Abstract
Objective: Liraglutide and dulaglutide have demonstrated similar glycemic efficacy and safety. However, they differ in treatment administration and injection devices. The purpose of this study was to examine and compare patient perceptions of the injection devices used with liraglutide and dulaglutide.
Methods: Patients with type 2 diabetes treated with liraglutide or dulaglutide were recruited from across the US. Patients completed the Diabetes Injection Device Experience Questionnaire (DID-EQ) to rate their current injection device. Patients who had experience with both treatments also completed the Diabetes Injection Device Preference Questionnaire (DID-PQ) to report preferences between the two devices. ANCOVAs were conducted to compare DID-EQ scores between dulaglutide and liraglutide patients, while controlling for covariates. Descriptive statistics are presented for preferences reported on the DID-PQ.
Results: A total of 404 patients were recruited from 49 states (mean age = 60.7 years; 54.0% female; 204 liraglutide; 200 dulaglutide). Mean DID-EQ item scores for both treatments were high, ranging from 3.48 to 3.90 on a 4 point scale. ANCOVAs found significantly higher scores for dulaglutide than liraglutide on DID-EQ global items assessing ease of use (3.82 vs. 3.73, p = .040) and convenience (3.79 vs. 3.66, p = .004). Among the 58 patients who had used both devices, more patients reported a preference for the dulaglutide device than the liraglutide device on every item of the DID-PQ.
Conclusions: High DID-EQ scores indicate positive perceptions of both the liraglutide and dulaglutide injection devices. The dulaglutide device was associated with slightly higher scores for ease of use and convenience than the liraglutide device.
Introduction
Glucagon-like peptide-1 (GLP-1) receptor agonists are often recommended as part of combination therapy for type 2 diabetes when oral medication alone does not provide sufficient glycemic controlCitation1,Citation2. These injectable treatments have been shown to be effective in lowering HbA1c with a low risk of hypoglycemia and a potential benefit of weight lossCitation3–5. Currently, the two most widely prescribed GLP-1 receptor agonists in the US are liraglutide and dulaglutideCitation6.
Liraglutide has been available in the US for use since 2010Citation7. Through the Liraglutide Effect and Action in Diabetes (LEAD) program, which included six randomized phase 3 trials and approximately 4500 patients, liraglutide has demonstrated efficacy for reduction of HbA1c and weight lossCitation8–13. The most common adverse events associated with liraglutide include mild to moderate nausea, vomiting, and diarrhea, but the treatment is generally well tolerated by patientsCitation8–13.
Dulaglutide was approved by the FDA in 2014Citation14. The safety and efficacy for HbA1c control were demonstrated in the six clinical trials of the Assessment of Weekly AdministRation of LY2189265 in Diabetes (AWARD) program involving over 5000 patientsCitation15–20. In one head-to-head trial comparing dulaglutide to liraglutide, HbA1c reductions were found to be similar between the two treatments, thus demonstrating non-inferiority of dulaglutide to liraglutideCitation16. Additionally, the two medications also had similar adverse event profiles with no differences observed among the principal gastrointestinal-related adverse events, and both treatments were found to be generally well tolerated. While both medications were associated with weight loss, liraglutide was associated with greater weight loss than dulaglutide in this head-to-head trial (mean difference of 0.71 kg across 26 weeks). In addition, lower rates of cardiovascular events and death relative to placebo were found for liraglutide in the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trialCitation21. A meta-analysis has found that dulaglutide does not increase the risk of major cardiovascular eventsCitation22, and cardiovascular outcomes associated with dulaglutide are currently under further investigation in the Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trialCitation23.
Whereas liraglutide and dulaglutide appear to be similar in terms of glycemic efficacy and safety, the two treatments differ in terms of treatment administration and injection devices. Liraglutide is administered once daily via a pre-filled injection pen that requires needle attachment/disposal and dose dialing with each useCitation24. In contrast, dulaglutide is administered once weekly via a single-dose auto-injector pen that does not require handling of the needleCitation25. Whereas the dulaglutide pen is disposed of after each use, the liraglutide injection pen may be used for up to 30 days before disposal.
Treatment administration and injection device attributes could have an impact on patient perceptions of treatment and patient preference between treatmentsCitation26–30. In the diabetes research and regulatory communities, there has been a growing emphasis on aspects of treatment beyond HbA1c reduction that are likely to be important to patients, such as treatment process attributesCitation31. Patient perceptions of the treatment process could have an impact on treatment adherence and, consequently, health outcomesCitation32,Citation33. Therefore, the purpose of this study was to examine and compare patient perceptions of the injection devices associated with liraglutide and dulaglutide.
