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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]

• 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]

• 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]

Cardiovascular disease (CVD) is a chronic non-communicable disease (NCD) and the predominant cause of morbidity and mortality worldwide. Substantial reductions in the CVD prevalence have been achieved in recent years by the attenuation of risk factors (particularly hypertension and dyslipidaemias) in primary and secondary prevention. Despite the remarkable success of lipid lowering treatments, and of statins in particular, in reducing the risk of CVD, there is still an unmet clinical need for the attainment of guideline lipid-targets in even 2/3 of patients. Bempedoic acid, the first in-class inhibitor of ATP-citrate lyase presents a new approach to lipid-lowering therapy. By reducing the endogenous production of cholesterol, upstream of the rate-limiting enzyme HMG-CoA-reductase, i.e., the target of statins, bempedoic acid reduces circulating plasma concentrations of low-density lipoprotein cholesterol (LDL-C), and major adverse CVD events (MACE). Bempedoic acid has the potential to contribute to the reduction of CVD risk not only as monotherapy, but even further as part of a lipid-lowering combination therapy with ezetimibe, reducing LDL-C cholesterol up to 40%. This position paper of the International Lipid Expert Panel (ILEP) summarises the recent evidence around the efficacy and safety of bempedoic acid and presents practical recommendations for its use, which complement the 'lower-is-better-for-longer' approach to lipid management, which is applied across international guidelines for the management of CVD risk. Practical evidence-based guidance is provided relating to the use of bempedoic acid in atherosclerotic CVD, familial hypercholesterolaemia, and statin intolerance. Although there are still no sufficient data avilable for the role of bempedoic acid in the primary prevention of CVD, its favourable effects on plasma glucose and inflammatory markers makes this drug a rational choice in the patient-centred care of specific groups of primary prevention. [ABSTRACT FROM AUTHOR]

Statins are first-line therapy for treating dyslipidemia because of their low-density lipoprotein cholesterol (LDL-C) lowering efficacy, superior event-reduction data and unrivaled cost-effectiveness. Yet, many people are intolerant of statins, whether due to true adverse events or the nocebo effect, so within one year about two-thirds of primary prevention patients and one-third of secondary prevention patients are no longer taking their prescription. Statins still dominate this landscape, but other agents, often used in combination, potently reduce LDL-C levels, regress atherosclerosis and lower risk of major adverse cardiovascular events (MACE). Ezetimibe lowers LDL-C by reducing intestinal absorption of cholesterol. Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) lower LDL-C by increasing the number and durability of hepatic LDL receptors. Bempedoic acid reduces hepatic cholesterol synthesis. Ezetimibe, PCSK9i and bempedoic are evidence-based, non-statin therapies that synergistically lower LDL-C and reduce risk of MACE; they also have benign side-effect profiles and are generally well tolerated. [ABSTRACT FROM AUTHOR]

• Bempedoic acid (BA) reduces hsCRP with minimal effect on fibrinogen, IL-6, or Lp(a). • No correlation between lipid changes and hsCRP changes with BA. • Findings for BA are almost identical to that of statin therapy. • BA may be an option to treat residual inflammatory and residual cholesterol risk. While bempedoic acid (BA), an inhibitor of ATP citrate lyase, lowers high-sensitivity C-reactive protein (hsCRP) and low-density lipoprotein cholesterol (LDL-C), the mechanisms underlying the potential anti-inflammatory effects of BA are uncertain, as are effects of this agent on lipoprotein(a). To address these issues, we conducted a secondary biomarker analysis of the randomized placebo-controlled multi-center CLEAR Harmony trial which included 817 patients with known atherosclerotic disease and/or heterozygous familial hypercholesterolemia who were taking maximally tolerated statin therapy and had residual inflammatory risk, defined as a baseline hsCRP ≥2 mg/L. Participants were randomly allocated in a 2:1 ratio to oral BA 180 mg once daily or matching placebo. Placebo-corrected median percent changes (95% CI) from baseline to 12 weeks associated with BA were −21.1% (−23.7 to −18.5) for LDL-C; −14.3% (−16.8 to −11.9) for non–high-density lipoprotein cholesterol; −12.8% (−14.8 to −10.8) for total cholesterol; −8.3% (−10.1 to −6.6) for high-density lipoprotein cholesterol (HDL-C); −13.1% (−15.5 to −10.6) for apolipoprotein B; 8.0% (3.7 to 12.5) for triglycerides; −26.5% (−34.8 to −18.4) for hsCRP; 2.1% (−2.0 to 6.4) for fibrinogen, −3.7% (−11.5, 4.3) for interleukin-6; and 2.4% (0.0 to 4.8) for lipoprotein(a). There was no correlation between BA associated lipid changes and BA associated change in hsCRP (all r <0.05), except for a weak correlation with HDL-C (r = 0.12). Thus, the pattern of lipid lowering and inflammation inhibition with BA is almost identical to what is observed with statin therapy suggesting that BA could be a useful treatment option to address both residual cholesterol risk and residual inflammatory risk. ClinicalTrials.gov Identifier: NCT02666664; https://clinicaltrials.gov/ct2/show/NCT02666664. [ABSTRACT FROM AUTHOR]

