Inhaled insulin as alternative delivery system for subjects with diabetes A literature review

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ABSTRACT

Application of insulin via the pulmonary route has been inves-tigated since about eighty years, and the first inhaled insulin prepa-ration might be commercially available soon. This review gives a detailed, tabulated overview of the available literature on the safe-ty and efficacy of inhaled insulin in pre-clinical and clinical tri-als. Data on the time-action profile of inhaled insulin will be pre-sented as-well as the published effects of inhaled insulin on clin-ical endpoints such as HbA1c, hypoglycemia, and treatment

sat-isfaction. Additionally, the potential risks of inhaled insulin, in particular concerning insulin antibodies and lung function para-meters will be discussed. Thus, the aim of this review is to give the reader sufficient details to assess the risk-benefit ratio of inhaled insulin on their own.

Key Words:Inhaled insulin; safety; HbA1c; hypoglycemia; treat-ment satisfaction

Revisión Av Diabetol 2005; 21: 91-102

T. Heise1_{, C. Kapitza}1_{, M. Hompesch}2_{, L. Heinemann}1

Inhaled Insulin as alternative

delivery system for subjects

with diabetes – A literature

review

Recibido:19 de Abril de 2005/ Aceptado:26 de Abril de 2005

Acrónimos:DLCO, carbon monoxide diffusion capacity; GIR, glucose infusion rates; MMAD, mass median aerodynamic diameter; sc, subcutaneous.

1_{Profil Institut für Stoffwechselforschung GmbH}

(Profil Institute for Metabolic Research, Limited) Neuss, Germany. 2_{Profil Institute for Clinical}

Research, Inc., Chula Vista, CA, USA

Corresponding author:

Tim Heise, MD

Profil Institut für Stoffwechselforschung GmbH Hellersbergstr, 9. 41460 Neuss. Germany e-mail: [email protected]

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INTRODUCTION

Recently, a lot of attention has been paid to the devel-opment of alternate routes of insulin administration, in par-ticular inhaled insulin. The first compound for insulin inhala-tion has been submitted for approval to European and American Health Authorities1_{, and thus might be available} soon. The look for an alternate insulin administration form might be surprising as, due to the development of modern insulin pens, subcutaneous (sc) insulin injection can nowa-days be considered as a safe and nearly painless adminis-tration form2_{. On the other hand, it has been well known} that, for many reasons, subjects with type 2 diabetes (and probably subjects with type 1 diabetes as-well) do not like insulin injections and therefore hesitate to start with insulin therapy, even if they can no longer achieve satisfactory glycemic control with oral antidiabetic agents3_. Further-more, due to the suboptimal pharmacodynamic properties of sc insulin, namely a too slow onset of action and a too long duration of action4_{, most patients fail to reach the} rec-ommended goals for glycemic control5_{. Finally, subjects} with diabetes often conceive the needle “not just as an irk-some necessity but a symbol of their bondage to an invis-ible parasite”6_.

In fact, alternate routes of insulin administration have been investigated very soon after the discovery of insulin7 – including dermal, oral, nasal and pulmonary application8_. Of these developments, inhaled insulin seems to be the most promising. The lung offers nearly ideal conditions for the absorption of peptides including a vast (in humans 50-140 m2_{, ~500 millions of alveoli) and well-perfused} absorp-tive surface (~5 l blood/min, pulmonary capillary blood volume ~0,25 l), a thin alveolar-capillary barrier, and the absence of both degrading peptidases (in contrast to e.g. the gastrointestinal tract) and a “first pass metabolism” in the liver9_{. Nevertheless, pulmonary insulin administration} is also involved with some difficulties: As larger amounts of insulin can only be absorbed in the alveoli, insulin par-ticles must be within a narrow range to reach the deep lung with the optimal particle size being in the range of 1-5 µm9,10_{. Indeed, the mass median aerodynamic diameter} (MMAD) of powder particles has been correlated with alve-olar deposition11_{. These technical difficulties have been} solved by several developments of inhaled insulin (com-prising pulmonary administration of both dry powder and liquid aerosols), so that to date a number of investigations on inhaled insulin have been published. The aim of this current review is to give an overview of the available

lit-erature on preclinical, and the early and late phase clini-cal development of inhaled insulin. Rather than trying to give a complete summary of the rather extensive literature, this review fill focus on publications representative for the clinical development of the various inhaled insulin prepa-rations. Details of these publications are summarized in Table I.

