There have been no studies directly comparing the effect of dipeptidyl peptidase-4 inhibitors with that of metformin on treatment-related quality of life (QOL) when used as first-line therapy in patients with type 2 diabetes mellitus (T2DM).
This study is a prospective, randomized, open-label, multicenter, parallel-group, comparative study. Forty-four participants who failed to achieve target glycemic control with diet and exercise therapy were randomly allocated to receive linagliptin or metformin therapy. We compared treatment-related QOL among the two groups using the Oral Hypoglycemic Agent Questionnaire, version 2 (OHA-Q version 2) and the self-administered Diabetes Therapy-Related QOL (DTR-QOL) questionnaire.
After randomization, 21 patients in the linagliptin group and 22 patients in the metformin treatment group were included in the full analysis set. Biochemical parameters, incidence of adverse effects, and rate of adherence to medication were comparable between the two groups. Over the 24-week treatment period, no significant differences in overall OHA-Q scores between the groups were observed, although the subscale 1 (treatment convenience) score was significantly higher in the linagliptin group than in the metformin group. The overall DTR-QOL score did not differ between the two groups; however, the DTR-QOL scores significantly improved after 24 weeks of linagliptin treatment, but not after metformin treatment.
We did not find significantly better treatment-related QOL with linagliptin among Japanese patients with T2DM. In terms of treatment convenience, our data showed that linagliptin was superior to metformin.
This study was financially supported by Nippon Boehringer Ingelheim Co., Ltd. and Eli Lilly and Company. The journal’s article processing fees were covered by a research fund from Juntendo University.
Clinical Trial Registration
One of the main objectives of diabetes management is to maintain quality of life (QOL) . It has been reported that advanced age, poor glycemic control, previous hypoglycemic episodes, and complex therapeutic regimens are associated with lower QOL in patients with type 2 diabetes mellitus (T2DM) [2,3,4,5]. Given that a lower treatment-related QOL is associated with reduced patient motivation and adherence with treatment among patients with T2DM , it is important that treatment-related QOL be taken into consideration in the choice of oral anti-hypoglycemic agents (OHAs).
Treatment guidelines by the American Diabetes Association and European Association for the Study of Diabetes recommend metformin as first-line therapy when lifestyle modification alone fails to achieve or maintain optimal glycemic goals . Metformin is effective in lowering blood glucose levels by improving insulin sensitivity without increasing the risk of hypoglycemia. Metformin is also associated with weight neutrality or loss, and is generally safe, well tolerated, and inexpensive . In addition, metformin might also reduce the incidence of cardiovascular events . However, a recent meta-analysis demonstrated that adherence to metformin was worse than that for other OHAs such as sulfonylureas and thiazolidinediones . The adverse effects associated with metformin therapy (e.g., gastrointestinal side effects) and the dosing frequency of this agent may negatively affect patient adherence to therapy.
Conversely, the Japan Diabetes Society treatment guidelines recommend choosing suitable therapies in line with the dominant pathophysiological condition in each patient, such as insufficient insulin secretion or insulin resistance , because T2DM in East Asians is more strongly associated with beta-cell dysfunction than with insulin resistance or adiposity . In this context, various types of OHAs, including metformin and dipeptidyl peptidase (DPP)-4 inhibitors, are often chosen as first-line therapy in Japan .
DPP-4 inhibitors, such as linagliptin, enhance glucose-dependent insulin secretion from pancreatic beta cells via inhibition of the degradation of active incretins by DPP-4. In general, DPP-4 inhibitors are safe and well tolerated and do not cause weight gain . More specifically, three recent randomized clinical studies showed that the use of DPP-4 inhibitors did not increase or decrease the cardiovascular event rate in T2DM patients compared to placebo [15,16,17]. A retrospective cohort study and meta-analysis demonstrated that DPP-4 inhibitors also did not increase the risk of cardiovascular disease compared to sulfonylurea [18, 19]. An additional advantage of linagliptin is that dose adjustment is not necessary in patients with end-stage renal disease because this DPP-4 inhibitor is mainly excreted in the feces. Consequently, it is relatively widely used in this patient population and has similar glucose-lowering effect as other DPP-4 inhibitors even in those patients . Due to those characteristics, DPP-4 inhibitors, including linagliptin, are now the most frequently prescribed first-line agents for T2DM in Japan .
