etc-1002 and Hypercholesterolemia

To provide an updated review of bempedoic acid's clinical application in lowering LDL-C in the setting of statin intolerance and the recent findings in the CLEAR Outcomes trial as well as summarize and synthesize the current state of knowledge regarding bempedoic acid while providing an in-depth analysis of the drug's pharmacological properties, mechanism of action, clinical trials, safety, and efficacy.. The CLEAR Outcomes trial has provided evidence to support bempedoic acid as a viable alternative to statins for the primary and secondary prevention of cardiovascular disease. Bempedoic acid is a promising treatment option for patients with hypercholesterolemia who are unable to tolerate statin therapy or require additional LDL-C reduction in the treatment of cardiovascular disease, with the newest lipid-lowering cardiovascular outcomes trials expanding on their generalizability particularly in the inclusion of women.

Topics: Cardiovascular Diseases; Cholesterol, LDL; Dicarboxylic Acids; Fatty Acids; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia

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

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

The central role of high low-density lipoprotein cholesterol levels in atherosclerotic cardiovascular disease has led to research focused on lipid-lowering agents for cardiovascular risk reduction. Bempedoic acid is an emerging treatment for hypercholesterolemia that has recently been approved for marketing in the United States and Europe. This review focuses on its mechanism of action and summarizes the main preclinical study findings. Furthermore, we report the clinical evidence supporting and guiding its use in hypercholesterolemia management.

Topics: Biomarkers; Cholesterol; Dicarboxylic Acids; Fatty Acids; Humans; Hypercholesterolemia; Hypolipidemic Agents

BACKGROUND AND OBJECTIVE: A limited number of trials have evaluated the efficacy of a fixed-dose combination of bempedoic acid and ezetimibe for the treatment of hypercholesterolemia. The aim of this meta-analysis of existing studies was to evaluate the efficacy and safety of fixed-dose bempedoic acid and ezetimibe combination therapy for the treatment of hypercholesterolemia.. A systematic literature search was conducted to identify randomized controlled trials (RCTs) comparing bempedoic acid and ezetimibe, versus placebo or ezetimibe alone, to 30 August 2020. A meta-analysis was conducted to investigate the efficacy of bempedoic acid and ezetimibe on lipid parameters and highly sensitive C-reactive protein (hsCRP) levels in patients with hypercholesterolemia or established atherosclerotic cardiovascular disease (ASCVD). Mean differences (MDs) or relative risk (RR) with their corresponding 95% confidence intervals (CIs), using random-effects models, were used to provide pooled estimates.. A total of three phase II and III RCTs, comprising 388 patients, of whom 49.2% were treated with bempedoic acid and ezetimibe, and 197 controls, were identified. The duration of treatment was 12 weeks. Bempedoic acid and ezetimibe significantly reduced low-density lipoprotein cholesterol (MD - 29.14%, 95% CI - 39.52 to - 18.76; p < .001), total cholesterol (MD - 15.78%, 95% CI - 20.84 to - 10.72; p = 0.01), non-high-density lipoprotein cholesterol (MD - 18.36%, 95% CI - 24.60 to - 12.12; p = 0.01), and hsCRP levels (MD - 30.48%, 95% CI - 44.69 to - 16.28; p = 0.04). No significant effects on triglycerides (MD - 8.35%, 95% CI - 16.08 to - 0.63; p = 0.72) and improvement in high-density lipoprotein cholesterol (MD 1.63%, 95% CI - 4.03 to 7.28; p = 0.92) were observed with the fixed-dose combination therapy. Regarding safety, bempedoic acid and ezetimibe combination was associated with a non-significant increased risk of drug-related adverse events (RR 1.61, 95% CI 0.86-2.35) and overall adverse events (RR 1.16. 95% CI 0.97-1.35); however, the incidence of discontinuation of therapy (RR 0.75, 95% CI 0.35-1.49) was lower.. This review found bempedoic acid and ezetimibe significantly lowered lipid parameters, attenuated hsCRP levels, and had an acceptable safety profile for the treatment of hypercholesterolemia and ASCVD.

Topics: Anticholesteremic Agents; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Dicarboxylic Acids; Drug Combinations; Ezetimibe; Fatty Acids; Humans; Hypercholesterolemia; Randomized Controlled Trials as Topic; Triglycerides

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.

Topics: Cholesterol, LDL; Coronary Artery Disease; Dicarboxylic Acids; Drug Tolerance; Fatty Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hypolipidemic Agents; Treatment Outcome

We review all the phase II and III studies carried out with bempedoic acid at the dose of 180mg, alone or in combination with different lipid-lowering drugs and in different subgroups of patients that unequivocally show the efficacy and safety of the drug. We point out some of the potential advantages of its use in clinical practice in patients with statin intolerance and the efficacy in reducing LDL-c when combined with statins, and with statins and ezetimibe, as well as in reducing inflammation markers pending the results of the CV Clear Outcomes trial that will end in 2022.

Topics: Cholesterol, LDL; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Dicarboxylic Acids; Drug Development; Drug Therapy, Combination; Ezetimibe; Fatty Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hypolipidemic Agents; Inflammation

Despite statin therapy being the cornerstone for the treatment of hypercholesterolemia, a significant number of patients do not tolerate statin therapy because of muscle-related adverse effects or cannot achieve their individual low-density lipoproteincholesterol (LDL-C) goals with statin therapy alone. Several nonstatin agents have been evaluated for the management of LDL-C levels and reduction of cardiovascular (CV) risk in these patients, but there are some limitations with their use. Bempedoic acid is a novel nonstatin agent for the management of lipid disorders, via the inhibition of adenosine triphosphate citrate lyase (ACL). It was recently approved by the US Food and Drug Administration based on several phase III trials which showed promising results regarding safety and efficacy. Though CV outcome data are not available yet, bempedoic acid may be a useful adjunct therapy for select patients. The purpose of this review is to evaluate the major findings in these clinical trials and discuss the potential role of bempedoic acid in clinical practice and its use in older people.

