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PURPOSE OF REVIEW: Cardiovascular disease is a leading cause of death worldwide. Dyslipidemia is a critical modifiable risk factor for the prevention of cardiovascular disease. Dyslipidemia affects a large population of women and is especially pervasive within racial/ethnic minorities. RECENT FINDINGS: Dyslipidemia in pregnancy leads to worse outcomes for patients and creates increased cardiovascular risk for women at an older age. However, women remain underscreened and undertreated compared to men. Females also comprise a small portion of clinical trial participants for lipid lowering agents with increased disease prevalence compared to trial representation. However, recent lipid trials have shown different efficacies of therapies such as ezetimibe, inclisiran, and bempedoic acid with a greater relative benefit for women. SUMMARY: Pathophysiology of dyslipidemia varies between men and women and across a womans lifetime. While increased lipid levels or lipid imbalances are more common in postmenopausal women over age 50, conditions such as PCOS and FH produce higher cardiovascular risk for young women.Best practices for management of women with dyslipidemia include early screening with lifestyle intervention and pharmacotherapy with statin and non-statin agents to achieve guideline directed LDL-C thresholds.

Aim: Statin intolerance and myopathy is a major issue with prolonged use of statins myopathy. Bempedoic acid can be a good alternative for those intolerant to statins. This systematic review aims to observe incidence of major adverse cardiovascular events (MACE) and other adverse events, in high-risk statin intolerant patients receiving bempedoic acid. Methods: Literature search was conducted via Google Scholar, Science Direct and PubMed, after which screening, selection and data extraction of articles was done. Meta-analysis was performed on RevMan 5.4. Subgroup analysis was also conducted and heterogeneity was evaluated. Risk of bias was performed using ROB2 assessment scale. (CRD42024536827). Results: Only six randomized controlled trials were used in final analysis consisting of 17,844 patients. Treatment with bempedoic acid was associated with a reduced risk of MACE compared with placebo (RR 0.86; 95% CI [0.79, 0.94] p = 0.0005), with myocardial infarction significantly reduced. Incidence of adverse effects was increased with bempedoic acid (RR: 1.02; 95% [1.00, 1.03] p = 0.01) but no significant difference was observed. Incidence of myalgia was reduced in bempedoic group as well. Conclusion: Bempedoic acid is a safe and effective alternative to statins in high-risk patients intolerant to statins, decreasing the risk of MACE. Plain Language Summary What is this summary about? Low density lipoprotein (LDL-C) also known as 'bad cholesterol', is the culprit behind many heart diseases. Statins are first-line treatment to reduce LDL-C. Despite being extremely effective, some people are intolerant and experience side effects such as sleep disorders, intestinal diseases and most commonly, effects on muscles ranging from muscle pain to breakdown of muscles leading to kidney damage. Bempedoic acid is a once-a-day medication, increasing LDL-C clearance from blood, reducing the risk of heart attack and diabetes and is effective for patients intolerant to statins. This article provides insights into incidences of major heart-related, and other adverse events in patients receiving bempedoic acid. What were the results? Muscle pain and major heart-related events were reduced (especially heart attack) in patients receiving bempedoic acid as compared with those receiving placebos. Muscle weakness and other adverse events were seen in patients receiving bempedoic acid, but serious adverse events were not significantly different from those receiving placebos. What do the results mean? Bempedoic acid is a safe and effective treatment that can be given to patients who cannot tolerate statins or develop side effects to it, as it reduces the risk of heart-related adverse events. Article highlights Statins are the first-line treatment for atherosclerotic cardiovascular diseases (ASCVD), as they reduce low density lipoprotein cholesterol (LDL-C). However, its considerable side effects such as myalgia and rhabdomyolysis lead to reduced adherence and intolerance. Bempedoic acid, an ATP-citrate lyase inhibitor, is an effective alternative to statins in high-risk patients who are intolerant to statins. Incidence of major adverse cardiovascular events (MACE), mainly myocardial infarction, as well as myalgias are reduced with the use of bempedoic acid. [ABSTRACT FROM AUTHOR]

Introduction: Dyslipidemia plays a crucial role in the development of atherosclerotic cardiovascular diseases. Areas covered: This article explores the emerging therapeutic targets for the treatment of dyslipidemia and provides novel insights into this field. Thus, it aims to contribute to the understanding and advancement of therapeutic options for managing dyslipidemia. Expert opinion: Optimizing the use of available first- and second-line lipid-lowering drugs allows us to adequately control low-density lipoprotein cholesterol (LDL-C) levels, even in statin-intolerant individuals and in patients at high and very high risk of developing cardiovascular diseases who must reach more aggressive LDL-C targets. The drugs under development will further improve our ability to manage the overall lipid-related cardiovascular disease risk and target other dyslipidemia biomarkers. [ABSTRACT FROM AUTHOR]

A simple, accurate and precise method was developed for the simultaneous estimation of the bempedoic acid and ezetimibe in pure and tablet dosage form. The developed method was validated as per International Conference on Harmonization guidelines. The chromatographic separation was achieved isocratically on a Waters‐ C18, 250 × 4.6 mm, 5 μm column. Mobile phase containing K2HPO4–methanol in the ratio 60:40 in buffer at pH 4.3 was pumped through column at a flow rate of 1.0 ml/min. The temperature was maintained at 25°C. The optimized wavelength selected was 242 nm. The separation of bempedoic acid and ezetimibe showed retention times of 3.090 and 4.268 min respectively. The RSD values of the bempedoic acid and ezetimibe were 0.34 and 0.08 respectively. The accuracy of method was determined at three levels (50,100 and 150%). The percentage recovery was obtained as 100.0 and 100.0% for bempedoic acid and ezetimibe, respectively. The limits of determination and quantitation obtained from regression equations of bempedoic acid and ezetimibe were 1.065, 3.550 and 0.203, 0.677, respectively. The regression equation of bempedoic acid is y = 20,795x + 24,168, and it is y = 6,885.7x + 11,000 for ezetimibe. The retention times were decreased and the run time was decreased, so that the method developed is simple and economical that can be adopted for regular quality control tests in industry. [ABSTRACT FROM AUTHOR]

Background: Bempedoic acid, an adenosine triphosphate citrate lyase inhibitor, was introduced to UK practice via a pre-reimbursement access scheme for adults with primary hypercholesterolaemia or mixed dyslipidaemia who are at high risk of cardiovascular disease, in whom statins are either not tolerated or contraindicated, who have not achieved target cholesterol, despite being on ezetimibe therapy, and do not qualify for PCSK9 inhibitor treatment. This retrospective multicentre audit aimed to evaluate the achievement of lipid-lowering targets with bempedoic acid in UK patients based on recommendations in the Joint British Societies (JBS) guidelines for the prevention of cardiovascular disease. Methods: Pseudo-anonymized medical record data for 221 adults treated with bempedoic acid as part of the UK scheme were entered into a bespoke data collection tool at four UK hospitals. Patient demographics, clinical characteristics, treatment pathways and lipid assessment results (against JBS lipid-lowering targets) were collected against pre-specified criteria. Results: Overall, 54% (99/184) of patients achieved the JBS2 audit standard (total cholesterol (TC)

Relevance. The leading position in mortality throughout the world is occupied by cardiovascular diseases, caused be atherosclerosis process. Statins used to be the gold standard of lipid-lowering therapy for a long time due to their high efficacy, optimal tolerance and safety. Nowadays it has been proved that statins reduce low-density lipoprotein levels in high doses by more than 50 %, in medium doses for about 30–49 %. However, often achieving the target level of lipoproteins is not possible due to a variety of reasons, what became a motivation for creating new drugs. The evidence base for the newest lipid-lowering drugs, some of which have already been approved for clinical use according to the publications in the scientific databases Scopus, PubMed, Web of Science for last 10 years. Main results of the most significant clinical trials of drugs’ effectiveness and safety are described including medicines: alirocumab, inclisiran, bococizumab, pelacarsen, mipomersen, bempedoic acid, lomitapide, evinocumab and also methods of therapeutic lipoprotein apheresis. Dyslipidemia pathogenetic points are considered like inhibition of proprotein convertase subtilisin-kexin type 9, suppression of genes synthesizing lipoprotein (a) by antisense oligonucleotides, cholesterol synthesis suppression by inactivation of adenosine triphosphate-citrate lyase enzyme; the action of microsomal inhibitors of triglyceride transfer protein. Conclusion. Searching for new lipid-lowering rational regimens is still ongoing, therefore it is necessary to carefully analyze effectiveness and safety profile for the newest drugs. Some of them like inhibition of proprotein convertase subtilisin-kexin type 9 are actively used in medicine today, while others, the most promising, will be in the future. Ensuring of atherogenic lipoproteins complete control will subsequently make a significant contribution to the primary and secondary cardiovascular diseases prevention, which will save many human lives.

