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

Study Protocol for the Initial Choice of DPP-4 Inhibitor in Japanese Patients with Type 2... Diabetes Ther (2018) 9:1403–1412 https://doi.org/10.1007/s13300-018-0437-x STUDY PROTOCOL 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 . . . . Tomoya Mita Toru Hiyoshi Hidenori Yoshii Hiroko Chimori . . Kazuo Ikeda Junko Sato Hirotaka Watada Received: April 18, 2018 / Published online: May 9, 2018 The Author(s) 2018 related QOL when used as first-line therapy in ABSTRACT patients with type 2 diabetes mellitus. Methods: This study is a prospective, random- Introduction: Consideration of treatment-re- ized, open-label, multicenter, parallel-group, lated quality of life (QOL) is important in dia- comparative study. Between June 2016 and betes management. However, no studies have December 2017, 44 participants who failed to compared the influence of dipeptidyl peptidase- achieve glycemic control despite diet and exer- 4 inhibitors versus metformin on treatment- cise therapy were recruited at 14 clinics and randomly allocated to linagliptin or metformin therapy. Treatment-related QOL was assessed Enhanced digital features To view enhanced digital features for this article go to https://doi.org/10.6084/ with the Oral Hypoglycemic Agent Question- m9.figshare.6200750. naire, version 2 (OHA-Q ver. 2) and the self- administered Diabetes Therapy-Related QOL T. Mita (&)  H. Watada (DTR-QOL) questionnaire. The primary study Department of Metabolism and Endocrinology, outcome is the difference in total OHA-Q ver. 2 Juntendo University Graduate School of Medicine, score between the two treatment groups at the Bunkyo-ku, Tokyo, Japan e-mail: tom-m@juntendo.ac.jp end of the study. The secondary outcomes include differences in the scores for each OHA- T. Hiyoshi Q ver. 2 subscale between the two treatment Division of Diabetes and Endocrinology, Japanese groups at the end of the study, change in total Red Cross Medical Center, Shibuya-ku, Tokyo, Japan DTR-QOL score and for each domain from H. Yoshii baseline to the end of treatment, changes in Department of Medicine, Diabetology and glycemic control, and adverse events. Endocrinology, Juntendo Tokyo Koto Geriatric Medical Center, Koto-ku, Tokyo, Japan Planned outcome: The present study is designed to assess the effects of linagliptin on H. Chimori the treatment-related QOL. Results will be Chimori Medical Clinic, Fukushima-ku, Osaka, available in the near future. Study findings are Osaka, Japan expected to provide useful information on how K. Ikeda to maintain or improve QOL in patients with Ikeda Shinryojyo, Higashiosaka, Osaka, Japan type 2 diabetes mellitus treated with insulin. J. Sato Funding: Nippon Boehringer Ingelheim Co., Department of Diabetes, Endocrinology and Ltd. and Eli Lilly and Company. Metabolism, Juntendo University Shizuoka Clinical trial registration: UMIN000022953. Hospital, Izunokuni, Shizuoka, Japan 1404 Diabetes Ther (2018) 9:1403–1412 Keywords: Linagliptin; Metformin; negatively affect patient adherence to therapy. Questionnaire; Treatment-related quality of These characteristics of metformin might life; Type 2 diabetes mellitus reduce treatment-related QOL. Conversely, the Japan Diabetes Society treatment guidelines recommend choosing INTRODUCTION suitable therapies in line with the dominant pathophysiological condition of each patient, One of the main objectives of diabetes man- such as insufficient insulin secretion or insulin agement is to maintain quality of life (QOL) by resistance [13], because T2DM in East Asians is preventing development or progression of more strongly associated with beta cell dys- complications [1]. In patients with type 2 dia- function than insulin resistance and adiposity betes mellitus (T2DM), advanced age, poor gly- [14]. In this context, various types of OHAs, cemic control, previous hypoglycemic episodes, including metformin and dipeptidyl peptidase and complex therapies are associated with lower (DPP)-4 inhibitors, are chosen as first-line ther- QOL [2–5]. On the other hand, intensive fre- apy in Japan [15]. quency of follow-up was associated with DPP-4 inhibitors such as linagliptin enhance improvements of QOL [6]. Given that decreased glucose-dependent insulin secretion from pan- treatment-related QOL is associated with creatic beta cells via inhibiting the degradation reduced patient motivation and adherence to of active incretins by DPP-4. In general, DPP-4 treatment in patients with T2DM [7], consider- inhibitors are safe and well tolerated and do not ation of treatment-related QOL is important cause weight gain [16]. Sitagliptin was shown to when choosing oral anti-hypoglycemic agents improve QOL in a single arm-study [17]. Owing (OHAs). to these characteristics, DPP-4 inhibitors are Treatment guidelines by the American Dia- now the most frequently prescribed first-line betes Association and European Association for agents for T2DM in Japan [18]. the Study of Diabetes recommend metformin as In this study, to investigate how these first-line therapy when lifestyle modification treatment regimens affect QOL of patients with alone fails to achieve or maintain optimal gly- T2DM, we evaluated the effect of linagliptin cemic goals [8]. Metformin reduces blood glu- versus metformin on treatment-related QOL cose levels by improving insulin sensitivity, using the Oral Hypoglycemic Agent Question- mainly in the liver. Metformin has an estab- naire, version 2 (OHA-Q ver. 2) and the self- lished evidence base showing that it is effica- administered Diabetes Therapy-Related QOL cious in lowering blood glucose levels without (DTR-QOL) questionnaire [19]. Although these increasing the risk of hypoglycemia, with questionnaires are newly developed, they are weight neutrality or loss. In addition, met- valid [19, 20]. formin is generally safe, well tolerated, and inexpensive [9]. Metformin might also reduce MATERIALS AND METHODS the incidence of cardiovascular events and improve survival [10]. However, a recent meta- Study Design analysis demonstrated that adherence to met- formin was worse than for other OHAs such as sulfonylureas and thiazolidinediones [11]. In The Initial choice of DPP-4 inhibitor in Japanese this regard, the most common adverse effects of T2DM patients: Effect of Linagliptin on QOL metformin are gastrointestinal effects, such as (INTEL-QOL) study is a prospective, random- nausea, vomiting, and diarrhea [12]. These ized, open-label, multicenter, parallel-group, symptoms might reduce patient adherence to comparative trial. This study is planned solely metformin treatment. In addition, given that a to evaluate the QOL. This study has been reg- sustained release preparation of metformin