Influence of an SGLT2 inhibitor, tofogliflozin, on the resting heart rate in relation to adipose tissue insulin resistance.

AIMS: To examine the effects of a sodium-glucose co-transporter 2 (SGLT2) inhibitor, tofogliflozin, on resting heart rate by exploring baseline factors that independently influenced changes in the resting heart rate. METHODS: Data on 419 participants in tofogliflozin phase 2/3 trials were analysed. Changes in resting heart rate from baseline to week 24 were analysed using an analysis of covariance (ANCOVA) model with groups (tofogliflozin/placebo) as a fixed effect and baseline values as covariates. The antilipolytic effect was evaluated as adipose tissue insulin resistance (Adipo-IR) and was calculated as the product of fasting insulin and free fatty acid. Multivariate analysis evaluated independent factors for changes in resting heart rate from baseline to week 24. RESULTS: Of the participants, 58% were men, and mean age, HbA1c , BMI and resting heart rate were 57.6 years, 65 mmol/mol (8.1%), 25.5 kg/m2 and 66 bpm, respectively. At week 24, adjusted mean difference vs. placebo in the change from baseline was -2.3 bpm [95% confidence interval (CI) -4.6, -0.1] with tofogliflozin. Changes in resting heart rate were positively correlated with changes in Adipo-IR, whereas reductions in HbA1c , body weight and blood pressure were similar independent of changes in resting heart among quartiles of resting heart rate change. On multivariate analysis, higher baseline resting heart rates and Adipo-IR values were significantly associated with greater reductions in resting heart rate. CONCLUSIONS: Tofogliflozin corrected resting heart rate levels in accordance with baseline levels. Correction of high resting heart rates may be attributed to improved adipose tissue insulin resistance, leading to correction of hyperinsulinaemia.

Bayesian reconstruction of a vancomycin-resistant Enterococcus transmission route using epidemiologic data and genomic variants from whole genome sequencing.

BACKGROUND: Outbreaks of vancomycin-resistant enterococcus (VRE) are a serious problem in hospitals. Inferring the transmission route is an important factor to institute appropriate infection control measures; however, the methodology has not been fully established. AIM: To reconstruct and evaluate the transmission model using sequence variants extracted from whole genome sequencing (WGS) data and epidemiological information from patients involved in a VRE outbreak. METHODS: During a VRE outbreak in our hospital, 23 samples were collected from patients and environmental surfaces and analysed using WGS. By combining genome alignment information with patient epidemiological data, the VRE transmission route was reconstructed using a Bayesian approach. With the transmission model, evaluation and further analyses were performed to identify risk factors that contributed to the outbreak. FINDINGS: All VREs were identified as Enterococcus faecium belonging to sequence type 17, which consisted of two VRE genotypes: vanA (N = 8, including one environmental sample) and vanB (N = 15). The reconstruction model using the Bayesian approach showed the transmission direction with posterior probability and revealed transmission through an environmental surface. In addition, some cases acting as VRE spreaders were identified, which can interfere with appropriate infection control. Vancomycin administration was identified as a significant risk factor for spreaders. CONCLUSION: A Bayesian approach for transmission route reconstruction using epidemiologic data and genomic variants from WGS can be applied in actual VRE outbreaks. This may contribute to the design and implementation of effective infection control measures.

Preformed C1q-binding Donor-specific Anti-HLA Antibodies and Graft Function After Kidney Transplantation.

