Insulin Therapy In Japanese Patients Research Articles

Long-term (52-week) efficacy and safety of dapagliflozin as an adjunct to insulin therapy in Japanese patients with type 1 diabetes: Subgroup analysis of the DEPICT-2 study.

AimTo examine the long‐term efficacy and safety of dapagliflozin, a sodium‐glucose co‐transporter‐2 (SGLT2) inhibitor used to treat type 1 diabetes, in the Japanese subpopulation of the DEPICT‐2 study.Materials and MethodsPatients with type 1 diabetes were randomized to dapagliflozin 5 mg (n = 55), dapagliflozin 10 mg (n = 41) or placebo (n = 58) plus insulin for a 24‐week, double‐blind period followed by a 28‐week, single‐blind extension phase.ResultsFrom baseline to 24 weeks, dapagliflozin reduced HbA1c compared with placebo (mean change of −0.58% and −0.80% for 5 and 10 mg, respectively), and an HbA1c reduction was observed up to 52 weeks. Compared with placebo, dapagliflozin 5 and 10 mg increased the proportion of patients achieving HbA1c reductions of 0.5% or more without severe hypoglycaemia events and reduced glycaemic variability assessed via continuous glucose monitoring. Both dapagliflozin doses decreased body weight and total daily insulin dose at 24 weeks compared with placebo; these reductions were maintained up to 52 weeks. Diabetic ketoacidosis occurred in both dapagliflozin groups (one and two cases, respectively) but not with placebo.ConclusionsEfficacy and safety results from the Japanese subpopulation of the DEPICT‐2 study were generally consistent with those from the overall population, indicating that long‐term dapagliflozin adjunct to insulin therapy improves glycaemic control without an increased risk of hypoglycaemia but with a risk of diabetic ketoacidosis in Japanese patients with type 1 diabetes.

Comparative study of the usefulness of a novel insulin therapy in Japanese patients with Type 2 diabetes for concomitant use of an oral antidiabetic agent with twice-daily dosing either of insulin aspart, biphasic insulin aspart-30, or insulin detemir: Two times Insulin injection Combined with oral therapy Efficacy Study (TWICE study).

It is common to treat type 2 diabetes by regular injections of insulin. We compared the efficacy and safety of twice-daily administration of short-acting, premixed, and long-acting insulins. This was a multi-center, randomized, open-label, 52-week study. Patients were randomized to administer twice daily short-acting analog insulin (Aspart) plus a sulfonylurea (SU), premixed 70/30 analog insulin (Mix), or long-acting insulin (Detemir) plus a glinide derivative. Twelve (mean baseline HbA1c 9.86±1.71%), eight (9.24±1.14%), and eight (11.26±1.81%) patients were treated with Aspart, Mix, or Detemir, respectively, for 52 weeks. After 12 weeks, the reductions in HbA1c were similar in the groups. A further significant reduction in HbA1c occurred between weeks 12 and 52 in the Detemir, but not the Aspart or Mix groups. After 52 weeks, the target of an HbA1c <7.4% was achieved in 16.7% of the Aspart group, 37.5% of the Mix group, and 12.5% of the Detemir group (no significant differences among the three groups by χ2 analysis). The mean changes from baseline in blood glucose concentration measured after breakfast, and before and after dinner, were also similar in each group. Early and meaningful reductions in HbA1c were achieved by twice-daily administration of a premix, aspart plus an SU, and detemir plus a glinide, without severe hypoglycemia or an increase in body mass. However, the target HbA1c was achieved in relatively few participants, perhaps due to an insufficient dose of insulin or the small study size.

Efficacy and safety of ipragliflozin as add-on therapy to insulin in Japanese patients with type 2 diabetes mellitus (IOLITE): a 36-week, open-label extension of a 16-week, randomized, placebo-controlled, double-blind study.