Purpose Of Review: Cardiovascular disease is the leading cause of death in the United States with incidence expected to increase in the coming decades. Recent years have produced a variety of new and novel therapeutics aimed at reducing the global burden of cardiovascular disease. This review highlights these recent advancements.Recent Findings: In addition to more rigorous therapeutic thresholds for traditional LDL lowering agents such as statins, recent studies have developed new pathways of lipid lowering for both typical cardiovascular disease and complex, genetic lipid disorders. This includes inhibition of the cholesterol synthesis enzyme ATP citrate lyase with bempedoic acid, prevention of PCSK9 mRNA translation with inclisiran, inhibition of the lipoprotein lipase inhibitor angiopoetin like 3 protein with evinacumab and the use of anti-sense oligonucleotides to lower lipoprotein(a) levels. Icosapent ethyl, while remaining a topic of debate and controversy, demonstrates efficacy in cardiovascular risk reduction when all available data are examined. Lastly fibrate therapy continues to produce negative results in terms of cardiovascular disease reduction.Summary: Recent years have yielded breadth and depth to cardiovascular treatments. This expanded armamentarium will allow for more effective and more consistent treatment and prevention of cardiovascular disease. [ABSTRACT FROM AUTHOR]

• There are many patients who will not reach LDL-C goals with statins. • Several novel lipid-lowering agents have come to the market recently. • Clinicians need to be familiar with the use of novel LLTs in their practice. • Lipids other than LDL-C [HDL-C or Lp(a)] are the pharmacotherapy targets for future. Dyslipidemia is a major modifiable risk factor for developing atherosclerotic cardiovascular disease. Despite increasing high intensity statin prescription and adherence to statin therapy, a considerable number of patients will not reach the guideline directed goals due to statin intolerance, lack of adherence or treatment efficacy. Several new lipid lowering medications have received approval by regulatory agencies in the past decade including proprotein convertase subtilisin/kexin type 9 modulators, ATP-citrate lyase inhibitors, angiopoietin-like 3 inhibitors, lomitapide, and icosapent ethyl. Although approved by regulatory agencies, these medications are still under-prescribed worldwide which may be related to cost issues, lack of cardiovascular outcome results, or clinicians not being familiar with their use. In this review, we propose a practical stepwise approach including each class' efficacy, place in therapy, adverse effects, warnings and precautions, and monitoring parameters. This information can help the clinicians to prescribing these novel lipid lowering medications to achieve treatment goals and reduce the risk of atherosclerotic cardiovascular disease. The aim is to shift the paradigm for high-intensity statins from watch and wait to initial combination therapy for high-risk patients. The stepwise approach to prescribing novel lipid-lowering medications; AF: Atrial Fibrillation; ASCVD : Atherosclerotic Cardiovascular Disease; CV: Cardiovascular; GI: Gastrointestinal; HDL-C : High Density Lipoprotein-Cholesterol; HoFH : Homozygous Familial Hypercholesterolemia; IPE : Icosapent Ethyl; LDL-C: Low Density Lipoprotein-Cholesterol; LLT : Lipid Lowering Therapy; mAb: Monoclonal Antibody; PCSK9 : Proprotein Convertase Subtilisin/Kexin type 9; TG : Triglyceride. [Display omitted] [ABSTRACT FROM AUTHOR]

• 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]

• 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]

