Figure 1— A: HbA1c (mean ± SD) during treatment with inhaled () versus subcutaneous () insulin at screening (n = 141 and 145, respectively), baseline (n = 143 and 145), and weeks 6 (n = 137 and 130), 12 (n = 143 and 145), and 24 (n = 134 and 140). B: Percentage of patients achieving defined levels of HbA1c at week 24 (LOCF) with inhaled (, n = 143) versus subcutaneous (, n = 145) insulin.------------------------------------------------------------------------------------------------
Efficacy and Safety of Inhaled Insulin (Exubera) Compared With Subcutaneous Insulin Therapy in Patients With Type 2 Diabetes
Results of a 6-month, randomized, comparative trial Priscilla A. Hollander, MD1, Lawrence Blonde, MD2, Richard Rowe, MD3, Adi E. Mehta, MD4, Joseph L. Milburn, MD5, Kenneth S. Hershon, MD6, Jean-Louis Chiasson, MD7 and Seymour R. Levin, MD8 for the Exubera Phase III Study Group
1 Baylor University Medical Center, Dallas, Texas2 Ochsner Clinic, New Orleans, Louisiana3 Division of Endocrinology, Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada4 Cleveland Clinic Foundation, Cleveland, Ohio5 North Texas Health Care Associates, Irving, Texas6 North Shore Diabetes and Endocrine Associates, New Hyde Park, New York7 Research Center, Department of Medicine, Centre Hospitalier de l’Université de Montréal, Campus Hôtel-Dieu, University of Montreal, Montreal, Quebec, Canada8 West Los Angeles VA Medical Center, Los Angeles, California
ABSTRACT
TOPABSTRACTINTRODUCTIONRESEARCH DESIGN AND METHODSRESULTSCONCLUSIONSReferences OBJECTIVE— Glycemic control using inhaled, dry-powder insulin plus a single injection of long-acting insulin was compared with a conventional regimen in patients with type 2 diabetes, which was previously managed with at least two daily insulin injections.
RESEARCH DESIGN AND METHODS— Patients were randomized to 6 months’ treatment with either premeal inhaled insulin plus a bedtime dose of Ultralente (n = 149) or at least two daily injections of subcutaneous insulin (mixed regular/NPH insulin; n = 150). The primary efficacy end point was the change in HbA1c from baseline to the end of study.
RESULTS— HbA1c decreased similarly in the inhaled (–0.7%) and subcutaneous (–0.6%) insulin groups (adjusted treatment group difference: –0.07%, 95% CI –0.32 to 0.17). HbA1c <7.0% name="BDY">
INTRODUCTION
TOPABSTRACTINTRODUCTIONRESEARCH DESIGN AND METHODSRESULTSCONCLUSIONSReferences Although the long-term benefits of tight glycemic control have been shown in patients with both type 1 and type 2 diabetes (1–5), insulin therapy is often delayed or suboptimally implemented despite elevated HbA1c levels, and a substantial number of patients remain poorly controlled (6).
Several factors contribute to the poor implementation of insulin therapy in the patient with type 2 diabetes, but the inconvenience and poor patient acceptability of a multiple daily injection regimen may play a major role (7). Currently, the majority of patients treated with insulin do not achieve recommended HbA1c goals (8). Reliance on fixed-ratio premixed insulins for treatment of a significant proportion of the type 2 diabetic population may significantly constrain the ability to achieve target glycemia. More acceptable forms of insulin delivery are required to improve the implementation of insulin therapy aiming for recommended treatment goals.
A dry-powder insulin delivery system that permits noninvasive application of rapid-acting insulin via inhalation has been developed. The pulmonary route exploits the large vascular bed and permeability of the alveoli to deliver insulin directly into the bloodstream (9). Inhaled insulin provides a rapid-acting insulin for management of both type 1 and type 2 diabetes, and preliminary short-term studies have shown that inhaled insulin provides reproducible and effective control of meal-related glycemia (10–12).
The time-action profile of human regular insulin injected subcutaneously limits its ability to control postprandial glycemia. Its relatively slow onset of action does not reproduce the physiologic secretion profile of insulin in response to a meal (13), thus resulting in excessive postprandial hyperglycemia and increased risk of hypoglycemia before the next meal. A study (14) in healthy subjects showed inhaled insulin to have a rapid onset of action that was significantly faster than regular insulin and a duration of action between that of insulin lispro and regular insulin. It has also been shown (15) in patients with type 2 diabetes that inhaled insulin is rapidly and reproducibly absorbed. As such, inhaled insulin appears to match the physiologic needs for mealtime use.
The present study aimed to 1) assess whether an insulin regimen involving pulmonary delivery of rapid-acting, dry-powder insulin plus a single injection of basal long-acting, subcutaneous insulin can provide glycemic control comparable to a conventional subcutaneous insulin regimen in a large cohort of patients with type 2 diabetes previously managed with at least two daily subcutaneous injections of insulin and 2) assess the tolerability of inhaled insulin over a 6-month period.