PRE-CLINICAL STUDIES

Animal studies have been conducted to characterize the pharmacology and disposition of insulin given by inhala-tion. These studies focused on the efficacy, but perhaps even more on the safety of inhaled insulin, i.e. on the effect of insulin on the lung itself. This is based on the assump-tion that, upon reaching the circulaassump-tion, the pharmaco-logical effects of inhaled insulin will be no different to that described in the literature for insulin administered by other routes.

A majority of the published research on lung absorp-tion of insulin resulted from experiments using rabbits. In 1971, Wigley, et al.12_{exposed rabbits by head-only} inhala-tion to aerosols of soluinhala-tions of regular insulin (80 U/mL) in a closed system which contained ~ 400 U of insulin aerosol. Over the course of two hours after inhalation of the insulin aerosols, blood glucose levels dropped from ~ 150 to ~ 90 mg/dl. Colthorpe et al13_{compared absorption} of radio-labeled insulin solutions after instillation into rab-bit lungs, or after inhalation of solution aerosols created by a compressed air nebulizer. Relative bioavailabilities, esti-mated from γ-scintigraphic analyses, were 5,6% and 57,2% for instilled and inhaled insulin, respectively. The signifi-cant (10-fold) enhancement of bioavailability after aerosol administration was most likely due to a more homogeneous distribution of the aerosol solution throughout the absorp-tive regions of the lung in comparison to the limited dis-tribution of the instilled liquid solutions13_{. Similar systemic} bioavailability of insulin aerosols compared to parenteral-ly administered insulin (~ 50%) was reported by Sakr14,15 who administered (estimated) doses of 2-5 U/kg purified porcine insulin to rabbits as aerosols. The times after dos-ing to reach peak serum insulin and nadir serum glucose levels were shorter following aerosol administration than after subcutaneous injection.

Pillai, et al16_{, repeatedly treated rhesus monkeys with} insulin aerosols and measured pharmacokinetic, pharma-codynamic, and pulmonary physiologic responses. All ani-mals tolerated repeated treatment with insulin aerosols well,

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and pulmonary function tests were all within the range of normal values.

In summary, inhaled insulin has been demonstrated to be safe and efficacious in animal trials.

EARLY PHASE CLINICAL STUDIES

A number of single-exposure studies using inhaled insulin have been conducted in normal healthy subjects and in diabetic patients (an overview is given in the review of Patton et al.17_{). A variety of formulations and} adminis-tration devices have been studied and the results suggest that insulin is rapidly absorbed after inhalation, regard-less of the administration technique used. The pharmaco-logical profile of inhaled insulin is notable for shorter time-to-peak-insulin values, and shorter time-to-glucose-nadir values vs. subcutaneously injected insulin18-24_{, (Fig. 1).} Over-all, regular insulin is absorbed more rapidly after inhala-tion than after subcutaneous (sc) injecinhala-tion (peak at 5 to 60 minutes for inhalation, 60 to 180 minutes for sc injection). In accordance with these findings, inhaled insulin decreas-es blood glucose in fasting subjects24-29 _{and blunts its rise} after meals29_.

The bioavailability values for inhaled insulin relative to subcutaneously administered insulin have mainly been in the 8-15% range13,22,28,30,31_{. The reasons for the loss of} approximately 85-90% of insulin during inhalation are not fully understood, but it seems to be due to a combination of several reasons32,33_:

• Part of the insulin remains in the (drug) container after inhalation.

• Another part adheres to the inner surfaces of the inhaler. • Larger particles are deposited in mouth and throat, and

in the bronchial tree.

