etc-1002 and Atherosclerosis

The clinical benefit of LDL cholesterol (LDL-C) lowering for cardiovascular disease prevention is well documented. This paper from the Italian Study Group on Atherosclerosis, Thrombosis and Vascular Biology summarizes current recommendations for treatment of hypercholesterolemia, barriers to lipid-lowering therapy implementation and tips to overcome them, as well as available evidence on the efficacy and safety of bempedoic acid. We also report an updated therapeutic algorithm for pharmacological LDL-C lowering in view of the introduction of bempedoic acid in clinical practice.

Topics: Atherosclerosis; Biology; Cardiovascular Diseases; Cholesterol, LDL; Consensus; Fatty Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Risk Factors; Thrombosis

It is clear from epidemiological studies that patients at high and very-high risk of atherosclerotic cardiovascular diseases (ASCVD) risk do not reach lipid guideline-recommended targets. Thus, fixed-dose combinations of statins/ezetimibe, bempedoic acid/ezetimibe and statins/fibrates may represent a further armamentarium in the field of lipid-lowering approaches in these individuals.. The combination therapy of moderate-intensity statin with ezetimibe is not inferior to high-intensity statin monotherapy in reducing cardiovascular outcomes. Drug discontinuation or dose reduction is inferior with fixed-dose combination. The fixed-dose combination of bempedoic acid with ezetimibe is superior to bempedoic acid in monotherapy in lowering LDL-C and in reducing high-sensitivity C-reactive protein concentrations. The combination fenofibrate with atorvastatin is superior to monotherapies in lowering triglycerides. Lipid-lowering fixed-dose combinations may guarantee a higher therapy adherence, representing a better approach to control plasma lipids and thus ameliorate ASCVD burden. Additional studies will define the advantages on cardiovascular outcomes in high and very high-risk patients.

Topics: Anticholesteremic Agents; Atherosclerosis; Cholesterol, LDL; Drug Therapy, Combination; Dyslipidemias; Ezetimibe; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Treatment Outcome

Epidemiological, randomized, controlled, clinical and genetic studies confirm that low-density lipoprotein cholesterol (LDL-C) is a causative factor for atherosclerotic diseases. The current European Society of Cardiology and European Atherosclerosis Society (ESC/EAS) guidelines on the management of dyslipidemia recommend a target LDL-C < 55 mg/dl and at least a 50% reduction in baseline LDL‑C for high-risk patients; however, these target values are often not achieved in routine clinical practice, as shown by recent cross-sectional data from EUROASPIRE or DaVinci. Therefore, combination treatment is recommended, which, as with treatment of blood pressure, can improve the success of treatment. Bempedoic acid is a new substance, which is suitable for combination treatment and represents an alternative particularly for patients with statin-associated muscular symptoms. Bempedoic acid reduces LDL‑C by approximately 25% in statin-naïve patients and by some 18% in addition to statins. In a fixed doses combination with ezetimibe, bempedoic acid can lower LDL‑C by up to 45% in statin-naïve patients and by 38% (placebo-corrected) in addition to statins. Bempedoic acid is generally very well tolerated: however, it can lead to a reversible increase in uric acid. Occasionally, a slight decrease in hemoglobin has been documented. Therefore, it is recommended that not only changes in lipid levels but also uric acid and hematological parameters should be monitored in the first 3 months.. Epidemiologische, randomisierte, kontrollierte, klinische und genetische Studien belegen, dass das LDL(„low-density lipoprotein“)-Cholesterin (LDL-C) einen ursächlichen Faktor für atherosklerotische Erkrankungen darstellt. Die aktuellen ESC/EAS-Leitlinien zum Management von Dyslipidämien empfehlen für Hochrisikopatienten einen LDL-C-Zielwert von weniger als 55 mg/dl und eine mindestens 50 %ige Reduktion des LDL-C-Ausgangswertes. Leider werden diese Zielwerte im klinischen Alltag häufig nicht erreicht, wie auch jüngste Studiendaten aus EUROASPIRE oder DaVinci belegen. Daher sind Kombinationstherapien empfohlen, die, wie auch bei der Blutdrucktherapie, den Therapieerfolg verbessern können. Bempedoinsäure ist eine neue Substanz, die für eine Kombinationstherapie geeignet ist und insbesondere für Patienten mit statinassoziierten Muskelsymptomen eine Alternative darstellt und den LDL-C-Wert bei statinnaiven Patienten um etwa 25 %, zusätzlich zu Statinen um etwa 18 % senkt. In einer Fixdosiskombination mit Ezetimib kann bei statinnaiven Patienten eine LDL-C-Senkung um bis zu 45 %, zusätzlich zu Statinen um 38 % (placebokorrigiert) erreicht werden. Bempedoinsäure ist in der Regel sehr gut verträglich, kann allerdings zu einem reversiblen Anstieg der Harnsäure führen. Gelegentlich wurde eine leichte Abnahme des Hämoglobins dokumentiert. Daher wird empfohlen, in den ersten 3 Monaten nicht nur die Veränderungen der Lipidwerte, sondern auch Harnsäure und hämatologische Parameter zu kontrollieren.

