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

¹ Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts
² Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts

Address correspondence and reprint requests to Marcia A. Testa, MPH, PhD, Department of Biostatistics, Harvard School of Public Health, 677 Huntington Ave., Boston, MA 02115. E-mail: testa{at}hsph.harvard.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION RESEARCH DESIGN AND METHODS-- RESULTS CONCLUSIONS-- References

 
OBJECTIVE—We sought to compare and evaluate the impact of inhaled versus injected insulin on potential mediators of patient acceptance of insulin therapy while maintaining comparable A1C levels.

RESEARCH DESIGN AND METHODS—During a noninferiority efficacy trial conducted in 40 centers in the U.S., we surveyed treatment satisfaction, quality of life, and adherence barriers at weeks –4, –1, 6, 12, 20, and 24 in adolescents aged 12–17 years and adults with type 1 diabetes who received premeal regular plus twice-daily NPH insulin during a 4-week run-in; then, subjects were randomized to premeal inhaled human insulin plus twice-daily NPH (adults, n = 102; adolescents, n = 60) (inhaled) or remaining on run-in therapy (n = 105 and 60, respectively) (subcutaneous injection).

RESULTS—Overall treatment satisfaction (0–100) increased by 13.2 ± 1.1 units for inhaled insulin (baseline = 63.3 ± 1.2) compared with 1.7 ± 0.8 for subcutaneous insulin injection (baseline = 64.1 ± 1.2, P < 0.0001). All 12 satisfaction subscales favored inhaled insulin (all P < 0.01), and effects did not vary by age or sex. Despite similar baseline-adjusted end point A1C for inhaled (7.7 ± 0.1%) and subcutaneous (7.9 ± 0.1%) regimens, quality-of-life scales of mental health, symptoms, health status, cognitive functioning, and adherence barriers during treatment were more favorable for inhaled insulin (all P < 0.05). Greater satisfaction was associated with fewer barriers to insulin adherence (rho = –0.78, P < 0.0001) and a greater reduction in A1C (rho = –0.18, P < 0.001).

CONCLUSIONS—Treatment satisfaction was substantially more favorable, adherence barriers moderately lower, and quality of life moderately higher for inhaled compared with subcutaneous regimen. It remains to be demonstrated whether these patient-reported outcomes will translate into improved adherence and glycemic control.

Abbreviations: FPG, fasting plasma glucose

	INTRODUCTION

TOP ABSTRACT INTRODUCTION RESEARCH DESIGN AND METHODS-- RESULTS CONCLUSIONS-- References

 
Maintaining A1C levels <7% in individuals with type 1 diabetes has been shown to reduce microvascular and some macrovascular complications (1,2). Reaching A1C goals by intensifying the insulin regimen often requires either an insulin pump or a basal/bolus multiple-injection insulin regimen. However, use of the pump has been limited by its cost, required technical expertise, and the relative paucity of health care providers trained in its use, and the acceptance of basal/bolus insulin regimens is hindered by the burden of multiple injections (3–6).

Clinical trials have demonstrated that inhaled insulin is comparable with injected insulin in lowering A1C in individuals with type 1 (7,8) and type 2 (9) diabetes. However, the clinical rationale for its use is based on the belief that multiple inhalations will be more acceptable to patients, thereby promoting increased adherence to intensive insulin regimens. However, evidence of this causal relationship has not been empirically established during clinical trials of efficacy since adherence to treatment and A1C goals are strictly enforced for all patients. Additionally, real-world clinical experience with the only form of inhaled insulin approved by the U.S. Food and Drug Administration is lacking since it has just recently become available.

While empirical data documenting the relationship between greater acceptance and superior glycemic control is not available, mediators in the pathway—namely, treatment satisfaction, quality of life, and barriers to insulin adherence—can be evaluated. Such measures could provide valuable insight when weighing the risks and benefits of incorporating inhaled insulin delivery as part of intensive insulin regimens. The purpose of our study was to compare the impact of inhaled versus injected insulin on potential mediators of adherence during a clinical trial (8) that previously reported that inhaled human insulin has comparable safety and efficacy to injected insulin in type 1 diabetic patients currently using multiple daily injections.

	RESEARCH DESIGN AND METHODS—

TOP ABSTRACT INTRODUCTION RESEARCH DESIGN AND METHODS-- RESULTS CONCLUSIONS-- References

 
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.

Assessments
Clinical.
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.

Patient-reported questionnaires.
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.

Statistical methods
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 = 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.

	RESULTS

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Study accrual, withdrawals, and baseline characteristics
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.

Patient-reported outcomes
Diabetes treatment satisfaction.
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.

View larger version (33K): [in this window] [in a new window]   Figure 1— Mean baseline-adjusted change in overall treatment satisfaction for inhaled insulin regimen ( ) and subcutaneous regimen () evaluated at baseline score of 63.7. P < 0.0001 and P < 0.01 versus inhaled insulin. A1C treatment changes were not statistically significantly different between inhaled insulin and subcutaneous regimens within the age- and sex-specific subgroups.

Symptom distress.
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).

Comparative treatment preference and associations between treatment satisfaction, quality of life, adherence barriers, and glycemic control.
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.

	CONCLUSIONS—

TOP ABSTRACT INTRODUCTION RESEARCH DESIGN AND METHODS-- RESULTS CONCLUSIONS-- References

 
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.

	Acknowledgments

 
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.

	Footnotes

 
Published ahead of print at http://care.diabetesjournals.org on 2 March 2007. DOI: 10.2337/dc06-1497. Clinical trial reg. no. NCT00424333, clinicaltrials.gov.

M.A.T. and D.C.S. have received research grants and honoraria from Pfizer.

Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/dc06-1497.

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received for publication July 20, 2006. Accepted for publication February 16, 2007.

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This Article Abstract Full Text (PDF) Online-Only Appendix All Versions of this Article: dc06-1497v1 30/6/1399    most recent Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Testa, M. A. Articles by Simonson, D. C. Search for Related Content PubMed PubMed Citation Articles by Testa, M. A. Articles by Simonson, D. C. Social Bookmarking                What's this?