is istered on the University Hospital Medical not available in all countries, the need to take Information Network Clinical Trials Registry metformin more than twice daily may (UMIN-CTR), a non-profit organization in Japan Diabetes Ther (2018) 9:1403–1412 1405 that meets the requirements of the Interna- mental disorder; (11) insufficient judgment tional Committee of Medical Journal Editors ability or illiteracy; (12) requiring consent for (ICMJE) (UMIN000022953). study participation from a legal representative; (13) pregnancy, lactation, possibly pregnancy, or planning to become pregnant during the Study Population study period; (14) history of hypersensitivity to investigational drugs; (15) present or past his- Japanese patients with T2DM who regularly tory of a malignant tumor, unless there was no attended the outpatient diabetes clinics of 14 current medical therapy, no recurrence to date, institutions (Chimori Clinic, Ikeda Clinic, and no risk of recurrence during this study; and Yamamoto Clinic, Japanese Red Cross Medical (16) judged as ineligible by the clinical Center, Juntendo Tokyo Koto Geriatric Medical investigators. Center (Department of Medicine, Diabetology The subjects were screened consecutively. and Endocrinology), Juntendo University Patients that met the above eligibility criteria Graduate School of Medicine (Department of were asked to participate in the present study. Metabolism and Endocrinology), Juntendo All patients who agreed to participate were University Shizuoka Hospital (Department of enrolled in the study. The protocol has been Diabetes, Endocrinology, and Metabolism), approved by the institutional review board of Sawaki Internal Medicine and Diabetes Clinic, each participating institution in compliance Shimizu Clinic, Tanaka Clinic, Menju Clinic, with the Declaration of Helsinki and current Misaki Naika Clinic, Musashino Family Clinic, legal regulations in Japan. All procedures fol- and Yasuda Clinic) in Japan were asked to par- lowed were in accordance with the ethical ticipate in this study. The inclusion criteria are standards of the responsible committee on as follows: (1) T2DM not at target blood glucose human experimentation (institutional and control as specified in the Treatment Guide for national) and with the 1964 Declaration of Diabetes by the Japan Diabetes Society [13] Helsinki, as revised in 2013. Informed consent despite the introduction of diet and/or exercise was obtained from all patients for being inclu- therapy; (2) patients who are considered to ded in the study. newly initiate OHAs in addition to dietary and/ or exercise therapy; (3) age C 20 years Randomization and Study Intervention and \ 75 years, regardless of gender; and (4) written informed consent for study participa- tion. The following exclusion criteria are used: Patients were registered at the INTEL-QOL trial’s (1) type 1 or secondary diabetes; (2) acute dia- administration office via the internet. Once betic complications within the past 6 months; enrolled, patients were randomly assigned to (3) congestive heart failure or myocardial either the linagliptin group or the metformin infarction requiring pharmacotherapy; (4) group. Randomization was performed using a unstable angina pectoris or coronary bypass dynamic allocation method based on age (\ 65 surgery within the past 6 months; (5) chronic or C 65 years) and gender (male or female). cirrhosis or chronic active hepatitis; (6) artificial Patients in the linagliptin group were started dialysis or moderate renal dysfunction; (7) on linagliptin 5 mg once daily. Patients in the aspartate aminotransferase or alanine amino- metformin group were started on metformin transferase levels more than three times higher 500 mg twice daily. The dose of metformin was than the upper limit of the normal range; (8) increased to a maximum dose of 2250 mg once direct bilirubin more than three times higher daily when HbA1c was C 7.0% [13]. The addi- than the upper limit of the normal range, clin- tion of OHAs other than the study drugs and ically abnormal thyroid-stimulating hormone insulin is not permitted in both groups during level, or fasting triglyceride levels [ 7.9 mmol/ the study. L; (9) treatment with any type of antidiabetic drug; (10) dementia, possible dementia, or 1406 Diabetes Ther (2018) 9:1403–1412 Study Variables and Schedule STUDY OUTCOMES The study variables and schedule are shown in The primary study outcome is the difference in Table 1 and Fig. 1. The study period consists of the total OHA-Q ver. 2 score between the two 24 weeks after registration (registration period, treatment groups at the end of the study. The June 2016 to December 2017; full study dura- secondary outcomes are (1) the difference in tion, June 2016 to September 2018). All ran- score for each OHA-Q ver. 2 subscale between domized participants will be followed until the the two treatment groups at the end of the end of the scheduled study, regardless of study; (2) change in total DTR-QOL score and adherence to or discontinuation of the study score for each DTR-QOL domain from baseline medication for any reason. Clinical outcome, to 24 weeks; (3) change in HbA1c from baseline adherence, and adverse events will be ascer- to 24 weeks; (4) differences in the proportion of tained. Clinical and biochemical data are col- patients who achieved HbA1c \ 6.0% or\ 7.0% lected at baseline and 24 weeks after at the end of the study or whose HbA1c levels randomization. Blood samples are obtained improved by more than 0.5% from baseline to after overnight fasting at baseline and 24 weeks 24 weeks; (5) change in fasting glucose levels after randomization. Urinary albumin excretion from baseline to 24 weeks; (6) differences in the is measured by latex agglutination assay using a proportion of patients who achieved HbA1c \ spot urine sample at baseline and 24 weeks after 7.0% and had an improved total DTR-QOL randomization. In addition, participants were score at the end of the study; (7) differences in asked to record usage of their study drug on a the prevalence of hypoglycemic events; (8) dif- medication record during the study period. ferences in the proportion of gastrointestinal symptoms such as nausea, vomiting, and Table 1 Variables and data collection schedule Registration Treatment period Baseline Baseline to week 24 Week 24 Patient characteristics s Body weight ss Blood pressure ss Blood chemistry ss Urinary albumin excretion ss Oral Hypoglycemic Agent Questionnaire, version 2 s Diabetes Therapy-Related Quality of Life questionnaire ss Hypoglycemic events ss s Gastrointestinal events ss s Other adverse events ss s Adherence ss s Includes aspartate aminotransferase, alanine aminotransferase, c-glutamyl