Bempedoic acid and ezetimibe - better together.
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ABSTRACT:
SUBMITTER: Khan SU
PROVIDER: S-EPMC7203625 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:AimsThe aim of this study was to evaluate the low-density lipoprotein cholesterol lowering efficacy and safety of a bempedoic acid 180 mg and ezetimibe 10 mg fixed-dose combination in patients with hypercholesterolemia and a high risk of cardiovascular disease receiving maximally tolerated statin therapy.MethodsThis phase 3, double-blind clinical trial enrolled adult patients at high risk of cardiovascular disease due to atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or multiple cardiovascular disease risk factors. Patients were randomly assigned (2:2:2:1) to treatment with the fixed-dose combination, bempedoic acid 180 mg, ezetimibe 10 mg or placebo added to stable background statin therapy for 12 weeks. The primary efficacy endpoint was the percentage change from baseline to week 12 in low-density lipoprotein cholesterol.ResultsAmong the 301 patients included in the primary analysis, the mean baseline low-density lipoprotein cholesterol level was 3.87 mmol/L (149.8 mg/dL). At week 12, the fixed-dose combination lowered low-density lipoprotein cholesterol (-36.2%) significantly more than placebo (1.8% (placebo-corrected difference -38.0%); P < 0.001), ezetimibe alone (-23.2%; P < 0.001) or bempedoic acid alone (-17.2%; P < 0.001). The fixed-dose combination lowered low-density lipoprotein cholesterol levels similarly across subgroups, including patients receiving high-intensity, other-intensity or no statin therapy. Improvements with the fixed-dose combination were also observed in secondary efficacy endpoints, including high-sensitivity C-reactive protein. In this trial, fixed-dose combination treatment had a generally similar safety profile compared with bempedoic acid, ezetimibe or placebo.ConclusionThe bempedoic acid and ezetimibe fixed-dose combination significantly lowered low-density lipoprotein cholesterol versus placebo or other oral monotherapies and had a favourable safety profile when added to maximally tolerated statin therapy in patients with hypercholesterolemia and high cardiovascular disease risk.Trial registrationClinicalTrials.gov identifier: NCT03337308.
| S-EPMC7153222 | biostudies-literature
Project description:Highlights • In patients with T2DM and hypercholesterolemia untreated with lipid-lowering drugs:• BA + EZE FDC lowered LDL-C levels by 38.8% at week 12• BA + EZE FDC significantly reduced LDL-C and non-HDL-C vs ezetimibe or placebo• BA + EZE FDC significantly reduced hsCRP vs ezetimibe or placebo• BA + EZE FDC was safe and generally well tolerated Objective Statins are sometimes associated with worsened glycemic control. Patients with type 2 diabetes mellitus (T2DM) may require non-statin therapies to achieve low-density lipoprotein cholesterol (LDL-C) lowering goals. This study evaluated the efficacy and safety of bempedoic acid 180 mg plus ezetimibe 10 mg fixed-dose combination (BA + EZE FDC) in patients with T2DM and hypercholesterolemia who were not receiving background statins or other lipid-lowering therapy. Methods Patients with T2DM and elevated LDL-C levels were enrolled into this phase 2, double-blind study (NCT03531905). Patients received placebo during a 5-week washout period where background lipid-lowering therapies (including statins) were discontinued. Eligible patients were then randomized 1:1:1 to receive either BA + EZE FDC, ezetimibe 10 mg, or placebo once daily for 12 weeks. Assessments included the percent change from baseline to week 12 in LDL-C, other lipid parameters, and high-sensitivity C-reactive protein (hsCRP); and the monitoring of safety and tolerability. Results Among 179 randomized patients, baseline characteristics following the washout period were similar across treatment groups, with mean LDL-C levels of 142.6 mg/dL and mean glycated hemoglobin of 8.0%. At week 12, BA + EZE FDC therapy lowered mean LDL-C levels by 38.8%, significantly more than ezetimibe alone (19.2%; difference, 19.5% [95% confidence interval (CI), 13.4%–25.7%]; p < 0.001) or placebo (increase of 0.9%; difference, 39.6% [95% CI, 33.4%–45.8%]; p < 0.001). BA + EZE FDC significantly reduced hsCRP levels from baseline vs ezetimibe (29.2%; p = 0.005) and vs placebo (36.7%; p < 0.001). Incidence of treatment-emergent adverse events was low in all treatment groups, with no indication of worsened glycemic control. Conclusion In patients with T2DM and hypercholesterolemia who were not receiving statins or other lipid-lowering drugs, BA + EZE FDC significantly lowered LDL-C levels and was generally well tolerated.
