Satisfaction and Quality of Life With Premeal Inhaled Versus Injected Insulin in Adolescents and Adults With Type 1 Diabetes

A detailed description of the clinical results of the parent protocol was published previously (8). Briefly, this open-label, randomized, multicenter trial consisted of a screening visit, 4-week lead-in, and 24-week treatment phase. A total of 419 individuals with type 1 diabetes for at least 1 year were screened at 40 centers in the U.S. and Canada. Inclusion criteria were age 12–65 years, stable on an insulin regimen of at least two injections daily for 2 months before screening, baseline A1C between 6 and 11% inclusive, fasting plasma C-peptide ≤0.2 pmol/ml, and BMI ≤30 kg/m². Exclusion criteria included poorly controlled asthma, recent smoking, and significant laboratory abnormalities. The protocol was approved by the institutional review board, and informed consent was obtained from all subjects.

To standardize baseline assessments during the 4 weeks before randomization, all patients were switched to subcutaneous premeal regular insulin plus twice-daily NPH insulin administered in four subcutaneous injections daily (subcutaneous regimen). Target glucose ranges were 80–120 mg/dl (4.4–6.7 mmol/l) before meals and 100–140 mg/dl (5.6–7.8 mmol/l) before bedtime. A total of 162 individuals were randomized to insulin human (rDNA origin) Inhalation Powder (Exubera; Pfizer and Nektar Therapeutics) and twice-daily NPH insulin (inhaled regimen); 165 individuals were instructed to continue on their prerandomization subcutaneous regimen. Inhaled insulin was administered as one to two inhalations within 10 min of starting each meal. The insulin powder was packaged in foil blisters of 1- and 3-mg doses, which are approximately equivalent to 3 IU and 8 IU of subcutaneous insulin, respectively. Insulin doses were adjusted weekly by the investigator to achieve target premeal glucose levels, and patients adjusted doses according to diet and exercise requirements.

A1C was measured at baseline (week −1 to 0) and end point (week 24 or last visit), and fasting plasma glucose (FPG) was recorded at each visit.

At week −4 (screening); week −1 (baseline); weeks 6, 12, 20, and 24; and early withdrawal, questionnaires were sent directly from clinical sites to the central survey laboratory. Validated instruments of treatment satisfaction, quality of life, and barriers to insulin adherence were used (10,11) (see online appendix available at http://dx.doi.org/10.2337/dc06-1497). These measures are responsive to the effects of therapeutic interventions (12–14), the impact of side effects of medication (15), symptoms of diabetes (16–18), and changes in A1C (19–21). An age-appropriate parallel version of the adult questionnaire was used for adolescents aged 12–17 years. All scales were coded such that higher scores reflected the more favorable response, i.e., higher satisfaction, better quality of life, and reduced barriers to adherence.

Treatment satisfaction and quality of life during treatment at weeks 6, 12, 20, and 24 were evaluated using linear mixed models with fixed (treatment) and baseline covariate effects. In addition, changes from baseline to end point (week 24 or last visit) satisfaction were compared using ANCOVA (adjusted for baseline). All P values report nominal significance levels at α = 0.05. For reference, a partial Bonferroni's adjustment for type I error for multiple end points is provided (22,23). Correlation analysis (Pearson r and Spearman's rho) and multiple regression were used to examine the relationships between treatment, glycemic control, satisfaction, adherence barriers, and quality of life. Data are given as means ± SE unless specified otherwise.

In total, 120 adolescents aged 12–17 years were randomized to the inhaled (n = 60) and subcutaneous (n = 60) regimens, and 207 adults were randomized to inhaled (n = 102) and subcutaneous (n = 105) regimens. For the 160 patients on inhaled regimen who completed baseline questionnaires, 154 (96.3%) completed the week 24 questionnaire and 159 (99.4%) completed week 12 or later; for the 162 subcutaneous regimen baseline completers, corresponding values were 152 (93.8%) and 155 (95.7%), respectively. Baseline demographics, clinical characteristics, and insulin treatments are summarized in Table 1. Baseline satisfaction scores indicated moderate satisfaction with the run-in subcutaneous insulin treatment (Table 2) (scale range was 0 [greatest dissatisfaction] to 100 [highest satisfaction]). The one exception was the low score of 35 for the preference scale, suggesting patients had a desire to seek new treatments.

Baseline-adjusted A1C at final visit was 7.7 ± 0.1% for inhaled insulin and 7.9 ± 0.1% for subcutaneous regimens (baseline = 8.0 ± 0.1% for both groups, P = 0.066 between treatment-adjusted A1C baseline to end point change). ANCOVA showed an overall age effect (P = 0.002); however, tests of the interactions indicated that the treatment impact on A1C did not vary by age (P = 0.59), sex (P = 0.92), or age and sex (P = 0.94). The 24-week change in FPG for inhaled insulin was −1.9 mmol/l (−35 mg/dl), whereas the subcutaneous group increased by 0.2 mmol/l (+4 mg/dl), with an adjusted treatment group difference of −2.2 mmol/l (−40 mg/dl) (95% CI −3.2 mmol/l [−58 mg/dl] to −1.2 mmol/l [−22 mg/dl]).