Topics: Anticholesteremic Agents; Atherosclerosis; Cholesterol, LDL; Cross-Sectional Studies; Dicarboxylic Acids; Fatty Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Uric Acid

Atherosclerotic heart disease is the leading cause of mortality and morbidity in the USA. Low density lipoprotein (LDL) has been the target for many hypolipidemic agents to modify atherosclerotic risk. Bempedoic acid is a novel hypolipidemic drug that inhibits the enzymatic activity of ATP citrate lyase in the cholesterol synthesis pathway. CLEAR Harmony, CLEAR Wisdom, CLEAR Tranquillity and CLEAR Serenity have shown safety and efficacy associated with long term administration of this drug. Studies have shown effectiveness in reducing LDL-C in both statin intolerant patients and in patients on maximally tolerated doses of statin. The fixed drug combination of bempedoic acid and ezetimibe in a recent phase III showed significant reduction in LDL compared with placebo, which might be a promising future for LDL reduction among statin intolerant patients. Bempedoic acid also reduced inflammatory markers like hs-CRP. Given these results, bempedoic acid alone and in combination with ezetimibe received the USA FDA approval for adults with heterozygous familial hypercholesterolaemia or established atherosclerotic cardiovascular disease. We present a comprehensive review exploring the underlying mechanism, pre-clinical studies, and clinical trials of bempedoic acid and discuss the potential future role of the drug in treating hyperlipidaemia.

Topics: Atherosclerosis; Cholesterol, LDL; Dicarboxylic Acids; Ezetimibe; Fatty Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Hypolipidemic Agents

To review the pharmacology, pharmacokinetics, safety, and efficacy of bempedoic acid for low-density lipoprotein cholesterol (LDL-C) reduction.. A PubMed search was conducted from January 2000 to June 15, 2020, using the keyword. Articles related to the Food and Drug Administration (FDA) approval of bempedoic acid and other trials relating to the safety and efficacy of this drug were included.. The findings from this review show that bempedoic acid is a safe and effective option for lowering LDL-C levels in patients requiring LDL-C lowering for primary or secondary prevention of cardiovascular events.. Statin therapy remains the mainstay of treatment for both primary and secondary prevention. However, many patients cannot tolerate statin therapy because of statin-associated muscle symptoms. Bempedoic acid may be a reasonable adjunct for LDL-C reduction, though further evaluation of cardiovascular outcomes with bempedoic acid in this population is needed.. The recent FDA approval of bempedoic acid offers an additional option for lowering LDL-C levels in patients with atherosclerotic cardiovascular disease or heterozygous familial hyperlipidemia. Additional data regarding effect on long-term cardiovascular outcomes with bempedoic acid are currently being studied.

