Background
In clinical trials, patient-reported outcome measures can complement clinical outcomes by providing information beyond traditional efficacy and safety measures. When new treatments have comparable efficacy, patient-reported instruments can be used to examine whether drug differences other than clinical efficacy have an impact on outcomes that may be important to patients [
1]. Two injectable treatments for patients with type 2 diabetes, insulin glargine and exenatide, have been found to have comparable efficacy as measured by HbA
1c reduction in a recent 26-week randomized controlled trial [
2]. When added to oral medications in this trial, both exenatide and insulin glargine reduced HbA
1c levels by 1.1%. Insulin, in conventional and analog forms, is a commonly used treatment for such patients [
3,
4]. Insulin glargine is a long-acting analog with absorption kinetics that provides a relatively consistent basal insulin supplied for approximately 24 hours [
5,
6]. Exenatide is a recently approved medication that elicits several of the glucoregulatory actions of glucagon-like peptide-1, an incretin hormone that is an essential regulator of normal glucose homeostasis [
2,
7‐
14]. Exenatide has post-parandial and fasting blood glucose effects [
2]. Although exenatide and insulin glargine appear to have similar efficacy for reduction of HbA
1c, there are several differences between the two treatments that could influence outcomes from the patient's perspective. Therefore, the purpose of the current study was to conduct a secondary analysis of clinical trial data to examine whether the two drugs were comparable as assessed by patient-reported outcomes.
One difference between these two medications that could lead to differences in patient-reported outcomes is that they have different effects on patients' body weight. Whereas insulin is associated with increased risk of weight gain [
15‐
17], exenatide has repeatedly been found to be associated with weight reduction [
7,
8,
11,
12,
14]. For example, in a 26-week head-to-head clinical trial, insulin glargine-treated patients had a mean body weight increase of 1.8 kg from a baseline mean of 88.3 kg, whereas exenatide-treated patients decreased in body weight by 2.3 kg from a baseline mean of 87.5 kg [
2]. Weight reduction is likely to lead to positive health outcomes for many patients as it has been shown to improve glycemic control and reduce long-term health risks [
16,
18‐
21]. Furthermore, lower weight has been found to be associated with greater patient-reported treatment satisfaction and health-related quality of life (HRQL) among patients with diabetes [
22‐
24]. HRQL can be defined as the patient's subjective perception of the impact of health status on physical, psychological, and social functioning [
1,
25].
Exenatide and insulin also differ in side effect profiles. In clinical trials, the most frequent adverse events reported by patients with exenatide have been gastrointestinal side effects, such as nausea and to a lesser extent vomiting, that tend to occur early in treatment [
2,
7,
8,
11,
12,
14]. These gastrointestinal symptoms are generally found to be mild-to-moderate, and they have only a negligible contribution to the weight effects of exenatide [
26,
27]. Patients treated with insulin glargine have reported a lower incidence of these side effects [
2]. Another difference between the two drugs involves dose frequency. Insulin glargine is administered once per day, whereas exenatide is administered twice per day. In general, reduced dose frequency is thought to be associated with greater treatment satisfaction, although there are exceptions for some patients, diseases, and medications [
28‐
32]. To assess the potential impact of these differences between exenatide and insulin glargine, the current study analyzed change in five patient-reported outcome measures, using data from a clinical trial in which the two drugs had comparable efficacy [
2]. These outcome measures assessed HRQL, treatment satisfaction, vitality, treatment flexibility, and impact of diabetes symptoms.
Results
A total of 549 patients were enrolled in the trial. The current analyses were conducted with data from the 455 patients that were considered per protocol (228 exenatide and 227 insulin glargine). Demographic and clinical characteristics of the total sample and two treatment groups are presented in Table
1. The total per protocol sample was primarily Caucasian (79.6%), with slightly more men (55.2%) than women. The mean age was 58.5 years, and patients had type 2 diabetes for a mean of 9.5 years. Mean HbA1
c and BMI at baseline were 8.3% and 31.5 kg/m
2, respectively. There were no statistically significant differences at baseline between the two treatment groups in these demographic and clinical variables.
