Diabetes Ther (2018) 9:1083–1097 https://doi.org/10.1007/s13300-018-0416-2 ORIGINAL RESEARCH Safety and Efﬁcacy of Teneligliptin in Patients with Type 2 Diabetes Mellitus and Impaired Renal Function: Interim Report from Post-marketing Surveillance . . . . . Masakazu Haneda Takashi Kadowaki Hiroshi Ito Kazuyo Sasaki Sonoe Hiraide . . Manabu Ishii Miyuki Matsukawa Makoto Ueno Received: February 26, 2018 / Published online: April 10, 2018 The Author(s) 2018 supporting its use in patients with moderate or ABSTRACT severe renal impairment are limited. This interim analysis of a post-marketing surveil- Introduction: Teneligliptin is a novel oral lance of teneligliptin, exploRing the long-term dipeptidyl peptidase-4 inhibitor for the treat- efﬁcacy and safety included cardiovascUlar ment of type 2 diabetes mellitus (T2DM). Safety events in patients with type 2 diaBetes treated and efﬁcacy of teneligliptin have been demon- bY teneligliptin in the real-world (RUBY), aims strated in clinical studies; however, data to verify the long-term safety and efﬁcacy of Enhanced Content To view enhanced content for this teneligliptin in Japanese patients with T2DM article go to https://doi.org/10.6084/m9.ﬁgshare. and impaired renal function. Methods: For this analysis, we used the data Electronic supplementary material The online from case report forms of the RUBY surveillance version of this article (https://doi.org/10.1007/s13300- between May 2013 and June 2017. The patients 018-0416-2) contains supplementary material, which is available to authorized users. were classiﬁed into G1–G5 stages of chronic kidney disease according to estimated glomerular ﬁltration rate (eGFR) at initiation of M. Haneda Department of Medicine, Asahikawa Medical teneligliptin treatment. Safety and efﬁcacy were University, Hokkaido, Japan evaluated in these subgroups. Patients on dial- ysis were also assessed. Safety was assessed from M. Haneda Medical Corporation Kyousoukai, Osaka, Japan adverse drug reactions (ADRs). Glycemic con- trol was evaluated up to 2 years after tene- T. Kadowaki ligliptin initiation. Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Results: A total of 11,677 patients were enrol- Tokyo, Tokyo, Japan led in the surveillance and 11,425 patient case- report forms were collected for the interim H. Ito analysis. The incidence of ADRs in each sub- Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry group was 2.98–6.98% of patients, with no dif- and Pharmaceutical Sciences, Okayama, Japan ferences in the ADR proﬁle (including hypoglycemia and renal function ADRs) K. Sasaki (&) S. Hiraide M. Ishii M. Matsukawa M. Ueno between subgroups. At 1 and 2 years after Ikuyaku. Integrated Value Development Division, starting teneligliptin, the least-squares mean Mitsubishi Tanabe Pharma Corporation, Osaka, change in HbA1c adjusted to the baseline was Japan - 0.68 to - 0.85% and - 0.71 to - 0.85% across e-mail: firstname.lastname@example.org 1084 Diabetes Ther (2018) 9:1083–1097 the eGFR groups, respectively. Treatment with optimal glycemic control, because the exposure teneligliptin in patients on dialysis reduced or of some antidiabetic agents that are eliminated tended to reduce glycated albumin levels via the renal route may be increased in these [- 2.29%, (p \ 0.001) after 1 year; - 1.64%, patients due to reduced urinary excretion . (p = 0.064) after 2 years]. Consequently, some antidiabetic agents are Conclusions: During long-term treatment, contraindicated or require signiﬁcant dose teneligliptin was generally well tolerated in reductions in advanced CKD . patients with any stage of renal impairment Dipeptidyl peptidase-4 (DPP-4) inhibitors are from normal to end-stage renal disease, includ- a relatively new class of antidiabetic agents. ing those on dialysis, and improved glycemic These agents enhance glucose-dependent insu- control. lin secretion from pancreatic b-cells by inhibit- Trial Registration Number: Japic CTI-153047. ing DPP-4-mediated degradation of Funding: Mitsubishi Tanabe Pharma Corpora- endogenously released incretin hormones such tion and Daiichi Sankyo Co, Ltd. as glucagon-like peptide-1 (GLP-1) . Impor- tantly, they present a low risk for hypoglycemia . Emerging evidence suggests that DPP-4 Keywords: Dialysis; Dipeptidyl peptidase-4 inhibitors may have pleiotropic effects beyond inhibitor; Post-marketing surveillance; Renal improving glycemic control, including renal impairment; Teneligliptin; Type 2 diabetes and cardiovascular protection [13–15]. mellitus Teneligliptin, a DPP-4 inhibitor, has been prescribed in Japan for the treatment of T2DM at a standard dose of 20 mg once daily since INTRODUCTION 2012 . Twice the standard dose (40 mg once daily) can be used if 20 mg/day is insufﬁcient to Type 2 diabetes mellitus (T2DM) is predicted to achieve glycemic control . Teneligliptin can be a large increasing global health problem in be administered to T2DM patients with renal the coming decades . A recent report from impairment, including patients on dialysis, the National Health and Nutrition survey esti- without the need for dose reduction [18, 19]. In mated that in Japan in 2016, there were 10 South Korea, teneligliptin has been prescribed million adults who were highly suspected to since 2014 . have diabetes, and a further 10 million who The safety and efﬁcacy of teneligliptin in would possibly develop diabetes . Japanese patients with T2DM has been demon- In order to reduce the risk of diabetic com- strated when used as either a monotherapy plications, guidelines for the management of [21–23] or in combination with pioglitazone, diabetes set goals for glycemic control [3–5]. metformin, glimepiride, insulin, canagliﬂozin, People with diabetes are at high risk of devel- glinide, or an alpha-glucosidase inhibitor in oping chronic kidney disease (CKD) as a result clinical trials for up to 52 weeks [23–27]. of microvascular damage caused by poor gly- To date, however, clinical trials of tene- cemic control and/or