transpeptidase, total bilirubin, blood urea nitrogen, creatinine, estimated glomerular filtration rate, uric acid, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, fasting plasma glucose, fasting inulin, HbA1c, amylase, and thyroid- stimulating hormone Diabetes Ther (2018) 9:1403–1412 1407 Fig. 1 Flow chart of the study schedule diarrhea; (9) differences in the proportion of (13 items), anxiety and dissatisfaction with patients with hospitalization for heart failure; treatment (8 items), hypoglycemia (4 items), and (10) differences in the proportion of other and satisfaction with treatment (4 items) adverse effects. (Table 3)[19]. The DTR-QOL can evaluate the effect of diabetes treatment on patient QOL with high reliability and validity [19]. The OHA-Q ver. 2 response to each question is scored using a seven-point Likert-type scale that ranges from 1 The OHA-Q ver. 2 is a 23-item, self-adminis- (strongly agree) to 7 (strongly disagree). The tered assessment with three subscales including scale for items 26–29 is reversed, so that 7 rep- treatment convenience (9 items; questions 1–9), resent the highest QOL score. Domain scores are somatic symptoms (8 items; questions 11–21), calculated by summing the response to the and satisfaction (3 items; questions 10, 22, and items in each domain. Scores are then con- 23) (Table 2)[20]. The response to each ques- verted to a range of 0–100. Higher scores rep- tion is scored using a four-point Likert-type resent higher QOL. In each domain, average scale that ranged from 1 to 4 points. Answers are scores are calculated. converted to scores of 0–3. Subscale scores are calculated by summing the response to the Sample Size items in each subscale. Higher scores represent higher satisfaction. The sample size was not calculated on the basis of scientific evidence because this was an DTR-QOL Questionnaire exploratory study. Assuming a treatment drop- out rate of 10%, the target number of enrolled The DTR-QOL is a 29-item, self-administered patients was set at 22 subjects per group, or 44 assessment with four primary scales including subjects in total. burden on social activities and daily activities 1408 Diabetes Ther (2018) 9:1403–1412 Table 2 Oral Hypoglycemic Agent Questionnaire, version 2 questionnaire and subscale structure Q1. Do you ever forget to take your diabetes medication? (How many times a week?) Q2. Are you concerned about the size of the tablets, difficulty swallowing the tablets, etc., when taking diabetes medication? Q3. Is handling/carrying/preparing to taking diabetes medicine troublesome? Q4. Are you concerned about being seen by others when taking diabetes medication outside of your home? Q5. Is it a burden to eat meals at regular times in order to take diabetes medication? Q6. Is being punctual in taking your diabetes medication and your meals troublesome? Q7. Is it a burden to take diabetes medication at predetermined times? Q8. Is the dosing frequency for diabetes medication a hassle? Q9. Is it difficult to take diabetes medication outside of your home? Q10. Do you want to continue to take your current diabetes medication? Q11. Are you concerned about passing gas or rumbling in your stomach? Q12. Are you concerned about diarrhea? Q13. Are you concerned about constipation? Q14. Are you concerned about weight gain? Q15. Are you concerned about readily becoming hungry? Q16. Are you concerned about having an upset stomach? Q17. Are you concerned about swelling of your body? Q18. Are you worried about hypoglycemia? Q19. Are you concerned about frequent urination? Q20. Are you concerned about thirsty? Q21. Are you concerned about discomfort with urination or genital pruritus? Q22. Are you satisfied with your current blood glucose control? Q23. Are you satisfied with your current treatment with the diabetes medication? The question numbers in the Oral Hypoglycemic Agent Questionnaire, version 2 questionnaire are used in this table Safety Evaluation not associated with the study drug by one of the investigators. All associated AEs that result in the withdrawal of a subject from the study are All adverse effects (AEs) during the study are monitored until resolution. Serious AEs are documented to ensure patient safety. AEs are defined as death or life-threatening events that defined as any untoward medical occurrence in required hospitalization, prolonged existing a clinical trial subject who has received a hospitalization, or resulted in persistent or sig- medicinal product. AEs do not necessarily have nificant disability or incapacity that requires a causal relationship with treatment. The asso- intervention to prevent permanent impairment ciation between AEs and the study medication or damage. is classified as either being associated with or Diabetes Ther (2018) 9:1403–1412 1409 Table 3 Diabetes Therapy-Related QOL questionnaire and domain structure Domain 1: Burden on social activities and daily activities Q1. My current diabetes treatment interferes with my work and activities Q2. My current diabetes treatment limits the scope of my activities Q3. It is difficult to find places on time for my current diabetes treatment Q4. My current diabetes treatment interferes with group activities and personal friendships Q5. It is a burden getting up at a certain time every morning for my current diabetes treatment Q6. With my current diabetes treatment, the restricted meal times are a burden Q7. When I eat out, it is difficult to manage my current diabetes treatment Q8. I feel like my current diabetes treatment takes away the enjoyment of eating Q9. With my current diabetes treatment, it is hard to curb my appetite Q10. The time and effort to manage my current diabetes treatment are a burden Q11. I am constantly concerned about time to manage my current diabetes treatment Q12. Pain due to my current diabetes treatment is uncomfortable Q13. Gastrointestinal symptoms (nausea, passing gas, diarrhea, abdominal pain) due to my current diabetes treatment are uncomfortable Domain 2: Anxiety and dissatisfaction with treatment Q14. I am bothered by weight gain with my current diabetes treatment Q19. I have uncomfortable symptoms due to hyperglycemia (high blood glucose) Q20. I am worried about high blood glucose Q21. I am dissatisfied that my blood glucose is unstable (high and low) Q22. I am worried that complications might worse with my current diabetes treatment Q23. I got anxious thinking about living while on my current diabetes treatment Q24. I find it unbearable to think that even if I continue my current diabetes treatment, my diabetes may not be cured Q25. I am concerned that if I continue my current diabetes treatment, the efficacy (effectiveness) may diminish Domain 3: Hypoglycemia Q15. I worry about