DRUG DEVELOPMENT RESEARCH 69:130–137 (2008)

Clinical Overview

The Science Behind Exuberas

Holly Schachner�

Pfizer Inc, New York, New York

Strategy, Management and Health Policy

Enabling

Technology,

Genomics,

Proteomics

Preclinical

Research

Preclinical Development

Toxicology, Formulation

Drug Delivery,

Pharmacokinetics

Clinical Development

Phases I-III

Regulatory, Quality,

Manufacturing

Postmarketing

Phase IV

ABSTRACT Fear of needles constitutes a significant barrier to the use of insulin. Lung tissue offers alarge permeable surface for rapid and predictable absorption of insulin into the bloodstream. Exuberainsulin was the first inhaled insulin to be approved and marketed for clinical use. The present review isintended to summarize the data to present with Exubera insulin. The pharmacodynamic effect of thisinhaled insulin is similar to that of injected regular human insulin. There are small changes in lung functionthat parallel age-related changes in patients who are not taking inhaled insulin. Cough occurs frequentlybut does not affect the overall insulin effect. Patients who start using insulin gain weight, but there is lessweight gain with Exubera use than with comparable doses of injected insulin. In multiple studies, theincidence of hypoglycemia with Exubera is similar to that with regular insulin. There is concern that insulinmay act as a growth factor on the lung epithelium. Recently, analysis of existing data showed that sixpatients on Exubera developed lung cancer compared to only one on comparator injectable insulin, allcases occurred in former smokers. However, studies were not powered for this safety issue and numberswere too small to conclude a causal relationship between Exubera exposure and occurrence of lungcancer. Pfizer decided to discontinue marketing Exubera on October 18, 2007. The decision was basedupon failure to meet financial landmarks rather than due to concern about possible safety issues. Drug DevRes 69:130–137, 2008. �c 2008 Wiley-Liss, Inc.

Key words: inhaled insulin; type 1 diabetes; type 2 diabetes

INTRODUCTION

Physicians and patients commonly delay or fail tooptimize therapy with exogenous insulin despite thewell-established risks of uncontrolled hyperglycemiaand the equally well-established effectiveness of insulinto control glycemia [Korytkowski, 2002]. Barriers toinitiation and optimization of insulin therapy includefear of needles or aversion to a permanent regimen ofmultiple daily injections. Patient and physician con-cerns about hypoglycemia and weight gain alsocontribute to reluctance to initiate insulin.

Alternatives for administering exogenous insulintherapy that were injection-free but still effective atmaintaining glycemic control have long been sought asa way to improve patient acceptance and compliance[Owens et al., 2003; Patton, 1996]. Oral, buccal, and

intranasal pathways of administration have beenpursued, but so far research has not overcome thebiological barriers to effective and predictable insulindelivery to those spaces. The deep tissues of the lungs,however, offer a large, permeable surface area(approximately 50–140 m2) that allows rapid and

DDR

Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ddr.20238

Grant sponsor: Pfizer Inc.

At the time of submission, Holly Schachner was a full timeemployee of Pfizer, Inc. Currently she is a full time employee ofBayer HealthCare.

�Correspondence to: Holly Schachner, Bayer Diabetes-Care, 777 Old Saw Mill River Road, Tarrytown, NY 10591.E-mail: holly.schachner.b@bayer.com

�c 2008 Wiley-Liss, Inc.

predictable absorption of large protein molecules suchas insulin into the bloodstream.

Exuberas (insulin human [rDNA origin]) Inhala-tion Powder; Pfizer Inc.) is the first inhaled insulinapproved in the United States and the European Unionfor the treatment of type 1 or type 2 diabetes. OnOctober 18, 2007, Pfizer Inc. announced that it wasreturning the worldwide rights for Exubera to Nektar,the company from which it licensed the inhaled insulintechnology.

The objective of this review is to provide acomprehensive overview of the current efficacy andsafety profile of Exubera in patients with type 1 or type2 diabetes to further contribute to the science ofpulmonary inhalation of insulin. Data from earlierregistrations trials and preclinical studies have beenpreviously summarized [Dailey, 2007; Strack, 2006].

