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.

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.

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.

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.

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.

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.

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.

Vildagliptin preserves the mass and function of pancreatic ß cells via the developmental regulation and suppression of oxidative and endoplasmic reticulum stress in a mouse model of diabetes.

AIM: We investigated the molecular mechanisms by which vildagliptin preserved pancreatic ß cell mass and function. METHODS: Morphological, biochemical and gene expression profiles of the pancreatic islets were investigated in male KK-A(y) -TaJcl(KK-A(y) ) and C57BL/6JJcl (B6) mice aged 8 weeks which received either vildagliptin or a vehicle for 4 weeks. RESULTS: Body weight, food intake, fasting blood glucose, plasma insulin and active glucagon-like peptide-1 were unchanged with vildagliptin treatment in both mice. In KK-A(y) mice treated with vildagliptin, increased plasma triglyceride (TG) level and islet TG content were decreased, insulin sensitivity significantly improved, and the glucose tolerance ameliorated with increases in plasma insulin levels. Furthermore, vildagliptin increased glucose-stimulated insulin secretion, islet insulin content and pancreatic ß cell mass in both strains. By vildagliptin, the expression of genes involved in cell differentiation/proliferation was upregulated in both strains, those related to apoptosis, endoplasmic reticulum stress and lipid synthesis was decreased and those related to anti-apoptosis and anti-oxidative stress was upregulated, in KK-A(y) mice. The morphological results were consistent with the gene expression profiles. CONCLUSION: Vildagliptin increases ß cell mass by not only directly affecting cell kinetics but also by indirectly reducing cell apoptosis, oxidative stress and endoplasmic reticulum stress in diabetic mice.

Efficacy and safety of dapagliflozin as a monotherapy for type 2 diabetes mellitus in Japanese patients with inadequate glycaemic control: a phase II multicentre, randomized, double-blind, placebo-controlled trial.

AIM: Dapagliflozin is a selective sodium-glucose co-transporter 2 (SGLT2) inhibitor under development as a treatment for type 2 diabetes mellitus (T2DM). This study assessed the efficacy and safety of dapagliflozin monotherapy in Japanese T2DM patients with inadequate glycaemic control. METHODS: Patients (n = 279) were randomized to receive dapagliflozin (1, 2.5, 5 or 10 mg/day) or placebo once daily for 12 weeks. The primary endpoint was change from baseline in haemoglobin A1c (HbA1c) at week 12. Secondary endpoints included change from baseline in fasting plasma glucose (FPG) and proportion of patients achieving HbA1c <7.0% at week 12. RESULTS: Significant reductions in HbA1c were seen with all dapagliflozin doses (-0.11 to -0.44%) versus placebo (+0.37%). Reductions were also observed in FPG with dapagliflozin (-0.87 to -1.77 mmol/l [-15.61 to -31.94 mg/dl]) versus placebo (+0.62 mmol/l [+11.17 mg/dl]). No significant difference in the proportion of patients achieving HbA1c levels <7.0% was noted with dapagliflozin versus placebo. Adverse events (AEs) were more frequent with dapagliflozin (40.7-53.8%) versus placebo (38.9%) and were mostly mild/moderate in intensity. Three hypoglycaemic events were reported (1 each with placebo, dapagliflozin 2.5 mg and 10 mg). The frequency of signs and symptoms suggestive of urinary tract or genital infections was 0-3.8 and 0-1.8% respectively with dapagliflozin and 1.9 and 0% with placebo. No AEs of pyelonephritis were observed. CONCLUSIONS: Compared with placebo, dapagliflozin significantly reduced hyperglycaemia over 12 weeks with a low risk of hypoglycaemia in Japanese T2DM patients with inadequate glycaemic control.

GPR40-induced insulin secretion by the novel agonist TAK-875: first clinical findings in patients with type 2 diabetes.