other comorbidities ligliptin in Japanese patients have only inclu- including hypertension and age-related ded a limited number of patients with moderate nephron loss [6, 7]. Diabetic nephropathy is the or severe renal impairment . Consequently, most frequent primary reason that patients there is insufﬁcient information concerning the require dialysis in Japan . Patients with T2DM safety and efﬁcacy of teneligliptin in this and renal impairment have a high risk of patient population. To help address this, a post- developing hypoglycemia due to reduced insu- marketing surveillance (PMS) of teneligliptin, lin clearance and impaired renal gluconeogen- exploRing the long-term efﬁcacy and safety esis, amongst other reasons . In addition, the included cardiovascUlar events in patients with reduction in glomerular ﬁltration rate (GFR) type 2 diaBetes treated bY teneligliptin in the that occurs with the progression of CKD limits real-world (RUBY), has been ongoing under the therapeutic options available for achieving Diabetes Ther (2018) 9:1083–1097 1085 clinical practice settings in [ 10,000 Japanese Interim Analysis of the Subgroup of Patients with T2DM and Renal patients with T2DM since May 2013 . In this interim analysis, we evaluated the Impairment long-term safety and efﬁcacy of teneligliptin in a subgroup of T2DM patients with renal For this analysis, the data from CRFs collected impairment using case report forms (CRFs) col- between May 2013 and June 2017 were used. lected from the RUBY surveillance during the Estimated GFR (eGFR) was calculated from age, period of May 2013 to June 2017. gender, and serum creatinine values recorded in the CRFs. eGFRs were not calculated for patients with missing serum creatinine values. METHODS Patients with baseline renal function data were divided into those receiving and those not RUBY Post-marketing Surveillance Design: receiving dialysis at the initiation of tene- Patients and Procedures ligliptin treatment. Non-dialysis patients with measurable eGFR at the initiation of tene- Japanese patients with T2DM who were starting ligliptin treatment were classiﬁed as follows treatment with teneligliptin and could be according to renal function using CKD staging observed long term were included in the ongo- : (i) normal or high (G1: eGFR C 90 mL/ ing RUBY surveillance (JapicCTI-153047) . min/1.73 m ), (ii) mild impairment (G2: eGFR The decision to start treatment with tene- C 60 to \ 90 mL/min/1.73 m ), (iii) mild-to- ligliptin was made by physicians in line with moderate impairment (G3a: eGFR C 45 the approved label. Teneligliptin was adminis- to \ 60 mL/min/1.73 m ); (iv) moderate-to-sev- tered once daily; the dose administered and any ere impairment (G3b: C 30 to \ 45 mL/min/ dose adjustments were decided by the prescrib- 1.73 m ), (v) severe impairment (G4: eGFR C 15 ing physician according to the prescribing to \ 30 mL/min/1.73 m ), and (vi) kidney fail- information. ure (G5: eGFR \ 15 mL/min/1.73 m ). Surveillance began in May 2013. Patients The safety and efﬁcacy of teneligliptin was were enrolled between May 2013 and February investigated in each subgroup of patients. Safety 2015 via a central registration system, and will was assessed from adverse drug reactions (ADRs) be observed for up to 3 years. reported throughout the surveillance period. An online electronic data capture system was ADRs were deﬁned as AEs for which a causal used to gather the patient data. Participating relationship with teneligliptin could not be physicians recorded patient demography and ruled out or was unknown. The type and baseline characteristics before teneligliptin was severity of each ADR and its relationship to initiated, and completed follow-up CRFs for all teneligliptin was reported by the physician at enrolled patients taking teneligliptin for up to each site. Serious hypoglycemia was deﬁned as a 3 years. Data in CRFs included information on blood glucose level of B 50 mg/dL or as judged pretreatment and concurrent drugs, response to by the physician. teneligliptin treatment in terms of glycemic Efﬁcacy was assessed in terms of glycemic control, and adverse events (AEs). control as measured by the change over time in The protocol for RUBY surveillance was glycated hemoglobin (HbA1c; for non-dialysis approved by the Ministry of Health, Labour and patients), and glycated albumin (GA; for dialysis Welfare of the Japanese Government. The RUBY patients). Measurements of HbA1c and GA were surveillance was performed by Mitsubishi Tan- made at 0, 3, 6, 12, 18, and 24 months after the abe Pharma Corporation, in accordance with initiation of teneligliptin treatment. The labo- the Japanese ministry directive on good post- ratory analyses were conducted using routine marketing study practice (GPSP). clinical assays in the institution participating in the surveillance. 1086 Diabetes Ther (2018) 9:1083–1097 Data Analysis proportions of patients had withdrawn across the subgroups (G1–G5 and dialysis). Of the 10,532 patients included in the safety analysis Continuous data were summarized based on the set, evaluable CRFs collected by June 28, 2017 number of patients (n), mean, and standard were available for 9234 non-dialysis patients deviation (SD), and discrete data were summa- with calculable eGFR and 152 patients receiving rized based on the n and percentage values for dialysis at the start of teneligliptin treatment each category. Least squares (LS) means and (see S1 in the Electronic supplementary mate- standard errors were calculated, with the base- rial, ESM). line as a covariate, to measure the change in Of the 9234 patients with calculable eGFR, HbA1c over time; one-sample t-tests were used most had mild impairment (G2: 53.4%); 21.5% to determine if the difference between the had normal/high renal function (G1), 16.2% HbA1c values before and after teneligliptin had mild to moderate impairment (G3a), 6.0% administration was statistically signiﬁcant. had moderate to severe impairment (G3b), 2.3% Laboratory data were counted only for patients had severe impairment (G4), and 0.6% had who had data both at baseline and after the kidney failure (G5). administration of teneligliptin. Chi-square tests Patient background characteristics and con- were performed to assess differences in ADR current medications for T2DM, hypertension, frequency between the eGFR categories. In and dyslipidemia in each subgroup are shown addition, in order to assess the difference in Table 1. Patients with severe renal impair- between the G2–G5 subgroups and G1, the 95% ment and those on dialysis had a longer dura- conﬁdence interval (CI) of the risk ratio for tion of T2DM; a greater proportion of those ADRs in the eGFR subgroups was used. Statisti- patients also had diabetic complications (G4: cal tests were two-sided with a 5% signiﬁcance 74.9%; G5: 70.0%; dialysis patients: 92.8%) level, and two-sided 95% CIs were calculated. compared with those with normal/high renal Statistical analysis was performed using SAS function or mild renal impairment (G1: 19.4%; version 9.1.3 and above (SAS Institute Inc., G2: 21.5%). A greater proportion of those with Cary, NC, USA). severe renal impairment and those on dialysis ADRs were categorized according to the had heart disease, including myocardial infarc- Medical Dictionary for Regulatory Activities, tion, angina pectoris, or heart failure (G4: Japanese version 20.0 (Pharmaceutical and 40.5%; G5: 33.3%; dialysis patients: 46.1%) and Medical Device Regulatory Science Society of hypertension (G4: 91.2%; G5: 88.3%; dialysis Japan, Tokyo, Japan). ADRs of special interest patients: 89.5%) as an underlying complication (previously associated with diabetes, antihy- compared with patients with normal/high renal perglycemic agents, or DPP-4 inhibitors) were function and mild renal impairment (G1: 7.8% deﬁned as those related to hypoglycemia, skin and 50.9%; G2: 15.4% and 61.5%, respectively). and subcutaneous tissue disorders, gastroin- Teneligliptin was prescribed as monotherapy testinal disorders, hepatic disorders, renal dis- for T2DM in 40.0–53.3% of patients across the orders, cardiovascular events, and tumor. subgroups with measurable eGFR and 53.9% of dialysis patients during the surveillance period. RESULTS The remaining 46.1–60.0% of patients were prescribed teneligliptin therapy in combination Patients with other antidiabetic drugs (Table 1). The mean starting daily doses of teneligliptin were 20.1–20.2 mg in all eGFR subgroups and In total, 11,677 patients were enrolled into the 20.3 mg in dialysis patients (Table 1). Mean RUBY surveillance from 1755 institutions, and daily dosages during the surveillance period 11,425 patient case report forms were collected were 20.3–20.7 mg/day in eGFR subgroups and for the interim analysis. As of June 28, 2017, the 21.3 mg/day in dialysis patients (Table 1). proportion of patients who had withdrawn from the surveillance was 26.9%; similar Diabetes Ther (2018) 9:1083–1097 1087 Table 1 Patient baseline characteristics Characteristic Non-dialysis patients, eGFR at initiation of treatment (mL/min/1.73 m ) Dialysis patients G1 G2 G3a G3b G4 G5 (n = 152) ‡ 90 ‡ 60 to < 90 ‡ 45 to < 60 ‡ 30 to < 45 ‡ 15 to < 30 <15 (n = 1982) (n = 4929) (n = 1496) (n = 552) (n = 215) (n = 60) Male sex, n (%) 1179 (59.5) 3057 (62.0) 879 (58.8) 303 (54.9) 118 (54.9) 32 (53.3) 110 (72.4) Age (years) n = 1982 n = 4929 n = 1496 n = 552 n = 215 n = 60 n = 152 56.8 (12.9) 65.6 (10.9) 72.3 (9.7) 74.3 (9.9) 74.4 (10.8) 69.5 (11.6) 67.4 (10.2) Duration of T2DM n = 1392 n = 3487 n = 1001 n = 384 n = 127 n = 36 n = 82 (years) 5.60 (6.24) 7.00 (7.55) 8.97 (8.73) 10.54 (8.96) 13.78 (9.78) 13.00 (11.13) 16.65 (9.23) HbA1c (%) n = 1864 n = 4629 n = 1405 n = 528 n = 200 n = 57 n = 99 8.51 (1.92) 7.64 (1.35) 7.38 (1.20) 7.28 (1.13) 7.35 (1.38) 6.94 (1.19) 6.72 (1.12) Glycated albumin (%) n = 85 n = 228 n = 66 n = 39 n = 26 n = 17 n = 91 21.60 (6.94) 19.27 (7.17) 20.20 (5.53) 21.20 (6.44) 19.53 (5.83) 20.02 (5.57) 23.48 (5.00) Fasting blood glucose n = 730 n = 1817 n = 529 n = 201 n = 67 n = 21 n = 32 (mg/dL) 169.0 (64.0) 147.8 (47.5) 143.4 (46.6) 148.3 (45.3) 140.1 (39.4) 131.3 (53.7) 146.5 (48.1) BMI (kg/m ) n = 1437 n = 3416 n = 991 n = 396 n = 137 n = 39 n = 96 25.92 (5.09) 25.09 (4.15) 25.18 (4.16) 25.16 (4.39) 24.90 (4.35) 23.77 (3.56) 22.88 (3.19) eGFR (mL/min/ n = 1982 n = 4929 n = 1496 n = 552 n = 215 n = 60 – 1.73 m ) 106.28 (18.94) 74.29 (8.18) 53.55 (4.23) 38.54 (4.23) 23.95 (4.23) 8.76 (4.23) – Diabetic complications, n (%) Any 385 (19.4) 1060 (21.5) 502 (33.6) 283 (51.3) 161 (74.9) 42 (70.0) 141 (92.8) Neuropathy 127 (6.4) 445 (9.0) 196 (13.1) 107 (19.4) 48 (22.3) 13 (21.7) 47 (30.9) Nephropathy 244 (12.3) 659 (13.4) 385 (25.7) 253 (45.8) 150 (69.8) 40 (66.7) 140 (92.1) Retinopathy 145 (7.3) 412 (8.4) 174 (11.6) 105 (19.0) 54 (25.1) 21 (35.0) 72 (47.4) Other complications, n (%) Renal disease 257 (13.0) 723 (14.7) 459 (30.7) 334 (60.5) 177 (82.3) 45 (75.0) 146 (96.1) Liver disease 550 (27.7) 1173 (23.8) 310 (20.7) 93 (16.8) 24 (11.2) 8 (13.3) 15 (9.9) Heart disease 155 (7.8) 759 (15.4) 396 (26.5) 201 (36.4) 87 (40.5) 20 (33.3) 70 (46.1) Hypertension 1009 (50.9) 3031 (61.5) 1099 (73.5) 475 (86.1) 196 (91.2) 53 (88.3) 136 (89.5) Dyslipidemia 1293 (65.2) 3342 (67.8) 1063 (71.1) 406 (73.6) 159 (74.0) 36 (60.0) 66 (43.4) Teneligliptin 901 (45.5) 2328 (47.2) 666 (44.5) 232 (42.0) 86 (40.0) 32 (53.3) 82 (53.9) monotherapy, n (%) Concurrent T2DM medication, n (%) Any 1081 (54.5) 2601 (52.8) 830 (55.5) 320 (58.0) 129 (60.0) 28 (46.7) 70 (46.1) Sulfonylurea 476 (24.0) 1231 (25.0) 406 (27.1) 152 (27.5) 53 (24.7) 8 (13.3) 1 (0.7) Thiazolidine 186 (9.4) 413 (8.4) 146 (9.8) 55 (10.0) 7 (3.3) 2 (3.3) 0 (0.0) Biguanide 540 (27.2) 1061 (21.5) 264 (17.6) 56 (10.1) 15 (7.0) 3 (5.0) 0 (0.0) a- GI 195 (9.8) 539 (10.9) 210 (14.0) 90 (16.3) 38 (17.7) 8 (13.3) 21 (13.8) Glinide 84 (4.2) 256 (5.2) 75 (5.0) 39 (7.1) 18 (8.4) 5 (8.3) 19 (12.5) Insulin 141 (7.1) 332 (6.7) 117 (7.8) 68 (12.3) 