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A Randomized Pilot Study of the Effect of Trelagliptin and Alogliptin on Glycemic Variability in Patients with Type 2 Diabetes

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A Randomized Pilot Study of the Effect of Trelagliptin and Alogliptin on Glycemic Variability in Patients with Type 2 Diabetes Adv Ther (2019) 36:3096–3109 https://doi.org/10.1007/s12325-019-01097-z ORIGINAL RESEARCH A Randomized Pilot Study of the Effect of Trelagliptin and Alogliptin on Glycemic Variability in Patients with Type 2 Diabetes Rimei Nishimura . Takeshi Osonoi . Yasuhiro Koike . Kouji Miyata . Yukio Shimasaki Received: August 9, 2019 / Published online: September 27, 2019 Ó The Author(s) 2019 ABSTRACT (day 22–28) of the treatment period. Secondary and additional efficacy endpoints included Introduction: This open-label, parallel-group, changes in glycemic parameters and the rate of exploratory study examined the effects of two DPP4 inhibition, respectively. Adverse events dipeptidyl peptidase 4 (DPP4) inhibitors on (AEs) were monitored to assess safety. glycemic variability (GV) in patients with type 2 Results: Mean change from baseline in the SD diabetes. of 24-h blood glucose (95% confidence interval) Methods: Randomized patients with glycated at day 28 was - 7.35 (- 15.13, 0.44) for tre- hemoglobin A1c of at least 6.5% to less than lagliptin and - 11.63 (- 18.67, - 4.59) for 8.5% received trelagliptin 100 mg (n = 13) once alogliptin. In both treatment groups, glycemic weekly or alogliptin 25 mg (n = 14) once daily parameters improved and the rate of DPP4 for 29 days. Continuous glucose monitoring inhibition was maintained. Three patients was performed before the start of the treatment reported AEs; no severe treatment-emergent AEs period (baseline) and from day 21 to 29, inclu- were reported in either group. sive. The primary endpoint was change from Conclusion: Once-weekly trelagliptin and baseline in the standard deviation (SD) of 24-h once-daily alogliptin improved glycemic con- blood glucose values, measured daily for 7 days trol and reduced GV without inducing hypoglycemia. Trial Registration: ClinicalTrials.gov (NCT027 Enhanced Digital Features To view enhanced digital 71093) and JAPIC (JapicCTI-163250). features for this article go to https://doi.org/10.6084/ m9.figshare.9805409. Funding: Takeda Pharmaceutical Company, Ltd. R. Nishimura Department of Diabetes, Metabolism and Keywords: Alogliptin; Continuous glucose Endocrinology, Jikei University School of Medicine, monitoring; Dipeptidyl peptidase 4 inhibitors; Minato-ku, Tokyo, Japan Efficacy; Glycemic variability; Hypoglycemia; T. Osonoi Safety; Trelagliptin; Type 2 diabetes Department of Internal Medicine, Nakakinen Clinic, Naka-city, Ibaraki, Japan Y. Koike Á K. Miyata (&) Á Y. Shimasaki INTRODUCTION Japan Medical Affairs, Japan Pharma Business Unit, Takeda Pharmaceutical Company Limited, The worldwide prevalence of diabetes mellitus Chuo-ku, Tokyo, Japan e-mail: [email protected] (DM) in adults was estimated to be 8.4% in 2017 Adv Ther (2019) 36:3096–3109 3097 and was predicted to rise to 9.9% in 2045 [1], patients with T2DM [15]. Trelagliptin is an oral which is similar to the estimated rise in preva- antidiabetic medication that inhibits DPP4 and lence in Japan (7.7% in 2017 to 8.3% in 2045) improves glycemic control in patients with [2]. The primary goal of diabetes treatment is to diabetes [16]. Unlike early DPP4 inhibitors, achieve optimal glycemic control [3]. Glycemic which are administered once or twice daily, control is currently assessed using the most trelagliptin is administered once weekly [17]. common marker, glycated hemoglobin A1c However, despite the less frequent dosing, a (HbA1c), which closely correlates with the phase 3 clinical study in patients with T2DM average plasma glucose level over a preceding 8- demonstrated that the efficacy of once-weekly to 12-week period [4], as well as fasting blood trelagliptin was non-inferior to that of once- glucose in a clinical setting. Although HbA1c daily alogliptin in lowering HbA1c [18]. provides a reliable measure of long-term gly- Although various oral hypoglycemic agents cemic control and chronic hyperglycemia [5], have been evaluated in Japan using the Guide- there is evidence to suggest that glycemic vari- line for Clinical Evaluation of Oral Hypo- ability (GV) may contribute independently to glycemic Agents [19], the effects of these agents, diabetes-related complications [3, 6–9]. GV including alogliptin and trelagliptin, on GV measured by standard deviation (SD) reflects have not been investigated. Therefore, the pre- blood glucose oscillations that occur through- sent exploratory pilot study was undertaken to out the day, including hypoglycemic and post- investigate the effect of trelagliptin 100 mg once prandial increases, and variability between daily weekly and alogliptin 25 mg once daily on GV means that are unlikely to be captured by