AIM: Free fatty acids act as signalling molecules for modulating insulin secretion, and their insulinotropic effects are glucose-dependent and mediated through G protein-coupled receptor 40 (GPR40). This mechanism is a potential target for new treatments for managing diabetes. In this study, we present the first clinical data for TAK-875, a novel highly selective, orally bioavailable GPR40 agonist, in Japanese patients with type 2 diabetes insufficiently controlled by diet or exercise therapy. METHODS: This was an exploratory phase II, multicentre, randomized, double-blind, parallel group study comparing the efficacy and tolerability of TAK-875 100 and 400 mg, and placebo, all administered once daily for 2 weeks. RESULTS: After 2 weeks of treatment, TAK-875 produced marked glucose lowering effects in a 75 g oral glucose tolerance test (OGTT) as evidenced by mean ± SE intergroup differences in plasma glucose AUC(0-3 h) of -12.98 ± 1.48 (p < 0.0001) and -8.12 ± 1.49 mmol·h/l (p < 0.0001), for TAK-875 400 mg vs. placebo and TAK-875 100 mg vs. placebo, respectively, and 2 h plasma glucose [-4.95 ± 0.71 (p < 0.0001) and -3.21 ± 0.71 mmol/l (p < 0.0001), respectively]. This was accompanied by a significant increase in insulin AUC(0-3 h) [34.68 ± 12.16 (p < 0.01) and 31.49 ± 12.20 (p < 0 · 05) µIU·h/ml, respectively]. Improvement in glycaemic profile was mirrored by a significant change in fasting plasma glucose [-2.37 ± 0·27 (p < 0.0001) and -1.88 ± 0.27 mmol/l (p < 0.0001), respectively]. No cases of hypoglycaemia were observed despite the significant reduction in plasma glucose. CONCLUSIONS: These exploratory findings provide evidence of the glucose-dependent insulinotropic potential of the GPR40 agonist TAK-875, and the promising clinical changes support future longer term clinical investigation.

Efficacy and safety of alogliptin added to metformin in Japanese patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial with an open-label, long-term extension study.

AIMS: To evaluate the efficacy and safety of alogliptin added to metformin versus metformin monotherapy in Japanese patients with type 2 diabetes who achieved inadequate glycaemic control on metformin (500 or 750 mg/day) + diet/exercise. METHODS: In a randomized, double-blind trial, 288 patients with type 2 diabetes mellitus T2DM received either 12.5 or 25 mg alogliptin once daily + metformin or placebo + metformin for 12 weeks. Thereafter, 276 patients continued on one of the two alogliptin dosages + metformin in an open-label extension for 40 weeks. The primary efficacy endpoint in the randomized, double-blind phase was the change in HbA1c from baseline (week 0) to the end of treatment (week 12). The primary endpoint during the long-term extension phase was adverse events. RESULTS: After 12 weeks both dosages of alogliptin + metformin produced significantly greater changes from baseline in HbA1c than placebo (metformin monotherapy: with changes in LS means - 0.55 and - 0.64% vs. 0.22%, respectively; p < 0.0001). Incidences of adverse effects were comparable between groups, with no increases in hypoglycaemia. Over 52 weeks, there were no safety or tolerability concerns with alogliptin when added to metformin. CONCLUSIONS: Alogliptin 12.5 and 25 mg once daily was safe and effective when added to metformin (500 or 750 mg/day) in Japanese patients with inadequately controlled type 2 diabetes on metformin alone.

The human glucagon-like peptide-1 analogue liraglutide preserves pancreatic beta cells via regulation of cell kinetics and suppression of oxidative and endoplasmic reticulum stress in a mouse model of diabetes.

AIMS/HYPOTHESIS: We investigated the molecular mechanism by which the human glucagon-like peptide-1 analogue liraglutide preserves pancreatic beta cells in diabetic db/db mice. METHODS: Male db/db and m/m mice aged 10 weeks received liraglutide or vehicle for 2 days or 2 weeks. In addition to morphological and biochemical analysis of pancreatic islets, gene expression profiles in the islet core area were investigated by laser capture microdissection and real-time RT-PCR. RESULTS: Liraglutide treatment for 2 weeks improved metabolic variables and insulin sensitivity in db/db mice. Liraglutide also increased glucose-stimulated insulin secretion (GSIS) and islet insulin content in both mouse strains and reduced triacylglycerol content in db/db mice. Expression of genes involved in cell differentiation and proliferation in both mouse strains was regulated by liraglutide, which, in db/db mice, downregulated genes involved in pro-apoptosis, endoplasmic reticulum (ER) stress and lipid synthesis, and upregulated genes related to anti-apoptosis and anti-oxidative stress. In the 2 day experiment, liraglutide slightly improved metabolic variables in db/db mice, but GSIS, insulin and triacylglycerol content were not affected. In db/db mice, liraglutide increased gene expression associated with cell differentiation, proliferation and anti-apoptosis, and suppressed gene expression involved in pro-apoptosis; it had no effect on genes related to oxidative stress or ER stress. Morphometric results for cell proliferation, cell apoptosis and oxidative stress in db/db mice islets were consistent with the results of the gene expression analysis. CONCLUSIONS/INTERPRETATION: Liraglutide increases beta cell mass not only by directly regulating cell kinetics, but also by suppressing oxidative and ER stress, secondary to amelioration of glucolipotoxicity.

