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Anandita Agarwala,1 Renato Quispe,2 Anne C Goldberg,3 Erin D Michos2 1Division of Cardiology, Baylor Scott and White Health, Heart Hospital Baylor Plano, Plano, TX, USA; 2Ciccarone Center for the Prevention of Cardiovascular Disease, Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 3Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, MO, USACorrespondence: Erin D MichosCiccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins Hospital, 600 N. Wolfe Street, Blalock 524-B, Baltimore, MD, 21287, USATel +410-502-6813Email edonnell@jhmi.eduAbstract: Bempedoic acid is a first-in-class, oral, inhibitor of cholesterol biosynthesis that is approved for use in patients with atherosclerotic cardiovascular disease (ASCVD) and for primary prevention in individuals with heterozygous familial hypercholesterolemia (HeFH) by the United States Food and Drug Administration. Pooled data from the phase III clinical trials, CLEAR Harmony and CLEAR Wisdom, have demonstrated the safety and efficacy of bempedoic acid with regard to lowering of low-density lipoprotein cholesterol (LDL-C) in patients with HeFH as an adjunct or alternative to currently existing lipid-lowering therapies. CLEAR Outcomes is a cardiovascular outcomes trial that is currently underway that will provide additional insight as to where bempedoic acid will fit into treatment regimens among the non-statin lipid-lowering therapy options. Patients who might particularly benefit from bempedoic acid are those with HeFH and those unable to take adequate doses of statins or take any statin therapy altogether who need additional LDL-C lowering. In this review, we will discuss the profile of bempedoic acid from its design, development, and its place in therapy for the management of LDL-C for the purposes of ASCVD prevention.Keywords: bempedoic acid, familial heterozygous hypercholesterolemia, lipids, atherosclerotic cardiovascular disease, prevention, low-density lipoprotein cholesterol

The bioequivalence of bempedoic acid oral suspension and commercial immediate release (IR) tablet formulations were assessed using a physiologically based pharmacokinetic (PBPK) model. The mechanistic model, developed from clinical mass balance results and in vitro intrinsic solubility, permeability, and dissolution data, was verified against observed clinical pharmacokinetics (PK) results. Model inputs included a fraction of a dose in solution (0.01%), viscosity (118.8 cps), and median particle diameter (50 µm) for the suspension and particle diameter (36.4 µm) for IR tablets. Dissolution was determined in the relevant media (pH 1.2–6.8) in vitro. Model simulations of bioequivalence predicted oral suspension (test) to IR tablet (reference) geometric mean ratio estimates of 96.9% (90% confidence interval [CI]: 92.6–101) for maximum concentration and 98.2% (90% CI: 87.3–111) for the area under the concentration–time curve. Sensitivity analyses showed gastric transit time had a minor impact on model predictions. Oral suspension biopharmaceutical safe space was defined by extremes of particle size and the percent of bempedoic acid in solution. PBPK model simulations predicted that the rate and extent of bempedoic acid absorption are unlikely to exhibit clinically meaningful differences when dosed as an oral suspension compared with an IR tablet without requiring a clinical bioequivalence study in adults.

The effects of bempedoic acid on mortality in the secondary prevention setting have not been examined. We used data from the overall and primary prevention reports of CLEAR – Outcomes to reconstruct data for the secondary prevention population. A Bayesian analyses was employed to calculate the posterior probability of benefit or harm for the outcomes of all-cause mortality, cardiovascular mortality, and major adverse cardiovascular events (MACE). Relative effect sizes are presented as risk ratios (RR) with 95% credible intervals (CrI), which represent the intervals that true effect sizes are expected to fall in with 95% probability, given the priors and model. In primary prevention, the posterior probability of bempedoic acid decreasing all-cause and cardiovascular mortality was 99.4% (RR: 0.70; 95% CrI: 0.51 to 0.92) and 99.7% (RR: 0.58; 95% CrI: 0.38 to 0.86) respectively. In secondary prevention, the posterior probability of bempedoic acid increasing all-cause and cardiovascular mortality was 96.6% (RR: 1.15; 95% CrI: 0.99 to 1.33) and 97.2% (RR: 1.21; 95% CrI: 1.00 to 1.45) respectively. The probability of bemepdoic acid reducing MACE in the primary and secondary prevention settings was 99.9% (RR: 0.70; 95% CrI: 0.54 to 0.88) and 95.8% (RR: 0.92; 95% CrI: 0.84 to 1.01) respectively. In contrast to its effect in the primary prevention subgroup of CLEAR – Outcomes, bempedoic acid resulted in a more modest MACE reduction and a potential increase in mortality in the secondary prevention subgroup. Whether these findings represent true treatment effect heterogeneity or the play of chance requires further evidence. [Display omitted] • Bempedoic acid had less favorable effects in secondary versus primary prevention. • The effect on major adverse cardiovascular events (MACE) was more modest in secondary prevention. • There was a potential increase in all-cause and cardiovascular mortality in secondary prevention. • The probability of increasing mortality was equal to that of reducing MACE in secondary prevention. • Further data is needed to verify if true treatment effect heterogeneity exists. [ABSTRACT FROM AUTHOR]

Atherosclerotic cardiovascular disease (ASCVD) is a silent epidemic, which is progressing relentlessly across the globe. Developing countries such as India have a high prevalence of dyslipidemia and consequently a huge burden of coronary artery disease (CAD) and ASCVD. Low-density lipoprotein is regarded as the primary culprit in the genesis of ASCVD, and statins are the first line therapy for LDL-C lowering. Statin therapy has unequivocally demonstrated the benefit of lowering LDL-C in patients across the spectrum of CAD and ASCVD. Muscle symptoms and worsening of glycemic homeostasis could be challenges with statin therapy, especially with the use of high doses. A large fraction of patients are also unable to achieve their LDL goals with statins alone in clinical practice. Moreover, LDL-C goals have become aggressive over years, necessitating a combination of lipid lowering therapies. PCSK-9 inhibitors and Inclisiran have emerged as robust and safe lipid-lowering agents, but parenteral administration and high cost precludes their widespread use. Bempedoic acid is a novel lipid-lowering agent working upstream of statins by inhibiting the enzyme ATP citrate lyase (ACL). The drug produces an average LDL lowering of 22–28% in statin-naïve patients and 17–18% when given to preexisting statin users. Because skeletal muscles lack the ACL enzyme, there is minimal risk of muscle-related symptoms. In combination with ezetimibe, the drug synergistically reduced LDL-C by 39%. Moreover, the drug has no adverse effect on glycemic parameters and lowers hsCRP (inflammation) like statin. The series of four randomized CLEAR trials, involving >4000 patients, have shown consistent LDL lowering across the spectrum of ASCVD patients with or without background therapy. The large and only cardiovascular outcome trial of the drug (CLEAR Outcomes) has recently demonstrated a 13% reduction of MACE at 40 months. Rise in levels of uric acid (four times) and acute gout (three times) are more common compared to placebo with the drug, owing to competitive renal transportation by OAT 2. In a nutshell, Bempedoic acid represents a value addition to the inventory of dyslipidemia management.