39 (18.1) 11 (18.3) 35 (23.0) SGLT2 inhibitor 91 (4.6) 151 (3.1) 24 (1.6) 5 (0.9) 1 (0.5) 1 (1.7) 0 (0.0) 1088 Diabetes Ther (2018) 9:1083–1097 Table 1 continued Characteristic Non-dialysis patients, eGFR at initiation of treatment (mL/min/1.73 m ) Dialysis patients G1 G2 G3a G3b G4 G5 (n = 152) ‡ 90 ‡ 60 to < 90 ‡ 45 to < 60 ‡ 30 to < 45 ‡ 15 to < 30 <15 (n = 1982) (n = 4929) (n = 1496) (n = 552) (n = 215) (n = 60) Non-T2DM medication, n (%) Hypertension drug 750 (37.8) 2438 (49.5) 912 (61.0) 413 (74.8) 165 (76.7) 43 (71.7) 117 (77.0) Dyslipidemia drug 671 (33.9) 2143 (43.5) 736 (49.2) 265 (48.0) 110 (51.2) 28 (46.7) 40 (26.3) Teneligliptin starting n = 1979 n = 4929 n = 1494 n = 551 n = 214 n = 60 n = 152 dose (mg/day) 20.2 (2.0) 20.2 (2.0) 20.1 (2.0) 20.2 (2.6) 20.1 (2.1) 20.2 (2.9) 20.3 (2.9) Teneligliptin dose n = 1914 n = 4778 n = 1447 n = 537 n = 212 n = 58 n = 146 during surveillance 20.3 (2.6) 20.4 (2.6) 20.4 (2.7) 20.5 (3.2) 20.7 (3.6) 20.7 (3.3) 21.3 (4.6) period (mg/day) Data are mean (SD) unless otherwise stated a-GI a-Glucosidase inhibitor, BMI body mass index, eGFR estimated glomerular ﬁltration rate, HbA1c glycated hemoglobin, SD standard deviation, SGLT2 sodium-glucose cotransporter-2, T2DM type 2 diabetes mellitus Includes diabetic nephropathy Safety with normal/high renal function [G1: 11 of 1982 (0.55%)]. ADRs and serious ADRs were observed in 5 and 1 of 152 dialysis patients In the safety analysis set, the mean duration of (3.29% and 0.66%), respectively. teneligliptin administration ranged from There were no signiﬁcant differences in the 534 days to 617 days across the subgroups incidence of each special interest ADR across (mean ± SD: G1: 581.45 ± 340.90 days; G2: the groups, including hypoglycemia, skin and 610.56 ± 340.87 days; G3a: 616.80 ± subcutaneous tissue disorders, gastrointestinal 336.73 days; G3b: 594.93 ± 341.58 days; G4: disorders, hepatic disorders, renal-impairment- 561.54 ± 341.68 days; G5: 533.62 ± related ADRs, cardiovascular events, and tumor 345.22 days; and dialysis: 580.91 ± 371.74 (Table 2). Five patients presenting the more days). advanced stages of renal impairment (G4/ The incidences of all ADRs and special G5/dialysis groups) experienced a hypoglycemic interest ADRs are shown in Table 2. Greater episode: 1 patient each experienced non-serious ADR incidence were observed in the G4 and G5 and serious hypoglycemia in the G4 group, 1 groups (15 of 215 patients (6.98%) and 4 of 60 patient had a non-serious hypoglycemic epi- patients (6.67%) respectively), compared with sode in the G5 group, and 2 patients had a non- 59 of 1982 patients in the G1 group (2.98%). Of serious hypoglycemic episode in the dialysis the ADRs reported in the 19 patients in the G4 group. All of these patients were administered and G5 subgroups, those occurring in 6 patients concomitant medication for T2DM (4 patients were considered to be possibly related to tene- were using insulin and/or sulfonylureas and 1 ligliptin, while the causal relationship between was administered a glinide). Renal-impairment- teneligliptin and the ADRs in 13 patients was related ADRs in the G4 group included hema- assessed as unknown, and 15 of 30 events in the turia (n =1), renal impairment (n =1), and 19 patients were also attributed to other causes increased blood creatinine (n =1); the physician (e.g., comorbidity or concomitant agent) by the reported that the causal relationship of each of prescribing physician. A higher incidence of these events with teneligliptin was unknown, serious ADRs occurred in the G4 and G5 groups and 2 of those ADRs were also attributed to [10 of 215 patients (4.65%) and 3 of 60 patients other causes (diabetic nephropathy comorbidity (5.00%), respectively] compared with patients Diabetes Ther (2018) 9:1083–1097 1089 Table 2 Incidences of ADRs and special interest ADRs Non-dialysis patients, eGFR at initiation of treatment (mL/min/1.73 m ) Dialysis patients G1 G2 G3a G3b G4 G5 (n =152) ‡ 90 ‡ 60 to < 90 ‡ 45 to < 60 ‡ 30 to < 45 ‡ 15 to < 30 <15 (n 5 1982) (n 5 4929) (n 5 1496) (n 5 552) (n 5 215) (n 5 60) Any ADR 59 (2.98) 186 (3.77) 53 (3.54) 16 (2.90) 15 (6.98) 4 (6.67) 5 (3.29) a a Serious ADR 11 (0.55) 42 (0.85) 12 (0.80) 7 (1.27) 10 (4.65) 3 (5.00) 1 (0.66) Special interest ADRs Hypoglycemia 6 (0.30) 13 (0.26) 7 (0.47) 1 (0.18) 2 (0.93) 1 (1.67) 2 (1.32) Serious 2 (0.10) 3 (0.06) 2 (0.13) 1 (0.18) 1 (0.47) 0 (0.00) 0 (0.00) SST disorders 10 (0.50) 16 (0.32) 4 (0.27) 3 (0.54) 1 (0.47) 0 (0.00) 0 (0.00) Serious 0 (0.00) 1 (0.02) 0 (0.00) 1 (0.18) 1 (0.47) 0 (0.00) 0 (0.00) GI disorders 8 (0.40) 37 (0.75) 13 (0.87) 2 (0.36) 1 (0.47) 0 (0.00) 1 (0.66) Serious 1 (0.05) 5 (0.10) 1 (0.07) 2 (0.36) 0 (0.00) 0 (0.00) 0 (0.00) Pancreatitis 1 (0.05) 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00) Intestinal 0 (0.00) 3 (0.06) 0 (0.00) 1 (0.18) 0 (0.00) 0 (0.00) 0 (0.00) obstruction Hepatic 3 (0.15) 29 (0.59) 4 (0.27) 3 (0.54) 1 (0.47) 0 (0.00) 0 (0.00) impairment Serious 1 (0.05) 1 (0.02) 1 (0.07) 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00) Renal 4 (0.20) 15 (0.30) 4 (0.27) 1 (0.18) 3 (1.40) 0 (0.00) – impairment Serious 1 (0.05) 1 (0.02) 0 (0.00) 0 (0.00) 2 (0.93) 0 (0.00) – Cardiovascular 2 (0.10) 8 (0.16) 1 (0.07) 2 (0.36) 0 (0.00) 0 (0.00) 0 (0.00) event Serious 1 (0.05) 7 (0.14) 1 (0.07) 1 (0.18) 0 (0.00) 0 (0.00) 0 (0.00) Tumor 4 (0.20) 11 (0.22) 4 (0.27) 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00) Serious 4 (0.20) 11 (0.22) 4 (0.27) 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00) Data are numbers of patients (%) Difference between eGFR subgroups is statistically signiﬁcant according to chi-square test, and the lower end of the 95% CI for the incidence rate for the subgroup is 1 or more Renal impairment cannot be evaluated in patients on dialysis ADR adverse drug reaction, CI conﬁdence interval, eGFR estimated glomerular ﬁltration rate, GI gastrointestinal, SST Skin and subcutaneous tissue 1090 Diabetes Ther (2018) 9:1083–1097 Fig. 