ABSTRACT
AIMS: Pemafibrate, a selective peroxisome proliferator-activated receptor α modulator that lowers serum triglyceride levels and increases high-density lipoprotein cholesterol levels, is approved for treating dyslipidemia as twice-daily immediate-release (IR) tablets. A once-daily extended-release (XR) tablet has also been developed. We aimed to confirm the non-inferiority of XR (0.2 or 0.4 mg/day; once daily) to IR (0.2 mg/day; twice daily) in lowering triglyceride levels in patients with hypertriglyceridemia. METHODS: This phase 3, multicenter, randomized, double-blind study included patients with fasting triglycerides ≥ 200 mg/dL who received IR (0.2 mg/day) or XR (0.2 or 0.4 mg/day). The primary efficacy endpoint was the percentage change in fasting triglyceride levels from baseline to 4, 8, and 12 weeks. Common treatment effects at weeks 4 through 12 were compared between groups using repeated analysis of covariance. RESULTS: In 356 randomized patients, fasting triglyceride levels decreased by 48.0%, 43.8%, and 48.0% with IR 0.2, XR 0.2, and XR 0.4 mg/day, respectively, confirming the non-inferiority of both XR regimens to IR. The proportion of patients who achieved fasting triglycerides ï¼150 mg/dL was 45.7%, 37.4%, and 51.7%, while the percentage change of triglycerides in the subgroup with baseline triglycerides ≥ 500 mg/dL was -59.3%, -52.2%, and -66.3% with IR 0.2, XR 0.2, and XR 0.4 mg/day, respectively. CONCLUSIONS: XR (0.2 and 0.4 mg/day) was non-inferior to IR (0.2 mg/day). XR 0.4 mg/day demonstrated a more potent triglyceride-lowering effect than XR 0.2 mg/day and should be considered for patients with high triglyceride levels.
ABSTRACT
BACKGROUND: The clinical outcomes of ST-segment elevation myocardial infarction (STEMI) due to the occlusion of left coronary artery are worse in patients with proximal occlusion than in those with non-proximal occlusion. However, there are few reports that focus on the comparison of clinical outcomes in patients with STEMI between proximal and non-proximal right coronary artery (RCA) occlusions. METHODS: We included 356 patients with STEMI whose infarct-related artery is RCA and divided them into the proximal group (nâ¯=â¯129) and the non-proximal group (nâ¯=â¯227). We defined segment 1 of RCA as proximal, and segments 2, 3, and 4 as non-proximal according to the reporting system of the American Heart Association. The primary endpoint was major cardiovascular events (MACE), which was defined as the composite of all-cause death, non-fatal myocardial infarction, readmission for heart failure, and ischemia-driven target vessel revascularization. RESULTS: Incidence of shock at admission, requirement for catecholamine during percutaneous coronary intervention (PCI), or mechanical support during PCI tended to be higher in the proximal group (42.6â¯%) than in the non-proximal group (33.5â¯%) (pâ¯=â¯0.088). Although the incidence of right ventricular infarction tended to be higher in the proximal group (17.8â¯%) than in the non-proximal group (10.6â¯%) without reaching statistical significance (pâ¯=â¯0.072), the incidence of in-hospital death was similar between the 2 groups (1.6â¯% versus 1.8â¯%, pâ¯=â¯1.000). The MACE-free survival curves were not different between the 2 groups (pâ¯=â¯0.400). Multivariate Cox hazard analysis revealed that proximal RCA occlusion was not associated with MACE (HR 1.095, 95%CI 0.691-1.737, pâ¯=â¯0.699). CONCLUSIONS: Although the acute phase conditions such as shock or right ventricular infarction tended to be more severe in patients with proximal occlusion, overall clinical outcomes including long-term outcomes were comparable between the proximal and distal RCA occlusions. Furthermore, multivariate analysis showed that the proximal RCA occlusion was not associated with MACE after hospital discharge.
ABSTRACT
Aims: The present study aimed to clarify the relationships between novel and traditional anthropometric indices and insulin sensitivity (SI) in young and middle-aged Japanese persons with normal glucose tolerance (NGT), and middle-aged Japanese persons with NGT and glucose intolerance. Methods: Plasma glucose and insulin levels were measured in 1270 young (age <40 years) and 2153 middle-aged persons with NGT (n = 1531) and glucose intolerance (n = 622) during a 75-g oral glucose tolerance test. Height (Ht), weight, and waist circumference (WC) were measured. The body mass index (BMI), WC, and the WC/Ht ratio were used as traditional anthropometric indices. A body shape index (ABSI) and the body roundness index (BRI) were calculated as novel indices. Indices of SI (Matsuda index and 1/homeostasis model assessment of insulin resistance) were calculated and compared with anthropometric indices. Results: The ABSI showed a weak correlation with SI indices in all groups. The BRI showed almost the same correlation with SI indices as the BMI, WC, and WC/Ht in all groups. The inverse correlation between each of the anthropometric indices other than ABSI and SI indices was weak in young persons, at 0.16-0.27 (Spearman's ρ values), but strong in middle-aged persons, at 0.38-1.00. On receiver-operating characteristic (ROC) curve analysis for detection of insulin resistance, the ABSI had a lower area under the ROC curve (AUC) than the other anthropometric indices, and the BRI and the WC/Ht ratio showed similar AUCs. The AUCs for the BRI and WC/Ht ratio were the highest in middle-aged men with NGT and glucose intolerance. Conclusions: The BRI, not the ABSI, was better correlated with SI in young and middle-aged Japanese persons. The BRI and WC/Ht ratio were comparable in their correlations with SI and the detection of insulin resistance in the participants of the present study.
Subject(s)
Glucose Intolerance , Insulin Resistance , Male , Middle Aged , Humans , Adult , Body Mass Index , Obesity/diagnosis , Risk Factors , Glucose Intolerance/diagnosis , Japan , Anthropometry , Waist CircumferenceABSTRACT
Recent evidence indicates ferroptosis is implicated in the pathophysiology of various liver diseases; however, the organ-specific regulation mechanism is poorly understood. Here, we demonstrate 7-dehydrocholesterol reductase (DHCR7), the terminal enzyme of cholesterol biosynthesis, as a regulator of ferroptosis in hepatocytes. Genetic and pharmacological inhibition (with AY9944) of DHCR7 suppress ferroptosis in human hepatocellular carcinoma Huh-7 cells. DHCR7 inhibition increases its substrate, 7-dehydrocholesterol (7-DHC). Furthermore, exogenous 7-DHC supplementation using hydroxypropyl ß-cyclodextrin suppresses ferroptosis. A 7-DHC-derived oxysterol metabolite, 3ß,5α-dihydroxycholest-7-en-6-one (DHCEO), is increased by the ferroptosis-inducer RSL-3 in DHCR7-deficient cells, suggesting that the ferroptosis-suppressive effect of DHCR7 inhibition is associated with the oxidation of 7-DHC. Electron spin resonance analysis reveals that 7-DHC functions as a radical trapping agent, thus protecting cells from ferroptosis. We further show that AY9944 inhibits hepatic ischemia-reperfusion injury, and genetic ablation of Dhcr7 prevents acetaminophen-induced acute liver failure in mice. These findings provide new insights into the regulatory mechanism of liver ferroptosis and suggest a potential therapeutic option for ferroptosis-related liver diseases.