To examine long-term efficacy/safety of ipragliflozin, a sodium-glucose cotransporter 2 inhibitor, added to ongoing insulin therapy in Japanese patients with type 2 diabetes. We conducted a 36-week, open-label extension of ipragliflozin therapy following a 16-week, randomized, placebo-controlled, double-blind period (treatment periods II and I, respectively). Prior to the open-label period, patients taking insulin with/without a dipeptidyl peptidase-4 (DPP-4) inhibitor were randomized to receive placebo or 50mg once-daily ipragliflozin. Oral antidiabetic drugs other than DPP-4 inhibitors were discontinued 4weeks before screening. Following treatment period I, all patients received open-label ipragliflozin 50mg, with the possibility of a dose increase to 100mg at week24 if HbA1c was ≥ 7.0% at week20. Efficacy endpoints were changes in HbA1c, fasting plasma glucose (FPG), self-monitored blood glucose, bodyweight, and metabolic hormones. Drug-related treatment-emergent adverse events (TEAEs) were monitored for safety. Of 175 patients randomized to ipragliflozin, 168 entered treatment period II, 121 (69%) of whom completed this period. The mean ± standard deviation changes in HbA1c, FPG, and bodyweight from baseline (start of treatment period I) to the end of treatment were - 0.83 ± 0.72%, - 31.5 ± 41.2mg/dL, and - 1.34 ± 1.80kg, respectively. Between weeks 8 and 32, HbA1c was lower in patients taking a DPP-4 inhibitor than in those without. The most common drug-related TEAE was hypoglycemia; no drug-related TEAEs not already reported for ipragliflozin were observed. Ipragliflozin was well tolerated, effective, and reduced bodyweight over a period of 52weeks in patients treated with insulin with/without a DPP-4 inhibitor. NCT02175784.

Efficacy and safety of luseogliflozin added to insulin therapy in Japanese patients with type 2 diabetes: a multicenter, 52-week, clinical study with a 16-week, double-blind period and a 36-week, open-label period

Objective: To evaluate the efficacy and safety of luseogliflozin in Japanese patients with type 2 diabetes (T2D) inadequately controlled with insulin monotherapy.Methods: This 52-week multicenter study entailed a 16-week, double-blind period followed by a 36-week, open-label period. Patients were randomized to receive either luseogliflozin 2.5 mg (n = 159) or placebo (n = 74) during the double-blind period. All patients who entered the open-label period received luseogliflozin. Major efficacy endpoints included the changes from baseline in HbA1c, fasting plasma glucose (FPG), postprandial plasma glucose (PPG) and bodyweight. Safety assessments included adverse events, laboratory tests and vital signs.Results: In the double-blind period, luseogliflozin significantly decreased HbA1c (−1.18%), FPG (−42.4 mg/dL), 2 hour PPG (−68.7 mg/dL) and bodyweight (−1.27 kg) compared with placebo (all p < .001); these reductions were maintained over 52 weeks. The changes from baseline at Week 52 were −1.00%, −35.1 mg/dL, −68.8 mg/dL and −1.81 kg, respectively (all p < .001). In the placebo group, favorable glycemic control and bodyweight reduction were also observed after switching to luseogliflozin. Most adverse events were mild in severity. During the double-blind period, the incidences of hypoglycemia were 20.8% and 13.5% in the luseogliflozin and placebo groups, respectively. During the 52 weeks of luseogliflozin treatment, the frequency of hypoglycemia was 33.3%, but no serious hypoglycemia occurred. The safety profile other than hypoglycemia was also acceptable. There were no new safety concerns about luseogliflozin added to insulin.Conclusion: Luseogliflozin added to insulin therapy significantly improved glycemic control with bodyweight reduction and was well tolerated in Japanese patients with T2D.Clinical trial registration: Japan Pharmaceutical Information Center (JapicCTI-142582).

Efficacy and safety of dapagliflozin over 1 year as add-on to insulin therapy in Japanese patients with type 2 diabetes: the DAISY (Dapagliflozin Added to patients under InSulin therapY) trial.

To evaluate the efficacy and safety of dapagliflozin as add-on to insulin in Japanese patients with type 2 diabetes. Insulin-treated Japanese patients were randomized to 5 mg dapagliflozin or placebo during a 16-week double-blind treatment period. Both groups then received dapagliflozin 5 or 10 mg (the dose was increased at or after week 24 if glycated haemoglobin [HbA1c] at the previous visit was >7.5%) during a 36-week open-label extension period. The exploratory efficacy endpoint was to assess the maintenance efficacy of 5/10 mg dapagliflozin + insulin over 52 weeks of treatment. Safety was assessed in terms of adverse events, laboratory variables and vital signs. The changes in HbA1c from baseline to weeks 16 and 52 were -0.62% and -0.74%, respectively, in the dapagliflozin group, vs -0.08% and -0.83%, respectively, in the placebo-dapagliflozin group. Body weight decreased at both time points in the dapagliflozin group and after switching to open-label dapagliflozin in the placebo-dapagliflozin group. The total insulin dose decreased slightly after starting dapagliflozin. Adverse events occurred in 82.9% and 71.7% of patients in the dapagliflozin and placebo-dapagliflozin groups, respectively. Hypoglycaemia occurred in 35.0% and 41.7% of patients in the dapagliflozin and placebo-dapagliflozin groups, respectively, but the incidence was not increased by use of dapagliflozin in either trial period. Genital/urinary tract infections, renal impairment/failure, volume depletion, fracture and hepatic disorders occurred in ≤5% of patients. This trial showed that administration of dapagliflozin as an add-on to insulin therapy was effective, was well tolerated and had insulin-sparing effects in Japanese patients with type 2 diabetes.