Table 1
Demographic and clinical characteristics
Age (mean, SD) | 59.4 (8.9) | 57.7 (9.4) | 58.5 (9.2) | 0.06 |
Gender (N, % male) | 125 (54.8%) | 126 (55.5%) | 251 (55.2%) | 0.92 |
Ethnicity (N, %) | | | | |
Caucasian | 181 (79.4%) | 181 (79.7%) | 362 (79.6%) | 0.69 |
Hispanic | 37 (16.2%) | 35 (15.4%) | 72 (15.8%) | |
Western Asian | 5 (2.2%) | 2 (0.9%) | 7 (1.5%) | |
African Descent | 1 (0.4%) | 3 (1.3%) | 4 (0.9%) | |
Native American | 0 (0.0%) | 1 (0.4%) | 1 (0.2%) | |
Other | 4 (1.8%) | 5 (2.2%) | 9 (2.0%) | |
Duration of Diabetes in years (mean, SD) | 9.7 (5.6) | 9.2 (5.9) | 9.5 (5.7) | 0.21 |
HBA1c (mean, SD) | 8.3% (0.9%) | 8.3% (1.0%) | 8.3% (1.0%) | 0.55 |
BMI (mean kg/m2, SD) | 31.6 (4.5) | 31.4 (4.5) | 31.5 (4.5) | 0.53 |
Paired t-tests revealed that both treatment groups demonstrated statistically significant baseline to endpoint change on several of the health outcomes instruments (Table
2). Both the exenatide-treated group and the insulin glargine-treated group demonstrated statistically significant improvement in the DSC-R total score (p < 0.0001 for exenatide and p = 0.0002 insulin glargine), the DTSQ satisfaction score (p < 0.0001 for both treatment groups), and the SF-36 Vitality subscale (p = 0.005 for exenatide and p < 0.04 for insulin glargine). Both groups also had statistically significant differences between baseline and endpoint scores on several of the DSC-R subscales (psychology: fatigue, psychology: cognitive, ophthalmology, hypoglycemia, hyperglycemia) as well as the hyperglycemia and hypoglycemia items of the DTSQ. In addition, the insulin glargine group demonstrated significant baseline to endpoint change on the EQ-5D index score and the DSC-R cardiology score.
Table 2
Paired t-tests comparing baseline and endpoint scores within each treatment group
|
Baseline
|
Endpoint
|
p value
|
Baseline
|
Endpoint
|
p value
|
DSC-R Overall Score | 1.07 (0.83) | 0.90 (0.80) | < 0.0001 | 0.99 (0.78) | 0.84 (0.73) | 0.0002 |
EQ-5D Index Score | 0.82 (0.22) | 0.85 (0.19) | 0.08 | 0.84 (0.22) | 0.87 (0.20) | 0.049 |
Diabetes Treatment Flexibility Score | 60.37 (22.24) | 60.48 (22.33) | 0.93 | 58.85 (22.81) | 58.95 (23.37) | 0.93 |
Diabetes Treatment Satisfaction Score | 26.41 (7.00) | 29.48 (6.12) | < 0.0001 | 26.31 (6.33) | 30.04 (5.21) | < 0.0001 |
SF-36 Vitality Subscale Score | 53.18 (20.87) | 56.30 (20.58) | 0.005 | 55.18 (21.35) | 57.62 (20.37) | 0.04 |
DSC-R Psychology: Fatigue Score | 1.83 (1.26) | 1.49 (1.21) | < 0.0001 | 1.60 (1.29) | 1.34 (1.17) | 0.0003 |
DSC-R Psychology: Cognitive Score | 1.18 (1.12) | 0.99 (1.08) | 0.0006 | 1.14 (1.09) | 0.91 (0.99) | 0.0001 |
DSC-R Neurology: Pain Score | 0.76 (0.98) | 0.70 (0.99) | 0.21 | 0.67 (0.90) | 0.63 (0.92) | 0.49 |
DSC-R Neurology: Sensory Score | 0.91 (1.07) | 0.83 (1.01) | 0.10 | 0.77 (0.94) | 0.78 (0.93) | 0.83 |
DSC-R Cardiology Score | 0.78 (0.89) | 0.71 (0.86) | 0.16 | 0.73 (0.86) | 0.61 (0.80) | 0.02 |
DSC-R Ophthalmology Score | 0.79 (1.00) | 0.62 (0.86) | 0.003 | 0.79 (0.98) | 0.64 (0.92) | 0.006 |
DSC-R Hypoglycemia Score | 1.09 (1.16) | 0.94 (1.09) | 0.03 | 1.10 (1.09) | 0.93 (1.00) | 0.009 |
DSC-R Hyperglycemia Score | 1.47 (1.31) | 1.07 (1.15) | < 0.0001 | 1.42 (1.25) | 1.02 (1.13) | < 0.0001 |
DTSQ Frequency High Blood Sugar | 3.61 (1.76) | 2.19 (1.61) | < 0.0001 | 3.57 (1.67) | 2.11 (1.45) | < 0.0001 |
DTSQ Frequency Low Blood Sugar | 1.02 (1.37) | 1.36 (1.56) | 0.007 | 0.80 (1.21) | 1.50 (1.43) | < 0.0001 |
Results of general linear models comparing change in health outcomes between the two treatment groups, controlling for country and baseline score, are presented in Table
3. Results of these models indicate that there were no statistically significant differences between groups in the health outcomes instruments.
