Dysregulated production of adipocytokines may be involved in the development of atherosclerotic cardiovascular disease in metabolic syndrome and chronic kidney disease (CKD) associated with metabolic syndrome. The aim of this study was to determine the effects of treatment with angiotensin II (Ang II) type-1 receptor blocker (ARB) on the regulation of adipocytokines. Olmesartan, an ARB, significantly blunted the age- and body weight-associated falls in plasma adiponectin both in genetically and diet-induced obese mice, without affecting body weight, but had no effect on plasma adiponectin levels in lean mice. Olmesartan also ameliorated dysregulation of adipocytokines in obesity, such as tumor necrosis factor-alpha, plasminogen activator inhibitor-1, monocyte chemotactic protein-1, and serum amyloid A3. Olmesartan significantly reduced reactive oxygen species originating from accumulated fat and attenuated the expression of nicotinamide adenine dinucleotide phospho hydrogenase oxidase subunits in adipose tissue. In cultured adipocytes, olmesartan acted as an antioxidant and improved adipocytokine dysregulation. Our results indicate that blockade of Ang II receptor ameliorates adipocytokine dysregulation and that such action is mediated, at least in part, by targeting oxidative stress in obese adipose tissue. Ang II signaling and subsequent oxidative stress in adipose tissue may be potential targets for the prevention of atherosclerotic cardiovascular disease in metabolic syndrome and also in metabolic syndrome-based CKD.

Sulfonylurea (SU) agents, including glimepiride and glibenclamide, are the most widely used oral hypoglycemic drugs, which stimulate insulin secretion primarily by binding to the SU receptor on the plasma membrane of pancreatic ␤-cells. Thiazolidinediones, such as pioglitazone and rosiglitazone, are other hypoglycemic agents that effectively improve peripheral insulin resistance through activation of peroxisome proliferator-activated receptor ␥ (PPAR␥). In the present study, we found that glimepiride specifically induced the transcriptional activity of PPAR␥ in luciferase reporter assays. Glimepiride enhanced the recruitment of coactivator DRIP205 and dissociation of corepressors such as nuclear receptor corepressor and silencing mediator for retinoid and thyroid hormone receptors. In addition, glimepride directly bound to PPAR␥ in a manner competitive to rosiglitazone, which is a proven ligand for PPAR␥. Furthermore, in 3T3-L1 adipocytes, glimepiride stimulated the transcriptional activity of the gene promoter containing PPAR-responsive element and altered mRNA levels of PPAR␥ target genes including aP2, leptin, and adiponectin. Finally, glimepiride induced adipose differentiation in 3T3-F442A cells, which was known to differentiate into adipocytes in a PPAR␥-dependent manner. Most effects observed with glimepiride were also seen with glibenclamide. These data strongly suggest that glimepiride and glibenclamide, both of which belong to SU agents, should have PPAR␥ agonist activity, whose potencies were 16 -25% of the maximum level achieved by pioglitazone. Our observation that glimepiride and glibenclamide could act not only on SU receptor but also on PPAR␥ may give an important clue to the development of novel antidiabetic drugs, which can enhance both insulin secretion from pancreatic ␤-cells and peripheral insulin sensitivity.