THE BASICS OF PULMONARY INHALATIONOF INSULIN

In order to achieve adequate deposition to thealveolar surface in the small airways of the lung,particles should have an aerodynamic diameter of 1 to5 mm. If the particle size is larger, the particles willlikely reach the upper airways only, and if they are toosmall (o1 mm), most of the particles may be exhaled[Patton et al., 2004, Strack, 2006]. The Exubera inhalerwas specifically designed to disperse the dry powderinsulin into suitably sized particles for delivery to thesmall airways and alveoli.

Pharmacokinetics and Pharmacodynamics

Compared with subcutaneous (SC) regular in-sulin, Exubera has been shown to have a significantlymore rapid mean time to maximal concentration inhealthy male subjects (55 min vs. 148 min, respectively;Po0.001) [Rave et al., 2005]/ Mean maximal seruminsulin levels are similar for Exubera and regular SCinsulin (66.9mU/mL vs. 61.0mU/mL, respectively).

Consistent with those findings, Exubera has anonset of glucose-lowering action similar to a rapid-acting analog, a peak action of glucose lowering similarto a rapid-acting analog, and an offset of glucose-lowering action and duration similar to regular insulin.These characteristics make it an effective control forprandial glucose excursions.

Intrasubject pharmacokinetic variability in pa-tients with healthy pulmonary function, including inelderly patients with obesity, is comparable to regularSC insulin [Exubera (US package insert), 2006;Mudaliar et al., 2003]. However, studies to date innondiabetic subjects with mild or moderate asthma orchronic obstructive pulmonary disease (COPD) sug-gest that there is an increased variability of absorption

of Exubera [Pfizer, 2006]. In a study of 24 nondiabeticsubjects with mild asthma who were not undertreatment with a bronchodilator, the absorption ofExubera was approximately 20% lower than in subjectswithout asthma. The administration of a bronchodilator(albuterol) 30 min prior to Exubera in nondiabeticsubjects with mild or moderate asthma reversed someof the decline in absorption in these populations.

CLINICAL STUDIES OF EXUBERA

The Exubera clinical trials program was designedto study the drug within current paradigms for thetreatment of patients with type 1 or type 2 diabetes. Alltrials were open label (as is the case with all insulinstudies, mainly due to the necessity for careful insulintitration). The primary end point of the original trialswas glycemic control as measured primarily by glycatedhemoglobin (A1C).

Clinical trials in patients with type 1 diabetes(absolute insulin deficiency) or type 2 diabetes (relativeinsulin deficiency) compared the safety profile andefficacy of Exubera with SC regular insulin or insulinanalogs. Clinical trials in patients with type 2 diabetes(relative insulin deficiency) also examined the safetyprofile and efficacy of Exubera in patients who wereuncontrolled on one or two oral agents (OAs), i.e.,metformin and/or a sulfonylurea, or on diet andexercise regimens. These trials compared the glucose-lowering effect of Exubera with that of additional OAsor SC insulins.

Results of the trials show that Exubera consis-tently improves glycemic control in patients with type 1or type 2 diabetes (Table 1). In patients with type 1 ortype 2 diabetes, Exubera in combination with long-acting (or basal) insulin provides a level of glycemiccontrol similar to that seen with conventional SCinsulin regimens. Also in patients with type 2 diabetes,Exubera effectively lowered A1C when added to faileddiet and exercise regimen, failed monotherapy regi-men, or failed combination OA regimen.

Efficacy in Type 1 Diabetes

In patients with type 1 diabetes, the preprandialadministration of Exubera has been studied as thepremeal (or bolus) in conventional basal-bolus regi-mens in comparison with intermediate-acting neutralprotamine Hagedorn (NPH) insulin and short-actingregular insulin in 6-month, randomized, multicenterstudies [Quattrin et al., 2004; Skyler et al., 2005]. At theend of those studies, patients in Exubera treatmentgroups exhibited mean decreases in A1C and post-prandial glucose (PPG) that were similar to thoseachieved by SC NPH and regular insulin.