1 Mean eGFR over time in patients with type 2 the mean ± SD. Datapoints are offset to aid clarity. eGFR diabetes and varying levels of renal impairment (eGFR estimated glomerular ﬁltration rate, SD standard deviation G1–G5), excluding dialysis patients. Data are presented as and dehydration). Cardiovascular-related ADRs period of evaluation; this was reported as an were reported in 13 patients (10 were serious); ADR in one patient in the G5 group, although no cardiovascular-related ADRs were reported in the causal relationship with teneligliptin was the G4, G5, and dialysis groups (Table 2). Car- unknown according to the reporting physician. diovascular AEs, including those not related to The eGFR proﬁles over time for the eGFR teneligliptin, were reported in 68 patients (G1, subgroups are shown in Fig. 1. Renal function n = 4; G2, n = 31; G3a, n = 12; G3b, n = 11; remained relatively stable over 2 years in all G4, n = 4; G5, n = 2; and dialysis, n = 4). subgroups. Tumor ADRs were reported in 19 patients; the relationship between all tumor ADRs and tene- Efﬁcacy ligliptin was unknown according to physician reports. Tumor AEs, including those with no Levels of HbA1c in the eGFR subgroups of non- relationship to teneligliptin, were reported in dialysis patients and the change over 2 years 87 patients (G1: n = 11; G2: n = 38; G3a: after starting treatment with teneligliptin are n = 20; G3b: n = 6; G4: n = 6; G5: n = 1; and shown in Fig. 2. At baseline, HbA1c levels were dialysis: n = 5). highest in patients with normal/high renal ADRs that were reported in at least ﬁve function (G1: 8.50%) and lowest in patients patients and serious ADRs reported in at least with kidney failure (G5: 7.04%) (Fig. 2a). There two patients across all subgroups are listed by was a signiﬁcant reduction in HbA1c levels preferred term in S2 of the ESM. The safety observed over 2 years in G1, G2, G3a, G3b, and proﬁle did not differ markedly among the sub- G4 patients (p \ 0.01) (Fig. 2a); G1: groups. In the G4 and G5 subgroups, 2 and 9 - 1.25 ± 1.7%; G2: - 0.67 ± 1.25%; G3a: patients, respectively, started dialysis during the - 0.51 ± 1.17%; G3b: - 0.37 ± 1.12%; G4: Diabetes Ther (2018) 9:1083–1097 1091 Fig. 2 Mean HbA1c over time (a) and LS mean change in **p \ 0.01; ***p \ 0.001 versus baseline (month 0). Dat- HbA1c over time (b, adjusted for baseline HbA1c) in apoints are offset to aid clarity. eGFR estimated glomerular patients with type 2 diabetes and varying levels of renal ﬁltration rate, HbA1c glycated hemoglobin, LS least impairment (eGFR G1–G5). Data are presented as the squares, SD standard deviation, SE standard error mean ± SD in a and the LS mean ± SE in b.*p \ 0.05; - 0.54 ± 1.13% at 2 years (all p \ 0.001). (- 0.53 ± 1.25%, p = 0.074), which may be due HbA1c levels decreased or tended to decrease in to the low baseline score and the limited num- G5 patients, although the reduction in HbA1c ber of patients. In order to adjust for differences levels was not signiﬁcant at 2 years of treatment in baseline HbA1c, the least squares mean of 1092 Diabetes Ther (2018) 9:1083–1097 Fig. 3 Mean glycated albumin levels over time in patients with type 2 diabetes on hemodialysis. Data are presented as the mean ± standard deviation. *p \ 0.05; **p \ 0.01; ***p \ 0.001 versus baseline (month 0) HbA1c change was calculated for each eGFR by this post-marketing surveillance is supported subgroup (Fig. 2b). Following adjustment, by a previous study exploring teneligliptin in HbA1c levels declined in all groups after the patients with end-stage renal disease . initiation of teneligliptin. There were no sig- Additionally, we showed that during 2 years of niﬁcant differences between eGFR subgroups in treatment with teneligliptin, glycemic control the reduction of HbA1c levels at 1 and 2 years improved in all subgroups of patients, from after starting teneligliptin; HbA1c levels were those with normal or high levels of renal func- reduced by 0.68–0.85% and 0.71–0.85%, tion to those with end-stage renal disease, respectively. including patients on dialysis. The mean GA level in patients receiving Although all DPP-4 inhibitors have a com- dialysis is illustrated in Fig. 3; the mean change mon mechanism of action, these agents show in GA level after the initiation of teneligliptin signiﬁcant structural heterogeneity, which dic- was - 2.29% (p \ 0.001) at 1 year and - 1.64% tate their differing pharmacokinetic and phar- at 2 years (p = 0.064); this ﬁnding is limited by macological properties . One of the key the number of patients available for analysis differentiators is the route of elimination; some after 2 years of teneligliptin treatment (n = 45). DPP-4 inhibitors are largely eliminated via the renal route (ranging from 75% to 87%) . The renal clearance of teneligliptin is approximately DISCUSSION 36% . Consequently, dose adjustments are required for patients with moderate or severe The aim of this interim analysis was to evaluate renal impairment with most DPP-4 inhibitors, the long-term safety and efﬁcacy of teneligliptin except for linagliptin and teneligliptin [31, 32]. in patients with T2DM and reduced renal In this interim analysis, the majority of patients function. In this analysis, we documented ADR received 20 mg/day of teneligliptin for an aver- incidences ranging from 2.98% to 6.98% across age duration ranging from 534 days to 617 days patients with each stage of renal impairment, across the subgroups. and no clear differences in the ADR proﬁles at Generally, patients with renal impairment the different stages of impairment were are at greater risk of AEs . The onset of AEs or observed. The well-tolerated proﬁle highlighted renal-related AEs has been shown to increase Diabetes Ther (2018) 9:1083–1097 1093 with the reduction in eGFR in placebo-treated those seen in other studies investigating the patients with T2DM [34, 35]. In the present efﬁcacy of DPP-4 inhibitors in T2DM patients surveillance, there was generally a higher with