FormalPara Key Summary Points

Why carry out the study?

Patients' preference and quality of life are important in deciding the treatment strategy for patients with type 2 diabetes mellitus.

This study aimed to assess the effect of omarigliptin on patients’ psychological attitudes and responses compared with daily dipeptidyl peptidase-4 inhibitors (DPP4is) by measuring the burden of pharmacotherapy using the Diabetic Treatment Burden Questionnaire (DTBQ).

What was learned from the study?

Although the change in the DTBQ total score did not differ between the groups that switched to omarigliptin and the group that continued daily DPP4is, the DTBQ subscale scores, implementation and flexibility burden scores significantly decreased in the group that switched to omarigliptin.

The results in this study may suggest the possibility of switching from daily DPP4is to omarigliptin to decrease the patients’ medication burden.

Introduction

Dipeptidyl peptidase-4 inhibitor (DPP4i) is a class of oral hypotensive agent (OHA) that carries a relatively low risk of hypoglycemia [1, 2]. Since DPP4is are more effective, especially in the East Asian population [3], they have become the most frequently prescribed OHA in Japan [4,5,6].

At the time of designing this study, physicians selected antidiabetic agents depending on the pathological condition of each patient, and the treatment guidelines for diabetes mellitus in Japan lack clear medication strategies [7, 8]. However, the current guidelines in Japan recommend pharmacotherapy considering appropriate targets for glucose control: pathological conditions such as obesity, safety, additional benefits regarding complications and other relevant factors, including medication adherence and medication costs, to prevent or suppress complications and maintain patients’ quality of life (QOL) [9]. The guidelines issued by the American Diabetes Association (ADA) also recommend focusing on the preference or QOL of patients in addition to the pathological conditions and efficacy, side effects and costs of medical agents [10]. The World Health Organization (WHO) warns of poor medication adherence in patients with a long duration of chronic illnesses [11]. For example, although metformin has the benefit of suppressing cardiovascular events [12] and was recommended as a first-line therapy for type 2 diabetes mellitus according to the consensus guidelines of the ADA and the European Association for the Study of Diabetes (EASD) at the planning of this study [13], a meta-analysis reported poor adherence to metformin compared with sulfonylurea [14]. Worsening blood glucose control and the onset of diabetic complications are factors that affect patient QOL [15, 16].

Omarigliptin is a once-weekly DPP4i launched in November 2015 in Japan. Omarigliptin has several characteristics: (1) it is minimally metabolized in the liver, (2) it is not deposited in a specific tissue and is distributed widely in the body, resulting in a low filtration rate in the kidney, and (3) when it is filtered in the renal glomeruli, approximately 60% of it is reabsorbed in the renal tubule in its unchanged form [17]. These characteristics result in stable inhibition of dipeptidyl peptidase-4 for a week after administration [18, 19] and persistent improvements in glycemic control with a safety profile compared to daily DPP4is [20]. Since dulaglutide, a once-weekly glucagon-like peptide 1 receptor agonist (GLP-1 RA), improved patient QOL compared to placebo or twice-daily GLP-1 RA [21], omarigliptin, a once-weekly DPP4i, might also contribute to improving patient QOL. Therefore, this study aimed to assess the effect of omarigliptin on patients’ psychological attitudes and responses compared with conventional once- or twice-daily DPP4is by measuring the burden of pharmacotherapy using the Diabetic Treatment Burden Questionnaire (DTBQ) [22].