Bempedoic acid is a novel adenosine triphosphate citrate lyase inhibitor shown to reduce low density lipoprotein cholesterol when used as an adjunct lipid-lowering therapy in patients with high cardiovascular disease (CVD) risk. Our analysis aimed to determine the price at which bempedoic acid would be cost-effective from the Australian health care perspective. A Markov model was designed using data from the Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen (CLEAR) Harmony trial, to model the clinical outcomes and costs of 1000 patients treated with bempedoic acid over a lifetime horizon. Relevant health states were " Alive with CVD," "Alive with recurrent CVD," and " Dead." With annual cycles, patients were at risk of a nonfatal myocardial infarction, coronary revascularization, and death from CVD or non-CVD causes. Costs and utilities were obtained from published sources. Outcomes of interest were the incremental cost-effectiveness ratios in terms of cost per quality-adjusted life year (QALY) gained and cost per year of life saved. Outcomes were discounted at 5% per annum. Among 1000 individuals, bempedoic acid in addition to statin therapy was estimated to save 122 (discounted) years of life and 103 (discounted) QALYs compared with statin therapy alone. At an acquisition cost of AU$584.40 per year (USD$397.01), bempedoic acid would be considered cost-effective within the Australian setting, with an incremental cost-effectiveness ratio of AU$49,890 per QALY gained (USD$33,893) and AU$42,433 per year of life saved (USD$28,827). Bempedoic acid may be cost-effective within the Australian health care setting at an annual acquisition price less than $600. • Bempedoic acid is a novel adjunct lipid-lowering therapy in cardiovascular disease. • CLEAR Harmony demonstrated bempedoic acid reduces low-density lipoprotein. • A Markov model was built to determine the price at which cost-effectiveness occurs. • The Markov model simulated the clinical outcomes and costs over a lifetime. • In Australia, cost-effectiveness is achieved when priced <$600 per person per annum. [ABSTRACT FROM AUTHOR]

Atherosclerotic cardiovascular disease (ASCVD) is the main cause of morbidity and mortality in the US. ASCVD is caused by elevated levels of ApoB lipoproteins, which over many years penetrate the arterial subendothelial space leading to plaque growth and eventually rupture causing clinical symptoms. ApoB lipoprotein levels are approximated in clinical practice by LDL-C measurement. LDL-C lowering agents (statins, ezetimibe, and PCSK9 inhibitors) reduce cardiovascular risk in primary and secondary prevention proportionally to LDL-C reduction (23% per 1 mmol/L of LDL). However, for a variety of reasons, many patients do not achieve their recommended LDL-C levels using currently available therapies. This has prompted the development of new LDL-C lowering drugs in the hope to reduce cardiovascular risk, such as bempedoic acid, inclisiran, gemcabene, and evinacumab. Drugs targeting other lipids (triglycerides, HDL-C, lipoprotein (a)), intravascular inflammation or acting by other mechanisms also have a role in atherosclerosis prevention, however, they will not be covered in this review.Abbreviations: ACLY: (ATP-citrate lyase); ANGPTL: (angiopoietin-like protein 3); ASCVD: (atherosclerotic cardiovascular disease); BPA: (bempedoic acid); CETP (cholesteryl ester transfer protein); CV: (cardiovascular); CVD: (cardiovascular diseases); FH (familial hypercholesterolemia); HMGCR (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase); HoFH (homozygous FH); LDL-C: (low density lipoprotein cholesterol); LDL-P: (low density lipoprotein particle); LDLr: (low density lipoprotein receptor); NPC1L1: (Niemann-Pick C1-like 1 protein); PCSK9: (proprotein convertase subtilisin/kexin type 9); SREBP-2: (sterol regulatory element binding protein 2). [ABSTRACT FROM AUTHOR]