• Smaller particles are exhaled without being deposit-ed.

• Insulin deposited in the alveoli is degraded by macrophages and peptidases.

Because of the limited absorption of inhaled insulin, investigators typically have employed doses ranging from 1,0-2,5 U/kg18,21,25-30,34_{. For example, Laube et al.}27 adminis-tered 1.0 U/kg insulin to type 2 diabetic patients, off other anti-diabetic therapy, after an overnight fast, and observed an approximately 55% decrease in blood glucose from base-line, without hypoglycemia. Recently, Laube et al. admin-istered 1,5 U/kg inhaled insulin 5 minutes before a meal in patients pre-treated with 1 U/kg inhaled insulin to nor-malize blood glucose29_{. Post-prandial mean blood glucose}

rose only modestly, from a baseline (after pre-treatment) value of 109 mg/dl to 144 mg/dl. There were no hypo-glycemic episodes among the 7 patients.

The impact of aerosol particle sizes and aerosoliza-tion times (2 s 4 s) were studied in healthy subjects23_{. From} the two aerosol particle sizes studied (3.5 vs. 4.4 µm) and the two aerosolization times (2 s 4 s) studied the impact of the aerosolization time on the metabolic effect induced was higher than the difference in the particle sizes. This trial also confirmed the earlier onset of action of inhaled in com-parison with sc insulin.

EFFICACY OF INHALED INSULIN IN LATER PHASE CLINICAL STUDIES

Recently, several studies with multiple dose applications have been completed that describe the inhalation of insulin using modern inhalers which create small particle sizes suit-ed for deep lung delivery35-45_{. The viability of longer-term} dosing regimens has been reported after recent phase II studies of a dry-powder formulation. Skyler, et al.37_and Cefalu, et al.38_{showed that in diabetic patients (type 1 and} type 2, respectively) inhaled insulin regimens, in combi-nation with a single subcutaneous daily dose of Ultralente insulin, resulted in the same degree of diabetes control as standard subcutaneous insulin regimens. The majority of patients in these studies elected to continue their inhaled insulin. Using the same device and formulation, Weiss et

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Inhaled insulin. Literature Review 93

Inhaled insulin Insulin Lispro Regular insulin GIR (mg/kg/min)

time (min)

600 540 480 420 360 300 240 180 120 60 0 0 2 4 6 8 12

10

Figura 1. Comparison of the metabolic effect (expressed as mean glucose infusion rates (GIR) during a euglycemic glucose clamp) of 165 IU inhaled insulin, sc injection of 18 IU regular insulin and sc injection of 18 IU insulin lispro31_{. The onset of action of inhaled}

insulin was significantly faster than that of both insulin lispro and regular insulin, whereas the duration of action was in-between those of the two sc insulin preparations.

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al.44_{showed that the addition of pre-meal insulin improves} the glycemic control of type 2 diabetic patients who are fail-ing oral agents. Cefalu, et al. reported stable glycemic con-trol spanning 2 years of inhalation therapy in 83 patients41_. With the same device, it was demonstrated that both type 1 and type 2 diabetic patients preferred inhaled over sc insulin40,45_{. It has even been shown that the availability of} inhaled insulin promotes greater acceptance of insulin ther-apy in patients with type 2 diabetes46_{–a finding, however,} which needs confirmation in a real treatment trial.

Recently published results of long-term (i.e., six months) studies with inhaled insulin in several hundreds of patients showed improved blood glucose control in patients with type 1 diabetes treated with preprandial administrations of inhaled insulin compared with patients on two to three injections of regular and NPH insulin42_{. While the mean} decreases in HbA1c values were comparable for inhaled and sc insulin groups, reductions in fasting and postpran-dial plasma glucose were greater for inhaled versus con-ventional regimen.