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Long-term efficacy of Exubera in patients withtype 1 diabetes was supported by a long-term study inwhich 582 patients were randomized to receive eitherSC basal insulin plus Exubera or basal insulin plus anSC short-acting insulin [Skyler et al., 2007]. Glycemiccontrol was maintained over 2 years in both treatmentgroups.

Efficacy in Type 2 Diabetes

Exubera was evaluated for its efficacy in patientswith type 2 diabetes who were previously managedwith at least two daily insulin injections [Hollanderet al., 2004]. The combination of Exubera plus abedtime dose of Ultralentes reduced A1C levels to thesame extent (0.7%) as the conventional SC regimenwith NPH and regular insulin (0.6%).

The efficacy of Exubera was also evaluated in thecontext of OA-only regimens in patients with type 2diabetes in five 3-month, randomized, clinical trials. Inthose trials, patients who were uncontrolled on diet andexercise alone were randomized to receive eitherExubera or an OA. Patients who were uncontrolled

on OA therapy were randomized to receive eitherExubera or an additional OA.

Patients who had been uncontrolled on diet andexercise alone achieved better reductions in A1C after3 months of Exubera (2.3%) than 3 months ofrosiglitazone (1.4%), and were more likely to reachthe American Diabetes Association goal of A1Co7.0%[DeFronzo et al., 2005]. Among patients who wereuncontrolled on 2 OAs, treatment with Exuberaresulted in better A1C reductions (2.3%) than acomparator regimen of 2 OAs alone (0.1%) [Weisset al., 2003]. Exubera also resulted in significantlygreater reductions in fasting plasma glucose (FPG) andpost-prandial glucose (PPG) (P 5 0.02 and Po0.01,respectively).

In a 3-month trial among a cohort of patients whowere uncontrolled on two OAs, patients were rando-mized to one of three treatment arms: existing therapywith two OAs plus Exubera, Exubera alone, or two OAsalone [Rosenstock et al., 2005]. Patients in the twoarms that included Exubera had better glycemiccontrol (mean A1C, �1.9% and �1.4%, respectively)

TABLE 1. Summary of efficacy data from Exubera clinical studiesa

Study Duration (Weeks) TreatmentMean reduction in A1C,

% (baseline A1C)

Type 1 diabetesQuattrin et al. [2004] 24 Exubera plus Ultralentes (n 5 170) 0.2 (8.1)

Regular plus NPH insulin (n 5 164) 0.4 (8.1)Skyler et al. [2005] 24 Exubera plus NPH insulin (n 5 162) 0.3 (8.0)

Regular plus NPH insulin (n 5 165) 0.1 (7.9)Skyler, et al. [2007] 104 Exubera plus basal insulin (n 5 288) �0.1 (7.4)

SC insulin plus basal insulin (n 5 286) 0.2 (7.5)Type 2 DiabetesHollander et al. [2004] 24 Exubera plus Ultralentes (n 5 149) 0.7 (8.1)

Mixed regular/NPH insulin (n 5 150) 0.6 (8.2)Weiss et al. [2003] 12 Exubera plus pre-study OAs (n 5 32) 2.3 (9.8)

Pre-study OAs alone (n 5 36) 0.1 (9.9)Rosenstock et al. [2005] 12 Exubera plus dual OAs (n 5 103) 1.9 (9.2)

Exubera (n 5 104) 1.4 (9.3)Dual OAs alone (n 5 99) 0.2 (9.3)

DeFronzo et al. [2005] Exubera (n 5 76) 2.3 (9.5)12 Rosiglitazone (n 5 69) 1.4 (9.4)

Barnett et al. [2006a] 24 A1C49.5%Exubera plus prior SU (n 5 113) 2.2 (10.5)Metformin plus prior SU (n 5 103) 1.8 (10.6)