Topics: Aged; Cholesterol, LDL; Dicarboxylic Acids; Fatty Acids; Humans; Hypercholesterolemia

Topics: Cholesterol, LDL; Dicarboxylic Acids; Fatty Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hypolipidemic Agents; Randomized Controlled Trials as Topic

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 widespread use of statins and ezetimibe to decrease low-density lipoprotein cholesterol (LDL-C) levels and associated atherosclerotic cardiovascular disease (ASCVD), many patients do not achieve adequate LDL-C lowering as per the recommended American College of Cardiology (ACC)/American Heart Association (AHA) and European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines and demonstrate residual cardiovascular risk. The introduction of proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors in 2015 was a promising addition to hypercholesterolemia therapies, but their cost and subcutaneous administration has limited their use, and therefore, new affordable and patient friendly treatment strategies are crucial to help reduce ASCVD risk. Bempedoic acid, a drug currently under investigation, is a small molecule that has been shown to upregulate LDL receptors, decrease LDL-C, and reduce atherosclerotic plaque formation in hypercholesterolemic patients. Furthermore, bempedoic acid is a prodrug that becomes activated by an enzyme expressed primarily in the liver, allowing it to avoid the potential myotoxicity associated with statin therapy. The purpose of this review is to summarize the major clinical studies evaluating bempedoic acid and describe its potential addition to currently approved lipid-lowering therapies.

Topics: Anticholesteremic Agents; Cholesterol, LDL; Dicarboxylic Acids; Drug Combinations; Dyslipidemias; Ezetimibe; Fatty Acids; Humans; Hypercholesterolemia; Hyperlipoproteinemia Type II; Randomized Controlled Trials as Topic; Receptors, LDL

Bempedoic acid is a non-statin antihyperlipidaemic drug being developed by Esperion Therapeutics for the treatment of hypercholesterolaemia. Based on positive findings in the phase III CLEAR clinical trial programme, bempedoic acid has been approved in the USA and in the EU as monotherapy (NEXLETOL

Topics: Dicarboxylic Acids; Drug Approval; Fatty Acids; Humans; Hypercholesterolemia; Hypolipidemic Agents; Molecular Structure

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

Although several lipid-lowering drugs are available, they are not sufficient for some patients. Bempedoic acid is a small molecule adenosine triphosphate-citrate lyase inhibitor indicated for the treatment of adults with hypercholesterolemia.. We performed a systematic review of the literature using PubMed database, and the following keywords were used: 'bempedoic acid,' 'hypercholesterolemia,' and 'adenosine triphosphate citrate lyase.' The chemical property, mechanism of action, pharmacokinetics, clinical efficacy, and safety of bempedoic acid are introduced in this paper.. Bempedoic acid can modulate the metabolism of cholesterol. Clinical trials indicated that bempedoic acid could significantly reduce low-density lipoprotein cholesterol levels. Bempedoic acid was well tolerated.

Topics: Cholesterol; Dicarboxylic Acids; Fatty Acids; Humans; Hypercholesterolemia; Hypolipidemic Agents; Treatment Outcome

The lowering of low-density lipoprotein cholesterol (LDL-C), regardless of the method used, results in a reduction of cardiovascular events. Bempedoic acid is a new and until now, the only approved adenosine triphosphate citrate lyase inhibitor that works through the cholesterol-synthesis pathway (similar to statins) that leads to a safe and effective reduction in LDL-C.. We review clinical phase 2 and 3 studies on bempedoic acid's lipid-lowering effect and approved indications.. In the United States, bempedoic acid is currently approved for use in secondary prevention. In primary prevention, its approval is limited to individuals with heterozygous familial hypercholesterolemia (FH). However, its tolerability and safety profile may warrant its use in primary prevention besides FH. Even though its efficacy appears weaker than high-intensity statins, it may be a useful adjunct in individuals who achieve less than desirable LDL-C reductions with statins or who cannot tolerate statins, where bempedoic acid alone or in combination with ezetimibe may be useful alternatives.

Topics: ATP Citrate (pro-S)-Lyase; Cholesterol, LDL; Dicarboxylic Acids; Drug Approval; Fatty Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hyperlipoproteinemia Type II; Hypolipidemic Agents; Lipids

Additional lipid-lowering therapy options are needed for patients who cannot achieve sufficient decreases in low-density lipoprotein cholesterol (LDL-C) levels using statins alone or for those who are statin intolerant.. To conduct a pooled analysis of phase 3 randomized clinical trials of bempedoic acid vs placebo.. This analysis pooled data from 4 double-blind, placebo-controlled randomized clinical trials conducted from 2016 to 2018. Patients were enrolled in North America and Europe. Eligibility criteria included hypercholesterolemia while receiving stable lipid-lowering therapy and high cardiovascular risk or hypercholesterolemia and statin intolerance.. Patients were randomized 2:1 to bempedoic acid, 180 mg (n = 2425), or placebo (n = 1198) once daily for 12 to 52 weeks.. Primary efficacy end point was percentage change from baseline in LDL-C level at week 12 in the intention-to-treat population. Patients were parsed into 2 groups according to enrollment criteria: (1) patients with hypercholesterolemia and atherosclerotic cardiovascular disease (ASCVD) or with heterozygous familial hypercholesterolemia (HeFH) or with both and receiving statins and (2) patients with hypercholesterolemia who were statin intolerant receiving maximally tolerated statins.. In this analysis of 3623 patients, the overall mean (SD) patient age was 65.5 (9.2) years (similar in both pools). Among patients with ASCVD or HeFH or both, the mean (SD) baseline LDL-C level was 107.6 (32.7) mg/dL. At week 12, the LDL-C level percentage change from baseline was -16.0% with bempedoic acid vs 1.8% with placebo (difference, -17.8%; 95% CI, -19.5% to -16.0%; P < .001). Patients with statin intolerance had a mean (SD) baseline LDL-C level of 144.4 (38.8) mg/dL. The percentage changes in LDL-C levels at week 12 were -23.0% in the bempedoic acid group and 1.5% in the placebo group (difference, -24.5%; 95% CI, -27.8% to -21.1%; P < .001). The decrease in LDL-C levels with bempedoic acid was sustained during long-term follow-up in both pools (patients with ASCVD or HeFH or both receiving a maximally tolerated statin, difference of -12.7% at week 52; patients with statin intolerance, difference of -22.2% at week 24). Decreases in non-high-density lipoprotein cholesterol, total cholesterol, apolipoprotein B, and high-sensitivity C-reactive protein levels were greater with bempedoic acid vs placebo. Treatment-emergent adverse events associated more frequently with bempedoic acid than with placebo included increased blood uric acid level (2.1% vs 0.5%), gout (1.4% vs 0.4%), decreased glomerular filtration rate (0.7% vs <0.1%), and increased levels of hepatic enzymes (2.8% vs 1.3%).. Bempedoic acid added to maximally tolerated statins, including moderate- or high-intensity statins or no background statin, was associated with decreased LDL-C levels vs placebo in patients with hypercholesterolemia with an acceptable safety profile. As a nonstatin adjunct or statin alternative, bempedoic acid has potential for use in a broad spectrum of patients.. ClinicalTrials.gov Identifiers: NCT02666664, NCT02991118, NCT03001076, and NCT02988115.