Topics: Atherosclerosis; Cholesterol, LDL; Clinical Trials, Phase III as Topic; Dicarboxylic Acids; Fatty Acids; Humans; Hypercholesterolemia; Hyperlipoproteinemia Type II; Hypolipidemic Agents; Treatment Outcome

This article discusses the pharmacology of bempedoic acid, the trials that led to United States Food and Drug Administration (FDA) approval of its use, and the overall safety and efficacy of this therapy in heterozygous familial hypercholesterolemia, established atherosclerotic cardiovascular disease (ASCVD), and hyperlipidemia.. A database search of PubMed and ClinicalTrials.gov was conducted for articles published between January 2012 to September 2020 and containing the key words bempedoic acid, ezetimibe, Nexletol and Nexlizet. Trials from the CLEAR series were selected, as they played a pivotal role in the establishment of FDA approval, along with additional trials published after FDA approval, which provided novel evidence on the use of bempedoic acid in the treatment of hypercholesterolemia. Publications that were not randomized, controlled trials were not included in this review. Only randomized controlled trials in which ezetimibe was used in conjunction with bempedoic acid were included in this review as they were relevant to the new FDA approval of bempedoic acid.. The findings of the present review show that bempedoic acid is both an effective and well-tolerated option for the treatment of hypercholesterolemia when used without ezetimibe in addition to standard therapy. It also appears that the combination with ezetimibe increases the cholesterol-lowering effect more than either agent alone when added to standard therapy.. Hypercholesteremia continues to be a major contributing factor leading to ASCVD. Bempedoic acid is an additional treatment option, along with both statins and diet and exercise, for reducing cholesterol levels and ASCVD events. With the new FDA approval, bempedoic acid may offer an effective therapy for reducing low-density lipoprotein cholesterol in patients at high risk for cardiovascular events due to established ASCVD or heterozygous familial hypercholesterolemia.

Topics: Atherosclerosis; Dicarboxylic Acids; Drug Therapy, Combination; Ezetimibe; Fatty Acids; Humans; Hyperlipidemias; Hyperlipoproteinemia Type II; Hypolipidemic Agents

Bempedoic acid is a first-in-class, oral, inhibitor of cholesterol biosynthesis that is approved for use in patients with atherosclerotic cardiovascular disease (ASCVD) and for primary prevention in individuals with heterozygous familial hypercholesterolemia (HeFH) by the United States Food and Drug Administration. Pooled data from the phase III clinical trials, CLEAR Harmony and CLEAR Wisdom, have demonstrated the safety and efficacy of bempedoic acid with regard to lowering of low-density lipoprotein cholesterol (LDL-C) in patients with HeFH as an adjunct or alternative to currently existing lipid-lowering therapies. CLEAR Outcomes is a cardiovascular outcomes trial that is currently underway that will provide additional insight as to where bempedoic acid will fit into treatment regimens among the non-statin lipid-lowering therapy options. Patients who might particularly benefit from bempedoic acid are those with HeFH and those unable to take adequate doses of statins or take any statin therapy altogether who need additional LDL-C lowering. In this review, we will discuss the profile of bempedoic acid from its design, development, and its place in therapy for the management of LDL-C for the purposes of ASCVD prevention.

Topics: Animals; Anticholesteremic Agents; Atherosclerosis; Cholesterol, LDL; Dicarboxylic Acids; Drug Design; Drug Development; Fatty Acids; Humans; Hyperlipoproteinemia Type II

In the last 50 years, several clinical and epidemiological studies during have shown that increased levels of low-density lipoprotein cholesterol (LDLc) are associated with the development and progression of atherosclerotic lesions. The discovery of β-Hydroxy β-methylglutaryl-CoA reductase inhibitors (statins), that possess LDLc-lowering effects, lead to a true revolution in the prevention and treatment of cardiovascular diseases. Statins remain the cornerstone of LDLc-lowering therapy. Lipid-lowering drugs, such as ezetimibe and bile acid sequestrants, are prescribed either in combination with statins or in monotherapy (in the setting of statin intolerance or contraindications to statins). Microsomal triglyceride transfer protein inhibitors and protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are other drug classes which have been investigated for their potential to decrease LDLc. PCSK9 have been approved for the treatment of hypercholesterolemia and for the secondary prevention of cardiovascular events. The present narrative review discusses the latest (2019) guidelines of the European Atherosclerosis Society/European Society of Cardiology for the management of dyslipidemia, focusing on LDLc-lowering drugs that are either already available on the market or under development. We also consider "whom, when and how" do we treat in terms of LDLc reduction in the daily clinical practice.