Bempedoic acid (BA) has shown significant progress in reducing cholesterol levels and is relatively free from the many side effects encountered with the use of other hyperlipidemic drugs such as statins. However, its efficacy in patients with statin intolerance is controversial with inconsistent results among studies. An electronic literature search was performed using various databases such as Medline, Google Scholar, and the International Registry of Clinical Trials. The primary endpoint was the change in LDL-C levels. The secondary endpoints included changes in HDL-C, non-HDL-C, triglycerides (TG), clinical outcomes such as MACE, all-cause mortality (ACM), cardiovascular mortality, myocardial infarction (MI), and additional safety outcomes. The least-square mean (LSM) percent change for assessing changes in lipid parameter levels from the baseline and the risk ratio (RR) were used for the evaluation of binary endpoints, with statistical significance set at p<0.05. Random-effects meta-analyses were performed for all the outcomes. Our analysis included 5 randomized controlled trials (RCTs) with a total of 18,848 participants. BA showed a significant reduction in LDL-C [LSM difference in %: -25.24; 95 % CI: -30.79 to -19.69; p < 0.00001], total cholesterol [LSM difference in %:-21.28; 95 % CI:-30.58 to-11.98; p < 0.00001], non-HDL-C [LSM difference in %: -23.27; 95 % Cl: -29.80 to -16.73 p < 0.00001], and HDL-C [LSM difference in %:-3.37, 95 % CI:-3.73 to-3.01, p < 0.00001] compared to placebo. In terms of clinical efficacy, BA was associated with a lower risk of coronary revascularization [RR:0.81; 95 % CI:0.66 to 0.99; p = 0.04], hospitalization for unstable angina [RR:0.67; 95 % CI:0.50 to 0.88; p = 0.005], and myocardial infarction [RR:0.76; 95 % CI:0.66 to 0.88; p = 0.0004]. No significant difference was observed in MACE [RR:0.81; p = 0.15], ACM [RR:0.86; p = 0.46], cardiovascular-related mortality [RR:0.79; p = 0.44], and stroke [RR:0.83; p = 0.08] between the two groups. In terms of safety efficacy, the risk for myalgia was significantly lower in BA-treated patients than in placebo [RR:0.80; p = 0.0002], while the risk for gout [RR:1.46; p < 0.0001] and hyperuricemia [RR:1.93; p < 0.00001] was higher for BA than for placebo. The risks for other adverse effects, such as neurocognitive disorder, nasopharyngitis urinary tract infection, upper respiratory infection, muscular disorder, and worsening hyperglycemia/DM were comparable between the two groups. Our analysis demonstrated that BA significantly reduced the levels of LDL-C, total cholesterol, non-HDL-C, HDL-C, ApoB, and hs-CRP compared with the placebo group. Additionally, patients who received BA had a lower likelihood of coronary revascularization and hospitalization due to unstable angina, MI, and myalgia. Further large-scale RCTs are required to generate more robust evidence. [ABSTRACT FROM AUTHOR]

• The meta-analysis underscores Bempedoic acid's efficacy in significantly reducing LDL-C levels, positioning it as a potent therapeutic alternative, especially for statin-intolerant or high-risk patients. • Bempedoic acid demonstrates a notable decrease in the risk of major adverse cardiac events (MACE), enhancing its profile as a protective agent in cardiovascular health management. • The treatment showcases a favorable safety profile, with no significant increase in adverse events compared to controls, reinforcing its suitability for long-term use. • The comprehensive analysis, spanning diverse patient groups and study designs, bolsters the reliability and applicability of the findings across various populations. • Despite the convincing benefits, the presence of heterogeneity in the analyzed studies necessitates cautious interpretation of results, advocating for more standardized and rigorous clinical trials. The management of LDL-C levels is pivotal in the prevention of cardiovascular morbidity, particularly among patients at high risk or those intolerant to statins. Bempedoic acid emerges as a novel agent in this therapeutic arena. This systematic review and meta-analysis endeavor to quantify the effectiveness of Bempedoic acid in attenuating LDL-C levels and explore its impact on cardiovascular morbidity, emphasizing its role as an adjunctive or alternative therapy in statin-intolerant or high-risk patients. A comprehensive search spanning PubMed, Google Scholar, and Cochrane Library databases furnished studies for this review. The inclusion was critiqued based on predefined PICOS parameters, ensuring a robust analytical framework. Bempedoic acid showcased a significant plunge in LDL-C levels (MD -20.69 %, 95 % CI [-23.20, -18.19]), outperforming placebo and ezetimibe monotherapy. The cardioprotective effect was further echoed with a reduced risk of major adverse cardiac events (MACE) in the Bempedoic acid cohort (RR 0.86, 95 % CI [0.80, 0.94]). However, a dive into the safety profile revealed no substantial augmentation in adverse events, affirming its tolerance and efficacy. Bempedoic acid represents a potent therapeutic ally, affirming its capacity to significantly pare down LDL-C levels and curtail cardiovascular events. Its favorable safety profile underscores its suitability, especially among those with statin intolerance or individuals categorized within the high-risk vascular bracket, necessitating a paradigm shift in current lipid management strategies. [ABSTRACT FROM AUTHOR]