A1C49.5%Exubera plus prior SU (n 5 93) 1.9 (8.8)Metformin plus prior SU (n 5 101) 1.8 (8.8)

Barnett et al. [2006b] 24 A1C49.5%Exubera plus prior metformin (n 5 109) 2.2 (10.4)Glibenclamide plus prior metformin (n 5 103) 1.9 (10.6)

A1Cr9.5%Exubera plus prior metformin (n 5 125) 1.8 (8.6)Glibenclamide plus prior metformin (n 5 119) 1.9 (8.7)

aNPH, neutral protamine Hagedorn; SC insulin, regular insulin, lispro insulin, or insulin aspart; basal insulin, NPH insulin, Ultralentes or insulinglargine; OA, oral antidiabetic agent; SU, sulfonylurea.

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at 3 months than patients in the OAs-only arm (meanA1C, �0.2%). Significantly greater reductions in FPGand PPG concentrations were also seen with Exuberatherapy compared with OAs alone, with the greatestreductions in those parameters seen in patientsreceiving OAs plus Exubera.

Barnett and colleagues [Barnett et al., 2006a,b]reported two separate 3-month randomized studiescomparing Exubera with either metformin or sulfony-lurea in patients uncontrolled on one OA. In bothstudies, patients were stratified into two groupsaccording to baseline A1C levels:Z8% tor9.5% (lowstrata) and 4 9.5% tor12% (high strata).

In the first study, subjects who were on asulfonylurea at study entry were randomized to receiveeither Exubera or metformin in addition to thatmedication [Barnett et al., 2006b]. Treatment withsulfonylurea plus Exubera resulted in a significantlygreater reduction in mean A1C than sulfonylurea plusmetformin in the high strata group (2.2% and �1.8%,respectively; P 5 0.002). In the low strata group, therewas a similar reduction in mean A1C in both treatmentgroups (1.9 and 1.9%, respectively; P 5 0.61). Theaddition of Exubera or metformin to sulfonylureaprovided similar effects on FPG and PPG levelsregardless of baseline A1C.

In the second study, subjects were on metforminat baseline. They were randomized to receive eitherExubera or sulfonylurea (glibenclamide) in addition tometformin [Barnett et al., 2006a]. In the high stratagroup, the addition of Exubera resulted in a signifi-cantly greater reduction in mean A1C than the additionof sulfonylurea (2.2 and 1.9%, respectively; P 5 0.004).In the low strata group, mean reductions in A1C weresimilar in both treatment groups (1.8 and 1.9%,respectively; P 5 0.73).

In long-term studies, glycemic control was main-tained for up to 2 years of treatment with Exubera[Barnett et al., 2007; Rosenstock et al., 2006]. Morerecently, a 6-month real-world study compared theeffects on glycemic control and treatment satisfactionwhen treatment options included Exubera along with SCinsulin and OAs versus treatment options that includedonly SC insulin and OAs [Del Prato et al., 2008].Patients who were offered Exubera were more likelythan those offered SC insulin alone to initiate insulintherapy (odds ratio [OR], 5.1; 95% confidence interval[CI], 3.6, 7.3; Po0.0001) and achieved greater glycemiccontrol (�2.0% and�1.7%, respectively) over 6 months.

Fasting Glucose Observations in Type 1 and Type 2Diabetes

Of interest, patients who received Exuberaconsistently had greater mean reductions in FPG levels

than patients who received other insulin regimensregardless of the SC insulin—regular, NPH, oranalogs—despite the fact that Exubera does not havethe pharmacokinetic profile of a basal insulin [Quattrinet al., 2004; Skyler et al., 2005, 2007]. These findingswere seen in the presence of similar reductions in A1C,with no increase in evening basal insulin doses and noevidence of overnight hypoglycemia. The reason for thegreater reduction in FPG in patients on Exubera isunknown. Preclinical studies in dogs comparingExubera to injected insulin have shown that inhalationof insulin is associated with greater peripheral uptakeand reduced hepatic uptake of glucose [Edgerton et al.,2005]. Researchers have speculated that the reducedhepatic uptake of glucose limits the repletion of liverglycogen, resulting in a reduction in glucose productionduring fasting and, therefore, a reduction in FPGlevels.