low blood glucose due to my current diabetes treatment Q16. I am scared because of low blood glucose Q17. I am sometimes bothered by low blood glucose Q18. Symptoms due to low blood glucose are uncomfortable Domain 4: Satisfaction with treatment Q26. Overall, I am satisfied with my current blood sugar control (glycemic control) Q27. With my current diabetes treatment, I am confident that I can maintain good blood glucose control Q28. I am hopeful about the future with my current diabetes treatment Q29. With regard to diabetes treatment, I am satisfied with current treatment methods The question numbers in the Diabetes Therapy-Related-QOL questionnaire are used in this table 1410 Diabetes Ther (2018) 9:1403–1412 Statistical Analysis ACKNOWLEDGMENTS Efficacy will be analyzed using the full analysis The authors wish to thank the study investiga- data set, except for the safety analysis. To tors for their contributions to this study and the compare the total OHA-Q ver. 2 score and each participants of study. OHA-Q ver. 2 domain score between the two treatment groups at the end of the study, sta- Funding. This study was financially sup- tistical analysis will include Student’s t test and ported by Nippon Boehringer Ingelheim Co., analysis of covariance (ANCOVA) models that Ltd. and Eli Lilly and Company. The article include treatment group as a fixed effect and processing charges and editorial assistance were the allocation factors of age (\ 65 or C 65 years) funded by the authors. All authors have full and gender (male or female) as covariates. To access to all of the data in this study and take compare the changes in total and domain DTR- complete responsibility for the integrity of the QOL scores, HbA1c, and fasting blood glucose data and accuracy of the data analysis. between the two treatment groups at the end of the study, statistical analysis will include Stu- Editorial Assistance. The authors thank all dent’s t test and ANCOVA models that include the clinical staff for their assistance with the treatment group as fixed effects and (1) each execution of the clinical trial, and Soiken Inc. baseline value as a covariate, (2) allocation fac- for their technical assistance in the launch and tors as covariates, and (3) each baseline value execution of this trial. and allocation factors as covariates. For the other variables, comparisons between the Authorship. All named authors meet the groups will be assessed using Student’s t test or International Committee of Medical Journal the Wilcoxon rank-sum test for continuous Editors (ICMJE) criteria for authorship for this variables, and the chi-square test or Fisher’s article, take responsibility for the integrity of exact test for categorical variables. Changes the work as a whole, and have given their from baseline to week 24 within a treatment approval for this version to be published. group will be assessed with the one-sample t test Disclosures. Tomoya Mita has received or Wilcoxon signed-rank test. The correlation between total OHA-Q ver. 2 score at the end of research funds from MSD K.K. and Takeda Pharmaceutical Co., Ltd., Kowa Pharmaceutical study or change in DTR-QOL score from base- line to 24 weeks will be evaluated using Pear- Co., Ltd., Sanwa Kagaku Kenkyusho Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Mit- son’s and Spearman’s correlation coefficients. All statistical tests will be two-sided with a sig- subishi Tanabe Pharma Co., and Ono Pharma- ceutical Co., Ltd. and lecture fees from nificance level of 5%. All analyses will be per- formed using SAS software, version 9.4 (SAS AstraZeneca K.K., Nippon Boehringer Ingelheim Co., Ltd., Eli Lilly and Company, Kowa Phar- Institute, Cary, NC). The statistical analysis plan maceutical Co., Ltd., Mitsubishi Tanabe Pharma will be written by an independent statistician. Co., MSD K.K., Ono Pharmaceutical Co., Ltd., Novo Nordisk Pharma Ltd., and Takeda Phar- Strengths and Limitations of Study maceutical Co., Ltd. Junko Sato has received Protocol research funds from research funds from MSD K.K. and Takeda Pharmaceutical Co., Ltd., Kowa The strength is a prospective, randomized, Pharmaceutical Co., Ltd., Sanwa Kagaku Ken- open-label, multicenter, parallel-group, com- kyusho Co., Ltd., Nippon Boehringer Ingelheim parative trial design. In addition, two ques- Co., Ltd., Mitsubishi Tanabe Pharma Co., and tionnaires for evaluating QOL used in this study Ono Pharmaceutical Co., Ltd. Hirotaka Watada are valid. On the other hand, the limitations are has received honoraria for scientific lectures the small number of participants and the open- from MSD K.K., Eli Lilly and Company, Takeda label, exploratory trial design. Pharmaceutical Co., Ltd., Novartis Pharma K.K., Diabetes Ther (2018) 9:1403–1412 1411 Diabetes Society. J Diabetes investig. Sumitomo Dainippon Pharma Co., Ltd., Sanofi 2017;8(1):123–5. K.K., and Daiichi Sankyo Co., Ltd., and research funds from MSD K.K., Eli Lilly and Company, 2. Papazafiropoulou AK, Bakomitrou F, Trikallinou A, Takeda Pharmaceutical Co., Ltd., Kowa Phar- et al. Diabetes-dependent quality of life (ADDQOL) and affecting factors in patients with diabetes mel- maceutical Co., Ltd., Mochida Pharmaceutical litus type 2 in Greece. BMC Res Notes. 2015;8:786. 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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

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Diabetes Ther (2018) 9:1403–1412 https://doi.org/10.1007/s13300-018-0437-x STUDY PROTOCOL 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 . . . . Tomoya Mita Toru Hiyoshi Hidenori Yoshii Hiroko Chimori . . Kazuo Ikeda Junko Sato Hirotaka Watada Received: April 18, 2018 / Published online: May 9, 2018 The Author(s) 2018 related QOL when used as first-line therapy in ABSTRACT patients with type 2 diabetes mellitus. Methods: This study is a prospective, random- Introduction: Consideration of treatment-re- ized, open-label, multicenter, parallel-group, lated quality of life (QOL) is important in dia- comparative study. Between June 2016 and betes management. However, no studies have December 2017, 44 participants who failed to compared the influence of dipeptidyl peptidase- achieve glycemic control despite diet and exer- 4 inhibitors versus metformin on treatment- cise therapy were recruited at 14 clinics and randomly allocated to linagliptin or metformin therapy. Treatment-related QOL was assessed Enhanced digital features To view enhanced digital features for this article go to https://doi.org/10.6084/ with the Oral Hypoglycemic Agent Question- m9.figshare.6200750. naire, version 2 (OHA-Q ver. 2) and the self- administered Diabetes Therapy-Related QOL T. Mita (&)  H. Watada (DTR-QOL) questionnaire. The