Primarily a consequence of sedentary lifestyle, atherosclerosis has already reached pandemic proportions, and with every year the burden of it is only increasing. As low-density lipoprotein cholesterol (LDL-C) represents a crucial factor in atherosclerosis formation and progression, stringent lipid-lowering therapy could conceivably be the key to preventing the unfavorable outcomes that arise as a consequence of atherosclerosis. The use of statins in lipid-lowering is often burdened by adverse events or is insufficient to prevent cardiovascular events as a monotherapy. Therefore, in the present review, the authors aimed to discuss the underlying mechanisms of dyslipidemia and associated atherosclerotic cardiovascular disease (ASCVD) and preclinical and clinical trials of novel therapeutic approaches to its treatment, some of which are still in the early stages of development. Apart from novel therapies, a novel change in perspective is needed. Specifically, the critical objective in the future management of ASCVD is to embrace emerging evidence in the field of atherosclerosis, because clinicians are often burden by common practice and personal experience, both of which have so far been shown to be futile in the setting of atherosclerosis.

• Bempedoic acid monotherapy lowered LDL-C in patients not taking a statin by 26.5% • Bempedoic acid + ezetimibe FDC lowered LDL-C in patients not on statins by 39.2% • Bempedoic acid was generally well tolerated in patients unable to take a statin • Muscle-related disorders with bempedoic acid were comparable to placebo Despite the high incidence of patients with statin tolerance problems, randomized evaluations of nonstatin oral treatment options for lowering of low-density lipoprotein cholesterol (LDL-C) in this population are sparse. To assess the LDL-C lowering effect of bempedoic acid in patients not taking statins. This was a pooled analysis of data from patients enrolled in four phase 3 bempedoic acid studies (12 to 52 weeks in duration) who were not taking concomitant statins (Phase 3 No Statin Cohort) and a phase 3 bempedoic acid plus ezetimibe fixed-dose combination study (BA+EZE FDC No Statin Cohort). The primary endpoint for all studies was the percent change from baseline to week 12 in LDL-C levels. Safety and tolerability were assessed by laboratory values and adverse events. In the Phase 3 No Statin Cohort, bempedoic acid (n = 394) lowered LDL-C levels at week 12 significantly more than placebo (n = 192; −26.5% [95% CI, −29.7%, −23.2%]; P <0.001). The fixed-dose combination of bempedoic acid with ezetimibe lowered LDL-C by 39.2% (95% CI, −51.7% to −26.7%; P <0.001). Muscle-related disorders occurred at a rate of 26.4 and 28.6 per 100 person-years with bempedoic acid and placebo, respectively. In patients with hypercholesterolemia unable to take statins, bempedoic acid lowered LDL-C levels by a mean of 26.5% vs placebo and bempedoic acid + ezetimibe fixed-dose combination lowered LDL-C by 39.2%. The treatments were generally well tolerated, suggesting that bempedoic acid may be efficacious and well tolerated in this challenging-to-treat patient population. [Display omitted] [ABSTRACT FROM AUTHOR]

The effective and fast reduction of circulating low-density lipoprotein cholesterol (LDL-C) is a cornerstone for secondary prevention of atherosclerotic disease progression. Despite the substantial lipid-lowering effects of the established treatment option with statins and ezetimibe, a significant proportion of very-high-risk patients with cardiovascular disease do not reach the recommended treatment goal of <55 mg/dL (<1.4 mmol/L). Novel lipid-lowering agents, including the proprotein convertase subtilisin/kexin type 9 (PCSK9) antibodies alirocumab and evolocumab, the small interfering ribonucleotide acid (si-RNA) inclisiran, as well as the recently approved bempedoic acid, now complete the current arsenal of LDL-C lowering agents. These innovative therapies have demonstrated promising results in clinical studies. Besides a strong reduction of LDL-C by use of highly effective agents, there is still discussion as to whether a very rapid achievement of the treatment goal should be a new strategic approach in lipid-lowering therapy. In this review, we summarize evidence for the lipid-modifying properties of these novel agents and their safety profiles, and discuss their potential pleiotropic effects beyond LDL-C reduction (if any) as well as their effects on clinical endpoints as cardiovascular mortality. In addition to a treatment strategy of "the lower, the better", we also discuss the concept of "the earlier, the better", which may also add to the early clinical benefit of large LDL-C reduction after an acute ischemic event. [ABSTRACT FROM AUTHOR]

Ivan Pećin,1,2 Željko Reiner1,2 1Zagreb School of Medicine, University of Zagreb, Zagreb, Croatia; 2Division of Metabolic Diseases, Department of Internal Medicine, University Hospital Center, Zagreb, CroatiaCorrespondence: Željko ReinerDivision of Metabolic Diseases, Department of Internal Medicine, University Hospital Center Zagreb Kispaticeva 12, Zagreb, 10 000, CroatiaTel + 385 1 2388772Fax + 385 1 2388623Email zreiner@kbc-zagreb.hrAbstract: Atherosclerotic cardiovascular diseases (ASCVD) are still the leading cause of morbidity and mortality in most developed countries and even more in developing countries. Dyslipidemia is a well known main risk factor for ASCVD. Lipid-lowering treatment, particularly lowering LDL-cholesterol (LDL-C), can decrease the risk for ASCVD. New data and guidelines based upon them suggest that we should go with LDL-C levels as low as we can. Therefore, conventional lipid lowering agents (statins and statins+ezetimibe) are not enough mainly because of poor compliance and statin intolerance which is in the real world mostly pseudo-intolerance. PCSK9 inhibitors provided a new hope to further decrease LDL-C but are still expensive, they have to be injected subcutaneously twice a month and their long-lasting adverse effects are not known. Therefore, there is a constant need to develop novel, more potent, more safe, less expensive, more user friendly regimens of hypolipemic agents (bempedoic acid, selective PPAR alpha receptor modulators etc). One of the ways to overcome poor compliance and increase the potency of therapy with less adverse effects are fixed combinations of established drugs (statin+ezetimibe). The future of hypolipemic agents is based on antisense therapy, ie. the use of specific oligonucleotide sequences blocking the translation of the selected protein (targeting apolipoprotein CIII, lipoprotein (a), apolipoprotein B) or RNA silencing technique (PCSK9 mRNA) and are in various stages of clinical trials. Some of them are almost ready to use in everyday clinical practice. High risk and very high risk patients (eg. familial hypercholesterolemia, familial severe chylomicronemia syndrome) will benefit most. The aim of this review is to inform about novel hypolipemic agents – potent and safe drugs for dyslipidemia which should reduce the risk of ASCVD.Keywords: dyslipidemia, novel hypolipemic drugs, cardiovascular risk, LDL-cholesterol, triglycerides, inclisiran, PCSK9 inhibitors, pemafibrate, bempedoic acid, ANGPTL3, pelacarsen