Topics: Aged; Cholesterol, LDL; Clinical Trials, Phase III as Topic; Dicarboxylic Acids; Drug Therapy, Combination; Fatty Acids; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hypolipidemic Agents; Male; Randomized Controlled Trials as Topic

Bempedoic acid is a first-in-class lipid-lowering drug recommended by guidelines for the treatment of hypercholesterolemia. Our objective was to estimate its average effect on plasma lipids in humans and its safety profile.. We carried out a systematic review and meta-analysis of phase II and III randomized controlled trials on bempedoic acid (PROSPERO: CRD42019129687). PubMed (Medline), Scopus, Google Scholar, and Web of Science databases were searched, with no language restriction, from inception to 5 August 2019. We included 10 RCTs (n = 3,788) comprising 26 arms (active arm [n = 2,460]; control arm [n = 1,328]). Effect sizes for changes in lipids and high-sensitivity C-reactive protein (hsCRP) serum concentration were expressed as mean differences (MDs) and 95% confidence intervals (CIs). For safety analyses, odds ratios (ORs) and 95% CIs were calculated using the Mantel-Haenszel method. Bempedoic acid significantly reduced total cholesterol (MD -14.94%; 95% CI -17.31%, -12.57%; p < 0.001), non-high-density lipoprotein cholesterol (MD -18.17%; 95% CI -21.14%, -15.19%; p < 0.001), low-density lipoprotein cholesterol (MD -22.94%; 95% CI -26.63%, -19.25%; p < 0.001), low-density lipoprotein particle number (MD -20.67%; 95% CI -23.84%, -17.48%; p < 0.001), apolipoprotein B (MD -15.18%; 95% CI -17.41%, -12.95%; p < 0.001), high-density lipoprotein cholesterol (MD -5.83%; 95% CI -6.14%, -5.52%; p < 0.001), high-density lipoprotein particle number (MD -3.21%; 95% CI -6.40%, -0.02%; p = 0.049), and hsCRP (MD -27.03%; 95% CI -31.42%, -22.64%; p < 0.001). Bempedoic acid did not significantly modify triglyceride level (MD -1.51%; 95% CI -3.75%, 0.74%; p = 0.189), very-low-density lipoprotein particle number (MD 3.79%; 95% CI -9.81%, 17.39%; p = 0.585), and apolipoprotein A-1 (MD -1.83%; 95% CI -5.23%, 1.56%; p = 0.290). Treatment with bempedoic acid was positively associated with an increased risk of discontinuation of treatment (OR 1.37; 95% CI 1.06, 1.76; p = 0.015), elevated serum uric acid (OR 3.55; 95% CI 1.03, 12.27; p = 0.045), elevated liver enzymes (OR 4.28; 95% CI 1.34, 13.71; p = 0.014), and elevated creatine kinase (OR 3.79; 95% CI 1.06, 13.51; p = 0.04), though it was strongly associated with a decreased risk of new onset or worsening diabetes (OR 0.59; 95% CI 0.39, 0.90; p = 0.01). The main limitation of this meta-analysis is related to the relatively small number of individuals involved in the studies, which were often short or middle term in length.. Our results show that bempedoic acid has favorable effects on lipid profile and hsCRP levels and an acceptable safety profile. Further well-designed studies are needed to explore its longer-term safety.

Topics: Anticholesteremic Agents; Apolipoproteins B; Cholesterol; Cholesterol, LDL; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Dicarboxylic Acids; Fatty Acids; Humans; Hypercholesterolemia; Peptide Fragments; Randomized Controlled Trials as Topic

Background Bempedoic acid (BA) is a novel lipid-lowering drug. We performed a systematic review and meta-analysis on efficacy and safety of BA compared with standard treatment in patients with hypercholesterolemia. Methods and Results Studies were systematically searched in the PubMed, Web of Science, Scopus, and EMBASE databases. Efficacy outcome was represented by percentage changes (mean difference [MD] with pertinent 95% CIs) in total cholesterol, low-density lipoprotein cholesterol, triglycerides, high-density lipoprotein cholesterol, apolipoprotein B, non-high-density lipoprotein cholesterol, and hs-CRP (high-sensitivity C-reactive protein) in BA patients and controls. Seven studies were included (2767 BA-treated patients and 1469 controls), showing a more significant reduction in low-density lipoprotein cholesterol (MD, -17.5%; 95% CI, -22.9% to -12.0%), total cholesterol (MD, -10.9%; 95% CI, -13.3% to -8.5%), non-high-density lipoprotein cholesterol (MD, -12.3%; 95% CI, -15.3% to -9.20%), apolipoprotein B (MD, -10.6%; 95% CI, -13.2% to -8.02%), and hs-CRP (MD, -13.2%; 95% CI, -16.7% to -9.79%) in BA-treated patients compared with controls. Results were confirmed when separately analyzing studies on patients with high cardiovascular risk, studies on statin-intolerant patients, and studies on patients with hypercholesterolemia on maximally tolerated lipid-lowering therapy. BA-treated subjects reported a higher rate of treatment discontinuation caused by adverse effects, of gout flare, and of increase in uric acid compared with controls. On the other hand, BA-treated patients showed a lower incidence of new-onset diabetes mellitus than controls. Conclusions BA is associated with a significant reduction in low-density lipoprotein cholesterol, total cholesterol, non-high-density lipoprotein cholesterol, apolipoprotein B, and hs-CRP compared with standard treatment. Documented efficacy is accompanied by an acceptable safety profile.

