Basal–Bolus Insulin Therapy with Gla-300 During Hospitalization Reduces Nocturnal Hypoglycemia in Patients with Type 2 Diabetes Mellitus: A Randomized Controlled Study

Basal–Bolus Insulin Therapy with Gla-300 During Hospitalization Reduces Nocturnal Hypoglycemia... Diabetes Ther (2018) 9:1049–1059 https://doi.org/10.1007/s13300-018-0419-z ORIGINAL RESEARCH Basal–Bolus Insulin Therapy with Gla-300 During Hospitalization Reduces Nocturnal Hypoglycemia in Patients with Type 2 Diabetes Mellitus: A Randomized Controlled Study . . . Fumitaka Okajima Yuko Nakamura Yuji Yamaguchi . . . Yuki Shuto Katsuhito Kato Hitoshi Sugihara Naoya Emoto Received: November 6, 2017 / Published online: April 4, 2018 The Author(s) 2018 Insulin doses were adjusted to maintain blood ABSTRACT glucose levels within 100–120 mg/dL at each meal. Plasma glucose and C-peptide profiles Introduction: Although reduction in the inci- were estimated serially after admission and dence of nocturnal hypoglycemia, as estimated before discharge. Daily CGM was also per- by symptom or self-monitored plasma glucose, formed before discharge. was shown to be more pronounced with Results: In the Gla-100 and Gla-300 groups, the 300 units/mL insulin glargine (Gla-300) than mean duration of hospitalization was 15 ± 2 with 100 units/mL insulin glargine (Gla-100) in and 15 ± 1 days, respectively, and the mean type 2 diabetes patients, the exact frequency of basal insulin dose before discharge was 13 ± 7 nocturnal hypoglycemia estimated with con- and 15 ± 10 units, respectively. The dose of tinuous glucose monitoring (CGM) has not meal-time insulin was not different between the been reported. two groups. Compared with the Gla-300 group, Methods: Forty patients with type 2 diabetes the Gla-100 group had significantly lower noc- who were admitted for glycemic control with turnal profiles of plasma glucose and C-peptide, basal–bolus insulin therapy (BBT) were ran- but significantly higher frequency of CGM-es- domized into the Gla-100 and Gla-300 groups. timated nocturnal hypoglycemia (10.7% ± Enhanced content To view enhanced content for this 18.4% versus 1.2% ± 3.6%, P = 0.033). article go to https://doi.org/10.6084/m9.figshare. Conclusion: In type 2 diabetic patients, reduc- tion in the incidence of CGM-estimated noc- turnal hypoglycemia by BBT under tightly F. Okajima (&)  Y. Nakamura  Y. Yamaguchi controlled diet therapy was higher with Gla-300 Y. Shuto  N. Emoto Department of Endocrinology, Chiba-Hokusoh than with Gla-100. Hospital, Nippon Medical School, Inzai, Chiba, Trial Registration: UMIN clinical trials registry Japan (UMIN000023360). e-mail: okaji@nms.ac.jp F. Okajima  Y. Nakamura  Y. Yamaguchi Keywords: Basal–bolus insulin therapy; Y. Shuto  H. Sugihara  N. Emoto Continuous glucose monitoring; Insulin Department of Endocrinology, Diabetes and glargine 300 U/mL; Nocturnal hypoglycemia; Metabolism, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan Type 2 diabetes mellitus K. Kato Department of Hygiene and Public Health, Nippon Medical School, Tokyo, Japan 1050 Diabetes Ther (2018) 9:1049–1059 INTRODUCTION METHODS Basal–bolus insulin therapy (BBT) is the most Subjects effective approach to ameliorate hyperglycemia, but has adverse effects, such as weight gain and In the present study, we included the type 2 hypoglycemia, which may increase the inci- diabetes patients, who consulted the outpatient dence of cardiovascular events. During the clinic of Nippon Medical School Chiba Hoku- daytime, a patient can become aware of the soh Hospital from November 2014 to October symptoms of hypoglycemia, such as palpita- 2016 if they had HbA1c level C 10% on the first tions, cold sweats, etc. However, nocturnal visit and had consented for hospitalization for hypoglycemia is difficult to notice for a patient. diabetic control. The hospital is one of the three With continuous glucose monitoring (CGM), base hospitals in a locality with a population of nocturnal hypoglycemia, including asymp- 700,000 that consists of several cities, towns, tomatic hypoglycemia, can be detected with and villages near the metropolitan city of high precision [1]. Because of a flatter pharma- Tokyo, Japan. The clinic provides care to cokinetics (PK) scope, therapy with insulin patients with diabetes referred by general prac- glargine 100 units/mL (Gla-100) was reported to titioners or other departments in the hospital significantly reduce the incidence of severe because the diabetes was difficult to control symptomatic nocturnal hypoglycemia, com- because of poor metabolic control or unsta- pared with therapy with neutral protamine ble complications. The socioeconomic status of Hagedorn insulin [2]. However, our previous the patients was previously reported [15]. Sub- investigation on hospitalized type 2 diabetic jects were excluded if they had been previously patients with tightly controlled blood sugar treated with insulin; were positive for anti-glu- under BBT showed that Gla-100 induced tamic acid decarboxylase antibody; or had his- asymptomatic hypoglycemia, confirmed by tory or evidence of recent myocardial CGM, in high frequency [3]. infarction, heart failure, cerebrovascular dis- On the other hand, insulin glargine ease, endocrine disease, or any carcinoma. 300 units/mL (Gla-300) is a new basal insulin A total of 54 patients with type 2 diabetes analogue that has a prolonged effect and flatter were assessed for eligibility. Patients were PK profile than Gla-100 [4–6]. Previous studies excluded because of the presence of concomi- on type 2 diabetic patients treated with BBT, tant disease (n = 7), insulin use (n = 3), and basal supported oral therapy, or oral antidia- rejection of approval (n = 4). The remaining 40 betic agents alone showed that compared with patients, aged 20–75 years, were enrolled in an Gla-100, Gla-300 could control HbA1c at the unblinded, randomized study (Fig. 1). same efficacy and with consistently less risk of nocturnal hypoglycemia at 3:00, as estimated by Study Protocol and Treatment symptoms and self-monitored plasma glucose [7–12]. Two studies that employed CGM The study protocol was approved by the ethics demonstrated the safety and efficacy of Gla-300 committee of Nippon Medical School Chiba in type 1 diabetics [13, 14]; however, research on Hokusoh Hospital (No.527009) and was regis- CGM in type 2 diabetic patients has not been tered at UMIN Clinical Trials Registry reported. (UMIN000023360). All procedures followed In the present study, we evaluated by CGM were in accordance with the ethical standards of the efficacy and safety of BBT with Gla-300 in the responsible committee on human experi- comparison with that with Gla-100 in well- mentation (institutional and national) and with controlled type 2 diabetic patients at the end of the Helsinki Declaration of 1964, as revised in short-term hospitalization. 