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Recent distributed acoustic sensing (DAS) experiments in ocean areas throughout the world have accumulated records for various wavefields. However, there are few tsunami records because tsunami observation depends on the DAS experimental period and its location. From continuous DAS records, we found tsunami signals at a frequency band of 5–30 mHz, which correspond to high‐frequency components of tsunamis and their propagation velocities differ from low‐frequency tsunamis. We estimated time series of the tsunami excitations at the source using the DAS records, which are consistent with those using records of ocean‐bottom absolute pressure gauges. Our study suggests that DAS records can be used for detecting tsunami propagations in the regions where other geophysical instruments are not available, and contribute to elucidating their excitation mechanisms. Plain Language Summary: Using distributed acoustic sensing (DAS) techniques, various types of wavefields, such as earthquake and ocean waves, have been captured by submarine fiber optic cables. However, the recording of tsunamis has been limited, as their observation depends on the timing and location of the DAS experiments. On 8 October 2023, in southern Japan, changes in sea level attributable to tsunamis were detected by tide gauges. Continuous DAS records in southern Japan have enabled the capture of signals associated with these tsunamis. The observed signals exhibit frequency‐dependent propagation velocities, which correspond to infragravity waves. These are essentially deep water waves or ocean surface gravity waves, representing the high‐frequency components of tsunamis. Using the DAS records alone, we were able to estimate the time‐series of the tsunami generation at the source location. The features obtained from the time‐series were consistent with those from records of absolute pressure gauges on the seafloor deployed in southwestern Japan. Our findings demonstrate the utility of DAS records in detecting tsunami propagations and also elucidating excitation mechanisms of tsunamis. Key Points: The countinuous records of our distributed acoustic sensing measuresment capture tsunami‐related signalsThe phase velocity dispersion of the obtained signals matches that of infragravity waves (high‐frequency tsunamis)The time‐series of the tsunami generation obtained by the cable data are consistent with those from nearby absolute pressure gauges [ABSTRACT FROM AUTHOR]

Distributed acoustic sensing (DAS) using existing optical fiber cables facilitates high‐density seismic observation. However, few studies have examined the reliability of the seismic waveform amplitude recorded by DAS. In this study, a DAS network was connected to optical fiber cables installed over a distance of 75 km along a high‐speed train (Shinkansen) railway in the Kumamoto prefecture, Japan. We successfully observed strong motions of the Mj6.6 earthquake (approximately 150 km from the fiber) on 22 January 2022, in Hyuga‐nada, in addition to several small local earthquakes. The observed strong motions from the Mj6.6 earthquake, using DAS, exhibited cycle skipping (clipping) issues due to dynamic range limitations at numerous channels. To address this, we estimated the shaking map, representing maximum strain distributions for Mj6.6, by replacing the clipped data with information from nearby unclipped channels and scaling their RMS amplitudes based on S‐coda (unclipped). Furthermore, we verified the reliability of the amplitude information obtained from DAS by estimating the distance attenuation of seismic waves while correcting for the differences in the structure type and coupling as much as possible. The distance attenuation property of local earthquakes was consistent with that of the peak ground velocities obtained from seismometers, indicating that DAS data acquired using fibers installed on infrastructure (various structures) can also be utilized to assess the spatial distribution of the relative amplitude values along the fiber. Obtaining high‐density seismic motion distributions is important for earthquake early warning and accurate damage estimation of strong motions. Plain Language Summary: In the past decade, the use of distributed acoustic sensing (DAS) for seismological purposes has grown rapidly. By utilizing existing dark fibers, such as telecommunication cables, high‐density seismic observation networks can be established in residential areas. In this study, DAS was applied to an existing optical fiber cable installed along a railway line, which recorded strong ground motions of Mj6.6 originating from a subduction zone, as well as numerous regional earthquakes. Although the technique uses optical phase differences for strain measurements and therefore has a poor response to strong ground motions, we resolve this