primary study Department of Metabolism and Endocrinology, outcome is the difference in total OHA-Q ver. 2 Juntendo University Graduate School of Medicine, score between the two treatment groups at the Bunkyo-ku, Tokyo, Japan e-mail: tom-m@juntendo.ac.jp end of the study. The secondary outcomes include differences in the scores for each OHA- T. Hiyoshi Q ver. 2 subscale between the two treatment Division of Diabetes and Endocrinology, Japanese groups at the end of the study, change in total Red Cross Medical Center, Shibuya-ku, Tokyo, Japan DTR-QOL score and for each domain from H. Yoshii baseline to the end of treatment, changes in Department of Medicine, Diabetology and glycemic control, and adverse events. Endocrinology, Juntendo Tokyo Koto Geriatric Medical Center, Koto-ku, Tokyo, Japan Planned outcome: The present study is designed to assess the effects of linagliptin on H. Chimori the treatment-related QOL. Results will be Chimori Medical Clinic, Fukushima-ku, Osaka, available in the near future. Study findings are Osaka, Japan expected to provide useful information on how K. Ikeda to maintain or improve QOL in patients with Ikeda Shinryojyo, Higashiosaka, Osaka, Japan type 2 diabetes mellitus treated with insulin. J. Sato Funding: Nippon Boehringer Ingelheim Co., Department of Diabetes, Endocrinology and Ltd. and Eli Lilly and Company. Metabolism, Juntendo University Shizuoka Clinical trial registration: UMIN000022953. Hospital, Izunokuni, Shizuoka, Japan 1404 Diabetes Ther (2018) 9:1403–1412 Keywords: Linagliptin; Metformin; negatively affect patient adherence to therapy. Questionnaire; Treatment-related quality of These characteristics of metformin might life; Type 2 diabetes mellitus reduce treatment-related QOL. Conversely, the Japan Diabetes Society treatment guidelines recommend choosing INTRODUCTION suitable therapies in line with the dominant pathophysiological condition of each patient, One of the main objectives of diabetes man- such as insufficient insulin secretion or insulin agement is to maintain quality of life (QOL) by resistance [13], because T2DM in East Asians is preventing development or progression of more strongly associated with beta cell dys- complications [1]. In patients with type 2 dia- function than insulin resistance and adiposity betes mellitus (T2DM), advanced age, poor gly- [14]. In this context, various types of OHAs, cemic control, previous hypoglycemic episodes, including metformin and dipeptidyl peptidase and complex therapies are associated with lower (DPP)-4 inhibitors, are chosen as first-line ther- QOL [2–5]. On the other hand, intensive fre- apy in Japan [15]. quency of follow-up was associated with DPP-4 inhibitors such as linagliptin enhance improvements of QOL [6]. Given that decreased glucose-dependent insulin secretion from pan- treatment-related QOL is associated with creatic beta cells via inhibiting the degradation reduced patient motivation and adherence to of active incretins by DPP-4. In general, DPP-4 treatment in patients with T2DM [7], consider- inhibitors are safe and well tolerated and do not ation of treatment-related QOL is important cause weight gain [16]. Sitagliptin was shown to when choosing oral anti-hypoglycemic agents improve QOL in a single arm-study [17]. Owing (OHAs). to these characteristics, DPP-4 inhibitors are Treatment guidelines by the American Dia- now the most frequently prescribed first-line betes Association and European Association for agents for T2DM in Japan [18]. the Study of Diabetes recommend metformin as In this study, to investigate how these first-line therapy when lifestyle modification treatment regimens affect QOL of patients with alone fails to achieve or maintain optimal gly- T2DM, we evaluated the effect of linagliptin cemic goals [8]. Metformin reduces blood glu- versus metformin on treatment-related QOL cose levels by improving insulin sensitivity, using the Oral Hypoglycemic Agent Question- mainly in the liver. Metformin has an estab- naire, version 2 (OHA-Q ver. 2) and the self- lished evidence base showing that it is effica- administered Diabetes Therapy-Related QOL cious in lowering blood glucose levels without (DTR-QOL) questionnaire [19]. Although these increasing the risk of hypoglycemia, with questionnaires are newly developed, they are weight neutrality or loss. In addition, met- valid [19, 20]. formin is generally safe, well tolerated, and inexpensive [9]. Metformin might also reduce MATERIALS AND METHODS the incidence of cardiovascular events and improve survival [10]. However, a recent meta- Study Design analysis demonstrated that adherence to met- formin was worse than for other OHAs such as sulfonylureas and thiazolidinediones [11]. In The Initial choice of DPP-4 inhibitor in Japanese this regard, the most common adverse effects of T2DM patients: Effect of Linagliptin on QOL metformin are gastrointestinal effects, such as (INTEL-QOL) study is a prospective, random- nausea, vomiting, and diarrhea [12]. These ized, open-label, multicenter, parallel-group, symptoms might reduce patient adherence to comparative trial. This study is planned solely metformin treatment. In addition, given that a to evaluate the QOL. This study has been reg- sustained release preparation of metformin is istered on the University Hospital Medical not available in all countries, the need to take Information Network Clinical Trials Registry metformin more than twice daily may (UMIN-CTR), a non-profit organization in Japan Diabetes Ther (2018) 9:1403–1412 1405 that meets the requirements of the Interna- mental disorder; (11) insufficient judgment tional Committee of Medical Journal Editors ability or illiteracy; (12) requiring consent for (ICMJE) (UMIN000022953). study participation from a legal representative; (13) pregnancy, lactation, possibly pregnancy, or planning to become pregnant during the Study Population study period; (14) history of hypersensitivity to investigational drugs; (15) present or past his- Japanese patients with T2DM who regularly tory of a malignant tumor, unless there was no attended the outpatient diabetes clinics of 14 current medical therapy, no recurrence to date, institutions (Chimori Clinic, Ikeda Clinic, and no risk of recurrence during this study; and Yamamoto Clinic, Japanese Red Cross Medical (16) judged as ineligible by the clinical Center, Juntendo Tokyo Koto Geriatric Medical investigators. Center (Department of Medicine, Diabetology The subjects were screened consecutively. and Endocrinology), Juntendo University Patients that met the above eligibility criteria Graduate School of Medicine (Department of were asked to participate in the present study. Metabolism and Endocrinology), Juntendo All patients who