Health state utilities associated with treatment process for oral and injectable GLP-1 receptor agonists for type 2 diabetes

This study was designed to elicit preferences and estimate health state utilities associated with the treatment process of GLP-1 receptor agonists for treatment of T2D. Several health technology assessment (HTA) guidelines recommend that utilities are derived from generic preference-based measures when possible [19‐22]. However, because generic instruments such as the EQ-5D are designed to assess overall health status, they are unlikely to be sensitive to differences in treatment process attributes such as mode of administration. In contrast, vignette-based methods are well-suited for isolating the utility impact of treatment process attributes such as mode of administration. Therefore, like most studies designed to estimate treatment process utilities [1], the current study used the vignette approach.

Four health state vignettes (also called scenarios or health states) were developed based on previous literature and package inserts for the relevant medications (see Online Appendix A for complete text of these health states). The health states each began with the same description of T2D, followed by a description of the treatment process, which varied across the four health states. Because all aspects of the four health states were identical except for treatment process, any difference in preference or utility can be attributed entirely to the treatment process. Two oral and two injectable health states were included so that preferences could be examined not only between oral and injectable ROA, but also between different oral processes and between different injectable processes.

The health states were used in a utility valuation study with a sample of participants with T2D in two UK locations (Edinburgh, London) in December 2019 and January 2020. Preferences between the four treatment processes were assessed by asking participants to rank the health states from most preferable to least preferable. Then, utilities were elicited in a time trade-off task (TTO). Written informed consent was obtained from each participant, and the study protocol was approved by an independent institutional review board (Ethical & Independent Review Services; Study 19,038-01).

The four health states began with the same description of T2D, which was derived from previous studies using similar methods [6, 9, 11, 23]. This series of bullet points referred to blood sugar levels, typical symptoms, and body weight. The description of T2D was intended to be general so that it could apply to many patients with T2D and plausibly be paired with any of the treatment process descriptions that followed in each of the four health states. The purpose of this T2D description was to provide brief context for the description of treatment process that followed. Most importantly, this description of diabetes remained constant so that it did not have an impact on preference between the four health states.

After the description of T2D, each health state continued by describing the treatment administration process, which varied across the four health states. Health state A described a simple daily oral medication administration without other specific requirements (“You take oral medication [pills or tablets] every day”). This description has been used in previously published studies [6, 9, 11, 23].

Health state B described administration of oral medication with requirements from the US package insert for oral semaglutide [15]. These bullet point statements were adopted directly from the language in this package insert, and exact language from the label was used as much as possible. Requirements included taking the tablet “on an empty stomach when you first wake up,” “with a sip of plain water,” and “wait at least 30 minutes after taking this tablet before eating, drinking, or taking other oral medications.” The US label was used because it was available at the time this study was conducted. The European Union (EU) label [14] was released after data collection was complete. The medication administration requirements in the US and EU labels are almost identical, with only one minor difference relevant to this health state. Both the US and EU versions direct patients to take the medication on an empty stomach and wait 30 min before eating or drinking, but they differ in their wording. The US version says the medication should be taken “when you first wake up.” The EU version says medication may be taken “at any time of day” but then instructs users to “wait at least 30 minutes before having your first meal or drink of the day or taking other oral medicines.” Despite this difference in wording, the meaning of these instructions appears to be the same.

Health states C and D described injectable treatment administration processes for two commonly used GLP-1 receptor agonists, dulaglutide (C) and semaglutide (D). While both medications are in the same class and administered weekly, they differ with regard to the injection device and steps for preparing the device. The health states described the weekly dose frequency, injection pen, steps for preparing the pen, and injection procedures. Dulaglutide was selected as a comparator because it is one of the most commonly used GLP-1 receptor agonists across multiple countries [24] and because its treatment process attributes have been preferred over procedures for administering other GLP-1 receptor agonists in previous studies [6, 11, 25]. Dulaglutide is administered with a single-dose, single-use auto-injector pen that does not require handling the needle [26]. Injectable semaglutide was selected as the other comparator because it has a different treatment process involving a multi-use, pre-filled injection pen that requires needle attachment/disposal and dose dialing with each use [27].