Efficacy and safety of dapagliflozin in addition to insulin therapy in Japanese patients with type 2 diabetes: Results of the interim analysis of 16-week double-blind treatment period.

IntroductionDapagliflozin treatment when added to insulin therapy in Japanese patients with type 2 diabetes remains to be evaluated.Materials and MethodsThis was a multicenter, randomized, double‐blind, parallel‐group, placebo‐controlled study to evaluate efficacy (at 16 weeks) and long‐term safety (at 52 weeks) of dapagliflozin in addition to insulin therapy. The interim analysis was carried out at week 16 to assess the efficacy and safety profiles. The patients receiving insulin (n = 182) were randomized to either dapagliflozin 5 mg or a placebo at a 2:1 ratio. The primary efficacy end‐point was the change in hemoglobin A1c (HbA1c) from baseline at week 16.ResultsPatients in the dapagliflozin group showed an adjusted decrease in HbA1c of −0.55% from baseline, whereas the placebo showed a marginal increase of 0.05%. The placebo‐corrected mean change of HbA1c from baseline to week 16 in dapagliflozin was −0.60% (P < 0.0001). In addition, the placebo‐corrected mean change of fasting plasma glucose and bodyweight from baseline to week 16 in the dapagliflozin group was −22.7 mg/dL (P < 0.0001) and −1.21 kg (P < 0.0001), respectively. The placebo‐corrected mean daily insulin dose in the dapagliflozin group was numerically decreased (treatment difference: −0.72 IU/day; P = 0.0743). No major episodes or discontinuations as a result of hypoglycemia were reported during the study period.ConclusionsDapagliflozin used as add‐on treatment to insulin therapy showed significantly greater reduction of HbA1c, fasting plasma glucose and bodyweight without severe hypoglycemia compared with the placebo at week 16. These results show the clinical benefit of prescribing dapagliflozin for Japanese patients with insufficient glycemic control even with insulin therapy.

Efficacy and safety of sitagliptin added to insulin in Japanese patients with type 2 diabetes: the EDIT randomized trial.

AimsTo clarify the efficacy and safety of adding sitagliptin to insulin therapy in Japanese patients with suboptimally controlled type 2 diabetes (T2DM).Study Design and MethodsThis was a 24-week, prospective, randomized, open-labeled, controlled trial. Patients with T2DM who were suboptimally controlled despite receiving at least twice daily injection of insulin were enrolled in the study. The patients were randomized to continuation of insulin treatment (Insulin group) or addition of sitagliptin 50 to 100 mg daily to insulin treatment (Ins+Sita group). The primary outcome was change in HbA1c at week 24.ResultsAdding sitagliptin to insulin significantly reduced HbA1c from 7.9 ± 1.0% at baseline to 7.0 ± 0.8% at week 24 (P <0.0001), while there was no significant change in HbA1c in the Insulin group (7.8 ± 0.7% vs. 7.8 ± 1.1%, P = 0.32). The difference in HbA1c reduction between the groups was 0.9% (95% confidence interval, 0.4 to 1.5, P = 0.01). There was no significant weight gain in either group. Incidence of hypoglycemia was significantly reduced in the Ins+Sita group compared with the Insulin group. Treatment satisfaction was improved in the Ins+Sita group. Baseline HbA1c level and beta cell function were associated with the magnitude of reduction in HbA1c in the Ins+Sita group.ConclusionAdding sitagliptin to insulin reduced HbA1c without weight gain or increase in hypoglycemia, and improved treatment satisfaction in Japanese patients with T2DM who were suboptimally controlled despite at least twice daily injection of insulin.Trial RegistrationThe University Hospital Medical Information Network (UMIN) Clinical Trials Registry UMIN000004678

Age-Specific Effectiveness and Safety of Newly Initiated Insulin Therapy in Japanese Patients with Uncontrolled Diabetes