Comparable results were seen in subjects with type 2 diabetes43_{. A higher proportion of subjects on inhaled insulin} (46,9%) achieved HbA1c levels below the recommended target of 7% in comparison to subjects taking insulin injec-tions alone (31,7%). Improvements in blood glucose levels in general were comparable between the two patients groups, however, fasting glucose levels in the inhaled insulin group showed a greater reduction (11,9 mg/dl) than in the injection group (8,4 mg/dl).

VARIABILITY OF INHALED INSULIN

In a clinical-experimental study non-smoking subjects with type 1 diabetes inhaled the same dose of insulin on four study days (n=9) or received a sc insulin injection together with a standardised test meal47_{. Serum insulin} excursions and blood glucose changes in the 6 hours showed similar or lower intra-individual variability of cer-tain pharmacokinetic and pharmacodynamic summary mea-sures compared to sc insulin administration. The satisfac-tory reproducibility of the effect of inhaled insulin has been confirmed in other trials: The variability in the metabolic response in 12 patients with type 2 diabetes after the inhala-tion of 100 IU insulin was comparable to previously report-ed variability results obtainreport-ed with sc regular insulin in healthy volunteers32_{. Similar results were obtained in a} head-to-head comparison with sc regular insulin with another inhaler in subjects with type 2 diabetes - again, no

signif-icant differences in variability between the inhaled and the sc insulin formulation48_{. No differences were observed in} the intra-subject variability of absorption or effect of inhaled insulin between young and elderly subjects with type 2 dia-betes49_.

METABOLIC EFFECTS OF INHALED INSULIN IN SMOKERS AND PATIENTS WITH ASTHMA

Inhalation of insulin induced a more rapid and larger increase in serum insulin levels in smokers compared to non-smokers, most probably due to increasing effect of smoking on the permeability of the alveolar-capillary bar-rier50_{. This was confirmed in a recently published} phar-macokinetic study which systematically investigated the impact of acute smoking (3 cigarettes immediately before insulin inhalation) and chronic smoking on absorption of inhaled insulin51_{. Maximal insulin levels were approximately} three times higher in smokers compared to non-smokers. Interestingly, maximal values tended to be lower after acute smoking, probably due to acute airway constriction induced by smoking. However, these differences between acute and chronic smoking in insulin absorption did not lead to dif-ferences in the pharmacodynamic effects of inhaled insulin in these two groups.

In another pharmacokinetic study the effect of inhaled insulin was compared between non-diabetic, non-smoking patients with mild-to-moderate asthma and healthy sub-jects52_{. Patients with asthma showed significantly lower} areas under serum insulin concentration curves, indicating poorer insulin absorption. Even high doses did not lead to any adverse effects on pulmonary function or airway reac-tivity, though, so that a reduced insulin effect could be com-pensated for by applying higher doses. Another clinical-experimental study proved that upper respiratory tract infec-tions do not induce clinically relevant changes in the phar-macokinetic responses to inhaled insulin53_.

SAFETY OF INHALED INSULIN

Both porcine27-29_{and human}18,19,21,26,30,31,35,37,38,54,55_insulin have been used in inhalation trials. In general, insulin administration via inhalation has been well-tolerated. In many studies, no adverse events occurred that were attrib-uted to the inhalation. Even in the six months trials the inci-dence of adverse events was comparable between inhaled and sc insulin treatment42,43_.

Nevertheless, certain adverse events were attributed to the inhalation of insulin including effects on pulmonary

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function parameters or coughing, episodes of hypoglycemia, and a rise in insulin antibodies.

Pulmonary function

No significant changes in pulmonary function (spirom-etry, lung volumes, diffusion capacity, peak expiratory flow, and oxygen saturation) were observed in any of the short-term efficacy trials of inhaled insulin in humans17,37,38,44_{. No} coughing was reported during or after inhalation in single-dose studies in type 2 diabetic patients22,23,27,34_{. However,} coughing did occur in other single-dose studies20,31,32,36_and was the most common side effect in an efficacy study involving patients with type 2 diabetes43_.

