Icosapent ethyl therapy for very high triglyceride levels: a 12-week, multi-center, placebo-controlled, randomized, double-blinded, phase III clinical trial in China.

OBJECTIVES: Eicosapentaenoic acid in its ethyl ester form is the single active component of icosapent ethyl (IPE). This study was a phase III, multi-center trial assessing the safety and efficiency of IPE for treating very high triglyceride (TG) in a Chinese cohort. METHODS: Patients having TG levels (5.6-22.6 mmol/L) were enrolled and randomly assigned to receive a treatment of oral intake of 4 g or 2 g/day of IPE, or placebo. Before and after 12 weeks of treatment, TG levels were assessed and the median was calculated to determine the change between the baseline and week 12. In addition to examining TG levels, the impact of such treatments on other lipid changes was also investigated. The official Drug Clinical Trial Information Management Platform has registered this study (CTR20170362). RESULTS: Random assignments were performed on 373 patients (mean age 48.9 years; 75.1% male). IPE (4 g/day) lowered TG levels by an average of 28.4% from baseline and by an average of 19.9% after correction for placebo (95% CI: 29.8%-10.0%, P < 0.001). In addition, plasma concentration of non-high-density lipoprotein cholesterol (non-HDL-C), very low-density lipoprotein (VLDL) cholesterol, and VLDL-TG remarkedly reduced after IPE (4 g/day) treatment by a median of 14.6%, 27.9%, and 25.2%, respectively compared with participants in placebo group. Compared to the placebo, neither 4 nor 2 g of IPE daily elevated LDL-C levels with statistical significance. IPE was well tolerated by all the treatment groups. CONCLUSIONS: IPE at 4 g/day dramatically lowered other atherogenic lipids without a noticeable increase in LDL-C, thereby decreasing TG levels in an exceptionally high-TG Chinese population.

Adverse drug events associated with ibrutinib for the treatment of elderly patients with chronic lymphocytic leukemia: A systematic review and meta-analysis of randomized trials.

BACKGROUND: Chronic lymphocytic leukemia (CLL) is a rare hematological malignancy classified in the non-Hodgkin's lymphoma category. Ibrutinib, a first-in-class Bruton tyrosine kinase inhibitor has been approved for use in the treatment of CLL. This drug has shown beneficial effects including a higher overall response rate, sustained remissions, and a tolerable toxicity level. In this meta-analysis, we aimed to compare the adverse drug events which were associated with the use of ibrutinib for the treatment of patients with CLL. METHODS: A careful search was carried out through the Cochrane Central, EMBASE, MEDLINE (PubMed), and through www.ClinicalTrials.com. The following criteria for inclusion were considered: Both randomized trials and observational cohorts; Studies comparing the adverse drug events observed with the use of ibrutinib versus a control group for the treatment of CLL. The RevMan software (version 5.3) was used to carry out this analysis and the analyzed data were represented by risk ratios (RR) and 95% confidence intervals (CI). RESULTS: A total number of 2456 participants with CLL were included in this analysis. One thousand one hundred thirteen participants were treated with ibrutinib whereas the remaining 1343 participants were assigned to the control (non-ibrutinib) group. Results of this current analysis showed Ibrutinib not to be associated with significantly higher risk of anemia (RR: 0.90, 95% CI: 0.67-1.21; P = .49), thrombocytopenia (RR: 0.61, 95% CI: 0.32-1.14; P = .12), neutropenia (RR: 0.50, 95% CI: 0.25-1.00; P = .05), and febrile neutropenia (RR: 0.89, 95% CI: 0.32-2.49; P = .83) in these patients with CLL. The risk for respiratory tract infection was also similarly manifested (RR: 1.01, 95% CI: 0.78-1.30; P = .96). However, ibrutinib was associated with a high risk of abdominal manifestations in comparison to the control group (RR: 1.62, 95% CI: 1.32-2.00; P = .00001). The risk for diarrhea was also significantly higher in the Ibrutinib group (RR: 2.14, 95% CI: 1.44-3.17; P = .0002). CONCLUSIONS: During the treatment of CLL, ibrutinib was not associated with significantly higher risks of anemia, thrombocytopenia, or neutropenia compared to the control group. However, abdominal manifestations were significantly higher with ibrutinib. Advanced phase trials should further confirm this hypothesis.

Short-Term Versus Long-Term Adverse Cardiovascular Outcomes Post Percutaneous Coronary Intervention in Patients with Insulin-Treated Type 2 Diabetes Mellitus: A Simple Meta-Analysis.

INTRODUCTION: Type 2 diabetes mellitus (T2DM) is a major health issue, especially in patients with coexisting coronary artery disease (CAD). Patients with insulin-treated T2DM (ITDM) have worse outcomes than those with non-insulin-treated T2DM. Very few studies have compared short-term to long-term adverse cardiovascular outcomes following percutaneous coronary intervention (PCI) in patients on insulin therapy. Therefore, in this meta-analysis, we systematically compared short-term to long-term adverse cardiovascular outcomes in a population of patients with ITDM following PCI. METHODS: We searched for English-language publications focusing on PCI in patients with ITDM using specific search terms/phrases. All the participants accepted for inclusion in this meta-analysis were treated with a drug-eluting stent. Post-intervention adverse cardiovascular outcomes observed during short-term and long-term follow-up periods were assessed and compared. Statistical analysis was carried out using the popular RevMan 5.3 software. Odd ratios (OR) with 95% confidence intervals (CI) were calculated. RESULTS: Six studies comprising 1568 participants with ITDM in total were included in this simple meta-analysis. Patient enrollment periods varied but enrollment occurred during the years 1993-2012. When a fixed-effects statistical model was used, post-PCI adverse cardiovascular outcomes-such as major adverse cardiac events (MACEs) (OR 3.33, 95% CI 2.64-4.21; P = 0.00001), all-cause mortality (OR 5.73, 95% CI 3.37-9.73; P = 0.00001), myocardial infarction (MI) (OR 1.47, 95% CI 1.05-2.07; P = 0.02), and repeated revascularization (OR 4.78, 95% CI 3.29-6.94; P = 0.00001)-were found to be significantly more likely during the long-term follow-up period. A similar result was observed with a random-effects statistical model. CONCLUSION: Adverse cardiovascular outcomes post PCI were significantly more likely during the long-term follow-up period than during the short-term follow-up period in these patients with T2DM on insulin therapy. This hypothesis requires confirmation via new comparative trials that consider short-term and long-term follow-up periods.