SAFETY PROFILE AND TOLERABILITY OF LONG-TERM USE OF EXUBERA

Observations on Lung Function

Pulmonary function testing (forced expiratoryvolume in 1 sec [FEV1] and carbon monoxide diffusingcapacity [DLCO]) has been an integral part of theExubera clinical development program. Early trialsutilized lung function tests that, while in accordancewith American Thoracic Society guidelines, were nothighly standardized from center to center. Subsequentstudies in patients with type 1 or type 2 diabetes wereundertaken using standardized methodology to assessthe pulmonary safety of Exubera over a prolongedperiod of time [Cefalu et al., 2007; Hollander et al.,2007a; Rosenstock et al., 2006; Skyler et al., 2007;Teeter and Riese, 2006].

The first study to examine the long-term effects ofExubera on pulmonary safety in patients with eithertype 1 or type 2 diabetes showed that small treatmentgroup differences in change from baseline in FEV1

favoring the comparator group were observed duringthe first 3 months and did not progress over theremainder of the 2 years of treatment [Barnett et al.,2007]. The treatment group differences resolved within12 weeks after discontinuation of treatment.

Subsequent 2-year studies with pulmonary inpatients with type 1 or type 2 diabetes as primaryendpoints used highly standardized pulmonary testing.These studies confirmed the decline in FEV1 andshowed that DLCO also declined [Rosenstock et al.,2006; Skyler et al., 2007]. However, treatment groupdifferences with comparators resolved upon disconti-nuation of Exubera. When Exubera was reinitiatedafter a 6-month washout period, the treatment group

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differences recurred by 1 month, and the magnitude ofthe Exubera-associated changes was similar to thatobserved initially [Cefalu et al., 2007; Hollander et al.,2007a]. Changes in FEV1 and DLCO were notcorrelated with total daily or cumulative dose ofExubera.

The Exubera-associated decline in FEV1 is drivenby small changes in the FEV1/forced vital capacity(FVC ) ratio and not by changes in FVC, consistentwith small alterations in airway function and lungemptying [Riese et al., 2007]. Bronchial alveolar lavage(BAL) studies confirmed that Exubera therapy for 12weeks has no effect on BAL leukocyte differentialcount, BAL total cell count, or BAL fluid solubleprotein constituents, even though Exubera-associatedchanges in lung function are fully manifested withinthe same time period [van Gundy et al., 2007]. Thus,during Exubera therapy, there is no indication thatinflammation is playing a role in the Exubera-associated changes in lung function.

Clinical trials were also undertaken to addressconcerns over the effect of the growth-promoting andvasodilatory characteristics of insulin on alveolar tissue[Hsia and Raskin, 2005]. Evidence to date, however,does not indicate a correlation between use of Exuberaand the occurrence of pulmonary edema or thedevelopment of malignant tumors [de Galan et al.,2006]. Also, toxicology studies of inhaled insulin in ratsand monkeys showed no adverse effects on lunghistology over 6 months of continued exposure [Cefaluet al., 2001; Patton and Platz, 1994].

A recently presented study showed that subjectstreated with Exubera as their exclusive preprandialinsulin for at least 8 years demonstrated annualizedchanges in FEV1 that are consistent with thosereported from external databases of normative diabeticlung function [Burge et al., 2007]. These patients alsodemonstrated respiratory adverse event (AE) profilesover the 8 years that were consistent with thosereported from 2-year controlled clinical studies. Thus,long-term use of Exubera was associated with declinesin FEV1 that were stable and predictable after 8 yearsof Exubera therapy.