Topics: Antibodies, Monoclonal, Humanized; Anticholesteremic Agents; Atherosclerosis; Benzimidazoles; Bile Acids and Salts; Carrier Proteins; Cholesterol, LDL; Dicarboxylic Acids; Europe; Ezetimibe; Fatty Acids; Gene Expression; Guidelines as Topic; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; PCSK9 Inhibitors; Proprotein Convertase 9; RNA, Small Interfering

Bempedoic acid has emerged as a potent inhibitor of ATP-citrate lyase (ACLY), a target for the reduction of LDL cholesterol (LDL-C). We review the impact of bempedoic acid treatment on lipoprotein metabolism and atherosclerosis in preclinical models and patients with hypercholesterolemia.. The liver-specific activation of bempedoic acid inhibits ACLY, a key enzyme linking glucose catabolism to lipogenesis by catalyzing the formation of acetyl-CoA from mitochondrial-derived citrate for de novo synthesis of fatty acids and cholesterol. Adenosine monophosphate-activated protein kinase activation by bempedoic acid is not required for its lipid-regulating effects in vivo. Mendelian randomization of large human study cohorts has validated ACLY inhibition as a target for LDL-C lowering and atheroprotection. In rodents, bempedoic acid decreases plasma cholesterol and triglycerides, and prevents hepatic steatosis. In apolipoprotein E-deficient (Apoe) mice, LDL receptor-deficient (Ldlr) mice and LDLR-deficient miniature pigs, bempedoic acid reduces LDL-C and attenuates atherosclerosis. LDLR expression and activity are increased in primary human hepatocytes and in Apoe mouse liver treated with bempedoic acid suggesting a mechanism for LDL-C lowering, although additional pathways are likely involved. Phase 2 and 3 clinical trials revealed that bempedoic acid effectively lowers LDL-C as monotherapy, combined with ezetimibe, added to statin therapy and in statin-intolerant hypercholesterolemic patients. Treatment does not affect plasma concentrations of triglyceride or other lipoproteins.. The LDL-C-lowering and attenuated atherosclerosis in animal models and reduced LDL-C in hypercholesterolemic patients has validated ACLY inhibition as a therapeutic strategy. Positive results from phase 3 long-term cardiovascular outcome trials in high-risk patients are required for bempedoic acid to be approved for prevention of atherosclerosis.

Topics: Animals; Atherosclerosis; ATP Citrate (pro-S)-Lyase; Dicarboxylic Acids; Fatty Acids; Humans; Lipoproteins; Molecular Targeted Therapy; Triglycerides

Patients with atherosclerotic cardiovascular disease who require additional low-density lipoprotein cholesterol (LDL-C) lowering despite maximally tolerated statins have a significant unmet medical need and are at increased risk of future cardiovascular events and a reduced quality of life.. We aimed to estimate the percentage of cardiovascular events avoided following treatment with a fixed-dose combination of bempedoic acid plus ezetimibe (BA+EZE FDC) versus ezetimibe (EZE) in patients with atherosclerotic cardiovascular disease receiving maximally tolerated statins across a range of baseline LDL-C levels.. A Markov cohort simulation model estimated major adverse cardiovascular events avoided over a lifetime horizon among patients with atherosclerotic cardiovascular disease and baseline LDL-C levels from 80 to >200 mg/dL. BA+EZE FDC was compared with EZE based on mean percent LDL-C reductions versus placebo reported in a phase III trial. Health outcomes for the average patient were extrapolated to a US population of 100,000 persons using evidence on contemporary LDL-C levels from the National Health and Nutrition Examination Survey.. Among patients with atherosclerotic cardiovascular disease not at the LDL-C goal with maximally tolerated statins, the addition of BA+EZE FDC compared with the addition of EZE was predicted to provide incremental absolute reductions in major adverse cardiovascular events dependent on baseline LDL-C levels at the population level. For those with baseline LDL-C of 101-110 mg/dL (n = 15,237), there were 4.9% (744) fewer events predicted, while for patients with baseline LDL-C of > 200 mg/dL (n = 1689), 10.9% (184) fewer events were predicted through the addition of BA+EZE FDC versus EZE.. Further LDL-C reductions through the addition of BA+EZE FDC to maximally tolerated statins are predicted to reduce major adverse cardiovascular events compared with the addition of EZE. Benefits are potentially greater among those with higher starting LDL-C.