Health states C and D were based on the EU Instructions for Use (IFU) provided as a package insert with dulaglutide [17] and injectable semaglutide [18], and exact language from the IFUs was used as much as possible. Both health states were included in a previously published utility elicitation study [11], but one revision was made for the current study. In the previous study, both health states described the weekly injection as an addition to daily oral medication. For the current study, the weekly injection was presented as monotherapy.

Participants were recruited through newspaper advertisements, online advertisements, and distribution of fliers. Potential participants responded via email or voicemail to provide their contact information. They were screened using a standardized screening script to confirm eligibility. All participants were required to be between 30 and 75 years old, reside in the UK, and have been diagnosed with T2D. Participants who received medication for diabetes were required to provide proof of treatment (e.g., a prescription for medication used to treat T2D). Participants who had been treated with either dulaglutide or semaglutide were not eligible. Although this sample cannot be considered nationally representative, recruitment targets were set based on the UK census [28] and the UK T2D population [29] to ensure that no demographic groups were over-represented with regard to age, gender, ethnic/racial background, and unemployment status.

The recruitment advertisements described the study as a “type 2 diabetes survey study” with an “interview about hypothetical health choices.” No further details about the study content were provided in the advertisement or the standardized screening script. For example, patients were not told in advance that they would be asked to consider oral and injectable treatment processes. Therefore, there was no apparent selection bias that would have contributed to preferences for oral or injectable treatments.

A pilot study was conducted with 41 participants in London with T2D (53.7% male; mean age = 55.2 years) to assess the clarity and comprehensibility of the interview procedures and health states. Participants completed the TTO valuation and then provided feedback. Health states were revised based on participant feedback and interviewer observations to ensure that health states were clear and easy to understand. The final versions of the health states and methods were used with the last 30 pilot study participants. These participants consistently reported that the health states and procedures were clear and comprehensible. These participants were not included in the main valuation analysis sample.

A utility elicitation study was conducted to value the four health states finalized in the pilot study. Six trained interviewers followed a semi-structured interview guide to conduct one-on-one interviews in private rooms. Each interviewer was observed by the study principal investigator multiple times to ensure consistency in interview procedures.

Participants were introduced to the health states, which were each presented on individual cards. After each participant reported that they understood the health states and had no further questions about health state content, they were asked to rank the health states from most preferable to least preferable. Respondents were also asked to explain reasons for their preferences between the health states.

After completing the ranking, participants valued the health states in a TTO task with a 20-year time horizon. For each health state, participants were offered a choice between spending a 20-year period in the health state versus spending varying amounts of time in full health. Choices were presented in one-year (i.e., 5%) increments, alternating between longer periods of time and shorter periods of time (i.e., 20 years, 0 years [dead], 19 years, 1 year, 18 years, 2 years, 17 years, 3 years…). Utility (u) was assigned based on the point of indifference between years in the health state being valued (y) and years in full health (x) (followed by dead). Utility with the anchors of dead (0) and full health (1) was then calculated as u = x/y.

When a respondent perceived a health state to be worse than dead, the interviewer adjusted the TTO task as described in previous literature [30]. Participants were offered a choice between dead (choice 1) and a 20-year life span (choice 2) beginning with varying amounts of time in the health state being rated, followed by full health for the remainder of the 20 years. The resulting negative utility scores were calculated with a bounded scoring approach that has been used to avoid highly skewed distributions for negative utility scores (u = -x/y, where x is time in full health, and y is the total life span of choice 2).

The EQ-5D-5L was administered to characterize the sample. The EQ-5D-5L is a self-administered, generic, preference-weighted measure designed to assess health status [31]. The instrument includes five dimensions assessing mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. For each dimension, the respondent selects one of five response options, and these responses were used to obtain an index score using a published mapping algorithm [32].

Statistical analyses were completed with SAS (version 9.4). Continuous variables (including utilities and utility difference scores) were summarized as means and standard deviations, and categorical variables were presented as frequencies and percentages. Paired t-tests were conducted to test whether there were statistically significant pairwise differences between heath state utilities (e.g., the utility of health state A vs. the utility of health state B). Paired t-tests were conducted to test for subgroup differences in utility scores. For these analyses, participants were categorized based on age, gender, employment status, education level, geographic location, and current treatment.