Introduction: The COVID‐19 pandemic disrupted clinical research. CLEAR Outcomes investigated the effect of bempedoic acid (BA) versus placebo in 13 970 patients with statin intolerance and high cardiovascular (CV) risk. BA reduced the risk of the primary endpoint (composite of CV death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization) by 13%. CLEAR Outcomes began before and continued for 2.7 years after the start of the pandemic. Methods: The impact of the COVID‐19 pandemic on patient disposition, adverse events, and major adverse CV events (MACE) in CLEAR Outcomes was assessed. Results: Rates of severe infection, hospitalization, or first MACE associated with a positive COVID‐19 test were low and balanced between treatment groups. Rates of all‐cause death, non‐CV death, and undetermined death increased in the pandemic period compared with the pre‐pandemic period, while rates of CV death with a known etiology remained stable. A sensitivity analysis excluding undetermined deaths occurring after the onset of the pandemic from the CV death designation yielded hazard ratios of 0.84 (95% CI, 0.76–0.93) for the primary endpoint and 0.94 (95% CI, 0.76–1.16) for the secondary endpoint of CV death, compared with 0.87 (95% CI, 0.79–0.96) and 1.04 (95% CI, 0.88–1.24), respectively, in the original analysis. Conclusion: The CLEAR Outcomes trial continued uninterrupted throughout the COVID‐19 pandemic. Certain trial endpoints may have been impacted by the pandemic. Specifically, the classification of undetermined deaths as CV deaths may have attenuated the effect of BA on key efficacy endpoints. [ABSTRACT FROM AUTHOR]

Atherosclerosis is characterised by the accumulation of fatty deposits and plaque as a result of a continuously high level of low-density lipoprotein cholesterol (LDL-C) in the blood. The primary objective of this research is to assess the current status of knowledge, research endeavours and developmental trajectories about proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in correlation with atherosclerosis treatment. Additionally, this study aims to compile bibliometric and scientometric investigations within this domain through rigorous scientometric analysis. Analysing the bibliometric landscape and global research trends associated with PCSK9 inhibitors can contribute valuable insights into comprehending atherosclerosis. This is exemplified by examining publications within the Web of Science Core Collection (WOSCC) database from 2008 to 2022. Citespace was used for frequency, co-occurrence, co-citation, grouping and burst analysis, and Microsoft Excel was used to manage descriptive datasets. Eight hundred eighty-five publications available from WOSCC database between the years 2008 and 2022 were extracted and examined. Over the period, 3,138 collaborating institutions from 87 countries, a staggering 7,750 writers involved and 325 distinct journals published about PCSK9 inhibitors studies. Among authors, Sabatine et al. and the journal The New England Journal of Medicine has had the most significant impact. Lipid-lowering therapy and bempedoic acid are the most prominent topical clusters associated with PCSK9 inhibitors, and the most often used keywords are efficacy, safety and PCSK9 inhibitors. We believe this is the first comprehensive analysis of PCSK9 inhibitors research and publications conducted using Scientometric. These results demonstrate the nascence of PCSK9 inhibitors research. They may encourage a wide range of stakeholders, particularly early career researchers from various disciplines, to work together in the future. [ABSTRACT FROM AUTHOR]

Statin-intolerance (SI) has prevalence between 8.0 % and 10 %, and muscular complaints are the most common reason for discontinuation. Bempedoic acid (BA), an ATP citrate lyase inhibitor, decreases hepatic generation of cholesterol, upregulates low-density lipoprotein (LDL) receptor expression in the liver, and eventually clears circulating LDL-cholesterol from the blood. Multiple randomized clinical trials studying BA demonstrate a reduction in LDL levels by 17–28 % in SI. The CLEAR OUTCOME trial established significant cardiovascular benefits with BA. A dose of 180 mg/day of BA showed promising results. BA alone or in combination with ezetimibe is US Food and Drug Administration-approved for use in adults with heterozygous familial hypercholesterolemia and/or established atherosclerotic cardiovascular disease. BA reduced HbA1c by 0.12 % (p < 0.0001) in patients with diabetes. Adverse events of BA include myalgia (4.7 %), anemia (3.4 %), and increased aminotransferases (0.3 %). BA can cause up to four times higher risk of gout in those with a previous gout diagnosis or high serum uric acid levels. Reports of increased blood urea nitrogen and serum creatinine were noted. Current evidence does not demonstrate a reduction in deaths from cardiovascular causes. More studies that include a diverse population and patients with both high and low LDL levels should be conducted. We recommend that providers consider BA as an adjunct to statin therapy in patients with a maximally tolerated dosage to specifically target LDL levels. [Display omitted] • Bempedoic acid (BA), an ATP citrate lyase inhibitor, decreases circulating LDL-C levels. • Randomized clinical trials showed reduction in LDL levels by 17–28 % in statin-intolerant patients with BA. • BA can be used as an adjunct to statin therapy in patients to target LDL levels. [ABSTRACT FROM AUTHOR]

Atherosclerotic cardiovascular disease poses a significant global health issue, with dyslipidemia standing out as a major risk factor. In recent decades, lipid-lowering therapies have evolved significantly, with statins emerging as the cornerstone treatment. These interventions play a crucial role in both primary and secondary prevention by effectively reducing cardiovascular risk through lipid profile enhancements. Beyond their primary lipid-lowering effects, extensive research indicates that these therapies exhibit pleiotropic actions, offering additional health benefits. These include anti-inflammatory properties, improvements in vascular health and glucose metabolism, and potential implications in cancer management. While statins and ezetimibe have been extensively studied, newer lipid-lowering agents also demonstrate similar pleiotropic effects, even in the absence of direct cardiovascular benefits. This narrative review explores the diverse pleiotropic properties of lipid-modifying therapies, emphasizing their non-lipid effects that contribute to reducing cardiovascular burden and exploring emerging benefits for non-cardiovascular conditions. Mechanistic insights into these actions are discussed alongside their potential therapeutic implications [ABSTRACT FROM AUTHOR]

Novel lipid-lowering therapies are being introduced. Few studies exist of the real-world effectiveness of adenosine-tri-phosphate citrate lyase inhibition with bempedoic acid. This study audited bempedoic acid therapy in 216 consecutive patients from three hospital centres – a university hospital (n = 77) and two district general hospitals (n = 106 and 33). Cardiovascular disease (CVD) risk factors, prescription qualification criteria, efficacy and adverse effects were assessed. The population was aged 65.9 ± 11.0 years, 42% were male, 25% had type 2 diabetes, and 31% had familial hypercholesterolaemia. CVD was present in 19% and multibed vascular disease in 8%. Statin intolerance was reported in 92%. Bempedoic acid reduced total cholesterol by 1.58 ± 1.44 mmol/L (20%), LDL-C by 1.37 ± 1.31 mmol/L (27%), triglycerides by 0.22 mmol/L (2%) with an 0.06 mmol/L (1%) increase in HDL-C after 22 ± 9 months follow-up. An LDL-C <2.5 mmol/L was achieved in 40% and <2 mmol/L in 20%. Efficacy (r2 =.33) was predicted by baseline LDL-C (β =.54; p <.001). No significant changes were seen in transaminases, creatinine, creatine kinase, urate or HbA1c. Treatment was discontinued by 33% of patients and occurred due to myalgia (43%), lack of efficacy (16%) and gastrointestinal adverse effects (15%). No cases of gout were observed. In a logistic regression only the number of previous drug classes not tolerated (β = 1.60; p =.009) was a contributing factor to discontinuation. This audit suggests that bempedoic acid therapy is effective but that adverse effects and discontinuation are common. This suggests nocebo effects might be generalizable to all lipid-lowering drug therapies in susceptible individuals. [ABSTRACT FROM AUTHOR]