Topics: Anticholesteremic Agents; Atherosclerosis; Azetidines; Cardiovascular Diseases; Cholesterol, LDL; Drug Therapy, Combination; Ezetimibe; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Quality of Life; Treatment Outcome

Sex-specific differences in the response to lipid-lowering therapies have been reported. Here, we assessed the effect of bempedoic acid in women and men using pooled, patient-level data from four phase 3 clinical trials of bempedoic acid.. Patients were grouped into two pools: 1) atherosclerotic cardiovascular disease (ASCVD) and/or heterozygous familial hypercholesterolemia (HeFH) "on statins" and 2) "low-dose or no statin". Percent changes from baseline to at least week 12 in low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), apolipoprotein B (Apo B), and high-sensitivity C-reactive protein (hsCRP), as well as safety, were analyzed by statin pool and sex.. Overall, 3623 patients were included (bempedoic acid, 2425; placebo, 1198). Significant reductions in lipid parameters and hsCRP were observed with bempedoic acid vs. placebo in both sexes in the ASCVD and/or HeFH on statins (n = 3009) and the low-dose or no statin (n = 614) pools (p ≤ 0.002). Compared with men, women had significantly greater placebo-corrected reductions in LDL-C (-21.2% vs. -17.4%; p = 0.044), non-HDL-C (-17.3% vs. -12.1%; p = 0.003), TC (-13.8% vs. -10.5%; p = 0.012), and Apo B (-16.0% vs. -11.3%; p = 0.004) in the ASCVD and/or HeFH on statins pool. Women had similar reductions to men in lipid parameters in the low-dose or no statin pool and hsCRP in both pools. The safety of bempedoic acid was comparable between sexes.. In this pooled analysis, women experienced significant improvements in levels of LDL-C and other lipid parameters with bempedoic acid.

Topics: Anticholesteremic Agents; Apolipoproteins B; Atherosclerosis; C-Reactive Protein; Cholesterol; Cholesterol, LDL; Dicarboxylic Acids; Fatty Acids; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Male; Treatment Outcome

Limited data exist on the long-term safety and efficacy of bempedoic acid, an adenosine triphosphate-citrate lyase inhibitor, for lowering low-density lipoprotein cholesterol (LDL-C). This 78-week, phase 3, open-label extension (OLE) study followed the CLEAR Harmony phase 3 study, in which patients were randomized 2:1 to bempedoic acid or placebo for 52 weeks; during the OLE, patients who received bempedoic acid continued treatment (≤130 weeks) and patients who received placebo initiated bempedoic acid (≤78 weeks). Safety assessments included treatment-emergent adverse events, adverse events of special interest, and clinical laboratory abnormalities. Efficacy assessments included % change from the parent study baseline in LDL-C, other lipid parameters, and high-sensitivity C-reactive protein (hsCRP). Of 1,462 patients who enrolled in the OLE study, 970 received bempedoic acid in the parent study; laboratory abnormalities and reductions in LDL-C, other lipid parameters, and hsCRP observed in the parent study remained stable through 130 weeks of treatment. On initiation of bempedoic acid treatment, 492 patients who received placebo in the parent study experienced reductions in LDL-C, other lipid parameters, and hsCRP, mirroring reductions observed in patients who received bempedoic acid in the parent study who remained stable through 78 weeks of therapy. During the OLE, incidence of treatment-emergent adverse events and adverse events of special interest were comparable in patients who received 130 weeks (78%) versus 78 weeks (78%) of bempedoic acid treatment. In conclusion, bempedoic acid was generally well tolerated and demonstrated sustained efficacy with up to 2.5 years of continuous treatment. Bempedoic acid safety profiles were similar between the parent and OLE studies.

