etc-1002 and Cardiovascular-Diseases

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

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

Despite treatment with statins, patients with elevated low-density lipoprotein cholesterol (LDL-C) and triglycerides remain at increased risk for adverse cardiovascular events. Consequently, novel pharmaceutical drugs have been developed to control and modify the composition of blood lipids to ultimately prevent fatal cardiovascular events in patients with dyslipidaemia. This article reviews established and emerging lipid-lowering drugs regarding their mechanism of action, development stage, ongoing clinical trials, side effects, effect on blood lipids and reduction in cardiovascular morbidity and mortality. We conducted a keyword search to identify studies on established and emerging lipid modifying drugs. Results were summarized in a narrative overview. Established pharmaceutical treatment options include the Niemann-Pick-C1 like-1 protein (NPC1L1) inhibitor ezetimibe, the protein convertase subtilisin-kexin type 9 (PCSK9) inhibitors alirocumab and evolocumab, fibrates as peroxisome proliferator receptor alpha (PPAR-α) activators, and the omega-3 fatty acid icosapent ethyl. Statins are recommended as the first-line therapy for primary and secondary cardiovascular prevention in patients with hypercholesterinaemia and hypertriglyceridemia. For secondary prevention in hypercholesterinaemia, second-line options such as statin add-on or statin-intolerant treatments are ezetimibe, alirocumab and evolocumab. For secondary prevention in hypertriglyceridemia, second-line options such as statin add-on or statin-intolerant treatments are icosapent ethyl and fenofibrate. Robust data for these add-on therapeutics in primary cardiovascular prevention remains scarce. Recent biotechnological advances have led to the development of innovative small molecules (bempedoic acid, lomitapide, pemafibrate, docosapentaenoic and eicosapentaenoic acid), antibodies (evinacumab), antisense oligonucleotides (mipomersen, volanesorsen, pelcarsen, olezarsen), small interfering RNA (inclisiran, olpasiran), and gene therapies for patients with dyslipidemia. These molecules specifically target new cellular pathways, such as the adenosine triphosphate-citrate lyase (bempedoic acid), PCSK9 (inclisiran), angiopoietin-like 3 (ANGPTL3: evinacumab), microsomal triglyceride transfer protein (MTP: lomitapide), apolipoprotein B-100 (ApoB-100: mipomersen), apolipoprotein C-III (ApoC-III: volanesorsen, olezarsen), and lipoprotein (a) (Lp(a): pelcarsen, olpasiran). The authors are hopeful that the de

Topics: Angiopoietin-Like Protein 3; Anticholesteremic Agents; Cardiovascular Diseases; Ezetimibe; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertriglyceridemia; Hypolipidemic Agents; Pharmaceutical Preparations; Proprotein Convertase 9; Secondary Prevention

Bempedoic acid has shown noteworthy progress in the prevention and management of atherosclerotic cardiovascular disease (ASCVD) in recent years. However, there has been a lack of high-quality evidence regarding the risk reduction of clinical events with bempedoic acid. Therefore, the aim of this article is to conduct a comprehensive evaluation of the impact of bempedoic acid on the incidence of cardiovascular events.. A systematic review and meta-analysis of randomized controlled trials pertaining to bempedoic acid was carried out. We conducted a systematic search across the Pubmed, Embase, and Cochrane Central Register of Controlled Trials databases to identify relevant studies published from inception to 23 April 2023. A total of four trials comparing the clinical benefit achieved with bempedoic acid versus placebo were included.. Our analysis comprised four trials that encompassed a total of 17,323 patients. In comparison to the placebo, bempedoic acid showed a significant reduction in the risk of major adverse cardiovascular events (MACE) [relative risk (RR), 0.86, 95% confidence interval (CI) 0.87-0.94]. Additionally, bempedoic acid substantially lowered the occurrence of fatal or nonfatal myocardial infarction (RR 0.76, 95% CI 0.66-0.89), hospitalization for unstable angina (RR 0.70, 95% CI 0.55-0.89), and coronary revascularization (RR 0.82, 95% CI 0.73-0.92). There was also a similar reduction in MACE in patients on the maximally tolerated statin therapy.. Bempedoic acid may reduce the risk of cardiovascular events regardless of whether the patient is taking stains or not.. PROSPERO registration number CRD42023422932.