Subtle alterations in lung function were observed in some longterm studies. For example, a small (0.75 to -1.69 ml/min/mmHg), but significantly higher decrease from baseline in the carbon monoxide diffusion capacity (DLCO) relative to sc insulin was reported in three phase III trials with dry powder inhaled insulin after six months of ther-apy in patients with type 1 and type 2 diabetes42,56,57_{. This} effect had not been observed in a 12-week study with another inhaled insulin device (delivering insulin aerosols rather than powder insulin)58_{. Furthermore, further} long-term studies with the same dry powder insulin which were specifically designed to investigate the previously observed changes in lung function, did not confirm any effect of inhaled insulin on DLCO, not even over a treatment peri-od of 4 years59,60_.

Hypoglycemia

As with sc insulin, treatment with inhaled insulin obvi-ously causes hypoglycemia. However, the available long-term data on inhaled insulin either shows no difference in the frequency and severity of hypoglycemia between inhaled and sc insulin37,38_{, or a significant reduction in} hypo-glycemia with inhaled insulin in comparison to sc regular insulin42,43_.

Insulin allergy and resistance

In several long-term studies with various inhaled insulin preparations, patients receiving inhaled insulin, particular-ly those with type 1 diabetes, have developed greater serum insulin antibody concentrations than patients receiving com-parator therapies37,58,61_{. Mean antibody titers with inhaled} insulin after six months of treatment were 28-29% bind-ing in patients with type 1 diabetes (3-4% in the group treat-ed with sc insulin) and 5% in patients with type 2 diabetes

(compared to 1.5% in patients on sc insulin)61_{. Differences} in antibody levels were maintained over the 24-month extension trials. Peak antibody levels across all groups were generally observed after 6-12 months of insulin therapy. The antibodies have been shown to consist of IgG, as is the case with antibodies associated with sc insulin61_. How-ever, there were no correlations between antibody bind-ing and glycemic control (measured usbind-ing HbA1c), insulin dose requirements, hypoglycemic events, or pulmonary function. Neither was inhaled insulin therapy associated with a greater incidence of allergy or other hypersensitiv-ity reactions. Thus, appearance of insulin binding antibodies appears not to be correlated to indices of metabolic con-trol and clinical safety.

A recently published six months trial investigated the impact of insulin antibodies associated with inhaled insulin treatment on postprandial glucose control, overall meta-bolic control, and the pharmacokinetic and pharmacody-namic properties of inhaled insulin62_{. High- or low-affinity} insulin antibodies did not impair postprandial glucose erance, alter the time-action profile of insulin or impact tol-erability. Thus, no clinical relevance of insulin antibodies has been identified so far.

CONCLUSIONS

Pulmonary insulin application might become the first available alternative to sc injections soon. Clinical-exper-imental studies show that the time-action profile of inhaled insulin offers some advantages over that of sc regular insulin by showing a more rapid onset of action (com-parable with or even slightly faster than that of sc fast-act-ing insulin analogues). The duration of action of inhaled insulin is in-between that of sc regular insulin and insulin analogues. Therefore, inhaled insulin seems to be an attractive alternative to sc insulin preparations for pran-dial insulin substitution, in particular for patients with type 2 diabetes mellitus who are often reluctant to take sc injec-tions.

However, so far no or only modest improvement of diabetes-related endpoints such as HbA1c or hypoglycemia have been reported for inhaled insulin in comparison with sc insulin preparations. Advantages have been demon-strated for inhaled insulin with regard to treatment satis-faction in numerous (open-label) studies. It remains to be proven, though, if this increased treatment satisfaction will facilitate the change from a therapy with oral agents to insulin in patients with type 2 diabetes, and therefore lead

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to improved metabolic control and finally to a reduction in macrovascular and microvascular endpoints. Potential risks of inhaled insulin involve the induction of insulin antibodies (which, however, do not seem to be of clini-cal relevance) and subtle deteriorations in lung function which was not confirmed in more recent long-term trials. Nevertheless, nowadays also the costs of any new thera-peutic option must be taken into account and (together with potential risks) outweighed against proven benefits. Thus, it will be interesting to see how US and European authority –and later health insurance providers– will decide on the availability and the reimbursement of inhaled insulin which, in view of a bioavailability of about 15%, should be considerably more expensive than sc insulin preparations.

