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JAMA Cardiology Mar 2024The ATP citrate lyase (ACL) inhibitor, bempedoic acid, reduces low-density lipoprotein cholesterol (LDL-C) level and major adverse cardiovascular events (MACE) by 13% in... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
The ATP citrate lyase (ACL) inhibitor, bempedoic acid, reduces low-density lipoprotein cholesterol (LDL-C) level and major adverse cardiovascular events (MACE) by 13% in patients at high cardiovascular risk with intolerance of statin and high-intensity statin medications. The effects of bempedoic acid on total cardiovascular events remain unknown.
OBJECTIVE
To determine the impact of bempedoic acid on the total incidence of MACE.
DESIGN, SETTING, AND PARTICIPANTS
Included in this prespecified analysis of the Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen (CLEAR) Outcomes trial were patients with, or at high risk for, cardiovascular disease, with hypercholesterolemia and inability to take guideline-recommended statins. Study data were analyzed from December 2016 to November 2022.
INTERVENTIONS
Patients were randomly assigned to treatment with bempedoic acid or placebo daily.
MAIN OUTCOMES AND MEASURES
The primary end point was the time to first event for a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization (MACE-4). The key secondary end point was time to first event for cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke (MACE-3). This prespecified analysis compared the total number of cardiovascular events in the treatment groups.
RESULTS
A total of 13 970 patients (mean [SD] age, 65 [9] years; 7230 male [51.8%]) were included in the study. A total of 9764 participants (69.9%) had prior atherosclerotic cardiovascular disease and a baseline LDL-C level of 139 mg/dL; treatment with bempedoic acid resulted in a 21% reduction in LDL-C level and a 22% reduction in high-sensitivity C-reactive protein (hsCRP) level at 6 months. Median (IQR) follow-up was 3.4 (3.1-3.9) years. A total of 1746 positively adjudicated first MACE-4 events and 915 additional MACE events in 612 patients were recorded, with coronary revascularization representing 32.8% (573 of 1746) of first events and 69.4% (635 of 915) of additional events. For the total incidence of cardiovascular events, treatment with bempedoic acid was associated with a reduction in risk of MACE-4 (hazard ratio [HR], 0.80; 95% CI, 0.72-0.89; P <.001), MACE-3 (HR, 0.83; 95% CI, 0.73-0.93; P = .002), myocardial infarction (HR, 0.69; 95% CI, 0.58-0.83; P < .001), and coronary revascularization (HR, 0.78; 95% CI, 0.68-0.89; P <.001), although no statistically significant difference was observed for stroke (HR, 0.80; 95% CI, 0.63-1.03). A lower HR for protection with bempedoic acid was observed with increasing number of MACE events experienced by patients.
CONCLUSION AND RELEVANCE
Lowering LDL-C level with bempedoic acid reduced the total number of cardiovascular events in patients with high cardiovascular risk, statin therapy intolerance, and elevated LDL-C levels.
Topics: Humans; Male; Aged; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Cholesterol, LDL; Treatment Outcome; Cholesterol; Myocardial Infarction; Stroke; Dicarboxylic Acids; Fatty Acids
PubMed: 38231501
DOI: 10.1001/jamacardio.2023.5155 -
MMW Fortschritte Der Medizin Aug 2023
Topics: Humans; Cardiovascular Diseases; Risk Factors; Dicarboxylic Acids; Heart Disease Risk Factors
PubMed: 37537473
DOI: 10.1007/s15006-023-2870-7 -
Journal of Immunology (Baltimore, Md. :... Aug 2023Immunometabolism is an interdisciplinary field that focuses on the relationship between metabolic pathways and immune responses. Dysregulated immunometabolism... (Review)
Review
Immunometabolism is an interdisciplinary field that focuses on the relationship between metabolic pathways and immune responses. Dysregulated immunometabolism contributes to many pathological settings, such as cytokine storm or immune tolerance. Aconitate decarboxylase 1 (ACOD1, also known as immunoresponsive gene 1), the mitochondrial enzyme responsible for catalyzing itaconate production, was originally identified as a bacterial LPS-inducible gene involved in innate immunity in mouse macrophages. We now know that the upregulation of ACOD1 expression in immune or nonimmune cells plays a context-dependent role in metabolic reprogramming, signal transduction, inflammasome regulation, and protein modification. The emerging function of ACOD1 in inflammation and infection is a double-edged sword. In this review, we discuss how ACOD1 regulates anti-inflammatory or proinflammatory responses in an itaconate-dependent or -independent manner. Further understanding of ACOD1 expression and function may pave the way for the development of precision therapies for inflammatory diseases.
Topics: Animals; Mice; Immunity, Innate; Inflammation; Macrophages; Succinates
PubMed: 37549395
DOI: 10.4049/jimmunol.2300101 -
Cell Metabolism Mar 2024Itaconate is a metabolite that synthesized from cis-aconitate in mitochondria and transported into the cytosol to exert multiple regulatory effects in macrophages....