BACKGROUND: De novo complement-binding donor-specific anti-human leukocyte antigen antibodies (DSAs) are reportedly associated with an increased risk of kidney graft failure, but there is little information on preformed complement-binding DSAs. This study investigated the correlation between preformed C1q-binding DSAs and medium-term outcomes in kidney transplantation (KT). METHODS: We retrospectively studied 44 pretransplant DSA-positive patients, including 36 patients who underwent KT between April 2010 and October 2016. There were 17 patients with C1q-binding DSAs and 27 patients without C1q-binding DSAs. Clinical variables were examined in the 2 groups. RESULTS: Patients with C1q-binding DSAs had significantly higher blood transfusion history (53.0% vs 18.6%; P = .0174), complement-dependent cytotoxicity crossmatch (CDC-XM)-positivity (29.4% vs 0%; P = .0012), and DSA median fluorescence intensity (MFI) (10,974 vs 2764; P = .0009). Among patients who were not excluded for CDC-XM-positivity and underwent KT, there was no significant difference in cumulative biopsy-proven acute rejection rate (32.5% vs 33.5%; P = .8354), cumulative graft survival, and 3-month and 12-month protocol biopsy results between patients with and without C1q-binding DSAs. Although patients with C1q-binding DSAs showed a higher incidence of delayed graft function (54.6% vs 20.0%; P = .0419), multivariate logistic regression showed that DSA MFI (P = .0124), but not C1q-binding DSAs (P = .2377), was an independent risk factor for delayed graft function. CONCLUSIONS: In patients with CDC-XM-negativity, preformed C1q-binding DSAs were not associated with incidence of antibody-mediated rejection and medium-term graft survival after KT. C1q-binding DSAs were highly correlated with DSA MFI and CDC-XM-positivity.

Preoperative Muscle Volume Predicts Graft Survival After Pancreas Transplantation: A Retrospective Observational Cohort Study.

BACKGROUND: Several studies have suggested that decreased muscle volume is associated with attenuation of immune function. The recipient's immune system is responsible for rejection of transplanted organs, which is a major cause of graft loss after transplantation. We aimed to determine whether muscle volume is correlated with graft survival after pancreas transplantation (PT). METHODS: Forty-three patients underwent PT for type 1 diabetes mellitus at our institution from August 2001 to May 2016. The quantity of skeletal muscle was evaluated using the psoas muscle mass index (PMI). The correlation between PMI and outcome after PT was assessed. RESULTS: A total of 32 and 11 recipients underwent simultaneous pancreas-kidney transplantation (SPK) and PT alone/pancreas after kidney transplantation, respectively. Patients with a surviving graft showed a significantly lower PMI than those with graft loss (P = .0451). We divided the recipients into two groups according to the PMI cutoff values, which were established using receiver operating characteristic curves. The cumulative graft survival rate was significantly higher in patients with a low PMI (P = .0206). A multivariate Cox regression analysis revealed that a low PMI (P = .0075) is an independent predictive factor for better graft survival. A low PMI was not a significant predictive factor for acute rejection, but was an independent predictive factor for graft survival after the first acute rejection (P = .0025). CONCLUSIONS: Our data suggest that muscle volume could be a predictor of graft survival after PT.

Durability of protective effect of dulaglutide on pancreatic ß-cells in diabetic mice: GLP-1 receptor expression is not reduced despite long-term dulaglutide exposure.

AIMS: It is well-known that chronic exposure to large amounts of ligand leads to downregulation of its receptor. It is not known, however, whether a GLP-1R agonist downregulates its receptor. For this reason, our study examined whether GLP-1R expression is reduced after long-term exposure to dulaglutide (Dula) in non-diabetic and diabetic mice. METHODS: Seven-week-old male db/db and db/m mice were given either Dula (0.6mg/kg×2/week) or a control vehicle (CTL) for 17 weeks. Various metabolic parameters, such as glucose-stimulated insulin secretion (GSIS), insulin and TG content in islets, were evaluated after the intervention. ß-cell-related gene expression was also analyzed by real-time RT-PCR. RESULTS: In db/m mice, GLP-1R expression in ß-cells did not decrease, not even after long-term administration of Dula, compared with control mice, while GLP-1R expression in 24-week-old db/db mice treated with Dula was augmented, rather than downregulated, compared with 24-week-old CTL db/db mice. This was probably due to improved glycaemic control. In db/db mice treated with Dula, food intake and blood glucose levels were significantly decreased up to 24 weeks of age compared with CTL db/db mice, and their expression levels of various ß-cell-related genes, insulin content and GSIS were also enhanced. In contrast, oxidative and endoplasmic reticulum stress, inflammation, fibrosis and apoptosis were suppressed with Dula treatment. CONCLUSION: Dula exerts beneficial effects on glycaemic control and has long-lasting protective effects on pancreatic ß-cells. GLP-1R expression levels were not reduced at all in non-diabetic as well as diabetic mice despite long-term dulaglutide exposure.