issue using the correct data from neighboring stations as a reference and estimated the shaking distribution every 5 m along 75 km of the railway line. Additionally, when we analyzed the distance attenuation of small regional earthquakes, we found that the attenuation characteristics were similar to those obtained from permanent seismometers. These findings will significantly impact society in the future, particularly as the fiber cables replace conventional seismic observation networks. As a result, ultra‐high‐density observation networks will be capable of issuing more accurate earthquake early warnings and estimating damage following earthquakes. Key Points: We successfully observed strong motion from the Mj6.6 earthquake in Hyuga‐nada using Distributed acoustic sensing (DAS) over 75 km along railwayThe shaking map of the Mj6.6 was estimated by replacing the clipped channels with nearby unclipped channels and scaling their RMS amplitudes of S‐codaDistance attenuation property of local earthquakes of DAS consistent with that of peak ground velocities from continuous seismometers [ABSTRACT FROM AUTHOR]

Seismic wave extractions have been performed using ambient noise records observed by distributed acoustic sensing (DAS) technology. Extractions of microseisms can be investigated at a local scale using such DAS records observed in the ocean. Here, we show P and Scholte wave extractions from ambient seafloor noise observed by DAS along a submarine cable deployed off Cape Muroto in the Nankai subduction zone, Japan. The P waves can be observed at a frequency band of 0.1–0.3 Hz and up to a distance of 8 km. The distance at which the P waves can be observed is controlled by the P incident angle and the DAS sensitivity to the observable apparent velocity. Effective extractions of P and Scholte waves, corresponding to large intensity of wave‐wave interaction at the sea surface, are performed, indicating that the waves are originated from pressure field at the sea surface. Plain Language Summary: The density of seismic observations on land is typically higher than that in the ocean. However, higher‐density observations in both land and ocean regions can be made using the recently developed distributed acoustic sensing (DAS). In this study, we focus on the waves persistently propagating through the Earth, which are excited by ocean swell and are called microseisms. Ocean swell at the sea surface primarily excites surface waves: however, P and S waves excited by ocean swell, especially during tropical storms, were observed on a global scale. Because this indicates that body waves may be locally excited by sea surface disturbances, we investigate the problem using DAS records. Our results show that large amplitudes of P waves occur when an atmospheric low pressure passes through Japan, and those amplitudes become weak when the wave‐wave interaction intensity at the ocean surface is weak. Although many previous studies at global or regional scales have indicated that microseisms are originated from fluid disturbances at the sea surface, the current study observed the excitation of P and surface waves right beneath the sea surface disturbances. Key Points: P waves were extracted from ambient seafloor noise records observed by distributed acoustic sensing (DAS) at a frequency band of 0.1–0.3 Hz and up to a distance of 8 kmExtraction of P waves depends on weather conditions, particularly for wave‐wave interaction intensity at the sea surfaceThe distance at which the P waves emerge is controlled by the P incident angle and the DAS sensitivity to apparent velocities [ABSTRACT FROM AUTHOR]

The spatial variation of azimuthal S‐wave phase velocity anisotropies caused by differential horizontal stress along the Nankai Trough was analyzed to understand the stress state of the overhung block of the forearc region, off Kii Peninsula, Japan. We conducted controlled‐source seismic surveys along the circumference of a 3 km radius circle centered at each seismometer of a cabled seafloor observatory installed in the Nankai subduction zone. We applied an anisotropy semblance method to estimate the orientation of fast and slow S‐wave velocities of shallow sediments and deep accretionary prism using the multi‐azimuth seismic dataset acquired at each seismometer location. The estimated orientations of fast S‐wave velocity are parallel to the convergent direction of the subducting place beneath the Kumano basin in the deeper accretionary prism while perpendicular to the convergent direction in the shallow sediments inside the Kumano basin. These fast S‐wave polarization orientations in shallow sediments show good agreement with horizontal maximum stress orientations estimated in situ borehole measurements in the observation area. We estimated the differential horizontal stress field in the Nankai Trough region from obtained S‐wave anisotropy