Abstract Background Bempedoic acid is a new drug that reduces cholesterol synthesis via inhibiting ATP citrate lyase. It remains unclear whether the combination of bempedoic acid and other lipid-lowering drugs is better than these drugs alone. This study systematically reviewed the efficacy and safety of bempedoic acid monotherapy or combination togethers in hypercholesterolemic patients. Methods Randomized controlled trials were searched across Medline, Embase, Cochrane library, web of science, etc. The net change scores [least squares mean (LSM) percentage change] in LDL-C level were meta-analyzed using weighted mean difference. The reductions in other lipids including total cholesterol (TC), non-high-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein (ApoB) and high sensitivity C reactive protein (hsCRP) were also assessed. Odds ratio (OR) of the incidence of adverse events (AEs) were calculated to evaluate the safety of bempedoic acid. Results A total of 13 trials (4858 participates) were included. Pooled data showed that the combination togethers resulted in greater reductions in LDL-C level than monotherapies (bempedoic acid + statin vs. statin: LSM difference (%), − 18.37, 95% CI, − 20.16 to − 16.57, I2 = 0; bempedoic acid + ezetimibe vs. ezetimibe: LSM difference (%), − 18.89, 95% CI, − 29.66 to − 8.13, I2 = 87%). But the difference in efficacy between bempedoic acid and ezetimibe was not obvious. Meta-regression analysis showed the treatment duration was a source of heterogeneity (adj R2 = 16.92, 95% CI, 0.04 to 0.72). Furthermore, the background therapy of statin before screening decreased the efficacy of bempedoic acid. In addition, bempedoic acid also resulted in a significant reduction in TC, non-HDL-C, ApoB and hsCRP level. The OR of muscle-related AEs by the combination of bempedoic acid and statin was 1.29 (95% CI, 1.00 to 1.67, I2 = 0) when compared with statin alone. Conclusion This study showed the efficacy of combination togethers were similar but stronger than these drugs alone. Of note, a trend of high risk of muscle-related AEs by the combination of bempedoic acid and statin was observed, though it is not statistically significant, such risk is needed to be confirmed by more trials, because it is important for us to determine which is the better combinative administration for statin-intolerant patients.

• Bempedoic acid required insurance approval or cost mitigation in 94.5% of cases • Bempedoic acid reduced LDL-C by 20.3%-36.7%, with wide inter-individual variability • Hyper- and hypo-responder phenotypes were present in 25% and 14% of patients • Drug discontinuations were common, occurring in 35.9% of patients • The most common TEAEs were musculoskeletal Lipid management for prevention and treatment of cardiovascular disease remains insufficient for many with currently available therapies. Evaluate real-world use of bempedoic acid. Retrospective study of patients in our Center for Preventive Cardiology who were prescribed bempedoic acid between February 2020 and July 2021. Patients were managed according to clinical standards of care, with lipid assessments at months ≤3, 6, and 12 post-bempedoic acid initiation. Seventy-three patients were prescribed bempedoic acid, with 64 initiating therapy. The majority had atherosclerosis (89%), familial hypercholesterolemia (64%), and statin intolerance (74%), with baseline low-density lipoprotein cholesterol (LDL-C) 120 mg/dL. Prior authorization requests and appeals of denials were required in 90% and 19% of cases, respectively. Cost-mitigating strategies reduced median monthly drug costs from $432 pre-insurance approval to $80 post-insurance approval, to $10 after financial assistance intervention. Bempedoic acid reduced LDL-C by -36.7%, -31%, and -20.3% at ≤3, 6, and 12, respectively, with >20% achieving LDL-C <70 mg/dL. There was substantial inter-individual heterogeneity in LDL-C lowering. We observed high rates of drug discontinuation (35.9%), mostly related to treatment-emergent adverse events (TEAEs) (32.8%), primarily musculoskeletal complaints. Use of reduced dose bempedoic acid (<180 mg) was associated similar LDL-C lowering but TEAE and drug discontinuation were still common. Real-world use of bempedoic acid was limited by insurance and cost barriers requiring substantial post-prescription interventions. In patients at heightened risk for atherosclerotic events and statin intolerance, bempedoic acid was associated with clinically meaningful LDL-C lowering, but high rates of TEAEs and drug discontinuations. [ABSTRACT FROM AUTHOR]

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

ATP-citrate lyase (Acly) is the target of the new class low-density lipoprotein-cholesterol (LDL-C)-lowering drug bempedoic acid (BA). Acly is a key metabolic enzyme synthesizing acetyl-CoA as the building block of cholesterol and fatty acids. Treatment with BA lowers circulating lipid levels and reduces systemic inflammation, suggesting a dual benefit of this drug for atherosclerosis therapy. Recent studies have shown that targeting Acly in macrophages can attenuate inflammatory responses and decrease atherosclerotic plaque vulnerability. Therefore, it could be beneficial to extend the application of Acly inhibition from solely lipid-lowering by liver-specific inhibition to also targeting macrophages in atherosclerosis. Here, we outline the possibilities of targeting Acly and describe the future needs to translate these findings to the clinic. Bempedoic acid targets ATP-citrate lyase (Acly) in the liver, thereby lowering low-density lipoprotein-cholesterol (LDL-C) and systemic inflammation. Acly is a metabolic enzyme at the crossroads between carbohydrate metabolism, lipid metabolism, and histone acetylation. Targeting Acly in macrophages yields additive therapeutic value to broaden the strategy from solely lipid-lowering to targeting inflammatory activation. [ABSTRACT FROM AUTHOR]

Purpose of Review: For many years, the lipid-lowering armamentarium consisted of statins and/or ezetimibe and/or bile acid sequestrants and/or fibrates. Now, with the availability of new drugs mostly injectables, the field has changed and the role of oral non-statin drugs (including bempedoic acid) must be reevaluated. Recent Findings: Ezetimibe remains a very important combination partner for statins with continuously increasing treatment numbers. Bempedoic acid is another interesting combination partner for statin/ezetimibe or ezetimibe alone but lacks in contrast to ezetimibe evidence from outcome trials. The role of fibrates is less clear as they have shown disappointing results in outcome trials but may still be used in selected, high-risk patients with combined dyslipidemia. Bile acid sequestrants are now rarely used as there are stronger, better tolerable ways to lower LDL-cholesterol. Summary: With the introduction of new injectable lipid-lowering drugs, some oral drugs such as ezetimibe and bempedoic acid still have an important spot in our treatment algorithm others such as fibrates have a less clear role while again others are now rarely used. [ABSTRACT FROM AUTHOR]

Bempedoic acid is a new oral lipid-lowering therapy which has been licenced for use in the United Kingdom. It can be used alone, with a statin, or with other lipid-lowering therapies where the target level for low density lipoprotein has not been achieved with these therapies alone. Bempedoic acid with ezetimibe can be prescribed for people who are unable to tolerate statins. This combination has received NICE approval following a technology appraisal. This paper discusses the place for of bempedoic acid as a lipid lowering drug and consider the mode of action, licensed indications, adverse drug reactions and the NICE technology appraisal recommendations. [ABSTRACT FROM AUTHOR]

Abstract Background 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. Methods 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. Results We identified 11 trials including a total of 4391 participants. Bempedoic acid use was associated with a reduction in composite cardiovascular outcome (RR 0.75, 95% CI 0.56–0.99; I2 = 0%). Bempedoic acid reduced LDL-C levels (MD − 22.91, 95% CI − 27.35 to − 18.47; I2 = 99%), and similarly reduced CRP levels (MD -24.70, 95% CI − 32.10 to − 17.30; I2 = 53%). Bempedoic acid was associated with a reduction in rates of new-onset or worsening diabetes (RR 0.65, 95% CI 0.44–0.96; I2 = 23%). Conclusions Bempedoic acid in patients with hypercholesterolemia was associated with a lower risk of cardiovascular events and diabetes.

