Articles

Prandial inhaled insulin plus basal insulin glargine versus twice daily biaspart insulin for type 2 diabetes: a multicentre randomised trial
Julio Rosenstock, Daniel L Lorber, Luigi Gnudi, Campbell P Howard, David W Bilheimer, P-C Chang, Richard E Petrucci, Anders H Boss, Peter C Richardson

Summary
Lancet 2010; 375: 224453 See Comment page 2199 Dallas Diabetes and Endocrine Center at Medical City, Dallas, TX, USA (J Rosenstock MD); Diabetes Control Foundation, Diabetes Care and Information Center, Flushing, NY, USA (D L Lorber MD); Unit for Metabolic Medicine, Cardiovascular Division, Kings College London, London, UK (L Gnudi MD); and MannKind Corporation, Valencia, CA, USA (C P Howard MD, D W Bilheimer MD, P-C Chang MS, R E Petrucci MD, A H Boss MD, P C Richardson MRCP) Correspondence to: Dr Julio Rosenstock, Dallas Diabetes and Endocrine Center at Medical City, 7777 Forest Lane C-685, Dallas, TX 75230, USA juliorosenstock@ dallasdiabetes.com

Background Insulin therapy is often a delayed strategy in patients with type 2 diabetes mellitus because it is associated with weight gain, hypoglycaemia, and the need for subcutaneous injections. We aimed to assess the ecacy and safety of prandial Technosphere inhaled insulin compared with twice daily biaspart insulin. Methods In this randomised, open-label, parallel-group study, adult patients with type 2 diabetes mellitus and poor glycaemic control despite insulin therapy, with or without oral antidiabetes drugs, were enrolled from ten countries between Feb 23, 2006, and Aug 8, 2007. Patients were randomly allocated in a 1:1 ratio to receive 52 weeks treatment with: prandial Technosphere inhaled insulin powder plus bedtime insulin glargine; or twice daily premixed biaspart insulin (70% insulin aspart protamine suspension and 30% insulin aspart of rDNA origin). The primary endpoint was a comparison of change in glycosylated haemoglobin (HbA1c) from baseline to week 52 between treatment groups; the non-inferiority margin was 04%. Analysis was by per protocol for non-inferiority testing of the primary endpoint. This study is registered with ClinicalTrials.gov, number NCT00309244. Findings 334 patients were allocated to inhaled insulin plus insulin glargine, and 343 to biaspart insulin; 107 patients on inhaled insulin plus insulin glargine and 85 on biaspart insulin discontinued the trial. 211 patients on inhaled insulin plus insulin glargine and 237 on biaspart insulin were included in per-protocol analyses. Change in HbA1c with inhaled insulin plus insulin glargine (068%, SE 0077, 95% CI 083 to 053) was similar and non-inferior to that with biaspart insulin (076%, 0071, 090 to 062). The between-group dierence was 007% (SE 0102, 95% CI 013 to 027). Patients had signicantly lower weight gain and had fewer mild-to-moderate and severe hypoglycaemic events on inhaled insulin plus insulin glargine than on biaspart insulin. The safety and tolerability prole was similar for both treatments, apart from increased occurrence of cough and change in pulmonary function in the group receiving inhaled insulin plus insulin glargine. Interpretation This study is part of a large clinical development programme addressing the ecacy and tolerability of use of Technosphere inhaled insulin in a wide variety of patients. Funding MannKind.

Introduction
The metabolic abnormalities of type 2 diabetes include insulin resistance and progressive insulin deciency aecting peripheral glucose uptake and suppression of hepatic glucose production in the postabsorptive and early postprandial periods.1 Although oral antidiabetes drugs might control hyperglycaemia early in disease, progressive -cell insuciency can eventually lead to the need for insulin therapy to achieve glycaemic control.24 Biphasic insulin can provide greater reduction in glycosylated haemoglobin (HbA1c) than can basal insulin glargine, but at the expense of increased insulin doses, hypoglycaemia, and weight gain.5 In the 4-T study,6 treatment with biphasic or prandial insulin for 1 year in patients with type 2 diabetes produced similar reductions in HbA1c, both of which were greater than with basal insulin detemir, but at the expense of increased hypoglycaemia and weight gain. At 3-year follow-up, most patients eventually needed intensied treatment
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with a basal prandial regimen, consistent with consensus recommendations.3,7 Present prandial insulin therapy has a late onset and extended duration of action, leading to early postprandial hyperglycaemia and increased risk of late postprandial hypoglycaemia. Technosphere (MannKind, Valencia, CA, USA) is an inhaled insulin formulation containing recombinant human insulin adsorbed onto powder (fumaryl diketopiperazine).8 Insulin and fumaryl diketopiperazine are almost completely cleared from the lungs of healthy individuals within 12 h of dosing. With Exubera inhaled insulin, the insulin concentration in epithelial lung uid of patients with diabetes 12 h after the dose was about 89% of the concentration immediately after the dose. By comparison, 12 h after healthy individuals were given 60 U Technosphere inhaled insulin, the lungs contained 03% of the insulin concentration and 04% of the fumaryl diketopiperazine concentration recorded at 30 min after inhalation.9,10
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The Technosphere system allows for pulmonary delivery of peptide hormones, resulting in safe and rapid absorption of large molecules.11 Once inhaled, the insulin dissolves immediately on contact with the lung surface, and is rapidly absorbed into the systemic circulation.8 Inhaled insulin reaches a maximum blood insulin concentration within 15 min and produces rapid glucose lowering with a short duration of action (about 23 h),1216 allowing suppression of endogenous glucose production earlier than do rapid-acting insulin analogues.17 We aimed to compare the ecacy and safety of prandial Technosphere inhaled insulin plus bedtime insulin glargine versus twice daily biaspart insulin for treatment of type 2 diabetes in patients previously treated with insulin, with or without oral agents.