Previously published studies have shown that women with type 2 diabetes have a higher risk of atherosclerotic cardiovascular disease than men with type 2 diabetes. The exact reason for this is not yet known. The association between metabolic dysfunction-associated steatotic liver disease and type 2 diabetes appears to be bidirectional, meaning that the onset of one may increase the risk of the onset and progression of the other. Dyslipidemia is common in both diseases. Our aim was therefore to investigate whether there is a sex difference in the pathogenesis and management of dyslipidemia in patients with type 2 diabetes and steatotic liver disease with metabolic dysfunction. While the majority of published studies to date have found no difference between men and women in statin treatment, some studies have shown reduced effectiveness in women compared to men. Statin treatment is under-prescribed for both type 2 diabetics and patients with dysfunction-associated steatotic liver disease. No sex differences were found for ezetimibe treatment. However, to the best of our knowledge, no such study was found for fibrate treatment. Conflicting results on the efficacy of newer cholesterol-lowering PCSK9 inhibitors have been reported in women and men. Results from two real-world studies suggest that up-titration of statin dose improves the efficacy of PCSK9 inhibitors in women. Bempedoic acid treatment has been shown to be effective and safe in patients with type 2 diabetes and more effective in lipid lowering in women compared to men, based on phase 3 results published to date. Further research is needed to clarify whether the sex difference in dyslipidemia management shown in some studies plays a role in the risk of ASCVD in patients with type 2 diabetes and steatotic liver disease with metabolic dysfunction.

Cardiovascular disease remains one of the leading causes of mortality worldwide, with elevated LDL cholesterol being a critical risk factor. Statins have long been the cornerstone of lipid-lowering therapy, but many patients fail to reach target LDL cholesterol levels due to statin intolerance or insufficient response, even when combined with ezetimibe. Recently, the lipid-lowering drug class has been expanded with the introduction of bempedoic acid, a novel agent that inhibits ATP-citrate lyase. Recent studies have demonstrated the efficacy and safety of bempedoic acid in reducing LDL cholesterol levels in patients with hypercholesterolemia, paving the way for its inclusion in clinical guidelines. This article provides a comprehensive overview of the latest evidence regarding bempedoic acid and its emerging role in lipid management. Despite the widespread use of statins, many patients fail to achieve target LDL-C levels due to statin intolerance or insufficient response. This comprehensive review explores the emerging role of bempedoic acid, a novel lipid-lowering agent that inhibits ATP-citrate lyase, in the management of dyslipidemia and cardiovascular risk reduction. Bempedoic acid, approved by the FDA in 2020, offers a unique mechanism of action that complements existing therapies. As a prodrug activated specifically in the liver, it avoids muscle-related side effects commonly associated with statins. Clinical trials have demonstrated its efficacy in reducing LDL-C levels, particularly in patients with statin intolerance or those requiring additional LDL-C lowering beyond maximally tolerated statin therapy. The review synthesizes data from multiple phase 3 clinical trials, including CLEAR Wisdom and CLEAR Outcomes, which have shown significant LDL-C reductions with bempedoic acid monotherapy and in combination with other lipid-lowering agents. Notably, bempedoic acid not only lowers LDL-C but also reduces high-sensitivity C-reactive protein (hs-CRP) levels, suggesting potential anti-inflammatory effects. Safety profiles from these trials indicate that bempedoic acid is generally well-tolerated, with minimal muscle-related adverse events. However, slight increases in serum creatinine and uric acid levels have been observed, warranting monitoring in certain patient populations. Recent updates to clinical guidelines, including the 2024 European Society of Cardiology guidelines on coronary heart disease, now recommend bempedoic acid for specific patient groups. These include statin-intolerant patients not achieving LDL-C goals on ezetimibe alone, and those not reaching targets on maximum tolerated statin doses combined with ezetimibe. This review concludes that bempedoic acid represents a significant advancement in lipid-lowering therapy, offering a valuable option for patients with hypercholesterolemia, particularly those with statin intolerance or requiring additional LDL-C reduction. As research continues, bempedoic acid's role in reducing cardiovascular events and its long-term safety profile will be further elucidated, potentially reshaping the landscape of dyslipidemia management and cardiovascular risk reduction.

Atherosclerotic cardiovascular disease (ASCVD) remains the main cause of death worldwide, and thus its prevention, early diagnosis and treatment is of paramount importance. Dyslipidemia represents a major ASCVD risk factor that should be adequately managed at different clinical settings. 2023 guidelines of the Hellenic Atherosclerosis Society focus on the assessment of ASCVD risk, laboratory evaluation of dyslipidemias, new and emerging lipid-lowering drugs, as well as diagnosis and treatment of lipid disorders in women, the elderly and in patients with familial hypercholesterolemia, acute coronary syndromes, heart failure, stroke, chronic kidney disease, diabetes, autoimmune diseases, and non-alcoholic fatty liver disease. Statin intolerance is also discussed.

Achieving guideline-recommended low-density lipoprotein cholesterol (LDL-C) targets remains a significant challenge in clinical practice. This review assesses the barriers to reaching LDL-C goals and explores the potential solutions to these issues. When aiming for the recommended LDL-C goal, strategies like "lower is better" and "strike early and strong" should be used. The evidence supports the safety and efficacy of intensive lipid-lowering therapy post-acute coronary syndrome (ACS), leading to improved long-term cardiovascular health and atherosclerotic plaque stabilization. Despite the availability of effective lipid-lowering therapies, such as high-intensity statins, ezetimibe, the combination of both, bempedoic acid, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, a substantial proportion of patients do not meet their LDL-C targets. Contributing factors include systemic healthcare barriers, healthcare provider inertia, patient non-adherence, and statin intolerance. Statin intolerance, often rather statin reluctance, is a notable obstacle due to perceived or expected side effects, which can lead to discontinuation of therapy. In conclusion, while there are obstacles to achieving optimal LDL-C levels post-ACS, these can be overcome with a combination of patient-centric approaches, clinical vigilance, and the judicious use of available therapies. The safety and necessity of reaching lower LDL-C goals to improve outcomes in patients post-ACS are well-supported by current evidence. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases (CVDs) are a leading global cause of mortality and are primarily driven by atherosclerotic coronary artery disease. Their pathogenesis involves multi-factorial mechanisms, among which low-density lipoprotein (LDL) plays a causative role. Recent ESC/EAS guidelines advocate for a shift toward new risk estimation algorithms that better emphasize non-fatal cardiovascular events, lifetime risk prediction, and tailored pharmacological approaches, including statin + ezetimibe and triple therapy, in specific cases. Intensive lipid-lowering therapy has been shown to be pivotal, especially in post-acute coronary events. Intracoronary imaging has revealed insights into the composition of plaque and demonstrated the significant regression that can be achieved through the use of statins such as rosuvastatin and atorvastatin. The positive effects of Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) inhibitors, particularly alirocumab and evolocumab, on plaque regression, have been demonstrated. Inclisiran, which targets PCSK9 gene expression, significantly reduces LDL cholesterol. The associated challenges include hesitancy to prescribe intensive regimens and limited treatment adherence, highlighting the need for pharmacological combinations to improve therapeutic outcomes. [ABSTRACT FROM AUTHOR]

Hyperlipidemia, characterized by elevated blood lipid levels, significantly contributes to cardiovascular diseases (CVDs), the leading cause of global mortality per the World Health Organization (WHO). Studies reveal a 20-30% increase in coronary heart disease risk for every 1 mmol/L rise in LDL-C levels. While statins are widely used, novel pharmacotherapeutic approaches are necessary for effective hyperlipidemia management and CVD risk reduction. Recent clinical trials demonstrate the efficacy of innovative drugs like proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in lowering LDL-C levels and reducing adverse cardiovascular events. These findings highlight the potential of new therapies to enhance existing treatments for hyperlipidemia. Additionally, safety evaluations of emerging lipid-lowering agents address concerns about adverse effects and long-term risks. Despite progress, challenges persist in refining treatment strategies and ensuring equitable access to advanced therapies, especially for marginalized populations. Incorporating innovative pharmacotherapies into current approaches offers personalized and efficient hyperlipidemia management. Continued research and interdisciplinary collaborations are vital for advancing our understanding of lipid metabolism and translating scientific discoveries into improved patient outcomes and cardiovascular health. Ongoing innovation and investment in tailored hyperlipidemia therapies are crucial for better outcomes in individuals at risk of CVDs. [ABSTRACT FROM AUTHOR]