The most commonly observed pulmonary AE inthe clinical studies was cough, which occurred morefrequently with Exubera than with SC insulin, butdecreased over time [Hollander et al., 2004; Quattrinet al., 2004; Skyler et al., 2005] The cough associatedwith Exubera administration has been consistentlycharacterized by patients as mild and nonproductive,occurring seconds to minutes following inhalation andnot occurring overnight. In registration clinical trials,only 1.2% of patients receiving Exubera discontinuedtreatment because of cough [Pfizer, 2006].

Smoking increases the permeability of thealveolar-capillary barrier [Jones et al., 1980; Wittenet al., 1985]. It has been shown that smokers have up tofivefold higher peak insulin concentrations and three-fold greater total insulin exposure after the adminis-tration of Exubera than nonsmokers, thus increasingtheir risk for hypoglycemia [Sha et al., 2002]. Subjectswho smoked at the time of or during the 6 months priorto the study were, therefore, excluded from long-termclinical studies with Exubera. Moreover, Exubera iscontraindicated in patients who smoke or who havesmoked in the past 6 months. Recently, analysis ofexisting data showed that six patients on Exuberadeveloped lung cancer compared to only one oncomparator injectable insulin, all cases occurred informer smokers. However, studies were not poweredfor this safety issue and numbers were too small toconclude a causal relationship between Exuberaexposure and occurrence of lung cancer.

Underlying lung disease such as asthma or COPDmay also affect the absorption of Exubera. Anincreased risk of both hypoglycemia and hyperglycemiais possible due to the unstable variations in lungfunction in these patient populations [Pfizer, 2006].

Hypoglycemia and Weight Gain

Long-term Exubera clinical trials addressed thesafety and tolerability for up to 3 years of treatment[Cefalu et al., 2001; DeFronzo et al., 2005; Fineberget al., 2005; Heise et al., 2005; Hollander et al., 2004;Quattrin et al., 2004; Rosenstock et al., 2005; Skyleret al., 2005; Weiss et al., 2003]. Studies comparing thesafety profile of Exubera versus SC insulin regimens inpatients with type 1 or type 2 diabetes determined thatthe rates of overall hypoglycemia in patients with type 1diabetes were higher than in patients with type 2diabetes [Hollander et al., 2004; Quattrin et al., 2004;Skyler et al., 2005]. However, the overall incidence ofhypoglycemia was similar with Exubera and injectedinsulin regimens in patients with type 1 or type 2diabetes. In addition, a low overall incidence ofhypoglycemia (r1.7 events/subject-month) has beenseen in studies comparing Exubera with OAs inpatients with type 2 diabetes [Cefalu et al., 2001;DeFronzo et al., 2005; Rosenstock et al., 2005; Weisset al., 2003]. The incidence of hypoglycemia was,however, higher with Exubera than with OA therapy.For instance, in a study comparing the efficacy andsafety profile of Exubera plus two OAs, Exubera alone,or two OAs alone in patients with type 2 diabetes, theoverall rate of the number of hypoglycemic episodesper subject-month was 1.7 in the Exubera plus twoOAs and 1.3 in the Exubera monotherapy group,compared with 0.1 in the two OAs group [Rosenstock

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et al., 2005]. This is not completely unexpected,however, given the superior A1C control seen in theExubera treatment arms [DeFronzo et al., 2005;Rosenstock et al., 2005; Weiss et al., 2003].

Increases in weight are fairly common as patientswith diabetes improve glycemic control. When com-pared to OAs, Exubera, in addition to providing betterimprovements in A1C, also demonstrated weight gainconsistent with the A1C reduction. Of note, however,in patients with type 2 diabetes utilizing Exuberacompared to injectable insulin, there was significantlyless weight gain in the Exubera group than in the SCinsulin group, which occurred with similar A1Creductions [Hollander et al., 2007b]. Why patientsreceiving Exubera gain less weight than those receivingSC insulin is unclear. The fact that these patients alsohave lower FPG levels than those receiving injectedinsulin suggests that the route of insulin administrationaffects glucose utilization.