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

Bempedoic acid is an oral, once-daily, first-in-class drug being developed for the treatment of hyperlipidemia. However, evidence of bempedoic acid use for the prevention of cardiovascular events and diabetes is lacking. Thus, we aim to evaluate the benefit and safety of bempedoic acid use for the prevention of cardiovascular events and diabetes.. We searched Medline, Embase, and the Cochrane Central Register of Controlled Trials with no language restriction from inception until March 3, 2020. Pairs of reviewers independently identified randomized controlled trials comparing the use of bempedoic acid with placebo or no treatment for primary prevention of cardiovascular events in statin-intolerant patients with hypercholesterolemia. The primary outcomes were major adverse cardiac events, and percent change in LDL-C.. Bempedoic acid in patients with hypercholesterolemia was associated with a lower risk of cardiovascular events and diabetes.

Topics: Aged; Biomarkers; Cardiovascular Diseases; Cholesterol, LDL; Diabetes Mellitus; Dicarboxylic Acids; Down-Regulation; Fatty Acids; Female; Humans; Hypercholesterolemia; Hypolipidemic Agents; Male; Middle Aged; Risk Assessment; Risk Factors; Treatment Outcome

Bempedoic acid is a new drug that reduces cholesterol synthesis via inhibiting ATP citrate lyase. It remains unclear whether the combination of bempedoic acid and other lipid-lowering drugs is better than these drugs alone. This study systematically reviewed the efficacy and safety of bempedoic acid monotherapy or combination togethers in hypercholesterolemic patients.. Randomized controlled trials were searched across Medline, Embase, Cochrane library, web of science, etc. The net change scores [least squares mean (LSM) percentage change] in LDL-C level were meta-analyzed using weighted mean difference. The reductions in other lipids including total cholesterol (TC), non-high-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein (ApoB) and high sensitivity C reactive protein (hsCRP) were also assessed. Odds ratio (OR) of the incidence of adverse events (AEs) were calculated to evaluate the safety of bempedoic acid.. A total of 13 trials (4858 participates) were included. Pooled data showed that the combination togethers resulted in greater reductions in LDL-C level than monotherapies (bempedoic acid + statin vs. statin: LSM difference (%), - 18.37, 95% CI, - 20.16 to - 16.57, I. This study showed the efficacy of combination togethers were similar but stronger than these drugs alone. Of note, a trend of high risk of muscle-related AEs by the combination of bempedoic acid and statin was observed, though it is not statistically significant, such risk is needed to be confirmed by more trials, because it is important for us to determine which is the better combinative administration for statin-intolerant patients.

Topics: Anticholesteremic Agents; Dicarboxylic Acids; Drug Therapy, Combination; Fatty Acids; Humans; Hypercholesterolemia; Hypolipidemic Agents; Randomized Controlled Trials as Topic; Treatment Outcome

Bempedoic acid (ETC-1002), a novel therapeutic approach for low-density lipoprotein cholesterol (LDL-C) lowering, inhibits ATP citrate lyase (ACL), an enzyme involved in fatty acid and cholesterol synthesis. Although rodent studies suggested potential effects of ACL inhibition on both fatty acid and cholesterol synthesis, studies in humans show an effect only on cholesterol synthesis. In phase 2 studies, ETC-1002 reduced LDL-C as monotherapy, combined with ezetimibe, and added to statin therapy, with LDL-C lowering most pronounced when ETC-1002 was combined with ezetimibe in patients who cannot tolerate statins. Whether clinically relevant favorable effects on other cardiometabolic risk factors such as hyperglycemia and insulin resistance occur in humans is unknown and requires further investigation. Promising phase 2 results have led to the design of a large phase 3 program to gain more information on efficacy and safety of ETC-1002 in combination with statins and when added to ezetimibe in statin-intolerant patients.

Topics: Anticholesteremic Agents; ATP Citrate (pro-S)-Lyase; Cholesterol, LDL; Dicarboxylic Acids; Drug Therapy, Combination; Ezetimibe; Fatty Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia

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

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

Many patients with hypercholesterolemia fail to achieve sufficient low-density lipoprotein cholesterol (LDL-C) lowering despite use of guideline-recommended lipid-lowering therapies. This study evaluated LDL-C lowering with the combination of bempedoic acid, ezetimibe, and atorvastatin.. This was a phase 2, randomized, double-blind, placebo-controlled study (NCT03051100). After washout of lipid-lowering drugs, patients were randomized 2:1 to triple therapy (bempedoic acid 180 mg, ezetimibe 10 mg, and atorvastatin 20 mg; n = 43) or placebo (n = 20) once daily for 6 weeks. The primary endpoint was percent change from baseline in LDL-C at week 6.. Mean age for the 63 randomized patients was 61.2 years; baseline LDL-C was 154.8 mg/dL. At week 6, mean LDL-C lowering with triple therapy (-63.6%) was significantly greater than with placebo [-3.1%; difference, -60.5% [(95% CI, -68.0% to -53.0%); p < 0.001]. Significant reductions with triple therapy vs. placebo were also observed for non-high-density lipoprotein cholesterol, total cholesterol, apolipoprotein B, and high-sensitivity C-reactive protein (p < 0.001 for all). With triple-therapy, 90% of patients achieved LDL-C <70 mg/dL and 95% of patients had ≥50% lower LDL-C from baseline to week 6; no patients in the placebo group met either goal. The majority of treatment-emergent adverse events were mild to moderate in severity. No patients experienced clinically relevant elevations in aminotransferase or creatine kinase levels.. Among patients with hypercholesterolemia, the combination of bempedoic acid, ezetimibe, and atorvastatin significantly lowered LDL-C, allowing more than 90% of patients in this study to reach guideline-recommended LDL-C goals.

Topics: Anticholesteremic Agents; Atorvastatin; Dicarboxylic Acids; Double-Blind Method; Drug Therapy, Combination; Ezetimibe; Fatty Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Middle Aged; Treatment Outcome

The efficacy and safety of bempedoic acid, including the occurrence of muscle-related adverse events, have been addressed by phase 2 and phase 3 clinical trials. Phase 3 clinical trials demonstrated that in patients with atherosclerotic cardiovascular disease and/or familial hypercholesterolemia who were treated with statins at maximum tolerated dose, with or without further lipid-lowering drugs, bempedoic acid treatment was associated with a significant reduction in low-density lipoprotein cholesterol in different groups of patients with a favorable safety profile. An ongoing phase 3 study is currently evaluating the effect of longer-term (median duration of 3-4 years) treatment with bempedoic acid on the incidence of cardiovascular events.