Purpose of Review: There is ample evidence of the benefits and safety of low-density lipoprotein (LDL)-lowering therapies in the prevention of atherosclerotic cardiovascular disease. While statins remain the first-line agent for LDL reduction, several new therapies are now available. This narrative review provides an overview of currently available non-statin LDL-lowering agents, specifically mechanisms of action and data on efficacy and safety. It also discusses recommendations on their use in clinical practice. Recent Findings: Ezetimibe, PCSK9 inhibitors, and bempedoic acid have proven safe and efficacious in reducing cardiovascular events in large randomized controlled trials. Inclisiran is a promising agent that suppresses PCSK9 mRNA translation and is currently under investigation in a large clinical outcomes randomized controlled trial assessing its effect on clinical outcomes. Summary: Expert consensus advocates for lower LDL targets in higher risk patients and escalation to or a combination of non-statin therapies as needed to achieve these goals. [ABSTRACT FROM AUTHOR]

Atherosclerotic cardiovascular disease (ASCVD) represents a major global health challenge, significantly contributing to mortality rates. This chronic inflammatory condition affecting blood vessels is intricately linked to hypercholesterolemia, with elevated levels of low-density lipoprotein cholesterol (LDL-C) recognized as a central and modifiable risk factor. The effectiveness of lipid-lowering therapy (LLT) in mitigating ASCVD risk is well established, with studies revealing a substantial reduction in major ischemic events correlating with LDL-C reduction. While statins, often combined with ezetimibe, remain fundamental in dyslipidemia management, a significant proportion of patients on statin therapy continue to experience cardiovascular events. Recent pharmacological advancements, driven by a deeper understanding of atherogenesis, have unveiled novel therapeutic targets and potent drugs. Notably, agents like bempedoic acid and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (evolocumab, alirocumab, inclisiran) have emerged as effective options to intensify LLT and achieve LDL-C goals, addressing limitations associated with statins, such as myopathy. Molecular insights into alternative pathways have spurred the investigation of emerging agents, offering promising perspectives for novel medications with efficacy comparable to established treatments, associated with advantages in cost and administration. This review provides a comprehensive overview of the evolving landscape of lipid-lowering strategies, highlighting the progress made in addressing ASCVD risk and the potential of upcoming therapies to further optimize cardiovascular prevention. [ABSTRACT FROM AUTHOR]

• Post hoc study using pooled data from two phase 3 bempedoic acid clinical trials. • Patients with and without heterozygous familial hypercholesterolemia were included. • In both groups, bempedoic acid lowered LDL-C and other lipid parameters vs. placebo. • Bempedoic acid was generally well tolerated in both patient groups. • No new safety findings in patients with heterozygous familial hypercholesterolemia. Patients with heterozygous familial hypercholesterolemia (HeFH) often cannot reach guideline-recommended low-density lipoprotein cholesterol (LDL-C) goals despite multidrug therapy. To evaluate the efficacy and safety of bempedoic acid as an add-on therapy for lowering LDL-C in patients with HeFH. Pooled data from two 52-week phase 3 clinical trials of patients with atherosclerotic cardiovascular disease and/or HeFH receiving maximally tolerated statin therapy (randomized 2:1 to bempedoic acid or placebo) were analyzed by HeFH status. Endpoints included changes from baseline to week 12 (and up to week 52) in LDL-C and other lipid parameters, achievement of LDL-C goals, and safety. A total of 217 (bempedoic acid, 146; placebo, 71) patients with HeFH and 2,792 (bempedoic acid, 1,864; placebo, 928) without HeFH were included (mean baseline LDL-C, 172.8 mg/dL and 102.6 mg/dL, respectively). Bempedoic acid significantly lowered LDL-C at week 12 vs. placebo regardless of HeFH status (with HeFH, −21.2%; without HeFH, −18.2% [both P <0.0001]). Bempedoic acid significantly reduced other lipid parameters and high-sensitivity C-reactive protein vs. placebo regardless of HeFH status (all P ≤0.01). Among patients with HeFH treated with bempedoic acid, 32% and 27% achieved LDL-C <100 mg/dL at weeks 12 and 52, respectively. Overall treatment-emergent adverse event incidence was comparable across all four groups (74.7–77.5%). Bempedoic acid significantly lowered LDL-C levels vs. placebo and was generally well tolerated in all patients, with no new safety findings in patients with HeFH, despite more intensive lipid-lowering therapy in patients with vs. without HeFH. [Display omitted] [ABSTRACT FROM AUTHOR]

Purpose of Review: Bempedoic acid is a novel therapeutic agent that is designed to reduce levels of low-density lipoprotein cholesterol (LDL-C). The purpose of this review is to provide the background for development of bempedoic acid, findings from clinical trials and to discuss clinical implications. Recent Findings: Bempedoic acid inhibits ATP citrate lyase within the liver and reduces cholesterol synthesis, with the potential to avoid muscle symptoms experienced by patients treated with statins. Early clinical studies demonstrated that administration of bempedoic acid resulted in lowering of LDL-C by 20–30% as monotherapy and by 40–50% when combined with ezetimibe, in addition to lowering of high sensitivity C-reactive protein by 20–30%. The CLEAR Outcomes trial of high cardiovascular risk patients, with elevated LDL-C levels and either unable or unwilling to take statins demonstrated that bempedoic acid reduced the rate of major adverse cardiovascular events. A greater incidence of elevation of hepatic transaminase and creatinine, gout, and cholelithiasis were consistently observed in bempedoic acid–treated patients. Summary: Bempedoic acid presents an additional therapeutic option to achieve more effective lowering of LDL-C levels and reduction in cardiovascular risk. [ABSTRACT FROM AUTHOR]

Hyperlipidemia is becoming more and more severe condition among modern society. High-fat diet, sedentary lifestyle, lack of physical activity are the common factors leading to overweight, obesity and problems with serum lipid control. Dyslipidemia is one of the most important agents contributing to cardiovascular diseases snd therefore lower quality of life, disability and preamature death. This forces to constatnt searching for lipid-lowering drugs, that can be successfully use in the patients suffering from poor lipid control. Bempedoic acid (ETC-1020) is one of the newest, first in the class medicine, firstly approved to use in the USA on 21st February 2020 in monotheraphy, and then on 26th February in combination with ezetimibe. It is a small synthetic prodrug molecule that is activated by acyl-CoA synthetase in the liver. Bempedoic acid inhibits competitively adenosine triphosphate citrate lyase (ACL) and as a result it stops the further production of cholesterol and fatty acids. Research shows the ability of ETC-1020 to decline of LDL-C cholesterol up to 24%. It is also responsible for total cholesterol, non-HDL-C, ApoB and hs-CRP reduction. Bempedoic acid is characterized by good pharmacokinetics and pharmacodynamics. ECT-1020 has also a good drug-to-drug interaction profile. Many clinical trials have reported efficacy and safety of use with minimal side effects. Because of its target point is located in the liver and kidney, it can be successfully use in patients with statin intolerance due to bypassing decline of muscle cholesterol biosyntheisis, that is the main cause of musculosketelar adverse effects.

Reducing levels of low-density lipoprotein cholesterol (LDL-C) below recommended thresholds is a core component of cardiovascular prevention strategies. We hypothesized that the addition of bempedoic acid to patients already on statin–ezetimibe therapy was more effective than titrating the statin dose in reducing LDL-C. The study enrolled 120 patients at high cardiovascular risk and with LDL-C above 70 mg/dL. They were randomly divided into two groups: the bempedoic acid (BA) group, taking bempedoic acid in addition to statin plus ezitimibe, and the statin titration (ST) group, including patients who doubled the dose of statin. At 12 weeks, the BA group presented a more significant decrease in LDL-C compared to the ST group (−22.9% vs. 7.5% p 0.002). The total cholesterol decreased significantly in the BA group compared to ST (−14.8% vs.−4.7%; p 0.013) No significant between-group changes in HDL and triglycerides occurred. At 12 weeks, the number of patients who reached LDL-C lower than 70 mg/dL was 38 (63%) in the BA group versus 22 (37%) in the ST group (between groups, p 0.034). In the BA group, the LDL-lowering effect of bempedoic acid was similar between patients taking atorvastatin and rosuvastatin. No side effects occurred during the follow up period. In conclusion, the addition of bempedoic acid to statin–ezetimibe combined treatment was more effective than doubling the dose of statin in reducing LDL-C levels and increased the number of patients reaching the LDL-C goal.