in patients with T2DM. HbA1c or fasting blood glucose measurements [3, 10]. Evidence from some studies suggests that, METHODS similar to chronic hyperglycemia [11], long- term high GV may increase the risk of Study Design microvascular and macrovascular complications associated with type 2 DM (T2DM) [8, 9], while This was a randomized, open-label, parallel- severe hypoglycemia is associated with group, exploratory study that evaluated the increased mortality [6, 7]. Although the precise effect of trelagliptin 100 mg administered once mechanism by which GV may adversely affect weekly or alogliptin 25 mg administered once cardiovascular risk is not fully understood, some daily for 4 weeks. GV was assessed in patients evidence suggests that acute GV increases with T2DM using continuous glucose monitor- oxidative stress [12] and endothelial dysfunc- ing (CGM) (Fig. 1). An assigned person gener- tion [13], both of which may contribute to the ated the allocation list. Allocation was development of cardiovascular complications. conducted at the enrollment center using a web GV has also been strongly associated with case enrollment system on day 1. Eligible increased incidence of hypoglycemia [10], as patients were randomized 1:1 using the alloca- well as contributing to increased mean blood tion list to receive either trelagliptin 100 mg or glucose values [3]. alogliptin 25 mg, stratified by baseline HbA1c Dipeptidyl peptidase 4 (DPP4) inhibitors are (less than 7.5% or at least 7.5%) and age (less antidiabetic agents that bind to the enzyme than 65 or at least 65 years). Randomization was DPP4 to inhibit the degradation of the incretins, preceded by a 2-day observation period, fol- glucagon-like peptide 1 (GLP-1), and glucose- lowed by a 29-day treatment period. All proce- dependent insulinotropic polypeptide (GIP), dures performed in studies involving human both of which play key roles in glucose home- participants were in accordance with the ethical ostasis and glycemic control [14]. By prolonging standards of the institutional and/or national the activity of endogenous GLP-1 and GIP, DPP4 research committee and with the 1964 Helsinki inhibitors can improve postprandial hyper- declaration and its later amendments or com- glycemia, without inducing hypoglycemia, in parable ethical standards. Informed consent was 3098 Adv Ther (2019) 36:3096–3109 Fig. 1 Study design. CGM continuous glucose monitoring obtained from all individual participants inclu- antidiabetic medications within 4 weeks of the ded in the study. The study protocol, informed start of the observation period, or patients who consent form, and other regulation-specified changed (including discontinuation or inter- documents were reviewed and approved by the ruption) 3-hydroxy-3-methylglutaryl-coenzyme Independent Ethics Committees at Nakakinen A (HMG-CoA) reductase inhibitors or received Clinic. The study was conducted between June new HMG-CoA reductase inhibitors within 2016 and April 2017 at two study sites (medical 4 weeks before the start of the observation per- institutions) in Japan, and is registered at Clin- iod. Concomitant use of medications that may icalTrials.gov (NCT02771093) and JAPIC affect efficacy evaluation was prohibited (JapicCTI-163250). The study was registered on throughout the duration of the study; these May 11, 2016. included antidiabetic medications other than the allocated study drugs, systemic glucocorti- Participants coids (excluding local/topical preparations), estrogen preparations, HMG-CoA reductase Patient eligibility criteria included patients aged inhibitors other than those used at the time of at least 20 years old with T2DM, HbA1c (Na- informed consent, and acetaminophen. tional Glycohemoglobin Standardization Pro- During CGM, patients presented pho- gram value) of at least 6.5% and less than 8.5%, tographs of their meals to allow the investigator and stable glycemic control with at most 1% to monitor patient compliance to diet therapy. change in HbA1c at the start of the observation period [day - 2 (visit 1)] vs the preceding CGM 6 weeks. Patients must have been receiving stable diet and exercise therapy (if required) for CGM was conducted using Medtronic iProÒ2 at least 4 weeks before the start of the observa- (Medtronic MiniMed, Inc. Northridge, CA, tion period (day - 2). Key exclusion criteria USA), and was performed for 2 days during the included patients who were receiving observation period and 9 days (day 21–29) Adv Ther (2019) 36:3096–3109 3099 during the treatment period (Fig. 1). Patients Statistical Analyses calibrated their CGM during the observation and treatment periods by measuring their daily The planned sample size of 30 patients was blood glucose levels at a minimum of three time determined with consideration of the feasibility points on the first day of the CGM (at least 2 h of performing CGM in numerous patients, and after the recorder was connected,
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