the bioavailability of buccal insulin was low, at less than 10%.[37] Insulin has also been formulated in a spray for nasal administration. Nasal insulin formulations contain absorption enhancers such as bile acids or chemical surfactants. However, bioavailability is low, at about 10%.[38] The absorption of nasal insulin is very rapid and the onset of action occurs 10–15 minutes after administration.[38,39] This pharmacokinetic profile is very attractive as it mimics physiological first-phase insulin secretion during a meal. However, clinical studies gave conflicting results. For instance, Coates et al.[40] found that the effect of nasal insulin was brief, resulting in less-than-optimal post-prandial glucose control. Attempts were made to improve glycaemic control by using two or three nasal insulin administrations to cover one meal, but this approach is not practical for patients. On the other hand, Frauman et al.[41] and Salzman et al.[39] found that the efficacy of nasal insulin was acceptable for long-term treatment of type 1 diabetes, and Lalej-Bennis et al.[42] reached the same conclusion for patients with type 2 diabetes. However, Hilsted et al. found a high rate of therapeutic failure and deterioration of metabolic control with nasal insulin in patients with type 1 diabetes.[43] In addition, nasal irritation was © Adis International Limited. All rights reserved.

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very frequent with the main problems being a congestive mucosa at rhinoscopy and loss of ciliary cells with reduced mucociliary clearance.[42,43] Another problem encountered with nasal insulin is the large inter- and intra-individual variation in bioavailability, probably because of the variable mucus production of the nasal mucosa.[29] 2.4 Pulmonary Insulin 2.4.1 Formulations

Inhalation of aerosolised insulin is a very promising route for insulin administration.[29,44-47] Innovative inhaler systems can generate particles of insulin of a suitable size (diameter <6μm) for deep penetration into the lung, a prerequisite for transport across the pulmonary epithelium into the blood. Larger particles precipitate in the oropharynx or bronchial tractus. Using a technetiumlabelled aerosol technique, Laube et al.[48] found that a mean 79% of the tracer (range 50–93%) was deposited in the lung with an inhaler system producing particles of 1.13μm diameter. Several formulations of inhaled insulin combined with different inhaler systems have been studied. Laube et al.[46,48,49] used a regular pork insulin solution and a nebulisation system comprising of aerosolisation by compressed air activation and a 700ml inhalation holding chamber with a mouthpiece. However, more convenient inhalers have been designed for the use of liquid insulin.[29,50] One formulation of human recombinant insulin dry powder was developed for use with a modern handheld inhaler.[51,52] Insulin 1 or 3mg was packaged into individual blisters which are then opened in the inhaler, resulting in powder dispersion and the generation of an aerosol cloud which is captured in a holding chamber. The patient then inhales, with one inhalation delivering to the systemic circulation the approximate equivalent of 3IU of subcutaneous insulin when the 1mg blister is used and 9IU with the 3mg blister. In another insulin dry powder formulation, a bile salt was added as an absorption enhancer.[53] Synthetic particles designed to be drug carriers (TechnoDrugs Aging 2003; 20 (4)

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sphereTM) were also used for pulmonary administration of insulin delivered via a simple inhaler.[54] 2.4.2 Absorption and Distribution

Inhaled insulin is transported through the alveolar capillary barrier, probably by a transcytosis mechanism.[44] Insulin appears in the systemic circulation 10 minutes after inhalation and its peak effect occurs after around 60 minutes,[55] which is similar to that of insulin analogue lispro and sooner than subcutaneously injected regular insulin, whose peak effect occurs 120–360 minutes after administration. This pharmacokinetic profile makes inhaled insulin suitable for mealtime administration and mimics the physiological time kinetics of endogenous insulin.[29,55] In addition, as the effect of inhaled insulin lasts for a shorter time than that of subcutaneous regular insulin, this might reduce the risk of hypoglycaemia occurring 2–4 hours after meals or at night.[44] The bioavailability of inhaled insulin was found to be 10–20% with a good intra-individual variability.[53] Part of the inhaled insulin is lost in the inhaler device, part is deposited in the mouth or larynx and the amount that reaches the alveoli is estimated at 20–40%.[29,44] About half of the insulin which reaches the alveoli is absorbed.[29] This bioavailability profile implies that large amounts of insulin must be placed in the inhaler device to obtain a significant rise in the plasma insulin level, as the relative bio-potency of inhaled insulin was found to be about 10% of subcutaneous regular insulin.[29,44] The dose to be administrated can be adjusted by placing different doses of insulin powder in the inhaler and also by the number of breaths to be taken.[51,52] 2.4.3 Efficacy

Clinical studies of inhaled insulin have been conducted in patients with type 1 and type 2 diabetes. Skyler et al.[51] conducted a 12-week open-label randomised trial in 73 young patients with type 1 diabetes, who at inclusion had been treated by a stable subcutaneous insulin schedule. Thirty-five patients were randomised to receive inhaled insulin before meals combined with subcutaneous injections of long-acting insulin at bedtime. In the © Adis International Limited. All rights reserved.