renal impairment (reduction in HbA1c prevalence of comorbidities other than diabetes 0.4–0.7%) [37, 38]. Teneligliptin signiﬁcantly (e.g., cardiovascular-related comorbidities such improved glycemic control in patients with as hypertension) in patients with greater T2DM on dialysis [30, 39]. Furthermore, tene- impairment of renal function compared to ligliptin was found to reduce insulin dose those with less impaired renal function at requirements in dialysis patients . Patients baseline. This could, in part, explain the higher on dialysis often show lower values for HbA1c incidence of ADRs and serious ADRs reported in that do not reﬂect actual blood glucose control G4 and G5 patients in our study. Indeed, a . In this study, we used GA as an indicator of causal relationship with teneligliptin for most blood glucose control for patients on dialysis. ADRs could not be determined by the prescrib- According to the Best Practice for Diabetic ing physicians. Additionally, there were limita- Patients on Hemodialysis 2012 by the Japanese tions of this interim analysis, including the Society for Dialysis Therapy , tentative glu- different numbers of patients in the subgroups, cose control targets in patients with diabetes on the limited number of patients in the G5 group dialysis are GA levels of \ 20% in patients in particular, and no matched control group for without a cardiovascular event history and each stage of renal impairment. For these rea- \ 24% in patients with a cardiovascular event sons, we cannot conﬁdently conﬁrm a greater history. In this interim analysis, GA levels in ADR risk for teneligliptin in the G4 and G5 dialysis patients decreased from 23.74% to patients based on results from this interim 21.34% after 1 year and 21.45% after 2 years of analysis. Instead, this analysis supports the need teneligliptin treatment. However, further anal- for further investigation of the ADR risk among ysis is required, as fewer CRF forms were col- patients with advanced renal impairment. lected from patients on dialysis than from those In this surveillance, there was no clear vari- in other groups. ation in the proﬁle of ADRs, including hypo- Although the data reported here were not glycemia, according to the stage of renal generated in a controlled setting as part of a impairment. Patients with diabetes who have clinical trial, the post-marketing surveillance impaired renal function are susceptible to data provide important insights into tene- developing hypoglycemia due to multiple fac- ligliptin use in routine practice and the type of tors, including reduced insulin clearance and ADRs that might occur among Japanese patients impaired renal gluconeogenesis . In this with renal impairment. A potential limitation interim analysis, hypoglycemic episodes were of the present analysis is that the data collected reported in 5 patients presenting the more after the administration of teneligliptin include advanced stages of renal impairment (G4/ that relating to cases in which other concurrent G5/dialysis groups). The majority of these drugs may have been added or altered. This is in patients were utilizing insulin and sulfonylurea addition to some of the typical limitations of a concomitantly—a treatment regimen associated post-marketing survellance design, which with increased hypoglycemic risk . There- include having incomplete data, possible fore, careful management is required to avoid reporting biases, no matched control group, hypoglycemic episodes when combining tene- and limitations in the generalizability of the ligliptin with the aforementioned regimen in ﬁndings. T2DM patients with renal impairment. In our study, the reduction in HbA1c levels CONCLUSION ranged between 0.71% and 0.85% (baseline- HbA1c-adjusted least-squares mean) after In summary, the present interim analysis of 2 years of treatment in all eGFR subgroups. teneligliptin after long-term treatment showed Improvements in HbA1c observed across the that the ADR proﬁles of patients with different subgroups in our surveillance were similar to 1094 Diabetes Ther (2018) 9:1083–1097 stages of renal impairment were similar. Tene- would also like to thank T. Yamakura, M. Kimura, ligliptin was also associated with improvements and M. Oohashi for insightful discussions. in glycemic control in T2DM patients with renal Disclosures. Masakazu Haneda has received impairment. speaker honorarium/lecture fees from Astellas Pharma Inc., Taisho Toyama Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., ACKNOWLEDGEMENTS Taisho Pharmaceutical Co., Ltd., Kowa Phar- maceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., MSD K.K., Novartis Pharma K.K., Novo Funding. Sponsorship for this surveillance Nordisk Pharma Ltd., Sanoﬁ K. K., and Mit- and article processing charges were funded by subishi Tanabe Pharma Corporation; has Mitsubishi Tanabe and Daiichi Sankyo Co. Ltd. received scholarship grants from Astellas All authors had full access to all of the data in Pharma Inc., Daiichi Sankyo Co., Ltd., MSD this study and take complete responsibility for K.K., Takeda Pharmaceutical Co., Ltd., Novo the integrity of the data and accuracy of the Nordisk Pharma Ltd., Taisho Toyama Pharma- data analysis. ceutical Co., Ltd., Eli Lilly Japan K. K., Nippon Boehringer Ingelheim Co., Kyowa Hakko Kirin Medical Writing. Medical writing support, Co., Ltd., Ono Pharmaceutical Co., Ltd., Kowa under the direction of the authors, was pro- Pharmaceutical Co., Ltd., Sanoﬁ K. K., Shionogi vided by Caroline Shepherd, BPharm of CMC & Co., Ltd., Johnson & Johnson K.K. Otsuka CONNECT, a division of Complete Medical Pharmaceutical Co., Ltd., Kissei Pharmaceutical Communications Ltd, Macclesﬁeld, UK, and Co., and Mitsubishi Tanabe Pharma Corpora- Janet Dawson PhD, on behalf of CMC CON- tion. Takashi Kadowaki has received speaker NECT. This was funded by Mitsubishi Tanabe honorarium/lecture fees from Takeda Pharma- Pharma Corporation, in accordance with good ceutical Co., Ltd., Ono