Cardiovascular disease (CVD) is the leading cause of death worldwide and one key factor associated with the increased CVD risk is dyslipidemia. Statin therapy remains the first-line treatment to manage dyslipidemia, yet many patients do not achieve optimal low-density lipoprotein-cholesterol (LDL-C) levels even after taking moderate- or high-intensity statins; therefore, additional, non-statin therapy is often needed. Bempedoic acid is a prodrug that, once activated, decreases LDL-C levels by the inhibition of adenosine triphosphate citrate lyase in the liver. Five clinical trials have demonstrated the safety and efficacy of bempedoic acid and the bempedoic acid/ezetimibe combination in lowering LDL-C in patients with atherosclerotic CVD and heterozygous familial hypercholesterolemia and also in high-risk primary prevention, and statin-intolerant patients. Bempedoic acid has been demonstrated to lower LDL-C levels by 15–25% in clinical trials and up to 38% when combined with ezetimibe. In 2020, the FDA approved bempedoic acid. Furthermore, the combination of bempedoic acid with ezetimibe is FDA approved for the treatment of adults with heterozygous familial hypercholesterolemia or established atherosclerotic CVD who require additional LDL-C lowering after maximally tolerated statin therapy. The ongoing CLEAR OUTCOMES trial aims to evaluate whether bempedoic acid can reduce cardiovascular events in patients with statin intolerance and results will be available in the next 3 years. This outcomes trial will be pivotal for determining the role of bempedoic acid in the non-statin lipid-lowering armamentarium.

Lipid-lowering drugs have been shown to have cardioprotective effects but may have hidden cardiotoxic properties. Therefore, here we aimed to investigate if chronic treatment with the novel lipid-lowering drug bempedoic acid (BA) exerts hidden cardiotoxic and/or cardioprotective effects in a rat model of acute myocardial infarction (AMI). Wistar rats were orally treated with BA or its vehicle for 28 days, anesthetized and randomized to three different groups (vehicle + ischemia/reperfusion (I/R), BA + I/R, and positive control vehicle + ischemic preconditioning (IPC)) and subjected to cardiac 30 min ischemia and 120 min reperfusion. IPC was performed by 3 × 5 min I/R cycles before ischemia. Myocardial function, area at risk, infarct size and arrhythmias were analyzed. Chronic BA pretreatment did not influence cardiac function or infarct size as compared to the vehicle group, while the positive control IPC significantly reduced the infarct size. The incidence of reperfusion-induced arrhythmias was significantly reduced by BA and IPC. This is the first demonstration that BA treatment does not show cardioprotective effect although moderately reduces the incidence of reperfusion-induced arrhythmias. Furthermore, BA does not show hidden cardiotoxic effect in rats with AMI, showing its safety in the ischemic/reperfused heart.

Objective: Statins are sometimes associated with worsened glycemic control. Patients with type 2 diabetes mellitus (T2DM) may require non-statin therapies to achieve low-density lipoprotein cholesterol (LDL-C) lowering goals. This study evaluated the efficacy and safety of bempedoic acid 180 mg plus ezetimibe 10 mg fixed-dose combination (BA + EZE FDC) in patients with T2DM and hypercholesterolemia who were not receiving background statins or other lipid-lowering therapy. Methods: Patients with T2DM and elevated LDL-C levels were enrolled into this phase 2, double-blind study (NCT03531905). Patients received placebo during a 5-week washout period where background lipid-lowering therapies (including statins) were discontinued. Eligible patients were then randomized 1:1:1 to receive either BA + EZE FDC, ezetimibe 10 mg, or placebo once daily for 12 weeks. Assessments included the percent change from baseline to week 12 in LDL-C, other lipid parameters, and high-sensitivity C-reactive protein (hsCRP); and the monitoring of safety and tolerability. Results: Among 179 randomized patients, baseline characteristics following the washout period were similar across treatment groups, with mean LDL-C levels of 142.6 mg/dL and mean glycated hemoglobin of 8.0%. At week 12, BA + EZE FDC therapy lowered mean LDL-C levels by 38.8%, significantly more than ezetimibe alone (19.2%; difference, 19.5% [95% confidence interval (CI), 13.4%–25.7%]; p < 0.001) or placebo (increase of 0.9%; difference, 39.6% [95% CI, 33.4%–45.8%]; p < 0.001). BA + EZE FDC significantly reduced hsCRP levels from baseline vs ezetimibe (29.2%; p = 0.005) and vs placebo (36.7%; p < 0.001). Incidence of treatment-emergent adverse events was low in all treatment groups, with no indication of worsened glycemic control. Conclusion: In patients with T2DM and hypercholesterolemia who were not receiving statins or other lipid-lowering drugs, BA + EZE FDC significantly lowered LDL-C levels and was generally well tolerated.

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disorder globally, characterized by fat accumulation in liver cells, which can progress to inflammation, fibrosis, and cirrhosis. The disease predominantly affects individuals with obesity and high body mass index (BMI). It is a globally prevalent condition, with variations in incidence across different regions. The pathophysiology of NAFLD involves insulin resistance, metabolic disturbances, and genetic and gut microbial factors. Current treatments primarily focus on lifestyle modifications and a limited range of pharmacological options. Bempedoic acid (BA), a novel cholesterol-lowering agent, targets adenosine triphosphate (ATP)-citrate lyase to reduce low-density lipoprotein (LDL) cholesterol and has shown potential in managing NAFLD by decreasing liver fat accumulation and improving lipid profiles. BA's unique mechanism offers a promising add-on therapy, particularly for the patient's intolerant to statins. Despite its potential, comprehensive clinical and preclinical studies are needed to further elucidate its efficacy and safety compared to other NAFLD treatments. Future research should focus on comparing BA with existing and emerging therapies to optimize its role in NAFLD management and enhance patient outcomes., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Anasdeen S et al.)

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) <5 mmol/L and low-density lipoprotein cholesterol (LDL-C) <3 mmol/L or ≥25% reduction in TC and ≥30% reduction in LDL-C) at 12 weeks post-initiation. At week 12, the mean absolute change in LDL-C was -1.0 mmol/L; the mean percentage reduction from baseline was 22.0%. Additionally, 52% (96/185) of patients had an LDL-C of <3 mmol/L and 10% (18/185) an LDL-C of <1.8 mmol/L at 12 weeks (as per JBS3)., Conclusion: This audit highlights the role of bempedoic acid as part of combination therapy for a population with previously limited treatment options., Competing Interests: Disclosure and potential conflicts of interest: SR has received research grants, travel grants and speakers’ honoraria from Besins Healthcare, Daiichi Sankyo, Novartis, and Amarin. EH is a trustee of HEARTUK and Dinwoodie Charity, received payment from Daiichi Sankyo UK Ltd., Amarin, Amgen, ACCEA and Novartis, and received funding from Sanofi and Amarin. TA has received funding and honoraria from Daiichi Sankyo UK Ltd. PS is an employee of Daiichi Sankyo UK Ltd. LB, NV and JK are former employees of Daiichi Sankyo UK Ltd. AM and KM have no conflicts of interest to declare. The International Committee of Medical Journal Editors (ICMJE) Potential Conflicts of Interests form for the authors is available for download at: https://www.drugsincontext.com/wp-content/uploads/2024/07/dic.2024-2-4-COI.pdf, (Copyright © 2024 Ramachandran S, Maarouf A, Mitchell K, Avades T, Smith P, Boulton L, Kelly J, Vekaria N, Hughes E.)