2064 patients screened for eligibility 1391 failed screening

4 included in randomisation in error after exclusion for screening failure

673 eligible for randomisation

677 randomly allocated

334 allocated to inhaled insulin plus insulin glargine

343 allocated to biaspart insulin

Methods
Patients
Patients aged 1880 years, with type 2 diabetes and glycosylated haemoglobin (HbA1c) of greater than 70% and of 110% or lower, were enrolled between Feb 23, 2006, and Aug 8, 2007, and the study was completed on Sept 8, 2008. Patients were enrolled and treated at hospitals and clinics in Argentina, Brazil, Canada, Chile, Mexico, Poland, Russia, Spain, UK, and USA (webappendix pp 15). At baseline, all patients were receiving any standard insulin regimen of two or three subcutaneous injections per day. Oral antidiabetes treatment with metformin or thiazolidinediones could be continued with insulin therapy, but use of sulphfonylureas, meglitinides, -glucosidase inhibitors, pramlintide, or incretins was not permitted. Eligible patients had been non-smokers for at least the preceding 6 months, had baseline forced expiratory volume in 1 s (FEV1) and diusing lung capacity (DLCO) of 70% or higher of predicted values, had total lung capacity of 80% or higher of predicted values, had body-mass index of 40 kg/m or lower, and needed less than 14 IU insulin per kg of bodyweight. Exclusion criteria were: clinically signicant diabetes complications; hepatic or renal disease; severe or several allergies; chronic pulmonary disease; present drug or alcohol abuse; major psychiatric disorders; myocardial infarction or stroke within the previous 3 months; or unstable diabetes. We dened unstable diabetes as two or more episodes of severe hypoglycaemia, or any admission to hospital or visit to an emergency department for diabetes within the preceding 6 months. Informed written consent was obtained from all patients before enrolment. Independent ethics committees or institutional review boards at clinical sites approved the study in accordance with the Declaration of Helsinki.

11 did not receive the study drug

12 did not receive the study drug

107 discontinued 29 adverse events 6 protocol violations 50 withdrew consent 4 deaths 5 investigator decision 6 lost to follow-up 7 other reasons

85 discontinued 12 adverse events 3 protocol violations 32 withdrew consent 1 death 8 investigator decision 22 lost to follow-up 7 other reasons

See Online for webappendix

216 completed study 323 analysed in safety population* 302 analysed in modied intention-to-treat population 211 analysed in per-protocol population 246 completed study 331 analysed in safety population* 316 analysed in modied intention-to-treat population 237 analysed in per-protocol population

Figure 1: Trial prole HbA1c=glycosylated haemoglobin. *Includes patients who received at least one dose of study drug. Includes patients who received at least one dose of study drug and had measurements of HbA1c at baseline and at least one timepoint after baseline. Includes patients who received at least one dose of study drug, had measurements of HbA1c at baseline and at least one timepoint after baseline, completed the study, and were deemed to be protocol compliant.

randomly allocated in a 1:1 ratio to receive: prandial Technosphere inhaled insulin powder plus bedtime insulin glargine by subcutaneous injection; or twice daily premixed biaspart insulin by subcutaneous injection. Premixed biaspart insulin was a human insulin analogue suspension containing 70% insulin aspart protamine suspension and 30% insulin aspart (rDNA origin). Treatment allocation was concealed by use of an interactive voice response system. No masking was used because of the study design and drug administration times.

Procedures
Patients allocated to inhaled insulin plus insulin glargine received about half of their total daily insulin as basal insulin. The remainder was given as a corresponding inhaled insulin dose that was distributed across main meals and individually adjusted in 15 U increments, as needed, up to a maximum of 90 U per meal, on the basis of self-monitoring blood glucose. Bioavailability was estimated at about 2428%, but for safety reasons a
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Randomisation and masking

The randomisation sequence was generated independently by a central computerised interactive voice response system (ClinPhone, East Windsor, NJ, USA), and was restricted with a block size of six, with stratication by centre. In this 52-week, open-label study, patients were
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Inhaled insulin plus insulin glargine (n=302) Sex Men Women Race White Black Hispanic Asian Other Age (years) Weight (kg) Body-mass index (kg/m2) HbA1c Fasting plasma glucose (mmol/L) Duration of diabetes (years) Concomitant drugs Metformin Dose (mg) Thiazolidinediones 118 (39%) 1800 23 (8%) 202 (67%) 25 (8%) 61 (20%) 8 (3%) 6 (2%) 559 (106) 883 (174) 316 (48) 87% (11) 94 (37) 130 (72) 153 (51%) 149 (49%)

Biaspart insulin (n=316)

137 (43%) 179 (57%) 215 (68%) 27 (9%) 64 (20%) 4 (1%) 6 (2%) 559 (100) 858 (180) 311 (49) 87% (11) 98 (37) 137 (79) 127 (40%) 1700 21 (7%)

Data are number (%) or mean (SD). HbA1c=glycosylated haemoglobin.

Table 1: Demographic and clinical characteristics at baseline (modied intention-to-treat population)

Inhaled insulin dose 75 U 105 U 135 U 165 U 195 U 210 U

Rapid-acting insulin analogue dose 20 IU 28 IU 36 IU 44 IU 52 IU 56 IU

15 U inhaled insulin is approximately equal to 38 IU subcutaneous rapid-acting insulin analogue on the basis of bioequivalence of 2428%.