RESEARCH DESIGN AND METHODS
TOPABSTRACTINTRODUCTIONRESEARCH DESIGN AND METHODSRESULTSCONCLUSIONSReferences Men and women (n = 520) diagnosed with type 2 diabetes for at least 1 year were screened at 39 centers in the U.S. and Canada. Inclusion criteria were age 35–80 years; stable subcutaneous insulin schedule involving two to three injections daily for at least 2 months before study entry and not receiving any oral antidiabetic agents; screening and prerandomization HbA1c values of 6–11% inclusive, fasting plasma C-peptide >0.2 pmol/ml, and BMI 35 kg/m2; willingness to perform self-monitoring of blood glucose (SMBG) and otherwise comply with the study protocol; and written informed consent.
Exclusion criteria included poorly controlled asthma, chronic obstructive pulmonary disease or other significant respiratory disease; smoking during the last 6 months; abnormal screening chest X-ray; abnormal pulmonary function at screening (carbon monoxide diffusing capacity [DLCO] <75%,>120%, and forced expiratory volume in 1 s [FEV1] <70%>150 units/day.
The study protocol was approved by the institutional review board at each center.
This was a phase 3, open-label, parallel-group, comparator study consisting of a screening visit, a 4-week baseline lead-in phase, and a 24-week randomized treatment phase. During the baseline period, patients received a subcutaneous insulin regimen consisting of two doses of mixed NPH/regular. If the patient had previously been treated with an insulin regimen consisting of mixed NPH/regular insulin before breakfast and supper, the patient continued with this regimen. Otherwise, the patient received an appropriate two-dose regimen based on insulin requirements and glycemic control before entering the study.
Three weeks before randomization, patients met a dietitian for instruction on a weight-maintaining diet, which they were to maintain for the study duration. Patients were also instructed to perform 30 min of moderate exercise at least three times each week. The importance of diet and exercise was reinforced at clinic visits. All patients received instruction in SMBG, which they were to perform four times daily: before breakfast, lunch, supper, and bedtime. Target glucose ranges were 80–140 mg/dl (4.4–7.8 mmol/l) before meals and 100–160 mg/dl (5.6–8.9 mmol/l) before bedtime.
Before randomization, patients received instruction regarding the use of the insulin inhalation device. Using a computer-generated randomization scheme, performed through interactive voice response technology, patients were randomized to receive an inhaled insulin regimen (n = 149) or continue receiving conventional subcutaneous therapy as described above for 24 weeks (n = 150). The inhaled insulin regimen consisted of premeal inhaled insulin plus a single bedtime dose of Ultralente insulin. Inhaled insulin was administered within 10 min of the start of each meal and given in one to two inhalations using a dry-powder aerosol delivery system (Nektar Therapeutics, San Carlos, CA). The insulin powder was packaged in foil blisters of 1- and 3-mg doses (1 mg is equivalent to 2–3 units of subcutaneous insulin) (11).
Initial recommended doses for inhaled insulin were based on the subject’s weight, baseline subcutaneous insulin dose, and previous response to insulin. Administration of insulin, inhaled or injection, was preceded by SMBG, and the dose was adjusted weekly at the discretion of the investigator, based on SMBG results, to achieve target premeal glucose. Patients were also allowed to adjust doses when preprandial glucose was outside the above ranges, in anticipation of a smaller- or larger-than-usual meal or on an "as-needed" basis.
AssessmentsThe primary efficacy end point was the change in HbA1c from baseline to week 24. HbA1c was measured before randomization (at weeks –4 and –1) and at weeks 0, 6, 12, and 24. Mean HbA1c from weeks –1 and 0 was taken as baseline. The percentage of patients achieving HbA1c <7% name="SEC2">
RESULTS
TOPABSTRACTINTRODUCTIONRESEARCH DESIGN AND METHODSRESULTSCONCLUSIONSReferences Characteristics of the study participants at study entry are given in Table 1. The groups were well matched for all baseline characteristics. Both groups used only subcutaneous insulin at baseline, and the use of short- and long/intermediate-acting insulins at baseline was similar between treatment groups (Table 1). Daily insulin use in both groups trended slightly higher from week 6 to week 24 (inhaled group: short acting, 15.0 and 16.6 mg at weeks 6 and 24, respectively, and long acting, 34.0 and 37.9 units, respectively; subcutaneous group: short acting, 24.0 and 25.5 units, respectively, and intermediate acting, 50.1 and 52.3 units, respectively). As the inhaled insulin regimen involved only one daily injection of long-acting Ultralente along with premeal short-acting insulin, the basal-to-bolus ratio was shifted (i.e., less basal and more bolus insulin) relative to the subcutaneous group, where two daily doses of both intermediate- and short-acting insulin were used.
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Table 1— Demographic and clinical characteristics at study entry
Of the 299 patients enrolled, 1 withdrew consent after randomization. In the inhaled group, 3 patients discontinued for reasons related to study treatment (two adverse events and one insufficient clinical response), and 12 subjects discontinued for administrative reasons (e.g., protocol violation or withdrawn consent). Two subjects in the inhaled group died of causes unrelated to treatment (one of metastatic esophageal cancer and one of esophageal bleeding of unknown etiology). In the subcutaneous insulin group, one subject discontinued for insufficient clinical response and two subjects discontinued due to adverse events not considered related to the study drug. Six subjects in the subcutaneous group discontinued for administrative reasons.