agreed to participate were University Shizuoka Hospital (Department of enrolled in the study. The protocol has been Diabetes, Endocrinology, and Metabolism), approved by the institutional review board of Sawaki Internal Medicine and Diabetes Clinic, each participating institution in compliance Shimizu Clinic, Tanaka Clinic, Menju Clinic, with the Declaration of Helsinki and current Misaki Naika Clinic, Musashino Family Clinic, legal regulations in Japan. All procedures fol- and Yasuda Clinic) in Japan were asked to par- lowed were in accordance with the ethical ticipate in this study. The inclusion criteria are standards of the responsible committee on as follows: (1) T2DM not at target blood glucose human experimentation (institutional and control as specified in the Treatment Guide for national) and with the 1964 Declaration of Diabetes by the Japan Diabetes Society [13] Helsinki, as revised in 2013. Informed consent despite the introduction of diet and/or exercise was obtained from all patients for being inclu- therapy; (2) patients who are considered to ded in the study. newly initiate OHAs in addition to dietary and/ or exercise therapy; (3) age C 20 years Randomization and Study Intervention and \ 75 years, regardless of gender; and (4) written informed consent for study participa- tion. The following exclusion criteria are used: Patients were registered at the INTEL-QOL trial’s (1) type 1 or secondary diabetes; (2) acute dia- administration office via the internet. Once betic complications within the past 6 months; enrolled, patients were randomly assigned to (3) congestive heart failure or myocardial either the linagliptin group or the metformin infarction requiring pharmacotherapy; (4) group. Randomization was performed using a unstable angina pectoris or coronary bypass dynamic allocation method based on age (\ 65 surgery within the past 6 months; (5) chronic or C 65 years) and gender (male or female). cirrhosis or chronic active hepatitis; (6) artificial Patients in the linagliptin group were started dialysis or moderate renal dysfunction; (7) on linagliptin 5 mg once daily. Patients in the aspartate aminotransferase or alanine amino- metformin group were started on metformin transferase levels more than three times higher 500 mg twice daily. The dose of metformin was than the upper limit of the normal range; (8) increased to a maximum dose of 2250 mg once direct bilirubin more than three times higher daily when HbA1c was C 7.0% [13]. The addi- than the upper limit of the normal range, clin- tion of OHAs other than the study drugs and ically abnormal thyroid-stimulating hormone insulin is not permitted in both groups during level, or fasting triglyceride levels [ 7.9 mmol/ the study. L; (9) treatment with any type of antidiabetic drug; (10) dementia, possible dementia, or 1406 Diabetes Ther (2018) 9:1403–1412 Study Variables and Schedule STUDY OUTCOMES The study variables and schedule are shown in The primary study outcome is the difference in Table 1 and Fig. 1. The study period consists of the total OHA-Q ver. 2 score between the two 24 weeks after registration (registration period, treatment groups at the end of the study. The June 2016 to December 2017; full study dura- secondary outcomes are (1) the difference in tion, June 2016 to September 2018). All ran- score for each OHA-Q ver. 2 subscale between domized participants will be followed until the the two treatment groups at the end of the end of the scheduled study, regardless of study; (2) change in total DTR-QOL score and adherence to or discontinuation of the study score for each DTR-QOL domain from baseline medication for any reason. Clinical outcome, to 24 weeks; (3) change in HbA1c from baseline adherence, and adverse events will be ascer- to 24 weeks; (4) differences in the proportion of tained. Clinical and biochemical data are col- patients who achieved HbA1c \ 6.0% or\ 7.0% lected at baseline and 24 weeks after at the end of the study or whose HbA1c levels randomization. Blood samples are obtained improved by more than 0.5% from baseline to after overnight fasting at baseline and 24 weeks 24 weeks; (5) change in fasting glucose levels after randomization. Urinary albumin excretion from baseline to 24 weeks; (6) differences in the is measured by latex agglutination assay using a proportion of patients who achieved HbA1c \ spot urine sample at baseline and 24 weeks after 7.0% and had an improved total DTR-QOL randomization. In addition, participants were score at the end of the study; (7) differences in asked to record usage of their study drug on a the prevalence of hypoglycemic events; (8) dif- medication record during the study period. ferences in the proportion of gastrointestinal symptoms such as nausea, vomiting, and Table 1 Variables and data collection schedule Registration Treatment period Baseline Baseline to week 24 Week 24 Patient characteristics s Body weight ss Blood pressure ss Blood chemistry ss Urinary albumin excretion ss Oral Hypoglycemic Agent Questionnaire, version 2 s Diabetes Therapy-Related Quality of Life questionnaire ss Hypoglycemic events ss s Gastrointestinal events ss s Other adverse events ss s Adherence ss s Includes aspartate aminotransferase, alanine aminotransferase, c-glutamyl transpeptidase, total bilirubin, blood urea nitrogen, creatinine, estimated glomerular filtration rate, uric acid, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, fasting plasma glucose, fasting inulin, HbA1c, amylase, and thyroid- stimulating hormone Diabetes Ther (2018) 9:1403–1412 1407 Fig. 1 Flow chart of the study schedule diarrhea; (9) differences in the proportion of (13 items), anxiety and dissatisfaction with patients with hospitalization for heart failure; treatment (8 items), hypoglycemia (4 items), and (10) differences in the proportion of other and satisfaction with treatment (4 items) adverse effects. (Table 3)[19]. The DTR-QOL can evaluate the effect of diabetes treatment on patient QOL with high reliability and validity [19]. The OHA-Q ver. 2 response to each question is scored using a seven-point Likert-type scale that ranges from 1 The OHA-Q ver. 2 is a 23-item, self-adminis- (strongly agree) to 7 (strongly disagree). The tered assessment with three subscales including scale for items 26–29 is reversed, so that 7 rep- treatment convenience (9 items; questions 1–9), resent the highest QOL score. Domain scores are somatic symptoms (8 items; questions 11–21), calculated by summing the response to the and satisfaction (3 items; questions 10, 22, and items in each domain. Scores are then con- 23) (Table 2)[20]. The response to each ques- verted to a range of 0–100. Higher scores rep- tion is scored using a four-point Likert-type resent