using a simple crack model. Using this method, we first suggest the convergent‐parallel horizontal maximum compression in the deeper part of the accretionary prism above the locked portion. Assuming obtained S‐wave anisotropy is attributed to the tectonic loading by the subducting plate, these results suggest that the S‐wave azimuthal anisotropy measurements can be used to monitor the subsurface stress field as a function of time. Plain Language Summary: In the Nankai Trough, Japan, giant megathrust earthquakes repeatedly occurred. Spatio‐temporal distribution of stress state in the subduction zone is a key parameter to understand the earthquake preparation and generation cycle. In the present study, we estimate the stress field along the Nankai Trough subduction zone from the S‐wave anisotropy analysis using active seismic data acquired by cabled seismic observatories deployed in the Nankai Trough. S‐wave anisotropy can be a proxy of the stress state if stress‐aligned microcracks are vertically distributed in the anisotropic medium. We estimate differential horizontal stress along the subduction zone using a new robust S‐wave analysis method and a simple stress‐induced microcrack model. The obtained orientations and amplitudes of the differential horizontal stress have good agreement with the existing results obtained by in‐situ borehole observations and other seismic surveys in the shallow sediment layer. In the deeper part, the accretionary prims layer above the plate interface, our results in the outer arc of the Kumano forearc basin indicate the plate convergence direction as orientation of maximum horizontal stress. The results are new insights, and can reflect the present stress state accumulating interseismic strain along the seismogenic fault. Key Points: S‐wave anisotropy is obtained from multi‐azimuth seismic dataset observed by cabled seismometers deployed in the Nankai Trough, JapanDifferential horizontal stress field in the Nankai Trough region is estimated from obtained S‐wave anisotropy using a simple crack modelThe estimated horizontal stress field can reflect the present stress state accumulating interseismic strain along the seismogenic fault [ABSTRACT FROM AUTHOR]

Abstract: One primary objective of Integrated Ocean Drilling Program Expedition 365, conducted as part of the Nankai Trough Seismogenic Zone Experiment, was to recover a temporary observatory emplaced to monitor formation pore fluid pressure and temperature within a splay fault in the Nankai subduction zone offshore SW Honshu, Japan. Here we use a 5.3 year time series of formation pore fluid pressure, and in particular the response to ocean tidal loading, to evaluate changes in pore pressure and formation and fluid elastic properties induced by earthquakes. Our analysis reveals 31 earthquake‐induced perturbations. These are dominantly characterized by small transient increases in pressure (28 events) and decreases in ocean tidal loading efficiency (14 events) that reflect changes to formation or fluid compressibility. The observed perturbations follow a magnitude‐distance threshold similar to that reported for earthquake‐driven hydrological effects in other settings. To explore the mechanisms that cause these changes, we evaluate the expected static and dynamic strains from each earthquake. The expected static strains are too small to explain the observed pressure changes. In contrast, estimated dynamic strains correlate with the magnitude of changes in both pressure and loading efficiency. We propose potential mechanism for the changes and subsequent recovery, which is exsolution of dissolved gas in interstitial fluids in response to shaking. [ABSTRACT FROM AUTHOR]

Aim To investigate whether Ad and C fibre pain threshold values, measured using intra-epidermal electrical stimulation (IES), in people with and without Type 2 diabetes are useful in evaluating diabetic polyneuropathy (DPN) severity. Methods Ad and C fibre pain threshold values were measured in Japanese people with (n = 120) and without (n = 76) Type 2 diabetes by IES. Nerve conduction studies and other tests were performed to evaluate diabetic complications. Results Ad and C fibre pain threshold values were high in people with diabetes compared with control subjects (Ad fibre: 0.050 vs. 0.030 mA, P < 0.01; C fibre: 0.180 vs. 0.070 mA, P < 0.01). Participants with diabetes and neuropathy had significantly higher Ad and C fibre pain threshold values than participants without neuropathy (Ad fibres 0.063 vs. 0.039 mA, P < 0.01; C fibres 0.202 vs. 0.098 mA, P < 0.05). C fibre pain threshold values were significantly higher in participants with diabetes and diabetic microvascular complications than in participants without complications. Threshold values increased with complication progression. When DPN was diagnosed according to the Diabetic Neuropathy Study Group in Japan criteria, the cut-off for the C fibre pain threshold values was 0.125 mA (area under the curve 0.758, sensitivity 81.5%, specificity 61.5%). The IES test took less time (P < 0.01) and was less invasive (P < 0.01) than the nerve conduction studies. Conclusions Intra-epidermal electrical stimulation is a non-invasive and easy measurement of small fibre pain threshold values. It may be clinically useful for C fibre measurement to diagnose early DPN as defined by the Diabetic Neuropathy Study Group in Japan criteria. [ABSTRACT FROM AUTHOR]