Genetic variants at CDC123/CAMK1D and SPRY2 are associated with susceptibility to type 2 diabetes in the Japanese population.

AIMS/HYPOTHESIS: Recently, rs10906115 in CDC123/CAMK1D, rs1359790 near SPRY2, rs1436955 in C2CD4A/C2CD4B and rs10751301 in ODZ4 were identified as genetic risk variants for type 2 diabetes by a genome-wide association study in a Chinese population. The aim of the present study was to ascertain the role of these four variants in conferring susceptibility to type 2 diabetes in the Japanese population. METHODS: We genotyped 11,530 Japanese individuals (8,552 type 2 diabetes cases, 2,978 controls) for the above single nucleotide polymorphisms (SNPs) and used logistic regression analysis to determine whether they were associated with type 2 diabetes. RESULTS: In accordance with the findings in a Chinese population, rs10906115 A, rs1359790 C and rs1436955 G were found to be risk alleles. Both rs10906115 and rs1359790 were significantly associated with susceptibility to type 2 diabetes in our study (rs10906115 OR 1.15, 95% CI 1.08, 1.22; p = 6.10 × 10(-6); rs1359790 OR 1.14, 95% CI 1.06, 1.21; p = 2.24 × 10(-4)). Adjustment for age, sex and BMI had no significant effects on the association between these variants and the disease. We did not observe any significant associations between the SNPs and any metabolic traits, e.g. BMI, fasting plasma glucose (determined for 1,332 controls), HOMA of beta cell function (900 controls) and HOMA of insulin resistance (900 controls; p > 0.05). CONCLUSIONS/INTERPRETATION: The SNPs rs10906115 A and rs1359790 C are significantly associated with susceptibility to type 2 diabetes in the Japanese population, confirming that these alleles are common susceptibility variants for type 2 diabetes in East Asian populations.

Efficacy and safety of alogliptin added to pioglitazone in Japanese patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial with an open-label long-term extension study.

AIM: To assess the efficacy and safety of alogliptin added to pioglitazone versus pioglitazone monotherapy, in Japanese patients with type 2 diabetes who achieved inadequate glycaemic control on pioglitazone plus diet/exercise. METHODS: Patients were stabilized on pioglitazone 15 or 30 mg/day plus diet/exercise during a 16-week screening period. Patients with HbA1c of 6.9-10.4% were randomized to 12 weeks' double-blind treatment with alogliptin 12.5 or 25 mg once daily or placebo, added to their stable pioglitazone regimen. The primary endpoint was the change in HbA1c from baseline to week 12. Patients had an option to continue in a 40-week, open-label extension study, with those originally randomized to alogliptin remaining on the same dosage regimen while patients treated with placebo were randomly allocated to alogliptin 12.5 or 25 mg (added to their stable pioglitazone). RESULTS: The change from baseline in HbA1c after 12 weeks was significantly greater with alogliptin 12.5 mg added to pioglitazone and alogliptin 25 mg added to pioglitazone than with placebo added to pioglitazone (-0.91 and -0.97% vs. -0.19%; p < 0.0001). Responder rates (HbA1c <6.9% and HbA1c <6.2%) and changes in fasting and postprandial blood glucose levels showed a similar positive trend in terms of glycaemic control. The benefits seen with alogliptin were sustained during the 40-week extension period. Alogliptin added to pioglitazone was generally well tolerated; hypoglycaemia was infrequent and increases in body weight were minor. CONCLUSIONS: Once-daily alogliptin was effective and generally well tolerated when given as add-on therapy to pioglitazone in Japanese patients with type 2 diabetes who achieved inadequate glycaemic control on pioglitazone plus lifestyle measures. Clinical benefits were maintained for 52 weeks.