Table 2: Dose conversion for inhaled insulin to rapid-acting insulin analogue

conversion of 5 U of subcutaneous rapid-acting insulin to 15 U of inhaled insulin was used for the initial dose. Inhaled insulin was given in 15 U and 30 U cartridges. For patients on biaspart insulin, dose was adjusted on the basis of target fasting plasma glucose and plasma glucose values before dinner of 4461 mmol/L. Insulin adjustments were made at investigators discretion. Standardised meal challenge was done at weeks 4, 26, and 52 to assess the postprandial glucose response. Patients who had fasted for 810 h were given a standard liquid meal challenge (540 kcal, 12 oz BoostPlus; Novartis, East Hanover, NJ, USA), with administration of preprandial inhaled insulin within 90 s of ingesting the meal or biaspart insulin 15 min before ingesting the meal. Plasma glucose samples were obtained 30 min before the meal challenge and at 0, 30, 60, 90, 105, 120, 180, 240, 300, and 360 min after meal ingestion.
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The primary ecacy endpoint was change in HbA1c from baseline to week 52. Secondary endpoints were: change from baseline in plasma glucose concentrations (after a standardised liquid meal, expressed as the area under the curve [AUC] at timepoints between 0 and 360 min) at week 52; the proportion of patients achieving HbA1c of 70% or lower; change from baseline to week 52 in fasting plasma glucose; 1 h and 2 h postprandial glucose at week 52; change in weight at 52 weeks relative to baseline; sevenpoint blood glucose prole (immediately before every meal, 2 h after every meal, and at bedtime) on any 3 days during the week preceding weeks 1, 2, 34, 6, 8, 10, 14, 26, 38, 45, and 52; the proportion of patients achieving HbA1c of 65% or lower and of 8% or lower; the number of patients attaining postprandial glucose of less than 10 mmol/L and of less than 78 mmol/L after meal challenges; and changes from baseline to week 45 in the SF-36 quality-of-life (QoL) instrument and the insulin treatment questionnaire. The proportion of patients achieving HbA1c of 65% or lower and of 8% or lower, and the number of patients attaining postprandial glucose of less than 10 mmol/L and of less than 78 mmol/L after meal challenges are not presented because the dierences in results were similar. Mild-to-moderate and severe cases of hypoglycaemia were recorded and analysed as event rates and as incidences. Mild-to-moderate hypoglycaemia was dened as: symptoms (lightheadedness, sweating, palpatations, tremulousness, or headache) and blood glucose measurement of 35 mmol/L or lower; symptoms in the absence of blood glucose measurements that were relieved with carbohydrate ingestion; or any blood glucose measurement of more than 20 mmol/L or of 27 mmol/L or lower, with or without symptoms. Severe hypoglycaemia was dened as blood glucose of 2 mmol/L or lower, or cases of simultaneous occurrence of: patient needing assistance from another person; patient exhibiting at least one cognitive neurological symptom; and blood glucose measurements of less than 27 mmol/L. In the absence of blood glucose measurements, symptoms were to be reversed by oral carbohydrates or subcutaneous glucagon. We assessed safety from adverse events, cough, hypoglycaemia, hyperglycaemia, vital signs, pulmonary function tests, 12-lead electrocardiography, chest radiography, clinical laboratory tests, and physical examinations. Hypoglycaemia and cough were events of interest, therefore additional information regarding cough episodes was recorded (frequency, duration, and time relation to insulin inhalation). Spirometry (FEV1 and forced vital capacity) and DLCO were done according to American Thoracic Society and European Respiratory Society guidelines18 before the rst dose of study drug was given and at weeks 14, 26, 38, and 52 (or at time of discontinuation). An independent data safety monitoring board monitored data throughout the study.
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Inhaled insulin plus insulin glargine Modied intention-to-treat population Number of patients Change in HbA1c Number of patients Change in HbA1c Per-protocol population Number of patients Change in HbA1c 211 068% (0077, 083 to 053) 213 066% (0078, 082 to 051) 302 059% (0063, 071 to 047)

Biaspart insulin

Dierence between inhaled insulin plus insulin glargine and biaspart insulin

243 072% (0071, 086 to 058) 316 071% (0061, 083 to 059) 237 076% (0071, 090 to 062)

NA 006% (0101, 014 to 025) NA 012% (0085, 005 to 029) NA 007% (0102, 013 to 027)

Modied intention-to-treat population (last observation carried forward)

Data are least squares mean (SE, 95% CI), and were calculated by ANCOVA. NA=not applicable.

Table 3: Change in glycosylated haemoglobin (HbA1c) from baseline to week 52 by analysis population

A 88 86 84 HbA1c (%) 82 80 78 76 0 0 Number of patients Inhaled insulin plus insulin glargine Biaspart insulin 211 237 14 208 234 26 Time (weeks) 205 234 211 235 211 237 38 52 Inhaled insulin plus insulin glargine Biaspart insulin Change in fasting plasma glucose from baseline (mmol/L)

B 0 0 05 10 15 20 25 4

Time (weeks) 26

52

302 274 316 288

238 258

197 218

Figure 2: (A) Glycosylated haemoglobin (HbA1c) values (per-protocol population) and (B) change in fasting plasma glucose from baseline (modied intention-totreat population) during 52 weeks Data are mean (SE), apart from data for week 52 of part (B), which are least squares mean (SE). Corresponding data are presented in webappendix p 6.

Statistical analysis
We calculated that a study size of 677 patients would provide more than 90% power for a non-inferiority comparison of HbA1c between inhaled insulin plus insulin glargine and biaspart insulin, with the assumption of a non-inferiority margin of 04%. We used the per-protocol population to analyse the primary endpoint of non-inferiority in HbA1c. The perprotocol population included all randomly allocated patients who had received at least one dose of study drug, had measurements of HbA1c at baseline and at least one timepoint after baseline, completed the study, and were deemed to be protocol compliant. Secondary ecacy analysis was done by use of the modied intention-to-treat principle, which included all randomly allocated patients who had received at least one dose of study drug and had measurements of HbA1c at baseline and at least one timepoint after baseline. The safety population used for all safety analyses included patients who had received at least one dose of study drug. No
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imputation was applied in analyses, apart from last observation carried forward for analysis of HbA1c. We used ANCOVA to analyse treatment dierences in change from baseline to week 52 for HbA1c, fasting plasma glucose, postprandial glucose, weight, and pulmonary function tests. Logistic regression analysis was done to assess the treatment dierence in responder rates. ANCOVA and logistic regression analyses included treatment, pooled site, and baseline measurement in the model. Odds ratios for the risk of at least one hypoglycaemic event were reported from the logistic regression analysis, which included pooled site and treatment in the model. For the rates of hypoglycaemic events, we implemented a Poisson regression model with terms of treatment and time periods based on the generalised estimating equation method. The SF-36 QoL and insulin treatment questionnaires were administered at baseline, week 14, and week 45. Within-treatment comparisons were done with a paired t test to assess the change from baseline at week 45; the between-treatment dierence was analysed by
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Postprandial glucose (mmol/L)

ANCOVA at week 45, and all analyses were based on the modied intention-to-treat population. All analyses were two-sided at a 5% signicance level, and programmed with SAS (version 9.1). This study is registered with ClinicalTrials.gov, number NCT00309244.