In this study, we evaluated the effect of linagliptin versus metformin on treatment-related QOL in patients with T2DM using the Oral Hypoglycemic Agent Questionnaire, version 2 (OHA-Q version 2)  and the self-administered Diabetes Therapy-Related QOL (DTR-QOL) questionnaire .
The INitial choice of DPP-4 inhibitor in Japanese T2DM patients: Effect of Linagliptin on QOL (INTEL-QOL) study is a prospective, randomized, open-label, multicenter, parallel-group, comparative trial that has been described previously . This study is registered on the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR), a non-profit organization in Japan that meets the requirements of the International Committee of Medical Journal Editors (ICMJE) (UMIN000022953).
Japanese patients with T2DM who regularly attended the outpatient diabetes clinics of 14 medical institutions in Japan (Chimori Clinic, Ikeda Clinic, Yamamoto Clinic, Japanese Red Cross Medical Center, Juntendo Tokyo Koto Geriatric Medical Center [Department of Medicine, Diabetology, and Endocrinology], Juntendo University Graduate School of Medicine [Department of Metabolism & Endocrinology], Juntendo University Shizuoka Hospital [Department of Diabetes, Endocrinology, and Metabolism], Sawaki Internal Medicine and Diabetes Clinic, Shimizu Clinic, Tanaka Clinic, Menju Clinic, Misaki Naika Clinic, Musashino Family Clinic, and Yasuda Clinic) were asked to participate in this study. The inclusion criteria were: (1) T2DM not at target blood glucose control as specified in the Treatment Guide for Diabetes by the Japan Diabetes Society , despite the introduction of diet and/or exercise therapy; (2) initiation of OHAs in addition to diet and/or exercise therapy; (3) age ≥ 20 years and < 75 years, regardless of gender; and (4) written informed consent for study participation. The exclusion criteria were: (1) type 1 or secondary diabetes; (2) acute complications of diabetes within the past 6 months; (3) congestive heart failure or myocardial infarction requiring pharmacotherapy; (4) unstable angina pectoris or coronary bypass surgery within the past 6 months; (5) chronic cirrhosis or chronic active hepatitis; (6) artificial dialysis or moderate renal dysfunction; (7) aspartate aminotransferase or alanine aminotransferase levels more than threefold the upper limit of the normal range; (8) direct bilirubin more than threefold the upper limit of the normal range, clinically abnormal thyroid-stimulating hormone level, or fasting triglyceride levels of > 7.9 mmol/L; (9) treatment with any type of antidiabetic medication; (10) dementia, possible dementia, or mental disorder; (11) insufficient capacity for judgment or illiteracy; (12) requiring consent for study participation from a legal representative; (13) pregnancy, lactation, possibly pregnancy, or planning to become pregnant during the study period; (14) history of hypersensitivity to the investigational drugs; (15) present or past history of cancer, unless there was no current medical therapy, no recurrence to date, and no risk of recurrence during this study; and (16) judged as ineligible by the clinical investigators.
Consecutive subjects were screened. Patients that met the above eligibility criteria were asked to participate in the present study. All patients who agreed to participate were enrolled in the study. The protocol was approved by the institutional review board of each participating institution. The study protocol is in compliance with the Declaration of Helsinki and current legal regulations in Japan. All procedures are in accordance with the ethical standards of the institutional and national committees responsible for human experimentation and with the Helsinki Declaration of 1964, as revised in 2013. Informed consent was obtained from all patients before being included in the study.
Randomization and Study Intervention
Patients were registered at the INTEL-QOL trial’s administration office via the internet. Once enrolled, patients were randomly assigned to either the linagliptin or metformin group. Randomization was performed using a dynamic allocation method based on age (< 65 or ≥ 65 years) and gender.
Patients in the linagliptin group were started on linagliptin 5 mg once daily. Patients in the metformin group were started on metformin 250 mg twice daily. The study protocol encouraged increasing the dose of metformin to a maximum dose of 2250 mg when the glycated hemoglobin (HbA1c) level was ≥ 7.0% . In both groups, the addition of OHAs other than the study drugs and insulin were not permitted during the study.