Topics: Cardiovascular Diseases; Dicarboxylic Acids; Fatty Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Myocardial Infarction

Dyslipidemia, specifically elevated low-density lipoprotein (LDL) cholesterol levels, causes atherosclerotic cardiovascular disease (ASCVD) and increases the risk of myocardial infarction and stroke. Statins, a class of drugs that exert their effects by inhibiting HMG-CoA reductase, a key enzyme in the synthesis of cholesterol, have been the mainstay of therapy for the primary prevention of cardiovascular disease and lipids reduction. Statins are associated with side effects, most commonly myopathy and myalgias, despite their proven efficacy. This review explores non-statin lipid-lowering therapies and examines recent advances and emerging research. Over the previous decades, several lipid-lowering therapies, both as monotherapy and adjuncts to statin therapy and lipid-targeting gene therapy, have emerged, thus redefining how we treat dyslipidemia. These drugs include Bile acids sequestrants, Fibrates, Nicotinic acid, Ezetimibe, Bempedoic acid, Volanesoren, Evinacumab, and the PCSK 9 Inhibitors Evolocumab and Alirocumab. Emerging gene-based therapy includes Small interfering RNAs, Antisense oligonucleotides, Adeno-associated virus vectors, CRISPR/Cas9 based therapeutics, and Non-coding RNA therapy. Of all these therapies, Bempedoic acid works most like statins by working through a similar pathway to decrease cholesterol levels. However, it is not associated with myopathy. Overall, although statins continue to be the gold standard, non-statin therapies are set to play an increasingly important role in managing dyslipidemia.

Topics: Anticholesteremic Agents; Cardiovascular Diseases; Cholesterol; Cholesterol, LDL; Dyslipidemias; Ezetimibe; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors

Topics: Cardiovascular Diseases; Diabetes Mellitus; Dicarboxylic Acids; Fatty Acids; Humans; Hypolipidemic Agents; Randomized Controlled Trials as Topic

Statins remain the preferred agent to reduce low-density lipoprotein cholesterol (LDL-C) and lower atherosclerotic cardiovascular disease (ASCVD) risk. Additional nonstatin agents are recommended to further lower LDL-C among patients at high-risk of ASCVD or those with heterozygous familial hypercholesterolemia, despite statin therapy. Patients unable to tolerate recommended doses of statin therapy due to adverse effects, including statin-associated muscle symptoms, may also require additional nonstatin agents to lower LDL-C and ASCVD risk. Bempedoic acid is a first-in-class, once-daily oral agent, recently approved as monotherapy and in combination with ezetimibe, as an adjunct to maximally tolerated statin therapy in patients with ASCVD or heterozygous familial hypercholesterolemia who require additional LDL-C lowering. Its novel mechanism is reported to avoid adverse muscle symptoms associated with statins. The effectiveness and safety of bempedoic acid and bempedoic acid/ezetimibe combination have been reported in multiple phase 2 and 3 trials. In this review, we report the lipid-lowering effects associated with bempedoic acid, and the safety profile from multiple clinical trials. Based on available data, bempedoic acid significantly lowers LDL-C and other atherogenic lipoprotein measures, and high-sensitivity C-reactive protein when added to background lipid-lowering therapy in patients with and without statin intolerance. Overall safety of bempedoic acid seems to be comparable to placebo, except for increased serum uric acid and tendon rupture. Ongoing clinical trials assessing the long-term safety and cardiovascular outcomes will provide additional insight into the role of bempedoic acid as an adjunct lipid-lowering medication.

Topics: Animals; Anticholesteremic Agents; Biomarkers; Cardiovascular Diseases; Cholesterol, LDL; Dicarboxylic Acids; Down-Regulation; Dyslipidemias; Fatty Acids; Humans; Risk Assessment; Risk Factors; Treatment Outcome

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

At the 2019 American College of Cardiology annual scientific sessions, major randomized clinical trials in cardiovascular disease (CVD) prevention were presented.. The CLEAR Wisdom trial examined the safety and efficacy of adding bempedoic acid to maximally tolerated statin for reducing low-density lipoprotein cholesterol. Post hoc analyses from the REDUCE-IT trial evaluated the efficacy of icosapent ethyl for lowering risk of total (first time and recurrent) CVD events. A sub-analysis of ODYSSEY OUTCOMES examined the effect of alirocumab on lipoprotein(a) lowering for reducing CVD risk. The CREOLE trial compared three different combination antihypertensive therapies for blood pressure lowering among black individuals in sub-Saharan Africa. The INFINITY trial examined the effect of intensive blood pressure control on progression of brain white matter changes and various components of mobility and cognitive function. Lastly, post hoc analyses from DECLARE-TIMI 58 evaluated the efficacy of dapagliflozin among patients with type 2 diabetes mellitus and heart failure or peripheral artery disease. These trials hold future promise for novel agents aimed at reducing CVD burden among high-risk patients who continue to experience CVD events despite treatment with currently available guideline-directed therapy.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antihypertensive Agents; Benzhydryl Compounds; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dicarboxylic Acids; Eicosapentaenoic Acid; Fatty Acids; Female; Glucosides; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Sodium-Glucose Transporter 2 Inhibitors; United States