Role of fatty liver in the association between obesity and reduced hepatic insulin clearance.

AIM: Hepatic insulin clearance (HIC) is important in regulating plasma insulin levels. Diminished HIC causes inappropriate hyperinsulinaemia, and both obesity and fatty liver (FL), which are known to decrease HIC, can be found either together in the same patient or on their own. The mechanism by which obesity reduces HIC is presumed to be mediated by FL. However, few reports have examined the role of FL in the relationship between obesity and HIC in type 2 diabetes (T2D) patients. Therefore, our study investigated the association of HIC with clinical factors, including insulin sensitivity indices, focusing on the presence or absence of FL and obesity in T2D patients. METHOD: Baseline data from 419 patients with T2D (279 men, 140 women; mean age: 57.6 years; body mass index: 25.5kg/m2) controlled by diet and exercise were analyzed. HIC was calculated from the ratio of fasting c-peptide to fasting insulin levels (HICCIR). Correlation analyses between HICCIR and clinical variables were performed using Pearson's product-moment correlation coefficients and single regression analysis in all participants and in those with obesity and FL either alone or in combination. RESULTS: HICCIR was significantly correlated with whole-body insulin sensitivity indices and influenced by FL, but only in the FL group was obesity independently influenced HIC level. HICCIR decreased in those with both FL and obesity compared with those with only one such complication. CONCLUSION: HICCIR may be used to evaluate whole-body insulin sensitivity in T2D. Also, compared with obesity, the influence of FL strongly contributed to a reduced HIC. TRIAL REGISTRATION NUMBER: These trials were registered by the Japan Pharmaceutical Information Centre clinical trials information (JapicCTI) as 101349 and 101351.

Laparoscopy-Assisted Spleen-Preserving Distal Pancreatectomy for Living-Donor Pancreas Transplantation.

BACKGROUND: Living pancreas transplantation plays an important role in the treatment of patients with severe type 1 diabetes. However, pancreatectomy is very invasive for the donor, and less-invasive surgical procedures are needed. Although some reports have described hand-assisted laparoscopic surgery for distal pancreatectomy in living-donor operations, less-invasive laparoscopy-assisted (LA) procedures are expected to increase the donor pool. We herein report the outcomes of four cases of LA spleen-preserving distal pancreatectomy (Warshaw technique [WT]) in living pancreas donors. PATIENTS AND METHODS: Four living pancreas donors underwent LA-WT at our institution from September 2010 to January 2013. All donors fulfilled the donor criteria established by the Japan Society for Pancreas and Islet Transplantation. RESULTS: The median donor age was 54 years. Two donors underwent left nephrectomy in addition to LA-WT for simultaneous pancreas-kidney transplantation. The median donor operation time for pancreatectomy was 340.5 minutes. The median pancreas warm ischemic time was 3 minutes. The median donor blood loss was 246 g. All recipients immediately achieved insulin independence. One donor required reoperation because of obstructive ileus resulting from a port-site hernia. Another donor developed a pancreatic fistula (International Study Group of Pancreatic Fistula grade B), which was controlled with conservative management. After a maximum follow-up of 73 months, no clinically relevant adverse events had occurred. These results were comparable with those of previous studies concerning living-donor pancreas transplantation. CONCLUSION: The LA-WT is a safe and acceptable operation for living-donor pancreas transplantation.

Clinical use of the co-formulation of insulin degludec and insulin aspart.