Study Variables and Study Schedule
The study variables and study schedule are shown in Table 1 and Electronic Supplementary Material (ESM) Fig. 1. The study period consisted of 24 weeks after registration. The registration period was from June 2016 to December 2017. The full study duration was from June 2016 to September 2018. All randomized participants were followed until the end of the scheduled study, regardless of adherence to or discontinuation of the study medication for any reason. The investigators were encouraged to provide standard medical care during the study. As a general rule, participants were asked to make routine visits to the clinic every 4–8 weeks during study. During this visit, clinical outcomes, adherence, and adverse events were ascertained. Clinical and biochemical data were collected at baseline and 24 weeks after randomization. Blood samples were obtained after overnight fasting. Urinary albumin excretion was measured using a latex agglutination assay on a spot urine sample at baseline and 24 weeks after randomization. Participants were also asked to record their usage of the study drug on a medication record during the study period.
The primary study outcome was the difference in the overall OHA-Q version 2 score between the two treatment groups at the end of the study. The secondary outcomes were: (1) the difference in score for each OHA-Q version 2 subscale between the two treatment groups at the end of the study; (2) change in overall DTR-QOL score and score for each DTR-QOL domain from baseline to 24 weeks; (3) change in HbA1c level from baseline to 24 weeks; (4) change in all other measured parameters, as reported by Mita et al. . Hypoglycemia was defined based on confirmation of a sign and symptoms of hypoglycemia without a capillary blood glucose measurement.
OHA-Q Version 2
The OHA-Q version 2 is a 23-item, self-administered assessment with three subscales: subscale 1, treatment convenience (9 items; questions 1–9); subscale 2, somatic symptoms (11 items; questions 11–21); and subscale 3, satisfaction (3 items; questions 10, 22, and 23) (ESM Table 1) . The response to each question is scored using a Likert-type scale that ranges from 1 to 4 points. Answers are converted to scores of 0 to 3. Subscale scores are calculated by summing the response to the items in each subscale. If there were missing values for any item in a subscale, the score of that subscale and the overall OHA-Q score are calculated as previously described . Higher scores represent higher QOL. We used the original Japanese version of the OHA-Q version 2.
The DTR-QOL questionnaire is a 29-item, self-administered assessment with four primary scales: domain 1, burden on social activities and daily activities (13 items); domain 2, anxiety and dissatisfaction with treatment (8 items); domain 3, hypoglycemia (4 items); domain 4, satisfaction with treatment (4 items) (ESM Table 1) . The DTR-QOL questionnaire can be used to evaluate the effect of diabetes treatment on patient QOL with high reliability and validity . The response to each question is scored using a Likert-type scale that ranges from 1 (strongly agree) to 7 (strongly disagree). The scale for items 26–29 is reversed, so that 7 represent the highest QOL score. Domain scores are calculated by summing the response to the items in each domain. If there are missing values for any item in a domain, they are handled as described in the original report . Scores are then converted to a range of 0–100. Higher scores represent higher QOL. In each domain, average scores are calculated. We used the original Japanese version of the DTR-QOL.
The sample size was not calculated using scientific methods because this was an exploratory study. Assuming a treatment dropout rate of 10%, the target number of enrolled patients was set at 22 subjects in each group, or 44 subjects in total.
The results are presented as the mean ± standard deviation or as the median with the interquartile range for continuous variables, and as a number with the proportion (percentage) of patients for categorical variables. Efficacy was analyzed using the full analysis set. To compare the overall OHA-Q version 2 score and each OHA-Q version 2 subscale score between the two treatment groups at the end of the study, we used Student’s t test and analysis of covariance models (ANCOVA) that included treatment group as a fixed effect and the allocation factors of age (< 65 or ≥ 65 years) and gender as covariates . To compare the changes in total and domain-specific DTR-QOL scores, HbA1c, and fasting blood glucose between the two treatment groups at the end of the study, we used Student’s t test and ANCOVA models that included treatment group as a fixed effect and (1) each baseline value as a covariate, (2) allocation factors as covariates, and (3) each baseline value and allocation factors as covariates. For other variables, comparisons between the groups were performed using Student’s t test or the Wilcoxon rank-sum test for continuous variables, and the Chi-square test or Fisher’s exact test for categorical variables. Changes from baseline to week 24 within each treatment group were assessed with the one-sample Student’s t test or Wilcoxon signed-rank test. The correlation between the overall OHA-Q version 2 score at the end of study or change in the DTR-QOL score from baseline to 24 weeks, and parameters such as (1) age, gender, body mass index (BMI), duration of diabetes, HbA1c, and estimated glomerular filtration rate (eGFR) at baseline, (2) change in BMI and change in HbA1c, and (3) adherence rate and dosing frequency, were evaluated using Pearson’s and Spearman’s correlation coefficients. All statistical tests were two-sided with a significance level of 5%. All analyses were performed using SAS software, version 9.4 (SAS Institute, Cary, NC, USA).