Mean change in HbA1cMean HbA1c decreased similarly in the two treatment groups (Fig. 1A). After 24 weeks of treatment, mean HbA1c levels decreased from 8.1% at baseline to 7.4% (–0.7%) at week 24 in patients receiving inhaled insulin. Patients receiving subcutaneous showed a decrease from 8.2 to 7.6% (–0.6%). The difference between the adjusted mean changes from baseline for the two treatments (inhaled-subcutaneous) was –0.07% (95% CI –0.32 to 0.17). Thus, the upper limit of the 95% CI was <0.5 name="F1">
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Figure 1— A: HbA1c (mean ± SD) during treatment with inhaled () versus subcutaneous () insulin at screening (n = 141 and 145, respectively), baseline (n = 143 and 145), and weeks 6 (n = 137 and 130), 12 (n = 143 and 145), and 24 (n = 134 and 140). B: Percentage of patients achieving defined levels of HbA1c at week 24 (LOCF) with inhaled (, n = 143) versus subcutaneous (, n = 145) insulin.
Sixty-seven patients (47%) receiving inhaled insulin achieved HbA1c <7% href="http://care.diabetesjournals.org/cgi/content/full/27/10/2356#F1">Fig. 1B.
FPG and PPGFPG decreased from 152 mg/dl (8.44 mmol/l) at baseline to 132 mg/dl (7.33 mmol/l) at week 24 in those receiving inhaled insulin compared with 158 mg/dl (8.77 mmol/l) to 149 mg/dl (8.27 mmol/l) in the subcutaneous group. The difference between the adjusted mean changes from baseline was –15.9 mg/dl in favor of inhaled insulin (95% CI –26.6 to –5.2).
The treatment groups were comparable in terms of change from baseline in the 2-h PPG concentration at week 24. In patients receiving inhaled insulin treatment, 2-h PPG decreased from 244 mg/dl (13.5 mmol/l) at baseline to 221 mg/dl (12.3 mmol/l) at week 24, compared with a reduction from 252 mg/dl (14.0 mmol/l) to 231 mg/dl (12.8 mmol/l) in patients receiving subcutaneous treatment. The difference between adjusted mean changes from baseline was –9.41 mg/dl (95% CI –26.9 to 8.0).
HypoglycemiaIn the inhaled insulin group, 109 (76.2%) patients experienced a total of 1,104 hypoglycemic events: a crude event rate of 1.40 events per subject-month. One hundred four patients (71.7%) in the subcutaneous insulin group experienced a total of 1,278 events: a crude event rate of 1.57 events per subject-month. This represents a risk ratio (inhaled/subcutaneous) for any hypoglycemic event of 0.89 (95% CI 0.82–0.97), indicating that there is a lower risk of hypoglycemia associated with inhaled insulin. There were very few severe hypoglycemic events in either treatment group. Only four events in the inhaled group were classed as severe (crude event rate 0.5/100 subject-months) and one event in the subcutaneous group (0.1/100 subject-months).
Body weight and lipid profileAfter 24 weeks, mean body weight in the inhaled insulin group remained stable at 90.5 kg. However, there was an increase in body weight in the subcutaneous treatment group (89.2 kg at baseline, 90.6 kg at week 24). The adjusted mean treatment group difference was –1.29 kg (95% CI –1.98 to –0.59).
No differences in serum lipid parameters were seen between the two groups. After 24 weeks of treatment, the median changes from baseline in lipid parameters in the inhaled and subcutaneous insulin groups, respectively, were total cholesterol, 0 and 3 mg/dl (0.0 and 0.08 mmol/l); HDL cholesterol, 0 and 1 mg/dl (0.0 and 0.03 mmol/l); LDL cholesterol, –3 and 0 mg/dl (–0.08 and 0.0 mmol/l); and triglycerides, 3.5 and 8.0 mg/dl (0.04 and 0.09 mmol/l).
Safety and tolerabilityThe frequency and nature of adverse events, with the exception of cough, were comparable between the two treatment groups. A total of 126 patients in the inhaled insulin group and 118 patients in the subcutaneous insulin group experienced adverse events (including the hypoglycemic events discussed above) that were possibly or probably related to the treatment regimen. The majority of these were mild or moderate. Treatment-related adverse events experienced by >10% of patients in the inhaled insulin group were tremor (43 patients, 29%), asthenia (27 patients, 18%), sweating (25 patients, 17%), and dizziness (23 patients, 15%). All of these adverse events are symptoms compatible with hypoglycemia. Treatment-related adverse events experienced by >10% of patients in the subcutaneous group were tremor (40 patients, 27%), sweating (29 patients, 20%), asthenia (21 patients, 14%), and dizziness (19 patients, 13%). All-cause cough was experienced by 21% (32 of 149) of patients in the inhaled insulin treatment group compared with 2% (3 of 149) in the subcutaneous group. Cough was judged as mild to moderate in the inhaled group and decreased in incidence over the study period; the median duration of the period of increased cough was 2.0 weeks. There were six treatment-related severe adverse events reported in the inhaled insulin group; three hypoglycemia, one hyperglycemia, one neuralgia, and one anxiety. There was one treatment-related severe adverse event in the subcutaneous group (unconsciousness associated with hypoglycemia).