Aims To evaluate 0.75 mg of dulaglutide, a once-weekly glucagon-like peptide-1 receptor agonist, compared with once-daily insulin glargine for glycaemic control in Japanese patients with type 2 diabetes ( T2D). Methods In this phase III, randomized, open-label, parallel-group, 26-week study, 361 patients with inadequately controlled T2D receiving sulphonylureas and/or biguanides, aged ≥20 years, with glycated haemoglobin ( HbA1c) levels 7.0-10.0% (53-86 mmol/mol), inclusive, were randomized (1 : 1) to receive dulaglutide or glargine. Participants and investigators were not masked to treatment allocation. The primary measure was change from baseline in HbA1c at 26 weeks, analysed using a mixed-effects model for repeated measures, with a predefined non-inferiority margin of 0.4%. Results At week 26, least-squares ( LS) mean (standard error) reductions in HbA1c were −1.44 (0.05)% [−15.74 (0.55) mmol/mol] in the dulaglutide group and −0.90 (0.05)% [−9.84 (0.55) mmol/mol] in the glargine group. The mean between-group treatment difference in HbA1c was −0.54% (95% CI −0.67, −0.41) [−5.90 mmol/mol (95% CI −7.32, −4.48)]; p < 0.001. Dulaglutide significantly reduced body weight compared with glargine at week 26 ( LS mean difference −1.42 kg, 95% CI −1.89, −0.94; p < 0.001). The most frequent adverse events with dulaglutide treatment were nasopharyngitis and gastrointestinal symptoms. The incidence of hypoglycaemia was significantly lower with dulaglutide [47/181 (26%)] compared with glargine [86/180 (48%)], p < 0.001. Conclusion In Japanese patients with T2D uncontrolled on sulphonylureas and/or biguanides, once-weekly dulaglutide was superior to once-daily glargine for reduction in HbA1c at 26 weeks. Although dulaglutide increased gastrointestinal symptoms, it was well tolerated, with an acceptable safety profile. [ABSTRACT FROM AUTHOR]

Aims To evaluate the safety and efficacy of empagliflozin for 52 weeks as add-on to one other oral antidiabetes therapy in Japanese patients with type 2 diabetes mellitus ( T2DM). Methods Patients on biguanide (n = 133), thiazolidinedione (n = 273), α-glucosidase inhibitor (n = 139), dipeptidyl-peptidase-4 inhibitor (n = 139) or glinide (n = 140) were randomized 1 : 1 to receive empagliflozin 10 or 25 mg double-blind as add-on therapy for 52 weeks. Patients on sulphonylurea ( SU; n = 336) were randomized 2 : 2 : 1 to receive empagliflozin 10 or 25 mg double-blind or open-label metformin as add-on therapy for 52 weeks. The primary objective was to evaluate safety. Change from baseline in glycated haemoglobin ( HbA1c) at week 52 was a secondary endpoint. Results Adverse events ( AEs) were reported in 67.6-84.6% of patients receiving empagliflozin. Confirmed hypoglycaemic AEs (plasma glucose ≤70 mg/dl and/or requiring assistance) were reported in 4.4 and 6.6%, respectively, of patients receiving empagliflozin 10 and 25 mg as add-on to SU and in 0.0 to 2.9%, respectively, of patients receiving empagliflozin 10 and 25 mg as add-on to other therapies. Baseline mean ± standard deviation HbA1c ranged from 7.51 ± 0.73 to 8.06 ± 0.76% across background therapy groups. At week 52, adjusted mean ± standard error changes from baseline in HbA1c ranged from −0.77 ± 0.06 to −1.00 ± 0.06% in patients receiving empagliflozin. Conclusions In Japanese patients with T2DM, empagliflozin 10 and 25 mg as add-on to one other oral antidiabetes therapy for 52 weeks were well tolerated and were associated with clinically meaningful reductions in HbA1c. [ABSTRACT FROM AUTHOR]

Aims In a phase III study conducted among Japanese patients with type 2 diabetes mellitus ( T2DM), linagliptin 5 and 10 mg showed clinically meaningful improvements in glycaemic parameters after 12 and 26 weeks compared with placebo and voglibose, respectively. This extension study assessed long-term tolerability of linagliptin over 52 weeks. Methods Japanese patients with T2DM who completed either phase of a 12-week/26-week study comparing linagliptin monotherapy with placebo or voglibose were eligible to enrol. In the extension study, the comparator groups switched to linagliptin 5 or 10 mg, while the linagliptin groups maintained dosage. Results In all, 540 patients received at least one dose of linagliptin 5 or 10 mg and 494 completed the extension. Long-term treatment with linagliptin