2013. Informed consent was obtained from all patients for inclusion in the study. On admis- sion, all subjects stopped taking oral Diabetes Ther (2018) 9:1049–1059 1051 Fig. 1 Participant flow antidiabetic agents, received diet therapy, and To assess the daily profile of plasma glucose were randomly assigned using a table of random and C-peptide (CPR), blood specimens were sampling numbers (block size of 4) to receive obtained from the cubital vein before and every BBT with insulin glulisine plus either Gla-100 2 h after each meal (8:00, 10:00, 12:00, 14:00, (Gla-100 group, n = 20) or Gla-300 (Gla-300 18:00, and 20:00); at night (23:00); in the early group, n = 20). morning (3:00); and on the next morning In both groups, the dose of insulin injection (8:00). These processes were performed on the was adjusted by the attending physicians to first and second days after admission and on the maintain pre-meal blood glucose levels within last 2 days before discharge. Analysis of daily 100–120 mg/dL. Within 3 days after admission, profile was performed for the whole day; during an ophthalmologist checked each patient for the daytime including 8:00, 10:00, 12:00, 14:00, the presence of diabetic retinopathy; if needed, 18:00, and 20:00; and at night including 23:00, fluorescent fundus angiography and retinal 3:00, and 8:00 of the next morning. The blood laser photocoagulation were immediately samples collected between 7:30 and 14:00 were performed. immediately centrifuged, whereas those 1052 Diabetes Ther (2018) 9:1049–1059 collected between 17:00 and 3:00 were stored at Statistics software (version 22; IBM Japan, 4C and centrifuged the next morning. Tokyo, Japan). A P value of less than 0.05 was Daily blood glucose profiles on the last considered statistically significant. 2 days before discharge were assessed by CGM TM (iPro 2; Medtronic, Minneapolis, MN, USA). RESULTS To assess daily glycemic variability, the mean glucose level, standard deviation (SD) of the The present study enrolled 40 patients, with daily glucose, and mean amplitude of glycemic mean age of 58 ± 14 years, who had type 2 excursion (MAGE) [16] were calculated. Hypo- diabetes for a mean duration of 5 ± 6 years; glycemia was defined as a CGM value of lower 72.5% were men (Table 1). Four patients, two than 70 mg/dL. A hypoglycemic episode that from each group, dropped out because of the occurred anytime from 0:00 to 8:00 was defined detection of malignancy or withdrawal of as nocturnal hypoglycemia. approval (Fig. 1). There were no significant dif- ferences in the baseline characteristics between Statistical Analysis the two treatment groups. The duration of hospitalization was 15 ± 2 All analyses except two-way repeated measures and 15 ± 1 days in the Gla-100 and Gla-300 analysis of variance were performed using the groups, respectively. The required insulin doses JMP 12.2 software (SAS Institute, Cary, NC). to maintain normoglycemia were not different Values were presented as mean ± SD or num- between the two groups; specifically, the ber. Statistical analyses of the gender differences required doses for Gla-100 and Gla-300 were and complications of diabetes at baseline were 10 ± 5 and 10 ± 6 units, respectively, before performed using the v test. The significance of breakfast; 3 ± 2 and 2 ± 2 units, respectively, the differences between two groups with regard before lunch; 9 ± 3 and 9 ± 4 units, respec- to the baseline characteristics and parameters of tively, before dinner; and 13 ± 7 and glycemic control before discharge was analyzed 15 ± 10 units, respectively, at bedtime. by Student’s t test. Two-way repeated measures The daily profiles of plasma glucose and CPR analysis of variance of the daily profile of PG were not significantly different between the two and CPR were performed using IBM SPSS groups upon admission, but were significantly Table 1 Baseline parameters of glycemic control, complications, and medications before admission Parameter Gla-100 Gla-300 P value Number of patients (men) 20 (13) 20 (16) NS Age (years) 61 ± 12 54 ± 15 NS Duration of diabetes (years)* 6 ±75 ±6NS BMI (kg/m ) 26.1 ± 3.9 25.5 ± 6.3 NS Designated dietary calorie (kcal/day) 1594 ± 231 1661 ± 217 NS FPG (mg/dL) 198 ± 54 199 ± 51 NS HbA1c (%)** 11.1 ± 2.1 11.0 ± 2.2 NS GA (%) 27 ± 6.8 28.6 ± 9.9 NS ALT (mg/dL) 29 ± 17 23 ±9NS AST (mg/dL) 30 ± 21 26 ± 13 NS GGT (mg/dL) 57 ± 72 43 ± 33 NS Diabetes Ther (2018) 9:1049–1059 1053 Table 1 continued Parameter Gla-100 Gla-300 P value Cre (mg/dL) 0.71 ± 0.21 0.73 ± 0.29 NS U-CPR (lg/day) 116 ± 67.5 133 ± 65 NS Complication Absent Achilles tendon reflex (n) 9 10 NS U-Alb (mg/day) 94.4 ± 188 311.2 ± 865.2 NS Diabetic retinopathy (DR)*** NS None (n)14 11 Simple DR (n)5 8 Preproliferative DR (n)1 1 Proliferative DR (n)0 0 Medication before admission* NS Sulfonylureas (n)4 4 Biguanides (n)3 4 Thiazolidinediones (n)1 0 Alpha-glucosidase inhibitors (n)3 1 Dipeptidyl peptidase-4 inhibitor (n)5 4 Data are expressed as mean ± standard deviation or number Gla-100 insulin glargine 100 units/mL, Gla-300 insulin glargine 300 units/mL, NS not significant, BMI body mass index, FPG fasting plasma glucose, HbA1c hemoglobin A1c, GA glycated albumin, AST aspartate aminotransferase, ALT alanine aminotransferase, GGT gamma glutamyl transpeptidase, Cre creatinine, U-CPR urinary C-peptide immunoreactivity, U-Alb urinary albumin *Reported by the general practitioners who referred the patients **HbA1c levels were determined by high-performance liquid chromatography using an HLC723G8 (Tosoh, Co., Tokyo, Japan) and presented as the equivalent National Glycohemoglobin Standardization Program values ***Evaluated by ophthalmologists who performed fundoscopy after pupillary dilatation following the Davis classification lower in the Gla-100 group than in the Gla-300 4). No patients reported nocturnal hypo- group only at night before discharge (Fig. 2 and glycemic symptoms, such as night sweats and Table 2). The mean glucose (119 ± 15 and nightmares, during the admission. 