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CONSIDERACIONES PRÁCTICAS

La administración no invasiva de insulina por inhalación puede ser una alternativa aceptable para pacientes con dia-betes tipo 1 y tipo 2.

La insulina inhalada tiene un perfil de acción intermedio entre los análogos de insulina rápid y la insulina regular, lo que hace que pueda ser utilizada como insulina prandial.

Diversos estudios han demostrado que la insulin inhalada tiene una eficacia comparable a la insulina subcutánea en diabetes tipo 1 y tipo 2, y una buena aceptación por los pacientes.

Los estudios a largo plazo no demuestran cambios impor-tantes de la función pulmonar ni alteraciones asociadas al aumento de anticuerpos antiinsulina.

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TABLA I. Inhaled Insulin. Recently Published Studies

First Author Sample Size Design Drug Device/ Manufacturer Principal Findings Adverse Events

Skyler37 _{n=70, type 1 patients} (35 randomized to inhalation arm)

Randomized, preprandial inhaled vs. subcutaneous insulin administration over 12 weeks

Dry powder formulation Pfizer, Inc./

Sanofi-Aventis/Nektar Therapeutics

Comparable HbA1c values in the 2 groups.

8/35 patients had “severe” hypoglycemic episodes after inhalation, vs. 10/35 after sc administration.

Capelleri40 _{n=56, type 2 patients} _{Open-label, ran-domized} control-led trial of inha-led vs. sc insu-lin over 12 weeks (Patient satisfac-tion substudy)

Dry powder formulation Pfizer, Inc./Sanofi-Aven-tis/Nektar Therapeutics

Higher global satisfaction and convenience ratings for inhaled insulin vs. sc

None listed.

Weiss44 _{n=66, type 2 patients,} failed oral agents

Randomized, oral agents plus inhaled insulin vs. oral agents alone for 3 months

Human dry powder for-mulation

Pfizer, Inc./Sanofi-Aven-tis/Nektar Therapeutics

HbA1c decreased by 2.3±1.2 in patients on inhaled insulin vs. con-trols.

One episode of severe hypoglycemia. No chan-ge in pulmonary function over 3 months.

Hermansen58 _{n=107, type 2 patients (54} on preprandial inhaled insulin, 165 on sc insu-lin), sc NPH at bedtime in both groups

Randomized, parallel-group study with pre-prandial inhaled vs. sub-cutaneous insulin admi-nistration over 12 weeks

Liquid insulin, formula-tion not specified

AERxTM_{(Aradigm, Inc./} Novo Nordisk)

Similar decrease in HbA1c in inhaled and sc group, significantly lower fasting serum glucose with inha-led insulin. No differences in hypoglycemia rate and intra-subject variability of fasting or prandial blood glucose between inhaled and sc insulin.

Similar rate of treatment emergent adverse event between inhaled and sc insulin. Higher insulin antibody levels with inhaled insulin without correlation to metabolic control or insulin dose.

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TABLA I. Inhaled Insulin. Recently Published Studies (Continuación)

First Author Sample Size Design Drug m-cresol conc. in formulation

Inhaled m-cresol dose

Device/ Manufacturer

Inhaled Insulin Dose

Principal Findings Adverse Events

Cefalu41 (abstract)

(n: see Princi-pal Findings column). type 1 and type 2 patients

Open-label extension of Phase II, treatment with inhaled or sc insulin over 24 months

Dry powder formulation

Pfizer, Inc./Sanofi-Aventis/Nektar Therapeutics

Stable HbA1c up to 24 months on therapy (mean 8.0 +/- 1.2 S.D., n=83). Stable flow rates and diffusion capacity vs. baseline up to 24 months on therapy (n=64)

Not included in abs-tract.

