Major Concepts in Treatment with Bempedoic Acid and Inclisiran that Clinicians Need To Know.

PURPOSE OF REVIEW: There have been recent developments of novel therapeutic agents for lipid lowering. This article reviews treatment concepts for two of the newest lipid-lowering medications. RECENT FINDINGS: Bempedoic acid inhibits adenosine citrate lyase, decreasing intracellular lipogenesis. This oral medication is a prodrug and requires activation by enzymes present in hepatocytes but absent in the skeletal muscle. Clinical trials demonstrated additive benefit with statin therapy, and it was well tolerated in statin-intolerant populations. Inclisiran uses RNA interference to prevent translation of PCSK9 mRNA. Due to its stability, it can be given as an injection every 6 months and produces consistent, durable, and potent cholesterol lowering. Bempedoic acid and inclisiran represent new avenues of treatment for the prevention and treatment of cardiovascular disease. This will allow for more comprehensive care by addressing challenges with medication adherence, such as adverse effects to prior medications as well as ease of dosing.

Special Considerations for Lipid-Lowering Therapy in Women Reflecting Recent Randomized Trials.

PURPOSE OF REVIEW: Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of mortality in women across all racial and ethnic groups within the USA. Despite robust evidence from randomized controlled trials demonstrating that treatment of hypercholesterolemia in women reduces cardiovascular events, women who are eligible for lipid-lowering therapy are less likely than men to be prescribed guideline-recommended therapy or to have therapy prescribed at the appropriate intensity. RECENT FINDINGS: Historically, women have been underrepresented in clinical trials. Recent randomized clinical trials have shown that women derive similar benefits as men when treated with lipid-lowering therapy, and recent studies demonstrate potential uses for lipid-lowering therapies that extend beyond their previously well-established indications. In this review, we will discuss lipid-lowering therapies in the context of recent clinical trials with a focus on special considerations in women.

Role of Bempedoic Acid in Clinical Practice.

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 ß-hydroxy ß-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.

Alterations in plasma triglycerides and ceramides: links with cardiac function in humans with type 2 diabetes.

Cardiac dysfunction in T2D is associated with excessive FA uptake, oxidation, and generation of toxic lipid species by the heart. It is not known whether decreasing lipid delivery to the heart can effect improvement in cardiac function in humans with T2D. Thus, our objective was to test the hypothesis that lowering lipid delivery to the heart would result in evidence of decreased "lipotoxicity," improved cardiac function, and salutary effects on plasma biomarkers of cardiovascular risk. Thus, we performed a double-blind randomized placebo-controlled parallel design study of the effects of 12 weeks of fenofibrate-induced lipid lowering on cardiac function, inflammation, and oxidation biomarkers, and on the ratio of two plasma ceramides, Cer d18:1 (4E) (1OH, 3OH)/24:0 and Cer d18:1 (4E) (1OH, 3OH)/16:0 (i.e., "C24:0/C16:0"), which is associated with decreased risk of cardiac dysfunction and heart failure. Fenofibrate lowered plasma TG and cholesterol but did not improve heart systolic or diastolic function. Fenofibrate treatment lowered the plasma C24:0/C16:0 ceramide ratio and minimally altered oxidative stress markers but did not alter measures of inflammation. Overall, plasma TG lowering correlated with improvement of cardiac relaxation (diastolic function) as measured by tissue Doppler-derived parameter e'. Moreover, lowering the plasma C24:0/C16:0 ceramide ratio was correlated with worse diastolic function. These findings indicate that fenofibrate treatment per se is not sufficient to effect changes in cardiac function; however, decreases in plasma TG may be linked to improved diastolic function. In contrast, decreases in plasma C24:0/C16:0 are linked with worsening cardiac function.

Beliefs, risk perceptions, and lipid management among patients with and without diabetes: Results from the PALM registry.

Intensive lipid management is critical to reduce cardiovascular (CV) risk for patients with diabetes mellitus (DM). METHODS: We performed an observational study of 7628 patients with (n = 2943) and without DM (n = 4685), enrolled in the Provider Assessment of Lipid Management (PALM) registry and treated at 140 outpatient clinics across the United States in 2015. Patient self-estimated CV risk, patient-perceived statin benefit and risk, observed statin therapy use and dosing were assessed. RESULTS: Patients with DM were more likely to believe that their CV risk was elevated compared with patients without DM (39.1% vs 29.3%, P < .001). Patients with DM were more likely to receive a statin (74.2% vs 63.5%, P < .001) but less likely to be treated with guideline-recommended statin intensity (36.5% vs 46.9%, P < .001), driven by the low proportion (16.5%) of high risk (ASCVD risk ≥7.5%) primary prevention DM patients treated with a high intensity statin. Patients with DM treated with guideline-recommended statin intensity were more likely to believe they were at high CV risk (44.9% vs 38.4%, P = .005) and that statins can reduce this risk (41.1% vs 35.6%, P = .02), compared with patients treated with lower than guideline-recommended statin intensity. Compared with patients with an elevated HgbA1c, patients with well-controlled DM were no more likely to be on a statin (77.9% vs 79.3%, P = .43). CONCLUSIONS: In this nationwide study, the majority of patients with DM were treated with lower than guideline-recommended statin intensity. Patient education and engagement may help providers improve lipid therapy for these high-risk patients.