Methods

Study Design

This study of omarigliptin, weekly DPP-4i, to evaluate the effect on psychological attitudes and responses compared with daily DPP-4is in patients with type 2 diabetes mellitus (ONWARD-DPP4 study) was a multicenter, open-label, randomized controlled trial conducted at 24 medical institutions in Japan under management of the Japan Society for Patient-Reported Outcome (PRO). Patient enrollment was conducted between March 2021 and December 2021, and each enrolled patient was followed up for 12 weeks. This study, including its protocols and all participating medical institutions, was inspected and approved by the Japan Physicians Association Clinical Research Review Board, which is certified by the Minister of Health, Labor, and Welfare in Japan, according to the requirements of the Clinical Trials Act. This study was registered in the Japan Registry of Clinical Trials (registration no. jRCTs031200437) after receiving approval from a certified review board, according to the requirements of the Clinical Trials Act. The study was conducted in accordance with the Declaration of Helsinki, Clinical Trials Act and other current legal regulations in Japan. Written informed consent was obtained from all enrolled patients who met the eligibility criteria prior to treatment.

Patient Population

The inclusion criteria were as follows: (1) patients with type 2 diabetes mellitus who use once- or twice-daily DPP-4is; (2) those who did not change the anti-diabetic agents (dose, usage or type) within 8 weeks before giving their consent; (3) male or female patients aged 20 years or older; a(4) patients who provided written informed consent. The exclusion criteria were as follows: (1) patients who use any combination tablets with DPP-4i; (2) patients who have a history of using omarigliptin or trelagliptin; (3) patients who use ≥ 10 pharmaceutical agents; (4) patients whose HbA1c was ≥ 10% upon giving their consent; (5) patients who had a history of severe hypoglycemia within a year before giving their consent; (6) patients with type 1 diabetes mellitus or secondary diabetes; (7) patients who routinely use any infusions such as insulin or GLP-1 receptor agonist; (8) patients with cognitive dysfunction or psychiatric disease; (9) patients with alcoholism or drug addiction; (10) patients in the perioperative period or with serious infection or injury; (11) patients with atrial fibrillation or frequent premature ventricular contraction; (12) patients with moderate-to-severe heart failure [class 3 or worse based on the New York Heart Association (NYHA) Functional Classification]; (13) patients with moderate-to-severe renal function (male: serum creatinine > 1.4 mg/dl, female: serum creatinine > 1.2 mg/dl; (14) patients with ascitic fluid or severe hepatic function (AST ≥ 100 IU/l); (15) patients with a history of poorly controlled hypertension or dyslipidemia within 12 weeks before giving their consent; (16) patients with contraindicating conditions to using the study agents; (17) patients who are pregnant, breastfeeding, possibly pregnant or planning to be pregnant; (18) patients who need a legal representative for giving consent; (19) patients with other conditions that the responsible investigator or subinvestigators thought made it inappropriate to participate in the study.

Randomization and Study Intervention

To balance the number of daily DPP4i medications across the groups, equal numbers of patients who used once daily DPP-4is and those who used twice daily DPP-4is were enrolled in this study. After obtaining informed consent, eligible patients were randomly assigned to either group to switch to omarigliptin or the group to continue daily DPP4is at a ratio of approximately 1:1. Randomization was performed using a computer-based dynamic allocation method with a minimization procedure to balance the two allocation factors (HbA1c level and age) across the groups. Patients who were assigned to the group to switch to omarigliptin discontinued the daily DPP4is, which were used after they had given their consent and switched to omarigliptin. Patients who were assigned to the group to continue daily DPP4is continued to take daily DPP4is, which were used at giving their consent. The patients were followed up for 12 weeks, with observation points at baseline and week 12. The detailed observation schedules and items are listed in Supplementary Table 1.