The incidence of clinical laboratory abnormalities was similar between the two treatment groups. Forty-three of 135 patients (32%) in the inhaled group had at least one laboratory test abnormality compared with 56 of 142 patients (39%) in the subcutaneous group. The most frequent laboratory abnormalities were in urinalysis (increases in urine glucose, urine white blood cells, and hyaline casts).
Inhaled insulin-treated patients developed increased insulin antibody serum binding. Median percentage binding was 5.0 and 1.5% (below the level of quantitation) in the inhaled and subcutaneous groups, respectively. Levels of antibodies did not correlate to HbA1c, insulin dose, or incidence of hypoglycemia, and there was no association with adverse events or pulmonary function.
Mean changes in FVC, FEV1, TLC, and DLCO were small and comparable between the two treatment groups (Table 2).
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Table 2— PFT results in subjects with a baseline and at least one postbaseline PFT measurement
Treatment satisfaction and quality of lifeThe mean overall satisfaction score improved significantly for the inhaled group (P < name="SEC3">
CONCLUSIONS
TOPABSTRACTINTRODUCTIONRESEARCH DESIGN AND METHODSRESULTSCONCLUSIONSReferences The results of this study show that inhaled insulin provides glycemic control comparable to a conventional insulin regimen in patients with type 2 diabetes, as assessed by the changes in HbA1c from baseline to week 24. The actual decrease in HbA1c in both treatment groups at week 24 was modest; however, such a change would be expected to reduce the development and/or progression of diabetes complications, as shown in the U.K. Prospective Diabetes Study (3,4). Moreover, the study was designed to demonstrate equivalence and was not target driven. Nevertheless, a greater proportion of patients in the inhaled insulin group reached the American Diabetes Association goal of HbA1c <7% href="http://care.diabetesjournals.org/cgi/content/full/27/10/2356#R16">16). The addition of premeal inhaled insulin reduced both FPG and PPG levels. Although both basal and postprandial glucose contribute to glucose exposure, the relative importance of each has been debated (17) and may depend on the severity of diabetes (18). Interestingly, FPG decreased more in the inhaled group than in the subcutaneous group. The bedtime administration of Ultralente basal insulin in the inhaled insulin group may have contributed to lower FPG.
Overall, inhaled insulin was well tolerated. The risk of a hypoglycemic event was lower in the inhaled group compared with the subcutaneous group, which is consistent with results from a previous study (12). As inhaled insulin is delivered systemically via the lungs, it is important to assess possible pulmonary adverse events. Cough of mild-to-moderate severity was observed with a greater frequency in the inhaled insulin group, although its incidence decreased as the study progressed, and no patient withdrew due to cough. In the present study, inhaled insulin treatment was not associated with adverse effects on pulmonary function parameters of FEV1, FVC, TLC, or DLCO. Long-term studies are underway to assess any potential effect more conclusively. Changes in lung function initially observed in a long-term extension study of the Exubera Phase III program remained small and nonprogressive. Furthermore, controlled discontinuation of Exubera in a subset of those patients resulted in lung function gains of similar magnitude to the initial small decrease (19).
Insulin antibodies with both animal and human insulins have previously been reported (20). In the present study, inhaled insulin–treated patients developed increased insulin antibody serum binding, but there was no correlation with parameters of clinical efficacy such as HbA1c, FPG, or hypoglycemia. Further analyses of combined data from a number of 3- to 6-month and extension studies (21) with inhaled insulin showed that antibody levels plateau after 12 months and also demonstrated no relation to efficacy measures or to pulmonary or other adverse events.
Both physicians and patients are often hesitant to initiate insulin therapy for several reasons. Weight gain has been a major concern (22), as has injection-related anxiety and/or phobia, all of which impede the timely use of insulin in patients with type 2 diabetes (23). During the present study, a greater increase in body weight occurred in patients who received subcutaneous insulin (1.4 kg) compared with inhaled insulin (no change). In a previous shorter study (11) in type 2 diabetes, inhaled insulin was not associated with increases in body weight. Whether the more physiologic insulin profile associated with inhaled insulin may have prevented weight gain remains to be established. Although the majority of patients in the present study had a BMI <35 href="http://care.diabetesjournals.org/cgi/content/full/27/10/2356#R24">24,25).
Reluctance to taking insulin by patients and reluctance to prescribe insulin by physicians contribute to poor glycemic control in many patients with type 2 diabetes, resulting in poor quality of life, greater risk for micro- and macrovascular complications, and increased long-term economic costs. By allowing the implementation of intensive insulin therapy with a noninvasive delivery system, inhaled insulin may allow patients to regard insulin therapy as a more positive treatment option. Although this was an open-label study in which patients volunteered to receive a novel therapeutic agent, a significantly higher level of patient satisfaction was seen with inhaled insulin. Many factors are likely to influence satisfaction; however, in the present study, the overall score as well as that of all satisfaction subscales favored inhaled insulin. Any effect of novelty with a new delivery system on satisfaction is likely to have diminished by the end of the study, and other studies show that that improved satisfaction with inhaled insulin peaks after 6 weeks, remains constant to 24 weeks (26), and is maintained after 1 year of continuous therapy (27). Therefore, the availability of inhaled insulin might help improve acceptance of insulin therapy by both patients and physicians.