Pharmaceutical Co., publication practice (GPP3) guidelines. Ltd., Kowa Pharmaceutical Co., Ltd, AstraZe- neca K.K., Astellas Pharma Inc., MSD K.K., Authorship. All named authors meet the Nippon Boehringer Ingelheim Co., Ltd., Novo International Committee of Medical Journal Nordisk Pharma Ltd., Eli Lilly Japan K. K., and Editors (ICMJE) criteria for authorship for this Mitsubishi Tanabe Pharma Corporation; has article, take responsibility for the integrity of received research grants from Takeda Pharma- the work as a whole, and have given their ceutical Co., Ltd., Novartis Pharma K.K., and approval for this version to be published. Daiichi Sankyo Co., Ltd.; has received scholar- Author Contributions. Masakazu Haneda, ship grants from Takeda Pharmaceutical Co., Takashi Kadowaki, and Hiroshi Ito all con- Ltd., Sumitomo Dainippon Pharma Co., Ltd., tributed to the data interpretation and provided Daiichi Sankyo Co., Ltd., Astellas Pharma Inc., medical advice. Kazuyo Sasaki, Sonoe Hiraide, Taisho Toyama Pharmaceutical Co., Ltd., and Makoto Ueno contributed to the concep- Kyowa Hakko Kirin Co., Ltd., Kissei Pharma- tion of the surveillance and data interpretation. ceutical Co., Ltd., Novo Nordisk Pharma Ltd., Manabu Ishii and Miyuki Matsukawa con- Sanoﬁ K. K., Ono Pharmaceutical Co., Ltd., and tributed to the analyses and data interpretation. Mitsubishi Tanabe Pharma Corporation, and All authors contributed to manuscript has taken courses endowed by Takeda Pharma- development. ceutical Co., Nippon Boehringer Ingelheim Co., MSD K.K., Novo Nordisk Pharma Ltd., Kowa Giving Thanks. We are deeply grateful to all Pharmaceutical Co., Ltd., Ono Pharmaceutical participants and physicians who cooperated in Co., Ltd., and Mitsubishi Tanabe Pharma Cor- this post-marketing surveillance, and to K. Yosh- poration. Hiroshi Ito has received speaker ida, who managed the collection of the CRFs. We honoraria/lecture fees from Daiichi Sankyo Co., Ltd., and Mitsubishi Tanabe Pharma Diabetes Ther (2018) 9:1083–1097 1095 2. Ministry of Health, Labour and Welfare. National Corporation, and has received scholarship Health and Nutrition Survey in Japan 2016; 2016. grants from Daiichi Sankyo Co., Ltd. and Mit- http://www.mhlw.go.jp/ﬁle/04-Houdouhappyou- subishi Tanabe Pharma Corporation. Kazuyo 10904750-Kenkoukyoku-Gantaisakukenkouzoushi Sasaki is an employee of Mitsubishi Tanabe nka/kekkagaiyou_7.pdf. Accessed 12 Jan 2018. Pharma Corporation. Manabu Ishii is an 3. American Diabetes Association. Glycemic targets:s- employee of Mitsubishi Tanabe Pharma Corpo- tandards of medical care in diabetes—2018. Dia- ration. Sonoe Hiraide is an employee of Mit- betes Care. 2018;41(Suppl 1):S55–64. subishi Tanabe Pharma Corporation. Miyuki 4. Araki E, Haneda M, Kasuga M, et al. New glycemic Matsukawa is an employee of Mitsubishi Tanabe targets for patients with diabetes from the Japan Pharma Corporation. Makoto Ueno is an Diabetes Society. J Diabetes Investig. employee of Mitsubishi Tanabe Pharma Corpo- 2017;8(1):123–5. ration. Takashi Kadowaki, Masakazu Haneda, 5. Inzucchi SE, Bergenstal RM, Buse JB, et al. Man- and Hiroshi Ito have not received honoraria agement of hyperglycaemia in type 2 diabetes, from Mitsubishi Tanabe Pharma Corporation 2015: a patient-centred approach. Update to a and Daiichi Sankyo Co., Ltd. for writing pro- position statement of the American Diabetes Asso- motional material with regard to this ciation and the European Association for the Study of Diabetes. Diabetologia. 2015;58(3):429–42. manuscript. 6. Thomas MC, Brownlee M, Susztak K, et al. Diabetic Compliance with Ethics Guidelines. The kidney disease. Nat Rev Dis Primers. 2015;1:15018. protocol for RUBY surveillance was approved by the Ministry of Health, Labour and Welfare of 7. Thomas MC, Cooper ME, Zimmet P. Changing epidemiology of type 2 diabetes mellitus and asso- the Japanese Government. The RUBY surveil- ciated chronic kidney disease. Nat Rev Nephrol. lance was performed by Mitsubishi Tanabe 2016;12(2):73–81. Pharma Corporation, in accordance with the Japanese ministry directive on good post-mar- 8. Masakane I, Nakai S, Ogata S, et al. Annual dialysis data report 2014, JSDT Renal Data Registry (JRDR). keting study practice (GPSP). Ren Replace Ther. 2017;3:18. Data Availability. The datasets analyzed 9. Tuttle KR, Bakris GL, Bilous RW, et al. Diabetic during the current study are not publicly avail- kidney disease: a report from an ADA consensus conference. Am J Kidney Dis. 2014;64(4):510–33. able to protect individual patient conﬁdential- ity, but are available from the corresponding 10. Avogaro A, Schernthaner G. Achieving glycemic author on reasonable request. control in patients with type 2 diabetes and renal impairment. Acta Diabetol. 2013;50(3):283–91. Open Access. This article is distributed 11. Schernthaner G, Ritz E, Schernthaner G-H. Strict under the terms of the Creative Commons glycaemic control in diabetic patients with CKD or Attribution-NonCommercial 4.0 International ESRD: beneﬁcial or deadly? Nephrol Dial Trans- License (http://creativecommons.org/licenses/ plant. 2010;25(7):2044–7. by-nc/4.0/), which permits any noncommercial 12. Cahn A, Cernea S, Raz I. An update on DPP-4 use, distribution, and reproduction in any inhibitors in the management of type 2 diabetes. medium, provided you give appropriate credit Expert Opin Emerg Drugs. 2016;21(4):409–19. to the original author(s) and the source, provide a link to the Creative Commons license, and 13. Groop PH, Cooper ME, Perkovic V, Emser A, Woerle HJ, von Eynatten M. Linagliptin lowers albumin- indicate if changes were made. uria on top of recommended standard treatment in patients with type 2 diabetes and renal dysfunction. Diabetes Care. 2013;36(11):3460–8. REFERENCES 14. Tanaka Y, Kume S, Chin-Kanasaki M, et al. Reno- protective effect of DPP-4 inhibitors against free 1. Guarı´guata L, Whiting DR, Hambleton I, Beagley J, fatty acid-bound albumin-induced renal proximal Linnenkamp U, Shaw JE. Global estimates of dia- tubular cell injury. Biochem Biophys Res Commun. betes prevalence for 2013 and projections for 2035. 