Methods
Study design
This was an observational study of patients with type 2 diabetes who were treated with either once weekly dulaglutide or once daily liraglutide. Eligible individuals participated in a one-on-one discussion in which the study was introduced by telephone. During this discussion, participants were consented, and clinical background information was confirmed. Participants were then instructed to independently complete and return the self-administered data collection forms including the Diabetes Injection Device Experience Questionnaire (DID-EQ), the Diabetes Injection Device Preference Questionnaire (DID-PQ) and a demographic form.
Participants
Patients were recruited from across the US via newspaper and online advertisements. To be enrolled in the study, participants were required to be: (1) currently residing in the US; (2) at least 18 years old; (3) diagnosed with type 2 diabetes by a recognized medical professional; (4) currently receiving treatment with either dulaglutide (dose amounts: 0.75 or 1.5 mg) or liraglutide (dose amounts: 0.6, 1.2, or 1.8 mg) with or without insulin for type 2 diabetes and be able to report/recall characteristics of the injection device; (5) able to provide proof of medication for dulaglutide or liraglutide; (6) able to read, speak and understand English; (7) able and willing to give written informed consent prior to study entry; and (8) able to complete protocol requirements. Patients receiving 3.0 mg of liraglutide were excluded from participation because this higher dose is indicated for treatment of obesity rather than type 2 diabetes.
All participants were required to provide proof of medication prior to the study assessment to confirm their eligibility. Proof of medication was provided via mail, fax, email or text message. Acceptable forms of proof included a scan or photo of the medication, injection device, injection device packaging, prescription with the participant’s name or a doctor’s note with the participant’s name.
Measures
In addition to a self-administered demographic and an interviewer-administered clinical form, all participants completed the DID-EQ to report perceptions of the injection device used with their current medication (i.e. either dulaglutide or liraglutide). The subset of patients who had experience with both dulaglutide and liraglutide also completed the DID-PQ. The DID instruments were developed based on qualitative research with patients treated with non-insulin injectable medicationCitation34,Citation35. The questionnaires also demonstrated reliability and validity in a psychometric study among patients using a wide range of non-insulin injection devicesCitation36,Citation37.
Diabetes Injection Device Experience Questionnaire (DID-EQ)
The DID-EQ is a 10 item measure designed to assess patients’ perceptions of the injection device and treatment process associated with their non-insulin injectable medication for type 2 diabetesCitation36,Citation37. Each of the 10 items is rated on a 4 point scale with higher scores indicating more positive perceptions of the injection device. Items 1 to 7 focus on specific characteristics of non-insulin injection delivery systems, and these seven items comprise the Device Characteristics subscale. In addition, there are three global items assessing overall satisfaction, ease of use, and convenience of non-insulin injection devices (items 8, 9, and 10). These three global items are each scored separately. To compute the Device Characteristics subscale score, the seven individual item scores are first summed, resulting in a subscale raw score. The lowest possible raw sum score is 7, and the highest possible raw sum score is 28. Then, for ease of interpretation, the score is transformed onto a scale with the possible range from 0 to 100, with higher scores indicating more positive perceptions of injection device characteristics.
Diabetes Injection Device Preference Questionnaire (DID-PQ)
The DID-PQ was developed in parallel with the DID-EQ and includes the same 10 items and concepts as the DID-EQCitation36,Citation37. On the DID-PQ, each item is rated on a 5 point scale allowing patients to indicate whether they prefer or strongly prefer one of the devices over the other. For each item, patients may also respond by selecting the “no preference” (i.e. neutral) response option, indicating that they have no preference between the two devices. Importantly, the response options of the DID-PQ are not on an ordinal scale assessing a single dimension. These five response options of the DID-PQ comprise a non-linear scale for which mean scores are not calculated. Instead, results are presented descriptively.
Data collection procedures
The study protocol and procedures were reviewed and approved by an institutional review committee (Chesapeake IRB; 1 November 2016; Pro00019313). Data collection occurred from November 2016 to June of 2017. Potential participants who responded to the advertisements were screened by telephone. Eligible individuals were scheduled for a study assessment to be initiated by telephone with a trained member of the study team, followed by independent completion of the study questionnaires. Prior to the scheduled study assessment, each participant was sent a packet of study materials by mail including an informed consent form and study questionnaires (DID-EQ, DID-PQ, demographic form). A member of the study team called the participant at the scheduled time to administer informed consent, collect clinical background information via an interviewer-administered form and provide instructions for independently completing the study questionnaires. Participants returned their completed consent forms and study questionnaires by mail.