higher QOL. In each domain, average scale that ranged from 1 to 4 points. Answers are scores are calculated. converted to scores of 0–3. Subscale scores are calculated by summing the response to the Sample Size items in each subscale. Higher scores represent higher satisfaction. The sample size was not calculated on the basis of scientific evidence because this was an DTR-QOL Questionnaire exploratory study. Assuming a treatment drop- out rate of 10%, the target number of enrolled The DTR-QOL is a 29-item, self-administered patients was set at 22 subjects per group, or 44 assessment with four primary scales including subjects in total. burden on social activities and daily activities 1408 Diabetes Ther (2018) 9:1403–1412 Table 2 Oral Hypoglycemic Agent Questionnaire, version 2 questionnaire and subscale structure Q1. Do you ever forget to take your diabetes medication? (How many times a week?) Q2. Are you concerned about the size of the tablets, difficulty swallowing the tablets, etc., when taking diabetes medication? Q3. Is handling/carrying/preparing to taking diabetes medicine troublesome? Q4. Are you concerned about being seen by others when taking diabetes medication outside of your home? Q5. Is it a burden to eat meals at regular times in order to take diabetes medication? Q6. Is being punctual in taking your diabetes medication and your meals troublesome? Q7. Is it a burden to take diabetes medication at predetermined times? Q8. Is the dosing frequency for diabetes medication a hassle? Q9. Is it difficult to take diabetes medication outside of your home? Q10. Do you want to continue to take your current diabetes medication? Q11. Are you concerned about passing gas or rumbling in your stomach? Q12. Are you concerned about diarrhea? Q13. Are you concerned about constipation? Q14. Are you concerned about weight gain? Q15. Are you concerned about readily becoming hungry? Q16. Are you concerned about having an upset stomach? Q17. Are you concerned about swelling of your body? Q18. Are you worried about hypoglycemia? Q19. Are you concerned about frequent urination? Q20. Are you concerned about thirsty? Q21. Are you concerned about discomfort with urination or genital pruritus? Q22. Are you satisfied with your current blood glucose control? Q23. Are you satisfied with your current treatment with the diabetes medication? The question numbers in the Oral Hypoglycemic Agent Questionnaire, version 2 questionnaire are used in this table Safety Evaluation not associated with the study drug by one of the investigators. All associated AEs that result in the withdrawal of a subject from the study are All adverse effects (AEs) during the study are monitored until resolution. Serious AEs are documented to ensure patient safety. AEs are defined as death or life-threatening events that defined as any untoward medical occurrence in required hospitalization, prolonged existing a clinical trial subject who has received a hospitalization, or resulted in persistent or sig- medicinal product. AEs do not necessarily have nificant disability or incapacity that requires a causal relationship with treatment. The asso- intervention to prevent permanent impairment ciation between AEs and the study medication or damage. is classified as either being associated with or Diabetes Ther (2018) 9:1403–1412 1409 Table 3 Diabetes Therapy-Related QOL questionnaire and domain structure Domain 1: Burden on social activities and daily activities Q1. My current diabetes treatment interferes with my work and activities Q2. My current diabetes treatment limits the scope of my activities Q3. It is difficult to find places on time for my current diabetes treatment Q4. My current diabetes treatment interferes with group activities and personal friendships Q5. It is a burden getting up at a certain time every morning for my current diabetes treatment Q6. With my current diabetes treatment, the restricted meal times are a burden Q7. When I eat out, it is difficult to manage my current diabetes treatment Q8. I feel like my current diabetes treatment takes away the enjoyment of eating Q9. With my current diabetes treatment, it is hard to curb my appetite Q10. The time and effort to manage my current diabetes treatment are a burden Q11. I am constantly concerned about time to manage my current diabetes treatment Q12. Pain due to my current diabetes treatment is uncomfortable Q13. Gastrointestinal symptoms (nausea, passing gas, diarrhea, abdominal pain) due to my current diabetes treatment are uncomfortable Domain 2: Anxiety and dissatisfaction with treatment Q14. I am bothered by weight gain with my current diabetes treatment Q19. I have uncomfortable symptoms due to hyperglycemia (high blood glucose) Q20. I am worried about high blood glucose Q21. I am dissatisfied that my blood glucose is unstable (high and low) Q22. I am worried that complications might worse with my current diabetes treatment Q23. I got anxious thinking about living while on my current diabetes treatment Q24. I find it unbearable to think that even if I continue my current diabetes treatment, my diabetes may not be cured Q25. I am concerned that if I continue my current diabetes treatment, the efficacy (effectiveness) may diminish Domain 3: Hypoglycemia Q15. I worry about low blood glucose due to my current diabetes treatment Q16. I am scared because of low blood glucose Q17. I am sometimes bothered by low blood glucose Q18. Symptoms due to low blood glucose are uncomfortable Domain 4: Satisfaction with treatment Q26. Overall, I am satisfied with my current blood sugar control (glycemic control) Q27. With my current diabetes treatment, I am confident that I can maintain good blood glucose control Q28. I am hopeful about the future with my current diabetes treatment Q29. With regard to diabetes treatment, I am satisfied with current treatment methods The question numbers in the Diabetes Therapy-Related-QOL questionnaire are used in this table 1410 Diabetes Ther (2018) 9:1403–1412 Statistical Analysis ACKNOWLEDGMENTS Efficacy will be analyzed using the full analysis The authors wish to thank the study investiga- data set, except for the safety analysis. To tors for their contributions to this study and the compare the total OHA-Q ver. 2 score and each participants of study. OHA-Q ver. 2 domain score between the two treatment groups at the end of the study, sta- Funding. This study was financially sup- tistical analysis will include Student’s t test and ported by Nippon Boehringer Ingelheim Co., analysis of covariance (ANCOVA) models that Ltd. and Eli Lilly and Company. The article include treatment group as a fixed effect and processing charges and editorial assistance were the allocation factors of age (\ 65 or C 