The modern history of cholesterol-lowering drugs started in 1972 when Dr. Akira Endo identified an active compound (compactin) that inhibited cholesterol biosynthesis from the culture broth of blue–green mold (Penicillium citrinum Pen-51). Since 1987, statins have represented the milestone for the treatment of atherosclerotic cardiovascular disease. A new therapy for the treatment of hypercholesterolemia since the discovery of statins is ezetimibe, the first and only agent inhibiting intestinal cholesterol absorption. Ezetimibe was approved by the FDA in October 2002. A year later, the association between gain-of-function PCSK9 genetic mutations and hypercholesterolemia was reported, and this discovery opened a new era in lipid-lowering therapies. Monoclonal antibodies and small-interfering RNA approaches to reduce PCSK9 were developed and approved for clinical use in 2015 and 2022, respectively. Finally, the newly approved bempedoic acid, an oral adenosine triphosphate citrate lyase inhibitor that lowers LDL-C, is able to reduce major adverse cardiovascular events in both primary and secondary prevention. In the present narrative review, we summarize the pharmacological properties and the clinical efficacy of all these agents currently used for a tailored therapy of hypercholesterolemia in patients with atherosclerotic cardiovascular disease. [ABSTRACT FROM AUTHOR]

Despite the proven effects of statins in preventing cardiovascular disease, their diabetogenic effect has caused concern. The mechanism of this diabetogenic effect is unknown. We suggest a novel mechanism that may contribute to the diabetogenic effect of statins, through an effect of statins that has apparently escaped previous consideration. Briefly, by inhibiting HMG-CoA reductase, statins may cause accumulation of acetate, which through FFA2 and FFA3 stimulation may inhibit insulin secretion. [ABSTRACT FROM AUTHOR]

Background: Low-density lipoproteins are now proven to be causal for atherosclerosis. Pharmacological treatment focuses on an increase of low-density lipoprotein (LDL) receptors, particularly in the hepatocyte, which leads to uptake of LDL from blood, thereby reducing the burden to the arterial wall. This mechanism has first been proven by statins to be effective to reduce cardiovascular morbidity and mortality. The concept of "the lower, the better" was shown by high-intensity statins and new compounds like ezetimibe, PCSK9 antibodies, inclisiran, and ultimately bempedoic acid. Summary: Although first considered only a relatively weak LDL-C lowering drug, bempedoic acid proved to be very effective, for example, in statin-intolerant patients to reduce cardiovascular events in the CLEAR-Outcomes study. In the era of personalized medicine, it should not be forgotten that the individual response to a LDL-C lowering drug can vary considerably. Bempedoic acid has a favorable safety profile, particularly it does not induce muscle problems because its precursor is not metabolized to the active drug in the muscle, and it does not induce hyperglycemia. Bempedoic acid probably is best used in combination with ezetimibe, which leads to LDL-C reductions in the range of moderately intensive statins; in an oral triple combination with a high-intensity statin, LDL-C reductions in the range of two-thirds can be achieved. Key Messages: Bempedoic acid is a further weapon against the atherogenic effect of LDL cholesterol – in both primary and secondary prevention. [ABSTRACT FROM AUTHOR]

• Long term use of bempedoic acid is well tolerated. • Exposure adjusted cholelithiasis rate with bempedoic acid is 0.6/100 patient years. • Patients with gout at baseline reported similar rates of gout. • Reports of tendinopathies were comparable between groups. Bempedoic acid is an oral adenosine triphosphate citrate lyase (ACL) inhibitor that lowers low-density lipoprotein cholesterol (LDL-C) blood levels. The Cholesterol Lowering via Bempedoic acid, an ACL-Inhibiting Regimen (CLEAR) Outcomes study demonstrated that bempedoic acid reduced cardiovascular (CV) risk in patients at high risk for CV events who were unwilling or unable to take guideline-recommended doses of statins. To describe detailed safety information from CLEAR Outcomes, including events in the United States (US) prescribing information based on previous phase 3 hyperlipidemia studies. CLEAR Outcomes was a double-blind trial conducted in 13,970 patients randomized to oral bempedoic acid 180 mg daily or placebo and followed for a median of 3.4 years. In patients who received at least one dose (7,001 bempedoic acid, 6,964 placebo), treatment emergent adverse events (AE) occurred in 86.3 % and 85 % of patients, respectively. COVID-19 was the most frequently reported AE in both groups. Changes in serum creatinine, blood urea nitrogen, hemoglobin, aminotransaminases, and uric acid were consistent with the known safety profile of bempedoic acid. Gout or gouty arthritis occurred in 3.2 % of bempedoic acid and 2.2 % of placebo patients. AE associated with tendinopathies, including tendon rupture, occurred in 2 % of patients in both treatment groups. Cholelithiasis occurred in 2.2 % of bempedoic acid and 1.2 % of placebo patients; AE related to gallbladder disease were similar between treatment groups. Bempedoic acid was well-tolerated compared with placebo. Safety data from the long-term CLEAR Outcomes study reinforce the positive benefit-risk profile of bempedoic acid. [Display omitted] [ABSTRACT FROM AUTHOR]

The aim of the project is to develop a fast, simple, precise, and cost-efficient RP-HPLC method for measuring the amounts of Bempedoic Acid and Ezetimibe simultaneously in both pharmaceutical products and bulk samples. This technique has effectively achieved the separation of Bempedoic Acid and Ezetimibe in large quantities. The separation was performed using a Kromosil C18 150 x 4.6 mm, 5m analytical column at a wavelength of 280 nm. The mobile phase consisted of a mixture of Potassium dihydrogen orthophosphate, acetonitrile, and water in a ratio of 25:60:15. The pH of the buffer was adjusted to 6.0. The separation was carried out in isocratic elution mode with a flow rate of 1.2 ml/min. Bempedoic Acid had a retention time of 2.252 minutes, whereas Ezetimibe showed a retention duration of 2.987 minutes. Quantitative analysis of Bempedoic Acid and Ezetimibe was achieved using PDA detection at 280 nm using a linear calibration curve. The concentration ranges of 5-25 μg/ml (with a correlation coefficient of 0.9998) and 10-50 μg/ml (with a correlation coefficient of 0.9996) were used for reliable quantification. The limit of detection (LOD) for Bempedoic Acid was 0.1345 μg/ml, whereas the LOD for Ezetimibe was 0.2456 μg/ml. The proposed method is highly suitable for use in qualitycontrol laboratories for the bulk and pharmaceutical quantitative analysis of pharmaceuticals, whether used individually or in combination. This technique is characterised by its simplicity and efficiency, while yet ensuring a high level of accuracy and precision. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases (CVDs) which consist of ischemic heart disease, stroke, heart failure, peripheral arterial disease, and several other cardiac and vascular conditions are one of the most common causes of death worldwide and often co-occur with diabetes mellitus and lipid disorders which worsens the prognosis and becomes a therapeutic challenge. Due to the increasing number of patients with CVDs, we need to search for new risk factors and pathophysiological changes to create new strategies for preventing, diagnosing, and treating not only CVDs but also comorbidities like diabetes mellitus and lipid disorders. As increasing amount of patients suffering from CVDs, there are many therapies which focus on new molecular targets like proprotein convertase subtilisin/kexin type 9 (PCSK9), angiopoietin-like protein 3, ATP-citrate lyase, or new technologies such as siRNA in treatment of dyslipidemia or sodium-glucose co-transporter-2 and glucagon-like peptide-1 in treatment of diabetes mellitus. Both SGLT-2 inhibitors and GLP-1 receptor agonists are used in the treatment of diabetes, however, they proved to have a beneficial effect in CVDs as well. Moreover, a significant amount of evidence has shown that exosomes seem to be associated with myocardial ischaemia and that exosome levels correlate with the severity of myocardial injury. In our work, we would like to focus on the above mechanisms. The knowledge of them allows for the appearance of new strategies of treatment among patients with CVDs. [ABSTRACT FROM AUTHOR]

Introduction Cardiovascular diseases are the most numerous group of diseases prevalent in the world. They are a challenge for many health systems, in terms of keeping life comfortable and also economics. The cause of selected disease entities is too much cholesterol in the blood. The most popular treatment for hypercholesterolemia is based on statins. Many patients are affected by intolerance to these drugs, so an important issue is the discovery and improvement of alternatives to statins. Purpose of work The purpose of this review is to collect literature data on the latest treatments for hypercholesterolemia with drugs other than statins and ezetimibe. Materials and methods Materials are from a review of recent literature available in PubMed. To search for articles, we used keywords such as: bempedoic acid, non-statin therapy, cardiovascular risk, inclisiran, alirocumab, cardiovascular disease, dyslipidemia, evolocumab. Summary Treatment of hypercholesterolemia with statins remains the most popular management strategy. Intolerance to treatment with these drugs creates serious clinical problems for patients. Recently, we could see the emergence of new drugs as alternatives to statins. As the results show, the new drugs can effectively replace statins in the hypolipemic treatment especially of patients who cannot be treated with them.