Topics: Atherosclerosis; C-Reactive Protein; Cardiovascular Diseases; Cholesterol, LDL; Dicarboxylic Acids; Double-Blind Method; Fatty Acids; Humans; Hypercholesterolemia; Hyperlipoproteinemia Type II; Treatment Outcome

Additional treatment options are needed for patients who do not achieve sufficient reduction in low-density lipoprotein cholesterol (LDL-C) level with available lipid-lowering therapies.. To assess the efficacy of bempedoic acid vs placebo in patients at high cardiovascular risk receiving maximally tolerated lipid-lowering therapy.. Phase 3, randomized, double-blind, placebo-controlled clinical trial conducted at 91 clinical sites in North America and Europe from November 2016 to September 2018, with a final date of follow-up of September 22, 2018. A total of 779 patients with atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or both met randomization criteria, which included LDL-C level 70 mg/dL (1.8 mmol/L) or greater while receiving maximally tolerated lipid-lowering therapy.. Patients were randomized 2:1 to treatment with bempedoic acid (180 mg) (n = 522) or placebo (n = 257) once daily for 52 weeks.. The primary end point was percent change from baseline in LDL-C level at week 12. Secondary measures included changes in levels of lipids, lipoproteins, and biomarkers.. Among 779 randomized patients (mean age, 64.3 years; 283 women [36.3%]), 740 (95.0%) completed the trial. At baseline, mean LDL-C level was 120.4 (SD, 37.9) mg/dL. Bempedoic acid lowered LDL-C levels significantly more than placebo at week 12 (-15.1% vs 2.4%, respectively; difference, -17.4% [95% CI, -21.0% to -13.9%]; P < .001). Significant reductions with bempedoic acid vs placebo were observed at week 12 for non-high-density lipoprotein cholesterol (-10.8% vs 2.3%; difference, -13.0% [95% CI, -16.3% to -9.8%]; P < .001), total cholesterol (-9.9% vs 1.3%; difference, -11.2% [95% CI, -13.6% to -8.8%]; P < .001), apolipoprotein B (-9.3% vs 3.7%; difference, -13.0% [95% CI, -16.1% to -9.9%]; P < .001), and high-sensitivity C-reactive protein (median, -18.7% vs -9.4%; difference, -8.7% [asymptotic confidence limits, -17.2% to -0.4%]; P = .04). Common adverse events included nasopharyngitis (5.2% vs 5.1% with bempedoic acid and placebo, respectively), urinary tract infection (5.0% vs 1.9%), and hyperuricemia (4.2% vs 1.9%).. Among patients at high risk for cardiovascular disease receiving maximally tolerated statins, the addition of bempedoic acid compared with placebo resulted in a significant lowering of LDL-C level over 12 weeks. Further research is needed to assess the durability and clinical effect as well as long-term safety.. ClinicalTrials.gov Identifier: NCT02991118.

Topics: Aged; Anticholesteremic Agents; Atherosclerosis; Cardiovascular Diseases; Cholesterol, LDL; Dicarboxylic Acids; Double-Blind Method; Drug Therapy, Combination; Fatty Acids; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemia, Familial Combined; Male; Middle Aged

The LDL cholesterol (LDL-C) treatment goals recommended by the 2019 ESC/EAS guidelines are only achieved in a minority of patients. The study objective was to estimate the impact of bempedoic acid treatment on LDL-C target attainment, drug costs, and atherosclerotic cardiovascular disease (ASCVD) events. The simulation used a Monte Carlo approach in a representative cohort of German outpatients at high or very-high cardiovascular risk. Additionally to statins, consecutive treatment with ezetimibe, bempedoic acid, and a PCSK9 inhibitor was simulated in patients not achieving their LDL-C goal. Considered were scenarios without and with bempedoic acid (where bempedoic acid was replaced by a PCSK9 inhibitor when LDL-C was not controlled).. The simulation cohort consisted of 105,577 patients, of whom 76,900 had very-high and 28,677 high cardiovascular risk. At baseline, 11.2% of patients achieved their risk-based LDL-C target. Sequential addition of ezetimibe and bempedoic acid resulted in target LDL-C in 33.1% and 61.9%, respectively. Treatment with bempedoic acid reduced the need for a PCSK9 inhibitor from 66.6% to 37.8% and reduced drug costs by 35.9% per year on stable lipid-lowering medication. Compared to using only statins and ezetimibe, this approach is projected to prevent additional 6,148 ASCVD events annually per 1 million patients, whereas PCSK9 inhibition alone would prevent 7,939 additional ASCVD events annually.. A considerably larger proportion of cardiovascular high- and very-high-risk patients can achieve guideline-recommended LDL-C goals with escalated lipid-lowering medication. Bempedoic acid is projected to substantially decrease the need for PCSK9 inhibitor treatment to achieve LDL-C targets, associated with reduced drug costs albeit with fewer prevented events.