124 ± 20 in Gla-100 and Gla-300 group, No adverse events, such as symptomatic respectively), SD (33 ± 11 and 31 ± 12), and hypoglycemia, injection-site reaction, infection MAGE (79 ± 36 and 74 ± 27) levels calculated gastrointestinal events, musculoskeletal com- with CGM data before discharge were not sig- plaints, or newly developed blood test abnor- nificantly different between the BBT groups. mality during admission, were reported. However, in both groups, the nadir of the blood glucose profile was around 0:00–1:00 a.m. DISCUSSION (Fig. 3). The frequency of nocturnal hypo- glycemia was significantly lower in the Gla-300 The present study, which employed CGM and group than in the Gla-100 group (1.2% ± 3.6% serial phlebotomies to compare Gla-300 and versus 10.7% ± 18.4%, P = 0.039) (Figs. 3 and 1054 Diabetes Ther (2018) 9:1049–1059 Fig. 2 Daily profiles of plasma glucose and serum C-pep- insulin glargine 300 units/mL group (filled circles and tide. Daily profiles of plasma glucose (a, c) and serum solid line; n = 18) on admission (a, b) and upon discharge C-peptide (b, d) in the insulin glargine 100 units/mL (c, d) group (open triangles and dashed line; n = 18) and in the Gla-100, revealed no difference in the required reduced absorption of the more concentrated dose of insulin and time to achieve normo- Gla-300 insulin in subcutaneous administra- glycemia. However, the frequency of nocturnal tion, even at equal doses with Gla-100 [4–6]. hypoglycemia was significantly lower with Gla- In the present study, the nocturnal plasma 300 than with Gla-100. In similar studies, glucose and CPR levels estimated by serial [7–9, 11, 12] the basal insulin dose required to phlebotomies were significantly lower in Gla- achieve the same fasting plasma glucose had a 100 than in Gla-300, probably owing to the non-significant and slight tendency to be stronger glucose-lowering effect of the infused higher with Gla-300 than with Gla-100. The Gla-100 in the nocturnal phase. The CGM-esti- required dose of prandial insulin was not dif- mated nocturnal glucose levels in the Gla-100 ferent between the two groups. group were lower in the hypoglycemic range at The higher required dose of Gla-300 proba- a high frequency than those in the Gla-300 bly reflects the slightly lower serum glargine group. concentration at 11 h after administration, The reduction of frequency in the nocturnal which could be explained by some PK–phar- hypoglycemia in type 2 diabetic patients in this macodynamics (PD) studies that showed study was the same as the results shown in Diabetes Ther (2018) 9:1049–1059 1055 Table 2 Analysis of the daily profiles of plasma glucose and serum C-peptide Whole day Daytime Night Treatment Time Time 3 treatment Treatment Time Time 3 treatment Treatment Time Time 3 treatment On admission Plasma glucose F 0.020 23 0.21 0.058 34 0.12 0.0065 30 0.11 P (95% 0.89 (- 50, \ 0.001 0.90 0.81 (- 53, \ 0.001 0.98 0.94 (- 47, 43) \ 0.001 0.82 CI) 57) 67) Serum CPR F 1.2 27 0.87 0.98 51 0.89 1.5 41 2.9 P (95% 0.29 (- 1.3, \ 0.001 0.45 0.33 (- 1.6, \ 0.001 0.44 0.30 (- 1.0, 0.26) \ 0.001 0.079 CI) 0.41) 0.54) Before discharge Plasma glucose F 3.1 29 1.35 0.98 46 0.67 5.6 7.8 3.2 P (95% 0.088 (- 22, \ 0.001 0.26 0.33 (- 20, \ 0.001 0.56 0.023 (- 30, 0.0017 0.069 CI) 1.6) 6.7) - 2.4) Serum CPR F 3.9 16 1.07 2.6 28 1.1 6.5 12 4.2 P (95% 0.058 (- 1.3 \ 0.001 0.35 0.12 (- 1.6, \ 0.001 0.33 0.0047 (- 0.93, \ 0.001 0.027 CI) 0.023) 0.19) - 0.18) Repeated multivariate analyses of variance were performed for the whole day (all point); during the daytime (8:00, 10:00, 12:00, 14:00, 18:00, and 20:00); and at night (23:00, 3:00, and 8:00 of the next day). The values of statistics (F), P value (p), and 95% confidence interval (95% CI) determine differences according to insulin treatment group (treatment), time course (time), and the interaction of time course and treatment group (time 9 treatment), as calculated by repeated multivariate analysis of variance 1056 Diabetes Ther (2018) 9:1049–1059 Fig. 3 Continuous glucose monitoring values before dis- monitoring data before discharge in the a insulin glargine charge. The mean values (solid black line) and the range of 100 units/mL and b insulin glargine 300 units/mL groups standard deviation (gray area) of the continuous glucose both Gla-100 and Gla-300 at 21:00 [4–6]. In the current study, no patients with nocturnal hypoglycemia reported symptoms or showed elevation of fasting plasma glucose, such as that seen in the Somogyi phenomenon [17]. Similar to previous reports, our study suggested that detection of nocturnal hypoglycemia could be challenging without the use of CGM. Hypoglycemia is known to activate the sympathetic nerves to ameliorate hypoglycemia [18, 19]; however, this might worsen heart failure. In some clinical trials, hypoglycemia significantly increased the mortality of patients with type 2 diabetes [20, 21]. Administration of beta blocker was reported to reduce the inci- Fig. 4 Frequency of nocturnal hypoglycemia. Data are dence of hospitalization for heart failure [22], expressed as mean ± standard deviation. Gla-100, insulin whereas intensive glycemic control increased glargine 100 units/mL; Gla-300, insulin glargine the incidence of cardiovascular deaths [23]. The 300 units/mL. *P \ 0.05 versus the Gla-100 group EMPA-REG OUTCOME study demonstrated that the sodium-glucose cotransporter 2 inhibitor (SGLT2I) reduced the incidence of cardiovascu- lar mortality and hospitalization for heart fail- phase 3a EDITION programs that compared Gla-300 with Gla-100 [7–12]. The CGM data in ure in patients with type 2 diabetes [24]. We this study