Introduction and Objectives: Only about 1 out of every 3 patients with acute myocardial infarction (AMI) achieve low-density lipoprotein cholesterol (LDL-C) values <55mg/dL in the first year. The present study aims to evaluate the impact of early intensive therapy on lipid control after an AMI., Methods: An independent, prospective, pragmatic, controlled, randomized, open-label, evaluator-blinded clinical trial (PROBE design) will analyze the efficacy and safety of an oral lipid-lowering triple therapy: high-potency statin+bempedoic acid (BA) 180mg+ezetimibe (EZ) 10mg versus current European-based guidelines (high-potency statin±EZ 10mg), in AMI patients. LDL-C will be determined within the first 48hours. Patients with LDL-C ≥ 115mg/dL (without previous statin therapy), ≥ 100mg/dL (with previous low-potency or high-potency statin therapy at submaximal dose), or ≥ 70mg/dL (with previous high-potency statin therapy at high dose) will be randomly assigned 1:1 between 24 and 72hours post-AMI to the BA/EZ combination or to statin±EZ, without BA. The primary endpoint is the proportion of patients reaching LDL-C <55mg/dL at 8 weeks after treatment., Results: The results of this study will provide novel information for post-AMI LDL-C control by evaluating the usefulness of an early intensive lipid-lowering strategy based on triple oral therapy., Conclusions: Early intensive lipid-lowering triple oral therapy vs the treatment recommended by current clinical practice guidelines could facilitate the achievement of optimal LDL-C levels in the first 2 months after AMI (a high-risk period)., Identification Number: EudraCT 2021-006550-31., (Copyright © 2024 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Dyslipidemia refers to the change in the normal levels of one or more lipid components in the bloodstream, which include triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C). Dyslipidemia represents a substantial source of danger for cardiovascular disease (CVD). Effectively managing dyslipidemia involves a thorough strategy that includes changing one's lifestyle and using medications that are specifically designed to target the complex processes involved in lipid metabolism. Lipid-lowering treatments play a crucial role in this approach, providing a wide range of medications that are developed to specifically target different components of dyslipidemia. Statins are the main drug among these medications. Other drugs that are used with statin or as monotherapy include fibrates, omega-3 fatty acids (OM3FAs), ezetimibe, bile acid sequestrants, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and bempedoic acid. Using the PubMed database, we reviewed the literature about dyslipidemia, drugs used for treating dyslipidemia, their efficacy parameters, and common adverse events. We also reviewed the international guidelines for treating dyslipidemia and discussed the future of lipid-lowering medications. More trials and experiments are still required to verify the effectiveness of many lipid-lowering drugs and to know their common adverse events to be able to manage them properly., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Alqahtani et al.)

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., Competing Interests: The authors declare no conflicts of interest.

Cardiovascular diseases are the leading causes of global mortality and morbidity. Hyperlipidemia is a significant risk factor for atherosclerosis and subsequent cardiovascular diseases. Hyperlipidemia is characterized by imbalances in blood cholesterol levels, particularly elevated low-density lipoprotein cholesterol and triglycerides, and is influenced by genetic and environmental factors. Current management consists of lifestyle modifications and pharmacological interventions most commonly consisting of statins. This review paper explores pathophysiology, management strategies, and pharmacotherapies including commonly used well-established medications including statins, fibrates, and ezetimibe, exciting novel therapies including proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and RNA interference therapies (inclisiran), lomitapide, and bempedoic acid, highlighting their mechanisms of action, clinical efficacy, and safety profiles. Additionally, emerging therapies under clinical trials including ApoC-III inhibitors, DGAT2 inhibitors, ACAT2 Inhibitors, and LPL gene therapies are examined for their potential to improve lipid homeostasis and cardiovascular outcomes. The evolving landscape of hyperlipidemia management underscores the importance of continued research into both established therapies and promising new candidates, offering hope for more effective treatment strategies in the future., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Abbasi et al.)

Introduction: Bempedoic acid (BA) has shown varied efficacy in managing hyperlipidemia. We conducted the most extensive up-to-date meta-analysis, the first to include recent studies by Nissen et al., which boast the largest sample size., Methods: Literature search was done on Medline, EMBASE, and Cochrane Library. The primary endpoint was a change in low-density lipoprotein-cholesterol (LDL-C) levels, while secondary endpoints encompassed changes in lipid parameters, clinical endpoints, and safety endpoints. The least-square mean (LSM) percent change was utilized for lipid changes, with statistical significance set at P  < 0.05., Results: This analysis included 12 randomized control trials with 22,249 participants. BA exhibited a substantial reduction in LDL-C levels [LSM % change, -24.34; 95% confidence interval (CI), -27.80 to -20.88; P  < 0.0001], total cholesterol levels (LSM % change, -16.62; 95% CI, -21.70 to -11.54; P  < 0.00001) and high-density lipoprotein-cholesterol (HDL-C) levels (LSM % change, -4.22; 95% CI, -5.51 to -2.92; P  < 0.00001) compared to the placebo., Conclusions: BA significantly lowers LDL-C, total cholesterol, HDL-C, non-HDL-C, high sensitivity C reactive protein, and apolipoprotein levels., Competing Interests: There are no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Rapid reduction of low-density lipoprotein cholesterol (LDL-C) to target levels immediately following acute coronary syndrome (ACS) event is critical to prevent future events. High-dose statins alone often fail to achieve LDL-C goals. Proprotein convertase subtilisin/kexin type-9 inhibitors (PCSK9i) combined with high-dose statins improves LDL-C goal attainment, but is unaffordable for many patients in India and worldwide. In a real-world open-label study, we demonstrated in a cohort of 122 patients with ACS, concurrent triple therapy with rosuvastatin 40 mg/d, ezetimibe 10 mg/d, and bempedoic acid 180 mg/d (REB) started at the time of hospital admission was associated with 57.7%, 61.7%, 61.9% and 60.6% reductions in LDL-C from 115.6 mg/dL at baseline to 48.9 mg/dL at week 1, 44.3 mg/dL at week 2, 44.1 mg/dL at week 4, and 45.6 mg/dL at week 6, respectively (each p < 0.001 compared to baseline; p < 0.001 across repeated measures). REB provided significant reductions in LDL-C within as early as one week and enabled 76.3% and 92.2% of patients to achieve the Lipid Association of India and American College of Cardiology recommended LDL-C targets of <50 mg/dl and <70 mg/dl within 2-weeks, respectively, which were sustained at 4-6 weeks. REB was generally well tolerated. Our study demonstrates the capacity to rapidly achieve LDL-C goals after ACS with triple REB therapy, an affordable regimen in India., Competing Interests: Declaration of competing interest Kunal Mahajan: None, Raman Puri: None, P Barton Duell: Advisory activities: Akcea/Ionis, Esperion, Regeneron, Kaneka, New Amsterdam, Novo Nordisk. Institutional grants: Regeneron, Regenxbio, Retrophin/Travere. Deep Dutta: None. Rahul Yadav: None. Surender Kumar: None. Jai Bharat Sharma: None. Prashant Patel: None. Savio Dsouza: None. Ashu Gupta: None. Aziz Khan: None. Nathan Wong: Research support through institution from Novo Nordisk, Novartis, and Regeneron and consultant for Amgen, Novartis and Ionis., (Copyright © 2024. Published by Elsevier Inc.)