Non-statin drugs find utility in the management of dyslipidaemia in mixed dyslipidaemia, patients with statin intolerance, and when guidelines directed low-density lipoprotein cholesterol (LDL-C) target cannot be achieved despite maximally tolerated statin. The most definite indication of fenofibrate monotherapy is fasting serum triglyceride >500 mg/dl to reduce the risk of acute pancreatitis It offers a modest reduction in cardiovascular events. The statin-ezetimibe combination is commonly used for lipid lowering particularly after ACS. Fish oils reduce serum triglycerides by about 25 %. EPA (and not DHA) seems to have cardioprotective effects. Despite cardiovascular outcome benefits, bile-exchange resins have limited use due to poor tolerance. Bempedoic acid added to maximally tolerated statin therapy is approved to lower LDL-C in adults with primary hypercholesterolemia or mixed dyslipidaemias, HeFH, in patients with ASCVD who require additional lowering of LDL-C, and in patients who are statin-intolerant. Inclisiran is a long-acting double-stranded small interfering RNA (siRNA) that inhibits the transcription of PCSK-9 leading to a decrease in PCSK9 generation in hepatocytes and an increase in LDL receptor expression in the liver cell membrane leading to about 50 % reduction in serum LDL-C levels. Lomitapide lowers plasma levels of all ApoB-containing lipoproteins, including VLDL, LDL, and chylomicrons by inhibiting the enzyme microsomal triglyceride transfer protein (MTP) and approved for the treatment of adult patients with homozygous familial hypercholesterolemia (HoFH). Close monitoring for hepatotoxicity is required. Mipomersen is a single-stranded synthetic antisense oligonucleotide (ASO) that affects the production and secretion of apoB-containing lipoproteins with demonstrated efficacy in both homozygous and heterozygous FH patients. It is approved for restricted use due to risk of hepatotoxicity. Pelacarsen is an antisense oligonucleotide that reduces the production of apo(a) in the liver.

IntroductionCardiovascular (CV) disease remains a leading cause of mortality despite statin therapy. Statin add-on lipid-lowering therapies have been investigated for CV risk reduction, but their effect on CV mortality has not been reviewed.MethodsThis review describes CV outcomes trials of add-on therapies to statins, highlighting findings related to the primary composite CV endpoints and the more patient-centric endpoint of CV-related mortality.ResultsAdd-on ezetimibe met its primary composite CV endpoint vs. statin alone (P = 0.016); however, the individual endpoint of death from CV causes did not differ between groups. Add-on therapy with proprotein convertase subtilisin/kexin type 9 inhibitors achieved the primary composite CV endpoints in the respective CV outcomes trials for alirocumab (P

Abstract Background and aims Bempedoic Acid (BA) is a novel Lipid-Lowering Therapy (LLT). We performed a systematic review and meta-analysis to assess the efficacy and safety of BA in patients with hypercholesterolemia. Methods PubMed, Scopus, and Cochrane library databases were searched for randomised controlled trials evaluating the efficacy and/or safety of BA compared with placebo. Trials investigating dosages other than 180 mg/die were excluded. Major adverse cardiovascular events (MACE) were the primary efficacy endpoint. LDL-cholesterol reduction was the primary laboratory endpoint. Pre-specified safety endpoints included muscle-related adverse events, new-onset diabetes, and gout. The protocol was registered on PROSPERO (temporary ID:399,867). Results Study search identified 275 deduplicated results. 11 studies, encompassing 18,315 patients (9854 on BA vs 8461 on placebo/no treatment) were included. BA was associated with a reduced risk of MACE (OR 0.86, 95% CI 0.79–0.95), myocardial infarction (OR 0.76, 95% CI 0.64–0.88) and unstable angina (OR 0.69, 95% CI 0.54–0.88) compared to control, over a median follow up of 87 (15–162) weeks. BA was associated with a reduction of LDL-Cholesterol (mean difference [MD]–22.42,95% CI − 24.02% to − 20.82%), total cholesterol (− 16.50%,95% − 19.21% to − 13.79%), Apo-B lipoprotein (− 19.55%, − 22.68% to − 16.42%) and high-sensitivity CRP (− 27.83%, − 31.71% to − 23.96%) at 12 weeks. BA was associated with a higher risk of gout (OR 1.55, 95% CI 1.27–1.90) as compared with placebo. Efficacy on laboratory endpoints was confirmed, with a variable extent, across patients on statin or ezetimibe background therapy. Conclusions The improved cholesterol control achieved with BA translates into a reduced risk of MACE, including myocardial infarction and coronary revascularisation. The drug has a satisfactory safety profile except for an increased risk of gout.

Scientific relevance. Lowering low-density lipoprotein cholesterol (LDL-C) levels with statins is a generally accepted standard treatment for dyslipidaemia. However, adverse reactions and intolerance to statins have motivated the search for lipid-modifying agents with alternative mechanisms of action. Bempedoic acid is one of these alternative agents.Aim. The study aimed to review published data on the mechanism of action, pharmacokinetics, pharmacodynamics, safety and efficacy of bempedoic acid used as a lipid-lowering agent.Discussion. Similar to statins, bempedoic acid inhibits cholesterol synthesis from acetyl-CoA. Statins and bempedoic acid differ in their mechanisms of action mainly because the conversion of bempedoic acid into its active metabolite takes place only in the liver. As a result, bempedoic acid does not cause adverse drug reactions in muscles. The main safety and efficacy data on bempedoic acid were obtained in phase III CLEAR trials. Compared to placebo, bempedoic acid reduced LDL-C levels by an additional 18% in combination with maximum tolerated doses of statins and by 25% in monotherapy in patients with statin intolerance. In the CLEAR Outcomes trial, long-term treatment with bempedoic acid reduced the risk of major adverse cardiovascular events in patients with statin intolerance (n=13970) by 13%. A slight increase in gout attack frequency was observed, primarily in patients with pre-existing hyperuricaemia.Conclusions. Therefore, bempedoic acid is a safe and effective treatment option for patients with dyslipidaemia at high risk of atherosclerotic cardiovascular disease. It can be used either in combination with statins or, in the case of statin intolerance, as monotherapy and with ezetimibe.

The article titled "Impact of Bempedoic Acid on Cardiovascular Outcomes by Sex" discusses the results of the CLEAR Outcomes trial, which examined the effects of bempedoic acid on cardiovascular risk in patients who are unable or unwilling to take statins. The study found that bempedoic acid reduced cardiovascular risk and LDL cholesterol levels similarly in both females and males. The incidence of adverse events did not differ significantly between the two sexes. These findings suggest that bempedoic acid may be an important option for reducing cardiovascular risk in both men and women. [Extracted from the article]

Atherosclerotic cardiovascular disease poses a significant global health issue, with dyslipidemia standing out as a major risk factor. In recent decades, lipid-lowering therapies have evolved significantly, with statins emerging as the cornerstone treatment. These interventions play a crucial role in both primary and secondary prevention by effectively reducing cardiovascular risk through lipid profile enhancements. Beyond their primary lipid-lowering effects, extensive research indicates that these therapies exhibit pleiotropic actions, offering additional health benefits. These include anti-inflammatory properties, improvements in vascular health and glucose metabolism, and potential implications in cancer management. While statins and ezetimibe have been extensively studied, newer lipid-lowering agents also demonstrate similar pleiotropic effects, even in the absence of direct cardiovascular benefits. This narrative review explores the diverse pleiotropic properties of lipid-modifying therapies, emphasizing their non-lipid effects that contribute to reducing cardiovascular burden and exploring emerging benefits for non-cardiovascular conditions. Mechanistic insights into these actions are discussed alongside their potential therapeutic implications

Metabolic dysfunction-associated steatotic liver disease (MASLD) involves excessive lipid accumulation in hepatocytes, impacting global healthcare due to its high prevalence and risk of progression to severe liver conditions. Its pathogenesis involves genetic, metabolic, and inflammatory factors, with cardiovascular events as the leading cause of mortality. This review examines the role of lipid-lowering therapies in MASLD, with a particular focus on bempedoic acid, a recently approved cholesterol-lowering agent for hypercholesterolemia and high cardiovascular-risk patients. It explores its potential in liver disease by modulating lipid metabolism and inflammatory pathways based on the most recent studies available. Bempedoic acid inhibits ATP-citrate lyase, reducing cholesterol and fatty acid synthesis while activating AMP-activated protein kinase to suppress gluconeogenesis and lipogenesis. Animal studies indicate its efficacy in reducing hepatic steatosis, inflammation, and fibrosis. Bempedoic acid holds promise as a therapeutic for MASLD, offering dual benefits in lipid metabolism and inflammation. Further clinical trials are required to confirm its efficacy and safety in MASLD patients, potentially addressing the multifaceted nature of this disease.