showed that the nadir of blood glu- previously reported that SGLT2I has a preven- cose profile was around 0:00–1:00 a.m., which is tive effect on nocturnal hypoglycemia in type 2 about 4 h after the injection of basal insulin. In diabetic patients on BBT [3]. This preventive some PK–PD studies, the peak glucose-lowering effect may have mediated the favorable results effect and serum glargine concentration were for the cardiovascular disease shown in the observed 4 h after the BBT administration of EMPA-REG OUTCOME study. Diabetes Ther (2018) 9:1049–1059 1057 Because of the long PD of insulin degludec, Funding. This study and the article process- another kind of new basal insulin analogue, a ing charges were supported by Grants-in-Aid for longer time is required to achieve a stable serum Scientific Research from Japan Society for the concentration of insulin degludec; insulin Promotion of Science (#17K08936). degludec also takes a long time to stabilize Editorial Assistance. The authors would like fasting plasma glucose after changing the dose to thank Enago (www.enago.jp) for the English of insulin compared with Gla-100. In the pre- language review. sent study, the duration of hospitalization depended on the time to achieve normal gly- Authorship. All named authors meet the cemic control, regardless of the BBT regimen International Committee of Medical Journal used. These data suggested that Gla-300 can Editors (ICMJE) criteria for authorship for this achieve a stable fasting glucose as fast as Gla- article, take responsibility for the integrity of the work as a whole, and have given their This study has some limitations. The approval for this version to be published. unblinded trial and the small sample size might impact the results in this study. Because physi- Auhtor Contributions. FO designed and cal activity during the admission was not prepared the study, and wrote the manuscript. assessed, a confounding bias might be intro- FO, YN, YY, and YS collected the data. FO and duced. We could not find previous studies about KK analyzed the data. HS and NE reviewed/ the comparison between Gla-100 and Gla-300 edited the manuscript. with tightly controlled blood glucose levels and diet therapy in hospitalization; hence, we could Disclosures. Naoya Emoto received research not perform a power analysis to determine the funds from Boehringer Ingelheim Pharmaceu- sample size. However, although the sample size ticals, Inc.; Daiichi-Sankyo Co., Ltd.; Dainippon is small, the preventive effect of Gla-300 on Sumitomo Pharma Co., Ltd.; Kowa Pharmaceu- nocturnal hypoglycemia in the present study is tical Co.; Kyowa Hakko Kirin Co.; Mitsubishi similar to the results of previous studies about Tanabe Pharma Co.; MSD K. K.; Ono Pharma- the comparison between Gla-100 and Gla-300 ceutical Co.; Takeda Pharmaceutical Co., Ltd.; at an outpatient clinic with a large sample size. and Taisho Toyama Pharmaceutical Co. Naoya Therefore, we believe that the results of the Emoto also received lecture fees from Boehrin- present study are conclusive. Further investiga- ger Ingelheim Pharmaceuticals, Inc.; Daiichi- tions on the possible complications of noctur- Sankyo Co., Ltd.; Kyowa Hakko Kirin Co.; MSD nal hypoglycemia are required. K. K.; Ono Pharmaceutical Co.; and Taisho Toyama Pharmaceutical Co. Hitoshi Sugihara received research funds from Daiichi-Sankyo CONCLUSION Co., Ltd.; MSD K. K.; Ono Pharmaceutical Co.; Taisho Toyama Pharmaceutical Co.; Astellas This study documented that Gla-300 had simi- Pharma Inc.; Eli Lilly Japan K. K.; Teijin Pharma lar efficacy with Gla-100 in controlling blood Ltd.; and Kaken Pharmaceutical Co., Ltd. glucose level, but with less frequent episodes of Hitoshi Sugihara also received lecture fees from nocturnal hypoglycemia in type 2 diabetic Daiichi-Sankyo Co., Ltd.; Kyowa Hakko Kirin patients under the tightly controlled diet ther- Co.; Mitsubishi Tanabe Pharma Co.; MSD K. K.; apy and careful monitoring of blood glucose in Novo Nordisk Inc.; Ono Pharmaceutical Co.; short-term hospitalization. Takeda Pharmaceutical Co., Ltd.; Kaken Phar- maceutical Co., Ltd.; and JCR Pharmaceutical Co., Ltd. Fumitaka Okajima received lecture fees ACKNOWLEDGEMENTS from Astellas Pharma Inc., Astra Zeneca, Boeh- ringer Ingelheim Pharmaceuticals, Inc.; Daiichi- We thank the participants of the study. Sankyo Co., Ltd.; Dainippon Sumitomo Pharma 1058 Diabetes Ther (2018) 9:1049–1059 2. Pieber TR, Eugene-Jolchine I, Derobert E. Efficacy Co., Ltd.; Eli Lilly Japan K. K.; Kowa Pharma- and safety of HOE 901 versus NPH insulin in ceutical Co.; Kyowa Hakko Kirin Co.; Mitsubishi patients with type 1 diabetes. The European Study Tanabe Pharma Co.; MSD K. K.; Novartis Group of HOE 901 in type 1 diabetes. Diabetes Care. Pharma K. K.; Novo Nordisk Inc.; Ono Phar- 2000;23(2):157–62. maceutical Co.; Sanofi K.K.; Takeda Pharma- 3. Okajima F, Nagamine T, Nakamura Y, et al. ceutical Co., Ltd.; Taisho Toyama Preventive effect of ipragliflozin on nocturnal Pharmaceutical Co.; and Terumo Co. The hypoglycemia in patients with type 2 diabetes funding agencies had no role in research design, treated with basal–bolus insulin therapy: an open- label, single-center, parallel, randomized control the results, or preparation of the manuscript. study. J Diabetes Investig. 2017;8(3):341–5. Yuko Nakamura,Yuji Yamaguchi, Yuki Shuto, and Katsuhito Kato have nothing to disclose. 4. Becker RH, Dahmen R, Bergmann K, et al. New -1 insulin glargine 300 units L provides a more even Compliance with Ethics Guidelines. The activity profile and prolonged glycemic control at steady state compared with insulin glargine study protocol was approved by the ethics -1 100 units L . Diabetes Care. 2015;38(4):637–43. committee of Nippon Medical School Chiba Hokusoh Hospital (No.527009) and was regis- 5. Shiramoto M, Eto T, Irie S, et al. Single-dose new tered at UMIN Clinical Trials Registry insulin glargine 300 U/ml provides prolonged, stable glycaemic control in Japanese and European (UMIN000023360). 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Basal–Bolus Insulin Therapy with Gla-300 During Hospitalization Reduces Nocturnal Hypoglycemia in Patients with Type 2 Diabetes Mellitus: A Randomized Controlled Study