14 13 12 11 10 9 8 7 6 0 0 60 120

Inhaled insulin plus insulin glargine (n=198) Biaspart insulin (n=217)

Role of the funding source

The study sponsor participated in the study design, data collection, data review, data analysis, and writing the report. All authors had full access to the data and are fully responsible for the content, editorial decisions, and opinions expressed in the report. JR had the nal decision to submit for publication.

180 Time (min)

240

300

360

Results
Of 2064 patients screened for eligibility, 677 (33%) were randomly allocated to treatment (gure 1). Baseline characteristics for age, sex, body-mass index, HbA1c, fasting plasma glucose, and diabetes duration were well balanced between groups (table 1). The mean total daily dose of inhaled insulin was titrated rapidly upwards during the rst 8 weeks of treatment, and began to plateau after the rst 12 weeks: 82 U (SD 42) at week 1, 189 U (72) at week 12, 190 U (71) from after 3 months up to 6 months, 193 U (73) from after 6 months up to 9 months, and 198 U (74) from after 9 months up to 12 months. Table 2 shows the dose conversion for inhaled insulin to rapid-acting insulin analogue. A similar temporal pattern was recorded with biaspart insulin: 61 IU (SD 32) at week 1, 81 IU (43) at week 12, 83 IU (43) from after 3 months up to 6 months, 85 IU (45) from after 6 months up to 9 months, and 88 IU (48) from after 9 months up to 12 months. Mealtime doses of inhaled insulin were evenly distributed between meals, but the mean daily dose of insulin glargine was 47 IU (SD 25) at study end. Concomitant use and doses of metformin and thiazolidinediones were similar between groups (table 1). Mean changes in HbA1c from baseline to week 52 were similar across all analysis populations with all upper 95% CIs less than 04, showing that inhaled insulin is non-inferior to biaspart insulin (table 3). The treatment eect remained stable from week 14 though week 52 (gure 2A). Additional information is provided in webappendix p 6. Mean fasting plasma glucose values at week 52 were 78 mmol/L (SD 31) for inhaled insulin plus insulin glargine and 87 mmol/L (33) for biaspart insulin. Changes from baseline were 20 mmol/L (SD 03, 95% CI 25 to 15) for inhaled insulin plus insulin glargine versus 10 mmol/L (02, 15 to 05) for biaspart insulin. The between-group dierence was 10 mmol/L (SD 03, 95% CI 16 to 03, p=00029; gure 2B). Additional information is provided in webappendix p 6. Seven-point blood glucose readings were recorded by patients at home on any 3 days during each week preceding a clinic visit. The variability between timepoints tended to be higher in
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Figure 3: Meal test results at week 52 (modied intention-to-treat population) Data are mean (SE). Some patients in the modied intention-to-treat population were not included in the analysis because they did not participate in meal challenge tests or had tests done at unscheduled visits. Corresponding absolute data are presented in webappendix p 8.

the biaspart insulin group than in the inhaled insulin group, and glucose concentrations in both groups increased during the day (webappendix p 7). At week 52, postprandial glucose AUC during 0360 min was similar between treatment groups: 598 mmol/h per L for inhaled insulin plus insulin glargine versus 567 mmol/h per L for biaspart insulin (gure 3). However, patients on inhaled insulin plus insulin glargine versus those on biaspart insulin had signicantly lower mean 1 h postprandial glucose (95 mmol/L [SD 37] vs 116 mmol/L [39], p=00001), and lower 1 h glucose excursion (18 mmol/L [SD 24] vs 29 mmol/L [24]). 2 h postprandial glucose was similar between treatment groups: 118 mmol/L (SD 41) for inhaled insulin plus insulin glargine versus 118 mmol/L (43) for biaspart insulin. After 2 h, glucose excursions were higher in patients on inhaled insulin plus insulin glargine than in those on biaspart insulin (data not shown). In the biaspart insulin group, postprandial glucose was lowered to below baseline after 200 min and remained below baseline thereafter (gure 3). Additional information is provided in webappendix p 8. The proportion of patients with HbA1c of 70% or less at week 52 was similar between patients on inhaled insulin and insulin glargine (47/213 [22%]) and those on biaspart insulin (65/243 [27%], p=02793). Mean weight gain was signicantly lower with inhaled insulin plus insulin glargine 09 kg (SD 03, 95% CI 0315) than with biaspart insulin 25 kg (03, 1930), with a treatment dierence of 16 kg (SD 04, 95% CI 24 to 07, p=00002). In the safety population, adverse events occurred in 272 patients (84%) on inhaled insulin plus insulin glargine and 296 (89%) of those on biaspart insulin. Treatment-emergent adverse events and serious adverse events are listed in table 4, and study drug-related adverse events are listed in webappendix pp 910.
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Inhaled insulin plus insulin glargine (n=323) Serious adverse events Overall* Blood and lymphatic system disorder Cardiac disorders Eye disorders Gastrointestinal disorders General and administration site disorders Hepatobiliary disorders Immune system disorders Infections and infestations Injury, poisoning, and procedural complications Investigations Increased international normalised ratio Metabolism and nutrition disorders Inadequate control of diabetes mellitus Hyperglycaemia Hypoglycaemia Hypoglycaemia seizure Obesity Musculoskeletal and connective tissue disorders Neoplasms: benign, malignant, and unspecied (including cysts and polyps) Adrenal adenoma Benign pancreatic neoplasm Breast cancer (early stage) Breast cancer (stage III) Colon cancer Gastrointestinal cancer metastatic to lung Pancreatic carcinoma Metastatic prostate cancer Uterine leiomyoma Nervous system disorders Psychiatric disorders Renal and urinary disorders Reproductive system and breast disorders Respiratory, thoracic, and mediastinal disorders Skin and subcutaneous tissue disorders Vascular disorders 37 (11%) 0 10 (3%) 2 (1%) 3 (1%) 1 (<1%) 0 1 (<1%) 6 (2%) 4 (1%) 1 (<1%) 1 (<1%) 6 (2%) 1 (<1%) 1 (<1%) 3 (1%) 1 (<1%) 0 5 (2%) 3 (1%) 0 0 0 1 (<1%) 0 1 (<1%) 0 1 (<1%) 0 6 (2%) 1 (<1%) 1 (<1%) 0 2 (1%) 1 (<1%) 0