Purpose: Statins are the cornerstone therapy for primary or secondary prevention of atherosclerotic cardiovascular disease (ASCVD). However, a significant portion of patients are intolerant to statin or show inadequate lipid-lowering. Bempedoic acid (BA) has been shown to decrease low-density lipoprotein cholesterol (LDL-C) in clinical trials. However, the evidence on the effect of BA on clinical cardiovascular outcomes was limited until the CLEAR Outcomes trial. Thus, to fully appraise the available data, we performed this meta-analysis. Methods: PubMed, Pubmed Central, Embase, and Scopus databases were searched for relevant articles published before May 1, 2023. Pertinent data from the included studies were extracted and analyzed using RevMan v5.4. Results: Out of 2209 studies evaluated, five randomized control trials with 17,384 patients with established ASCVD or at high risk of ASCVD were included for analysis. The BA therapy reduced major adverse cardiovascular events (OR 0.85, CI 0.77-0.93;

Background and aims: Bempedoic Acid (BA) is a novel Lipid-Lowering Therapy (LLT). We performed a systematic review and meta-analysis to assess the efficacy and safety of BA in patients with hypercholesterolemia. Methods: PubMed, Scopus, and Cochrane library databases were searched for randomised controlled trials evaluating the efficacy and/or safety of BA compared with placebo. Trials investigating dosages other than 180 mg/die were excluded. Major adverse cardiovascular events (MACE) were the primary efficacy endpoint. LDL-cholesterol reduction was the primary laboratory endpoint. Pre-specified safety endpoints included muscle-related adverse events, new-onset diabetes, and gout. The protocol was registered on PROSPERO (temporary ID:399,867). Results: Study search identified 275 deduplicated results. 11 studies, encompassing 18,315 patients (9854 on BA vs 8461 on placebo/no treatment) were included. BA was associated with a reduced risk of MACE (OR 0.86, 95% CI 0.79–0.95), myocardial infarction (OR 0.76, 95% CI 0.64–0.88) and unstable angina (OR 0.69, 95% CI 0.54–0.88) compared to control, over a median follow up of 87 (15–162) weeks. BA was associated with a reduction of LDL-Cholesterol (mean difference [MD]–22.42,95% CI − 24.02% to − 20.82%), total cholesterol (− 16.50%,95% − 19.21% to − 13.79%), Apo-B lipoprotein (− 19.55%, − 22.68% to − 16.42%) and high-sensitivity CRP (− 27.83%, − 31.71% to − 23.96%) at 12 weeks. BA was associated with a higher risk of gout (OR 1.55, 95% CI 1.27–1.90) as compared with placebo. Efficacy on laboratory endpoints was confirmed, with a variable extent, across patients on statin or ezetimibe background therapy. Conclusions: The improved cholesterol control achieved with BA translates into a reduced risk of MACE, including myocardial infarction and coronary revascularisation. The drug has a satisfactory safety profile except for an increased risk of gout. [ABSTRACT FROM AUTHOR]

Aim: This systematic review and meta-analysis was conducted to synthesize the efficacy and safety of bempedoic acid in patients requiring lipid-lowering therapy. Methods: PubMed, Embase, and Scopus databases were searched for randomized controlled trials from inception till June 2023. The primary outcome was major adverse cardiovascular events (MACE), and secondary outcomes were all-cause mortality, serum lipid profile, and adverse events between bempedoic acid and comparators. ROB2 was used for risk of bias assessment. We pooled mean differences or relative risks (RR) along with 95% confidence intervals (random-effects model). Results: Five-hundred and thirty-one studies were screened and 17 (n = 21,131) were included for review. There was a significant reduction in the risk of MACE [RR, 0.88 (95% CI: 0.77 to 0.99), p = 0.03)] and all-cause mortality [RR, 0.90 (95% CI: 0.82 to 0.98), p = 0.02] following bempedoic acid treatment. Treatment with bempedoic acid led to a significant reduction in the mean serum total cholesterol [− 34.41 mg/dl (95% CI: − 42.43 to − 26.39), p < 0.001], low-density lipoprotein cholesterol (LDL-C) [− 33.91 mg/dl (95% CI: − 39.66 to − 28.17), p < 0.001], as well as high-density lipoprotein cholesterol (HDL-C) [− 2.40 mg/dl (95% CI: − 3.09 to − 1.71), p < 0.001] levels. However, there was a significant increase in the risk of hyperuricemia [RR, 2.05 (95% CI: 1.81 to 2.33), p < 0.001] following bempedoic acid treatment. The number needed to harm was large for all safety outcomes. The GRADE of evidence was moderate for all outcomes. Conclusion: Bempedoic acid reduces the risk of MACE and all-cause mortality, lowers serum total cholesterol and LDL-C levels, and has a favorable safety profile. Trial registration ClinicalTrial.gov Identifier: CRD42023412837. [ABSTRACT FROM AUTHOR]

Bempedoic acid is an adenosine triphosphate citrate lyase inhibitor that lowers low‐density lipoprotein cholesterol by inhibiting cholesterol synthesis and upregulating hepatic low‐density lipoprotein receptor expression. After oral dosing, bempedoic acid was readily absorbed, attaining maximum concentrations with a median time of 3.5 hours, and may be taken without regard to food. Steady‐state oral pharmacokinetics in healthy adults receiving bempedoic acid at the approved 180 mg/day dose were characterized by mean maximum concentration of 20.6 µg/mL, area under the concentration–time curve over 24 hours of 289 µg·h/mL, and elimination half‐life of 21.1 hours. Multiple‐dose pharmacokinetics were linear at bempedoic acid doses of 120–220 mg/day. Circulating concentrations of the active metabolite ESP15228 were 18.0% of bempedoic acid concentrations on average. Comparisons of bempedoic acid 180 mg/day pharmacokinetics after single and multiple dosing revealed no clinically meaningful differences between Japanese, Chinese, and Western subjects. Mean estimates of bempedoic acid elimination half‐life in Japanese (25.2 hours) and Chinese (20.0 hours) subjects were comparable to Western subjects (23.9 hours) following 14 days of once‐daily dosing. Bempedoic acid was generally safe and well tolerated up to a dose of 220 mg/day across the study populations described herein. [ABSTRACT FROM AUTHOR]