In conclusion, this study demonstrated that inhaled insulin treatment in type 2 diabetes was effective, well tolerated, and comparable in glycemic control to a conventional subcutaneous insulin regimen. Ongoing studies will establish the long-term safety of inhaled insulin, but results from this 6-month study, together with those of other clinical studies of inhaled insulin (10–12), suggest that it may prove a novel and well-accepted treatment approach for the management of many patients with diabetes.
Results of a 6-month, randomized, comparative trial Priscilla A. Hollander, MD1, Lawrence Blonde, MD2, Richard Rowe, MD3, Adi E. Mehta, MD4, Joseph L. Milburn, MD5, Kenneth S. Hershon, MD6, Jean-Louis Chiasson, MD7 and Seymour R. Levin, MD8 for the Exubera Phase III Study Group
1 Baylor University Medical Center, Dallas, Texas2 Ochsner Clinic, New Orleans, Louisiana3 Division of Endocrinology, Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada4 Cleveland Clinic Foundation, Cleveland, Ohio5 North Texas Health Care Associates, Irving, Texas6 North Shore Diabetes and Endocrine Associates, New Hyde Park, New York7 Research Center, Department of Medicine, Centre Hospitalier de l’Université de Montréal, Campus Hôtel-Dieu, University of Montreal, Montreal, Quebec, Canada8 West Los Angeles VA Medical Center, Los Angeles, California
ABSTRACT
TOPABSTRACTINTRODUCTIONRESEARCH DESIGN AND METHODSRESULTSCONCLUSIONSReferences OBJECTIVE— Glycemic control using inhaled, dry-powder insulin plus a single injection of long-acting insulin was compared with a conventional regimen in patients with type 2 diabetes, which was previously managed with at least two daily insulin injections.
RESEARCH DESIGN AND METHODS— Patients were randomized to 6 months’ treatment with either premeal inhaled insulin plus a bedtime dose of Ultralente (n = 149) or at least two daily injections of subcutaneous insulin (mixed regular/NPH insulin; n = 150). The primary efficacy end point was the change in HbA1c from baseline to the end of study.
RESULTS— HbA1c decreased similarly in the inhaled (–0.7%) and subcutaneous (–0.6%) insulin groups (adjusted treatment group difference: –0.07%, 95% CI –0.32 to 0.17). HbA1c <7.0% name="BDY">
INTRODUCTION
TOPABSTRACTINTRODUCTIONRESEARCH DESIGN AND METHODSRESULTSCONCLUSIONSReferences Although the long-term benefits of tight glycemic control have been shown in patients with both type 1 and type 2 diabetes (1–5), insulin therapy is often delayed or suboptimally implemented despite elevated HbA1c levels, and a substantial number of patients remain poorly controlled (6).
Several factors contribute to the poor implementation of insulin therapy in the patient with type 2 diabetes, but the inconvenience and poor patient acceptability of a multiple daily injection regimen may play a major role (7). Currently, the majority of patients treated with insulin do not achieve recommended HbA1c goals (8). Reliance on fixed-ratio premixed insulins for treatment of a significant proportion of the type 2 diabetic population may significantly constrain the ability to achieve target glycemia. More acceptable forms of insulin delivery are required to improve the implementation of insulin therapy aiming for recommended treatment goals.
A dry-powder insulin delivery system that permits noninvasive application of rapid-acting insulin via inhalation has been developed. The pulmonary route exploits the large vascular bed and permeability of the alveoli to deliver insulin directly into the bloodstream (9). Inhaled insulin provides a rapid-acting insulin for management of both type 1 and type 2 diabetes, and preliminary short-term studies have shown that inhaled insulin provides reproducible and effective control of meal-related glycemia (10–12).
The time-action profile of human regular insulin injected subcutaneously limits its ability to control postprandial glycemia. Its relatively slow onset of action does not reproduce the physiologic secretion profile of insulin in response to a meal (13), thus resulting in excessive postprandial hyperglycemia and increased risk of hypoglycemia before the next meal. A study (14) in healthy subjects showed inhaled insulin to have a rapid onset of action that was significantly faster than regular insulin and a duration of action between that of insulin lispro and regular insulin. It has also been shown (15) in patients with type 2 diabetes that inhaled insulin is rapidly and reproducibly absorbed. As such, inhaled insulin appears to match the physiologic needs for mealtime use.
The present study aimed to 1) assess whether an insulin regimen involving pulmonary delivery of rapid-acting, dry-powder insulin plus a single injection of basal long-acting, subcutaneous insulin can provide glycemic control comparable to a conventional subcutaneous insulin regimen in a large cohort of patients with type 2 diabetes previously managed with at least two daily subcutaneous injections of insulin and 2) assess the tolerability of inhaled insulin over a 6-month period.
RESEARCH DESIGN AND METHODS
TOPABSTRACTINTRODUCTIONRESEARCH DESIGN AND METHODSRESULTSCONCLUSIONSReferences Men and women (n = 520) diagnosed with type 2 diabetes for at least 1 year were screened at 39 centers in the U.S. and Canada. Inclusion criteria were age 35–80 years; stable subcutaneous insulin schedule involving two to three injections daily for at least 2 months before study entry and not receiving any oral antidiabetic agents; screening and prerandomization HbA1c values of 6–11% inclusive, fasting plasma C-peptide >0.2 pmol/ml, and BMI 35 kg/m2; willingness to perform self-monitoring of blood glucose (SMBG) and otherwise comply with the study protocol; and written informed consent.