was well tolerated; adverse events ( AEs) of special interest and serious AEs occurred in small percentages of patients. Drug-related AEs occurred in 10.2 and 10.6% of patients in the linagliptin 5- and 10-mg groups, respectively, and discontinuations due to drug-related AEs occurred in 1.1 and 0.7%, respectively. Only one (0.4%) patient in each dose group experienced investigator-defined hypoglycaemia during the treatment period (both events were non-severe). Body weight was not clinically altered in either group. The glycated haemoglobin A1c profiles over time were similar with linagliptin 5 and 10 mg. Conclusions These findings provide evidence for the safety and tolerability of oral linagliptin at either 5 or 10 mg for up to 52 weeks for the treatment of Japanese patients with T2DM, without clinically relevant increase in the risk of hypoglycaemia or weight gain. [ABSTRACT FROM AUTHOR]

Aims: To evaluate the efficacy and safety of linagliptin 5 and 10 mg vs. placebo and voglibose in Japanese patients with type 2 diabetes mellitus (T2DM). Methods: This study enrolled patients with inadequately controlled T2DM who were previously treated with one or two oral antidiabetics or were drug naÏve. After a 2 to 4-week washout and placebo run-in, 561 patients were randomized (2 : 2 : 2 : 1) to double-blind treatment with linagliptin 5 or 10 mg qd, voglibose 0.2 mg tid or placebo. The primary endpoint was the change from baseline in haemoglobin A1c (HbA1c) with linagliptin vs. placebo after 12 weeks and vs. voglibose after 26 weeks. Results: Baseline characteristics were well balanced across treatment groups (overall mean HbA1c was 8.01%). The adjusted mean (95% confidence interval) treatment differences at week 12 were −0.87% (−1.04, −0.70; p < 0.0001) and −0.88% (−1.05, −0.71; p < 0.0001) for linagliptin 5 and 10 mg vs. placebo and at week 26 were −0.32% (−0.49, −0.15; p = 0.0003) and −0.39% (−0.56, −0.21; p < 0.0001) for linagliptin 5 and 10 mg vs. voglibose. At week 12, mean HbA1c was 7.58, 7.48 and 8.34% in patients receiving linagliptin 5 mg, linagliptin 10 mg and placebo, respectively. At week 26, mean HbA1c was 7.63% with linagliptin 5 mg, 7.50% with linagliptin 10 mg and 7.91% with voglibose. Drug-related adverse event rates were comparable across treatment groups over 12 weeks (9.4% linagliptin 5 mg, 8.8% linagliptin 10 mg and 10.0% placebo) and 26 weeks (11.3% linagliptin 5 mg, 10.6% linagliptin 10 mg and 18.5% voglibose). There were no documented cases of hypoglycaemia. Conclusions: Linagliptin showed superior glucose-lowering efficacy and comparable safety and tolerability to both placebo and voglibose in Japanese patients with T2DM. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to evaluate the efficacy of two group-based lifestyle interventions in ameliorating the risk factors of metabolic syndrome (MS) and insulin resistance. Methods: Ninety-eight subjects who had at least one component of MS were randomized into standard intervention (SI) (4-month intervention; n = 50) and extended intervention (EI) (10-month intervention; n = 48) groups, and 39 subjects were followed up for a control group. The effects of intervention were evaluated after 10, 22 and 34 months. Results: At month 10, the standard and EI groups showed improved body mass index (BMI) (SI, −0.28; EI, −0.47; control, −0.09), high-density lipoprotein (HDL) cholesterol, fasting plasma glucose and A1c and a decreased mean number of components of MS (SI, −0.37; EI, −0.51; control, 0.08). At month 34, the effects on BMI (SI, −0.66; EI, −0.60; control, −0.05) and HDL-cholesterol were sustained for both the intervention groups. In controls, the increases in fasting plasma glucose and the mean number of components of MS from the baseline to month 34 were greater than those in the standard and EI groups. Whole body insulin sensitivity index and hepatic insulin resistance index were also improved at month 10. Conclusions: Group-based lifestyle intervention could be an efficient way to prevent MS. Its effects were sustainable, at least in part, for 2 years. These effects may be mediated by an improvement in insulin sensitivity. [ABSTRACT FROM AUTHOR]