Baseline to end point changes across all 12 satisfaction subscales were more favorable for inhaled insulin (Table 2). For the seven regimen-related subscales, improvements for inhaled insulin were substantially greater than for subcutaneous regimen. The two outcome-related subscales, satisfaction with glycemic control and side effects (primarily weight gain and hypoglycemia), also were more favorable for inhaled insulin. The three “net benefit” measures of preference (desire to seek alternative diabetes treatment), advocacy (would recommend treatment), and general satisfaction confirmed that patients found inhaled insulin more acceptable after balancing regimen processes and outcomes. For inhaled insulin, the overall treatment satisfaction scale increased to 75.3 ± 1.1 by week 6 and remained constant at that level until end point, whereas subcutaneous regimen did not change. Subgroup treatment comparisons by age-group and sex are shown in Fig. 1. None of the two- and three-way interactions from ANCOVA were statistically significant, indicating that differences between inhaled insulin and subcutaneous regimens were comparable across these demographic subgroups.

Between screening and baseline there was 0.4% decrease in A1C (P < 0.001) with a corresponding improvement in overall quality of life (P = 0.024) for both groups combined. Overall quality of life (absolute scale range of 500 units and operative range of ∼64 units [17]) improved at end point by 12.2 ± 3.3 units for inhaled insulin and 2.6 ± 3.4 units for subcutaneous regimens (P = 0.043), representing a 15% difference in the operative range (0.31 ± 0.15 SD responsiveness units). This difference is within the range of values that are likely to be clinically relevant (10,11,17,21). As shown in Table 3, treatment differences in the quality-of-life scales were more favorable for inhaled insulin, including symptom distress, symptom interference in daily activities, cognitive functioning, and general health. The more positive mental and emotional health scores were driven primarily by improvements in anxiety and behavioral and emotional control. Both age and sex modified the treatment effect on mental health (treatment interactions with age-group [P = 0.001], sex [P = 0.002], and age-group by sex [P < 0.0001]). Adult female subjects showed the largest inhaled insulin regimen gain in mental health (+10.9 units) in contrast to adult male (−3.6 units), adolescent male (+5.9 units), and adolescent female (+5.4 units) subjects.

As shown in Table 3, the inhaled insulin group scored more favorably on six of the seven questions relating to barriers to insulin adherence, and these effects did not vary by age. There was no difference with regard to self-consciousness when using insulin away from home. Six questions addressing barriers specific to injectable insulin revealed that inhaled insulin rated fewer barriers with insulin (regardless of delivery) (total score 74.2 ± 1.4 for inhaled insulin vs. 67.0 ± 1.6 for subcutaneous regimens [higher score reflects fewer/lower barriers], P = 0.001). Answers to the 12 inhaler device–specific insulin questions confirmed positive endorsement for the inhaler device itself, with the highest endorsement rating of 94.9 ± 1.0 (on a scale of 0–100) for reduced pain. All ratings were significantly higher than a neutral endorsement score of 50.0 (P < 0.0001), and the average total rating was 78.3 ± 1.4 (P < 0.0001 vs. 50.0). Inhaled insulin patients rated the bother and hassle associated with their inhaler device consistently lower at weeks 6, 12, 20, and 24 ([mean ± SE] 83.3 ± 1.9, 82.2 ± 2.0, 80.3 ± 2.1, and 82.4 ± 2.0, respectively) than their NPH injections (68.6 ± 2.0, 68.4 ± 2.1, 66.1 ± 2.1, and 67.6 ± 2.3, respectively, P < 0.001).

Of the 53 patient-reported symptoms, the inhaled insulin group reported less symptom distress and severity overall (Table 3, symptom distress scale). Forty symptom scores were less distressing for the inhaled insulin group. For symptom distress treatment differences >0.10–0.19 SD responsiveness units, 13 were more favorable for inhaled insulin and 1 was more favorable for subcutaneous regimen. All seven symptom distress treatment differences >0.20 SD responsiveness units, a typical threshold for clinically important differences (10,11,17,21), favored inhaled insulin, including general weakness or fatigue (+0.21), sugar in urine (+0.23), feelings of high blood glucose (+0.27), impaired or worsening vision (+0.27, P < 0.05), lethargy, no energy to do things (+0.36, P < 0.001), tired, feeling weary (+0.36, P < 0.001), and feeling overweight (+0.37, P < 0.01). Adult female subjects on inhaled insulin had a decrease in weight of 0.4 ± 0.3 kg, while those on subcutaneous regimen gained 0.6 ± 0.3 kg (difference of −1.0 ± 0.4 kg, P = 0.01). The reduction in distress with feeling overweight was attributed primarily to adult female subjects (treatment difference of +0.71 SD units), and actual weight loss was associated with less distress (r = 0.30, P < 0.001).