Statistical analysis procedures
Descriptive statistics were performed on demographic and clinical variables, as well as the DID questionnaires. For each continuous variable, the mean and standard deviation are presented. Categorical variables are summarized in terms of frequencies and percentages. Analyses of the DID-PQ data were conducted with participants who had experience with devices used for both dulaglutide and liraglutide.
Perceptions of the dulaglutide device were compared to perceptions of the liraglutide device using DID-EQ data. A series of four analysis of covariance models (ANCOVAs) were run. In each model, the dependent variable was one of the four DID-EQ scores: the three global item scores (i.e. satisfaction, ease of use, convenience) and the Device Characteristics subscale score. In each model, the key independent variable was treatment group (two level variable: dulaglutide, liraglutide). Each model also included covariates that were selected because they could influence perceptions of injection devices and responses to the DID-EQ: gender; age; race (white vs. non-white); time on current treatment (weeks); years with diabetes; and geographical region.
Results
Sample description
A total of 612 patients were screened for eligibility, and 517 of these met eligibility criteria and were scheduled for a study assessment. Of the 517 potential participants who were originally scheduled, 67 could not be reached at the time of their scheduled appointment; 34 declined to participate after being scheduled; four were determined to be ineligible based on suspected cognitive impairment or inability to understand study measures; five did not return the necessary study questionnaires; two submitted their study questionnaires but did not complete the telephone portion of the assessment; and one was determined to be ineligible based on information provided prior to starting the study assessment. This resulted in an analysis sample of 404 participants. Of the 404 participants, 200 were being treated with dulaglutide and 204 were being treated with liraglutide (see patient disposition flowchart in ).
Figure 1. Data disposition flowchart.Note: Thicker lines bordering the boxes in this figure indicate groups or subgroups used in the analyses.
Demographic and clinical characteristics of the sample are presented in . The mean age (SD) of the total sample was 60.7 (11.4) years. More than half the sample was female (54.0%), while a majority was white (79.2%) and married (62.9%). Most participants were either retired (38.9%) or employed full-time (31.4%). Over half the participants (56.2%) had a college degree or higher degree. Participants were recruited from 49 states across the US, with at least one participant from every state except North Dakota. States with the greatest number of participants were Texas (n = 90), Michigan (n = 25), Massachusetts (n = 24), Illinois (n = 20) and New Jersey (n = 20). All four Census Bureau geographic regionsCitation38 were represented: 44.1% of the sample was from the South, 22.8% from the Midwest, 20.5% from the Northeast, and 12.6% from the West.
Table 1. Demographic and clinical characteristics.
Mean age (SD) at the time of diabetes diagnosis was 47.0 (11.6) years, and mean duration (SD) of having had type 2 diabetes was 13.7 (9.0) years. A majority of the sample (80.4%) was taking oral medication for type 2 diabetes with the three most common orals being metformin (65.3%), glipizide (12.1%) and glimepiride (6.7%). Less than half the sample (41.1%) was taking an insulin. Most participants (92.3%) reported at least one comorbid condition with the most commonly reported comorbidities being hypertension (65.6%), arthritis (44.3%) and depression (29.0%).
The dulaglutide and liraglutide subgroups were nearly identical in terms of age, gender and race/ethnicity, with no significant differences between treatment groups (). The liraglutide group had a somewhat lower frequency of married individuals (57.4% vs. 68.5%, p = .020). There were also some differences in employment and education status. Compared to the dulaglutide sample, the liraglutide group had fewer full-time workers (27.0% vs. 36.0%, p = .050), and a lower proportion of individuals with a college degree (46.1% vs. 66.5%, p < .001).
The dulaglutide and liraglutide subgroups were similar in terms of duration of type 2 diabetes (13.6 years and 13.8 years, respectively) and concurrent use of oral medication for type 2 diabetes (79.5% and 81.4%) (). The mean length of time (SD) on dulaglutide for participants treated with dulaglutide at the time of the study was 12.1 (11.2) months while the mean length of time (SD) on liraglutide was 34.8 (63.8) months. A majority of dulaglutide participants (73.0%) were taking the 1.5 mg dose, while a majority of the liraglutide participants were taking the 1.8 mg dose (59.8%). A higher proportion of the liraglutide patients (45.6%) were also taking an insulin to treat their diabetes compared to the dulaglutide patients (36.5%).