Aims: To evaluate, through exploratory post hoc subgroup analyses, the efficacy and safety of oral semaglutide versus comparators in Japanese patients enrolled in the global PIONEER 1, 3, 4 and 8 clinical trials., Materials and Methods: Patients were randomized to once-daily oral semaglutide 3, 7 or 14 mg or comparator (placebo, sitagliptin 100 mg or liraglutide 1.8 mg). Change from baseline in glycated haemoglobin (HbA1c) and body weight, and proportions of patients attaining HbA1c <7.0% (53 mmol/mol) and body weight loss ≥5%, were analysed at week 26 for all Japanese patients in each trial separately using the treatment policy estimand (regardless of treatment discontinuation or rescue medication use). Adverse events (AEs) were analysed descriptively., Results: Reductions in HbA1c from baseline in Japanese patients were 1.0% to 1.2% (11.3 mmol/mol to 13.3 mmol/mol) and 1.4% to 1.7% (15.7 mmol/mol to 18.3 mmol/mol) for oral semaglutide 7 mg and 14 mg, respectively. HbA1c reductions were similar or greater than with comparators. Body weight reductions were 1.0% to 2.7% and 3.7% to 4.7% for oral semaglutide 7 mg and 14 mg, respectively, and were generally greater with oral semaglutide than comparators. As expected, the main class of AEs was gastrointestinal, and these AEs comprised most commonly mild-to-moderate constipation, nausea and diarrhoea., Conclusions: Oral semaglutide appears efficacious and well tolerated in Japanese patients across the type 2 diabetes spectrum., (© 2021 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aim: To 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 Methods: Patients 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., Results: From 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., Conclusions: Efficacy 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., (© 2021 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aim: To evaluate the efficacy and safety of adjunct dapagliflozin therapy in patients with type 1 diabetes (T1D)., Materials and Methods: DEPICT-1 and -2 were randomized, double-blind, parallel-group, 24-week studies, with 28-week extension periods. Adults with T1D and HbA1c 7.5%-10.5% were randomized (1:1:1) to receive dapagliflozin 5 mg, 10 mg or placebo. The short- and long-term efficacy and safety of dapagliflozin were examined in an exploratory pooled analysis of both studies., Results: Efficacy analyses included 530, 529 and 532 and safety analysis included 548, 566 and 532 patients in the dapagliflozin 5 mg, 10 mg and placebo groups, respectively. Baseline characteristics were similar between treatment groups. At week 24, reductions were seen with dapagliflozin 5 and 10 mg compared with placebo in HbA1c (-0.40%, -0.43% vs. 0.00%) and body weight (-2.45, -2.91 vs. 0.11 kg). HbA1c and body weight reductions versus placebo were also seen after 52 weeks of treatment. There was no imbalance in occurrence of severe hypoglycaemic events between groups. The proportion of patients experiencing definite diabetic ketoacidosis (DKA) was higher with dapagliflozin 5 mg (4.0%) and 10 mg (3.5%) compared with placebo (1.1%) over 52 weeks; most events were of mild or moderate severity, and all resolved with treatment., Conclusions: Over 52 weeks, dapagliflozin provided glycaemic and weight benefits, with no increased frequency of severe hypoglycaemia compared with placebo. More DKA events were reported with dapagliflozin than placebo, highlighting the importance of appropriate patient selection, education and risk-mitigation strategies., (© 2020 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aim: To investigate the long-term efficacy and safety of dapagliflozin as an adjunct to adjustable insulin in adults with type 1 diabetes (T1D) and inadequate glycaemic control., Materials and Methods: Dapagliflozin Evaluation in Patients with Inadequately Controlled Type 1 Diabetes (DEPICT-2) was a placebo-controlled, double-blind, multicentre, phase III study of adults with T1D (HbA1c 7.5%-10.5%) randomized (1:1:1) to receive dapagliflozin 5, 10 mg, or placebo. The efficacy and safety of dapagliflozin over 52 weeks were exploratory endpoints in this extension to DEPICT-2., Results: Of 813 participants randomized, 88.2% completed the study. From baseline to 52 weeks, dapagliflozin 5 and 10 mg were associated with reduction in HbA1c (difference [95% CI] vs. placebo: -0.20% [-0.34, -0.06] and -0.25% [-0.38, -0.11], respectively) and adjusted mean percentage change in body weight (difference [95% CI] vs. placebo: -4.42% [-5.19, -3.64] and -4.86% [-5.63, -4.08], respectively). Serious adverse events were reported in the dapagliflozin 5, 10 mg, and placebo groups (32 [11.8%], 19 [7.0%] and 16 [5.9%], respectively). The proportion of hypoglycaemic events was similar across groups; severe hypoglycaemia was uncommon. More participants with events adjudicated as definite diabetic ketoacidosis (DKA) were in the dapagliflozin 5 and 10 mg groups versus placebo (11 [4.1%], 10 [3.7%] and 1 [0.4%], respectively); the majority of events were mild or moderate in severity and all were resolved with treatment., Conclusions: Dapagliflozin led to long-term reductions in HbA1c and body weight in adults with T1D, but increased DKA risk compared with placebo., (© 2020 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims: To investigate the safety and tolerability of 5 and 10 mg dapagliflozin added to insulin therapy over 52 weeks in Japanese patients with inadequately controlled type 1 diabetes mellitus (T1DM)., Materials and Methods: This