Table 3
Change in health outcomes associated with exenatide and insulin glargine
| N | LS Mean | SE | N | LS Mean | SE | p value1
|
DSC-R Overall Score | 223 | -0.16 | 0.04 | 219 | -0.16 | 0.05 | 0.96 |
EQ-5D Index Score | 217 | 0.02 | 0.01 | 215 | 0.03 | 0.01 | 0.35 |
Diabetes Treatment Flexibility Score | 222 | 0.32 | 1.28 | 219 | -0.46 | 1.27 | 0.59 |
Diabetes Treatment Satisfaction Score | 213 | 3.42 | 0.43 | 213 | 3.85 | 0.43 | 0.38 |
SF-36 Vitality Subscale Score | 223 | 2.41 | 1.24 | 220 | 2.81 | 1.25 | 0.78 |
DSC-R Psychology: Fatigue Score | 222 | -0.28 | 0.08 | 220 | -0.31 | 0.08 | 0.73 |
DSC-R Psychology: Cognitive Score | 223 | -0.24 | 0.06 | 220 | -0.29 | 0.06 | 0.52 |
DSC-R Neurology: Pain Score | 222 | -0.04 | 0.06 | 219 | -0.03 | 0.06 | 0.93 |
DSC-R Neurology: Sensory Score | 223 | -0.03 | 0.06 | 219 | 0.02 | 0.06 | 0.45 |
DSC-R Cardiology Score | 223 | -0.08 | 0.06 | 219 | -0.14 | 0.06 | 0.30 |
DSC-R Ophthalmology Score | 222 | -0.19 | 0.06 | 219 | -0.16 | 0.06 | 0.68 |
DSC-R Hypoglycemia Score | 221 | -0.20 | 0.07 | 219 | -0.22 | 0.07 | 0.81 |
DSC-R Hyperglycemia Score | 223 | -0.35 | 0.07 | 220 | -0.39 | 0.07 | 0.58 |
DTSQ Frequency High Blood Sugar | 219 | -1.40 | 0.12 | 218 | -1.48 | 0.12 | 0.58 |
DTSQ Frequency Low Blood Sugar | 218 | 0.37 | 0.12 | 216 | 0.58 | 0.12 | 0.13 |
Finally, because exenatide has been found to be associated with a higher incidence of nausea than insulin glargine, treatment satisfaction was examined separately among subgroups of patients who experienced nausea at any time during the trial. In the exenatide group, 126 patients reported experiencing nausea at any time during the trial, compared with 22 insulin glargine-treated patients. The subgroup of 126 exenatide-treated patients had mean DTSQ satisfaction scores of 26.9 (SD = 6.8) at baseline and 29.0 (SD = 6.2) at endpoint. A paired t-test found that this improvement (change score = 2.1; SD = 7.4) was statistically significant (t = 3.1, p = 0.002). Findings for the 22 insulin glargine-treated patients were similar. The baseline mean DTSQ satisfaction score was 24.1 (SD = 6.3), and the endpoint score was 30.4 (SD = 4.8). This improvement was also statistically significant (change score = 6.2; SD = 6.3; t = 4.6, p = 0.0001).
Discussion
The current findings add to previous literature suggesting that, among patients whose glucose levels and symptoms are not adequately controlled by oral medications, the improved efficacy offered by the addition of injectable medication may lead to improved treatment satisfaction and quality of life [
57,
59,
60]. This analysis found that both exenatide and insulin glargine were associated with significant improvements in patient-reported outcomes when added to oral medications among patients with type 2 diabetes. Patients in both treatment groups demonstrated statistically significant baseline-to-endpoint improvement in overall treatment satisfaction as measured by the DTSQ and vitality as measured by a subscale of the SF-36. Both groups also had significant reductions in overall symptom impact and problems with several specific symptom domains as measured by the DSC-R (e.g., fatigue, cognition, ophthalmology, hypoglycemia, hyperglycemia). Insulin glargine-treated patients also had statistically significant improvement in overall HRQL as assessed by the EQ-5D. Some studies have reported that patients with type 2 diabetes on oral medications have greater HRQL than patients on insulin [
24,
51,
61‐
63]. However, current findings are consistent with other studies showing increased HRQL and patient satisfaction after initiating insulin therapy [
57,
59,
60]. Findings were consistent for both drugs despite different side effect profiles and the fact that exenatide was administered twice daily while insulin glargine was administered once daily.