Study Outcomes

The primary endpoint was the change in DTBQ score from baseline to week 12. DTBQ is a specific questionnaire to assess the burden of pharmacotherapy on patients with type 2 diabetes mellitus, composed of 18 questions and three subscales: implementation burden (sum of item scores 1–10), flexibility burden (sum of item scores 11–13) and blood glucose control burden (sum of item scores 14–18) [22]. Each item is scored on a 7-point Likert scale ranging from (1) strongly disagree, (2) mostly disagree, (3) slightly disagree, (4) neither agree nor disagree, (5) slightly agree, (6) mostly agree to (7) strongly agree. Since larger answer number means a heavier treatment burden in items 1–10, answer numbers were converted to 0–6; 0 indicates minimum and 6 maximum treatment burden. In contrast, because a larger answer number indicates a smaller treatment burden in items 11–18, the answer numbers were inverted and then converted to 0–6. Finally, the DTBQ total, implementation burden, flexibility burden and blood glucose control burden scores ranged from 0 to 108, 0 to 60, 0 to 18 and 0 to 30, respectively. The secondary endpoints included changes in blood tests, medication preferences, medication adherence and frequency of any adverse events. The DTBQ and medication preferences were answered by the study participants on a paper questionnaire. Medication adherence was measured using a paper medication diary recorded by the participants. Other clinical outcomes were collected from investigators’ case report forms.

Sample Size Calculation

In a previous study, the total score of DTBQ was 21.1 ± 12.9 in patients who were taking once-daily oral hypoglycemic agents (OHAs), 33.9 ± 15.8 for those taking OHAs twice daily or more and 17.0 ± 12.0 for those taking once weekly OHAs. Based on these previous results, we assumed that the total score of DTBQ at baseline, change in the DTBQ total score in the group that switched to omarigliptin, change in the group to continue daily DPP4is and the standard deviation in change in this study were 27.5, − 10.5, 0 and 21.0, respectively. Under these assumptions, 86 patients per group provided a power of 90% to detect intergroup differences using a two-sided t-test at 5% significance. The dropout rate was estimated to be approximately 20%. Thus, 108 participants were required per group, yielding a total sample size of 216 participants.

Statistical Analysis

Analyses of the primary and secondary endpoints were performed on the full analysis set (FAS), which included all patients assigned to the study intervention. However, patients with a significant violation of the study protocol (e.g., registration without consent or registration outside the enrollment period) were excluded from the FAS. Sensitivity analysis was performed using the per-protocol set by excluding patients with protocol violations, such as violation of eligibility criteria, use of prohibited drugs or poor medication adherence to the study or control agent (< 75% or > 120%). The safety analysis included all treated patients. All tests were two sided, and statistical significance was set at p < 0.05. The primary endpoint, the change in DTBQ score from baseline to week 12, was tested using analysis of covariance (ANCOVA), with the treatment groups as the fixed effect and allocation factors (HbA1c and age at registration) as covariates. Summary statistics for measurement and change from baseline were calculated for the analysis of secondary endpoints. The one-sample t-test or Wilcoxon signed-rank test for intragroup comparison and the two-sample t-test or Wilcoxon rank-sum test for intergroup comparison were performed for continuous variables. Chi-square test or Fisher’s exact test was used for categorical variables. Medication adherence to the study agent was calculated as (number of medications/planned number of medications during the observation period) × 100 (%). In the case of discontinuation or dropout, the planned number of medications until discontinuation or dropout was used as the denominator. A two-sample t-test was performed for the intergroup comparison of medication adherence. Medication preference was asked of the study patients at three levels (prefer once-weekly agent, prefer daily agent, or either). The number and proportion of participants at each level were calculated, and Bowker’s test of symmetry for intragroup comparisons and chi-square tests for intergroup comparisons were performed. To determine the frequency of adverse events, Fisher’s exact test was used for intergroup comparisons. Correlation analysis was performed using Pearson’s and Spearman’s rank correlation coefficients. To explore the background characteristics associated with improvement in DTBQ, logistic regression analysis was performed with improvement of DTBQ total score (change in DTBQ total score from baseline to week 12 is < 0) as a response variable and background characteristics as explanatory variables. The SAS statistical software package version 9.4 (SAS, Cary, NC, USA) was used to perform all statistical analyses. To avoid bias and ensure quality, data collection, management and statistical analyses were performed by third-party entities (Soiken Inc., Osaka, Japan).