Sestrin2 Suppresses Classically Activated Macrophages-Mediated Inflammatory Response in Myocardial Infarction through Inhibition of mTORC1 Signaling.

Myocardial infarction (MI) triggers an intense inflammatory response that is essential for dead tissue clearance but also detrimental to cardiac repair. Macrophages are active and critical players in the inflammatory response after MI. Understanding the molecular mechanisms by which macrophage-mediated inflammatory response is regulated is important for designing new therapeutic interventions for MI. In the current study, we examined the role of Sestrin2, which is a stress-inducible protein that regulate metabolic homeostasis, in the regulation of inflammatory response of cardiac macrophages after MI. We found that cardiac macrophages upregulated Sestrin2 expression in a mouse MI model. Using a lentiviral transduction system to overexpress Sestrin2 in polarized M1 and M2 macrophages, we revealed that Sestrin2 predominantly functioned on M1 rather than M2 macrophages. Sestrin2 overexpression suppressed inflammatory response of M1 macrophages both in vitro and in vivo. Furthermore, in the mouse MI model with selective depletion of endogenous macrophages and adoptive transfer of exogenous Sestrin2-overexpressing macrophages, the anti-inflammatory and repair-promoting effect of Sestrin2-overexpressing macrophages was demonstrated. Furthermore, Sestrin2 significantly inhibited mTORC1 signaling in M1 macrophages. Taken together, our study indicates the importance of Sestrin2 for suppression of M1 macrophage-mediated cardiac inflammation after MI.

mTORC1 signaling is crucial for regulatory T cells to suppress macrophage-mediated inflammatory response after acute myocardial infarction.

Post-infarction inflammatory response results in worse remodeling and dysfunction following myocardial infarction (MI). Supression of post-infarction inflammation would be a logical approach of alleviating post-infarction injury and promoting cardiac repair. In this study, we investigated the significance of mTORC1 signaling in the anti-inflammatory activity of regulatory T cells (Tregs) after MI. Using the murine MI model with wild type and Rag1(-/-) mice, we found that the mechanistic target of rapamycin compex 1 (mTORC1) signaling was upregulated in Tregs infiltrating into the infarcted myocardium, rather than in circulating Tregs after MI. The anti-inflammatory activity of infiltrating Tregs was significantly stronger than that of circulating Tregs. This was demonstrated by a higher expression of anti-inflammatory cytokines in the infiltrating Tregs and a robust suppression of proinflammatory cytokine production by macrophages. In an adoptive transfer analysis, compared with normal splenic Tregs, rapamycin-treated splenic Tregs ineffectively suppressed the post-infarction inflammatory response of infiltrating macrophages. In addition, in vitro cultured primary cardiomyocytes treated with mild oxygen glucose deprivation induced mTORC1 activation and a higher anti-inflammatory activity of Tregs in a coculture assay. Our study identified a new mechanism by which infiltrating Tregs subdue post-infarction inflammation. Understanding and utilizing this information would be helpful for designing new therapeutic interventions for MI.

Combination of D942 with curcumin protects cardiomyocytes from ischemic damage through promoting autophagy.

Myocardial ischemia is one of the main causes of sudden cardiac death. Autophagy has been demonstrated to protect cardiomyocytes from ischemia/reperfusion (I/R)-induced damage. A small molecule compound 5-(3-(4-(2-(4-fluorophenyl)ethoxy)phenyl)propyl)furan-2-carboxylic acid (D942) has been previously shown to specifically activate adenosine monophosphate-activated protein kinase (AMPK) in cancer cells. Another reagent, curcumin, has been shown to inhibit mammalian target of rapamycin (mTOR) signal pathway in tumor cells. Since AMPK signaling induces autophagy, while mTOR signaling inhibits autophagy, here we tested the potential protective efficacy of D942 with curcumin for cardiomyocytes under oxygen-glucose deprivation and reoxygenation (OGD/R). Mouse neonatal cardiomyocytes were treated with D942 and curcumin after being subjected to OGD/R. Cell survival and autophagy-related signal pathways were measured after treatment. Our data indicated both D942 and curcumin enhanced cell survival after OGD/R. The D942 and curcumin induced autophagy in cardiomyocytes through activating AMPK pathway or inhibiting mTOR signaling. Induction of autophagy by D942 and curcumin was the cause of cardioprotection, since inhibition of autophagy abolished the protective efficacy. Furthermore, combination treatment with D942 and curcumin profoundly upregulated autophagy after OGD/R and significantly promoted cell survival. Treatment with D942 and curcumin significantly upregulated autophagy in a murine myocardial I/R model. Taken together, our research suggests that D942 and curcumin could be promising therapeutic agents for myocardial I/R.