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

Objectives: Machine learning has potential to improve the management of lipid disorders. We explored the utility of machine learning in high-risk patients in primary care receiving cholesterol-lowering medications. Methods: Machine learning algorithms were created based on lipid management guidelines for England [National Institute for Health and Care Excellence (NICE) CG181] to reproduce the guidance with >95% accuracy. Natural language processing and therapy identification algorithms were applied to anonymized electronic records from six South London primary care general practices to extract medication information from free text fields. Results: Among a total of 48,226 adult patients, a subset of 5630 (mean ± standard deviation, age = 67 ± 13 years; male:female = 55:45) with a history of lipid-lowering therapy were identified. Additional major cardiometabolic comorbidities included type 2 diabetes in 13% (n = 724) and hypertension in 32% (n = 1791); all three risk factors were present in a further 28% (n = 1552). Of the 5630 patients, 4290 (76%) and 1349 (24%) were in primary and secondary cardiovascular disease prevention cohorts, respectively. Statin monotherapy was the most common current medication (82%, n = 4632). For patients receiving statin monotherapy, 71% (n = 3269) were on high-intensity therapy aligned with NICE guidance with rates being similar for the primary and secondary prevention cohorts. In the combined cohort, only 46% of patients who had been prescribed lipid-lowering therapy in the previous 12 months achieved the NICE treatment goal of >40% reduction in non–high-density lipoprotein cholesterol from baseline pretreatment levels. Based on the most recent data entry for patients not at goal the neural network recommended either increasing the dose of statin, adding complementary cholesterol-lowering medication, or obtaining an expert lipid opinion. Conclusions: Machine learning can be of value in (a) quantifying suboptimal lipid-lowering prescribing patterns, (b) identifying high-risk patients who could benefit from more intensive therapy, and (c) suggesting evidence-based therapeutic options. [ABSTRACT FROM AUTHOR]

Background: To date, optimal agents for low-density lipoprotein cholesterol (LDL-C) reduction in patients with established atherosclerotic cardiovascular disease are still being explored. Thus, we evaluated the efficiency of novel LDL-C-lowering therapies in the secondary prevention of cardiovascular events. Methods: We included randomized clinical trials (RCTs) that explored the effects of different LDL-C lowering agents including alirocumab, evolocumab, and bempedoic acid in adult patients with cardiovascular disease. Several databases were searched from inception through 2022. The safety endpoint includes new-onset diabetes, serious adverse events, and neurocognitive disorders with at least 1 year of follow-up. The efficacy outcomes included composite adverse cardiovascular outcomes, all-cause death, and cardiovascular death. Results: Seven RCTs comprising 53,106 patients were included in this research. Bempedoic acid ranked first in reducing the risk of new-onset diabetes (risk ratio [RR] 0.72, 95% credible interval [CrI] 0.52–0.99) and risk of the composite cardiovascular outcome (RR 0.75, 95% CrI 0.57–0.99). Meta-regression analysis demonstrated that elevated risk of new-onset diabetes was positively correlated with a significant reduction in LDL-C levels (p = 0.03). All treatment agents were associated with a decreased risk of a composite adverse cardiovascular outcome. Conclusions: The present analysis showed that bempedoic acid ranked first in reducing the risk of a composite cardiovascular outcome. In addition, it ranked first in reducing the risk of new-onset diabetes compared with placebo and evolocumab. Our analysis also suggests that the increased risk of new-onset diabetes might be associated with a reduction in LDL-C levels. Besides, the present analysis found that alirocumab ranked first in decreasing all-cause mortality and cardiovascular mortality. [ABSTRACT FROM AUTHOR]

Population pharmacokinetics (popPK) of bempedoic acid and the popPK/pharmacodynamic (popPK/PD) relationship between bempedoic acid concentrations and serum low-density lipoprotein cholesterol (LDL-C) from baseline were characterized. A two-compartment disposition model with a transit absorption compartment and linear elimination best described bempedoic acid oral pharmacokinetics (PK). Multiple covariates, including renal function, sex, and weight, had statistically significant effects on the predicted steady-state area under the curve. Mild (estimated glomerular filtration rate (eGFR) 60 to < 90 mL/min vs. ≥ 90 mL/min) and moderate (eGFR 30 to < 60 mL/min vs. ≥ 90 mL/min) renal impairment, female sex, low (< 70 kg vs. 70–100 kg) and high (> 100 kg vs. 70–100 kg) body weight were predicted to have a 1.36-fold (90% confidence interval (CI) 1.32, 1.41), 1.85-fold (90% CI 1.74, 2.00), 1.39-fold (90% CI 1.34, 1.47), 1.35-fold (90% CI 1.30, 1.41), and 0.75-fold (90% CI 0.72, 0.79) exposure difference relative to their reference populations, respectively. An indirect response model described changes in serum LDL-C with a model-predicted 35% maximal reduction and bempedoic acid IC50 of 3.17 µg/mL. A 28% reduction from LDL-C baseline was predicted for a steady-state average concentration of 12.5 µg/mL after bempedoic acid (180 mg/day) dosing, accounting for approximately 80% of the predicted maximal LDL-C reduction. Concurrent statin therapy, regardless of intensity, reduced the maximal effect of bempedoic acid but resulted in similar steady-state LDL-C levels. While multiple covariates had statistically significant effects on PK and LDL-C lowering, none were predicted to warrant bempedoic acid dose adjustment. [ABSTRACT FROM AUTHOR]

Atherosclerotic cardiovascular disease is the leading cause of death globally. LDL cholesterol is a key risk factor for cardiovascular disease. The most common group of medicines for lowering LDL cholesterol are the statins, as they reduce the risk of cardiovascular events. However, some subjects are statin-intolerant and remain at high risk. CLEAR Outcomes; a phase 3 clinical trial of bempedoic acid, an ATP citrate lyase (ACL) inhibitor, in subjects who do not tolerate statins or are unable to take the recommended dose. It enrolled subjects with prior cardiovascular events (secondary prevention) and at high risk (primary prevention). The primary endpoint was a composite of major adverse cardiovascular events, and this occurred in less subjects in the bempedoic acid than the placebo group. Bempedoic acid is suitable for use as monotherapy in the prevention of cardiovascular events in statin intolerant subjects, and it has a good safety profile in most subjects. However, the effects of bempedoic acid in lowering LDL cholesterol and cardiovascular events are modest. This suggests that more benefits may ensue ifbempedoic acid was used in combination with other lipid lowering agents to cause larger decreases in LDL cholesterol. [ABSTRACT FROM AUTHOR]

Bempedoic acid is an orally administered prodrug that, like statins, reduces cholesterol biosynthesis (by inhibiting ATP citrate lyase, a key enzyme in cholesterol synthesis prior to 3-hydroxy-3-methyl-glutaryl CoA reductase). Its lipid efficacy has been evaluated in several clinical trials, achieving a 17-28% reduction in LDL-c levels, and showing an anti-inflammatory effect. Unlike statins, their use is not associated with myotoxic effects. Recently, the cardiovascular benefit of bempedoic acid in patients intolerant to statins has been confirmed in the CLEAR OUTCOMES clinical trial. The use of bempedoic acid has been approved as an adjunct to diet and statins, alone or in combination with ezetimibe, in patients with hypercholesterolemia, mixed dyslipidemia, or statin intolerance. New recommendations also suggest their use as alternative drugs in individuals at high cardiovascular risk or with very high LDL-c levels who do not reach lipid targets with other lipid-lowering drugs. Likewise, it could be considered as a second- or third-line therapy in patients intolerant to statins. [ABSTRACT FROM AUTHOR]

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Purpose of Review: 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. Recent Findings: 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. Summary: 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. [ABSTRACT FROM AUTHOR]

Bempedoic acid is a new cholesterol-lowering drug that recently received approval from the US Food and Drug Administration and the European Medicines Agency. This drug targets lipid and glucose metabolism as well as inflammation by downregulating the ATP citrate lyase and upregulating of AMP-activated protein kinase (AMPK). The main effect is to reduce cholesterol synthesis in the liver, and its use is generally not associated with undesirable muscle disorders. Bempedoic acid can reduce the processes of gluconeogenesis, which leads to an improvement in insulin sensitivity, glucose metabolism and features of the metabolic syndrome. The anti-inflammatory effect of bempedoic acid is mainly achieved by activating the AMPK pathway in immune cells, which helps reduce the level of C-reactive protein in plasma. The effects of bempedoic acid on the course of atherosclerotic cardiovascular disease, type 2 diabetes and chronic liver disease have been evaluated in randomi­zed clinical trials that require further research. Phase III clinical safety trial show that bempedoic acid is generally well tolerated in combination with statins, ezetimibe, or proprotein convertase subti­lisin/kexin type 9 inhibitors in achieving target levels of low-density lipoprotein cholesterol. The aim of this review is to analyze the main mechanisms of action, potential clinical targets of bempedoic acid and describe the existing evidence from clinical trials. The search was done in the Scopus, Science Direct (from Elsevier), and PubMed databases, including the Medline. The following keywords were used: bempedoic acid, low-density lipoprotein cholesterol, atherosclerotic cardiovascular diseases, diabetes. In order to identify research results that could not be found during the online search, a manual search of the bibliography of publications was used.