| S-EPMC8550983 | biostudies-literature
Project description: Not available
| S-EPMC6865332 | biostudies-literature
Project description:Many patients do not achieve optimal low-density lipoprotein cholesterol (LDL-C) levels with statins alone; others are unable to tolerate statin therapy. Additional non-statin treatment options including ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors, and bile acid sequestrants are often necessary to further reduce the risk of atherosclerotic cardiovascular disease. This review provides practical guidance as to the use of bempedoic acid to lower LDL-C and includes direction as to which patients may benefit and advice for safety monitoring during treatment. Bempedoic acid, a new class of agent, is a prodrug converted to bempedoyl-CoA by very long-chain acyl-CoA synthetase 1, an enzyme with high expression in the liver but that is undetectable in the skeletal muscle. Bempedoic acid inhibits the enzyme adenosine triphosphate (ATP)-citrate lyase, which lies two steps upstream from β-hydroxy β-methylglutaryl-CoA reductase in the cholesterol biosynthesis pathway. In clinical trials conducted in patients with or at risk for atherosclerotic cardiovascular disease or familial heterozygous hypercholesterolemia, bempedoic acid in combination with statins and/or ezetimibe significantly reduced LDL-C, apolipoprotein B, and high-sensitivity C-reactive protein compared with placebo. Bempedoic acid is generally well tolerated with no clinically meaningful increase in muscle-related symptoms relative to placebo, even in patients taking maximally tolerated statins. A small increase in serum uric acid (mean increase 0.8 mg/dL) is the most noteworthy adverse effect. Bempedoic acid provides an effective and generally well-tolerated medication to further reduce LDL-C in patients taking maximally tolerated statins or manage LDL-C levels in those who are unable to take statins. The potential for a reduced incidence of major cardiovascular events with bempedoic acid is being investigated in the CLEAR Outcomes trial, with results expected in 2023.
| S-EPMC8266788 | biostudies-literature
Project description:Cardiovascular disease (CVD) is the leading cause of death worldwide and one key factor associated with the increased CVD risk is dyslipidemia. Statin therapy remains the first-line treatment to manage dyslipidemia, yet many patients do not achieve optimal low-density lipoprotein-cholesterol (LDL-C) levels even after taking moderate- or high-intensity statins; therefore, additional, non-statin therapy is often needed. Bempedoic acid is a prodrug that, once activated, decreases LDL-C levels by the inhibition of adenosine triphosphate citrate lyase in the liver. Five clinical trials have demonstrated the safety and efficacy of bempedoic acid and the bempedoic acid/ezetimibe combination in lowering LDL-C in patients with atherosclerotic CVD and heterozygous familial hypercholesterolemia and also in high-risk primary prevention, and statin-intolerant patients. Bempedoic acid has been demonstrated to lower LDL-C levels by 15-25% in clinical trials and up to 38% when combined with ezetimibe. In 2020, the FDA approved bempedoic acid. Furthermore, the combination of bempedoic acid with ezetimibe is FDA approved for the treatment of adults with heterozygous familial hypercholesterolemia or established atherosclerotic CVD who require additional LDL-C lowering after maximally tolerated statin therapy. The ongoing CLEAR OUTCOMES trial aims to evaluate whether bempedoic acid can reduce cardiovascular events in patients with statin intolerance and results will be available in the next 3 years. This outcomes trial will be pivotal for determining the role of bempedoic acid in the non-statin lipid-lowering armamentarium.
| S-EPMC7449648 | biostudies-literature
Project description:Cellulose nanopapers have gained significant attention in recent years as large-scale reinforcement for high-loading cellulose nanocomposites, substrates for printed electronics and filter nanopapers for water treatment. The mechanical properties of nanopapers are of fundamental importance for all these applications. Cellulose nanopapers can simply be prepared by filtering a suspension of nanocellulose, followed by heat consolidation. It was already demonstrated that the mechanical properties of cellulose nanopapers can be tailored by the fineness of the fibrils used or by modifying nanocellulose fibrils for instance by polymer adsorption, but nanocellulose blends remain underexplored. In this work, we show that the mechanical and physical properties of cellulose nanopapers can be tuned by creating nanopapers from blends of various grades of nanocellulose, i.e. (mechanically refined) bacterial cellulose or cellulose nanofibrils extracted from never-dried bleached softwood pulp by chemical and mechanical pre-treatments. We found that nanopapers made from blends of two or three nanocellulose grades show synergistic effects resulting in improved stiffness, strength, ductility, toughness and physical properties.This article is part of a discussion meeting issue 'New horizons for cellulose nanotechnology'.