A total of 44 participants were randomly allocated to either the linagliptin group (n = 21) or the metformin group (n = 23). After excluding one patient in the metformin group from the analysis because no data were available due to transfer of care, 21 patients in the linagliptin group and 22 patients in the metformin treatment group were included in the full analysis set (ESM Fig. 1). The two groups were well balanced at baseline, with comparable mean age, sex, BMI, estimated duration of diabetes, HbA1c level, blood pressure, biochemical parameters, and background treatment for hypertension, hyperlipidemia, and other conditions, with the exception of eGFR (Tables 1, 2).
Patients in the linagliptin group were started on linagliptin 5 mg once daily. No dose change occurred during the study. Patients in the metformin group were started on metformin 250 mg twice daily. Although investigators were encouraged to increase the dose of metformin to a maximum dose of 2250 mg when the HbA1c level was ≥ 7.0%, the dose was increased in only five patients. The dose was increased from 500 to 750 mg in one patient, and from 500 to 1000 mg in four patients. The dose was decreased from 500 to 250 mg in one patient. The mean metformin dose was 500 ± 0.0 mg/day at baseline and 568.2 ± 246.2 mg/day at week 24. In one patient in the metformin group, a sodium-glucose co-transporter-2 inhibitor was added at the investigator’s discretion.
The two groups had a similar mean change in BMI at 24 weeks (Table 2). HbA1c levels and fasting serum glucose levels were significantly lower at 24 weeks than at baseline in both groups (Table 2). However, the change in HbA1c and fasting serum blood glucose levels did not differ between the two groups (Table 2). In addition, there were no significant differences in other biochemical parameters between the two groups at the end of the study, with the exception of urinary albumin excretion (Table 2).
Over the 24-week treatment period, none of the patients experienced hypoglycemia. There were no intergroup differences in the incidence of adverse effects, including gastrointestinal symptoms (one patient in the linagliptin group vs. three patients in the metformin group) and serious adverse events (linagliptin group: subarachnoid hemorrhage (n = 1), recurrence of liver cancer (n = 1), effort angina (n = 1); metformin group: none). Although recent studies suggest that DPP-4 inhibitors are associated with increased risk for acute pancreatitis [26, 27], patients on linagliptin did not experience acute pancreatitis in this short-term study. There was no significant difference in the rate of adherence to medication between the two groups (100% [97.5–100%] in the linagliptin group vs. 97.3% [92.8–100.0%] in the metformin group; P = 0.08].
OHA-Q Score and Change in DTR-QOL Scores
At 24 weeks, the two groups had comparable overall OHA-Q scores (Table 3). An ANCOVA model that included treatment group as a fixed effect and the allocation factors of age (< 65 or ≥ 65 years) and gender as covariates produced similar findings.
With respect to subscale scores, the subscale 1 “treatment convenience” score was significantly higher in the linagliptin group than in the metformin group (Table 3). Similar findings were noted in an ANCOVA model that included treatment group as a fixed effect and the allocation factors of age (< 65 or ≥ 65 years) and gender as covariates (mean change 5.35; 95% confidence interval 2.20–8.50; P = 0.001). In contrast, there were no differences in subscale 2 (somatic symptoms) and subscale 3 (satisfaction) scores between the two groups (Table 3). At the question level, scores for questions 1, 2, and 6–9 were significantly higher after 24 weeks of linagliptin treatment (Table 3).
Regarding the DTR-QOL questionnaire, changes in the overall DTR-QOL score and domain-specific scores over 24 weeks were similar in the two groups (Table 4). However, the change in the score for question 22 (“I am worried that complications might get worse with my current diabetes treatment”) was significantly higher in the linagliptin group than in the metformin group (Table 4).
The overall DTR-QOL scores and scores for domains 1, 2, and 4 significantly improved after 24 weeks of linagliptin treatment, but not after metformin treatment. At the question level, scores for questions 10–14, 17–20, 22, 23, 26, 27, and 29 also significantly improved after 24 weeks of linagliptin treatment (data not shown). For participants on metformin treatment, only the score for question 29 significantly improved after 24 weeks of treatment (data not shown).
