Sodium glucose cotransporter-2 inhibitors (SGLT2is) are now widely used to treat diabetes, but their effects on nonalcoholic fatty liver disease (NAFLD) remain to be determined. We aimed to evaluate the effects of SGLT2is on the pathogenesis of NAFLD. A multicenter, randomized, controlled trial was conducted in patients with type 2 diabetes with NAFLD. The changes in glycemic control, obesity, and liver pathology were compared between participants taking ipragliflozin (50 mg/day for 72 weeks; IPR group) and participants being managed without SGLT2is, pioglitazone, glucagon-like peptide-1 analogs, or insulin (CTR group). In the IPR group (n = 25), there were significant decreases in hemoglobin A1c (HbA1c) and body mass index (BMI) during the study (HbA1c, −0.41%, P < 0.01; BMI, −1.06 kg/m 2 , P < 0.01), whereas these did not change in the CTR group (n = 26). Liver pathology was evaluated in 21/25 participants in the IPR/CTR groups, and hepatic fibrosis was found in 17 (81%) and 18 (72%) participants in the IPR and CTR groups at baseline. This was ameliorated in 70.6% (12 of 17) of participants in the IPR group and 22.2 % (4 of 18) of those in the CTR group (P < 0.01). Nonalcoholic steatohepatitis (NASH) resolved in 66.7% of IPR-treated participants and 27.3% of CTR participants. None of the participants in the IPR group developed NASH, whereas 33.3% of the CTR group developed NASH. Conclusion: Long-term ipragliflozin treatment ameliorates hepatic fibrosis in patients with NAFLD. Thus, ipragliflozin might be effective for the treatment and prevention of NASH in patients with diabetes, as well as improving glycemic control and obesity. Therefore, SGLT2is may represent a therapeutic choice for patients with diabetes with NAFLD, but further larger studies are required to confirm these effects. (Hepatology Communications 2021;0:1-13).

Background Comparative effects on physical activity of mono and dual bronchodilators remain unclear in patients with treatment-naïve chronic obstructive pulmonary disease (COPD). We sought to compare the changes in physical activity before and after tiotropium and tiotropium/olodaterol treatment in treatment-naïve COPD patients. Methods A prospective, multicenter, randomized, open-labeled, and parallel interventional study was conducted. Eighty Japanese patients with treatment-naïve COPD were randomized to receive either tiotropium or tiotropium/olodaterol treatment for 12 weeks. Spirometry and dyspnea index were assessed, and COPD assessment test (CAT) and the 6-minute walk distance (6MWD) were conducted before and after treatment. Evaluation of physical activity was assessed by a triaxle accelerometer over a 2-week period before and after treatment. Results There were no differences in the mean age (69.8 vs 70.4 years), body mass index (BMI) (22.5 vs 22.6 kg/m 2 ) and mean % forced expiratory volume in 1 second (%FEV1) at baseline (61.5 vs 62.6%) between the two groups. Changes in FEV1 (mean±standard error, 242.8±28.8 mL) and transient dyspnea index (TDI) (2.4±0.3 points) before and after tiotropium/olodaterol treatment were greater than with tiotropium treatment (104.1±31.9 mL, p<0.01 and 1.5±0.3, p=0.02, respectively). Changes in the duration of physical activity with 1.0–1.5 metabolic equivalents (METs) estimated in the sedentary position following tiotropium/olodaterol treatment (−38.7±14.7 min) tended to be reduced more than with tiotropium treatment (−4.6±10.6 min) (p=0.06), although those with ≥2.0 METs numerically increased with both treatments (+10.8±7.6 min for tiotropium/olodaterol vs +8.3±7.6 min for tiotropium, p=0.82). Tiotropium/olodaterol treatment reduced the duration of physical activity with 1.0–1.5 METs (regression coefficient, −43.6 [95% CI −84.1, −3.1], p=0.04) in a multiple regression model adjusted for cofounding factors such as age, FEV1, total CAT scores, 6MWD, and TDI. Conclusion This is the first study to report the impact of dual bronchodilator on physical activity in treatment-naïve COPD patients of Japanese with low BMI.