Immunological Responses

Increases in insulin antibodies (IAbs) have beenobserved in patients treated with Exubera in clinicaltrials with SC insulin or OA comparators in patientswith type 1 or type 2 diabetes. In clinical studies withExubera, patients with type 1 diabetes exhibited higherlevels of antibody development than those with type 2diabetes; patients with type 2 diabetes who had beenpreviously treated with insulin exhibited higher anti-body development than patients with type 2 diabeteswho had not used insulin previously [Fineberg et al.,2005].

IAbs associated with Exubera treatment arestructurally identical to those seen in response to SCinsulin administration (primarily of the immunoglobu-lin G subtype), and long-term studies have revealedthat IAb levels plateau within 12 months of treatmentand decrease after cessation of Exubera therapy[Fineberg et al., 2005]. An anamnestic response didnot occur upon readministration of Exubera [Fineberget al., 2007]. No correlation has been found betweenIAb levels and glycemic control parameters, theincidence of hypoglycemia, insulin dose or serumconcentration, or the incidence of allergic and/orrespiratory events [Fineberg et al., 2005, 2007; Heiseet al., 2005].

SUMMARY

Exubera is the first inhaled insulin deliverysystem that utilizes inhalation via the mouth toeffectively reduce serum glucose levels. Treatmentwith Exubera has been shown to result in glycemiccontrol comparable to that of standard SC insulinregimens in patients with type 1 diabetes or insulin-

requiring type 2 diabetes. Long-term evidence showedthat A1C reductions were maintained over 3 yearscompared to regimens that contained insulin analogs.Safety concerns, as with SC insulins, include hypogly-cemia and weight gain. Hypoglycemia with Exuberawas comparable to that of other injectable insulins.Weight gain with Exubera was greater than with OAs,but was less than that seen with other injectableinsulins.

Safety measures that appear to be specific toinhaled insulin delivery include increased incidence ofcough as well as declines in FEV1 and DLCO, whichhave been reversible with discontinuation of Exuberaand reproducible with reinitiation of Exubera. A 3-yearinterim analysis of pulmonary function studies showedthat with 2 years of continuous exposure to Exubera,FEV1 and DLCO reductions were seen in bothExubera-treated and SC comparator arms, with greaterreductions occurring in the Exubera arms. The meandifferences between treatment groups in these reduc-tions were small, occurred early (by 3 months), andwere nonprogressive. Upon washout, these differencesresolved, and upon reinitiation, the mean treatmentgroup differences were consistent and predictablyoccurred early, were small, and were nonprogressive.

CONCLUSIONS

Reducing the barriers to the initiation of appro-priate glucose-lowering therapy, including insulin, hasthe potential to improve health in people with diabetesand thus has the potential to reduce the medical andfinancial burdens faced by patients and the commu-nities. Many patients associate the initiation of insulintherapy to be associated with negative outcomesbeyond the fear of needles such as hypoglycemia andweight gain. Still others hold onto the hope that theycan exercise more often or be better on their diet, andtheir diabetes will go away.

Both physicians and patients need to recognizethe truth about diabetes: it is a progressive disease thatrequires progressive therapies, and many will requireinsulin to replace the insulin that their bodies are nolonger making due to the nature of the disease.Excellent, tight glycemic control, as evidenced byA1C o7%, and not A1C levels that are ‘‘good enough,’’have been consistently demonstrated to reduce therisks of both microvascular and macrovascular diseasethat often complicate diabetes.

Alternative insulin delivery methods such aspulmonary inhalation have been explored as a meansto overcome some of the barriers of both patients andphysicians to the optimal treatment of diabetes. Severalinhaled insulin formulations and devices are being

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evaluated in ongoing clinical trials for the managementof type 1 and type 2 diabetes.

ACKNOWLEDGMENTS

These studies were sponsored by Pfizer Inc.Editorial support was provided by Mark Poirier andTom Claus, PhD, of PAREXEL. Note: On October 18,2007, Pfizer Inc announced that it was returning theworldwide rights for Exubera (insulin human [rDNAorigin]) Inhalation Powder) back to Nektar, thecompany from which it licensed the inhaled insulintechnology.

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