Topics: Anticholesteremic Agents; Atherosclerosis; Cardiovascular Diseases; Cholesterol, LDL; Ezetimibe; Health Care Costs; Heart Disease Risk Factors; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; PCSK9 Inhibitors; Risk Factors

One of the common pathophysiological basis of atherosclerosis is intimal hyperplasia. ATP citrate lyase (ACLY) has been reported as a promising therapeutic target for treatment of dyslipidemia and atherosclerosis. However, the role of ACLY in intimal hyperplasia has yet to be clarified.. The current investigation studies the molecular effects of ACLY and bempedoic acid, an ACLY inhibitor, on platelet-derived growth factor (PDGF)-induced primary human aortic smooth muscle cells (HASMCs) proliferation in vitro and on femoral arterial wire-injured neointimal hyperplasia in mouse in vivo. The role of ACLY in intimal hyperplasia was further investigated in mice treated with bempedoic acid. Cell proliferation was measured by CCK8 and BrdU assays. We explored further mechanisms using western blot, qPCR and immunofluorescence.. We found that ACLY was significantly increased in dedifferentiated VSMC in vitro and vivo. Bempedoic acid which can inhibit ACLY expression effectively blocked PDGF-induced VSMC proliferation and dedifferentiation by activating AMPK/ACC signaling pathway. Moreover, bempedoic acid also attenuated VSMC proliferation and inhibited VSMC dedifferentiation in the wire-injured mouse femoral arteries, resulting in reduced neointima formation.. We demonstrates that bempedoic acid reduces ACLY expression to restrain VSMC proliferation and dedifferentiation by activating AMPK/ACC signaling pathway, which may provide a potential therapeutic strategy for diseases associated with intimal hyperplasia including restenosis and atherosclerosis.

Topics: Acyltransferases; AMP-Activated Protein Kinases; Animals; Atherosclerosis; ATP Citrate (pro-S)-Lyase; Enzyme Inhibitors; Humans; Hyperplasia; Mice; Platelet-Derived Growth Factor; Signal Transduction

Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of morbidity and mortality. The fact that elevated levels of low-density lipoprotein-cholesterol (LDL-C) play a causal role in the development of ASCVD is now well accepted, given the results of numerous epidemiological and genetic studies, as well as randomized controlled clinical trials. Statins have become a primary therapeutic cornerstone in ASCVD prevention since they have been shown to reduce CV events by reducing levels of LDL-C. But despite the proven efficacy and safety of statin therapy, several aspects indicate a substantial need for additional or alternative LDL-C lowering therapies. These aspects include not only a high variability in individual response to therapy, but also possible side effects, potentially reducing adherence to treatment. Most importantly, an elevated risk for cardiovascular (CV) events remains in a large proportion of high-risk patients, especially in those with persistent elevation of LDL-C levels despite a maximum tolerated dose of statin therapy. Also, large clinical trials currently investigate a potential CV benefit of drug therapies targeting elevated levels of triglycerides and lipoprotein (a), respectively.