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Medicine & Public Health; Internal Medicine; Diabetes; Cardiology; Endocrinology
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Diabetes Ther (2018) 9:1049–1059 https://doi.org/10.1007/s13300-018-0419-z ORIGINAL RESEARCH Basal–Bolus Insulin Therapy with Gla-300 During Hospitalization Reduces Nocturnal Hypoglycemia in Patients with Type 2 Diabetes Mellitus: A Randomized Controlled Study . . . Fumitaka Okajima Yuko Nakamura Yuji Yamaguchi . . . Yuki Shuto Katsuhito Kato Hitoshi Sugihara Naoya Emoto Received: November 6, 2017 / Published online: April 4, 2018 The Author(s) 2018 Insulin doses were adjusted to maintain blood ABSTRACT glucose levels within 100–120 mg/dL at each meal. Plasma glucose and C-peptide profiles Introduction: Although reduction in the inci- were estimated serially after admission and dence of nocturnal hypoglycemia, as estimated before discharge. Daily CGM was also per- by symptom or self-monitored plasma glucose, formed before discharge. was shown to be more pronounced with Results: In the Gla-100 and Gla-300 groups, the 300 units/mL insulin glargine (Gla-300) than mean duration of hospitalization was 15 ± 2 with 100 units/mL insulin glargine (Gla-100) in and 15 ± 1 days, respectively, and the mean type 2 diabetes patients, the exact frequency of basal insulin dose before discharge was 13 ± 7 nocturnal hypoglycemia estimated with con- and 15 ± 10 units, respectively. The dose of tinuous glucose monitoring (CGM) has not meal-time insulin was not different between the been reported. two groups. Compared with the Gla-300 group, Methods: Forty patients with type 2 diabetes the Gla-100 group had significantly lower noc- who were admitted for glycemic control with turnal profiles of plasma glucose and C-peptide, basal–bolus insulin therapy (BBT) were ran- but significantly higher frequency of CGM-es- domized into the Gla-100 and Gla-300 groups. timated nocturnal hypoglycemia (10.7% ± Enhanced content To view enhanced content for this 18.4% versus 1.2% ± 3.6%, P = 0.033). article go to https://doi.org/10.6084/m9.figshare. Conclusion: In type 2 diabetic patients, reduc- tion in the incidence of CGM-estimated noc- turnal hypoglycemia by BBT under tightly F. Okajima (&)  Y. Nakamura  Y. Yamaguchi controlled diet therapy was higher with Gla-300 Y. Shuto  N. Emoto Department of Endocrinology, Chiba-Hokusoh than with Gla-100. Hospital, Nippon Medical School, Inzai, Chiba, Trial Registration: UMIN clinical trials registry Japan (UMIN000023360). e-mail: okaji@nms.ac.jp F. Okajima  Y. Nakamura  Y. Yamaguchi Keywords: Basal–bolus insulin therapy; Y. Shuto  H. Sugihara  N. Emoto Continuous glucose monitoring; Insulin Department of Endocrinology, Diabetes and glargine 300 U/mL; Nocturnal hypoglycemia; Metabolism, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan Type 2 diabetes mellitus K. Kato Department of Hygiene and Public Health, Nippon Medical School, Tokyo, Japan 1050 Diabetes Ther (2018) 9:1049–1059 INTRODUCTION METHODS Basal–bolus insulin therapy (BBT) is the most Subjects effective approach to ameliorate hyperglycemia, but has adverse effects, such as weight gain and In the present study, we included the type 2 hypoglycemia, which may increase the inci- diabetes patients, who consulted the outpatient dence of cardiovascular events. During the clinic of Nippon Medical School Chiba Hoku- daytime, a patient can become aware of the soh Hospital from November 2014 to October symptoms of hypoglycemia, such as palpita- 2016 if they had HbA1c level C 10% on the first tions, cold sweats, etc. However, nocturnal visit and had consented for hospitalization for hypoglycemia is difficult to notice for a patient. diabetic control. The hospital is one of the three With continuous glucose monitoring (CGM), base hospitals in a locality with a population of nocturnal hypoglycemia, including asymp- 700,000 that consists of several cities, towns, tomatic hypoglycemia, can be detected with and villages near the metropolitan city of high precision [1]. Because of a flatter pharma- Tokyo, Japan. The clinic provides care to cokinetics (PK) scope, therapy with insulin patients with diabetes referred by general prac- glargine 100 units/mL (Gla-100) was reported to titioners or other departments in the hospital significantly reduce the incidence of severe because the diabetes was difficult to control symptomatic nocturnal hypoglycemia, com- because of poor metabolic control or unsta- pared with therapy with neutral protamine ble complications. The socioeconomic status of Hagedorn insulin [2]. However, our previous the patients was previously reported [15]. Sub- investigation on hospitalized type 2 diabetic jects were excluded if they had been previously patients with tightly controlled blood sugar treated with insulin; were positive for anti-glu- under BBT showed that Gla-100 induced tamic acid decarboxylase antibody; or had his- asymptomatic hypoglycemia, confirmed by tory or evidence of recent myocardial CGM, in high frequency [3]. infarction, heart failure, cerebrovascular dis- On the other hand, insulin glargine ease, endocrine disease, or any carcinoma. 300 units/mL (Gla-300) is a new basal insulin A total of 54 patients with type 2 diabetes analogue that has a prolonged effect and flatter were assessed for eligibility. Patients were PK profile than Gla-100 [4–6]. Previous studies excluded because of the presence of concomi- on type 2 diabetic patients treated with BBT, tant disease (n = 7), insulin use (n = 3), and basal supported oral therapy, or oral antidia- rejection of approval (n = 4). The remaining 40 betic agents alone showed that compared with patients, aged 20–75 years, were enrolled in an Gla-100, Gla-300 could control HbA1c at the unblinded, randomized study (Fig. 1). same efficacy and with consistently less risk of nocturnal hypoglycemia at 3:00, as estimated by Study Protocol and Treatment symptoms and self-monitored plasma glucose [7–12]. Two studies that employed CGM The study protocol was approved by the ethics demonstrated the safety and efficacy of Gla-300 committee of Nippon Medical School Chiba in type 1 diabetics [13, 14]; however, research on Hokusoh Hospital (No.527009) and was regis- CGM in type 2 diabetic patients has not been tered at UMIN Clinical Trials Registry reported. (UMIN000023360). All procedures followed In the present study, we evaluated by CGM were in accordance with the ethical standards of the efficacy and safety of BBT with Gla-300 in the responsible committee on human experi- comparison with that with Gla-100 in well- mentation (institutional and national) and with controlled type 2 diabetic patients at the end of the Helsinki Declaration of 1964, as revised in short-term hospitalization. 