2016;470(3):539–45. Diabetes Res Clin Pract. 2014;103(2):137–49. 1096 Diabetes Ther (2018) 9:1083–1097 15. Aroor AR, Sowers JR, Jia G, DeMarco VG. Pleiotropic 26. Kadowaki T, Inagaki N, Kondo K, et al. Efﬁcacy and effects of the dipeptidylpeptidase-4 inhibitors on safety of teneligliptin added to canagliﬂozin the cardiovascular system. Am J Physiol Heart Circ monotherapy in Japanese patients with type 2 dia- Physiol. 2014;307(4):H477–92. betes mellitus: a multicentre, randomized, double- blind, placebo-controlled, parallel-group compara- 16. Mitsubishi Tanabe Pharma Corporation, Daiichi tive study. Diabetes Obes Metab. 2018;20(2):453–7. Sankyo Co. Ltd. Launch of Tenelia 20 mg tablets: a DPP-4 inhibitor for type 2 diabetes mellitus origi- 27. Kadowaki T, Kondo K, Sasaki N, et al. Efﬁcacy and nating from Japan; 2012. http://www.mt-pharma. safety of teneligliptin add-on to insulin monother- co.jp/e/release/nr/2012/pdf/eMTPC120828_DS.pdf. apy in Japanese patients with type 2 diabetes mel- Accessed 12 Oct 2017. litus: a 16-week, randomized, double-blind, placebo-controlled trial with an open-label period. 17. Daiichi Sankyo Company Ltd. Teneligliptin pre- Expert Opin Pharmacother. 2017;18(13):1291–300. scribing information; 2016. http://www.rad-ar.or. jp/siori/english/kekka.cgi?n=32722. Accessed 8 Sep 28. Kadowaki T, Haneda M, Ito H, et al. Safety and 2017. efﬁcacy of long-term treatment with teneligliptin: interim analysis of a post-marketing surveillance of 18. Halabi A, Maatouk H, Siegler KE, Faisst N, Lufft V, more than 10,000 Japanese patients with type 2 Klause N. Pharmacokinetics of teneligliptin in sub- diabetes mellitus. Expert Opin Pharmacother. jects with renal impairment. Clin Pharmacol Drug 2018;19(2):83–91. Dev. 2013;2(3):246–54. 29. KDIGO CWG. KDIGO 2012 clinical practice guide- 19. Sharma SK, Panneerselvam A, Singh KP, Parmar G, line for the evaluation and management of chronic Gadge P, Swami OC. Teneligliptin in management kidney disease (Chapter 1). Kidney Int Suppl. of type 2 diabetes mellitus. Diabetes Metab Syndr 2013;3:19–62. Obes. 2016;9:251–60. 30. Otsuki H, Kosaka T, Nakamura K, Shimomura F, 20. Singh AK. Efﬁcacy and safety of teneligliptin. Kuwahara Y, Tsukamoto T. Safety and efﬁcacy of Indian J Endocrinol Metab. 2017;21(1):11–7. teneligliptin: a novel DPP-4 inhibitor for hemodialysis patients with type 2 diabetes. Int Urol 21. Eto T, Inoue S, Kadowaki T. Effects of once-daily Nephrol. 2014;46(2):427–32. teneligliptin on 24-h blood glucose control and safety in Japanese patients with type 2 diabetes 31. Chen XW, He ZX, Zhou ZW, et al. Clinical phar- mellitus: a 4-week, randomized, double-blind, pla- macology of dipeptidyl peptidase 4 inhibitors cebo-controlled trial. Diabetes Obes Metab. indicated for the treatment of type 2 diabetes mel- 2012;14(11):1040–6. litus. Clin Exp Pharmacol Physiol. 2015;42(10):999–1024. 22. Kadowaki T, Kondo K. Efﬁcacy, safety and dose-re- sponse relationship of teneligliptin, a dipeptidyl 32. Schernthaner G, Mogensen CE, Schernthaner GH. peptidase-4 inhibitor, in Japanese patients with The effects of GLP-1 analogues, DPP-4 inhibitors type 2 diabetes mellitus. Diabetes Obes Metab. and SGLT2 inhibitors on the renal system. Diab 2013;15(9):810–8. Vasc Dis Res. 2014;11(5):306–23. 23. Kadowaki T, Marubayashi F, Yokota S, Katoh M, 33. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu Iijima H. Safety and efﬁcacy of teneligliptin in CY. Chronic kidney disease and the risks of death, Japanese patients with type 2 diabetes mellitus: a cardiovascular events, and hospitalization. N Engl J pooled analysis of two phase III clinical studies. Med. 2004;351(13):1296–305. Expert Opin Pharmacother. 2015;16(7):971–81. 34. Yamout H, Perkovic V, Davies M, et al. Efﬁcacy and 24. Kadowaki T, Kondo K. Efﬁcacy and safety of tene- safety of canagliﬂozin in patients with type 2 dia- ligliptin in combination with pioglitazone in Japa- betes and stage 3 nephropathy. Am J Nephrol. nese patients with type 2 diabetes mellitus. 2014;40(1):64–74. J Diabetes Investig. 2013;4(6):576–84. 35. Mann JFE, Orsted DD, Brown-Frandsen K, et al. 25. Kadowaki T, Kondo K. Efﬁcacy and safety of tene- Liraglutide and renal outcomes in type 2 diabetes. ligliptin added to glimepiride in Japanese patients N Engl J Med. 2017;377(9):839–48. with type 2 diabetes mellitus: a randomized, dou- ble-blind, placebo-controlled study with an open- 36. Mogensen UM, Andersson C, Fosbøl EL, et al. Sul- label, long-term extension. Diabetes Obes Metab. fonylurea in combination with insulin is associated 2014;16(5):418–25. with increased mortality compared with a combi- nation of insulin and metformin in a retrospective Diabetes Ther (2018) 9:1083–1097 1097 Danish nationwide study. Diabetologia. type 2 diabetes mellitus on hemodialysis: evalua- 2015;58(1):50–8. tion by continuous glucose monitoring. J Diabetes Complications. 2015;29(8):1310–3. 37. Thomas MC, Palda´nius PM, Ayyagari R, Ong SH, Groop PH. Systematic literature review of DPP-4 40. Yajima T, Yajima K, Hayashi M, Takahashi H, inhibitors in patients with type 2 diabetes mellitus Yasuda K. Efﬁcacy and safety of teneligliptin in and renal impairment. Diabetes Ther. addition to insulin therapy in type 2 diabetes mel- 2016;7(3):439–54. litus patients on hemodialysis evaluated by con- tinuous glucose monitoring. Diabetes Res Clin 38. Abubaker M, Mishra P, Swami OC. Teneligliptin in Pract. 2016;122:78–83. management of diabetic kidney disease: a review of place in therapy. J Clin Diagn Res. 2017;11(1):05–9. 41. Nakao T, Inaba M, Abe M, et al. Best practice for diabetic patients on hemodialysis 2012. Ther Apher 39. Wada N, Mori K, Nakagawa C, et al. Improved gly- Dial. 2015;19(Suppl 1):40–66. cemic control with teneligliptin in patients with
Diabetes Therapy – Springer Journals
Published: Apr 10, 2018
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