Results

Baseline Characteristics of Study Participants

A total of 367 potential participants were screened, and 151 were excluded from the study. Of the 151 excluded participants, 115 did not meet the eligibility criteria, 25 did not provide consent to participate, and 11 were not registered because the planned number of participants had been registered prior to their registration. Finally, 216 participants were registered and randomly categorized to the treatment groups (Fig. 1). Of these, 109 patients were assigned to the group that switched to omarigliptin and 107 were assigned to the group that continued daily DPP4is.

Fig. 1
figure 1

Study flow chart showing patient enrollment, allocation and analysis. DPP4i dipeptidyl-peptidase 4 inhibitor

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The baseline characteristics of the registered participants were well balanced between the groups, except for the blood glucose level, comorbidity of dyslipidemia and number of medications per day (Table 1).

Table 1 Backgrounds of the patients
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Change in Burden of Pharmacotherapy

The DTBQ total score significantly decreased from baseline to week 12 in both groups; however, no significant intergroup difference was observed (Table 2). Among the three DTBQ subscales, the implementation and flexibility burden scores significantly decreased in the group that switched to omarigliptin, although no significant intergroup differences were observed.

Table 2 Changes in the diabetes treatment burden questionnaire
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In each item of the DTBQ among the 18 questions, scores for items 1, 2, 6, 7, 11, 12, and 13 showed a significant intragroup decrease, and scores for item 14 showed a significant increase in the group that switched to omarigliptin (Table 3). Items 6 and 7 significantly decreased or tended to decrease in the group that switched to omarigliptin compared with the group that continued daily DPP4is. Meanwhile, items 14 and 15 significantly increased in the group that switched to omarigliptin compared with the group that continued daily DPP4is.

Table 3 Change in each item of the Diabetes Treatment Burden Questionnaire
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When stratified by medication preference at baseline, in patients who preferred a once-weekly agent at baseline, the DTBQ total score as well as implementation and flexibility burden scores significantly decreased in the group that switched to omarigliptin, and in patients who preferred either. Meanwhile, the flexibility burden score significantly decreased while the DTBQ total score and implementation burden score numerically decreased in the group that switched to omarigliptin (Table 4).

Table 4 Changes in the Diabetes Treatment Burden Questionnaire stratified by medication preference at baseline
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Medication Preference and Adherence

Medication preferences differed significantly between the baseline and week 12 (Table 5). At baseline, the proportion of patients who preferred once-weekly agents was higher in the group that switched to omarigliptin than in the group that continued daily DPP4is, and the proportion of patients who preferred daily agents was higher in the group that continued daily DPP4is than in the group that switched to omarigliptin. At week 12, the medication preference for the assigned study agent increased in both groups. Medication adherence was as high as 97% in both groups without significant intergroup differences.

Table 5 Medication preference and adherence
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Glucose Metabolism Biomarkers

HbA1c and fasting blood glucose levels significantly increased in the group that switched to omarigliptin compared to the group that continued daily DPP4is (Table 6).

Table 6 Changes in glucose metabolism biomarkers
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Factors Associated with Change in DTBQ Scores

The DTBQ total score and subscale scores at baseline were significantly associated with the improvement in DTBQ (change in DTBQ total score from baseline to week 12 was < 0), with an odds ratio > 1, indicating that higher DTBQ scores at baseline were associated with a higher proportion of patients whose DTBQ scores improved from baseline to week 12 (Table 7). In particular, the DTBQ total score and all subscale scores at baseline were significantly associated with improvement in DTBQ in all registered participants or in the group that switched to omarigliptin, whereas only the flexibility burden score at baseline was significantly associated with improvement in DTBQ in the group that continued daily DPP4is.