Improved glycaemic control with minimal hypoglycaemia and no weight change with the once-daily human glucagon-like peptide-1 analogue liraglutide as add-on to sulphonylurea in Japanese patients with type 2 diabetes.

AIM: Sulphonylureas (SUs) are often used as first-line treatments for type 2 diabetes in Japan, hence it is important to study new antidiabetic drugs in combination with SUs in Japanese patients. METHODS: The efficacy and safety of the once-daily human glucagon-like peptide-1 (GLP-1) analogue liraglutide were compared in 264 Japanese subjects [mean body mass index (BMI) 24.9 kg/m(2); mean glycated haemoglobin (HBA1c) 8.4%] randomized and exposed to receive liraglutide 0.6 mg/day (n = 88), 0.9 mg/day (n = 88) or placebo (n = 88) each added to SU monotherapy (glibenclamide, glicazide or glimeprimide) in a 24-week, double-blind, parallel-group trial. RESULTS: The mean change in HBA1c from baseline to week 24 (LOCF) was -1.56 (s.d. 0.84) and -1.46 (s.d. 0.95) with liraglutide 0.9 and 0.6 mg respectively, and -0.40 (s.d. 0.93) with placebo. HBA1c decreased in the placebo group from 8.45 to 8.06%, while liraglutide reduced HBA1c from 8.60 to 7.14%, and from 8.23 to 6.67% at the 0.6 and 0.9 mg doses respectively. Mean HBA1c at week 24 of the two liraglutide groups were significantly lower than the placebo group (p < 0.0001 for both). More subjects reached HBA1c < 7.0% with liraglutide (0.6 mg: 46.5%; 0.9 mg: 71.3%) vs. placebo (14.8%). Fasting plasma glucose (FPG) levels were significantly improved with liraglutide (difference -1.47 mmol/l and -1.80 mmol/l with 0.6 and 0.9 mg vs. placebo; p < 0.0001). Overall safety was similar between treatments: no major hypoglycaemic episodes were reported, while 84/77/38 minor hypoglycaemic episodes occurred in the 0.6 mg/0.9 mg and placebo treatment groups (all in combination with SU), reflecting lower ambient glucose levels. No relevant change in mean body weight occurred in subjects receiving liraglutide (0.6 mg: 0.06 kg; 0.9 mg: -0.37 kg), while mean body weight decreased in subjects receiving placebo (-1.12 kg). CONCLUSIONS: The addition of liraglutide to SU treatment for 24 weeks dose-dependently improved glycaemic control vs. SU monotherapy, without causing major hypoglycaemia or weight gain or loss.

Replication study for the association of new meta-analysis-derived risk loci with susceptibility to type 2 diabetes in 6,244 Japanese individuals.

AIMS/HYPOTHESIS: Additional susceptibility loci for type 2 diabetes have been identified by a meta-analysis of genome-wide association studies (GWASs) in European populations. To examine further the roles of these new loci, we performed a replication study for the association of these single-nucleotide polymorphism (SNP) loci with the disease in three independent Japanese populations. METHODS: We genotyped seven of the 11 SNPs that emerged in stage 2 of the meta-analysis for European GWASs (rs864745 in JAZF1, rs12779790 near CDC123/CAMK1D, rs7961581 near TSPAN8/LGR5, rs4607103 near ADAMTS9, rs10923931 in NOTCH2, rs1153188 near DCD and rs9472138 near VEGFA) for three independent Japanese populations (first set, 1,630 type 2 diabetes patients vs 1,064 controls; second set, 1,272 type 2 diabetes patients vs 856 controls; third set, 486 type 2 diabetes patients vs 936 controls) using a TaqMan assay. The association of the SNP loci in each population was analysed using a logistic regression analysis, adjusting for age, sex and BMI, and the data were evaluated by a meta-analysis. RESULTS: A meta-analysis for the three case-control studies identified a nominal association of rs864745 in JAZF1 with type 2 diabetes (OR 1.148, 95% CI 1.034-1.275, p = 0.0098, corrected p = 0.069). The association of other loci did not reach statistically significant levels (nominal p > 0.05). CONCLUSIONS/INTERPRETATION: From these results the contribution of these seven loci in conferring susceptibility to type 2 diabetes is considered minor in the Japanese population, if they are present.

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.