Exclusion criteria included poorly controlled asthma, chronic obstructive pulmonary disease or other significant respiratory disease; smoking during the last 6 months; abnormal screening chest X-ray; abnormal pulmonary function at screening (carbon monoxide diffusing capacity [DLCO] <75%,>120%, and forced expiratory volume in 1 s [FEV1] <70%>150 units/day.
The study protocol was approved by the institutional review board at each center.
This was a phase 3, open-label, parallel-group, comparator study consisting of a screening visit, a 4-week baseline lead-in phase, and a 24-week randomized treatment phase. During the baseline period, patients received a subcutaneous insulin regimen consisting of two doses of mixed NPH/regular. If the patient had previously been treated with an insulin regimen consisting of mixed NPH/regular insulin before breakfast and supper, the patient continued with this regimen. Otherwise, the patient received an appropriate two-dose regimen based on insulin requirements and glycemic control before entering the study.
Three weeks before randomization, patients met a dietitian for instruction on a weight-maintaining diet, which they were to maintain for the study duration. Patients were also instructed to perform 30 min of moderate exercise at least three times each week. The importance of diet and exercise was reinforced at clinic visits. All patients received instruction in SMBG, which they were to perform four times daily: before breakfast, lunch, supper, and bedtime. Target glucose ranges were 80–140 mg/dl (4.4–7.8 mmol/l) before meals and 100–160 mg/dl (5.6–8.9 mmol/l) before bedtime.
Before randomization, patients received instruction regarding the use of the insulin inhalation device. Using a computer-generated randomization scheme, performed through interactive voice response technology, patients were randomized to receive an inhaled insulin regimen (n = 149) or continue receiving conventional subcutaneous therapy as described above for 24 weeks (n = 150). The inhaled insulin regimen consisted of premeal inhaled insulin plus a single bedtime dose of Ultralente insulin. Inhaled insulin was administered within 10 min of the start of each meal and given in one to two inhalations using a dry-powder aerosol delivery system (Nektar Therapeutics, San Carlos, CA). The insulin powder was packaged in foil blisters of 1- and 3-mg doses (1 mg is equivalent to 2–3 units of subcutaneous insulin) (11).
Initial recommended doses for inhaled insulin were based on the subject’s weight, baseline subcutaneous insulin dose, and previous response to insulin. Administration of insulin, inhaled or injection, was preceded by SMBG, and the dose was adjusted weekly at the discretion of the investigator, based on SMBG results, to achieve target premeal glucose. Patients were also allowed to adjust doses when preprandial glucose was outside the above ranges, in anticipation of a smaller- or larger-than-usual meal or on an "as-needed" basis.
AssessmentsThe primary efficacy end point was the change in HbA1c from baseline to week 24. HbA1c was measured before randomization (at weeks –4 and –1) and at weeks 0, 6, 12, and 24. Mean HbA1c from weeks –1 and 0 was taken as baseline. The percentage of patients achieving HbA1c <7% name="SEC2">
RESULTS
TOPABSTRACTINTRODUCTIONRESEARCH DESIGN AND METHODSRESULTSCONCLUSIONSReferences Characteristics of the study participants at study entry are given in Table 1. The groups were well matched for all baseline characteristics. Both groups used only subcutaneous insulin at baseline, and the use of short- and long/intermediate-acting insulins at baseline was similar between treatment groups (Table 1). Daily insulin use in both groups trended slightly higher from week 6 to week 24 (inhaled group: short acting, 15.0 and 16.6 mg at weeks 6 and 24, respectively, and long acting, 34.0 and 37.9 units, respectively; subcutaneous group: short acting, 24.0 and 25.5 units, respectively, and intermediate acting, 50.1 and 52.3 units, respectively). As the inhaled insulin regimen involved only one daily injection of long-acting Ultralente along with premeal short-acting insulin, the basal-to-bolus ratio was shifted (i.e., less basal and more bolus insulin) relative to the subcutaneous group, where two daily doses of both intermediate- and short-acting insulin were used.
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Table 1— Demographic and clinical characteristics at study entry
Of the 299 patients enrolled, 1 withdrew consent after randomization. In the inhaled group, 3 patients discontinued for reasons related to study treatment (two adverse events and one insufficient clinical response), and 12 subjects discontinued for administrative reasons (e.g., protocol violation or withdrawn consent). Two subjects in the inhaled group died of causes unrelated to treatment (one of metastatic esophageal cancer and one of esophageal bleeding of unknown etiology). In the subcutaneous insulin group, one subject discontinued for insufficient clinical response and two subjects discontinued due to adverse events not considered related to the study drug. Six subjects in the subcutaneous group discontinued for administrative reasons.
