etc-1002 and Hyperlipidemias

Reduction of low-density lipoprotein cholesterol (LDL-C) decreases cardiovascular mortality and morbidity. Bempedoic acid represents a promising novel lipid-modifying agent for patients who cannot reach guideline recommended LDL-C goals or statin-intolerant patients, but data on safety and cardiovascular outcomes are limited. We therefore aimed to systematically review randomized controlled trials investigating bempedoic acid vs. placebo in patients with hyperlipidaemia.. A systematic search on the databases PubMed, Web of Science, and Embase until 20 March 2023 was performed. All randomized trials comparing bempedoic acid (180 mg daily) with placebo in patients with an indication for lipid-lowering therapy were included. As a primary endpoint, we analysed three-point major adverse cardiovascular events (MACEs) consisting of cardiovascular death, non-fatal myocardial infarction (MI), or non-fatal stroke. The analysis was carried out using the odds ratio (OR) as the outcome measure. Due to the expected heterogeneity across studies, a random-effects model was fitted to the data.. Out of 258 manuscripts, 10 manuscripts fulfilled the inclusion criteria. In total, these trials included 18 200 patients (9765 on bempedoic acid, 8435 on placebo). Bempedoic acid significantly reduced MACEs compared with placebo (OR 0.84 [95% confidence interval (CI) 0.76-0.96]; P < 0.001; I2 = 0%). The endpoint reduction was driven by a lower rate of non-fatal MI, whereas bempedoic acid had no significant effect on stroke (OR 0.86 [95% CI 0.69-1.08]; P = 0.20, I2 = 0%) and all-cause mortality (OR 1.19 [95% CI 0.73-1.93]; P = 0.49; I2 = 18%).. Bempedoic acid reduced non-fatal MI in patients with hyperlipidaemia, whereas it had no significant effect on stroke and all-cause mortality.

Topics: Cholesterol, LDL; Humans; Hyperlipidemias; Myocardial Infarction; Stroke

A number of new cholesterol-lowering drugs have been recently developed and approved, enriching the pharmacological armamentarium beyond and above statins. Ezetimibe, available since two decades, and bempedoic acid, a new drug inhibiting the same biosynthetic pathway targeted by statins but at an early step, represent valuable tools for the treatment of hypercholesterolemia, particularly in specific groups of patients.. Bempedoic acid, either alone or in combination with ezetimibe, appears to reduce significantly LDL-C levels, an effect that has been observed also in patients with statin intolerance. A Mendelian randomization study has anticipated a protective cardiovascular effect of bempedoic acid; a randomized clinical trial is currently assessing whether the pharmacological control of hypercholesterolemia with bempedoic acid translates into a clinical benefit. Bempedoic acid, as well as ezetimibe, does not appear to induce adverse events in muscles; moreover, whereas statins are associated with a modest, although significant, increased risk of new-onset diabetes, bempedoic acid does not, at least based on the available evidence.. On the basis of available data, and while awaiting the results of the outcome trial, bempedoic acid appears to represent a valuable approach for the treatment of hypercholesterolemia, either alone or in combination in ezetimibe.

Topics: Anticholesteremic Agents; Cholesterol, LDL; Dicarboxylic Acids; Ezetimibe; Fatty Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hyperlipidemias; Randomized Controlled Trials as Topic; Treatment Outcome

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

Statin therapy has been the cornerstone for the reduction of cholesterol and circulating low-density lipoprotein (LDL) in patients with cardiovascular diseases. However, statin monotherapy has disadvantages attributable to myopathies and to the insufficient cholesterol reduction observed in some patients. There is a need for new well-tolerated therapies for lowering LDL. This review will focus on bempedoic acid in combination with traditional statin therapy or other lipid-lowering agents and its emerging role in LDL-C lowering. Bempedoic acid is also a viable alternative for reducing LDL cholesterol in the treatment of some patients suffering from heterozygous familial hypercholesterolemia.