AIMS: To provide a review of the available data and practical use of insulin degludec with insulin aspart (IDegAsp). Premixed insulins provide basal and prandial glucose control; however, they have an intermediate-acting prandial insulin component and do not provide as effective basal coverage as true long-acting insulins, owing to the physicochemical incompatibility of their individual components, coupled with the inflexibility of adjustment. The molecular structure of the co-formulation of IDegAsp, a novel insulin preparation, allows these two molecules to coexist without affecting their individual pharmacodynamic profiles. METHODS: Clinical evidence in phase 2/3 trials of IDegAsp efficacy and safety in type 1 and type 2 diabetes mellitus (T1DM and T2DM) have been assessed and summarised. RESULTS: In people with T2DM, once- and twice-daily dosing provides similar overall glycaemic control (HbA1c ) to current modern insulins, but with lower risk of nocturnal hypoglycaemia. In prior insulin users, glycaemic control was achieved with lower or equal insulin doses vs. other basal+meal-time or premix insulin regimens. In insulin-naïve patients with T2DM, IDegAsp can be started once or twice-daily, based on individual need. People switching from more than once-daily basal or premix insulin therapy can be converted unit-to-unit to once-daily IDegAsp, although this strategy should be assessed by the physician on an individual basis. CONCLUSIONS: IDegAsp offers physicians and people with T2DM a simpler insulin regimen than other available basal-bolus or premix-based insulin regimens, with stable daytime basal coverage, a lower rate of hypoglycaemia and some flexibility in injection timing compared with premix insulins.

Long-term safety and efficacy of fasiglifam (TAK-875), a G-protein-coupled receptor 40 agonist, as monotherapy and combination therapy in Japanese patients with type 2 diabetes: a 52-week open-label phase III study.

This multicentre, open-label, phase III study investigated the safety and efficacy of the G-protein-coupled receptor 40 agonist fasiglifam. Japanese patients with type 2 diabetes and inadequate glycaemic control despite diet and/or exercise (n = 282), or despite diet and/or exercise plus one oral antidiabetic agent [sulphonylurea (n = 262), rapid-acting insulin secretagogue (n = 124), α-glucosidase inhibitor (n = 141), biguanide (n = 136), thiazolidinedione (n = 139) or dipeptidyl peptidase-4 inhibitor (n = 138)] were randomized to treatment with fasiglifam 25 or 50 mg once daily for 52 weeks. The primary endpoints were safety variables. The overall incidence of treatment-emergent adverse events (TEAEs) was 75.4-85.1% in the 25 mg group and 78.9-89.9% in the 50 mg group; most TEAEs were mild. Hypoglycaemia was negligible with fasiglifam monotherapy and most common with sulphonylurea combination therapy (12.4 and 9.1% for 25 and 50 mg groups, respectively). Abnormal liver-related laboratory values were uncommon. Glycated haemoglobin levels decreased from week 2 in all groups and were maintained to week 52. Although fasiglifam as monotherapy or in combination regimens was well tolerated during long-term treatment, global concerns about liver safety led to termination of its development after study completion.

Efficacy and safety of pioglitazone added to alogliptin in Japanese patients with type 2 diabetes mellitus: a multicentre, randomized, double-blind, parallel-group, comparative study.

A phase IV, multicentre, randomized, double-blind, parallel-group, comparative study was conducted in Japanese subjects with type 2 diabetes mellitus (T2DM) who had inadequate glycaemic control, despite treatment with alogliptin in addition to diet and/or exercise therapy. Subjects with glycated haemoglobin (HbA1c) concentrations of 6.9-10.5% were randomized to receive 16 weeks' double-blind treatment with pioglitazone 15 mg, 30 mg once daily or placebo added to alogliptin 25 mg once daily. The primary endpoint was the change in HbA1c from baseline at the end of treatment period (week 16). Both pioglitazone 15 and 30 mg combination therapy resulted in a significantly greater reduction in HbA1c than alogliptin monotherapy [-0.80 and -0.90% vs 0.00% (the least squares mean using analysis of covariance model); p < 0.0001, respectively]. The overall incidence rates of treatment-emergent adverse events were similar among the treatment groups. Pioglitazone/alogliptin combination therapy was effective and generally well tolerated in Japanese subjects with T2DM and is considered to be useful in clinical settings.

Sitagliptin improves glycaemic excursion after a meal or after an oral glucose load in Japanese subjects with impaired glucose tolerance.