Mean change in HbA1cMean HbA1c decreased similarly in the two treatment groups (Fig. 1A). After 24 weeks of treatment, mean HbA1c levels decreased from 8.1% at baseline to 7.4% (–0.7%) at week 24 in patients receiving inhaled insulin. Patients receiving subcutaneous showed a decrease from 8.2 to 7.6% (–0.6%). The difference between the adjusted mean changes from baseline for the two treatments (inhaled-subcutaneous) was –0.07% (95% CI –0.32 to 0.17). Thus, the upper limit of the 95% CI was <0.5 name="F1">
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Figure 1— A: HbA1c (mean ± SD) during treatment with inhaled () versus subcutaneous () insulin at screening (n = 141 and 145, respectively), baseline (n = 143 and 145), and weeks 6 (n = 137 and 130), 12 (n = 143 and 145), and 24 (n = 134 and 140). B: Percentage of patients achieving defined levels of HbA1c at week 24 (LOCF) with inhaled (, n = 143) versus subcutaneous (, n = 145) insulin.
Sixty-seven patients (47%) receiving inhaled insulin achieved HbA1c <7% href="http://care.diabetesjournals.org/cgi/content/full/27/10/2356#F1">Fig. 1B.
FPG and PPGFPG decreased from 152 mg/dl (8.44 mmol/l) at baseline to 132 mg/dl (7.33 mmol/l) at week 24 in those receiving inhaled insulin compared with 158 mg/dl (8.77 mmol/l) to 149 mg/dl (8.27 mmol/l) in the subcutaneous group. The difference between the adjusted mean changes from baseline was –15.9 mg/dl in favor of inhaled insulin (95% CI –26.6 to –5.2).
The treatment groups were comparable in terms of change from baseline in the 2-h PPG concentration at week 24. In patients receiving inhaled insulin treatment, 2-h PPG decreased from 244 mg/dl (13.5 mmol/l) at baseline to 221 mg/dl (12.3 mmol/l) at week 24, compared with a reduction from 252 mg/dl (14.0 mmol/l) to 231 mg/dl (12.8 mmol/l) in patients receiving subcutaneous treatment. The difference between adjusted mean changes from baseline was –9.41 mg/dl (95% CI –26.9 to 8.0).
HypoglycemiaIn the inhaled insulin group, 109 (76.2%) patients experienced a total of 1,104 hypoglycemic events: a crude event rate of 1.40 events per subject-month. One hundred four patients (71.7%) in the subcutaneous insulin group experienced a total of 1,278 events: a crude event rate of 1.57 events per subject-month. This represents a risk ratio (inhaled/subcutaneous) for any hypoglycemic event of 0.89 (95% CI 0.82–0.97), indicating that there is a lower risk of hypoglycemia associated with inhaled insulin. There were very few severe hypoglycemic events in either treatment group. Only four events in the inhaled group were classed as severe (crude event rate 0.5/100 subject-months) and one event in the subcutaneous group (0.1/100 subject-months).
Body weight and lipid profileAfter 24 weeks, mean body weight in the inhaled insulin group remained stable at 90.5 kg. However, there was an increase in body weight in the subcutaneous treatment group (89.2 kg at baseline, 90.6 kg at week 24). The adjusted mean treatment group difference was –1.29 kg (95% CI –1.98 to –0.59).
No differences in serum lipid parameters were seen between the two groups. After 24 weeks of treatment, the median changes from baseline in lipid parameters in the inhaled and subcutaneous insulin groups, respectively, were total cholesterol, 0 and 3 mg/dl (0.0 and 0.08 mmol/l); HDL cholesterol, 0 and 1 mg/dl (0.0 and 0.03 mmol/l); LDL cholesterol, –3 and 0 mg/dl (–0.08 and 0.0 mmol/l); and triglycerides, 3.5 and 8.0 mg/dl (0.04 and 0.09 mmol/l).
Safety and tolerabilityThe frequency and nature of adverse events, with the exception of cough, were comparable between the two treatment groups. A total of 126 patients in the inhaled insulin group and 118 patients in the subcutaneous insulin group experienced adverse events (including the hypoglycemic events discussed above) that were possibly or probably related to the treatment regimen. The majority of these were mild or moderate. Treatment-related adverse events experienced by >10% of patients in the inhaled insulin group were tremor (43 patients, 29%), asthenia (27 patients, 18%), sweating (25 patients, 17%), and dizziness (23 patients, 15%). All of these adverse events are symptoms compatible with hypoglycemia. Treatment-related adverse events experienced by >10% of patients in the subcutaneous group were tremor (40 patients, 27%), sweating (29 patients, 20%), asthenia (21 patients, 14%), and dizziness (19 patients, 13%). All-cause cough was experienced by 21% (32 of 149) of patients in the inhaled insulin treatment group compared with 2% (3 of 149) in the subcutaneous group. Cough was judged as mild to moderate in the inhaled group and decreased in incidence over the study period; the median duration of the period of increased cough was 2.0 weeks. There were six treatment-related severe adverse events reported in the inhaled insulin group; three hypoglycemia, one hyperglycemia, one neuralgia, and one anxiety. There was one treatment-related severe adverse event in the subcutaneous group (unconsciousness associated with hypoglycemia).
The incidence of clinical laboratory abnormalities was similar between the two treatment groups. Forty-three of 135 patients (32%) in the inhaled group had at least one laboratory test abnormality compared with 56 of 142 patients (39%) in the subcutaneous group. The most frequent laboratory abnormalities were in urinalysis (increases in urine glucose, urine white blood cells, and hyaline casts).