Biaspart insulin (n=331)

31 (9%) 1 (<1%) 6 (2%) 1 (<1%) 3 (1%) 2 (1%) 2 (1%) 0 3 (1%) 4 (1%) 0 0 7 (2%) 0 0 6 (2%) 0 1 (<1%) 2 (1%) 5 (2%) 1 (<1%) 1 (<1%) 1 (<1%) 0 1 (<1%) 0 1 (<1%) 0 1 (<1%) 5 (2%) 0 1 (<1%) 2 (1%) 1 (<1%) 0 2 (1%) (Continues on next page)

Hypoglycaemia was the most frequent adverse event attributed to study drugs, occurring in 99 patients (31%) on inhaled insulin plus insulin glargine and 163 (49%) on biaspart insulin. In the safety population, mild-tomoderate and total hypoglycaemia was signicantly lower with inhaled insulin plus insulin glargine than with biaspart insulin (table 5). Severe hypoglycaemia event rate during the late night was lower with inhaled insulin plus insulin glargine than with biaspart insulin (table 6). In the safety population, 103 patients (32%) treated with inhaled insulin plus insulin glargine reported cough compared with 14 (4%) receiving biaspart insulin. 142 events of cough were reported in patients on inhaled insulin plus insulin glargine, and most were
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characterised as intermittent (91 [64%]) or as a singledened episode (48 [34%]). Furthermore, most of these cough events occurred within 10 min of insulin inhalation (109 [77%]) and were non-productive (127 [89%]), and most coughing episodes were reported during the rst week of treatment (41 [29%]) and declined to about two (1%) per week by week 6. Between patients on inhaled insulin plus insulin glargine and those on biaspart insulin, mean changes from baseline to week 52 were similar for FEV1 (013 L [SD 022] vs 009 L [02], p=02173), forced vital capacity (012 L [SD 025] vs 009 L [022], p=05265), and DLCO (080 mL/min per mm Hg [SD 245] vs 111 mL/min per mm Hg [251], p=00946). Mean changes in laboratory parameters were similar
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Inhaled insulin plus insulin glargine (n=323) (Continued from previous page) Adverse events (of any severity) reported by 5% of patients Overall* Infections and infestations Upper-respiratory-tract infection Nasopharyngitis Inuenza Urinary-tract infection Metabolism and nutrition disorders Hypoglycaemia Nervous system disorders Headache Respiratory, thoracic, and mediastinal disorders Cough 272 (84%) 146 (45%) 39 (12%) 30 (9%) 18 (6%) 11 (3%) 165 (51%) 155 (48%) 47 (15%) 18 (6%) 133 (41%) 106 (33%)

Biaspart insulin (n=331)

296 (89%) 135 (41%) 24 (7%) 28 (8%) 18 (5%) 21 (6%) 232 (70%) 228 (69%) 43 (13%) 12 (4%) 41 (12%) 20 (6%)

Data are number of patients (%). *Some patients had more than one event; preferred terms are summarised as per the Medical Dictionary for Regulatory Activities (version 7.1) and are independent of one another, so patients can be listed in more than one category. The total number of cough episodes in the adverse event database was dierent from the total number of cough episodes in the cough database because the cough case report form page recorded every episode of cough in a given day to allow for the analysis of frequency, whereas the adverse event page recorded only a single event of cough for a given date.

Table 4: Treatment-emergent adverse events (safety population)

between groups, as were occurrences of cardiovascular events, cerebrovascular events, and cancer. Of patients randomly allocated to treatment, 191 (28%) withdrew from the study, with a greater number in those on inhaled insulin plus insulin glargine (32%) than on biaspart insulin (24%; gure 1). In the safety population, the proportion of patients discontinuing because of adverse events was higher with inhaled insulin plus insulin glargine (29 [9%]) than with biaspart insulin (12 [4%]; gure 1), mainly as a result of treatment-emergent adverse events aecting the respiratory tract, which accounted for 19 (58%) discontinuations on inhaled insulin plus insulin glargine. The most common respiratory event leading to discontinuation in patients on inhaled insulin plus insulin glargine was cough (6 [2%]). Hyperglycaemia led to two discontinuations from inhaled insulin plus insulin glargine and none from biaspart insulin, whereas hypoglycaemia led to no discontinuations from inhaled insulin plus insulin glargine and three from biaspart insulin. Of patients randomly allocated to treatment, four (1%) on inhaled insulin plus insulin glargine died (haemorrhagic stroke, myocardial infarction, sepsis, and worsening ischaemic heart disease), compared with one (<1%) on biaspart insulin (cardiac arrest). No deaths were judged to be related to the study drug in either group. Insulin antibody concentrations increased in both groups at week 14 and continued to increase until they reached a plateau, with a slight decline, at about 10 months. The size of the increase was greater in patients treated with inhaled insulin plus insulin glargine. Insulin antibody concentrations were not correlated with changes in key clinical parameters such as HbA1c, fasting plasma glucose, insulin dose, hypoglycaemia, or pulmonary function tests.
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From the SF-36 QoL and insulin treatment questionnaires, diabetes worries decreased signicantly from baseline in the group on inhaled insulin plus insulin glargine (p=00083) but not in the biaspart insulin group; the between-group dierence was not signicant (p=01825). Attitudes towards insulin therapy, treatment satisfaction, and treatment preference signicantly improved from baseline in both treatment groups (p<00001), with no signicant between-group dierence (p=05276). No between-group dierences (p=02452) or within-group dierences (p=01105) were recorded in any SF-36 component scales at week 45. Initiation of inhaled insulin plus insulin glargine was not associated with deterioration in overall physical quality of life or quality of life related to mental health, and we recorded signicant improvements in diabetes worries, attitudes toward insulin therapy, treatment satisfaction, and treatment preference. These ndings suggest that patients accepted treatment with inhaled insulin.