Atherosclerosis, a multifaceted pathogenic process affecting the arteries and aorta, poses a significant threat because of its potential to impede or entirely obstruct blood flow by narrowing blood vessels. This intricate progression involves various factors such as dyslipidemia, immunological responses, inflammation, and endothelial dysfunction. The initial phase manifests as the formation of fatty streaks, considered a pivotal hallmark in the inception of atherosclerotic plaques, a process that can commence as early as childhood. Over time, this process evolves, characterized by the thickening of the arterial inner layer (intima) and accumulation of lipid-laden macrophages, commonly known as foam cells, along with the buildup of the extracellular matrix. Subsequent stages witness the proliferation and aggregation of smooth muscle cells, culminating in the formation of atheroma plaques. As these lesions progress, apoptosis can occur in the deeper layers, further recruiting macrophages, which may undergo calcification and transform into atherosclerotic plaques. Notably, mechanisms such as arterial remodeling and intraplaque hemorrhage also contribute significantly to the progression of atherosclerotic cardiovascular disease, although these facets fall beyond the scope of this article. This study aimed to systematically review and conduct a meta-analysis of randomized controlled trials investigating the efficacy and safety of bempedoic acid in statin-intolerant patients with hyperlipidemia and to provide conclusions and recommendations accordingly. A systematic search of databases, such as PubMed, Web of Science, and Embase, will be performed. Only randomized trials will be included comparing bempedoic acid with placebo in statin-intolerant patients. This study aimed to provide a comprehensive understanding of the role of bempedoic acid in managing hyperlipidemia in statin-intolerant patients. In primary prevention, for patients unable to tolerate recommended statins, bempedoic acid was associated with a significant reduction in major adverse cardiovascular events (MACE) as the primary endpoint., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Serour et al.)

Bempedoic acid is a small-molecule inhibitor of adenosine triphosphate-citrate lyase (ACL) that is effective in the treatment of hypercholesterolemia and hypertension. In this paper, a new, six-step synthesis of bempedoic acid with 42% overall yield is reported. Ketone formation by electrochemical decarboxylation of dialkylated malonic acid is introduced as the key step of this process. This method uses mild conditions and its high efficiency makes it potentially suitable for industrial production. [ABSTRACT FROM AUTHOR]

Low-density lipoprotein cholesterol (LDL-C) is a modifiable risk factor for the development of atherosclerotic cardiovascular disease. Statins have been the gold standard for managing cholesterol levels and reducing the risks associated with atherosclerotic cardiovascular disease; however, many patients do not achieve their cholesterol goals or are unable to tolerate this drug class due to adverse drug events. Recent studies of non-statin cholesterol lowering drugs (i.e., ezetimibe, PCSK9 inhibitors) have demonstrated cardiovascular benefits; and new drugs [i.e., bempedoic acid (BDA), inclisiran] have produced promising results in pre-clinical and clinical outcome trials. This narrative review aims to discuss the place in therapy of ezetimibe, PCSK9 inhibitors, BDA, and inclisiran and describe their relative pharmacokinetic (PK) profiles, efficacy and safety as monotherapy and combination therapy, and cardiovascular benefit(s) when used for hypercholesterolemia.

Many patients do not achieve optimal low-density lipoprotein cholesterol (LDL-C) levels with statins alone; others are unable to tolerate statin therapy. Additional non-statin treatment options including ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors, and bile acid sequestrants are often necessary to further reduce the risk of atherosclerotic cardiovascular disease. This review provides practical guidance as to the use of bempedoic acid to lower LDL-C and includes direction as to which patients may benefit and advice for safety monitoring during treatment. Bempedoic acid, a new class of agent, is a prodrug converted to bempedoyl-CoA by very long-chain acyl-CoA synthetase 1, an enzyme with high expression in the liver but that is undetectable in the skeletal muscle. Bempedoic acid inhibits the enzyme adenosine triphosphate (ATP)-citrate lyase, which lies two steps upstream from β-hydroxy β-methylglutaryl-CoA reductase in the cholesterol biosynthesis pathway. In clinical trials conducted in patients with or at risk for atherosclerotic cardiovascular disease or familial heterozygous hypercholesterolemia, bempedoic acid in combination with statins and/or ezetimibe significantly reduced LDL-C, apolipoprotein B, and high-sensitivity C-reactive protein compared with placebo. Bempedoic acid is generally well tolerated with no clinically meaningful increase in muscle-related symptoms relative to placebo, even in patients taking maximally tolerated statins. A small increase in serum uric acid (mean increase 0.8 mg/dL) is the most noteworthy adverse effect. Bempedoic acid provides an effective and generally well-tolerated medication to further reduce LDL-C in patients taking maximally tolerated statins or manage LDL-C levels in those who are unable to take statins. The potential for a reduced incidence of major cardiovascular events with bempedoic acid is being investigated in the CLEAR Outcomes trial, with results expected in 2023. [ABSTRACT FROM AUTHOR]

An elevated plasma low-density lipoprotein cholesterol (LDL-C) level is a well-established atherosclerotic cardiovascular disease (ACSVD) risk factor. Randomized studies with statins (alone or in combination with other lipid-lowering drugs) have demonstrated their clinical efficacy in lowering LDL-C. Several classes of new, non-statin agents have been successfully studied and used (e.g., ezetimibe and inhibitors of proprotein convertase subtilisin/kexin type 9 [i-PSCK9]). However, many high ACSVD risk patients remain at a high residual cardiovascular risk, with at least 10% being statin intolerant. Bempedoic acid (ETC-1002) is a new inhibitor of cholesterol synthesis that targets ATP citrate lyase (ACL). Importantly, ETC-1002 is only converted into an active form in the liver and is free of muscle side effects. Area Covered: Mechanism of action of ETC-1002, clinical pharmacology, completed clinical studies with bempedoic acid, lipid-lowering efficacy/safety issues, and recent meta-analyses of trials with ETC-1002. Expert Opinion: ETC-1002 has been extensively studied in phase I–III clinical studies in over 4000 individuals from different patient populations (statin intolerance, familial hypercholesterolemia, and high ACSVD risk patients), ETC-1002 has been demonstrated to have moderate cholesterol-lowering efficacy and a good safety profile at a dose of 180 mg/day as a monotherapy and in combination with statins and ezetimibe. The ongoing study CLEAR Outcomes, with composite cardiovascular endpoints, will elucidate the role of bempedoic acid in the management of high ACSVD risk and statin-intolerant patients with hypercholesterolemia. Long-term safety data on bempedoic acid are needed to fully establish this agent in evidence-informed guidelines for managing of patients with dyslipidemias. [ABSTRACT FROM AUTHOR]