A total of 227 potential participants were scheduled for interviews, and 207 attended their interviews. Two of the 207 participants had difficulty understanding the utility interview procedures and were therefore unable to provide valid data. Two individuals declined to sign the consent form and did not complete any study procedures. An additional two individuals were found to be ineligible during review of inclusion criteria at the beginning of the interview (one had previously used dulaglutide or semaglutide; the other had not received a diagnosis of T2D). Therefore, the analysis includes data from 201 interviews (88 Edinburgh, 113 London).

The sample was 52.7% male, with a mean age of 58.7 years. The majority of participants reported ethnicity as White (80.1%). More than half of the participants were employed (33.8% full-time and 22.9% part-time), while less than half (42.8%) reported having a university degree. There was no significant difference between the London and Edinburgh samples in age, gender, employment status, or marital status. Compared with the London sample, the Edinburgh sample had a greater percentage of White participants (92.0% vs.70.8%) and fewer participants with a university degree (31.8% vs. 51.3%). Demographic information is presented in Table 1.

Participants reported being diagnosed with T2D an average of 8.3 years (SD = 7.0) prior to their interview. Most participants were currently receiving medication to treat their diabetes (83.6%) (Table 1). The most commonly reported health conditions included: hypertension (28.9%), anxiety (23.4%), depression (20.4%), and arthritis (19.4%). The mean EQ-5D-5L index score was 0.81 (SD = 0.23), which is similar to scores for patients with T2D without serious diabetes-related complications in previous studies [33].

Participants ranked the four health states in order of preference from 1 (most preferable health state) to 4 (least preferable health state) (Table 2). The simple oral health state (A) was ranked as most preferable by a majority of participants (n = 139; 69.2%), while 60 participants (29.9%) said one of the injection health states (C or D) was most preferable. The semaglutide injection health state (D) was most commonly ranked as least preferable (n = 144; 71.6%).

Ranking for each individual health state relative to each other health state is presented in Table 3. For example, almost all the participants (97.0%) preferred the simple oral health state (A) over the oral semaglutide health state (B), and 88.6% preferred the dulaglutide health state (C) over the injectable semaglutide health state (D). Preferences between the oral semaglutide (B) and injectable dulaglutide (C) health states varied. While 53.2% of the sample preferred the daily oral semaglutide health state, 46.8% preferred weekly injectable dulaglutide. Participants provided reasons for their preferences, and a selection of these qualitative responses is provided in Table 4.

The simple oral health state had the highest mean utility score (0.890), followed by semaglutide oral (0.880), dulaglutide injection (0.878), and semaglutide injection (0.859) (Fig. 1). Pairwise comparisons between health state utilities were performed with t-tests (Table 5). There was no significant difference between utilities of the oral semaglutide health state (B) and the dulaglutide health state (C). All other pairwise comparisons found statistically significant differences between utilities (p < 0.001).

Utilities were compared between subgroups. For health states A, B, and C, there were no statistically significant between-group differences with regard to age (median split: younger [n = 108] vs. older [n = 93]), gender, employment status (retired [n = 61] vs. employed full-time or part-time [n = 114]), geographic location (Edinburgh [n = 88] vs. London [n = 113]), education level (university degree [n = 86] vs. no university degree [n = 115]), or current treatment (three groups: only oral medication [n = 139]; injectable medication with or without oral medication [n = 29]; no medication [n = 33]). The fourth health state (D representing injectable semaglutide) had the lowest mean utility across all subgroups, and there was no significant difference by geographic location, education level, treatment group, or employment status. However, for health state D, younger participants had a significantly greater mean utility than older participants (0.883 vs. 0.831; p < 0.05), and men had a significantly greater mean utility than women (0.882 vs. 0.833; p < 0.05).

Only one participant had negative utility scores, indicating that she perceived health states B, C, and D to be worse than dead. All other participants had positive utilities for all four health states.