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Previous reports demonstrated that adiponectin has antiatherosclerotic properties. Obstructive sleep apnea-hypopnea syndrome (OSAHS) is reported to exacerbate atherosclerotic diseases. We investigated nocturnal alternation of serum adiponectin levels before sleep and after wake-up in OSAHS patients and the effect of sustained hypoxia on adiponectin in vivo and in vitro. We measured serum adiponectin concentrations in 75 OSAHS patients and 18 control subjects before sleep and after wake-up and examined the effect of one-night nasal continuous positive airway pressure (nCPAP) on adiponectin in 24 severe OSAHS patients. We investigated the effects of hypoxia on adiponectin in mice and cultured adipocytes with a sustained hypoxia model. Circulating adiponectin levels before sleep and after wake-up were lower in severe OSAHS patients than in control subjects [before sleep: 5.9 Ϯ 2.9 vs. 8.8 Ϯ 5.6 g/ml (P Ͻ 0.05); after wake-up: 5.2 Ϯ 2.6 vs. 8.5 Ϯ 5.5 g/ml (P Ͻ 0.01), respectively; means Ϯ SD]. Serum adiponectin levels diminished significantly during sleep in severe OSAHS patients (P Ͻ 0.0001), but one-night nCPAP improved the drop in serum adiponectin levels [Ϫ18.4 Ϯ 13.4% vs. Ϫ10.4 Ϯ 12.4% (P Ͻ 0.05)]. In C57BL/6J mice and 3T3-L1 adipocytes, hypoxic exposure decreased adiponectin concentrations by inhibiting adiponectin regulatory mechanisms at secretion and transcriptional levels. The present study demonstrates nocturnal reduction in circulating adiponectin levels in severe OSAHS. Our experimental studies showed that hypoxic stress induced adiponectin dysregulation at transcriptional and posttranscriptional levels. Hypoxic stress is, at least partly, responsible for the reduction of serum adiponectin in severe OSAHS. Nocturnal reduction in adiponectin in severe OSAHS may be an important risk for cardiovascular events or other OSAHSrelated diseases during sleep. nasal continuous positive airway pressure RECENT STUDIES HAVE DEMONSTRATED that adipose tissue is not only a passive reservoir for energy storage but also produces and secretes a variety of bioactive molecules called adipocytokines, including adiponectin (1a, 20), tumor necrosis factor-␣, leptin, and plasminogen activator inhibitor type 1 (PAI-1) (36). Dysregulated production of adipocytokines is associated with the pathophysiology of obesity-related diseases (1a, 9, 27). The biological functions of adiponectin, which we identified as an adipocytokine in the human adipose cDNA library (20), include improvement of glucose (21) and lipid metabolism (26), prevention of inflammation (31) and atherosclerosis (24), and cardiovascular protection (14,30,38). Serum adiponectin levels are low in visceral obesity (1a), insulin resistance (10), type 2 diabetes (9), and cardiovascular diseases (29). Previous studies demonstrated the possible association between visceral obesity and obstructive sleep apnea-hypopnea syndrome (OSAHS) (39,40). More recent studies reported that obese subjects with OSAHS had hypoadiponectinemia (36,46).In patients with OSAHS, repetitive noctu...

Aim To evaluate the effectiveness of empagliflozin in clinical practice in East Asia in the Empagliflozin Comparative Effectiveness and Safety (EMPRISE) East Asia study. Materials and methods Data were obtained from the Medical Data Vision database (Japan), National Health Insurance Service database (South Korea) and National Health Insurance database (Taiwan). Patients aged ≥ 18 years with type 2 diabetes initiating empagliflozin or a dipeptidyl peptidase‐4 (DPP‐4) inhibitor were 1:1 propensity score (PS) matched into sequentially built cohorts of new users naïve to both drug classes. This design reduces confounding due to switching treatments, time lag and immortal time biases. Outcomes included hospitalization for heart failure (HHF), end‐stage renal disease (ESRD) and all‐cause mortality. Hazard ratios (HRs) and 95% CIs were estimated using Cox proportional models, controlling for > 130 baseline characteristics in each data source and pooled by random‐effects meta‐analysis. Results Overall, 28 712 pairs of PS‐matched patients were identified with mean follow‐up of 5.7‐6.8 months. Compared with DPP‐4 inhibitors, the risk of HHF was reduced by 18% and all‐cause mortality was reduced by 36% with empagliflozin (HR 0.82; 95% CI 0.71‐0.94, and HR 0.64; 95% CI 0.50‐0.81, respectively). Reductions were consistent across countries, and in patients with and without baseline cardiovascular disease. ESRD was also significantly reduced with empagliflozin versus DPP‐4 inhibitors (HR 0.37; 95% CI 0.24‐0.58). Conclusions Empagliflozin treatment was associated with reduced risk for HHF, all‐cause mortality and ESRD compared with DPP‐4 inhibitors in routine clinical practice in Japan, South Korea and Taiwan.