| S-EPMC5746558 | biostudies-literature
Project description: Not available
| S-EPMC7566933 | biostudies-literature
Project description:The management of low-density lipoprotein cholesterol (LDL-C) levels is a central strategy for the prevention of atherosclerotic cardiovascular disease. Current United States (2018 American Heart Association/American College of Cardiology/Multisociety) and European (2019 European Society of Cardiology/European Atherosclerosis Society) guidelines endorse statin therapy as the first-line therapy for pharmacologic LDL-C lowering. However, in clinical practice up to 30% of patients report partial or complete intolerance to statin therapy. While the nocebo effect with statins is well described, perceived statin intolerance prevents many patients from achieving LDL-C thresholds associated with clinical benefit. Bempedoic acid is a novel, oral, non-statin lipid-l owering therapy that works by inhibiting adenosine triphosphate-citrate lyase, an enzymatic reaction upstream of 3-hydroxy-3-methylglutaryl coenzyme A reductase in the hepatic cholesterol synthesis pathway. Bempedoic acid confers reduction in LDL-C of ~18% on background statin therapy,~21% in patients with statin intolerance, and ~38% when given in fixed-dose combination with ezetimibe. The CLEAR Outcomes trial, which enrolled high-risk primary and secondary prevention patients with reported statin intolerance and LDL-C levels ≥100 mg/dL, showed that bempedoic acid compared with placebo reduced 4-component major adverse cardiovascular events (MACE) by 13% (hazard ratio 0.87, 95% confidence interval 0.79-0.96). Bempedoic acid also reduced 3-component MACE by 15%, myocardial infarction by 23% and coronary revascularization by 19%. The benefit was even greater in the primary prevention cohort (hazard ratio 0.70, 95% confidence interval 0.55-0.89) for 4-component MACE. Bempedoic acid was associated with increases in uric acid levels and cholelithiasis, but numerically fewer events of myalgia and new-onset diabetes. These findings confirm that bempedoic acid is an effective approach to reduce cardiovascular outcomes in high-risk patients with statin intolerance who require further reduction in LDL-C.
| S-EPMC10900064 | biostudies-literature
Project description:Following phagocytosis, the nascent phagosome undergoes maturation to become a phagolysosome with an acidic, hydrolytic, and often oxidative lumen that can efficiently kill and digest engulfed microbes, cells, and debris. The fusion of phagosomes with lysosomes is a principal driver of phagosomal maturation and is targeted by several adapted intracellular pathogens. Impairment of this process has significant consequences for microbial infection, tissue inflammation, the onset of adaptive immunity, and disease. Given the importance of phagosome-lysosome fusion to phagocyte function and the many virulence factors that target it, it is unsurprising that multiple molecular pathways have evolved to mediate this essential process. While the full range of these pathways has yet to be fully characterized, several pathways involving proteins such as members of the Rab GTPases, tethering factors and SNAREs have been identified. Here, we summarize the current state of knowledge to clarify the ambiguities in the field and construct a more comprehensive phagolysosome formation model. Lastly, we discuss how other cellular pathways help support phagolysosome biogenesis and, consequently, phagocyte function.
| S-EPMC7946854 | biostudies-literature
Project description:PurposeEating disorders are prevalent public health problems associated with broad psychosocial impairments and with elevated rates of psychiatric and medical comorbidities. Critical reviews of the treatment literature for eating disorders indicate that although certain specialized psychological treatments and specific medications show efficacy to varying degrees across the different eating disorders, many patients fail to derive sufficient benefit from existing treatments. This article addresses whether combining psychological and pharmacologic interventions confers any additional benefits for treating eating disorders.MethodsThis study was a critical review of randomized controlled trials (RCTs) testing combined psychological and pharmacologic treatment approaches for eating disorders with a focus on anorexia nervosa (AN), bulimia nervosa (BN), and binge-eating disorder (BED).FindingsFor AN, 3 of the 4 RCTs reported no significant advantage for combining treatments; the fourth reported a statistically significant, albeit clinically modest, advantage. For BN, 10 of the 12 RCTs reported no significant advantage for combining treatments; 2 RCTs found that combining fluoxetine with specific psychological treatments enhanced outcomes relative to medication only but not relative to the psychological treatments only. For BED, of the 12 RCTs, only 2 (both with antiseizure medications) significantly enhanced both binge-eating and weight outcomes, and only 2 (with orlistat, a weight-loss medication) enhanced weight loss but not binge-eating outcomes.ImplicationsDespite the public health significance of eating disorders, the scope of research performed on the utility of combining treatments is limited. To date, the few RCTs testing combined pharmacologic plus psychological treatments for eating disorders have yielded mostly nonsignificant findings. Future RCTs should focus on testing additive benefits of medications with relevant mechanisms of action to available effective psychological interventions. In addition, future RCTs that test additive effects should use adaptive designs, which could inform treatment algorithms to enhance outcomes among both responders and nonresponders to initial interventions.
| S-EPMC8243253 | biostudies-literature