Diabetes Injection Device Experience Questionnaire (DID-EQ)
The majority of participants receiving either dulaglutide or liraglutide rated their injection device favorably on each of the 10 DID-EQ items. On nine of the 10 items, less than 10% of the total sample selected one of the negative response options (e.g. Very difficult, Somewhat difficult, Strongly disagree, Disagree). The only exception was item 3 (How difficult is it to bring the injection device with you when it is necessary to inject away from home?) where 12.9% of the sample selected one of the two negative response options (Very difficult or Somewhat difficult). For items 1, 2, 7, 9 and 10, 80% or more of the sample selected the most favorable response (e.g. Very easy, Very satisfied or Strongly agree). Mean individual item scores for the total sample were in the upper range of the scale, ranging from 3.48 (item 3) to 3.90 (item 1) on a 4 point scale.
ANCOVA models were conducted to examine differences between dulaglutide and liraglutide on the DID-EQ Device Characteristics subscale and the three global items. There were statistically significant differences between the dulaglutide device and the liraglutide device for the ease of use (3.82 vs. 3.73, p = .040) and convenience (3.79 vs. 3.66, p = .004) items (). The overall model F values for both models were statistically significant (p < .01). In addition to the differences associated with medication group, there were significant findings for the gender and race covariates in these two models. Women had higher scores than men (ease of use: 3.89 vs. 3.77, p = .006; convenience: 3.85 vs. 3.71, p = .002), and white participants had higher scores than non-white participants (ease of use: 3.86 vs. 3.72, p = .021; convenience: 3.81 vs. 3.69, p = .045) for both the ease of use and convenience global items.
Table 2. ANCOVAs comparing patient perceptions of the dulaglutide and liraglutide devices on the DID-EQTable Footnotea (N = 404).
Diabetes Injection Device Preference Questionnaire (DID-PQ)
The DID-PQ was completed by the subset of 58 participants who had been treated with both dulaglutide and liraglutide. Of these 58 participants, 52 (89.7%) were being treated with dulaglutide at the time of the study and had previously been treated with liraglutide, whereas six (10.3%) of the liraglutide patients were previously treated with dulaglutide. Demographic characteristics of the DID-PQ subset were similar to those of the total sample noted above, although the 58 patients who completed the DID-PQ had a higher proportion of males compared to the total sample (53.4% vs. 46.0%).
Frequencies and percentages of participants who selected each response option for the 10 items of the DID-PQ are presented in (and percentages of participants who selected each response to the three DID-PQ global items are also presented in ). Among these patients who had used both injection devices, there was a consistent tendency to prefer the dulaglutide device over the liraglutide device. This preference was evident on every item of the DID-PQ. For example, when asked which injection device they preferred with regard to overall ease of use (item 9), 41 of the 58 respondents (70.7%) indicated a preference for dulaglutide over liraglutide (i.e. 33 indicating “strongly prefer” plus eight indicating “prefer”). Thirteen of the 58 respondents (22.4%) indicated a preference for liraglutide over dulaglutide, while four respondents reported no preference between the two devices. Results for the other nine items generally followed a similar pattern.
Figure 2. Percentages of respondents who selected each response option of the DID-PQCitation1 global items (N = 58).
Table 3. Frequencies and percentages of respondents who selected each response option of the DID-PQa (N = 58).
Discussion
High DID-EQ scores indicated positive perceptions of both the liraglutide and dulaglutide injection devices, while analyses comparing the two devices revealed some differences. The dulaglutide device was associated with slightly higher DID-EQ scores for ease of use and convenience than the liraglutide device. This finding favoring the dulaglutide device is consistent with previous research. For example, in the DID-EQ validation study, a smaller sample of patients (n = 38, liraglutide; n = 38, dulaglutide) also resulted in higher scores for the dulaglutide device than the liraglutide deviceCitation36,Citation37. In addition, previous studies using preference-based methods suggest that characteristics of the dulaglutide injection experience are likely to be preferable to patients, including weekly rather than daily administration, no requirement for needle handling, and minimal preparation requirements for the medication or deviceCitation26,Citation27,Citation29,Citation39. In the current study, the DID-PQ results from the subset of 58 patients who had tried both treatments also indicate a preference for the dulaglutide device over the liraglutide device, which was consistently evident across all 10 items of the instrument (). Overall, these results suggest that the dulaglutide device has some advantages from the patient perspective.