Hyperlipidemia plays a crucial role in the underlying pathogenesis of multiple cardiovascular diseases (CVD), including coronary artery disease, peripheral arterial disease, carotid stenosis, and heart failure. The risk of developing such diseases in the diabetic population is relatively high. Diabetes mellitus (DM) is an independent risk factor for premature atherosclerosis. The hallmark of DM dyslipidemia is a demonstrably high level of atherogenic triglyceride rich lipids including very low-density lipoprotein, chylomicrons, and small dense low-density lipoprotein (LDL). Moderate to high intensity statins, targeting LDL cholesterol reduction, remain the cornerstone in the management of this unique disorder. Many 'non-statin' drugs have recently been studied in the DM patients who were either on a 'maximally tolerated statin' or 'statin intolerant'. Ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are particularly important and were incorporated in the recent guidelines by the European Society of Cardiology, American College of Cardiology, American Heart Association, and American Diabetes Association. Icosapent Ethyl has garnered huge interest this year following publication of the REDUCE-IT trial. There are several newer hypolipidemic drugs, including Bempedoic acid, Inclisiran and RVX-208, that are in different phases of clinical trials. In this article, we review the underlying pathophysiology of DM dyslipidemia, existing guidelines related to its management, and the potential of newer hypolipidemic and anti-inflammatory drugs being incorporated in the management of DM. [ABSTRACT FROM AUTHOR]

Bempedoic acid is an oral, once-daily, first-in-class medication being developed to treat hypercholesterolemia. The aim of the study was to assess the low-density lipoprotein cholesterol (LDL-C)–lowering efficacy of bempedoic acid added to stable high-intensity atorvastatin background therapy and multiple-dose plasma pharmacokinetics of atorvastatin alone and combined with steady-state bempedoic acid. This was a phase 2 study in patients with hypercholesterolemia (NCT02659397). Patients received once-daily open-label atorvastatin 80 mg for 4 weeks then were randomized 2:1 at baseline to receive double-blind bempedoic acid 180 mg (n = 45) or placebo (n = 23) plus open-label atorvastatin 80 mg for 4 weeks. Efficacy was assessed 4 weeks after randomization. Atorvastatin and metabolites' steady-state levels were analyzed before first dosing with bempedoic acid and after 2 weeks of treatment. The 4-week stabilization phase with 80 mg atorvastatin resulted in approximately 40% lowering of LDL-C values from screening. The placebo-adjusted least squares mean lowering of LDL-C from baseline to Day 29 with bempedoic acid was 22% (P =.003). Placebo-adjusted reductions from baseline with bempedoic acid also were significant for total cholesterol (−10%; P =.014), non–high-density lipoprotein cholesterol (−13%; P =.015), apolipoprotein B (−15%; P =.004), and high-sensitivity C-reactive protein (−44%; P =.002). Point estimates of bempedoic acid effects on steady-state atorvastatin and ortho-hydroxy atorvastatin area under the curve were <30% and not clinically meaningful. Bempedoic acid 180 mg added to stable high-dose atorvastatin therapy effectively lowers LDL-C in patients with hypercholesterolemia without causing clinically important increases in atorvastatin exposure. • Bempedoic acid added to high-dose atorvastatin significantly lowers low-density lipoprotein cholesterol. • Atherogenic lipids and high-sensitivity C-reactive protein are lowered by bempedoic acid added to atorvastatin. • Bempedoic acid does not meaningfully increase steady-state atorvastatin exposure. • The combination of bempedoic acid and high-dose atorvastatin is well tolerated. [ABSTRACT FROM AUTHOR]

Atherosclerotic cardiovascular disease is a leading cause of morbidity and mortality, and statins have become a cornerstone in its treatment and prevention. Despite the well-documented benefits of statins, many patients stop taking them, with adverse muscle symptoms being a commonly cited reason. Although some statin-associated adverse muscle effects are real, some can be attributed to the nocebo effect, which is the patient's perception of harm. The purpose of this article is to review the literature on statin safety, particularly that related to muscle, to analyze adverse effects, and to propose various treatment strategies for the statin intolerant patient. [ABSTRACT FROM AUTHOR]