Quattrin42 _{n=335, type 1} patients

Preprandial adminis-trations of inhaled insulin or sc regular insulin for 24 weeks

Similar changes in HbA1c, but greater reductions in post-prandial and fasting blood glucose with inhaled insulin. Lower rates of hypoglycemia with inhaled insulin.

Increased antibody levels with inhaled insulin, but no associa-ted clinical or labora-tory changes. Compara-ble rates of adverse events, but more fre-quent coughing in inha-led insulin group. Grea-ter decrease in DLCO with inhaled insulin.

Hollander43 _{n=299, type 2} patients

Preprandial adminis-trations of inhaled insulin or sc regular insulin for 6 months

Similar changes in HbA1c, but more patients with inhaled insulin achieved HbA1c<7.0%. Lower rates of hypoglycemia with inhaled insulin. Greater treatment satis-faction in the inhaled insulin group.

Increased antibody levels with inhaled insu-lin, but no associated clinical or laboratory changes. Comparable rates of adverse events, but more frequent coug-hing in inhaled insulin group. Similar changes in lung function tests.

Gerber55 _{n=69, type 1} patients

Open-label extension of Phase 2 trial, treat-ment with inhaled or sc insulin over 12 weeks

N/A N/A Pfizer,

Inc./Sanofi-Aventis/Nektar Therapeutics

As clinically indicated

Higher global satisfac-tion and convenience ratings for inhaled insulin vs. sc

None listed.

MULTIPLE-DOSE STUDIES WITH A DURATION OF UP TO 12 WEEKS (CONTINUED)

MULTIPLE-DOSE STUDIES WITH A DURATION OF MORE THAN 12 WEEKS UP TO 6 MONTHS

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Skyler56 _{n=328, type 1 patients} (163 on preprandial inha-led insulin, 165 on sc insulin)

Randomized, parallel-group study with pre-prandial inhaled vs. sub-cutaneous insulin admi-nistration over 6 months

Similar decrease in HbA1c in inhaled and sc group, significantly lower fasting blood glucose, lower rate of overall (but higher rate of severe) hypoglycaemia, and hig-her treatment satisfaction with inhaled insulin.

Inhaled insulin led to higher levels of insulin antibody without attribu-table clinical manifesta-tions, more frequent coughing, and a higher decrease in DLCO, but not FEV1

Belanger57 _{n=299, type 2 patients} (149 on preprandial inha-led insulin, 150 on sc insulin)

Randomized, preprandial inhaled vs. subcutaneous insulin administration over 6 months

Similar decrease in HbA1c in inhaled and sc group, but significantly more patients on inhaled insulin achieved HbA1c<7%. Higher treat-ment satisfaction with inhaled insulin

Inhaled insulin led to higher levels of insulin antibody without attribu-table clinical manifesta-tions, more frequent coughing, and a higher decrease in DLCO, but not FEV1

Heise62 _{45, type 1 patients} _{Randomized, preprandial} administrations of inhaled versus sc insulin over 24 weeks, standardized meal tests and glucose clamps at 0, 12 and 24 weeks

No change in postprandial blood glucose profiles and pharmacodynamic/phar-maco-kinetic profiles. No difference in HbA1c-chan-ges and fasting blood glu-cose changes or rates of hypoglycemia

Significant rise in insulin antibodies with inhaled insulin, but no correla-tion to any of the macodynamic and phar-macokinetic parameters studied

Rosenstock45 _{N=70, type 1 patients and} n=51, type 2 patients (pooled analysis)

Preprandial administra-tions of inhaled insulin or sc regular insulin over 1 year, after twelve weeks patients could choose tre-atment

85% of patients on inha-led insulin continued tre-atmen compared to 21% on sc insulin. 75% of patients on sc switched to inhaled insulin. Higher overall satisfaction with inhaled insulin.

None listed, similar chan-ges in pulmonary func-tion tests between sc and inhaled insulin.