Although statins are first-line therapy for low-density lipoprotein cholesterol (LDL-C) reduction, many individuals on maximally tolerated statin therapy have elevated LDL-C. Bempedoic acid (ETC-1002) is a novel once-daily LDL-C-lowering agent in phase 3 clinical trials. In phase 1 and 2 studies, ETC-1002 was efficacious in lowering LDL-C when used as monotherapy and when added to statin and/or ezetimibe and was well tolerated in patients with statin intolerance. ETC-1002 also improved cardiometabolic risk factors. Ongoing phase 3 studies of ETC-1002 are evaluating its long-term efficacy and safety, and effects on cardiovascular events. This article discusses current evidence and future directions for ETC-1002.

Topics: Administration, Oral; Cardiovascular Diseases; Dicarboxylic Acids; Energy Metabolism; Fatty Acids; Humans; Hypolipidemic Agents; Receptors, LDL

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

Over the past three decades, statins have become first-line treatment for reducing LDL cholesterol (LDL-C) and cardiovascular disease (CVD). They have provided a clear, robust, and reproducible relationship between the absolute LDL-C reduction and the decrease in CVD; every 1 mmol/L (~40 mg/dL) in LDL-C reduction results in a 22 % decrease in CVD events. This relationship has recently been extended to reduction in LDL-C with a non-statin, ezetimibe, on top of statin therapy, further consolidating LDL-C as the cornerstone in CVD risk reduction. Despite these two effective and safe LDL-C-lowering drugs, there remains a need for additional drugs to reduce LDL-C, the focus of this review which covers agents which produce sufficient LDL-C reduction to potentially help address this unmet need and are either recently approved or currently in clinical trials.

Topics: Acetyl-CoA Carboxylase; Antibodies, Monoclonal; Anticholesteremic Agents; Cardiovascular Diseases; Carrier Proteins; Cholesterol Ester Transfer Proteins; Cholesterol, LDL; Dicarboxylic Acids; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Discovery; Fatty Acids; Humans; Oligonucleotides; PPAR delta; Proprotein Convertase 9; Proprotein Convertases; Serine Endopeptidases

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

Bempedoic acid, an ATP citrate lyase inhibitor, reduces low-density lipoprotein (LDL) cholesterol levels and is associated with a low incidence of muscle-related adverse events; its effects on cardiovascular outcomes remain uncertain.. We conducted a double-blind, randomized, placebo-controlled trial involving patients who were unable or unwilling to take statins owing to unacceptable adverse effects ("statin-intolerant" patients) and had, or were at high risk for, cardiovascular disease. The patients were assigned to receive oral bempedoic acid, 180 mg daily, or placebo. The primary end point was a four-component composite of major adverse cardiovascular events, defined as death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization.. A total of 13,970 patients underwent randomization; 6992 were assigned to the bempedoic acid group and 6978 to the placebo group. The median duration of follow-up was 40.6 months. The mean LDL cholesterol level at baseline was 139.0 mg per deciliter in both groups, and after 6 months, the reduction in the level was greater with bempedoic acid than with placebo by 29.2 mg per deciliter; the observed difference in the percent reductions was 21.1 percentage points in favor of bempedoic acid. The incidence of a primary end-point event was significantly lower with bempedoic acid than with placebo (819 patients [11.7%] vs. 927 [13.3%]; hazard ratio, 0.87; 95% confidence interval [CI], 0.79 to 0.96; P = 0.004), as were the incidences of a composite of death from cardiovascular causes, nonfatal stroke, or nonfatal myocardial infarction (575 [8.2%] vs. 663 [9.5%]; hazard ratio, 0.85; 95% CI, 0.76 to 0.96; P = 0.006); fatal or nonfatal myocardial infarction (261 [3.7%] vs. 334 [4.8%]; hazard ratio, 0.77; 95% CI, 0.66 to 0.91; P = 0.002); and coronary revascularization (435 [6.2%] vs. 529 [7.6%]; hazard ratio, 0.81; 95% CI, 0.72 to 0.92; P = 0.001). Bempedoic acid had no significant effects on fatal or nonfatal stroke, death from cardiovascular causes, and death from any cause. The incidences of gout and cholelithiasis were higher with bempedoic acid than with placebo (3.1% vs. 2.1% and 2.2% vs. 1.2%, respectively), as were the incidences of small increases in serum creatinine, uric acid, and hepatic-enzyme levels.. Among statin-intolerant patients, treatment with bempedoic acid was associated with a lower risk of major adverse cardiovascular events (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization). (Funded by Esperion Therapeutics; CLEAR Outcomes ClinicalTrials.gov number, NCT02993406.).