Discussion
Treatment with Technosphere inhaled insulin plus insulin glargine led to reductions in HbA1c concentrations that were maintained throughout the 52-week trial, and were similar to those of biaspart insulin. A study of similar design comparing Exubera inhaled insulin with subcutaneous injection of prandial insulin showed a decline in HbA1c of 04% and 05%, respectively, which was similar to the reduction in HbA1c that we recorded in this study.19 In our study, inhaled insulin plus insulin glargine also provided signicantly greater reduction in fasting plasma glucose and 1 h postprandial glucose concentrations than did biaspart insulin. Furthermore, fewer hypoglycaemic episodes (both mild to moderate
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Incidence* Inhaled insulin plus insulin glargine (n=323) Mild to moderate Severe Total 4799% (n=155) 433% (n=14) 4799% (n=155) Biaspart insulin (n=331) Odds ratio (95% CI) p value 6888% (n=228) 997% (n=33) 6888% (n=228) 0417 (0303 0573) 0409 (0215 0780) 0417 (0303 0573) <00001 00066 <00001

Event rate (per patient-months) Inhaled insulin plus Biaspart insulin insulin glargine 040 072 041 059 219 061 p value 00029 00591 00027

*Some patients had both mild-to-moderate and severe events. Data for severe hypoglycaemia are per 100 patient-months.

Table 5: Hypoglycaemia incidence and event rate (safety population)

and severe) and lower weight gain occurred in patients on inhaled insulin plus insulin glargine than in those on biaspart insulin. HbA1c reductions through 52 weeks and postprandial glucose AUC values for 0360 min at 52 weeks were each similar between groups, but each group reached these AUC values dierently. Consistent with the pharmacokinetic and pharmacodynamic properties of the treatments, AUC for 0120 min was slightly lower with inhaled insulin plus insulin glargine, whereas AUC for 120360 min was lower with biaspart insulin. However, the biaspart insulin group had long-term eects beyond 4 h with signicantly more episodes of hypoglycaemia. Insulin titration to glycaemic targets was encouraged and guided by an algorithm on the basis of selfmonitoring blood glucose proles. However, titration was not enforced, which explains the modest HbA1c reductions in both groups that were previously treated with dierent conventional insulin regimens. However, forced titration used in a study of another inhaled insulin resulted in robust and clinically meaningful reductions in HbA1c concentrations.20 Many studies have shown the ecacy of insulin therapy in type 2 diabetes.5,2123 Basal insulin alone improves glycaemic control, but as HbA1c concentrations decrease, the eect of postprandial glucose control on HbA1c increases.24 Present regimens for intensied insulin therapy by use of a prandial insulin to achieve aggressive HbA1c targets are hampered by the occurrence of increased hypoglycaemia and weight gain, raising concerns about the long-term safety of this approach.2527 Findings from the 4-T study6 at 1 year showed that prandial insulin aspart and biaspart insulin produced better HbA1c control than did insulin detemir, but with a greater risk of increased hypoglycaemia and weight gain. However, forced insulin titration in the APOLLO study28 led to similar lowering of HbA1c with insulin lispro thrice daily as with insulin glargine once daily. Compared with subcutaneously administered rapidacting insulin analogues, the pharmacokinetics of Technosphere inhaled insulin more closely mimic early phase insulin release.15,29 The reduced risk of hypoglycaemia with inhaled insulin plus insulin glargine was
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Inhaled insulin plus insulin glargine (n=323) Exposure time (patient-months) Morning (per 100 patient-months) Afternoon (per 100 patient-months) Evening (per 100 patient-months) Late night (per 100 patient-months) 30166 033 023 003 010

Biaspart insulin (n=331) 33630 071 036 068 042

Event rates are the numbers of events divided by the exposure time.

Table 6: Severe hypoglycaemia event rates by time of the day (safety population)

correlated with the rapid onset and shorter duration of action of Technosphere inhaled insulin versus biaspart insulin, suggesting that Technosphere inhaled insulin might become an option to reduce risk of hypoglycaemia in patients with insulin-treated type 2 diabetes. In our study, the standard meal challenge was associated with a lower 1 h postprandial glucose and fasting plasma glucose with inhaled insulin plus insulin glargine than with biaspart insulin, which was probably related to greater suppression of endogenous glucose production.17 The reduced weight gain seen with inhaled insulin plus insulin glargine relative to biaspart insulin might relate to better synchronisation between the ultrarapid pharmacokinetics of inhaled insulin and the mealtime blood glucose prole, and could also be a clinical indication of lower hypoglycaemia with inhaled insulin plus insulin glargine, but the mechanism is not well understood. Reduced weight gain with inhaled insulin plus insulin glargine was not attributed to metformin use, which was equal in both treatment groups. In our study, inhaled insulin was well tolerated apart from an increased frequency of cough, and an increased risk of infections, especially upper-respiratory-tract infections. For all patients with type 2 diabetes who had been treated for up to 2 years, the integrated summary of safety of the Technosphere inhaled insulin development programme, reported to the US Food and Drug Administration, recorded infections in 30% (537/1795) of those on inhaled insulin and 32% (435/1345) of those receiving a comparator. Furthermore, upper-respiratorytract infections were recorded in 8% (151/1795) of patients on inhaled insulin and 10% (131/1345) of those
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in comparator groups. No dierences were shown in the occurrence of cancer, cardiovascular events, or cerebrovascular events between groups. Long-term safety studies are planned with Technosphere inhaled insulin after regulatory approval. The occurrence of cough rarely led to study discontinuation. The pattern and characteristics of cough in the group receiving inhaled insulin plus insulin glargine was probably due to stimulation of the cough reex by inhalation of a dry powder formulation, which abated with continued use. Changes in pulmonary function tests were small, asymptomatic, and not judged to be clinically signicant by investigators. In a study assessing pulmonary function at 3 months after cessation of Technosphere inhaled insulin, the small, non-progressive dierences from baseline FEV1 and DLCO disappeared in patients with type 1 and type 2 diabetes, indicating that changes in pulmonary function are reversible when treatment has ended.30 These results are consistent with another study of inhaled insulin in which dierences in pulmonary function compared with conventional insulin were resolved when Exubera was discontinued after 2 years of treatment.31 Our study is limited by the fact that the design and the dierent administration times of the comparator drugs did not allow masking. However, because of the need to titrate insulin doses and monitor glycaemia, masking in studies assessing insulin is not judged to be feasible by some regulatory authorities. Greater reductions in HbA1c might have been achieved if insulin titration to glycaemic targets was systematically enforced during the study, rather than allowing clinicians to treat patients to their perceived glycaemic targets. This study was designed to compare a prandial-based inhaled insulin therapy with a premix-based therapy since the selected premixed therapy is widely used in patients with type 2 diabetes. With the increased use of basal bolus regimens for the treatment of patients with type 2 diabetes, future studies comparing such regimens are warranted. Safety considerations restricted the population in this study, but the safety data gathered in this trial will allow larger and more diverse populations to be included in future trials. Our ndings show that inhaled insulin plus insulin glargine, alone or in combination with an oral antidiabetes drug (eg, metformin), is an eective alternative to conventional insulin therapy (biaspart insulin) in uncontrolled type 2 diabetes. We believe that use of Technosphere inhaled insulin, an ultrarapid prandial insulin, along with a basal insulin, could provide improved glycaemic control with lower weight gain and rates of hypoglycaemia in many individuals with type 2 diabetes.
Contributors JR, DLL, and LG were study investigators and participated in the data collection, study analysis, interpretation of data, and development of the report. CPH, DWB, REP, AHB, and PCR participated in the study analysis, interpretation of data, and development of the report. P-CC was the study statistician. The nal version was reviewed and approved by all authors. JR was the lead author during the review process.