Diabetes is a major risk factor for atherosclerotic cardiovascular disease (ASCVD) in which dyslipidaemia plays a crucial role. Statins are first line therapy for primary and secondary prevention of ASCVD; however, adverse events include reversible musculoskeletal and liver side effects in addition to a diabetogenic association. In this short review, we provide a succinct narrative of the future role and current trial data of a novel first-in-class molecule, bempedoic acid. The authors provide their expert insight with a focus on Phase III randomised controlled trials (RCT) of bempedoic acid. Bempedoic acid was approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in February and March 2020, respectively, and is a novel molecule which inhibits cholesterol biosynthesis in the same mechanistic pathway as statins. It is a first-in-class small molecule, delivered as a prodrug and administered as an oral, once-daily dose that decreases low-density lipoprotein cholesterol (LDL-C) levels. Phase II and III RCTs have demonstrated efficacy with adequate safety data as mono- or combination therapy with statins and ezetimibe. Bempedoic acid is hepatically converted to the active drug with a lack of activation in skeletal muscle. Due to this novel mechanism, musculoskeletal-related adverse events exhibit a lower prevalence providing an alternative pharmacotherapy in statin-intolerant patients. Bempedoic acid may be used as an adjunct to diet and maximally tolerated statin therapy or in statin-intolerant patients for the treatment of dyslipidaemia. The recent National Institute of Health and Care Excellence (NICE) (UK) technology appraisal guidance [TA694] published in April 2021 recommended bempedoic acid with ezetimibe as a treatment option for primary hypercholesterolaemia or mixed dyslipidaemia if statins are not tolerated or contraindicated and if there is inadequate control of LDL-C with ezetimibe alone. Additionally, outcomes trials evaluating 'hard' endpoints in statin-intolerant patients or those with ASCVD are currently underway. [ABSTRACT FROM AUTHOR]

Purpose of Review: Elevation in apolipoprotein B-containing lipoproteins in the blood is a cause of atherosclerosis. Statins have changed the preventive cardiology scenario, and more recently monoclonal proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors were added as robust agents to further reduce pro-atherogenic lipoproteins and therefore prevent cardiovascular events. However, despite this many dyslipidemic individuals persist with inadequate LDL-C levels and still at risk. The purpose of this review was to discuss current status and describe advances in therapies beyond statins and monoclonal PCSK9 inhibitors. Recent Findings: Ezetimibe and lomitapide have been used for many years to further reduce LDL-C and longer term data reinforce their safety. Bempedoic acid, an inhibitor of adenosine triphosphate-citrate lyase, has been shown to add LDL-C reduction on top of statins and ezetimibe, furthermore it may be an alternative for statin intolerant patients. Inclisiran is a small interfering ribonucleic acid inhibitor that reduces the hepatic production of PCSK9 that induces robust LDL-C lowering, similar to monoclonal antibodies, with the advantage of 2 or 3 injections per year. So far, no safety signs were seen with its use. Evinacumab, a monoclonal antibody that binds angiopoietin-like protein 3 (ANGPTL3), induces robust LDL-C lowering in either homozygous familial hypercholesterolemia or severe hypercholesterolemia patients with good tolerability. Summary: Many high-risk individuals persist with elevated LDL-C, newer medications further lower LDL-C on top of standard lipid-lowering therapies and are well tolerated. Ongoing clinical trials may prove if these novel medications will reduce cardiovascular events with safety. [ABSTRACT FROM AUTHOR]

Dyslipidaemia is a well-known risk factor for the development of cardiovascular disease, a leading cause of morbidity and mortality in developed countries. As a consequence, the medical community has been dealing with this problem for decades, and traditional statin therapy remains the cornerstone therapeutic approach. However, clinical trials have observed remarkable results for a few agents effective in the treatment of elevated serum lipid levels. Ezetimibe showed good but limited results when used in combination with statins. Bempedoic acid has been thoroughly studied in multiple clinical trials, with a reduction in LDL cholesterol by approximately 15%. The first approved monoclonal antibodies for the treatment of dyslipidaemia, PCSK9 inhibitors, are currently used as second-line treatment for patients with unregulated lipid levels on statin or statin combination therapy. A new siRNA molecule, inclisiran, demonstrates great potential, particularly concerning compliance, as it is administered twice yearly and pelacarsen, an antisense oligonucleotide that targets lipoprotein(a) and lowers its levels. Volanesorsen is the first drug that was designed to target chylomicrons and lower triglyceride levels, and olezarsen, the next in-line chylomicron lowering agent, is currently being researched. The newest possibilities for the treatment of dyslipidaemia are ANGPTL3 inhibitors with evinacumab, already approved by the FDA, and EMA for the treatment of familial hypercholesterolemia. This article provides a short summary of new agents currently used or being developed for lipid lowering treatment.

Bempedoic acid (BemA) is an ATP-citrate lyase (ACLY) inhibitor used to treat hypercholesterolemia. We studied the anti-steatotic effect of BemA, and the mechanisms involved, in a model of fatty liver in female rats obtained through the administration of a high-fat diet supplemented with liquid fructose (HFHFr) for three months. In the third month, a group of rats was treated with BemA (30 mg/kg/day) by gavage. Plasma analytes, liver histology, adiposity, and the expression of key genes controlling fatty acid metabolism were determined, and PPAR agonism was explored by using luciferase reporter assays. Our results showed that, compared to HFHFr, BemA-treated rats exhibited lower body weight, higher liver/body weight, and reduced hepatic steatosis. In addition to ACLY inhibition, we found three novel mechanisms that could account for the anti-steatotic effect: (1) reduction of liver ketohexokinase, leading to lower fructose intake and reduced de novo lipogenesis; (2) increased expression of patatin-like phospholipase domain-containing protein 3, a protein related to the export of liver triglycerides to blood; and (3) PPARα agonist activity, leading to increased hepatic fatty acid β-oxidation. In conclusion, BemA may represent a novel approach to treat hepatic steatosis, and therefore to avoid progression to advanced stages of non-alcoholic fatty liver disease.

Lipids and lipoproteins are the target of many novel therapeutics and are an area with great potential for the prevention and treatment of cardiovascular disease (CVD). Reduction of low-density lipoprotein cholesterol has been the mainstay of reducing the burden of CVD, however, several other atherogenic particles have more recently come into the spotlight as potential avenues for primary and/or secondary prevention of CVD. These include triglycerides, high sensitivity C-reactive protein, apolipoprotein A, apolipoprotein C3 and lipoprotein(a). In this review, we showcase novel therapeutics to target lipid and cardiovascular risk reduction that are either in development or that have recently been approved for use. We discuss the mechanisms of action, data from clinical trials and expected effects of each therapy based on the current body of literature. [ABSTRACT FROM AUTHOR]

Dyslipidemia is a common condition that increases the risk of heart diseases and stroke. High levels of low-density lipoprotein-cholesterol (LDL-C) are correlated with a higher risk for heart disease. A drug class known as 'statins' is the gold standard for LDL-C-lowering, but its use in some patients is limited by its adverse effects of myalgias and myopathies. Use of other LDL-C-lowering agents is frequently limited by cost and degree of efficacy. Additionally, many high-risk atherosclerotic cardiovascular disease patients fail to meet LDL-C goals despite maximally tolerated statin therapy with or without the addition of a non-statin agent. This review covers the pharmacology, pharmacokinetics, clinical trials, and clinical implications of bempedoic acid. A PubMed search was conducted using the terms bempedoic, bempedoic acid, Nexletol, ETC-1002, and adenosine triphosphate citrate lyase inhibitor. Additional data were obtained from the prescribing information and relevant guidelines. All clinical trials were included. Bempedoic acid has not been shown to cause myalgias or myopathies and is likely to be competitively affordable compared to other LDL-C-lowering agents. Bempedoic acid has been shown to be superior compared to placebo and provides additional LDL-C lowering on top of maximally tolerated statin therapy or combined with ezetimibe alone. [ABSTRACT FROM AUTHOR]