IntroductionOne consequence of population aging is an increase in the number of elderly patients with diabetes mellitus. These elderly patients often experience atherosclerotic complications, and diabetes prevention and management are strongly desired to promote health and reduce the financial burden on the healthcare system. In this study, we conducted an age-specific evaluation of the effectiveness and safety of comprehensive management with newly initiated insulin therapy over a 1-year period in elderly (≥65 years) compared with non-elderly (≤64 years) Japanese patients with uncontrolled diabetes [glycated hemoglobin (HbA1c) ≥ 8% for ≥ 3 months].MethodsThis retrospective single-center cohort study was conducted in Japan. We screened all outpatients with diabetes mellitus who visited the clinic for diabetes treatment between December 2006 and March 2011. Of these patients, 132 with type 2 diabetes who were newly initiated on insulin therapy for continued poor glycemic control and undergoing comprehensive management through self-monitoring of blood glucose (SMBG) were registered to the study.ResultsThirty-two of 132 registered patients were excluded from the analysis. Among the 100 patients (67 non-elderly, 33 elderly) included in the analysis, median age and proportion of male patients was 69 years and 66.7%, respectively, among the elderly, and 52 years and 68.7%, respectively, among the non-elderly patients. After initiation of insulin therapy, median HbA1c levels improved from 9.6% to 7.2% in elderly patients, and from 10.8% to 7.3% in non-elderly patients at baseline and 12 months. Severe hypoglycemic events were not observed in either patient group; however, uncontrolled diabetes was ongoing in 31.8% of non-elderly and 15.4% of elderly patients, and obesity was associated with poor glycemic control.ConclusionOur results indicate that the effectiveness and safety of newly initiated insulin therapy are similar between elderly and non-elderly Japanese patients with uncontrolled diabetes, and highlight the importance of comprehensive management using SMBG to avoid hypoglycemia. Better glycemic control supported by adequate intensive management is required to improve mortality and morbidity.Electronic supplementary materialThe online version of this article (doi:10.1007/s13300-013-0049-4) contains supplementary material, which is available to authorized users.

Determinants of the HbA1c-lowering effect of sitagliptin when added to ongoing insulin therapy in Japanese patients with type 2 diabetes

Aims This study assessed the independent predictors of the HbA1c-lowering effect of sitagliptin when added to ongoing insulin therapy in Japanese patients with type 2 diabetes.

Postprandial serum C-peptide to plasma glucose ratio predicts future insulin therapy in Japanese patients with type 2 diabetes

Type 2 diabetes is a progressive disease, and most patients with type 2 diabetes eventually need insulin therapy to maintain glycemic control. Recent studies have shown that early insulin treatment improved beta cell function as well as insulin resistance in patients with type 2 diabetes[1], suggesting that early introduction of insulin treatment may delay disease progression and be able to maintain good glycemic control thereafter. However, since predictive biomarkers for future insulin therapy have not been established, the introduction of insulin treatment is often delayed in clinical settings [2]. We have recently reported that lower 2 h postprandial C-peptide immunoreactivity (CPR) to plasma glucose ratio (postprandial CPR index; PCPRI) was associated with subsequent need for insulin treatment in Japanese subjects with type 2 diabetes who were admitted to our hospital between 2000 and 2007 [3]. In that study, however, since most patients were started on insulin treatment during the baseline admission, the time-to-event relationship of insulin initiation could not be accounted for in the analysis. Here, we report a sub analysis of this cohort in whom insulin therapy had not been introduced at baseline (N = 190), to establish the predictive value of PCPRI for future insulin therapy using univariate and multivariate Cox proportional hazard models. In addition, the prognostic performance of PCPRI was estimated using receiver operating characteristic (ROC) curve analysis. Baseline characteristics of the subjects were as follows; male 57.9 %, age 65 ± 13 years (mean ± SD), duration of diabetes 10 ± 9 years, BMI 25.3 ± 4.7, HbA1c 9.5 ± 1.8 % (80 ± 20 mmol/mol), fasting CPR 2.14 ± 0.95 ng/ml, fasting CPRI 1.56 ± 0.74, PCPR 5.62 ± 2.59 ng/ml, PCPRI 2.72 ± 1.62 and urinary CPR 78.4 ± 54.7 lg/day. Of the subjects, 52.1 % were treated with a sulfonylurea at baseline. During the observation period (mean 4.2 ± 2.3 years, median 3.0 years), insulin therapy was introduced in 34 subjects (18 %). Higher PCPRI at baseline was associated with a lower risk of future insulin therapy (hazard ratio (HR) for 1 unit increase in PCPRI was 0.48, 95 % CI: 0.32 to 0.73, P \ 0.001). However, neither fasting CPRI nor urinary CPR predicted future insulin therapy (P = 0.30 and P = 0.72, respectively). After adjustment for age, sex, duration of diabetes, family history of diabetes, BMI, HbA1c and sulfonylurea use at baseline, PCPRI remained an independent predictor of future insulin therapy (HR = 0.42, 95 % CI: 0.25 to 0.70, P = 0.001). The optimal cutoff value of PCPRI for predicting insulin therapy was 2.16, with 70.6 % sensitivity and 64.1 % specificity (area under the curve (AUC) of ROC curve = 0.698, 95 % CI: 0.609 to 0.788, P \ 0.001). In the present study, PCPRI predicted future insulin therapy in patients with type 2 diabetes. Interestingly, neither fasting CPR index nor urinary CPR was significantly associated with future insulin therapy, suggesting that PCPRI is the superior marker for future insulin therapy Communicated by Renato Lauro.