65 years) funded by the authors. All authors have full and gender (male or female) as covariates. To access to all of the data in this study and take compare the changes in total and domain DTR- complete responsibility for the integrity of the QOL scores, HbA1c, and fasting blood glucose data and accuracy of the data analysis. between the two treatment groups at the end of the study, statistical analysis will include Stu- Editorial Assistance. The authors thank all dent’s t test and ANCOVA models that include the clinical staff for their assistance with the treatment group as fixed effects and (1) each execution of the clinical trial, and Soiken Inc. baseline value as a covariate, (2) allocation fac- for their technical assistance in the launch and tors as covariates, and (3) each baseline value execution of this trial. and allocation factors as covariates. For the other variables, comparisons between the Authorship. All named authors meet the groups will be assessed using Student’s t test or International Committee of Medical Journal the Wilcoxon rank-sum test for continuous Editors (ICMJE) criteria for authorship for this variables, and the chi-square test or Fisher’s article, take responsibility for the integrity of exact test for categorical variables. Changes the work as a whole, and have given their from baseline to week 24 within a treatment approval for this version to be published. group will be assessed with the one-sample t test Disclosures. Tomoya Mita has received or Wilcoxon signed-rank test. The correlation between total OHA-Q ver. 2 score at the end of research funds from MSD K.K. and Takeda Pharmaceutical Co., Ltd., Kowa Pharmaceutical study or change in DTR-QOL score from base- line to 24 weeks will be evaluated using Pear- Co., Ltd., Sanwa Kagaku Kenkyusho Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Mit- son’s and Spearman’s correlation coefficients. All statistical tests will be two-sided with a sig- subishi Tanabe Pharma Co., and Ono Pharma- ceutical Co., Ltd. and lecture fees from nificance level of 5%. All analyses will be per- formed using SAS software, version 9.4 (SAS AstraZeneca K.K., Nippon Boehringer Ingelheim Co., Ltd., Eli Lilly and Company, Kowa Phar- Institute, Cary, NC). The statistical analysis plan maceutical Co., Ltd., Mitsubishi Tanabe Pharma will be written by an independent statistician. Co., MSD K.K., Ono Pharmaceutical Co., Ltd., Novo Nordisk Pharma Ltd., and Takeda Phar- Strengths and Limitations of Study maceutical Co., Ltd. Junko Sato has received Protocol research funds from research funds from MSD K.K. and Takeda Pharmaceutical Co., Ltd., Kowa The strength is a prospective, randomized, Pharmaceutical Co., Ltd., Sanwa Kagaku Ken- open-label, multicenter, parallel-group, com- kyusho Co., Ltd., Nippon Boehringer Ingelheim parative trial design. In addition, two ques- Co., Ltd., Mitsubishi Tanabe Pharma Co., and tionnaires for evaluating QOL used in this study Ono Pharmaceutical Co., Ltd. Hirotaka Watada are valid. On the other hand, the limitations are has received honoraria for scientific lectures the small number of participants and the open- from MSD K.K., Eli Lilly and Company, Takeda label, exploratory trial design. Pharmaceutical Co., Ltd., Novartis Pharma K.K., Diabetes Ther (2018) 9:1403–1412 1411 Diabetes Society. J Diabetes investig. Sumitomo Dainippon Pharma Co., Ltd., Sanofi 2017;8(1):123–5. K.K., and Daiichi Sankyo Co., Ltd., and research funds from MSD K.K., Eli Lilly and Company, 2. Papazafiropoulou AK, Bakomitrou F, Trikallinou A, Takeda Pharmaceutical Co., Ltd., Kowa Phar- et al. Diabetes-dependent quality of life (ADDQOL) and affecting factors in patients with diabetes mel- maceutical Co., Ltd., Mochida Pharmaceutical litus type 2 in Greece. BMC Res Notes. 2015;8:786. Co., Ltd., Sanwa Kagaku Kenkyusho Co., Ltd., Novo Nordisk Pharma Ltd., Kissei Pharmaceu- 3. Yfantopoulos J, Hatzikou M, Rombopoulos G, tical Co., Ltd., Novartis Pharma K.K., Nippon Panitti E, Latsou D. The prevalence of hypo- glycemia and its impact on the quality of life of Boehringer Ingelheim Co., Ltd., AstraZeneca type 2 diabetes mellitus patients in Greece (the K.K., Astellas Pharma Inc., Mitsubishi Tanabe Hypo study). Value Health. 2014;17(7):A356. Pharma Co., Sumitomo Dainippon Pharma Co., Ltd., Abbott Japan Co., Ltd., Sanofi K.K., Pfizer 4. Depablos-Velasco P, Salguero-Chaves E, Mata-Poyo J, Derivas-Otero B, Garcia-Sanchez R, Viguera-Ester Japan Inc., and Daiichi Sankyo Co., Ltd. Toru P. Quality of life and satisfaction with treatment in Hiyoshi, Hidenori Yoshii, Hiroko Chimori, and subjects with type 2 diabetes: results in Spain of the Kazuo Ikeda have nothing to disclose. PANORAMA study. Endocrinol Nutr. 2014;61(1):18–26. Compliance with Ethics Guidelines. The 5. Imayama I, Plotnikoff RC, Courneya KS, Johnson protocol has been approved by the institutional JA. Determinants of quality of life in adults with review board of each participating institution in type 1 and type 2 diabetes. Health Qual Life Out- compliance with the Declaration of Helsinki comes. 2011;9:115. and current legal regulations in Japan. All pro- 6. Hu M, Zhou Z, Zeng F, Sun Z. Effects of frequency of cedures followed were in accordance with the follow-up on quality of life of type 2 diabetes ethical standards of the responsible committee patients on oral hypoglycemics. Diabetes Technol on human experimentation (institutional and Ther. 2012;14(9):777–82. national) and with the Helsinki Declaration of 7. Ishii H, Anderson JH Jr, Yamamura A, Takeuchi M, 1964, as revised in 2013. Informed consent was Ikeda I. Improvement of glycemic control and obtained from all patients for being included in quality-of-life by insulin lispro therapy: assessing the study. benefits by ITR-QOL questionnaires. Diabetes Res Clin Pract. 2008;81(2):169–78. Data Availability. The analyzed data sets 8. Inzucchi SE, Bergenstal RM, Buse JB, et al. Man- are available from the corresponding author on agement of hyperglycemia in type 2 diabetes, 2015: reasonable request. a patient-centered approach: update to a position statement of the American Diabetes Association Open Access. This article is distributed and the European Association for the Study of Diabetes. Diabetes Care. 2015;38(1):140–9. under the terms of the Creative Commons Attribution-NonCommercial 4.0 International 9. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil License (http://creativecommons.org/licenses/ HA. 10-year follow-up of intensive glucose control by-nc/4.0/), which permits any noncommer- in type 2 diabetes. 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Journal

Diabetes TherapySpringer Journals

Published: May 9, 2018

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