Topics: Cholesterol, LDL; Dicarboxylic Acids; Fatty Acids; Humans; Hypercholesterolemia

The 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.. This 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.. Among 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%);. The 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.. ClinicalTrials.gov identifier: NCT03337308.

Topics: Aged; Anticholesteremic Agents; Biomarkers; Cardiovascular Diseases; Cholesterol, LDL; Dicarboxylic Acids; Double-Blind Method; Down-Regulation; Drug Combinations; Ezetimibe; Fatty Acids; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Male; Middle Aged; Time Factors; Treatment Outcome; United States

Short-term studies have shown that bempedoic acid, an inhibitor of ATP citrate lyase, reduces levels of low-density lipoprotein (LDL) cholesterol. Data are limited regarding the safety and efficacy of bempedoic acid treatment in long-term studies involving patients with hypercholesterolemia who are receiving guideline-recommended statin therapy.. We conducted a randomized, controlled trial involving patients with atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or both. Patients had to have an LDL cholesterol level of at least 70 mg per deciliter while they were receiving maximally tolerated statin therapy with or without additional lipid-lowering therapy. (Maximally tolerated statin therapy was defined as the highest intensity statin regimen that a patient was able to maintain, as determined by the investigator.) Patients were randomly assigned in a 2:1 ratio to receive bempedoic acid or placebo. The primary end point was safety, and the principal secondary end point (principal efficacy end point) was the percentage change in the LDL cholesterol level at week 12 of 52 weeks.. The trial involved 2230 patients, of whom 1488 were assigned to receive bempedoic acid and 742 to receive placebo. The mean (±SD) LDL cholesterol level at baseline was 103.2±29.4 mg per deciliter. The incidence of adverse events (1167 of 1487 patients [78.5%] in the bempedoic acid group and 584 of 742 [78.7%] in the placebo group) and serious adverse events (216 patients [14.5%] and 104 [14.0%], respectively) did not differ substantially between the two groups during the intervention period, but the incidence of adverse events leading to discontinuation of the regimen was higher in the bempedoic acid group than in the placebo group (162 patients [10.9%] vs. 53 [7.1%]), as was the incidence of gout (18 patients [1.2%] vs. 2 [0.3%]). At week 12, bempedoic acid reduced the mean LDL cholesterol level by 19.2 mg per deciliter, representing a change of -16.5% from baseline (difference vs. placebo in change from baseline, -18.1 percentage points; 95% confidence interval, -20.0 to -16.1; P<0.001). Safety and efficacy findings were consistent, regardless of the intensity of background statin therapy.. In this 52-week trial, bempedoic acid added to maximally tolerated statin therapy did not lead to a higher incidence of overall adverse events than placebo and led to significantly lower LDL cholesterol levels. (Funded by Esperion Therapeutics; CLEAR Harmony ClinicalTrials.gov number, NCT02666664.).

Topics: Aged; Apolipoproteins B; ATP Citrate (pro-S)-Lyase; C-Reactive Protein; Cholesterol; Cholesterol, LDL; Dicarboxylic Acids; Drug Therapy, Combination; Fatty Acids; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hypoglycemic Agents; Male; Middle Aged; Peptide Fragments; Treatment Outcome

Background Inability to tolerate statins because of muscle symptoms contributes to uncontrolled cholesterol levels and insufficient cardiovascular risk reduction. Bempedoic acid, a prodrug that is activated by a hepatic enzyme not present in skeletal muscle, inhibits ATP -citrate lyase, an enzyme upstream of β-hydroxy β-methylglutaryl-coenzyme A reductase in the cholesterol biosynthesis pathway. Methods and Results The phase 3, double-blind, placebo-controlled CLEAR (Cholesterol Lowering via Bempedoic acid, an ACL-Inhibiting Regimen) Serenity study randomized 345 patients with hypercholesterolemia and a history of intolerance to at least 2 statins (1 at the lowest available dose) 2:1 to bempedoic acid 180 mg or placebo once daily for 24 weeks. The primary end point was mean percent change from baseline to week 12 in low-density lipoprotein cholesterol. The mean age was 65.2 years, mean baseline low-density lipoprotein cholesterol was 157.6 mg/dL, and 93% of patients reported a history of statin-associated muscle symptoms. Bempedoic acid treatment significantly reduced low-density lipoprotein cholesterol from baseline to week 12 (placebo-corrected difference, -21.4% [95% CI, -25.1% to -17.7%]; P<0.001). Significant reductions with bempedoic acid versus placebo were also observed in non-high-density lipoprotein cholesterol (-17.9%), total cholesterol (-14.8%), apolipoprotein B (-15.0%), and high-sensitivity C-reactive protein (-24.3%; P<0.001 for all comparisons). Bempedoic acid was safe and well tolerated. The most common muscle-related adverse event, myalgia, occurred in 4.7% and 7.2% of patients who received bempedoic acid or placebo, respectively. Conclusions Bempedoic acid offers a safe and effective oral therapeutic option for lipid lowering in patients who cannot tolerate statins. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT 02988115.

Topics: Administration, Oral; Canada; Dicarboxylic Acids; Double-Blind Method; Drug Hypersensitivity; Fatty Acids; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hypolipidemic Agents; Male; Middle Aged; Muscular Diseases; Treatment Outcome; United States