AIMS: To evaluate the efficacy and tolerability of sitagliptin in subjects with impaired glucose tolerance (IGT). METHODS: In a double-blind, parallel-group study, 242 Japanese subjects with IGT, determined by a 75-g oral glucose tolerance test (OGTT) at week -1, were randomized (1 : 1 : 1) to placebo (n = 83), sitagliptin 25 mg (n = 82) or 50 mg (n = 77) once daily for 8 weeks. Glycaemic variables were assessed using another OGTT at week 7 and meal tolerance tests (MTTs) at weeks 0 and 8. Primary and secondary endpoints were percent change from baseline in glucose total area under the curve 0-2 h (AUC(0 -2 h)) during the MTT and OGTT, respectively. RESULTS: Least squares mean percent change from baseline in glucose AUC(0 -2 h) during the MTT were -2.4, -9.5 and -11.5%, and during the OGTT were -3.7, -21.4 and -20.1% with placebo, sitagliptin 25 mg once daily, and 50 mg once daily, respectively (p < 0.001 for either sitagliptin dose vs placebo in both tests). Sitagliptin treatment enhanced early insulin response during the OGTT and decreased total insulin response, assessed as the total AUC(0 -2 h) during the MTT. Sitagliptin treatment also suppressed glucagon response during the MTT. The incidence of adverse events, including hypoglycaemia, was low and generally similar in all treatment groups. CONCLUSIONS: Treatment with sitagliptin significantly reduced glucose excursions during both an MTT and an OGTT; this effect was associated with an increase in early insulin secretion after oral glucose loading as well as a blunted glucagon response during an MTT. Sitagliptin was generally well tolerated in subjects with IGT.

Living donor kidney transplantation preceding pancreas transplantation reduces mortality in type 1 diabetics with end-stage renal disease.

BACKGROUND: Simultaneous pancreas-kidney transplantation (SPK) is a definitive treatment for type 1 diabetics with end-stage renal disease (ESRD). Because of the shortage of deceased donors in Japan, the mortality rate during the waiting period is high. We evaluated mortality risk in patients with type 1 diabetes waiting for SPK, and the benefit of living-donor kidney transplantation (LDK) preceding pancreas transplantation, which may reduce mortality in patients awaiting SPK. METHODS: This retrospective study included 71 patients with type 1 diabetes. Twenty-six patients underwent SPK, 15 underwent LDK, and 30 were waiting for SPK. Their cumulative patient and graft survival rates were retrospectively evaluated. Risk factors contributing to mortality in patients with type 1 diabetes awaiting SPK were evaluated with the use of a Cox proportional hazards model. RESULTS: The 5-year cumulative patient survival rates in the SPK and LDK groups were 100% and 93.3%, respectively (P = .19), and 5-year kidney graft survival rates were 95.7% and 100% (P = .46), respectively. The cumulative survival rate in patients awaiting SPK was 77.7% at 5 years after registration. Duration of dialysis was the only factor significantly associated with patient and graft survivals according to both univariate and multivariate analyses. CONCLUSIONS: Patient and graft survival rates were similar in the SPK and LDK groups, but the survival rate of patients awaiting SPK decreased over time. Duration of dialysis was an independent risk factor for patient and graft survival. LDK preceding pancreas transplantation may be an effective therapeutic option for patients with type 1 diabetes and ESRD.

Outcome of renal transplantation in patients with type 2 diabetic nephropathy: a single-center experience.

BACKGROUND: Renal transplantation has been established as a treatment for end-stage renal disease (ESRD) due to diabetic nephropathy. However, few studies have focused on the outcome after renal transplantation in patients with ESRD and type 2 diabetic nephropathy. To investigate the effect of renal transplantation on ESRD with type 2 diabetic nephropathy, we retrospectively analyzed patients who received renal transplantation at our facility. This study aimed to compare the outcome of renal transplantation for type 2 diabetic nephropathy with that for nondiabetic nephropathy. METHODS: We studied 290 adult patients, including 65 with type 2 diabetic nephropathy (DM group) and 225 with nondiabetic nephropathy (NDM group), who underwent living-donor renal transplantation at our facility from February 2008 to March 2013. We compared the 2 groups retrospectively. RESULTS: In the DM and NDM groups, the 5-year patient survival rates were 96.6% and 98.7%, and the 5-year graft survival rates were 96.8% and 98.0%, respectively, with no significant differences between the groups. There were no significant differences in the rates of surgical complications, rejection, and infection. The cumulative incidence of postoperative cardiovascular events was higher in the DM group than in the NDM group (8.5% vs 0.49% at 5 years; P = .002). CONCLUSIONS: Patient and graft survival rates after renal transplantation for type 2 diabetic nephropathy are not inferior to those for recipients without diabetic nephropathy. Considering the poor prognosis of patients with diabetic nephropathy on dialysis, renal transplantation can provide significant benefits for these patients.