Topics: Cholesterol, LDL; Clinical Trials as Topic; Dicarboxylic Acids; Drug Therapy, Combination; Fatty Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Hypolipidemic Agents

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

Topics: Cholesterol, LDL; Dicarboxylic Acids; Fatty Acids; Humans; Hyperlipidemias; Hyperlipoproteinemia Type II; Hypolipidemic Agents

Bempedoic acid is a novel oral drug, which has been increasingly researched to play an important role in the treatment of hypercholesterolemia recently. However, results from original studies were inconsistent and inconclusive. We aimed to conduct a meta-analysis to quantitatively appraise the efficacy and safety of bempedoic acid.. PubMed, Embase, Web of Science and Scopus were searched from inception to 30 January 2020. We included randomized controlled trials that compared the efficacy and safety of bempedoic acid with placebo in patients with hypercholesterolemia. Results from trials were presented as mean differences or odds ratios (ORs) with 95% confidence intervals (CIs) and were pooled by random or fixed effects model. The risk of bias and heterogeneity among trials were also assessed and analyzed.. Pooled analysis of 10 eligible trials showed that bempedoic acid treatment resulted in greater lowering of the low-density lipoprotein cholesterol level than the placebo group (mean difference -23.16%, 95% CI -26.92% to -19.04%). We also found that improvements in lipid parameters and biomarkers were still maintained at weeks 24 and 52 from the long-term trials. As for safety, bempedoic acid did not increase the risk of overall adverse events (OR 1.02, 95% CI 0.88 to 1.18). However, the incidence of adverse events leading to discontinuation was higher in the bempedoic acid group (OR 1.44, 95% CI 1.14 to 1.82).. Available evidence from randomized controlled trials suggests that bempedoic acid provides a well-tolerated and effective therapeutic option for lipid lowering in patients with hyperlipidemia.

Topics: Dicarboxylic Acids; Fatty Acids; Humans; Hypercholesterolemia; Hyperlipidemias; Hypolipidemic Agents; Randomized Controlled Trials as Topic

Despite the effectiveness of statins in the treatment of lipid disorders, residual risk still exists, and hitherto studies where additional drugs were added to statin therapy have been mainly negative or the outcomes were very modest. Therefore there is still a need for new and effective oral agents in the combination therapy of lipid disorders. Areas covered: The review covers the current state of knowledge on the mechanism of action of bempedoic acid (ETC-1002) and results from recent clinical studies. Expert opinion: ETC-1002 is a novel oral lipid-lowering therapy. The reduction of both low-density lipoprotein cholesterol (LDL-C) and high sensitivity C-reactive protein (hsCRP) demonstrated by ETC-1002 in clinical trials suggests that agent may have the potential for CV risk reduction. Adverse effects of current lipid-lowering agents can be dose-limiting, and combination approaches to lipid-lowering may often be utilized for optimal CV risk reduction. Because of this, new lipid-modulating drugs are urgently required. ETC-1002 has a unique mechanism of action (adenosine triphosphate-citrate lyase inhibition). It has been shown to be safe in combination with statins as well as ezetimibe, and appears to effectively lower LDL-C and has the potential to reduce the risk of muscle-related adverse events, which can limit the utilization and effectiveness of statin therapy.

Topics: C-Reactive Protein; Cardiovascular Diseases; Cholesterol, LDL; Dicarboxylic Acids; Fatty Acids; Humans; Hyperlipidemias; Hypolipidemic Agents

ETC-1002 is a new investigational low density lipoprotein cholesterol (LDL-C)-lowering agent (Esperion Therapeutics, Inc.). ETC-1002 is a dicarboxylic acid derivative with a novel mechanism of action targeting two hepatic enzymes--adenosine triphosphate-citrate lyase (ACL) and adenosine monophosphate-activated protein kinase (AMPK), inhibiting sterol and fatty acid synthesis and promoting mitochondrial long-chain fatty acid oxidation. This agent is currently in phase II clinical research. Available data report that ETC-1002 significantly decreased LDL-C levels (up to 32%) in both patients with normal and elevated baseline levels of triglycerides. Such beneficial effect is superior to currently approved non-statin lipid lowering agents. The levels of apolipoprotein B (apoB) and non-high density lipoprotein cholesterol (non-HDL-C) were also reduced with beneficial effect on other cardiometabolic factors such as inflammatory markers, blood pressure and body weight. Although, the safety and tolerability of ETC-1002 needs to be confirmed in ongoing and future, larger studies, this agent has, so far, been generally safe and well tolerated. This novel, oral, once-daily, small molecule may lead to effective LDL-C lowering treatment in hypercholesterolaemic subjects who are statin intolerant or as add-on therapy in those who are unable to reach the LDL-C goals despite being on statin therapy. This agent might not only exert lipid-lowering related benefits, but also favourable cardiometabolic effects.