Patients with hyperlipidemia who are unable to tolerate optimal statin therapy are at increased cardiovascular risk due to ongoing elevations in low-density lipoprotein cholesterol (LDL-C). The objective of CLEAR Tranquility (NCT03001076) was to evaluate the efficacy and safety of bempedoic acid when added to background lipid-modifying therapy in patients with a history of statin intolerance who require additional LDL-C lowering.. This phase 3, multicenter, randomized, double-blind, placebo-controlled study enrolled patients with a history of statin intolerance and an LDL-C ≥100 mg/dL while on stable lipid-modifying therapy. After a 4-week ezetimibe 10 mg/day run-in period, patients were randomized 2:1 to treatment with bempedoic acid 180 mg or placebo once daily added to ezetimibe 10 mg/day for 12 weeks. The primary endpoint was the percent change from baseline to week 12 in LDL-C.. The study population comprised 269 patients (181 bempedoic acid, 88 placebo). Bempedoic acid added to background lipid-modifying therapy that included ezetimibe reduced LDL-C by 28.5% more than placebo (p < 0.001; -23.5% bempedoic acid, +5.0% placebo). Significant reductions in secondary endpoints, including non-high-density lipoprotein cholesterol (-23.6%), total cholesterol (-18.0%), apolipoprotein B (-19.3%), and high-sensitivity C-reactive protein (-31.0%), were observed with bempedoic acid vs. placebo (p < 0.001). Bempedoic acid was well tolerated; rates of treatment-emergent adverse events, muscle-related adverse events, and discontinuations were similar in the bempedoic acid and placebo treatment groups.. Bempedoic acid may provide an oral therapeutic option complementary to ezetimibe in statin intolerant patients who require additional LDL-C lowering.

Topics: Aged; Biomarkers; Canada; Cholesterol, LDL; Dicarboxylic Acids; Double-Blind Method; Down-Regulation; Drug Therapy, Combination; Europe; Ezetimibe; Fatty Acids; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hypolipidemic Agents; Male; Middle Aged; Time Factors; Treatment Outcome; United States

ETC-1002 is an oral, once-daily medication that inhibits adenosine triphosphate citrate lyase, an enzyme upstream of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, to reduce cholesterol biosynthesis. ETC-1002 monotherapy has demonstrated significant reduction in low-density lipoprotein cholesterol (LDL-C) compared with placebo in phase 2 studies. The objective of this study was to compare the lipid-lowering efficacy of ETC-1002 versus placebo when added to ongoing statin therapy in patients with hypercholesterolemia. This phase 2b, multicenter, double-blind trial (NCT02072161) randomized 134 hypercholesterolemic patients (LDL-C, 115 to 220 mg/dl) on stable background statin therapy to 12 weeks of add-on treatment with ETC-1002 120 mg, ETC-1002 180 mg, or placebo. The primary efficacy end point was the percent change in calculated LDL-C from baseline to week 12. For LDL-C, the least-squares mean percent change ± standard error from baseline to week 12 was significantly greater with ETC-1002 120 mg (-17 ± 4%, p = 0.0055) and ETC-1002 180 mg (-24 ± 4%, p <0.0001) than placebo (-4 ± 4%). ETC-1002 also dose dependently reduced apolipoprotein B by 15% to 17%, non-high-density lipoprotein cholesterol by 14% to 17%, total cholesterol by 13% to 15%, and LDL particle number by 17% to 21%. All these reductions in ETC-1002-treated cohorts were significantly greater than those with placebo. Rates of adverse events (AEs), muscle-related AEs, and discontinuations for AEs with ETC-1002 were similar to placebo. In conclusion, ETC-1002 120 mg or 180 mg added to stable statin therapy significantly reduced LDL-C compared to placebo and has a similar tolerability profile.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Cholesterol, LDL; Dicarboxylic Acids; Double-Blind Method; Drug Therapy, Combination; Fatty Acids; Female; Follow-Up Studies; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hypolipidemic Agents; Male; Middle Aged; Prospective Studies; Simvastatin; Time Factors; Treatment Outcome; Young Adult

8-Hydroxy-2,2,14,14-tetramethylpentadecanedioic acid (ETC-1002) is a small molecule with a unique mechanism of action shown in nonclinical studies to modulate pathways of cholesterol, fatty acid, and carbohydrate metabolism. In previous phase 2 clinical trials, once daily oral treatment with ETC-1002 significantly reduced low-density lipoprotein-cholesterol in patients with hypercholesterolemia. In this trial, the lipid-lowering efficacy of ETC-1002 was evaluated in patients with type 2 diabetes mellitus and hypercholesterolemia. Additional cardiometabolic biomarkers, including glycemic measures, were also assessed.. A single-center, double-blind, placebo-controlled trial evaluated 60 patients with type 2 diabetes mellitus and elevated low-density lipoprotein-cholesterol. Patients discontinued all diabetes mellitus and lipid-regulating drugs and were randomized to receive ETC-1002 80 mg QD for 2 weeks followed by 120 mg QD for 2 weeks or placebo for 4 weeks. ETC-1002 lowered low-density lipoprotein-cholesterol levels by 43±2.6% (least squares mean±SE), compared with a reduction of 4±2.5% by placebo at day 29 (P<0.0001; primary end point). Non-high-density lipoprotein-cholesterol and total cholesterol were also significantly lowered by ETC-1002 compared with placebo (P<0.0001). High-sensitivity C-reactive protein was reduced by 41% (median) compared with a placebo reduction of 11% (P=0.0011). No clinically meaningful safety findings were observed.. ETC-1002 lowered low-density lipoprotein-cholesterol and other lipids and demonstrated improvement in high-sensitivity C-reactive protein in patients with type 2 diabetes mellitus and hypercholesterolemia without worsening glycemic control. ETC-1002 was well tolerated in this population.. http://www.clinicaltrials.gov. Unique identifier: NCT# 01607294.

Topics: Aged; Anticholesteremic Agents; Antihypertensive Agents; Blood Glucose; Blood Pressure; C-Reactive Protein; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Dicarboxylic Acids; Double-Blind Method; Fasting; Fatty Acids; Female; Humans; Hypercholesterolemia; Hypertension; Hypoglycemic Agents; Male; Middle Aged; Treatment Outcome; Triglycerides