Topics: Atherosclerosis; Cholesterol, LDL; Dicarboxylic Acids; Fatty Acids; Fatty Acids, Omega-3; Humans; Hypolipidemic Agents; Oligonucleotides, Antisense; RNA, Small Interfering

Tolerability problems in treating hypercholesterolemic patients undergoing statin treatment are of growing concern to physicians and patients, thus underlining the need for an agent with a similar mechanism but minimal side effects. A drug with a somewhat similar mechanism to statins but free of muscular side effects is ETC-1002 (bempedoic acid). It inhibits cholesterol biosynthesis at a step preceding HMG-CoA reductase, i.e. ATP citrate lyase (ACLY). A prodrug, ETC-1002 is converted to the active agent only in liver, not in skeletal muscle, and this may prevent any myotoxic activity. Area covered: The mechanism of ETC-1002 activity is described in detail, considering that ACLY inhibition markedly attenuated atherosclerosis in animal models. Clinical studies are also reported. Expert opinion: Present day LDL-C lowering treatments lead to significant reductions of cardiovascular (CV) events but, at times, the need to interrupt statin treatment appears to be dangerous due to a rapid rise in CV risk. The excellent tolerability of ETC-1002 makes it a useful alternative, either alone or as an adjunct to ezetimibe, for patients with statin intolerance needing to achieve significant CV risk reduction. ETC-1002 is also associated with a marked fall in high-sensitivity C-reactive protein.

Topics: Animals; Anticholesteremic Agents; Atherosclerosis; ATP Citrate (pro-S)-Lyase; C-Reactive Protein; Clinical Trials as Topic; Dicarboxylic Acids; Drug Therapy, Combination; Ezetimibe; Fatty Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Liver

Bempedoic acid (BemA; ETC-1002) is a novel drug that targets hepatic ATP-citrate lyase to reduce cholesterol biosynthesis. In phase 2 studies, BemA lowers elevated low-density lipoprotein cholesterol (LDL-C) in hypercholesterolemic patients. In the present study, we tested the ability of BemA to decrease plasma cholesterol and LDL-C and attenuate atherosclerosis in a large animal model of familial hypercholesterolemia.. Gene targeting has been used to generate Yucatan miniature pigs heterozygous (. In a large animal model of LDLR deficiency and atherosclerosis, long-term treatment with BemA reduces LDL-C and attenuates the development of aortic and coronary atherosclerosis in both

Topics: Animals; Animals, Genetically Modified; Anticholesteremic Agents; Aortic Diseases; Atherosclerosis; Biomarkers; Cholesterol, LDL; Coronary Artery Disease; Dicarboxylic Acids; Disease Models, Animal; Down-Regulation; Fatty Acids; Female; Gene Expression Regulation; Genetic Predisposition to Disease; Hyperlipoproteinemia Type II; Male; Phenotype; Plaque, Atherosclerotic; Receptors, LDL; Swine; Swine, Miniature

Despite widespread use of statins to reduce low-density lipoprotein cholesterol (LDL-C) and associated atherosclerotic cardiovascular risk, many patients do not achieve sufficient LDL-C lowering due to muscle-related side effects, indicating novel treatment strategies are required. Bempedoic acid (ETC-1002) is a small molecule intended to lower LDL-C in hypercholesterolemic patients, and has been previously shown to modulate both ATP-citrate lyase (ACL) and AMP-activated protein kinase (AMPK) activity in rodents. However, its mechanism for LDL-C lowering, efficacy in models of atherosclerosis and relevance in humans are unknown. Here we show that ETC-1002 is a prodrug that requires activation by very long-chain acyl-CoA synthetase-1 (ACSVL1) to modulate both targets, and that inhibition of ACL leads to LDL receptor upregulation, decreased LDL-C and attenuation of atherosclerosis, independently of AMPK. Furthermore, we demonstrate that the absence of ACSVL1 in skeletal muscle provides a mechanistic basis for ETC-1002 to potentially avoid the myotoxicity associated with statin therapy.

Topics: Adenylate Kinase; Animals; Atherosclerosis; ATP Citrate (pro-S)-Lyase; Cholesterol, LDL; Dicarboxylic Acids; Disease Progression; Enzyme Activation; Enzyme Inhibitors; Fatty Acids; Hepatocytes; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipid Metabolism; Liver; Mice, Inbred C57BL; Mice, Knockout; Models, Biological; Organ Specificity; Receptors, LDL; Up-Regulation