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control group, the patients’ usual insulin regimen (two or three injections daily) was continued. Glycated haemoglobin was 8.5% at entry and dropped nonsignificantly to 7.9 and 7.7% in the treatment and control groups, respectively, after 12 weeks. Another study by the same group was conducted in 26 patients with type 2 diabetes who had also been treated by a stable schedule of subcutaneous insulin.[52] They were relatively young, with a mean age of 51 years (range 39–64 years). Inhaled insulin combined with bedtime long-acting subcutaneous insulin was given for 12 weeks. Glycated haemoglobin significantly decreased during the trial from 8.6% at baseline to 7.1% after the 12week treatment period. No respiratory symptoms were reported in either of these two trials and pulmonary function tests were not affected by insulin inhalation.[51,56] On average, patients with type 1 diabetes experienced 5.5 mild to moderate hypoglycaemic episodes per patient.month and 0.08 severe episodes per patient.month.[51] In patients with type 2 disease, the incidence of mild to moderate hypoglycaemia was 0.83 per patient.month and no severe hypoglycaemia was recorded.[52] 3. Potential Clinical Use of Inhaled Insulin In Elderly Patients with Diabetes: More Questions Than Answers The use of alternative delivery routes to subcutaneous administration for insulin administration has several advantages. In particular, inhaled insulin appears, at present, to be the most promising non-invasive route for insulin administration. A major advantage of a non-invasive route is to suppress or reduce the number of subcutaneous injections and alleviate the discomfort they involve. A randomised controlled trial of 69 young patients with type 1 diabetes showed that patients definitely prefer a treatment regimen of inhaled insulin three times daily plus bedtime subcutaneous insulin to a standard regimen of subcutaneous insulin.[57] A 15item questionnaire about satisfaction with treatment showed a significant improvement in overall satisfaction, convenience/ease of use and social comfort with inhaled insulin compared with a Drugs Aging 2003; 20 (4)

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standard insulin administration schedule of two or three injections daily.[57] Another study has examined treatment satisfaction in a randomised trial comparing a three times daily inhaled insulin regimen with a standard subcutaneous insulin regimen in type 2 diabetes.[58] A significantly higher satisfaction level was also documented in this trial. Note, however, that in these studies, patients used syringes and standard needles whereas the use of a pen-injector device with smaller and sharper needles would have been more convenient and less painful. Treatment satisfaction with inhaled insulin should be compared with that of peninjector devices.[59] Furthermore, in our view, convenience and ease of use should also be studied specifically in elderly patients with diabetes. Many of them may have limitations as regards dexterity, the ability to prepare inhaled powder and the inhaler, and the ability to breathe deeply and appropriately when using the inhaler. In elderly patients with diabetes who need help for treatment administration, their ability to co-operate with caregivers for inhaled insulin administration should also be studied. Inhaled insulin might also modify, to some extent, the mental approach of patients and physicians to insulin therapy. Insulin injections are often considered a symbol of psychological bondage and dependency on a life-long treatment and affect patients’ self-image, social relations and daily existence. Therefore, as insulin is probably underused in elderly patients with type 2 diabetes because of the fear or refusal of injections, the availability of less invasive delivery routes might lead to an increase in the number of patients treated with insulin. An expected consequence is an improvement in the metabolic control of type 2 diabetes; thus, improving the outcome and quality of life of these patients. Note, however, that inhaled insulin has so far only been used in combination with bedtime long-acting subcutaneous insulin injection, a regimen that does not completely suppress the need for subcutaneous insulin.[51,52,56] The pharmacokinetic profile of inhaled insulin is very suitable for elderly patients with diabetes © Adis International Limited. All rights reserved.