Efficacy and safety of fasiglifam (TAK-875), a G protein-coupled receptor 40 agonist, in Japanese patients with type 2 diabetes inadequately controlled by diet and exercise: a randomized, double-blind, placebo-controlled, phase III trial.

AIM: To assess the efficacy and safety of fasiglifam 25 and 50 mg in Japanese patients with type 2 diabetes inadequately controlled by diet and exercise. METHODS: This phase III, double-blind, placebo-controlled, multicentre study included 192 patients randomized to once-daily treatment with fasiglifam 25 mg (n = 63) or 50 mg (n = 62) or placebo (n = 67) for 24 weeks. The primary efficacy endpoint was the change from baseline in glycated haemoglobin (HbA1c) at week 24. RESULTS: At week 24, both fasiglifam groups had significantly reduced HbA1c levels compared with the placebo group (p < 0.0001). The least squares mean change from baseline in HbA1c was 0.16% with placebo, -0.57% with fasiglifam 25 mg and -0.83% with fasiglifam 50 mg. The percentage of patients who achieved an HbA1c target of <6.9% at week 24 was also significantly higher (p < 0.05) for fasiglifam 25 mg (30.2%) and 50 mg (54.8%) compared with placebo (13.8%). Fasiglifam significantly reduced fasting plasma glucose levels at all assessment points, starting from week 2. The incidence and types of treatment-emergent adverse events in each fasiglifam group were similar to those in the placebo group, and hypoglycaemia was reported in 1 patient receiving fasiglifam 50 mg. There were no clinically meaningful changes in body weight in any treatment group. CONCLUSIONS: Fasiglifam significantly improved glycaemic control and was well tolerated, with a low risk of hypoglycaemia in Japanese patients with type 2 diabetes inadequately controlled by diet and exercise; however, in a recent review of data from overall fasiglifam global clinical trials, concerns about liver safety arose and the clinical development of fasiglifam was terminated after this trial was completed.

Efficacy and safety of dapagliflozin monotherapy in Japanese patients with type 2 diabetes inadequately controlled by diet and exercise.

AIMS: To evaluate the efficacy and safety of the selective sodium glucose co-transporter 2 inhibitor dapagliflozin in Japanese patients with type 2 diabetes mellitus (T2DM) inadequately controlled by diet and exercise. METHODS: Patients received placebo or dapagliflozin (5 or 10 mg) once daily for 24 weeks. The primary outcome measure was change from baseline in glycated haemoglobin (HbA1c). RESULTS: Patients (N = 261) had modestly elevated baseline HbA1c (mean ≈ 7.5%) and most had mild or moderate renal impairment (estimated glomerular filtration rate range 43-103 ml/min/1.73 m(2)). Greater reductions in mean HbA1c level were observed with dapagliflozin (5 mg, -0.41%; 10 mg, -0.45%) than with placebo (-0.06%) at week 24 and these were greater in patients with higher baseline HbA1c levels. Fasting plasma glucose (FPG) was also significantly reduced with dapagliflozin (5 mg, -8.6 mg/dl; 10 mg, -13.7 mg/dl) compared with placebo (+5.8 mg/dl). Dapagliflozin significantly reduced body weight (5 mg, -2.13 kg; 10 mg, -2.22 kg) compared with placebo (-0.84 kg). Overall, 47.7 and 64.8% of patients with dapagliflozin 5 and 10 mg, respectively, and 51.7% with placebo experienced ≥ 1 adverse event, mostly mild or moderate, and unrelated to study treatment. Two patients on dapagliflozin 10 mg reported hypoglycaemia. Four patients across all groups reported events suggestive of genital infection and four of urinary tract infection. No events of pyelonephritis were reported. CONCLUSION: Dapagliflozin (5 and 10 mg) was well tolerated and effective in reducing HbA1c, FPG and body weight over 24 weeks in Japanese patients with T2DM inadequately controlled by diet and exercise.