In addition to providing insight into patient perceptions of injection devices, the current results also offer additional support for construct validity of the DID-EQ. The high DID-EQ scores for both dulaglutide and liraglutide are what would be expected given the relatively convenient injection devices used with these medications. Furthermore, the statistically significant advantage for dulaglutide is consistent with the added conveniences of the dulaglutide injection experience compared to liraglutide (e.g. weekly instead of daily administration, no needle handling, no dialing for dose selection). These results add to previous psychometric data suggesting the DID-EQ measures the concepts it was designed to assessCitation36,Citation37.
Several study limitations should be noted. Most patients who could complete the DID-PQ to compare liraglutide and dulaglutide were currently on dulaglutide and previously on liraglutide (i.e. 52 of 58 patients). This could have been due to health insurance drug requirements or due to liraglutide having been available (since February 2010) for a longer period of time than dulaglutide (since November 2014) in the US. Thus, it is possible that the DID-PQ results could be affected by bias if patients have a general tendency to prefer their current device over the previous device. It is hoped that future research can re-examine these preferences with a larger sample, perhaps in a study with a crossover design to address any potential issues that could arise from the order in which the devices are experienced.
Another limitation is that the DID-EQ is a recently developed instrument, and the extent to which statistically significant between-group differences can be considered clinically important is not yet known. Future research may estimate a minimally important difference to guide interpretation of DID-EQ findings. Another possible limitation is that both therapeutic agents are available outside the US, but this study only included US patients, and generalizability of these patient perceptions to other geographic regions is unknown.
It should also be noted that the item focusing on size of the needle (item 6 on the DID-EQ and DID-PQ) does not necessarily apply to both injection devices in the same way. Whereas the liraglutide device requires patients to handle and see the needle, the dulaglutide needle is initially hidden from view, although patients can choose to look at the needle inside the injection pen and see its width. This raises the question of how patients judged the size of the dulaglutide needle when responding to this item. Some patients may have judged the dulaglutide needle size based on looking inside the injection pen. Patients may also have judged the size of both devices’ needles based on how the injections feel. It is not known how patients formed their opinions regarding needle size.
Overall, results suggest patients who are treated with the most commonly used GLP-1 receptor agonists have positive perceptions of their injection devices, and the dulaglutide device was associated with slightly higher scores for ease of use and convenience than the liraglutide device. Positive perceptions of injection devices could lead to better treatment adherence, which has been shown to have an impact on treatment outcomes in patients with type 2 diabetesCitation32,Citation33. Therefore, it may be useful for clinicians to consider not only the efficacy, safety and cardiovascular effects of GLP-1 receptor agonists, but also attributes of injection devices and administration requirements when selecting the most appropriate treatment for patients with type 2 diabetes.
Transparency
Declaration of funding
Funding for this study was provided by Eli Lilly and Company, Indianapolis, IN, USA.
Author contributions: L.S.M. and K.S.B. co-directed all aspects of the study. B.M.C., R.P., L.F.L., R.M. and J.J. made substantive contributions to the study design, analysis and interpretation. J.J. wrote the study protocol. L.S.M. and B.M.C. co-wrote this manuscript, and all other authors provided input and approval.
Declaration of financial/other relationships
K.S.B., R.P., L.F.L. and R.M. have disclosed that they are employees and shareholders of Eli Lilly and Company. L.S.M., B.M.C. and J.J. have disclosed that they are employed by Evidera, which provides consulting and other research services to pharmaceutical, medical device and related organizations. In their salaried positions, they work with a variety of companies and organizations, and are precluded from receiving payment or honoraria directly from these organizations. Evidera received funding from Lilly for time spent on this study.
A CMRO peer reviewer on this manuscript declares receiving research grants from Novo Nordisk and AstraZeneca, lectures for Eli Lilly, Novo Nordisk and advisory-board participation for Novo Nordisk and MSD. Other CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Acknowledgements
The authors would like to thank Karin Coyne for consultation; Julia Ingram for project management; Katie Stewart, Regina Buachie, Timothy Howell, Michael Celone, Rachel Styles, Andrea Schulz, Christopher Langelotti and Melissa Garcia for assistance with data collection; Ren Yu and Robyn Cyr for statistical programming; Sandra Macker for data management; and Amara Tiebout for production assistance.
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