Treatment Satisfaction With Inhaled Insulin in Patients With Type 1 Diabetes: A randomized controlled trial

The design and clinical results of this trial in type 1 diabetes have been reported previously (5). In brief, the trial was a 12-week randomized, open-label, multicenter, parallel study conducted at 10 centers in the U.S. It consisted of a 4-week baseline lead-in phase, in which subjects continued their usual injected insulin regimen (two to three injections daily) and received instruction on a weight-maintaining diet and blood glucose monitoring, followed by randomization to either an inhaled insulin regimen or a conventional subcutaneous insulin regimen for 12 weeks. The inhaled insulin regimen consisted of rapid-onset inhaled insulin administered immediately before meals using a dry powder aerosol delivery system (Inhale Therapeutic Systems, San Carlos, CA) plus bedtime subcutaneous ultralente insulin. The subcutaneous insulin regimen involved the subject’s usual split/mixed insulin regimen given two or three times per day. The target glucose range was 5.6–8.9 mmol/l. Administration of insulin, inhaled or injected, was preceded by a blood glucose measurement. Patients were followed weekly for review of blood glucose monitoring and adjustment of insulin dosage, if required. Each center’s institutional review board approved the protocol, and all subjects gave written informed consent.

Subjects were aged 18–55 years and were following a stable insulin administration schedule (for at least 2 months) involving two to three injections daily. Screening and prerandomization HbA_1c values were between 7.0 and 11.9%, with fasting plasma C-peptide ≤0.2 pmol/ml. Body weight of each subject was 80–130% of ideal (Metropolitan Life Insurance Tables). Subjects were nonsmokers (for at least 6 months), gave normal results on a chest x-ray and pulmonary function tests, and had an electrocardiogram showing normal sinus rhythm (rate 50–100 bpm). All subjects performed blood glucose monitoring four times daily: before breakfast, before lunch, before supper, and at bedtime.

A 15-item self-administered patient satisfaction questionnaire, the Patient Satisfaction with Insulin Therapy (PSIT) Questionnaire, was completed by each subject at baseline and week 12. The PSIT Questionnaire is shown in Table 1 and is available from the corresponding author of this study upon request. The PSIT underwent rigorous empirical development, had reliable properties, and had an interpretable and rich factor structure (9,10). The PSIT measures global (overall) satisfaction and two domains (subscales): convenience/ease of use and social comfort (9,10). The questionnaire asks subjects to rate statements such as “I find it easy to take insulin the way I take it now,” “I have no discomfort taking insulin,” “I find it convenient to take insulin,” and “I am self-conscious about taking insulin away from home.” Responses to each item consisted of a five-point Likert scale ranging from “strongly agree” to “strongly disagree.”

Patient satisfaction scores for overall satisfaction, convenience/ease of use, and social comfort were calculated. Responses to each item were analyzed so that a higher item score indicated more satisfaction. All 15-item scores were summed equally to arrive at the overall satisfaction score (range 15–75). Pearson correlations (r) and analysis of covariance were used to assess the association between overall satisfaction and 12-week change in HbA_1c, after controlling for treatment regimen.

Item scores were summed equally to create scores for the domains on convenience/ease of use and social comfort. Scores on convenience/ease of use (10 items, range 10–50) and social comfort (5 items, range 5–25) were each used to calculate a percentage change in satisfaction from baseline for each subject. Within-group percent change was evaluated with a paired Student’s t test (11). The difference in the (arithmetic) mean percent change between treatment groups was evaluated with a Student’s t test for two independent samples (11). Statistical significance was based on a 5% two-tailed test.

One statement was rated only at the end of the study: “I would like to continue to take insulin the way I took it during the study.” It was analyzed like other items on the PSIT so that a score of 1 correlated with “strongly disagree” and 5 correlated with “strongly agree.” A treatment group difference on its 5-point ordinal response was evaluated by the Wilcoxon’s rank-sum test (11).

A total of 73 subjects with type 1 diabetes were enrolled in the trial. One subject discontinued treatment before randomization during the inpatient evaluation period. Two subjects randomized to subcutaneous insulin dropped out of the study for administrative reasons and are not included in the analysis. Identical results, therefore, would be obtained from an evaluable analysis and an intent-to-treat analysis on treatment satisfaction. One subject in the subcutaneous group did not fill out a questionnaire at baseline; therefore, only 69 subjects were considered for analysis. At baseline, there were no statistical differences between groups randomized to the two treatment regimens (Table 2).

As reported previously (5), for subjects who responded to all 15 items on the survey, the mean percentage improvement from baseline in global (overall) satisfaction with inhaled insulin (35.1%, 95% CI 18.0–52.2) was considerably greater (P < 0.01) than with subcutaneous insulin (10.6%, 4.7–16.5) (Fig. 1). Therefore, inhaled insulin resulted in 24.5% (6.6–42.5) more improvement in overall satisfaction than subcutaneous insulin. The mean percentage improvement within each treatment group was statistically significant from zero (P < 0.01).

In the current research, a significant relationship between better glycemic control and greater satisfaction was found. The 12-week change in HbA_1c was associated with improved overall satisfaction (r = −0.27, P = 0.04). In addition, a 1% absolute improvement (reduction) in HbA_1c from baseline to week 12 was associated with an average 9.7% improvement in overall satisfaction, after controlling for treatment regimen.

The mean percentage improvement in convenience/ease of use was substantially greater with inhaled insulin (41.3%, 22.9–59.6) than with subcutaneous insulin (11.2%, 4.1–18.3; P < 0.01) (Fig. 1). Therefore, inhaled insulin resulted in 30.1% (10.7–49.5) more improvement in convenience/ease of use than subcutaneous insulin. The mean percentage improvement within each treatment group was statistically significant from zero (P < 0.01).