randomized, open-label, parallel-group, multicentre phase III clinical trial was conducted from October 26, 2015 to June 15, 2017. The primary endpoint was the occurrence of adverse events such as hypoglycaemia and diabetic ketoacidosis. Secondary endpoints included changes in glycaemic parameters, total daily insulin dosage and body weight over time. The efficacy of dapagliflozin in patients stratified by body mass index (BMI) <25.0 and ≥25.0 kg/m 2 was evaluated in a subgroup analysis., Results: In total, 151 patients received 5 mg (n = 76) or 10 mg (n = 75) dapagliflozin once daily for 52 weeks. Adverse events were observed in 88.2% and 73.3% of patients in the 5 and 10 mg dapagliflozin groups, respectively. Severe hypoglycaemia was reported in 2.6% (n = 2) and 6.7% (n = 5) of patients, and diabetic ketoacidosis in 2.6% (n = 2) and 1.3% (n = 1) of patients in the 5 and 10 mg dapagliflozin groups, respectively. The adjusted mean (95% confidence interval) changes in glycated haemoglobin at week 52 were -0.33% (-0.50, -0.15) and -0.36% (-0.53, -0.18) in the 5 and 10 mg dapagliflozin groups, respectively. There were no differences in efficacy parameters when stratified by BMI., Conclusions: This study demonstrated the long-term safety and tolerability of dapagliflozin added to insulin therapy in Japanese patients with inadequately controlled T1DM., (© 2019 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims: To investigate the efficacy and safety of insulin degludec/liraglutide (IDegLira) compared with its individual components in Japanese people with type 2 diabetes (T2D) uncontrolled on an oral antidiabetic drug (OAD)., Materials and Methods: This 52-week, open-label, multicentre, treat-to-target trial randomized participants (n = 819) 1:1:1 to IDegLira, liraglutide 1.8 mg or degludec, as add-on to their pre-trial OAD. The maximum IDegLira dose was 50 dose steps (50 U degludec/1.8 mg liraglutide), there was no maximum dose for degludec, and both were titrated based on individual blood glucose measurements., Results: After 52 weeks, glycated haemoglobin (HbA1c) decreased by 26 mmol/mol with IDegLira vs 20 mmol/mol with degludec and liraglutide: estimated treatment differences were -6.91 mmol/mol (95% confidence interval [CI] -8.18; -5.64) and -5.30 mmol/mol (95% CI -6.58; -4.03), confirming non-inferiority of IDegLira to degludec and superiority of IDegLira to liraglutide (P < .0001 for both [primary endpoint]). Mean body weight changes were 2.9 kg, 4.1 kg and -1.0 kg with IDegLira, degludec and liraglutide, respectively, showing superiority of IDegLira versus degludec (P = .0001), but a significant difference in favour of liraglutide (P < .0001). Rates of severe or blood glucose-confirmed hypoglycaemia for IDegLira were lower versus degludec (rate ratio 0.48 [95% CI 0.35; 0.68]; P < .0001), but higher versus liraglutide (rate ratio 37.58 [95% CI 19.80; 71.31]; P < .0001). Mean daily total insulin dose was lower with IDegLira (27.7 U) versus degludec (34.8 U; P < .0001). Overall adverse event (AE) rates were similar. In total, 34.9%, 22.9% and 41.8% of IDegLira-, degludec- and liraglutide-treated participants experienced gastrointestinal AEs., Conclusion: IDegLira was superior to degludec and liraglutide in terms of HbA1c reduction and superior to degludec in terms of body weight change and rates of hypoglycaemia in Japanese people with T2D., (© 2019 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

The aim of this study was to evaluate the efficacy and safety of pemafibrate in people with type 2 diabetes and hypertriglyceridaemia over a 52-week period. Participants were randomly assigned to receive treatment with placebo or pemafibrate at a dose of 0.2 or 0.4 mg/d for 24 weeks (treatment period 1). The main results from treatment period 1 have been reported previously. The assigned treatment was continued up to week 52, except that the placebo was changed to pemafibrate 0.2 mg/d after week 24 (treatment period 2). The percentage changes in fasting serum triglyceride (TG) levels at week 52 (last observation carried forward) were -48.2%, -42.3%, and -46.4% in the placebo/pemafibrate 0.2 mg/d (n = 57), pemafibrate 0.2 mg/d (n = 54), and pemafibrate 0.4 mg/d (n = 55) groups, respectively. Levels of TG, non-HDL cholesterol and total cholesterol stably decreased, whereas levels of HDL cholesterol increased with pemafibrate treatments over 52 weeks. Pemafibrate was well tolerated throughout the study period. The present study is the first to show that pemafibrate treatment substantially ameliorated lipid abnormalities and was well tolerated for 52 weeks in people with type 2 diabetes and hypertriglyceridaemia., (© 2019 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims: To assess the pharmacokinetics/pharmacodynamics (PK/PD) of dapagliflozin, a sodium-glucose co-transporter 2 inhibitor that increases urinary