Itaconate is a metabolite that synthesized from cis-aconitate in mitochondria and transported into the cytosol to exert multiple regulatory effects in macrophages. However, the mechanism by which itaconate exits from macrophages remains unknown. Using a genetic screen, we reveal that itaconate is exported from cytosol to extracellular space by ATP-binding cassette transporter G2 (ABCG2) in an ATPase-dependent manner in human and mouse macrophages. Elevation of transcription factor TFEB-dependent lysosomal biogenesis and antibacterial innate immunity are observed in inflammatory macrophages with deficiency of ABCG2-mediated itaconate export. Furthermore, deficiency of ABCG2-mediated itaconate export in macrophages promotes antibacterial innate immune defense in a mouse model of S. typhimurium infection. Thus, our findings identify ABCG2-mediated itaconate export as a key regulatory mechanism that limits TFEB-dependent lysosomal biogenesis and antibacterial innate immunity in inflammatory macrophages, implying the potential therapeutic utility of blocking itaconate export in treating human bacterial infections.
Topics: Animals; Humans; Mice; Anti-Bacterial Agents; ATP Binding Cassette Transporter, Subfamily G, Member 2; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Immunity, Innate; Lysosomes; Neoplasm Proteins; Succinates
PubMed: 38181789
DOI: 10.1016/j.cmet.2023.12.015 -
Drug and Therapeutics Bulletin Nov 2023Nissen SE, Lincoff AM, Brennan D, et al. Bempedoic acid and cardiovascular outcomes in statin-intolerant patients. 2023;388:1353-64.
Nissen SE, Lincoff AM, Brennan D, et al. Bempedoic acid and cardiovascular outcomes in statin-intolerant patients. 2023;388:1353-64.
Topics: Humans; Dicarboxylic Acids; Fatty Acids; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Cardiovascular Diseases
PubMed: 37833039
DOI: 10.1136/dtb.2023.000054 -
American Family Physician Jun 2024Rosacea is a chronic inflammatory skin disease of the central face, affecting 5% of the population. The exact etiology is unknown. A diagnosis is made based on the... (Review)
Review
Rosacea is a chronic inflammatory skin disease of the central face, affecting 5% of the population. The exact etiology is unknown. A diagnosis is made based on the updated 2017 National Rosacea Society Expert Committee guidelines, including fixed erythema, phymatous changes of skin thickening due to sebaceous gland hyperplasia and fibrosis, papules, pustules, telangiectasia, and flushing. Delays in an accurate diagnosis and treatment may occur in skin of color due to difficulty visualizing erythema and telangiectasia. The daily use of sunscreen, moisturizers, and mild skin cleansers and avoidance of triggers are essential aspects of maintenance treatment. Effective topical treatment options include alpha-adrenergic receptor agonists for flushing and ivermectin, metronidazole, and azelaic acid for papules and pustules. Systemic treatments include nonselective beta blockers for flushing, low-dose doxycycline, and isotretinoin for papules and pustules. Rosacea can significantly affect a patient's emotional health and quality of life. A referral for care is recommended for fixed phymatous changes and ocular rosacea. (Am Fam Physician. 2024;109(6):533-542.
Topics: Rosacea; Humans; Dermatologic Agents; Quality of Life; Dicarboxylic Acids
PubMed: 38905551
DOI: No ID Found -
Cellular & Molecular Biology Letters Dec 2023Metabolic states greatly influence functioning and differentiation of immune cells. Regulating the metabolism of immune cells can effectively modulate the host immune... (Review)
Review
Metabolic states greatly influence functioning and differentiation of immune cells. Regulating the metabolism of immune cells can effectively modulate the host immune response. Itaconate, an intermediate metabolite derived from the tricarboxylic acid (TCA) cycle of immune cells, is produced through the decarboxylation of cis-aconitate by cis-aconitate decarboxylase in the mitochondria. The gene encoding cis-aconitate decarboxylase is known as immune response gene 1 (IRG1). In response to external proinflammatory stimulation, macrophages exhibit high IRG1 expression. IRG1/itaconate inhibits succinate dehydrogenase activity, thus influencing the metabolic status of macrophages. Therefore, itaconate serves as a link between macrophage metabolism, oxidative stress, and immune response, ultimately regulating macrophage function. Studies have demonstrated that itaconate acts on various signaling pathways, including Keap1-nuclear factor E2-related factor 2-ARE pathways, ATF3-IκBζ axis, and the stimulator of interferon genes (STING) pathway to exert antiinflammatory and antioxidant effects. Furthermore, several studies have reported that itaconate affects cancer occurrence and development through diverse signaling pathways. In this paper, we provide a comprehensive review of the role IRG1/itaconate and its derivatives in the regulation of macrophage metabolism and functions. By furthering our understanding of itaconate, we intend to shed light on its potential for treating inflammatory diseases and offer new insights in this field.
Topics: Kelch-Like ECH-Associated Protein 1; NF-E2-Related Factor 2; Succinates; Immunity
PubMed: 38042791
DOI: 10.1186/s11658-023-00503-3 -
Journal of the American Society of... Feb 2024In this study, we demonstrate that a common, low-cost compound known as octanedioic acid (DC 8 ) can protect mice from kidney damage typically caused by...