Postprandial serum C-peptide is a useful parameter in the prediction of successful switching to liraglutide monotherapy from complex insulin therapy in Japanese patients with type 2 diabetes

AimsLiraglutide improves glycemic control in patients with type 2 diabetes. However, no information is available about an indicator of successful switching to liraglutide monotherapy from complex insulin therapy in Japanese patients with type 2 diabetes. MethodsWe studied 69 patients with type 2 diabetes, including 39 consecutive successful patients and 30 consecutive unsuccessful patients from insulin therapy to liraglutide monotherapy. Before switching, we measured urinary C-peptide, fasting C-peptide and postprandial C-peptide at 30, 60 and 120 min loading a test meal. In successful patients, HbA1c and body weight were measured at 4, 8, and 12weeks after switching. ResultsUsing univariate analysis, duration of disease was significantly higher in unsuccessful patients than in successful patients. Urinary C-peptide, fasting C-peptide, and postprandial C-peptides were significantly higher in successful patients than in unsuccessful patients. Multiple logistic regression analysis showed that postprandial C-peptide at 60 min was an independent predictor of successful switching to liraglutide monotherapy from insulin therapy (odds ratio, 7.28; 95% confidence interval, 2.89–18.36). In the receiver operating characteristic analyses, 2.9ng/mL of postprandial C-peptide at 60 min was the best cut-off value, providing that sensitivity and specificity were 95% and 93%, respectively. In the follow-up period, successful patients showed a sustained reduction in HbA1c and body weight without hypoglycemia. ConclusionsPostprandial C-peptide at 60 min is a useful parameter in the prediction of successful switching from insulin therapy to liraglutide monotherapy in Japanese patients with type 2 diabetes.

Replacement of neutral protamine Hagedorn insulin with the long-acting insulin analogue, detemir, improves glycemic control without weight gain in basal-bolus insulin therapy in Japanese patients with type 1 diabetes.

Aims/Introduction: The aim of the present study was to evaluate the efficacy of replacing neutral protamine Hagedorn insulin (NPH) with the long-acting insulin analogue, detemir, in clinical practice. We carried out a retrospective study to compare the effects of replacing NPH with detemir in basal-bolus insulin therapy in Japanese patients with type 1 diabetes. A total of 19 patients were enrolled in the study, and changes in hemoglobin A1c (HbA1c), insulin dose, bodyweight, fasting blood glucose levels (FBG), within-patient variability in FBG and prevalence in hypoglycemia were monitored for 12 weeks before replacement and during three periods after replacement; 1-12 weeks (period 1), 13-24 weeks (period 2) and 25-36 weeks (period 3). HbA1c values improved significantly in periods 2 and 3. Despite the total insulin dose remaining unchanged throughout the study, the basal insulin dose increased from 0.24 to 0.27 IU/kg/day in period 2 and 0.28 IU/kg/day in period 3. Bodyweight decreased from 61.8 to 60.8 kg in period 1, whereas FBG improved throughout the study. Within-patient variability in FBG was lower with detemir treatment than with NPH, despite the number of hypoglycemic episodes increasing significantly after replacement. These findings show that the weight loss observed in patients was independent of the reduction in calorie intake resulting from less frequent hypoglycemic attacks. In Japanese patients with diabetes who received NPH, replacing NPH with detemir led to improvements in glycemic control without any weight gain. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00066.x, 2010).

Long-Term Intensive Insulin Therapy for Japanese Patients with Type 2 Diabetes Mellitus

To determine the clinical usefulness of long-term intensive insulin therapy in Japanese patients with type 2 diabetes. Various clinical indicators and potential of withdrawal from insulin therapy were investigated in 20 type 2 diabetic patients receiving treatment in the outpatient clinic over a period of 8 years after starting intensive insulin therapy between April 1997 and March 1999. The mean glycated hemoglobin (HbA1c) was approximately 6.5%, and there was no significant increase in insulin dose over a period of 8 years after commencement of intensive insulin therapy. Withdrawal from insulin therapy could be sustained in previously untreated patients. Our results indicated the clinical usefulness of intensive insulin therapy over the long term in Japanese patients with type 2 diabetes and that such therapy could be especially useful for previously untreated patients.