Topics: Administration, Oral; Cardiovascular Diseases; Double-Blind Method; Fatty Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Myocardial Infarction; Myocardial Revascularization; Stroke

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

Although statins play a pivotal role in the prevention of atherosclerotic cardiovascular disease, many patients fail to achieve recommended lipid levels due to statin-associated muscle symptoms. Bempedoic acid is an oral pro-drug that is activated in the liver and inhibits cholesterol synthesis in hepatocytes, but is not activated in skeletal muscle which has the potential to avoid muscle-related adverse events. Accordingly, this agent effectively lowers atherogenic lipoproteins in patients who experience statin-associated muscle symptoms. However, the effects of bempedoic acid on cardiovascular morbidity and mortality have not been studied. STUDY DESIGN: Cholesterol Lowering via Bempedoic acid, an ACL-Inhibiting Regimen (CLEAR) Outcomes is a randomized, double-blind, placebo-controlled clinical trial. Included patients must have all of the following: (i) established atherosclerotic cardiovascular disease or have a high risk of developing atherosclerotic cardiovascular disease, (ii) documented statin intolerance, and (iii) an LDL-C ≥100 mg/dL on maximally-tolerated lipid-lowering therapy. The study randomized 14,014 patients to treatment with bempedoic acid 180 mg daily or matching placebo on a background of guideline-directed medical therapy. The primary outcome is a composite of the time to first cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization. The trial will continue until 1620 patients experience a primary endpoint, with a minimum of 810 hard ischemic events (cardiovascular death, nonfatal myocardial infarction or nonfatal stroke) and minimum treatment duration of 36 months and a projected median treatment exposure of 42 months. CONCLUSIONS: CLEAR Outcomes will determine whether bempedoic acid 180 mg daily reduces the incidence of adverse cardiovascular events in high vascular risk patients with documented statin intolerance and elevated LDL-C levels.

Topics: Aged; Biomarkers; Cardiovascular Diseases; Cholesterol, LDL; Dicarboxylic Acids; Double-Blind Method; Drug Tolerance; Fatty Acids; Female; Global Health; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Incidence; Male; Treatment Outcome

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

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

Low-density lipoprotein cholesterol (LDLc) is the lead effector of atherosclerosis and main treatment target. Bempedoic acid is a novel oral drug in the therapeutic armamentarium which is able to reduce LDLc. The objectives of this study were (1) to select the potential patients for administering bempedoic acid such as those with a very high cardiovascular risk in which objectives of LDLc were not achieved despite conventional treatment with PCSK9 inhibitors (PCSK9i) and/or statins and ezetimibe and (2) to estimate the cost-effectiveness of bempedoic acid in different scenarios. The methods used were a multicenter and retrospective study of 652 patients initiating treatment with any PCSK9 inhibitor in 17 different hospitals. Before and on-treatment LDLc cholesterol levels, medical treatments, clinical indication, and baseline characteristics were recorded. The results obtained from 443 subjects in secondary prevention were analyzed. The mean (±) LDLc level at baseline was 142.5 ± 46.4 mg/dL and 61.5 ± 40.5 mg/dL in the follow-up, with a reduction of 55.9% ( P < 0.0001); 71.6% of the patients reached the target of LDL < 55 mg/dL or >50% reduction. Of those patients treated with medium-intensity and low-intensity statins plus PCSK9 inhibitors (with or without ezetimibe), only 5.7% of them were able to reduce LDL below 55 mg/dL and the main LDLc reduction in this group was the lowest (42.9% on average). Patients with TG values >135 mg/dL represented 41.6% of the sample, of which approximately 10% of them were using fibrates. Assuming only LDLc reduction and the UK price, the incremental cost-effectiveness ratio was 88,359€; 83,117€; 82,378€; and 79,015€ for different discount rates. In conclusion, one-third of the patients could achieve the target LDL proposed in the 2019 ESC/EAS guidelines. Approximately 10% of them could also benefit from treating hypertriglyceridemia as indicated in the 2021 ESC guidelines on cardiovascular disease prevention. Patients with medium-intensity and low-intensity statins plus PCSK9i and ezetimibe would be the most benefited. Bempedoic acid could be a not cost-efficacy therapy in all the scenarios, but we need to wait for the CLEAR OUTCOMES Trial results.

