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• 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]

• 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]

• 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]

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.)

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]

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]