Table 7 Background characteristics associated with improvement in DTBQ
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Discussion

This ONWARD-DPP4 study was the first prospective randomized controlled trial to compare the impact of switching from daily DPP4is to omarigliptin, a once-weekly DPP4i, with continuing daily DPP4is, on patients’ QOL, especially in terms of the burden of pharmacotherapy. The primary endpoint of this study, the change in the DTBQ total score from baseline to week 12, did not differ significantly between the groups. To calculate the target sample size, change in DTBQ total score from baseline to week 12 was assumed as − 10.5 and 0.0 in the group that switched to omarigliptin and the group that continued daily DPP4is, respectively. However, the actual change in DTBQ total score from baseline to week 12 in this study was − 4.0 and − 2.0 in the group that switched to omarigliptin and the group that continued daily DPP4is, respectively. Since the change in the DTBQ total score in the group that switched to omarigliptin was less than half of the assumption and a significant intragroup decrease in the DTBQ total score was observed in the group that continued daily DPP4is, a significant intergroup difference in the primary endpoint was not observed in this study. In addition, although this study employed HbA1c and age as allocation factors, the baseline characteristics of the participants were significantly different between the groups in blood glucose level, comorbidity of dyslipidemia and number of medications per day and tended to be different in comorbidity of hypertension. Further studies are required with target sample size calculated by the mean change and standard deviation obtained in this study and considering the allocation factors by adding the number of medications per day, for example.

The implementation and flexibility burden scores, as well as the item scores 1, 2, 6 and 7, which comprise the implementation burden score and 11–13, which comprise the flexibility burden score, were significantly improved in the group that switched to omarigliptin, suggesting a decrease in the treatment burden. Compared with the group that continued daily DPP4is, significantly increased (worsened) score was observed in items 14 and 15, which asked about the burden on glycemic control, and significantly higher changes were observed in the group that switched to omarigliptin. These findings were consistent with the significant increase in HbA1c and fasting blood glucose levels in the group that switched to omarigliptin, although the respective values were 0.1% and 5.8 mg/dl, which seemed not to be clinically meaningful. Nevertheless, attending physicians should pay attention to the worsening of the glycemic control and patients’ treatment burden upon switching from daily DPP4is to omarigliptin.

Based on the results of this study, DTBQ and medication preference can be considered in determining pharmaceutical strategy for type 2 diabetes mellitus. Since higher DTBQ scores at baseline were associated with improvement in DTBQ (Table 7), and the DTBQ scores were improved in patients who preferred once-weekly agents at baseline (Table 4), once-weekly agents may be considered in patients whose DTBQ is high and who prefer once-weekly agent. Once-weekly agents can be an option in patients whose DTBQ is high but prefer daily agent or in patients whose DTBQ is low but prefer once-weekly agents. In contrast, continuation of daily agents may be considered in patients with low DTBQ scores and who prefer daily agents.

This study has several limitations. First, this was an open-label study that lacked the blinding of both patients and physicians, and the primary endpoint was PRO. This may have caused a bias in the results of this study. In addition, the DTBQ total score significantly decreased from baseline to week 12 even in the group that continued the daily DPP4is. This may also be one of the biases of the open-label nature of PRO. Second, all patients in this study were Japanese, and weekly DPP4is, omarigliptin and trelagliptin were launched in Japan, but not in the US and Europe. Therefore, the generalizability of the results in this study to other countries or patients of other ethnicities is unknown. Third, although this study enrolled patients with type 2 diabetes mellitus who were taking one of the daily DPP4is, the number of medications per day of other OHAs or medical agents for other chronic illnesses were not restricted, because we aimed to assess the effect of omarigliptin on patients’ psychological attitudes and responses in the real-world situation. Since the mean of medication tablets per day and the mean of medication tablets of OHAs per day in the group that switched to omarigliptin were 6.8 and 3.8, respectively, it might be overwhelming to feel the decrease in the burden of medication by switching of only a tablet from daily to weekly. Further investigations are required considering the total number of medications.

Conclusion

Although this study failed to demonstrate the improvement of DTBQ total score by switching from daily DPP4is to omarigliptin compared with continuing the daily DPP4is; DTBQ subscale scores, implementation and flexibility burden score were significantly improved only in the group that switched to omarigliptin, suggesting the possibility of switching from daily DPP4is to omarigliptin to decrease the patients’ burden on medication.