Adding to the foundation of statins, ezetimibe and proprotein convertase subtilisin-kexin type 9 inhibitors (PCSK9i), novel, emerging low-density lipoprotein cholesterol (LDL-C)-lowering therapies are under development for the prevention of cardiovascular disease. Inclisiran, a small interfering RNA molecule that inhibits PCSK9, only needs to be dosed twice a year and has the potential to help overcome current barriers to persistence and adherence to lipid-lowering therapies. Bempedoic acid, which lowers LDL-C upstream from statins, provides a novel alternative for patients with statin intolerance. Angiopoetin-like 3 protein (ANGPTL3) inhibitors have been shown to provide potent LDL-C lowering in patients with homozygous familial hypercholesterolemia without major adverse effects as seen with lomitapide and mipomersen, and may reduce the need for apheresis. Finally, CETP inhibitors may yet be effective with the development of obicetrapib. These novel agents provide the clinician the tools to effectively lower LDL-C across the entire range of LDL-C-induced elevation of cardiovascular risk, from primary prevention and secondary prevention to null-null homozygous familial hypercholesterolemia patients. [ABSTRACT FROM AUTHOR]

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

Non-alcoholic fatty liver disease (NAFLD) and Non-alcoholic steatohepatitis (NASH) are chronic liver disorders, the prevalence of which is increasing worldwide. Long term High Fat Diet (HFD) induced NASH animal models closely mimic the characteristics of human NASH and hence used by investigators as a model system for studying the mechanism of action of new drugs. Bempedoic acid (ETC-1002), a ATP citrate lyase (ACLY) inhibitor that lowers the LDL cholesterol was recently approved by US FDA for the treatment of heterozygous familial hypercholesterolemia (HeFH) and established atherosclerotic cardiovascular disease (ASCVD). ACLY is one of the genes modulated in NASH patients and hence we studied the effect of ACLY inhibitor Bempedoic acid in long term HFD induced NASH animal model to understand the pharmacological benefits and the associated mechanism of action of this newly approved drug in NASH. Mice fed with 60% Kcal High Fat Diet for 32 weeks were used for the study and the animals were given Bempedoic acid for 5 weeks at doses of 10 ​mg ​kg−1, po, qd, and 30 ​mg ​kg−1, po, qd. Bempedoic acid treatment resulted in inhibition of body weight gain and improved the glycemic control. Bempedoic acid treated group showed statistically significant reduction in plasma ALT, AST, hepatic triglycerides (TG) and total cholesterol (TC), along with statistically significant reduction in steatosis score by histological analysis. Hepatic gene expression analysis showed significant reduction in inflammatory and fibrotic genes such as Mcp-1/Ccl2, Timp-1 & Col1α1. Histological analysis showed significant improvement in NAS score. Overall, Bempedoic acid alleviated HFD induced Non-Alcoholic Steatohepatitis through inhibition of body weight gain, improvement in glycemic control, reduction of hepatic triglycerides & total cholesterol, modulation of inflammatory & fibrotic genes, and improvement in NAS score. Hence, Bempedoic acid can be a potential therapeutic option for metabolic syndrome and NASH.

Nowdays a small proportion of patients with high/very high/extreme atherosclerotic cardiovascular disease risk achieves the optimal target of LDL-cholesterol, because of drug intolerance, poor adherence to the therapy, or inapplicability of the stepwise strategy in lipid lowering therapy, recommended by the current guidelines. The new oral agent bempedoic acid lowers plasma LDL-cholesterol by inhibiting adenosine triphosphate-citrate lyase, an enzyme involved in the synthesis of cholesterol, and, ultimately, by up-regulating the LDL receptors. Several clinical trials in patients with atherosclerotic cardiovascular disease or familial heterozygous hypercholesterolemia demonstrated that bempedoic acid alone or combined with statins and/or ezetimibe significantly reduced LDL-cholesterol and high-sensitivity C-reactive protein. Bempedoic acid is well tolerated with no significant increase in muscle-related symptoms, since it can be activated only in the liver but not in the skeletal muscles. Bempedoic acid provides an effective tool to further reduce LDL-cholesterol as add on therapy in patients unable to reach the target despite maximally tolerated lipid lowering therapy.

The effective and fast reduction of circulating low-density lipoprotein cholesterol (LDL-C) is a cornerstone for secondary prevention of atherosclerotic disease progression. Despite the substantial lipid-lowering effects of the established treatment option with statins and ezetimibe, a significant proportion of very-high-risk patients with cardiovascular disease do not reach the recommended treatment goal of

This article reviews seven drugs recently approved by the FDA, including indications, precautions, adverse reactions, and nursing considerations. [ABSTRACT FROM AUTHOR]

Purpose An update on clinical development of a first-in-class oral medication for adjunctive cholesterol lowering in high-risk patients with persistent elevation of low-density lipoprotein cholesterol (LDL-C) despite statin therapy is reviewed. Summary Despite the proven efficacy of statin therapy, many patients cannot reach LDL-C goals with statins alone, largely due to inadequate response or intolerance. Nonstatin treatment options to reduce LDL-C include ezetimibe, bile acid sequestrants, and proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors; however their use has been limited by modest clinical benefit or high treatment costs. Novel nonstatin treatments are in development to further address the needs of this population. Bempedoic acid is a first-in-class oral adenosine triphosphate (ATP) citrate lyase inhibitor being evaluated as an additional treatment option for high-risk patients requiring further reduction in LDL-C. Bempedoic acid has been evaluated in multiple phase 2 and phase 3 trials as monotherapy or for use in combination with ezetimibe and/or statin therapy. Treatment with bempedoic acid has been demonstrated to result in significant reductions in LDL-C and several other cardiovascular risk markers without the myalgia associated with statin therapy. Conclusion Bempedoic acid, used alone or with ezetimibe in a fixed-dose combination formulation, may be an effective alternative to current guideline-recommended nonstatin therapies in patients who do not attain adequate LDL-C lowering with maximally tolerated statin therapy and in statin-intolerant patients at risk for atherosclerotic cardiovascular disease. [ABSTRACT FROM AUTHOR]

Although numerous trials have convincingly shown benefits of statin therapy in both primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD), most showed relative risk reductions of 25–40%, and thus many individuals continue to have ASCVD events despite statin therapy. Substantial progress has been made in developing therapies that address the residual risk for ASCVD despite statin therapy. In this review, we summarize progress of currently available therapies along with therapies under development that further reduce low-density lipoprotein cholesterol and apolipoprotein B–containing lipoproteins, reduce lipoprotein(a), reduce ASCVD events in patients with high triglycerides, and directly target inflammation to reduce ASCVD risk. [ABSTRACT FROM AUTHOR]