We investigated the correlation between either OHA-Q score or change in DTR-QOL score and some parameters, at baseline and the change over 24 weeks. Medication adherence rate was the only parameter significantly associated with OHA-Q score (Pearson’s correlation coefficient 0.40; P = 0.022) and the subscale 1 score (Pearson’s correlation coefficient 0.52;P = 0.002).
Linagliptin and metformin provide clinically meaningful improvement in glycemic control with an acceptable side effect profile and a low risk of hypoglycemia. The results of this study demonstrated that the linagliptin and metformin groups had similar overall OHA-Q scores, although the linagliptin group had a significantly higher subscale 1 (treatment convenience) score than the metformin group. While overall DTR-QOL scores were comparable between the groups, scores for approximately half of the DTR-QOL items significantly improved after 24 weeks of linagliptin treatment. However, this study did not show that linagliptin was superior to metformin in terms of treatment-related QOL. Nonetheless, linagliptin did not have a negative impact on any aspects of treatment-related QOL compared with metformin, but rather had a positive impact on several aspects of treatment-related QOL.
Previous studies have reported that the initiation of diabetes treatment is associated with improvements in QOL as assessed by various types of patient-reported outcome evaluations [28, 29, 30]. Consistent with these findings, we found that the overall DTR-QOL questionnaire score was significantly higher after 24 weeks of linagliptin treatment. DPP-4 inhibitors are generally safe and well tolerated. They do not increase body weight and have a low risk for hypoglycemia and unacceptable side effects . These characteristics of linagliptin probably contributed the higher QOL reported in the present study, as previous reports have demonstrated that weight gain, hypoglycemic episodes, and other side effects during diabetes treatment negatively affect QOL [30,31,32]. In addition, linagliptin is a medicine taken once daily. In this regard, recent clinical studies have demonstrated that once-daily dosing is associated with a higher rate of adherence than more frequent dosing [33,34,35,36]. Thus, it is not difficult to imagine that the once-daily dosing regimen for linagliptin might place a lower burden on patients’ social and daily activities. Accordingly, the DTR-QOL questionnaire scores related to burden on social activities and daily activities, anxiety, and dissatisfaction with treatment, hypoglycemia, and satisfaction with treatment significantly improved after the initiation of linagliptin treatment. Although such improvements were not found in the metformin group, the DTR-QOL questionnaire score did increase from 64.4 at baseline to 70.2 at the end of study in the metformin group. Metformin is also generally safe, well tolerated, and inexpensive ; in fact, the score for question 29 (“With regards to diabetes treatment, I am satisfied with current treatment methods”) improved significantly at 24 weeks. Taken together, both linagliptin and metformin are reasonable OHAs from the QOL perspective.
Even though both linagliptin and metformin have the potential to improve treatment-related QOL, patients in the linagliptin group were more likely to be satisfied with their treatment than those in the metformin group. However, the reduction in HbA1c level in the linagliptin group was similar to that in the metformin group. In particular, the linagliptin group had a significantly higher subscale 1 (treatment convenience) score than the metformin group. Similarly, Ishii et al. demonstrated that DPP-4 inhibitors are the most favorable option among the four classes of OHAs (DPP-4 inhibitors, metformin, α-glucosidase inhibitors, and sulfonylureas) as first-line therapy, in terms of improving treatment satisfaction . In contrast, they found that a significantly higher overall OHA-Q score in the DPP-4 inhibitor group than in the metformin group over a 4-week treatment period. The differences in results may be due to differences in study design and the length of the observation period. In the present study, we directly compared the influence of a specific DPP-4 inhibitor, linagliptin, with that of metformin on treatment-related QOL for a longer duration.
Significant differences were observed between the two treatment groups in terms of subscale 1 scores for items such as missed dose, difficulty swallowing, interval between taking the agent and a meal, compliance with treatment schedule, number of doses, and taking the agent while not at home. In this study, the majority of patients were taking metformin twice daily according to the study protocol. Increased dosing frequency might result in treatment inconvenience. In addition, the metformin tablet is larger, so patients might experience difficulty in swallowing the metformin tablet. These factors may be associated with increased patient burden and reduced motivation to comply with treatment, leading to worsening of glycemic control in the long term. In fact, subscale 1 (treatment convenience) and overall OHA-Q scores are positively associated with the rate of adherence to medication. These points are very important when choosing OHAs; the American Diabetes Association emphasized the importance of considering patient preferences in addition to efficacy, hypoglycemic risk, impact on weight, potential side effects, and cost .