2013. Informed consent was obtained from all patients for inclusion in the study. On admis- sion, all subjects stopped taking oral Diabetes Ther (2018) 9:1049–1059 1051 Fig. 1 Participant flow antidiabetic agents, received diet therapy, and To assess the daily profile of plasma glucose were randomly assigned using a table of random and C-peptide (CPR), blood specimens were sampling numbers (block size of 4) to receive obtained from the cubital vein before and every BBT with insulin glulisine plus either Gla-100 2 h after each meal (8:00, 10:00, 12:00, 14:00, (Gla-100 group, n = 20) or Gla-300 (Gla-300 18:00, and 20:00); at night (23:00); in the early group, n = 20). morning (3:00); and on the next morning In both groups, the dose of insulin injection (8:00). These processes were performed on the was adjusted by the attending physicians to first and second days after admission and on the maintain pre-meal blood glucose levels within last 2 days before discharge. Analysis of daily 100–120 mg/dL. Within 3 days after admission, profile was performed for the whole day; during an ophthalmologist checked each patient for the daytime including 8:00, 10:00, 12:00, 14:00, the presence of diabetic retinopathy; if needed, 18:00, and 20:00; and at night including 23:00, fluorescent fundus angiography and retinal 3:00, and 8:00 of the next morning. The blood laser photocoagulation were immediately samples collected between 7:30 and 14:00 were performed. immediately centrifuged, whereas those 1052 Diabetes Ther (2018) 9:1049–1059 collected between 17:00 and 3:00 were stored at Statistics software (version 22; IBM Japan, 4C and centrifuged the next morning. Tokyo, Japan). A P value of less than 0.05 was Daily blood glucose profiles on the last considered statistically significant. 2 days before discharge were assessed by CGM TM (iPro 2; Medtronic, Minneapolis, MN, USA). RESULTS To assess daily glycemic variability, the mean glucose level, standard deviation (SD) of the The present study enrolled 40 patients, with daily glucose, and mean amplitude of glycemic mean age of 58 ± 14 years, who had type 2 excursion (MAGE) [16] were calculated. Hypo- diabetes for a mean duration of 5 ± 6 years; glycemia was defined as a CGM value of lower 72.5% were men (Table 1). Four patients, two than 70 mg/dL. A hypoglycemic episode that from each group, dropped out because of the occurred anytime from 0:00 to 8:00 was defined detection of malignancy or withdrawal of as nocturnal hypoglycemia. approval (Fig. 1). There were no significant dif- ferences in the baseline characteristics between Statistical Analysis the two treatment groups. The duration of hospitalization was 15 ± 2 All analyses except two-way repeated measures and 15 ± 1 days in the Gla-100 and Gla-300 analysis of variance were performed using the groups, respectively. The required insulin doses JMP 12.2 software (SAS Institute, Cary, NC). to maintain normoglycemia were not different Values were presented as mean ± SD or num- between the two groups; specifically, the ber. Statistical analyses of the gender differences required doses for Gla-100 and Gla-300 were and complications of diabetes at baseline were 10 ± 5 and 10 ± 6 units, respectively, before performed using the v test. The significance of breakfast; 3 ± 2 and 2 ± 2 units, respectively, the differences between two groups with regard before lunch; 9 ± 3 and 9 ± 4 units, respec- to the baseline characteristics and parameters of tively, before dinner; and 13 ± 7 and glycemic control before discharge was analyzed 15 ± 10 units, respectively, at bedtime. by Student’s t test. Two-way repeated measures The daily profiles of plasma glucose and CPR analysis of variance of the daily profile of PG were not significantly different between the two and CPR were performed using IBM SPSS groups upon admission, but were significantly Table 1 Baseline parameters of glycemic control, complications, and medications before admission Parameter Gla-100 Gla-300 P value Number of patients (men) 20 (13) 20 (16) NS Age (years) 61 ± 12 54 ± 15 NS Duration of diabetes (years)* 6 ±75 ±6NS BMI (kg/m ) 26.1 ± 3.9 25.5 ± 6.3 NS Designated dietary calorie (kcal/day) 1594 ± 231 1661 ± 217 NS FPG (mg/dL) 198 ± 54 199 ± 51 NS HbA1c (%)** 11.1 ± 2.1 11.0 ± 2.2 NS GA (%) 27 ± 6.8 28.6 ± 9.9 NS ALT (mg/dL) 29 ± 17 23 ±9NS AST (mg/dL) 30 ± 21 26 ± 13 NS GGT (mg/dL) 57 ± 72 43 ± 33 NS Diabetes Ther (2018) 9:1049–1059 1053 Table 1 continued Parameter Gla-100 Gla-300 P value Cre (mg/dL) 0.71 ± 0.21 0.73 ± 0.29 NS U-CPR (lg/day) 116 ± 67.5 133 ± 65 NS Complication Absent Achilles tendon reflex (n) 9 10 NS U-Alb (mg/day) 94.4 ± 188 311.2 ± 865.2 NS Diabetic retinopathy (DR)*** NS None (n)14 11 Simple DR (n)5 8 Preproliferative DR (n)1 1 Proliferative DR (n)0 0 Medication before admission* NS Sulfonylureas (n)4 4 Biguanides (n)3 4 Thiazolidinediones (n)1 0 Alpha-glucosidase inhibitors (n)3 1 Dipeptidyl peptidase-4 inhibitor (n)5 4 Data are expressed as mean ± standard deviation or number Gla-100 insulin glargine 100 units/mL, Gla-300 insulin glargine 300 units/mL, NS not significant, BMI body mass index, FPG fasting plasma glucose, HbA1c hemoglobin A1c, GA glycated albumin, AST aspartate aminotransferase, ALT alanine aminotransferase, GGT gamma glutamyl transpeptidase, Cre creatinine, U-CPR urinary C-peptide immunoreactivity, U-Alb urinary albumin *Reported by the general practitioners who referred the patients **HbA1c levels were determined by high-performance liquid chromatography using an HLC723G8 (Tosoh, Co., Tokyo, Japan) and presented as the equivalent National Glycohemoglobin Standardization Program values ***Evaluated by ophthalmologists who performed fundoscopy after pupillary dilatation following the Davis classification lower in the Gla-100 group than in the Gla-300 4). No patients reported nocturnal hypo- group only at night before discharge (Fig. 2 and glycemic symptoms, such as night sweats and Table 2). The mean glucose (119 ± 15 and nightmares, during the admission. 