Preference choices are shown in Table 3, and, except for “easier to adjust dose,” all favored inhaled insulin. Analyses between end point overall treatment satisfaction and insulin adherence barriers demonstrated greater satisfaction with lower barriers (rho = −0.78, P < 0.0001). A1C and overall treatment satisfaction correlation analysis indicated that better glycemic control was only weakly associated with higher satisfaction (rho = −0.18, P < 0.001) since the lack of change in A1C in this noninferiority design limited the ability to detect an association.

For individuals with type 1 diabetes treated with two or more daily injections of regular/NPH insulin and moderately satisfied with their current therapy, there is opportunity to improve their experience with insulin therapy. Inhaled insulin patients reported substantial and stable improvement in their satisfaction ratings between weeks 6 and 24 in contrast to no change for those remaining on the run-in subcutaneous regimen. These findings are consistent with other recent studies suggesting that ease of use, convenience, social comfort, and flexibility of the treatment process are important issues to both type 1 and type 2 diabetic patients for insulin administration (24,25). Our findings also documented that more positive perceptions of glycemic control, side effects, cognitive function, and physical and psychological well being accompanied the higher satisfaction ratings for patients on the inhaled insulin regimen. It is important to note that our comparative findings may not apply to other insulin regimens.

Although inhaled insulin is not approved for individuals aged ≤17 years, our study demonstrates its impact on satisfaction and quality of life in a younger adolescent population with an average age of 14 years. Using age-appropriate instruments, improvements with inhaled insulin were found to be similar to adults among both male and female subjects. In this age-group, most patient-reported outcome studies evaluating intensive insulin regimens have focused on comparing insulin pumps with multiple daily injections. Results have varied depending on the responsiveness and sensitivity of the patient-reported measures used and the study design used, but improvement in patient satisfaction and ability to adhere to intensive regimens are typically higher for the pump. Our study used very sensitive measures and a longitudinal design during which patients answered nearly 2,400 questions over 6 months. As such, we were able to detect improvements in many domains of satisfaction, quality of life, and barriers to adherence for the inhaled insulin group. While the stability and durability of the satisfaction scores argue against a novelty effect, we cannot rule out that openly positive or negative reactions of the clinic staff to the inhaler device could have impacted patient attitudes.

The reasons for the positive effects of inhaled insulin on the quality-of-life outcomes are uncertain; however, it is possible that the rapidly acting premeal inhaled insulin resulted in a more favorable metabolic profile that mediated these improvements. Also, FPG was lower by 40 mg/dl, and the inhaled insulin group reported “better glycemic control” even though both groups had statistically comparable A1C. A1C might be too insensitive a measure to detect quality-of-life improvements that are important and salient to patients. Indeed, the higher symptom distress reported by patients on the subcutaneous regimen were for thirst, general weakness or fatigue, impaired or worsening vision, lethargy, no energy to do things, tiredness, and feeling weary, all of which are associated with hyperglycemia.

One of the most intriguing findings was that out of 53 symptoms, the symptom that was ameliorated most by inhaled insulin was “feeling overweight.” Although it was previously reported that body weight increased comparably in both groups (8), the gains were predominant in the growing adolescent subjects, which masked the treatment differential in adult female subjects who were most distressed by weight gain. Weight gain with insulin is a significant barrier to adhering to insulin regimens, especially in women.

Because of the noninferiority design of this trial, during which adherence was purposely and strictly enforced in both groups, there was little opportunity to observe differences in A1C resulting from differences in adherence. As such, we chose to focus assessment on patient ratings of barriers to insulin adherence such as “how much difficulty they had taking every dose of insulin as recommended.” It was not surprising that individuals who expressed the most difficulty had the lowest overall satisfaction with treatment. Since it has been previously observed that clinical trials substantially underestimate discontinuation with drug therapy and overestimate adherence and that quality of life may better predict outcomes in actual practice (26,27), we might anticipate that the more favorable satisfaction and quality-of-life outcomes observed for inhaled insulin might translate into greater acceptance and better adherence with insulin therapy in clinical practice.

The barriers to effective diabetes management are multifactorial, but our study supports the belief that psychological, behavioral, and attitudinal factors play a role in patient satisfaction with insulin therapy. The use of inhaled insulin in type 1 diabetic patients should proceed with caution since the long-term consequences (both positive and negative) will not be known until real-world use, and experience yields the long-term safety and efficacy data that only postmarketing surveillance can provide. Communication between physicians and patients pertaining to these patient-centered factors, especially in individuals failing to intensify or maintain their insulin regimen, might better inform the clinical decision process when weighing risks and benefits of alternative methods of delivering intensive insulin regimens.

We thank the investigators (see ref. 8 for a complete list), Ralph R. Turner, PhD, MPH; Johanna F. Hayes, ScM; Sharon Murphy; and the staff at Phase V Technologies, Inc., for managing the survey data.