Overweight and obesity are associated with one of the severe phenotypes of asthma, with an increased rate of exacerbations, low level of lung function, and reduced response to corticosteroid therapy. The present study focused on identifying useful biomarkers of severity in overweight patients with adult-onset asthma using real-world data. Patients and Methods: A total of 56 patients with adult-onset asthma who visited Saga University Hospital between 2018 and 2019 were retrospectively reviewed. Overweight was defined as a body mass index (BMI) greater than 25 kg/m 2. Blood eosinophils, cytokines, and chemokines were compared between non-overweight asthma and overweight asthma patients. Results: Overweight asthma patients had a higher annual exacerbation rate, lower pulmonary function even when treated frequently with high-dose inhaled corticosteroids, and a significantly lower percentage of eosinophils and lower eosinophil count compared to nonoverweight asthma patients (p<0.01, p=0.03). Moreover, the percentage of eosinophils was significantly negatively correlated with BMI (ρ=−0.38, p<0.01) (Figure 1). On serum cytokine and chemokine analyses, the overweight asthma group included significantly more patients with a lower level of tissue growth factor α (TGF-α) (1.1 pg/mL) and higher levels of hsIL-6 (2.5 pg/mL), RANTES/CCL5 (298.5 pg/mL), and vascular endothelial growth factor A (VEGF-A) (63.7 pg/mL), than the non-overweight asthma group (p=0.02, p<0.01, p=0.02, p=0.01, respectively). Conclusion: The present study showed that overweight patients with adult-onset asthma were characterized by a higher rate of annual exacerbations and worse lung function despite treatment with high-dose inhaled corticosteroids and lower blood eosinophil counts than nonoverweight patients with asthma. On blood cytokine and chemokine analyses, a low level of TGF-α and high levels of hsIL-6, RANTES/CCL5, and VEGF-A might be biomarkers reflecting the pathophysiology in overweight patients with asthma.

Background Exacerbations are critical events in chronic pulmonary obstructive disease (COPD). The frequency of COPD exacerbations is associated with the prognosis, including mortality, but no useful biomarker has been established. Methods The present retrospective study investigated 481 COPD patients. Clinical features in the stable period were compared between patients who experienced severe exacerbation (n = 88, 18.3%) and those who never experienced severe exacerbation (n = 393, 81.7%). In the patients who experienced exacerbations, clinical features were also compared between frequent exacerbators (exacerbation rate ≥ 2 times/year, n = 27, 30.7%) and infrequent exacerbators (1 time/year, n = 61, 69.3%). Results Compared to COPD patients who never experienced exacerbations, body mass index (BMI), serum albumin, and pulmonary functions were significantly lower, and the cardiovascular disease comorbidity rate, COPD assessment test score, modified Medical Research Council dyspnea scale, and use of long-term oxygen therapy, long-acting β2 adrenergic agonist therapy, inhaled corticosteroid therapy, and macrolide therapy were significantly higher in COPD patients with exacerbations (all p < 0.01). In patients who experienced exacerbations, frequent exacerbators had significantly lower % forced expiratory volume in 1.0 s and a higher risk of critical exacerbations, percentage of blood eosinophils, history of mechanical ventilation use, and use of long-term oxygen therapy and of macrolide therapy than infrequent exacerbators (all p < 0.01). On multivariate analysis, the percentage of blood eosinophils was the parameter most correlated with exacerbation frequency (β value [95% confidence interval] 1.45 [1.12–1.88], p < 0.01). Conclusion Blood eosinophil in the stable period is the factor most correlated with the frequency of severe exacerbations. Trial registration: The patients in this study was registered retrospectively

Decreasing exercise tolerance is one of the key features related to a poor prognosis in patients with chronic obstructive pulmonary disease (COPD). Cardiopulmonary exercise testing (CPET) is useful for evaluating exercise tolerance. The present study was performed to clarify the correlation between exercise tolerance and clinical parameters, focusing especially on the cross-sectional area (CSA) of skeletal muscle. The present study investigated 69 patients with COPD who underwent CPET. The correlations between oxygen uptake ($${{\dot{\text{V}} \text{O}}}_{2}$$ V ˙ O 2 ) at peak exercise and clinical parameters of COPD, including skeletal muscle area measured using single-section axial computed tomography (CT), were evaluated. The COPD assessment test score (ρ = − 0.35, p = 0.02) was weakly correlated with $${{\dot{\text{V}} \text{O}}}_{2}$$ V ˙ O 2 at peak exercise. In addition, forced expiratory volume in one second (FEV1) (ρ = 0.39, p = 0.0009), FEV1/forced vital capacity (ρ = 0.33, p = 0.006), and the CSA of the pectoralis muscles (PMs) (ρ = 0.36, p = 0.007) and erector spinae muscles (ECMs) (ρ = 0.39, p = 0.003) were correlated with $${{\dot{\text{V}} \text{O}}}_{2}$$ V ˙ O 2 at peak exercise. Multivariate analysis adjusted by age and FEV1 indicated that PMCSA was weakly correlated after adjustment (β value [95% confidence interval] 0.175 [0.03–0.319], p = 0.02). In addition, ECMCSA tended to be correlated, but not significantly after adjustment (0.192 [− 0.001–0.385] p = 0.052). The COPD assessment test, FEV1, FEV1/FVC, PMCSA, and ECMCSA were significantly correlated with $${{\dot{\text{V}} \text{O}}}_{2}$$ V ˙ O 2 at peak exercise.