MKC-TI-102 primary investigators A F Comes, L Maei, M Damiano, L Litwak, I Sinay, J Alvarinas, L A T Russo, M L Castro, R Kupfer, C J Chrisman, V F de Oliveira, M C Dinato, F G Eliaschewitz, J L Gross, C Y Hayashida, G Repetto, M H Takahashi, M T Zanella, P Ziter, A Bell, R Goldenberg, R Aronson, M Chilvers, S Dharamshi, M OMahony, Y Twum-Barima, N Velasco, M E Martinez, G Godoy, J Diaz, M C Biehl, R Vidal, P G Hernandez, C Gonzalez-Villalpando, M G G Soria, C M Riojas, H E Tamez-Perez, K Jusiak, M Arciszewska, J Loba, I Jakubowska, K Cypryk, M Stepka, J Sieradzki, O Aleksandrov, I G Fomina, G V Rodoman, M V Kotelnikov, M G Pavlova, N Shilkina, G Reshedko, A Ametov, V Yakusevich, E Grineva, O Barbarash, N Zhavoronkova, M Baluda, A Gorelov, A Rakov, V Marasaev, L M Prieto-Sanchez, E Grineva, G Cuatrecasas, A Becerra, A Sendon, F Losada, S Duran, J F Cano, G Gimenez, A Gomez-Pan, A Palaudaries, L Borthwick, L Gnudi, A Graham, F Raymond, S Schwartz, R Bergenstal, J Rosenstock, M Warren, A Miller, D Tran, A O Odugbesan, H Knapp, K Latif, A Falahati, K Patricia, J Dhali, H Studdard, P Rask, M Rendell, A Sussman, K Pudi, P Norwood, P Rosenblit, L Rudolph, L Glaser, C Romney, S Miller, D Ajani, R Graf, M Robinson, J-L Selam, R Gaona Jr, G Argoud, R Garcia, K Hershon, L Stonesifer, R Sievert, P Bressler, J McGettigan, J Eberly, S Hijazi, M Posey, I Hartman, H Bruce, L Koehler, L Ratcli, D Wombolt, A Ahmann, E Popa, J Baumgartner, H Suh, C Breton, O Brkic-Vukotic, M Brown, R Canadas, J A Cohen, J Dicke, T Fagan, J Flack, L Fogelfeld, I Ahmed, M C Hagan, P Hollander, C Ketels, D Lender, M Lin, J Mossberg, K Pierce, A Radparvar, K Ravakhah, J Rothman, J W Sensenbrenner, S Smallow, W Spuhler, R Tanenberg, S P Thomson, R Zimmerman, E Schwarz, F Ellyin, M Patel, B J Redmon, S Ghandi. Conicts of interest JR has served on advisory boards and received honoraria or consulting fees from Pzer, Roche, Sano-Aventis, Novo Nordisk, Eli Lilly, MannKind, GlaxoSmithKline, Takeda, Daiichi Sankyo, Forest, Johnson & Johnson, Novartis, Boehringer Ingelheim, and Amylin; and has received research grants from Merck, Pzer, Sano-Aventis, Novo Nordisk, Roche, Bristol-Myers Squibb, Eli Lilly, Forest, GlaxoSmithKline, Takeda, Novartis, AstraZeneca, Amylin, Johnson & Johnson, Daiichi Sankyo, MannKind, and Boehringer Ingelheim. DLLs institution has received research support and DLL has received travel reimbursement related to this study from MannKind. DLL has received research support and honoraria from Novo Nordisk; has served as a consultant and speaker for Novo Nordisk; has received travel reimbursement from MannKind; and is a board member for and stockholder in Biodel. LGs institution has received research support and LG has received travel reimbursement related to this study from MannKind; and LG has received honoraria from Takeda, Johnson & Johnson, GlaxoSmithKline, Sirtris, and Servier. CPH, DWB, P-CC, REP, AHB, and PCR are employees of and have shares or stocks in MannKind. No author received honoraria related to the development of this report. Acknowledgments This study was funded by MannKind. We thank the MKC-TI-102 investigators, their sta, and the clinical trial personnel; the patients for their participation in this trial; Marjorie Pestel Zimmerman and Jane Moore of Peloton Advantage for writing and editorial assistance (supported by MannKind); and Alfred E Mann for his encouragement and support. References 1 Ramlo-Halsted BA, Edelman SV. The natural history of type 2 diabetes. Implications for clinical practice. Prim Care 1999; 26: 77189. 2 Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009; 360: 12939. 3 Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 2009; 52: 1730. 4 Roden M. Optimal insulin treatment in type 2 diabetes. N Engl J Med 2009; 361: 180103. 5 Raskin P, Allen E, Hollander P, et al. Initiating insulin therapy in type 2 diabetes: a comparison of biphasic and basal insulin analogs. Diabetes Care 2005; 28: 26065.

