Effects of Insulin Degludec and Insulin Glargine U300 on Day-to-Day Fasting Plasma Glucose Variability in Individuals with Type 1 Diabetes: A Multicenter, Randomized, Crossover Study (Kobe Best Basal Insulin Study 2).

INTRODUCTION: Administered basal insulin markedly influences the fasting plasma glucose (FPG) level of individuals with type 1 diabetes. Insulin degludec (IDeg) and insulin glargine U300 (IGlar U300) are now available as ultra-long-acting insulin formulations, but whether or how their glucose-stabilizing effects differ remains unclear. We will compare the effects of these basal insulins on parameters related to blood glucose control, with a focus on day-to-day glycemic variability, in individuals with type 1 diabetes treated with multiple daily injections. METHODS: A multicenter, randomized, open-label, crossover, comparative study (Kobe Best Basal Insulin Study 2) will be performed at 13 participating institutions in Japan. A total of 46 C-peptide-negative adult outpatients with type 1 diabetes will be randomly assigned 1:1 by a centralized allocation process to IGlar U300 (first period)/IDeg (second period) or IDeg (first period)/IGlar U300 (second period) groups, in which subjects will be treated with the corresponding basal insulin for consecutive 4-week periods. The basal insulin will be titrated to achieve an FPG of less than 130 mg/dL initially and then less than 110 mg/dL if feasible. In the last week of each period, plasma glucose will be determined seven times a day by self-monitoring of blood glucose (SMBG) and intraday and day-to-day glucose excursions will be determined by flash glucose monitoring (FGM). The primary end point is comparison of day-to-day glycemic variability as evaluated by the standard deviation (SD) of FPG during the last week of each treatment period. Secondary end points include the coefficient of variance of FPG, the frequency of severe hypoglycemia as evaluated by SMBG, the duration of hypoglycemia as evaluated by FGM, intraday glycemic variability calculated from both SMBG and FGM data, and the administered insulin dose. PLANNED OUTCOMES: The results of the study will be submitted for publication in a peer-reviewed journal to report differences in the effects of two ultra-long-acting basal insulins, IDeg and IGlar U300. CONCLUSION: This head-to-head comparison will be the first study to compare the effects of IDeg and IGlar U300 on day-to-day FPG variability in C-peptide-negative individuals with type 1 diabetes. TRIAL REGISTRATION: Registered in University Hospital Medical Information Network (UMIN) Clinical Trials Registry as 000029630 on 20 June 2017. FUNDING: Novo Nordisk Pharma Ltd.

Effects of insulin degludec and insulin glargine on day-to-day fasting plasma glucose variability in individuals with type 1 diabetes: a multicentre, randomised, crossover study.

AIMS/HYPOTHESIS: We compared the effects of insulin degludec (IDeg; Des(B30)LysB29(γ-Glu Nε-hexadecandioyl) human insulin) and insulin glargine (IGlar; A21Gly,B31Arg,B32Arg human insulin) on the day-to-day variability of fasting plasma glucose (FPG) levels in individuals with type 1 diabetes treated with basal-bolus insulin injections. METHODS: The effects of basal-bolus insulin therapy for 4 weeks with either IDeg or IGlar as the basal insulin in adult C-peptide-negative outpatients with type 1 diabetes were investigated in an open-label, multicentre, randomised, crossover trial. Randomisation was conducted using a centralised allocation process. The primary endpoints were the SD and CV of FPG during the final week of each treatment period. Secondary endpoints included serum glycoalbumin level, daily dose of insulin, intraday glycaemic variability and frequency of severe hypoglycaemia. RESULTS: Thirty-six randomised participants (17 in the IDeg/IGlar and 19 in the IGlar/IDeg groups) were recruited, and data for 32 participants who completed the trial were analysed. The mean (7.74 ± 1.76 vs 8.56 ± 2.06 mmol/l; p = 0.04) and SD (2.60 ± 0.97 vs 3.19 ± 1.36 mmol/l; p = 0.03) of FPG were lower during IDeg treatment than during IGlar treatment, whereas the CV did not differ between the two treatments. The dose of IDeg was smaller than that of IGlar (11.0 ± 5.2 vs 11.8 ± 5.6 U/day; p < 0.01), but other secondary endpoints did not differ between the treatments. CONCLUSIONS/INTERPRETATION: IDeg yielded a lower FPG level and smaller day-to-day variability of FPG at a lower daily dose compared with IGlar in participants with type 1 diabetes. IDeg serves as a good option for basal insulin in the treatment of type 1 diabetes. TRIAL REGISTRATION: University Hospital Medical Information Network 000009965. FUNDING: This research recieved no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

Prospective short-term effects of glucocorticoid treatment on glucose and lipid metabolism in Japanese.