Topics: AMP-Activated Protein Kinases; Animals; Apolipoproteins B; ATP Citrate (pro-S)-Lyase; Blood Pressure; Body Weight; Cholesterol, LDL; Clinical Trials, Phase II as Topic; Dicarboxylic Acids; Disease Models, Animal; Fatty Acids; Humans; Hypercholesterolemia; Hyperlipidemias; Hypolipidemic Agents; Liver; Mice; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Rats

Bempedoic acid (BA) is a novel first-in-class oral lipid-lowering therapy. BA has been approved by the European Medicinal Agency and Food and Drug Administration and has been commercialised throughout Europe since the end of 2020 as an add-on therapy in patients at high/very-high cardiovascular risk that are not at LDL-C goals with current lipid-lowering treatments. Recently, Italian lipid management experts gathered to discuss several open questions on BA characteristics and BArelated practical clinical issues. The panel permitted collection of its opinions in a ten Q&A format.. The aim of this viewpoint is to discuss and answer several open questions on BA characteristics and BA-related practical clinical issues.. The data includes main phase III studies, subanalysis and meta-analysis on BA.. The panel permitted collection of its opinions in a ten Q&A format.

Topics: Cholesterol, LDL; Dicarboxylic Acids; Fatty Acids; Humans; Hyperlipidemias; Hypolipidemic Agents

Control of hyperlipidemia is believed to reduce major cardiovascular events such as cardiovascular death, myocardial infarction, nonfatal stroke, hospitalization for unstable angina, and coronary revascularization. The benefits of monotherapy with Bempedoic acid (BA) as a hypolipidemic agent given after induction of myocardial infarction (MI) in reducing the risk of acute MI worth being investigated, therefore this study was designed to investigate the effectiveness of Bempedoic acid on reducing cardiovascular risk factors in rats with induced hyperlipidemia and myocardial infarction compared to Rosuvastatin. Male albino rats (n=40) were divided into five equal groups, each with eight rats, the first group served as a negative control group, the second group (diet-induced hyperlipidemia and Isoprenaline induced myocardial infarction) served as a positive control group, the third group (diet-induced hyperlipidemia and Isoprenaline induced myocardial infarction) received daily oral administration of Rosuvastatin for 12 weeks, the fourth group (diet-induced hyperlipidemia, DIH) received Bempedoic acid for 4 weeks as prophylaxis and then myocardial infarction was induced and Bempedoic acid administration was continued for the remaining 8 weeks, and the fifth group (diet-induced hyperlipidemia and Isoprenaline induced myocardial infarction) received a daily oral administration of Bempedoic acid for 12 weeks as a treatment. After 12 weeks, blood samples were withdrawn by cardiac puncture for measuring and evaluating lipid profiles and other parameters. Bempedoic acid and Rosuvastatin significantly reduce mean serum levels of lipid profiles; Total cholesterol, LDL and triglyceride, increase HDL and reduce cardiac enzyme levels as compared with the positive control group. The findings from this study suggested that Bempedoic acid as monotherapy either as a therapy or as prophylaxis was effective in reducing lipid parameters, LDL, Tch, and TG and cardiac enzymes creatine kinase-MB (CK-MB) and serum level of cardiac troponin-I (cTn-I) compared with the positive control group and was not superior to Rosuvastatin in these parameters but taking BA as prophylaxis could prevent the morbidity with cardiovascular events as it was effective in reducing the above parameters by greater percentages than BA and Rosuvastatin therapy.. Both drugs showed similar profiles in blood pressure and heart rate measurements.

Topics: Adenosine Triphosphate; Animals; Cardiovascular Diseases; Cholesterol, LDL; Enzyme Inhibitors; Fatty Acids; Heart Disease Risk Factors; Hyperlipidemias; Isoproterenol; Male; Myocardial Infarction; Rats; Risk Factors; Rosuvastatin Calcium

Cholesterol and triglycerides are risk factors for developing cardiovascular disease. Therefore, appropriate cells and assays are required to discover and develop dual cholesterol and fatty acid inhibitors. A predictive hyperlipidemic animal model is needed to evaluate mechanism of action of lead molecule for therapeutic indications.. Taken together, ETC-1002 reduced proatherogenic lipoproteins, hepatic lipids and adipose tissues in hyperlipidemic hamsters via induction of LPL, CPT1-α, PDK4, and PLIN1, and downregulation of DGAT2. These characteristics may be useful in the treatment of fatty livers that causes non-alcoholic steatohepatitis.

Topics: Animals; Carnitine O-Palmitoyltransferase; Cells, Cultured; Cholesterol; Dicarboxylic Acids; Diet, High-Fat; Disease Models, Animal; Fatty Acids; Hepatocytes; Humans; Hyperlipidemias; Hypolipidemic Agents; Lipogenesis; Lipoprotein Lipase; Male; Mesocricetus; Perilipin-1; Protein Kinases; Rabbits; Rats, Wistar

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