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because it mimics the physiological response time of insulin secretion after a meal. The duration of its effect is shorter than that of subcutaneous regular insulin,[47,49] which, as already mentioned, might reduce the risk of late-onset hypoglycaemia. This may be clinically meaningful, particularly in overweight elderly patients with type 2 diabetes who show higher post-prandial insulinaemia than patients with type 1 diabetes or healthy subjects. However, as yet, no reduction in the frequency of hypoglycaemic episodes has been demonstrated with inhaled insulin in studies in the elderly, making this advantage more theoretical than established. However, the pharmacokinetic profile of inhaled insulin does make it more appropriate for tight metabolic control. Such a goal of therapy should be considered for otherwise healthy elderly patients with diabetes, with no life-threatening disease,[18] and participation of the patients and their caregivers in the treatment regimen is crucial. On the other hand, in frail elderly patients with diabetes with severe diseases and/or dependency which limits their life expectancy or active involvement in the treatment, tight metabolic control is not an appropriate goal and may be harmful.[14,27] For such patients, inhaled insulin is not of interest unless perhaps, in the future, inhaled long-acting insulin becomes available. A point which underlines the need for specific clinical trials involving elderly patients with diabetes is the possible existence of age-related changes in the pharmacokinetics of inhaled insulin. With advancing age, several changes in lung structure and functions have been described, including reduced alveolar area,[60] elastic recoil and qualitative changes in the elastic and collagen fibres of the alveoli,[60] low-grade inflammation,[61] fall in alveolar capillary volume associated with ventilation-perfusion mismatch,[62] decreased diffusion of carbon monoxide across the alveolar capillary membrane,[63-65] and increased residual volume and closing capacity.[66] In addition, the alveolar clearance of diethylene triamine pentaacetate was found to be reduced in elderly subjects,[67,68] indicating an age-related decrease in Drugs Aging 2003; 20 (4)

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the transport of this compound across the alveolar capillary membrane. Aging can therefore be expected to reduce the bioavailability of inhaled insulin. Concern has been expressed about the tolerability of inhaled insulin in patients with heart or lung diseases. Even if inhaled insulin has no detectable short-term effects on pulmonary function tests,[51,56] its long-term effects should be studied to establish that it is well tolerated. Smoking was found to increase the bioavailability of inhaled insulin,[69] but it is not known whether pulmonary diseases modify its bioavailability and/or intra-individual reproducibility. Since insulin is a potent vasodilator which stimulates the release of nitric oxide by the vascular endothelium,[70] the effects of inhaled insulin on the pulmonary vascular bed of patients with diabetes and heart disease is a matter of concern, because inhaled nitric oxide can induce pulmonary oedema in patients with cardiac dysfunction.[71] This point is probably very relevant for elderly patients with diabetes who often have cardiac dysfunction, which is often subclinical, because of cardiovascular aging, diabetic cardiomyopathy and/or cardiac complications of hypertension and coronary atherosclerosis.[72] In a recent study, insulin antibodies were assessed in patients with type 2 diabetes, refractory to combination oral agents, who were treated with inhaled insulin therapy. After 3 months of therapy, patients developed increased serum insulin antibody titre (5% vs 1.5% in the control group who continued to receive oral agents), without any apparent clinical change.[73] The economic aspects of inhaled insulin administration should also be taken into account, irrespective of the age of the patient with diabetes. Because of low bioavailability, large amounts of insulin have to be administrated by the inhaled route to obtain the same efficacy as that of subcutaneous injections of regular insulin. In the study by Cefalu et al.,[52] patients with type 2 diabetes were given on average 14.6mg of inhaled insulin per day (more than 400IU) whereas they were previously given only 19IU per day of subcutaneous © Adis International Limited. All rights reserved.

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regular insulin. Thus, with inhalation, more than 90% of the insulin is lost in the air, the device or the upper airways, which is a considerable waste considering the costly manufacturing process. Inhaled insulin might therefore be a very expensive alternative treatment to subcutaneous insulin[74] and indeed was qualified by Gale as ‘a new luxury insulin’.[59] 4. Conclusion In more and more elderly patients with diabetes, the need for strict glycaemic control is justified. This requires multiple insulin administrations. Alternative routes of insulin delivery seem to have potential to help patients achieve this goal and improve satisfaction and comfort with their treatment regimen. In particular, insulin inhalation appears to be an interesting way of insulin delivery for elderly patients with diabetes. However, no studies have been conducted in elderly patients with diabetes to assess this route’s acceptability, convenience and ease of use in this particular population. In addition, it is necessary to conduct pharmacokinetic studies in the elderly because lung aging might reduce the bioavailability of inhaled insulin. Acknowledgements No sources of funding were used to assist in the preparation of this manuscript. The authors have no conflicts of interest that are directly relevant to the content of this manuscript.

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Correspondence and offprints: Professor Joël Belmin, Service Hospitalo-Universitaire de Gériatrie, Hôpital Charles Foix et Université Paris Nord, 7 avenue de la République, Ivry-sur-Seine, 94200, France. E-mail: [email protected]

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