Topics: Anticholesteremic Agents; Cardiovascular Diseases; Cholesterol, LDL; Cost-Effectiveness Analysis; Ezetimibe; Heart Disease Risk Factors; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; PCSK9 Inhibitors; Proprotein Convertase 9; Retrospective Studies; Risk Factors

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

This Medical News article discusses research presented at the American College of Cardiology and World Congress of Cardiology conference this March.

Topics: Cardiology; Cardiovascular Diseases; Diet, Ketogenic; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; United States; Wearable Electronic Devices

Topics: Cardiovascular Diseases; Dicarboxylic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents

The effects of bempedoic acid on cardiovascular outcomes in statin-intolerant patients without a prior cardiovascular event (primary prevention) have not been fully described.. To determine the effects of bempedoic acid on cardiovascular outcomes in primary prevention patients.. This masked, randomized clinical trial enrolled 13 970 statin-intolerant patients (enrollment December 2016 to August 2019 at 1250 centers in 32 countries), including 4206 primary prevention patients.. Participants were randomized to oral bempedoic acid, 180 mg daily (n = 2100), or matching placebo (n = 2106).. The primary efficacy measure was the time from randomization to the first occurrence of any component of a composite of cardiovascular death, nonfatal myocardial infarction (MI), nonfatal stroke, or coronary revascularization.. Mean participant age was 68 years, 59% were female, and 66% had diabetes. From a mean baseline of 142.2 mg/dL, compared with placebo, bempedoic acid reduced low-density lipoprotein cholesterol levels by 30.2 mg/dL (21.3%) and high-sensitivity C-reactive protein levels by 0.56 mg/L (21.5%), from a median baseline of 2.4 mg/L. Follow-up for a median of 39.9 months was associated with a significant risk reduction for the primary end point (111 events [5.3%] vs 161 events [7.6%]; adjusted hazard ratio [HR], 0.70 [95% CI, 0.55-0.89]; P = .002) and key secondary end points, including the composite of cardiovascular death, MI, or stroke (83 events [4.0%] vs 134 events [6.4%]; HR, 0.64 [95% CI, 0.48-0.84]; P < .001); MI (29 events [1.4%] vs 47 events [2.2%]; HR, 0.61 [95% CI, 0.39-0.98]); cardiovascular death (37 events [1.8%] vs 65 events [3.1%]; HR, 0.61 [95% CI, 0.41-0.92]); and all-cause mortality (75 events [3.6%] vs 109 events [5.2%]; HR, 0.73 [95% CI, 0.54-0.98]). There was no significant effect on stroke or coronary revascularization. Adverse effects with bempedoic acid included a higher incidence of gout (2.6% vs 2.0%), cholelithiasis (2.5% vs 1.1%), and increases in serum creatinine, uric acid, and hepatic enzyme levels.. In a subgroup of high-risk primary prevention patients, bempedoic acid treatment was associated with reduced major cardiovascular events.. ClinicalTrials.gov Identifier: NCT02993406.

Topics: Aged; Cardiovascular Diseases; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Myocardial Infarction; Primary Prevention; Stroke

Topics: Cardiovascular Diseases; Fatty Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Primary Prevention

Nissen SE, Lincoff MA, Brennan D, et al; CLEAR Outcomes Investigators.

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

Topics: Cardiovascular Diseases; Dicarboxylic Acids; Heart Disease Risk Factors; Humans; Risk Factors

Topics: Cardiovascular Agents; Cardiovascular Diseases; Dicarboxylic Acids; Fatty Acids; Humans; Primary Prevention

Topics: Cardiovascular Agents; Cardiovascular Diseases; Dicarboxylic Acids; Fatty Acids; Humans; Primary Prevention

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

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

Topics: Cardiovascular Diseases; Dicarboxylic Acids; Eicosapentaenoic Acid; Ezetimibe; Fatty Acids; Heart Disease Risk Factors; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; PCSK9 Inhibitors; RNA, Small Interfering

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

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

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

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

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