OBJECTIVE: Glucocorticoid (GC) causes various metabolic abnormalities; however, few prospective studies have examined the changes in glucose and lipid metabolism in newly GC-treated patients. METHODS AND PATIENTS: The present study was therefore performed to analyze markers of glucose and lipid metabolism on days 0, 3, 7, 14, 28 and at month 3 of treatment in patients starting GC therapy. Then, we analyzed the relationships between the changes in these parameters and the initial dose of prednisolone (PSL), separating groups into different regimens by the GC dose. RESULTS: The fasting plasma glucose (FPG) level transiently increased on day 3 of PSL administration but was restored by day 7. The immunoreactive insulin (IRI) level and HOMA-R transiently increased on day 3 and then fell, although remaining significantly higher than each basal level by day 7. A transient elevation in FPG level on day 3 was observed only in groups with a PSL dose >or=40 mg. On the other hand, total cholesterol and low-density lipoprotein cholesterol levels increased on day 3 of PSL administration and similar levels were maintained after day 7. High density-lipoprotein cholesterol levels were significantly increased on day 3; subsequently then gradually increased from days 3 to day 28. Triglyceride levels did not change during treatment. No relationship was apparent between the GC dose and the changes in each lipid parameter. CONCLUSION: GC treatment induced changes in FPG, IRI, LDL-CHOL and HDL-CHOL levels from day 3 after start of GC. The dose of GC seemed to influence glucose metabolism, but not lipid metabolism.

Short-term effects of glucocorticoid therapy on biochemical markers of bone metabolism in Japanese patients: a prospective study.

Glucocorticoid (GC) therapy induces rapid bone loss, but the early changes in calcium and bone metabolism in patients treated with GC have not been clarified. To investigate the changes in calcium and bone metabolism during the early stage of GC therapy, we analyzed various biochemical markers of bone metabolism. The serum levels of calcium (Ca), phosphorus, parathyroid hormone (PTH), osteocalcin (OC), bone alkaline phosphatase (BAP), and type I collagen cross-linked N-telopeptide (NTx), as well as the urinary levels of Ca, creatinine, and NTx, were measured on days 0, 3, 7, and 28 of GC therapy. The subjects were divided into the following four groups: 9 patients receiving pulse therapy (P), 18 patients receiving prednisolone (PSL) at doses > or =40 mg/day (H), 9 patients receiving PSL at doses > or =20 mg/day (M), and 11 patients receiving PSL at doses < or =10 mg/day (S). The serum OC level showed a marked decrease on day 3 of GC therapy (-41.2% +/- 6.6%, P < 0.01), while the BAP level decreased gradually. Both serum and urinary NTx levels significantly increased on day 7 of GC therapy (9.9% +/- 4.5%, P < 0.05, and 42.2% +/- 10.6%, P < 0.01, respectively). Urinary Ca excretion was increased on day 3 of GC therapy and continued to increase until 4 weeks, while intact PTH showed an increase on day 3 and then remained constant until 4 weeks. In groups P and H, there were significant early changes in OC, BAP, NTx, and intact PTH levels, as well as urinary Ca excretion. Even a PSL dose of <10 mg/day caused a decrease in the serum OC level. In conclusion, the biochemical markers of Ca and bone metabolism showed different kinetics depending on the dose of GC, and it is important for patients on high-dose GC therapy to receive prophylaxis for bone loss from the start of GC treatment.

A case of multiple skeletal lesions of brown tumors, mimicking carcinoma metastases.

Brown tumor is not a true tumor, being an unusual reactive lesion in association with primary or secondary hyperparathyroidism. We report a 23-year-old woman, who initially presented with lower back pain caused by ureterolithiasis. The initial diagnosis of brown tumor was delayed, but later pain in her leg worsened and a sacral lesion was incidentally discovered on lumbar magnetic resonance imaging (MRI); multiple destructive bone lesions were then found radiologically. The radiological features of the multiple bone lesions, which mimicked multiple metastatic tumors, seemed to be those of the terminal stage of malignancy. However, pathological examination and abnormal laboratory data showing elevated serum calcium, alkaline phosphatase, and parathyroid hormone and low serum phosphate confirmed the diagnosis of brown tumor. Adenoma in the parathyroid gland was confirmed and surgically resected. The clinical symptoms of bone pain, and abnormal radiological findings and laboratory data were resolved 6 months after surgery. Synthetic analysis of the clinical, radiological, and laboratory findings was necessary for the definite diagnosis of brown tumor.