124 ± 20 in Gla-100 and Gla-300 group, No adverse events, such as symptomatic respectively), SD (33 ± 11 and 31 ± 12), and hypoglycemia, injection-site reaction, infection MAGE (79 ± 36 and 74 ± 27) levels calculated gastrointestinal events, musculoskeletal com- with CGM data before discharge were not sig- plaints, or newly developed blood test abnor- nificantly different between the BBT groups. mality during admission, were reported. However, in both groups, the nadir of the blood glucose profile was around 0:00–1:00 a.m. DISCUSSION (Fig. 3). The frequency of nocturnal hypo- glycemia was significantly lower in the Gla-300 The present study, which employed CGM and group than in the Gla-100 group (1.2% ± 3.6% serial phlebotomies to compare Gla-300 and versus 10.7% ± 18.4%, P = 0.039) (Figs. 3 and 1054 Diabetes Ther (2018) 9:1049–1059 Fig. 2 Daily profiles of plasma glucose and serum C-pep- insulin glargine 300 units/mL group (filled circles and tide. Daily profiles of plasma glucose (a, c) and serum solid line; n = 18) on admission (a, b) and upon discharge C-peptide (b, d) in the insulin glargine 100 units/mL (c, d) group (open triangles and dashed line; n = 18) and in the Gla-100, revealed no difference in the required reduced absorption of the more concentrated dose of insulin and time to achieve normo- Gla-300 insulin in subcutaneous administra- glycemia. However, the frequency of nocturnal tion, even at equal doses with Gla-100 [4–6]. hypoglycemia was significantly lower with Gla- In the present study, the nocturnal plasma 300 than with Gla-100. In similar studies, glucose and CPR levels estimated by serial [7–9, 11, 12] the basal insulin dose required to phlebotomies were significantly lower in Gla- achieve the same fasting plasma glucose had a 100 than in Gla-300, probably owing to the non-significant and slight tendency to be stronger glucose-lowering effect of the infused higher with Gla-300 than with Gla-100. The Gla-100 in the nocturnal phase. The CGM-esti- required dose of prandial insulin was not dif- mated nocturnal glucose levels in the Gla-100 ferent between the two groups. group were lower in the hypoglycemic range at The higher required dose of Gla-300 proba- a high frequency than those in the Gla-300 bly reflects the slightly lower serum glargine group. concentration at 11 h after administration, The reduction of frequency in the nocturnal which could be explained by some PK–phar- hypoglycemia in type 2 diabetic patients in this macodynamics (PD) studies that showed study was the same as the results shown in Diabetes Ther (2018) 9:1049–1059 1055 Table 2 Analysis of the daily profiles of plasma glucose and serum C-peptide Whole day Daytime Night Treatment Time Time 3 treatment Treatment Time Time 3 treatment Treatment Time Time 3 treatment On admission Plasma glucose F 0.020 23 0.21 0.058 34 0.12 0.0065 30 0.11 P (95% 0.89 (- 50, \ 0.001 0.90 0.81 (- 53, \ 0.001 0.98 0.94 (- 47, 43) \ 0.001 0.82 CI) 57) 67) Serum CPR F 1.2 27 0.87 0.98 51 0.89 1.5 41 2.9 P (95% 0.29 (- 1.3, \ 0.001 0.45 0.33 (- 1.6, \ 0.001 0.44 0.30 (- 1.0, 0.26) \ 0.001 0.079 CI) 0.41) 0.54) Before discharge Plasma glucose F 3.1 29 1.35 0.98 46 0.67 5.6 7.8 3.2 P (95% 0.088 (- 22, \ 0.001 0.26 0.33 (- 20, \ 0.001 0.56 0.023 (- 30, 0.0017 0.069 CI) 1.6) 6.7) - 2.4) Serum CPR F 3.9 16 1.07 2.6 28 1.1 6.5 12 4.2 P (95% 0.058 (- 1.3 \ 0.001 0.35 0.12 (- 1.6, \ 0.001 0.33 0.0047 (- 0.93, \ 0.001 0.027 CI) 0.023) 0.19) - 0.18) Repeated multivariate analyses of variance were performed for the whole day (all point); during the daytime (8:00, 10:00, 12:00, 14:00, 18:00, and 20:00); and at night (23:00, 3:00, and 8:00 of the next day). The values of statistics (F), P value (p), and 95% confidence interval (95% CI) determine differences according to insulin treatment group (treatment), time course (time), and the interaction of time course and treatment group (time 9 treatment), as calculated by repeated multivariate analysis of variance 1056 Diabetes Ther (2018) 9:1049–1059 Fig. 3 Continuous glucose monitoring values before dis- monitoring data before discharge in the a insulin glargine charge. The mean values (solid black line) and the range of 100 units/mL and b insulin glargine 300 units/mL groups standard deviation (gray area) of the continuous glucose both Gla-100 and Gla-300 at 21:00 [4–6]. In the current study, no patients with nocturnal hypoglycemia reported symptoms or showed elevation of fasting plasma glucose, such as that seen in the Somogyi phenomenon [17]. Similar to previous reports, our study suggested that detection of nocturnal hypoglycemia could be challenging without the use of CGM. Hypoglycemia is known to activate the sympathetic nerves to ameliorate hypoglycemia [18, 19]; however, this might worsen heart failure. In some clinical trials, hypoglycemia significantly increased the mortality of patients with type 2 diabetes [20, 21]. Administration of beta blocker was reported to reduce the inci- Fig. 4 Frequency of nocturnal hypoglycemia. Data are dence of hospitalization for heart failure [22], expressed as mean ± standard deviation. Gla-100, insulin whereas intensive glycemic control increased glargine 100 units/mL; Gla-300, insulin glargine the incidence of cardiovascular deaths [23]. The 300 units/mL. *P \ 0.05 versus the Gla-100 group EMPA-REG OUTCOME study demonstrated that the sodium-glucose cotransporter 2 inhibitor (SGLT2I) reduced the incidence of cardiovascu- lar mortality and hospitalization for heart fail- phase 3a EDITION programs that compared Gla-300 with Gla-100 [7–12]. The CGM data in ure in patients with type 2 diabetes [24]. We this study showed that the nadir