The mean percentage improvement in social comfort with inhaled insulin (28.0%, 8.0–47.9) was higher than subcutaneous insulin (18.0%, 2.9–33.0) but not statistically significant from it (95% CI −14.6 to 34.6%; P = 0.42) (Fig. 1). The mean percentage improvement within each treatment group was statistically significant from zero (inhaled insulin, P < 0.01; subcutaneous insulin, P = 0.02).

Subjects in the inhaled insulin group gave significantly more agreement than those in the subcutaneous group (Wilcoxon’s rank-sum test; P < 0.01) on the 5-point Likert scale item “I would like to continue to take insulin the way I took it during the study” asked at the end of the study.

As reported previously (5), the adjusted mean difference between the 12-week change in HbA_1c for inhaled insulin (n = 35; −0.64 ± 0.98%) and for subcutaneous insulin (n = 35; −0.83 ± 0.92%) was deemed equivalent (95% CI −0.2 to 0.5%). Changes in fasting and postprandial glucose concentrations as well as occurrence and severity of hypoglycemia were also similar between groups. Inhaled insulin was well tolerated and had no effect on pulmonary function.

Administration of rapid-onset insulin by dry aerosol inhalation in patients with type 1 diabetes maintained glycemic control and achieved greater patient satisfaction. Complementary to the reported satisfaction results, and possibly more telling of overall satisfaction, are the preferences indicated by subjects. In total, 82% of subjects already on inhaled insulin elected to continue on a 1-year extension with inhaled insulin. For those who elected not to continue, the most common reason cited was the rigor of the clinical study protocol, particularly blood glucose monitoring and frequency of clinic visits (5). Furthermore, subjects using inhaled insulin indicated a greater desire to continue taking insulin the way it was taken during the trial than those using injected insulin.

These results have shown that, in a 12-week randomized, controlled trial, inhaled insulin provided greater improvement in treatment satisfaction than subcutaneous insulin among patients with type 1 diabetes. Previous research (5) from an item analysis showed that this improvement stemmed mainly from aspects relating to convenience and ease of use of taking insulin. In particular, six individual items showed significant evidence (P < 0.05) that inhaled insulin resulted in more improvement from baseline than subcutaneous insulin. Specifically, compared with subcutaneous insulin, inhaled insulin was rated higher with regard to ease of administration, comfort, convenience, time with dosing, flexibility of eating schedule, and ease of taking insulin many times a day. Patients on subcutaneous insulin therapy, however, were less self-conscious about taking insulin away from home.

The effect on social comfort is not as large as the effect on convenience and, therefore, is not statistically significant (see Fig. 1). However, this does not necessarily imply that there is no effect on social comfort. A type II error is a possibility. More likely, a larger sample size would have increased the sensitivity to detect an effect on social comfort.

Interestingly, some improvements in patient satisfaction were also observed in subjects taking insulin subcutaneously, even though they continued their usual insulin regimen. One possible reason may be that subjects were involved in a controlled clinical trial and many may have reaped the subsequent benefits of monitoring and care (for example, study clinicians and coordinators attended to subjects at least on a weekly basis).

In addition to quantifying the improvements in satisfaction, we sought to better understand the relationship between patient satisfaction and glycemic control, which would provide useful and clinically meaningful information to patients and clinicians. Baseline data from this trial indicated that higher overall satisfaction scores were associated with lower HbA_1c (r = −0.24, P < 0.05) (10). Results on other relationships of satisfaction with demographic and clinical variables are given elsewhere (10). Moreover, a previous study showed that improved satisfaction was observed with improved HbA_1c (8), whereas another study demonstrated that it was not (12).

In clinical practice, we expect that the interplay between increased satisfaction and improved glycemic control would be bidirectional: increased satisfaction leads to better glycemic control through better adherence to medication and that better glycemic control in turn leads to increased satisfaction. The clinical trial reported in this study, however, was not designed to measure this complex causal relationship, because glycemic control was tightly monitored for dose adjustments to optimize glycemic control based on results of glucose monitoring. As such, data from this clinical trial were not intended to show meaningful reduction in HbA_1c with a given increase in satisfaction. Nonetheless, the clinical trial data indicated that a 1% absolute improvement (reduction) in HbA_1c from baseline to week 12 was associated with an average 9.7% improvement in overall satisfaction (r = −0.27, P = 0.04), after controlling for treatment regimen. Further research in clinical practice settings is encouraged to investigate the relationship between satisfaction and glycemic control.

In summary, these results suggest that an inhaled insulin regimen is preferred and provides substantially more improvement in patient satisfaction than a conventional subcutaneous insulin regimen. In patients with type 1 diabetes, administration of rapid-onset inhaled insulin may offer the first practical, noninvasive alternative to regular insulin injections. Improved satisfaction and convenience may, in clinical practice, increase willingness of patients to initiate and comply with insulin therapy and, therefore, achieve better glycemic control.

This study was supported by Pfizer Inc.

We thank the Inhaled Insulin Phase II Study Group investigators and coordinators [see Skyler et al. (5) for complete listing], Inhale Therapeutic Systems, and Cecile Balagtas, Linda Chandler, Shu-lin Cheng, Larry Gorkin, Joyce Healey, William Landschulz, Mitra Mehrban, Charles Petrie, Joann Reis, Pamela Schwartz, Arthur Shaw, and Pe Thinnyun for their support.

This study is based on an oral presentation delivered at the Annual Meeting of the American Diabetes Association, San Diego, California, June 1999 (9).