The aim of this study was to assess the lipid-altering efficacy and safety of ETC-1002 in subjects with hypercholesterolemia.. ETC-1002 is a small molecule that modulates pathways of cholesterol, fatty acid, and carbohydrate metabolism and may have therapeutic benefits in treating hypercholesterolemia and other cardiometabolic risk factors.. This multicenter, randomized, double-blind, placebo-controlled, parallel-group trial evaluated patients (n = 177) with elevated low-density lipoprotein cholesterol (LDL-C) (130 to 220 mg/dl), who were stratified by baseline triglycerides (not elevated [<150 mg/dl] or elevated [150-<400 mg/dl]) and randomized to receive 40, 80, or 120 mg of ETC-1002 or placebo once daily for 12 weeks. Outcomes included changes in LDL-C (primary endpoint), other lipids, and cardiometabolic risk factors; and safety.. ETC-1002 40, 80, and 120 mg lowered least-squares mean ± SE LDL-C levels by 17.9 ± 2.2%, 25.0 ± 2.1%, and 26.6 ± 2.2%, respectively, versus a reduction of 2.1 ± 2.2% with placebo (all, p < 0.0001); LDL-C lowering was similar between the subgroups with nonelevated and elevated triglycerides. ETC-1002 also lowered non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B, and LDL particle number (all, p < 0.0001) in a dose-dependent manner; HDL-C and triglyceride levels were relatively unchanged. Post-hoc analyses suggest that ETC-1002 may have favorable effects on other cardiometabolic risk factors. The ETC-1002 and placebo groups did not demonstrate clinically meaningful differences in adverse events or other safety assessments.. ETC-1002 significantly lowered LDL-C levels up to 27% across a broad range of baseline triglycerides and was generally safe and well tolerated. ETC-1002 has a novel mechanism of action and may be useful for reducing LDL-C. (A Study to Assess the Efficacy and Safety of ETC-1002 in Subjects With Elevated Blood Cholesterol and Either Normal or Elevated Triglycerides; NCT01262638).

Topics: Aged; AMP-Activated Protein Kinases; ATP Citrate (pro-S)-Lyase; Dicarboxylic Acids; Double-Blind Method; Fatty Acids; Female; Humans; Hypercholesterolemia; Hypolipidemic Agents; Male; Middle Aged; Risk Factors

Topics: Dicarboxylic Acids; Fatty Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hypolipidemic Agents

Topics: Dicarboxylic Acids; Fatty Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hypolipidemic Agents

Growing evidence supporting the central role of hypercholesterolemia in atherosclerotic disease pathogenesis and progression has led to the development of new therapeutic approaches. Bempedoic acid has recently been approved for marketing following several studies that demonstrated its efficacy and safety. This drug represents a new therapeutic option that, like statins, acts on the enzymatic cascade that is involved in cholesterol synthesis. However, its hepatic selectivity of action reduces the risk of muscle adverse effects. This ANMCO document highlights clinical settings in which bempedoic acid represents a particularly useful therapeutic option. Furthermore, the document discusses the possibilities of use based on both international recommendations and current national regulations. Finally, we report practical guidance on hypercholesterolemia management in light of the available therapeutic armamentarium.

Topics: Cholesterol, LDL; Fatty Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia

Topics: Cholesterol, LDL; Dyslipidemias; Female; Healthy Volunteers; Humans; Hypercholesterolemia

Bempedoic acid significantly lowers low-density lipoprotein cholesterol (LDL-C) in patients with hypercholesterolemia but its effects in patients with metabolic syndrome (MetS) have not been well characterized. We sought to determine the efficacy and safety of bempedoic acid in patients with hypercholesterolemia by baseline MetS status.. This study used pooled data from four phase 3 studies. Using modified International Atherosclerosis Society guidelines, patients were grouped into two pools: those with and those without MetS. Patients with diabetes were excluded. Endpoints assessed change from baseline to week 12 in lipid and glycemic parameters and high-sensitivity C-reactive protein (hsCRP), and safety.. The study included 936 patients with MetS (bempedoic acid, 648; placebo, 288) and 1573 without MetS (bempedoic acid, 1037; placebo, 536). Significant placebo-corrected reductions in LDL-C were observed with bempedoic acid (p < 0.0001), with a slightly larger decrease in patients with vs. without MetS (-22.3% vs. -18.4%; interaction p = 0.0472). Compared with placebo, bempedoic acid significantly (p < 0.0001) lowered total cholesterol, non-high-density lipoprotein cholesterol, apolipoprotein B, and hsCRP, with a similar magnitude of benefit observed between MetS categories. Triglycerides increased with bempedoic acid but only to a lesser extent than with placebo in patients without MetS (placebo-corrected difference, -4.4%; p = 0.02). Only patients with MetS experienced decreases in glycated hemoglobin (-0.07%; p < 0.0001) and fasting plasma glucose (-2.4 mg/dL; p = 0.002). Safety was comparable between MetS categories and treatment groups.. These data suggest that bempedoic acid is a suitable therapy for patients with and without MetS who require additional lipid lowering.

Topics: Anticholesteremic Agents; C-Reactive Protein; Cholesterol; Cholesterol, LDL; Dicarboxylic Acids; Fatty Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Metabolic Syndrome; Treatment Outcome

Topics: Dicarboxylic Acids; Fatty Acids; Humans; Hypercholesterolemia

Topics: Atorvastatin; Dicarboxylic Acids; Ezetimibe; Fatty Acids; Humans; Hypercholesterolemia

In the last decades, scientific evidence regarding the key role of cholesterol in atherosclerosis pathogenesis has led to the development of lipid-lowering treatments that can be used in addition to statins or in place of them in case of intolerance. Bempedoic acid represents an effective and safe new therapeutic option in hypercholesterolemia management. Clinical studies have demonstrated that bempedoic acid can significantly reduce low-density lipoprotein cholesterol in several clinical settings. Furthermore, bempedoic acid has also been associated with the improvement of other biomarkers, including reduced apolipoprotein B and high-sensitivity C-reactive protein, effects that can increase the clinical benefits of this treatment.

Topics: Cholesterol, LDL; Dicarboxylic Acids; Fatty Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia

Topics: Dicarboxylic Acids; Fatty Acids; Humans; Hypercholesterolemia

Topics: Dicarboxylic Acids; Ezetimibe; Fatty Acids; Humans; Hypercholesterolemia

Topics: Dicarboxylic Acids; Ezetimibe; Fatty Acids; Humans; Hypercholesterolemia

Bempedoic acid is a new lipid-lowering drug that inhibits cholesterol biosynthesis in liver cells selectively. Results from phase 2 and phase 3 studies showed a complementary effect on LDL-cholesterol lowering when combining bempedoic acid and ezetimibe without increasing side effects. Moreover, bempedoic acid seems to represent a good treatment option for the management of hypercholesterolemia, especially in patients at increased risk of cardiovascular events, such as patients with impaired glucose metabolism, elderly patients, patients with prior acute coronary syndrome, and patients with familial hypercholesterolemia. Based on the scientific evidence, this paper provides practical recommendations on the management of hypercholesterolemia with bempedoic acid.