of blood glu- previously reported that SGLT2I has a preven- cose profile was around 0:00–1:00 a.m., which is tive effect on nocturnal hypoglycemia in type 2 about 4 h after the injection of basal insulin. In diabetic patients on BBT [3]. This preventive some PK–PD studies, the peak glucose-lowering effect may have mediated the favorable results effect and serum glargine concentration were for the cardiovascular disease shown in the observed 4 h after the BBT administration of EMPA-REG OUTCOME study. Diabetes Ther (2018) 9:1049–1059 1057 Because of the long PD of insulin degludec, Funding. This study and the article process- another kind of new basal insulin analogue, a ing charges were supported by Grants-in-Aid for longer time is required to achieve a stable serum Scientific Research from Japan Society for the concentration of insulin degludec; insulin Promotion of Science (#17K08936). degludec also takes a long time to stabilize Editorial Assistance. The authors would like fasting plasma glucose after changing the dose to thank Enago (www.enago.jp) for the English of insulin compared with Gla-100. In the pre- language review. sent study, the duration of hospitalization depended on the time to achieve normal gly- Authorship. All named authors meet the cemic control, regardless of the BBT regimen International Committee of Medical Journal used. These data suggested that Gla-300 can Editors (ICMJE) criteria for authorship for this achieve a stable fasting glucose as fast as Gla- article, take responsibility for the integrity of the work as a whole, and have given their This study has some limitations. The approval for this version to be published. unblinded trial and the small sample size might impact the results in this study. Because physi- Auhtor Contributions. FO designed and cal activity during the admission was not prepared the study, and wrote the manuscript. assessed, a confounding bias might be intro- FO, YN, YY, and YS collected the data. FO and duced. We could not find previous studies about KK analyzed the data. HS and NE reviewed/ the comparison between Gla-100 and Gla-300 edited the manuscript. with tightly controlled blood glucose levels and diet therapy in hospitalization; hence, we could Disclosures. Naoya Emoto received research not perform a power analysis to determine the funds from Boehringer Ingelheim Pharmaceu- sample size. However, although the sample size ticals, Inc.; Daiichi-Sankyo Co., Ltd.; Dainippon is small, the preventive effect of Gla-300 on Sumitomo Pharma Co., Ltd.; Kowa Pharmaceu- nocturnal hypoglycemia in the present study is tical Co.; Kyowa Hakko Kirin Co.; Mitsubishi similar to the results of previous studies about Tanabe Pharma Co.; MSD K. K.; Ono Pharma- the comparison between Gla-100 and Gla-300 ceutical Co.; Takeda Pharmaceutical Co., Ltd.; at an outpatient clinic with a large sample size. and Taisho Toyama Pharmaceutical Co. Naoya Therefore, we believe that the results of the Emoto also received lecture fees from Boehrin- present study are conclusive. Further investiga- ger Ingelheim Pharmaceuticals, Inc.; Daiichi- tions on the possible complications of noctur- Sankyo Co., Ltd.; Kyowa Hakko Kirin Co.; MSD nal hypoglycemia are required. K. K.; Ono Pharmaceutical Co.; and Taisho Toyama Pharmaceutical Co. Hitoshi Sugihara received research funds from Daiichi-Sankyo CONCLUSION Co., Ltd.; MSD K. K.; Ono Pharmaceutical Co.; Taisho Toyama Pharmaceutical Co.; Astellas This study documented that Gla-300 had simi- Pharma Inc.; Eli Lilly Japan K. K.; Teijin Pharma lar efficacy with Gla-100 in controlling blood Ltd.; and Kaken Pharmaceutical Co., Ltd. glucose level, but with less frequent episodes of Hitoshi Sugihara also received lecture fees from nocturnal hypoglycemia in type 2 diabetic Daiichi-Sankyo Co., Ltd.; Kyowa Hakko Kirin patients under the tightly controlled diet ther- Co.; Mitsubishi Tanabe Pharma Co.; MSD K. K.; apy and careful monitoring of blood glucose in Novo Nordisk Inc.; Ono Pharmaceutical Co.; short-term hospitalization. Takeda Pharmaceutical Co., Ltd.; Kaken Phar- maceutical Co., Ltd.; and JCR Pharmaceutical Co., Ltd. Fumitaka Okajima received lecture fees ACKNOWLEDGEMENTS from Astellas Pharma Inc., Astra Zeneca, Boeh- ringer Ingelheim Pharmaceuticals, Inc.; Daiichi- We thank the participants of the study. Sankyo Co., Ltd.; Dainippon Sumitomo Pharma 1058 Diabetes Ther (2018) 9:1049–1059 2. Pieber TR, Eugene-Jolchine I, Derobert E. Efficacy Co., Ltd.; Eli Lilly Japan K. K.; Kowa Pharma- and safety of HOE 901 versus NPH insulin in ceutical Co.; Kyowa Hakko Kirin Co.; Mitsubishi patients with type 1 diabetes. The European Study Tanabe Pharma Co.; MSD K. K.; Novartis Group of HOE 901 in type 1 diabetes. Diabetes Care. Pharma K. K.; Novo Nordisk Inc.; Ono Phar- 2000;23(2):157–62. maceutical Co.; Sanofi K.K.; Takeda Pharma- 3. Okajima F, Nagamine T, Nakamura Y, et al. ceutical Co., Ltd.; Taisho Toyama Preventive effect of ipragliflozin on nocturnal Pharmaceutical Co.; and Terumo Co. The hypoglycemia in patients with type 2 diabetes funding agencies had no role in research design, treated with basal–bolus insulin therapy: an open- label, single-center, parallel, randomized control the results, or preparation of the manuscript. study. J Diabetes Investig. 2017;8(3):341–5. Yuko Nakamura,Yuji Yamaguchi, Yuki Shuto, and Katsuhito Kato have nothing to disclose. 4. Becker RH, Dahmen R, Bergmann K, et al. New -1 insulin glargine 300 units L provides a more even Compliance with Ethics Guidelines. The activity profile and prolonged glycemic control at steady state compared with insulin glargine study protocol was approved by the ethics -1 100 units L . Diabetes Care. 2015;38(4):637–43. committee of Nippon Medical School Chiba Hokusoh Hospital (No.527009) and was regis- 5. Shiramoto M, Eto T, Irie S, et al. Single-dose new tered at UMIN Clinical Trials Registry insulin glargine 300 U/ml provides prolonged, stable glycaemic control in Japanese and European (UMIN000023360). 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Journal

Diabetes TherapySpringer Journals

Published: Apr 4, 2018

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