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Articles

10

11

12

13

14

15

16

17

18

Holman RR, Thorne KI, Farmer AJ, et al. Addition of biphasic, prandial, or basal insulin to oral therapy in type 2 diabetes. N Engl J Med 2007; 357: 171630. Holman RR, Farmer AJ, Davies MJ, et al. Three-year ecacy of complex insulin regimens in type 2 diabetes. N Engl J Med 2009; 361: 173647. Pftzner A, Mann AE, Steiner SS. Technosphere/insulina new approach for eective delivery of human insulin via the pulmonary route. Diabetes Technol Ther 2002; 4: 58994. Brain J, Finch GL, Rice RJ, Schwartz PF, Teeter JG. Trough insulin levels in bronchoalveolar lavage following inhalation of human insulin (Exubera) in patients with diabetes mellitus. American Thoracic Society Annual Meeting; Toronto, ON, Canada; May 1621, 2008. Abstr 616. Cassidy JP, Marino MT, Amin N, et al. Lung deposition and absorption of insulin from AFRESA (Technosphere insulin). American Diabetes Association 69th Scientic Sessions; New Orleans, LA, USA; June 59, 2009. Abstr 433-P. Leone-Bay A, Grant M. Technosphere/insulin: mimicking endogenous insulin release. In: Rathbone M, Hadgraft J, Roberts M, Lane M, eds. Modied release drug delivery technology, 2nd edn, vol 2. New York, NY: Informa Healthcare USA, 2008: 67379. Boss AH, Rave K, Cheatham WW, Heise T. Inhaled Technosphere/ insulin: glucose elimination at the right time? American Diabetes Association 65th Scientic Sessions; San Diego, CA, USA; June 1014, 2009. Abstr 443-P. Pftzner A, Forst T. Pulmonary insulin delivery by means of the Technosphere drug carrier mechanism. Expert Opin Drug Deliv 2005; 2: 1097106. Rave K, Heise T, Pftzner A, Boss AH. Coverage of postprandial blood glucose excursions with inhaled Technosphere insulin in comparison to subcutaneously injected regular human insulin in subjects with type 2 diabetes. Diabetes Care 2007; 30: 230708. Rosenstock J, Bergenstal R, DeFronzo RA, et al. Ecacy and safety of Technosphere inhaled insulin compared with Technosphere powder placebo in insulin-naive type 2 diabetes suboptimally controlled with oral agents. Diabetes Care 2008; 31: 217782. Steiner S, Pftzner A, Wilson BR, Harzer O, Heinemann L, Rave K. Technosphere/insulinproof of concept study with a new insulin formulation for pulmonary delivery. Exp Clin Endocrinol Diabetes 2002; 110: 1721. Potocka E, Hovorka R, Baughman R, et al. AFRESA suppresses endogenous glucose production earlier than a rapid-acting analog (lispro) and inhaled Exubera. American Diabetes Association 69th Scientic Sessions; New Orleans, LA, USA; June 59, 2009. Abstr 232-OR. Hsia CC, Hyde DM, Ochs M, Weibel ER. An ocial research policy statement of the American Thoracic Society/European Respiratory Society: standards for quantitative assessment of lung structure. Am J Respir Crit Care Med 2010; 181: 394418.

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20

21

22

23

24 25 26 27

28

29

30

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Rosenstock J, Cefalu WT, Hollander PA, et al. Two-year pulmonary safety and ecacy of inhaled human insulin (Exubera) in adult patients with type 2 diabetes. Diabetes Care 2008; 31: 172328. Hollander PA, Cefalu WT, Mitnick M, Lawrence D, Rosenstock J. Titration of inhaled human insulin (Exubera) in a treat-to-target regiment for patients with type 2 diabetes. Diabetes Technol Ther 2010; 12: 18591. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008; 359: 157789. Khutsoane D, Sharma SK, Almustafa M, et al. Biphasic insulin aspart 30 treatment improves glycaemic control in patients with type 2 diabetes in a clinical practice setting: experience from the PRESENT study. Diabetes Obes Metab 2008; 10: 21222. Rosenstock J, Ahmann AJ, Colon G, Scism-Bacon J, Jiang H, Martin S. Advancing insulin therapy in type 2 diabetes previously treated with glargine plus oral agents: prandial premixed (insulin lispro protamine suspension/lispro) versus basal/bolus (glargine/ lispro) therapy. Diabetes Care 2008; 31: 2025. Monnier L, Colette C. Target for glycemic control: concentrating on glucose. Diabetes Care 2009; 32 (suppl 2): S199204. Swinnen SG, Hoekstra JB, Devries JH. Insulin therapy for type 2 diabetes. Diabetes Care 2009; 32 (suppl 2): S25359. Heller SR. A summary of the ADVANCE trial. Diabetes Care 2009; 32 (suppl 2): S35761. The Action to Control Cardiovascular Risk in Diabetes Study Group. Eects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358: 254559. Bretzel RG, Nuber U, Landgraf W, Owens DR, Bradley C, Linn T. Once-daily basal insulin glargine versus thrice-daily prandial insulin lispro in people with type 2 diabetes on oral hypoglycaemic agents (APOLLO): an open randomised controlled trial. Lancet 2008; 371: 107384. Cassidy J, Baughman R, Schwartz S, Haworth PA, Boss AH, Richardson PC. AFRESA (Technosphere insulin) dosage strengths are interchangeable. American Diabetes Association 69th Scientic Sessions; New Orleans, LA, USA; June 59, 2009. Abstr 425-P. Petrucci R, Amin N, Lovertin P, Boss A, Richardson P. Pulmonary function tests remain similar in patients who received Technosphere insulin and in patients currently receiving standard antidiabetic therapy. Diabetologia 2009; 52 (suppl 1): S361 (abstr 919). Rosenstock J, Cefalu WT, Hollander PA, Klioze SS, Reis J, Duggan WT. Safety and ecacy of inhaled human insulin (Exubera) during discontinuation and readministration of therapy in adults with type 2 diabetes: a 3-year randomized controlled trial. Diabetes Technol Ther 2009; 11: 697705.

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