Inhaled insulin-treated patients developed increased insulin antibody serum binding. Median percentage binding was 5.0 and 1.5% (below the level of quantitation) in the inhaled and subcutaneous groups, respectively. Levels of antibodies did not correlate to HbA1c, insulin dose, or incidence of hypoglycemia, and there was no association with adverse events or pulmonary function.
Mean changes in FVC, FEV1, TLC, and DLCO were small and comparable between the two treatment groups (Table 2).
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Table 2— PFT results in subjects with a baseline and at least one postbaseline PFT measurement
Treatment satisfaction and quality of lifeThe mean overall satisfaction score improved significantly for the inhaled group (P < name="SEC3">
CONCLUSIONS
TOPABSTRACTINTRODUCTIONRESEARCH DESIGN AND METHODSRESULTSCONCLUSIONSReferences The results of this study show that inhaled insulin provides glycemic control comparable to a conventional insulin regimen in patients with type 2 diabetes, as assessed by the changes in HbA1c from baseline to week 24. The actual decrease in HbA1c in both treatment groups at week 24 was modest; however, such a change would be expected to reduce the development and/or progression of diabetes complications, as shown in the U.K. Prospective Diabetes Study (3,4). Moreover, the study was designed to demonstrate equivalence and was not target driven. Nevertheless, a greater proportion of patients in the inhaled insulin group reached the American Diabetes Association goal of HbA1c <7% href="http://care.diabetesjournals.org/cgi/content/full/27/10/2356#R16">16). The addition of premeal inhaled insulin reduced both FPG and PPG levels. Although both basal and postprandial glucose contribute to glucose exposure, the relative importance of each has been debated (17) and may depend on the severity of diabetes (18). Interestingly, FPG decreased more in the inhaled group than in the subcutaneous group. The bedtime administration of Ultralente basal insulin in the inhaled insulin group may have contributed to lower FPG.
Overall, inhaled insulin was well tolerated. The risk of a hypoglycemic event was lower in the inhaled group compared with the subcutaneous group, which is consistent with results from a previous study (12). As inhaled insulin is delivered systemically via the lungs, it is important to assess possible pulmonary adverse events. Cough of mild-to-moderate severity was observed with a greater frequency in the inhaled insulin group, although its incidence decreased as the study progressed, and no patient withdrew due to cough. In the present study, inhaled insulin treatment was not associated with adverse effects on pulmonary function parameters of FEV1, FVC, TLC, or DLCO. Long-term studies are underway to assess any potential effect more conclusively. Changes in lung function initially observed in a long-term extension study of the Exubera Phase III program remained small and nonprogressive. Furthermore, controlled discontinuation of Exubera in a subset of those patients resulted in lung function gains of similar magnitude to the initial small decrease (19).
Insulin antibodies with both animal and human insulins have previously been reported (20). In the present study, inhaled insulin–treated patients developed increased insulin antibody serum binding, but there was no correlation with parameters of clinical efficacy such as HbA1c, FPG, or hypoglycemia. Further analyses of combined data from a number of 3- to 6-month and extension studies (21) with inhaled insulin showed that antibody levels plateau after 12 months and also demonstrated no relation to efficacy measures or to pulmonary or other adverse events.
Both physicians and patients are often hesitant to initiate insulin therapy for several reasons. Weight gain has been a major concern (22), as has injection-related anxiety and/or phobia, all of which impede the timely use of insulin in patients with type 2 diabetes (23). During the present study, a greater increase in body weight occurred in patients who received subcutaneous insulin (1.4 kg) compared with inhaled insulin (no change). In a previous shorter study (11) in type 2 diabetes, inhaled insulin was not associated with increases in body weight. Whether the more physiologic insulin profile associated with inhaled insulin may have prevented weight gain remains to be established. Although the majority of patients in the present study had a BMI <35 href="http://care.diabetesjournals.org/cgi/content/full/27/10/2356#R24">24,25).
Reluctance to taking insulin by patients and reluctance to prescribe insulin by physicians contribute to poor glycemic control in many patients with type 2 diabetes, resulting in poor quality of life, greater risk for micro- and macrovascular complications, and increased long-term economic costs. By allowing the implementation of intensive insulin therapy with a noninvasive delivery system, inhaled insulin may allow patients to regard insulin therapy as a more positive treatment option. Although this was an open-label study in which patients volunteered to receive a novel therapeutic agent, a significantly higher level of patient satisfaction was seen with inhaled insulin. Many factors are likely to influence satisfaction; however, in the present study, the overall score as well as that of all satisfaction subscales favored inhaled insulin. Any effect of novelty with a new delivery system on satisfaction is likely to have diminished by the end of the study, and other studies show that that improved satisfaction with inhaled insulin peaks after 6 weeks, remains constant to 24 weeks (26), and is maintained after 1 year of continuous therapy (27). Therefore, the availability of inhaled insulin might help improve acceptance of insulin therapy by both patients and physicians.
In conclusion, this study demonstrated that inhaled insulin treatment in type 2 diabetes was effective, well tolerated, and comparable in glycemic control to a conventional subcutaneous insulin regimen. Ongoing studies will establish the long-term safety of inhaled insulin, but results from this 6-month study, together with those of other clinical studies of inhaled insulin (10–12), suggest that it may prove a novel and well-accepted treatment approach for the management of many patients with diabetes.
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