Despite differences in treatment convenience between the linagliptin and metformin groups, there was no significant difference in the rate of medication adherence. This unexpected finding might be related to the small sample size, short study duration, and failure to increase the dose of metformin. In particular, the dose of metformin was not increased to ≥ 750 mg/day in approximately 80% of patients based on study protocol recommendations. This may be related to investigators’ concern about gastrointestinal side effects as the metformin dose increases, although a recent study conducted in Japan showed that increased metformin dosing is not associated with more gastrointestinal side effects . Thus, difficulties in increasing the dose of metformin are also a major barrier to using metformin as first-line therapy in clinical practice in Japan.
There are several limitations to the present study. First, the study was an exploratory study with a relatively small sample size. Second, as this study was limited to subjects not previously taking OHAs, it is not possible to conclude that the effects of linagliptin and metformin on treatment-related QOL can be generalized to patients already on other OHAs. In addition, only one patient with cardiovascular disease were registered in this study. Thus, we could not evaluate the effect of linagliptin versus metformin on treatment-related QOL in patients with cardiovascular disease. Third, we did not assess the long-term effects of these agents on QOL. Finally, we did not consider the influence of the frequency, number, and types of drugs other than OHAs on adherence to study drugs.
In conclusion, we did not find a significant improvement in treatment-related QOL with linagliptin among Japanese patients with T2DM. However, linagliptin did not have a negative impact on any aspects of treatment-related QOL compared with metformin, but rather had a positive impact on several aspects of treatment-related QOL.
Araki E, Haneda M, Kasuga M, Nishikawa T, Kondo T, Ueki K, et al. New glycemic targets for patients with diabetes from the Japan Diabetes Society. J Diabetes Investig. 2017;8(1):123–5.
Papazafiropoulou AK, Bakomitrou F, Trikallinou A, Ganotopoulou A, Verras C, Christofilidis G, et al. Diabetes-dependent quality of life (ADDQOL) and affecting factors in patients with diabetes mellitus type 2 in Greece. BMC Res Notes. 2015;8:786.
Yfantopoulos J, Hatzikou M, Rombopoulos G, Panitti E, Latsou D. The prevalence of hypoglycemia and its impact on the quality of life of type 2 diabetes mellitus patients in Greece (the Hypo study). Value Health. 2014;17(7):A356.
Depablos-Velasco P, Salguero-Chaves E, Mata-Poyo J, Derivas-Otero B, Garcia-Sanchez R, Viguera-Ester P. Quality of life and satisfaction with treatment in subjects with type 2 diabetes: results in Spain of the PANORAMA study. Endocrinol Nutr. 2014;61(1):18–26.
Imayama I, Plotnikoff RC, Courneya KS, Johnson JA. Determinants of quality of life in adults with type 1 and type 2 diabetes. Health Qual Life Outcomes. 2011;9:115.
Ishii H, Anderson JH Jr, Yamamura A, Takeuchi M, Ikeda I. Improvement of glycemic control and quality-of-life by insulin lispro therapy: assessing benefits by ITR-QOL questionnaires. Diabetes Res Clin Pract. 2008;81(2):169–78.
Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38(1):140–9.
Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15):1577–89.
UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352(9131):854–65.
McGovern A, Tippu Z, Hinton W, Munro N, Whyte M, de Lusignan S. Comparison of medication adherence and persistence in type 2 diabetes: a systematic review and meta-analysis. Diabetes Obes Metab. 2017;Nov:14.
Haneda M, Noda M, Origasa H, Noto H, Yabe D, Fujita Y, et al. Japanese clinical practice guideline for diabetes 2016. Diabet Int. 2018;9:1–45.
Kodama K, Tojjar D, Yamada S, Toda K, Patel CJ, Butte AJ. Ethnic differences in the relationship between insulin sensitivity and insulin response: a systematic review and meta-analysis. Diabetes Care. 2013;36(6):1789–96.
Oishi M, Yamazaki K, Okuguchi F, Sugimoto H, Kanatsuka A, Kashiwagi A, et al. Changes in oral antidiabetic prescriptions and improved glycemic control during the years 2002–2011 in Japan (JDDM32). J Diabetes Investig. 2014;5(5):581–7.
Ohmura H, Mita T, Taneda Y, Sugawara M, Funayama H, Matsuoka J, et al. Efficacy and safety of sitagliptin in Japanese patients with type 2 diabetes. J Clin Med Res. 2015;7(4):211–9.