Topics: Aged; Anticholesteremic Agents; Cholesterol, LDL; Dicarboxylic Acids; Fatty Acids; Humans; Hypercholesterolemia

Bempedoic acid acts by inhibiting adenosine triphosphate-citrate lyase (ACL) and consequently cholesterol biosynthesis, leading to increased expression of LDL receptors and increasing low-density lipoproteins (LDL-C) plasma clearence. It is a prodrug for oral administration with intracellular activation. It is activatedin liver cells and to a lesser extent in kidney cells, being absent in adipose tissue and muscle cells. Therefore, unlike statins, its potential myotoxic effect is very limited. It has recently been approved as a lipid-lowering drug in combination with diet, with statins, or with other lipid-lowering drugs in patients with hypercholesterolaemia, mixed dyslipidaemia, statin intolerance, or when these are contraindicated. The marketing of bempedoic acid implies, in clinical practice, having a new family of lipid-lowering drugs.

Topics: Dicarboxylic Acids; Drug Therapy, Combination; Dyslipidemias; Fatty Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hypolipidemic Agents

Topics: Coronary Artery Disease; Cost-Benefit Analysis; Dicarboxylic Acids; Drug Therapy, Combination; Fatty Acids; Humans; Hypercholesterolemia; Hypolipidemic Agents; Models, Economic; RNA, Small Interfering; Secondary Prevention; Treatment Outcome

Last European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) guidelines on dyslipidemia published in 2019 recommend an LDL-cholesterol goal < 1.4 mmol/l (< 55 mg/dl) for people at very high cardiovascular risk. They propose combinations of lipid lowering therapies in addition to statins if necessary to meet this objective, which is very rarely reached in this at risk population. Two new drugs have recently received European Medicines Agency (EMA) approval for the treatment of hypercholesterolaemia, bempedoic acid, a small oral molecule that inhibits hepatic cholesterol synthesis, and inclisiran, a small interfering RNA that reduces PCSK9 levels after its subcutaneous injection. This article summarizes the mode of action, efficacy data, safety/tolerance profile and indications of these two innovative drugs.. Les recommandations de 2019 de l’European Society of Cardiology et de l’European Atherosclerosis Society pour le traitement des dyslipidémies préconisent un cholestérol lipoprotéine de basse densité (LDL) < 1,4 mmol/l (< 55 mg/dl) chez les sujets à très haut risque cardiovasculaire. Elles proposent des associations de médicaments hypolipémiants en addition aux statines pour rencontrer cet objectif, souvent non atteint dans cette population. Deux nouvelles médications ont reçu l’approbation de l’Agence européenne du médicament pour le traitement de l’hypercholestérolémie, l’acide bempédoïque, une médication orale qui réduit la synthèse hépatique de cholestérol, et l’inclisiran, un petit acide ribonucléique interférent qui réduit les concentrations de proprotéine convertase subtilisine/kexine de type 9. Nous résumons le mode d’action, les données d’efficacité, le profil de sécurité et les indications de ces deux classes thérapeutiques innovantes.

Topics: Dicarboxylic Acids; Fatty Acids; Humans; Hypercholesterolemia; Pharmaceutical Preparations; Proprotein Convertase 9; RNA, Small Interfering

Topics: Anticholesteremic Agents; ATP Citrate (pro-S)-Lyase; Cholesterol, LDL; Dicarboxylic Acids; Fatty Acids; Humans; Hypercholesterolemia

Topics: Aged; Cardiovascular Diseases; Cholesterol; Dicarboxylic Acids; Fatty Acids; Female; Global Health; Humans; Hypercholesterolemia; Hypolipidemic Agents; Incidence; Male; Meta-Analysis as Topic

Identify the benefits and limitations of statin therapy as a treatment option for lowering LDL-C. Intensify treatment in appropriate patients or refer for intensification. Describe the safety and efficacy of ezetimibe, bempedoic acid, PCSK9 inhibitors, LDL apheresis. Describe the safety and efficacy of medications in late-stage development or under review by the FDA for LDL-C reduction.

Topics: Cholesterol, LDL; Dicarboxylic Acids; Education, Medical, Continuing; Fatty Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; PCSK9 Inhibitors; Proprotein Convertase 9; Review Literature as Topic

Topics: Cardiovascular Diseases; Dicarboxylic Acids; Ezetimibe; Fatty Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia

ATP citrate lyase is an enzyme in the cholesterol-biosynthesis pathway upstream of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), the target of statins. Whether the genetic inhibition of ATP citrate lyase is associated with deleterious outcomes and whether it has the same effect, per unit decrease in the low-density lipoprotein (LDL) cholesterol level, as the genetic inhibition of HMGCR is unclear.. We constructed genetic scores composed of independently inherited variants in the genes encoding ATP citrate lyase (. A total of 654,783 participants, including 105,429 participants who had major cardiovascular events, were included in the study. The. Genetic variants that mimic the effect of ATP citrate lyase inhibitors and statins appeared to lower plasma LDL cholesterol levels by the same mechanism of action and were associated with similar effects on the risk of cardiovascular disease per unit decrease in the LDL cholesterol level. (Funded by Esperion Therapeutics and others.).

Topics: ATP Citrate (pro-S)-Lyase; Cardiovascular Diseases; Cholesterol, LDL; Diabetes Mellitus; Dicarboxylic Acids; Fatty Acids; Female; Genetic Predisposition to Disease; Humans; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hypolipidemic Agents; Lipoproteins; Male; Membrane Proteins; Membrane Transport Proteins; Mendelian Randomization Analysis; Middle Aged; Neoplasms; Odds Ratio; Risk; Triglycerides

See Article by Laufs et al.

Topics: Dicarboxylic Acids; Fatty Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia

Topics: Anticholesteremic Agents; Cholesterol, LDL; Diabetes Mellitus, Type 2; Dicarboxylic Acids; Fatty Acids; Female; Humans; Hypercholesterolemia; Male

Topics: Dicarboxylic Acids; Fatty Acids; Female; Humans; Hypercholesterolemia; Hypolipidemic Agents; Male