SIGNIFICANCE STATEMENT
In this study, we demonstrate that a common, low-cost compound known as octanedioic acid (DC 8 ) can protect mice from kidney damage typically caused by ischemia-reperfusion injury or the chemotherapy drug cisplatin. This compound seems to enhance peroxisomal activity, which is responsible for breaking down fats, without adversely affecting mitochondrial function. DC 8 is not only affordable and easy to administer but also effective. These encouraging findings suggest that DC 8 could potentially be used to assist patients who are at risk of experiencing this type of kidney damage.
BACKGROUND
Proximal tubules are rich in peroxisomes, which are damaged during AKI. Previous studies demonstrated that increasing peroxisomal fatty acid oxidation (FAO) is renoprotective, but no therapy has emerged to leverage this mechanism.
METHODS
Mice were fed with either a control diet or a diet enriched with dicarboxylic acids, which are peroxisome-specific FAO substrates, then subjected to either ischemia-reperfusion injury-AKI or cisplatin-AKI models. Biochemical, histologic, genetic, and proteomic analyses were performed.
RESULTS
Both octanedioic acid (DC 8 ) and dodecanedioic acid (DC 12 ) prevented the rise of AKI markers in mice that were exposed to renal injury. Proteomics analysis demonstrated that DC 8 preserved the peroxisomal and mitochondrial proteomes while inducing extensive remodeling of the lysine succinylome. This latter finding indicates that DC 8 is chain shortened to the anaplerotic substrate succinate and that peroxisomal FAO was increased by DC 8 .
CONCLUSIONS
DC 8 supplementation protects kidney mitochondria and peroxisomes and increases peroxisomal FAO, thereby protecting against AKI.
Topics: Animals; Humans; Mice; Acute Kidney Injury; Cisplatin; Dicarboxylic Acids; Dietary Supplements; Fatty Acids; Proteomics; Reperfusion Injury
PubMed: 38044490
DOI: 10.1681/ASN.0000000000000266 -
Current Atherosclerosis Reports Mar 2024Bempedoic acid is a novel therapeutic agent that is designed to reduce levels of low-density lipoprotein cholesterol (LDL-C). The purpose of this review is to provide... (Review)
Review
PURPOSE OF REVIEW
Bempedoic acid is a novel therapeutic agent that is designed to reduce levels of low-density lipoprotein cholesterol (LDL-C). The purpose of this review is to provide the background for development of bempedoic acid, findings from clinical trials and to discuss clinical implications.
RECENT FINDINGS
Bempedoic acid inhibits ATP citrate lyase within the liver and reduces cholesterol synthesis, with the potential to avoid muscle symptoms experienced by patients treated with statins. Early clinical studies demonstrated that administration of bempedoic acid resulted in lowering of LDL-C by 20-30% as monotherapy and by 40-50% when combined with ezetimibe, in addition to lowering of high sensitivity C-reactive protein by 20-30%. The CLEAR Outcomes trial of high cardiovascular risk patients, with elevated LDL-C levels and either unable or unwilling to take statins demonstrated that bempedoic acid reduced the rate of major adverse cardiovascular events. A greater incidence of elevation of hepatic transaminase and creatinine, gout, and cholelithiasis were consistently observed in bempedoic acid-treated patients. Bempedoic acid presents an additional therapeutic option to achieve more effective lowering of LDL-C levels and reduction in cardiovascular risk.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Cholesterol, LDL; Fatty Acids; Dicarboxylic Acids
PubMed: 38294660
DOI: 10.1007/s11883-024-01188-5 -
Nature Immunology Nov 2023The malate shuttle is traditionally understood to maintain NAD/NADH balance between the cytosol and mitochondria. Whether the malate shuttle has additional functions is...
The malate shuttle is traditionally understood to maintain NAD/NADH balance between the cytosol and mitochondria. Whether the malate shuttle has additional functions is unclear. Here we show that chronic viral infections induce CD8 T cell expression of GOT1, a central enzyme in the malate shuttle. Got1 deficiency decreased the NAD/NADH ratio and limited antiviral CD8 T cell responses to chronic infection; however, increasing the NAD/NADH ratio did not restore T cell responses. Got1 deficiency reduced the production of the ammonia scavenger 2-ketoglutarate (2-KG) from glutaminolysis and led to a toxic accumulation of ammonia in CD8 T cells. Supplementation with 2-KG assimilated and detoxified ammonia in Got1-deficient T cells and restored antiviral responses. These data indicate that the major function of the malate shuttle in CD8 T cells is not to maintain the NAD/NADH balance but rather to detoxify ammonia and enable sustainable ammonia-neutral glutamine catabolism in CD8 T cells during chronic infection.
Topics: Humans; Oxidation-Reduction; NAD; Ketoglutaric Acids; Ammonia; Malates; CD8-Positive T-Lymphocytes; Persistent Infection; Antiviral Agents
PubMed: 37813964
DOI: 10.1038/s41590-023-01636-5