White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369(14):1327–35.
Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. New Engl J Med. 2013;369(14):1317–26.
Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;Jun:8.
Wang F, He Y, Zhang R, Zeng Q, Zhao X. Combination therapy of metformin plus dipeptidyl peptidase-4 inhibitor versus metformin plus sulfonylurea and their association with a decreased risk of cardiovascular disease in type 2 diabetes mellitus patients. Medicine. 2017;96(36):e7638.
Chin HJ, Nam JH, Lee EK, Shin JY. Comparative safety for cardiovascular outcomes of DPP-4 inhibitors versus glimepiride in patients with type 2 diabetes: A retrospective cohort study. Medicine. 2017;96(25):e7213.
Park SH, Nam JY, Han E, Lee YH, Lee BW, Kim BS, et al. Efficacy of different dipeptidyl peptidase-4 (DPP-4) inhibitors on metabolic parameters in patients with type 2 diabetes undergoing dialysis. Medicine. 2016;95(32):e4543.
Seino Y, Kuwata H, Yabe D. Incretin-based drugs for type 2 diabetes: focus on East Asian perspectives. J Diabetes Investig. 2016;7[Suppl 1]:102–9.
Nakajima H, Okada S, Mohri T, Kanda E, Inaba N, Hirasawa Y, et al. Dapagliflozin improves treatment satisfaction in overweight patients with type 2 diabetes mellitus: a patient reported outcome study (PRO study). Diabetol Metab Syndrome. 2018;10:11.
Ishii H. Development and psychometric validation of the Diabetes Therapy-Related QOL (DTR-QOL) questionnaire. J Med Econ. 2012;15(3):556–63.
Mita T, Hiyoshi T, Yoshii H, Chimori H, Ikeda K, Sato J, et al. Study protocol for the initial choice of DPP-4 inhibitor in Japanese patients with type 2 diabetes mellitus: effect of linagliptin on QOL (INTEL-QOL) trial. Diabetes Ther. 2018;9(3):1403–12.
Society TJD (2010) Treatment guide for diabetes. In: Editorial Committee Members (eds) Treatment Guide for Diabetes (eds) o “ “ (Araki E, Iwamoto Y, Kadowaki T, Kashiwagi A, Kitaoka M, Nanjo K, Tajima N) Bunkodo Co, Ltd, Tokyo, Japan. .
Lai YJ, Hu HY, Chen HH, Chou P. Dipeptidyl peptidase-4 inhibitors and the risk of acute pancreatitis in patients with type 2 diabetes in taiwan: a population-based cohort study. Medicine. 2015;94(43):e1906.
Chen S, Zhao E, Li W, Wang J. Association between dipeptidyl peptidase-4 inhibitor drugs and risk of acute pancreatitis: a meta-analysis. Medicine. 2017;96(48):e8952.
Sakamoto Y, Oyama J, Ikeda H, Kuroki S, Gondo S, Iwamoto T, et al. Effects of sitagliptin beyond glycemic control: focus on quality of life. Cardiovasc Diabetol. 2013;12:35.
Pratley RE, Nauck M, Bailey T, Montanya E, Cuddihy R, Filetti S, et al. Liraglutide versus sitagliptin for patients with type 2 diabetes who did not have adequate glycaemic control with metformin: a 26-week, randomised, parallel-group, open-label trial. Lancet. 2010;375(9724):1447–56.
Genovese S, Tedeschi D. Effects of vildagliptin/metformin therapy on patient-reported outcomes: work productivity, patient satisfaction, and resource utilization. Adv Ther. 2013;30(2):152–64.
Anderson RT, Girman CJ, Pawaskar MD, Camacho FT, Calles J, Kelly WS, et al. Diabetes medication satisfaction tool: a focus on treatment regimens. Diabetes Care. 2009;32(1):51–3.
Kleefstra N, Ubink-Veltmaat LJ, Houweling ST, Groenier KH, Meyboom-de Jong B, Bilo HJ. Cross-sectional relationship between glycaemic control, hyperglycaemic symptoms and quality of life in type 2 diabetes (ZODIAC-2). Neth J Med. 2005;63(6):215–21.
Dezii CM, Kawabata H, Tran M. Effects of once-daily and twice-daily dosing on adherence with prescribed glipizide oral therapy for type 2 diabetes. South Med J. 2002;95(1):68–71.