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Barnett59 _{n=627, type 2 patients} _{Pooled data of two} extensions of randomi-zed, parallel group stu-dies. 336 patients treated with inhaled insulin plus one oral agent (glibencla-mide or metformin), 291 with glibenclamide and metformin over 52 weeks

Dry powder formulation Similar decrease in HbA1c and rate in hypoglycaemia in both groups.

Similar decrease in HbA1c in inhaled and sc group, significantly lower fasting blood glucose, lower rate of overall (but higher rate of severe) hypoglycaemia, and hig-her treatment satisfaction with inhaled insulin.

Changes in FEV1 slightly larger with inhaled insu-lin at week 24, but no further increase of this difference in weeks 36 and 52. No difference in DLCO between the two groups

Skyler60 _{n=112, type 1 and 2} patients (89 on inhaled insulin and 23 on oral agents or sc insulin (4 year data)

Open-label continuation of inhaled insulin over at least 4 years in patients participating in phase 2 trials

Dry powder formulation Similar decrease in HbA1c and rate in hypoglycaemia in both groups.

HbA1c was 8.23±1.21% after 4 years compared with 8.71 ± 1.49% at the start of treatment with inhaled insulin

Similar decline in FEV1 and DLCO in patients on inha-led insulin and on other forms of diabetes therapy (oral agents or sc insulin)

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Inhaled insulin. Literature Review 101

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Gesam-te Inn Med 1992; 47:266-9.

3. Hunt LM, Valenzuela MA, Pugh JA. NIDDM patients’ fears and hopes about insulin therapy: the basis of patient reluctance. Dia-betes Care 1997; 20:292–8.

4. Heise T, Heinemann L. Rapid and long-acting insulin analogues as an approach to improve insulin therapy: an evidence-based medicine assessment. Curr Pharmaceut Des 2001; 7:1303-25. 5. Koro CE, Bowlin SJ, Bourgeois N, Fedder DO, Glycemic control

from 1988 to 2000 among U.S. adults diagnosed with type 2 dia-betes: a preliminary report. Diabetes Care 2004; 27:17–20. 6. Gale EA. Two cheers for inhaled insulin. Lancet 2001; 357:324-25. 7. Gaensslen M. Ueber Inhalation von Insulin. Klin Wochenschr 1925;

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8. Saudek CD. Future developments in insulin delivery systems. Dia-betes Care 1993; 16 (Suppl. 3):122-32.

9. Wall DA: Pulmonary absorption of peptides and proteins. Drug Delivery 1995; 2:1-20.

10. Patton JS, Bukar J, Nagarajan S. Inhaled insulin. Adv Drug Deliv Rev 1999; 35;235-247.

11. James AC, Stahlhofen W, Rudolf G, Briant JK, Egan MJ, Nixon W, Birchall A. Annexe D: “Deposition of Inhaled Particles.” In: Inter-national Commission on Radiological Protection (ICRP) Human Respiratory Tract Model for Radiological Protection. ICRP Publi-cation 1994; 66. Ann. ICRP 24(1/4).

12. Wigley FW, Londono JH, Wood SH, Shipp JC, Waldman RH. Insu-lin across respiratory tract mucous by aerosol delivery. Diabetes 1971; 20:552-6.

13. Colthorpe P, Farr SJ, Taylor G, Smith IJ, Wyatt D. The pharmaco-kinetics of pulmonary-delivered insulin: a comparison of intratra-cheal and aerosol administration to the rabbit. Pharmaceutical Rese-arch 1992; 9:764-8.

14. Sakr FM. A new approach for insulin delivery via the pulmonary route: Design and Pks in non-diabetic rabbits. International J Phar-maceutics 1992; 86:1-7.

15. Sakr FM. Pharmacokinetics of pulmonary nebulized insulin and its effect on glucose tolerance in streptozotocin-induced diabetic rab-bits. Int J Pharm 1996; 128:215-222.

16. Pillai RS, Hughes BL, Wolff RK, Heissermann JA, Dorato MA. The effect of pulmonary delivered insulin on blood glucose levels using two nebulizer systems. J Aerosol Med 1996; 9:227-40.

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