Analyses comparing patient-reported outcomes of the two drugs found no significant differences between treatment groups despite drug differences in several areas such as weight change, side effect profile, and dose frequency. Although exenatide is associated with increased injections and gastrointestinal side effects compared with insulin glargine, these potential problems did not appear to result in less patient satisfaction among the exenatide-treated patients. It is possible that, for patients who experienced gastrointestinal side effects from exenatide, the weight reduction benefits associated with the drug outweighed its disadvantages, thus resulting in the observed gains in treatment satisfaction. In addition, although increased dosing frequency often leads to reduced patient satisfaction, this finding is not consistent across all diseases and medications [
32]. For example, one previous study conducted with patients who had type 2 diabetes found no treatment satisfaction differences between patients receiving once-daily injections and those receiving twice-daily injections [
28]. Both current results and these previous findings suggest that dosing frequency may not be of primary importance to patients receiving injectable medication for type 2 diabetes.
Several aspects of the current study design may have limited the ability to detect true differences in patient experience with these two medications. First, is possible that a naturalistic study conducted with less structure than a clinical trial might yield different findings. For example, if patients have less contact with medical professionals, they might be less adherent to a more complicated dosing regimen. A second possible limitation is the relatively brief study duration. In longer trials of these medications, patients have experienced greater weight change than in this 26-week trial [
64], and greater weight change is likely to have a stronger impact on treatment satisfaction and vitality. Third, a larger sample size would provide greater statistical power for detecting statistically significant differences between treatment groups, if in fact there are true differences. Finally, the only HRQL instrument administered in this trial was the brief EQ-5D, which may not be sufficiently sensitive to between-treatment group HRQL differences in this population. Perhaps a multidimensional generic HRQL measure or a condition-specific HRQL measure would have been able to detect differences.
Another factor limiting the interpretation of data is that minimally important differences (MIDs) have not been identified for the three condition-specific instruments used in this study (i.e., DSC-R, DTSQ, and TFS). MID is defined as the smallest change score that a patient would perceive as beneficial [
65,
66]. For patient-reported outcome measures, the minimally important difference (MID) is used as a guideline to interpret whether improvement can be considered clinically significant or meaningful to patients. Although both treatment groups demonstrated statistically significant change in most of the condition-specific scales, it is not known whether these changes are clinically meaningful.
Previous research has identified MIDs of the two generic instruments used in the current study. MIDs have been suggested to be roughly 3 to 5 for the SF-36 and 0.07 for the EQ-5D, although these MIDs were not derived within samples of patients with diabetes [
67,
68]. Neither treatment group in the current study met the MID criterion for the EQ-5D. On the SF-36 vitality subscale, the exenatide-treated group changed by 3.12 points, which does exceed the lower estimate of MID for this scale, while the insulin glargine group improved by 2.44 points. However, interpretation of treatment effects should not be made based solely on these generic measures because generic instruments tend to be less responsive to change than condition-specific instruments [
37]. Therefore, future research on MIDs in the three diabetes-specific measures is necessary in order to estimate the clinical significance of patient-reported improvement in the current study.
Treatment satisfaction is important largely because it is thought to provide an indication of treatment adherence [
69‐
71]. In general, patients who are satisfied with their treatment can be expected to adhere to prescribed treatment regimens more than patients who are unsatisfied. Therefore, patient satisfaction is necessary in order to maximize treatment effectiveness. In sum, current results indicate that both exenatide and insulin glargine were associated with increased treatment satisfaction and vitality as well as decreased symptom burden.
Competing interests
KS is an employee and stock holder of Eli Lilly and Company. LM was a paid consultant. AO is an employee and stock holder of Eli Lilly and Company. KM was a paid consultant. SK was a paid consultant. RH is an employee and stock holder of Eli Lilly and Company. RB is an employee and stock holder of Eli Lilly and Company.
Authors' contributions
KS formulated the study hypotheses, guided the project, provided input into data analyses/interpretation, and critically reviewed the manuscript. LM wrote the manuscript and provided input into the statistical analyses and data interpretation. AO provided input into data interpretation and critically reviewed the manuscript. KM performed statistical analyses and critically reviewed the manuscript. SK performed statistical analyses and critically reviewed the manuscript. RH initiated the quality of life study design, provided input into the statistical analyses, and critically reviewed the manuscript. RB provided input into the study design, provided diabetes-related clinical expertise to help interpret the results, and critically reviewed the manuscript. All authors have read and approved the final manuscript.