glucose excretion (UGE) and its major metabolite, dapagliflozin-3-O-glucuronide (D3OG), in Japanese patients with type 1 diabetes (T1D) and inadequate glycaemic control (HbA1c 7%-10%)., Materials and Methods: Japanese patients (18-65 years) with inadequately controlled T1D were randomized 1:1:1 to dapagliflozin 5 mg, 10 mg or placebo (n = 14 each) once daily for 7 days, with adjustable insulin. The PK/PD characteristics of dapagliflozin and D3OG were assessed on Day 7. Patients underwent follow-up evaluation on Days 8 and 14. Adverse events (AEs), hypoglycaemic episodes and events of diabetic ketoacidosis (DKA) were recorded over the treatment and follow-up periods., Results: A total of 42 randomized patients received dapagliflozin or placebo. PK variables increased in a dose-dependent manner. D3OG was generated rapidly, with a median time to maximum plasma concentration of 2.0 hours (1.0-3.0). The dapagliflozin dose-UGE relationship was attenuated, with larger insulin dose reductions than anticipated. Mean percent (standard error) changes in total daily insulin dose from baseline to Day 7 were - 36.86% (3.32), -39.13% (2.68) and - 4.97% (5.28) for dapagliflozin 5 mg and 10 mg and for placebo, respectively. No DKA was reported. AEs were consistent with the established dapagliflozin safety profile. There was no increase in hypoglycaemia., Conclusions: The PK and safety profiles of dapagliflozin in Japanese patients with T1D were consistent with previous studies, but with an unanticipated attenuation of the PD dose-response measured as UGE., (© 2018 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims: To evaluate the efficacy and safety of dapagliflozin as add-on to insulin in Japanese patients with type 2 diabetes., Materials and Methods: 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., Results: 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., Conclusion: 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., (© 2016 John Wiley & Sons Ltd.)

The efficacy and safety of once-weekly dulaglutide 0.75 mg (dulaglutide) in Japanese patients with type 2 diabetes (T2D) were evaluated according to subgroups defined by concomitant oral hypoglycaemic agents. This exploratory analysis included data from a randomized, open-label, phase III study that compared dulaglutide with insulin glargine (glargine) (n = 361). The three subgroups were dulaglutide or glargine in combination with sulphonylurea (SU) alone, biguanide (BG) alone or SU and BG combined. There were no clinically relevant differences in glycated haemoglobin (HbA1c) changes among the three subgroups in the dulaglutide group; in the glargine group, a numerically greater reduction was observed in combination with BG alone compared to the other two groups (SU alone and SU + BG). Weight loss was observed with dulaglutide in combination with BG alone or with SU + BG. The incidence of adverse events among subgroups was significantly different in the glargine group but not in the dulaglutide group. Incidence of hypoglycaemia was highest in combination with SU for both treatments. For patients with T2D, dulaglutide added to concomitant BG may be more likely to result in weight loss than dulaglutide added to concomitant SU., (© 2016 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Pseudoxanthoma elasticum (PXE) primarily affects organs that are abundant in elastic fibers, such as the skin, eye and blood vessels, and may eventually cause loss of vision or cardiovascular disease (CVD). Because CVD is a potentially life-threatening complication, its early detection is important for improving the quality of life of PXE patients. To determine the relationship between the distribution of skin and mucous membrane lesions and the prevalence of CVD in patients with PXE, we examined 14 PXE cases who presented between 2004 and 2007. All patients had angioid streaks (AS) and positive pathological findings. The skin lesions in PXE patients are distributed discontinuously and thus the degrees of skin involvement were assessed by determining the presence or absence of PXE skin and mucous membrane lesions in six sites (oral mucosa, neck, periumbilical region, cubital fossa, axillae and inguinal regions). Each site was given a binary score (i.e. present = 1, absent = 0) irrespective of severity and the scores were summed to yield a total distribution score (potential range of 0-6). Four cases had PXE-associated CVD. Their mean distribution score was 5.7, which was significantly higher than the score of the cases without CVD (1.8) (P = 0.0049). There was also significant correlation between the high distribution score (P = 0.0053) as well as CVD (P = 0.029) with the maximum width of AS. A higher distribution score and the presence of oral mucosal lesions were associated with CVD. This scoring method may be useful for predicting the presence of CVD in PXE patients.