Background: Observational studies using large claims databases for diabetes patients have been increasingly conducted. While validation of outcomes is important in such studies, validation studies from Japan are still scarce and small in scale with questions remaining on the representativeness of their findings. We examined the positive predictive value (PPV) of outcomes that often develop in type 2 diabetes patients: cardiovascular outcomes including congestive heart failure (CHF), myocardial infarction (MI), stroke-related diseases, and renal outcomes including end stage renal disease (ESRD), and death using a large Japanese database containing administrative claims and electronic medical record (EMR) data. Patients and Methods: We used patient-level administrative claims data from 2003 and EMR data from 1985 to the most recent data up to December 2018 provided by Real World Data Co., Ltd. The database consisted of data from over 200 hospitals including ≥12 million uniquely identifiable patients. Among patients who had ≥1 type 2 diabetes diagnosis in the EMR, those who had administrative claims for each outcome were identified, and then the PPV was calculated for each outcome using the EMR as the gold standard. Results: The numbers of patients identified for each outcome were 1,700 for MI, 2,027 for hemorrhagic stroke, 3,722 for ESRD, 4,723 for ischemic stroke, 5,404 for CHF, 6,678 for any type of stroke, and 10,815 for death. PPVs ranged from 67.4% for ESRD, 78.7% for MI, 80.3% for death, 85.7% for ischemic stroke, 88.9% for any type of stroke, 89.9% for hemorrhagic stroke, and 95.7% for CHF. A post hoc analysis showed PPV for ESRD as 83.8%. Conclusion: This large-scale validation study on diagnosis in administrative claims showed reasonable PPVs for the outcomes. We believe that the definitions of outcomes can be considered to be appropriate for future studies using Japanese administrative claims data.

AimsThis phase 2, double‐blind, randomized, placebo‐controlled trial (http://clinicaltrials.gov NCT02702011) with 4 sites in Japan investigated the pharmacodynamics (PD), pharmacokinetics (PK) and safety profile of empagliflozin in Japanese participants with type 1 diabetes mellitus (T1DM) as adjunctive therapy to insulin.Materials and methodsParticipants using multiple daily injections of insulin for ≥12 months, with HbA1c of 7.5%‐10.0%, entered a 2‐week, open‐label, placebo run‐in period, followed by a 4‐week, double‐blind period during which participants were randomized 1:1:1:1 to receive empagliflozin 2.5 mg (n = 13), empagliflozin 10 mg (n = 12), empagliflozin 25 mg (n = 12) or placebo (n = 11). The primary objective was to assess the effect of empagliflozin vs placebo on urinary glucose excretion (UGE) after 7 days of treatment.ResultsPD: Empagliflozin resulted in a dose‐dependent significant increase in 24‐hour UGE compared with placebo (UGE placebo‐corrected mean [95% confidence interval] change from baseline: 2.5 mg, 65.10 [43.29, 86.90] g/24 h; 10 mg, 81.19 [58.80, 103.58] g/24 h; 25 mg, 98.11 [75.91, 120.31] g/24 h). After 4 weeks of treatment, UGE increase was associated with improved glycaemic control, reduced body weight and decreased insulin needs. Empagliflozin treatment also resulted in dose‐dependent increases in serum ketone bodies and free fatty acids. PK: Plasma empagliflozin levels increased in a dose‐dependent manner and peaked at 1.5 hours. In this short study, empagliflozin was well tolerated, with no increase in rate of hypoglycaemia and no diabetic ketoacidosis events reported.ConclusionsBased on this short‐duration phase 2 study, the PK/PD profile of empagliflozin in Japanese participants with T1DM is comparable to that of non‐Japanese participants.

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