Winkler A, Teuscher AU, Mueller B, Diem P. Monotoring adherence to prescribed medication in type 2 diabetic patients treated with sulfonylureas. Swiss Med Wkly. 2002;132(27–28):379–85.
Pullar T, Birtwell AJ, Wiles PG, Hay A, Feely MP. Use of a pharmacologic indicator to compare compliance with tablets prescribed to be taken once, twice, or three times daily. Clin Pharmacol Ther. 1988;44(5):540–5.
Kardas P. The DIACOM study (effect of DosIng frequency of oral Antidiabetic agents on the COMpliance and biochemical control of type 2 diabetes). Diabetes Obes Metab. 2005;7(6):722–8.
Ishii H, Hayashino Y, Akai Y, Yabuta M, Tsujii S. Dipeptidyl peptidase-4 inhibitors as preferable oral hypoglycemic agents in terms of treatment satisfaction: Results from a multicenter, 12-week, open label, randomized controlled study in Japan (PREFERENCE 4 study). J Diabetes Investig. 2018;9(1):137–45.
American Diabetes Association. 8. Pharmacologic approaches to glycemic treatment. Diabetes Care. 2017;40[Suppl 1]:S64–S74.
Kanto K, Ito H, Noso S, Babaya N, Hiromine Y, Taketomo Y, et al. Effects of dosage and dosing frequency on the efficacy and safety of high-dose metformin in Japanese patients with type 2 diabetes mellitus. J Diabetes Investig. 2017. https://doi.org/10.1111/jdi.12755
The authors wish to thank the study investigators and participants for their contributions to this study. The authors thank all of the clinical staff for their assistance with the execution of the clinical trial, and Soiken Inc. for technical assistance in the launch and execution of this trial.
This study was financially supported by Nippon Boehringer Ingelheim Co., Ltd. and Eli Lilly and Company. They did not provide funding for the journal’s article processing fees. The journal’s article processing fees were covered by a research fund from Juntendo University.
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published. All authors have full access to all of the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis, and have given final approval to the version to be published.
Tomoya Mita has received research funds from MSD K.K., Takeda Pharmaceutical Co., Ltd., Kowa Pharmaceutical Co., Ltd., Sanwa Kagaku Kenkyusho Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Mitsubishi Tanabe Pharma Co., and Ono Pharmaceutical Co., Ltd.; and lecture fees from AstraZeneca K.K., Nippon Boehringer Ingelheim Co., Ltd., Eli Lilly and Company, Kowa Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., MSD K.K., Ono Pharmaceutical Co., Ltd., Novo Nordisk Pharma Ltd., and Takeda Pharmaceutical Co., Ltd. Junko Sato has received research funds from MSD K.K., Takeda Pharmaceutical Co., Ltd., Kowa Pharmaceutical Co., Ltd., Sanwa Kagaku Kenkyusho Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Mitsubishi Tanabe Pharma Co., and Ono Pharmaceutical Co., Ltd. Hirotaka Watada has received grants from Astellas Pharma, Sanofi, Mitsubishi Tanabe Pharma, Novo Nordisk, Takeda Pharmaceutical Company, Novartis Pharma, Nippon Boehringer Ingelheim, MSD, Sumitomo Dainippon Pharma, Kissei Pharmaceutical, Daiichi Sankyo, Pfizer Japan, and Teijin Pharma; and has received personal fees from Eli Lilly, Mitsubishi Tanabe Pharma, Sanofi, Takeda Pharmaceutical Company, Novo Nordisk, Nippon Boehringer Ingelheim, Daiichi Sankyo, Ono Pharmaceutical, Astellas Pharma, FUJIFILM Pharma, Terumo Corporation, and MSD. Toru Hiyoshi, Hidenori Yoshii, Hiroko Chimori, Kazuo Ikeda, Miho Shimizu, Yuichi Kojima, Hareaki Yamamoto and Daijiro Yasuda declare that they have no conflicts of interest.
Compliance with Ethics Guidelines
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964, as revised in 2013. Informed consent was obtained from all individual participants included in the study.
The datasets during and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Mita, T., Hiyoshi, T., Yoshii, H. et al. The Effect of Linagliptin versus Metformin Treatment-Related Quality of Life in Patients with Type 2 Diabetes Mellitus. Diabetes Ther 10, 119–134 (2019). https://doi.org/10.1007/s13300-018-0539-5