Correction to: Recognition and Treatment of Homozygous Familial Hypercholesterolemia by Primary Care Physicians: a Survey from the National Lipid Association.

The funding information in this paper was presented incorrectly.

Practice-level variation in statin use and low-density lipoprotein cholesterol control in the United States: Results from the Patient and Provider Assessment of Lipid Management (PALM) registry.

BACKGROUND: Adherence to guideline-recommended statin recommendations in the United States is suboptimal. Patients' likelihood to be treated according to guidelines may vary by the practice in which they are treated. METHODS: Variation in the use of statin therapy in 5445 patients, with known or at high risk for atherosclerotic cardiovascular disease (ASCVD) and meeting a statin treatment indication, was examined across 74 US Patient and Provider Assessment of Lipid Management (PALM) Registry clinics. Multivariable generalized linear mixed modeling was used to determine the median odds ratio (MOR) for statin use and 2013 American College of Cardiology/American Heart Association guideline-recommended statin intensity by practice. MOR quantifies between-practice variation by comparing the odds of receiving guideline-recommended statin treatment in a patient from a randomly selected practice with a similar patient from another random practice. Risk-adjusted low-density lipoprotein cholesterol (LDL-C) control (<100 and <70 mg/dL) was compared among practice tertiles based on percentage of eligible patients receiving recommended statin intensity. RESULTS: Among 74 practices (43.2% cardiology) comprised of 300 healthcare providers enrolling 5445 patients (56.2% with ASCVD), statin use at the guideline-recommended intensity at practices varied widely (12.7-71.4%; adjusted MOR 1.45, 95% confidence interval [CI] 1.35-1.64). Results were consistent when evaluated for any statin use overall (adjusted MOR 1.75, 95% CI 1.48-1.99) and when stratified by primary versus secondary prevention patients. Relative to practices with lowest or mid-tertile statin use of statins, highest tertile clinics were more frequently cardiology practices (68.0% vs 48.0% vs 12.5%, P < .001). Compared with lowest tertile clinics, patients at highest tertile clinics were more likely to achieve LDL-C <70 mg/dL (adjusted odds ratio [OR] 1.49, 95% CI 1.08-2.04) and <100 mg/dL (adjusted OR 1.78, 95% CI 1.41-2.25). CONCLUSIONS: US clinics varied widely in their adherence to guideline recommendations for statin therapy, which contributed to significant differences in LDL-C levels.

Effect of Bempedoic Acid vs Placebo Added to Maximally Tolerated Statins on Low-Density Lipoprotein Cholesterol in Patients at High Risk for Cardiovascular Disease: The CLEAR Wisdom Randomized Clinical Trial.

Importance: Additional treatment options are needed for patients who do not achieve sufficient reduction in low-density lipoprotein cholesterol (LDL-C) level with available lipid-lowering therapies. Objective: To assess the efficacy of bempedoic acid vs placebo in patients at high cardiovascular risk receiving maximally tolerated lipid-lowering therapy. Design, Setting, and Participants: Phase 3, randomized, double-blind, placebo-controlled clinical trial conducted at 91 clinical sites in North America and Europe from November 2016 to September 2018, with a final date of follow-up of September 22, 2018. A total of 779 patients with atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or both met randomization criteria, which included LDL-C level 70 mg/dL (1.8 mmol/L) or greater while receiving maximally tolerated lipid-lowering therapy. Interventions: Patients were randomized 2:1 to treatment with bempedoic acid (180 mg) (n = 522) or placebo (n = 257) once daily for 52 weeks. Main Outcomes and Measures: The primary end point was percent change from baseline in LDL-C level at week 12. Secondary measures included changes in levels of lipids, lipoproteins, and biomarkers. Results: Among 779 randomized patients (mean age, 64.3 years; 283 women [36.3%]), 740 (95.0%) completed the trial. At baseline, mean LDL-C level was 120.4 (SD, 37.9) mg/dL. Bempedoic acid lowered LDL-C levels significantly more than placebo at week 12 (-15.1% vs 2.4%, respectively; difference, -17.4% [95% CI, -21.0% to -13.9%]; P < .001). Significant reductions with bempedoic acid vs placebo were observed at week 12 for non-high-density lipoprotein cholesterol (-10.8% vs 2.3%; difference, -13.0% [95% CI, -16.3% to -9.8%]; P < .001), total cholesterol (-9.9% vs 1.3%; difference, -11.2% [95% CI, -13.6% to -8.8%]; P < .001), apolipoprotein B (-9.3% vs 3.7%; difference, -13.0% [95% CI, -16.1% to -9.9%]; P < .001), and high-sensitivity C-reactive protein (median, -18.7% vs -9.4%; difference, -8.7% [asymptotic confidence limits, -17.2% to -0.4%]; P = .04). Common adverse events included nasopharyngitis (5.2% vs 5.1% with bempedoic acid and placebo, respectively), urinary tract infection (5.0% vs 1.9%), and hyperuricemia (4.2% vs 1.9%). Conclusions and Relevance: Among patients at high risk for cardiovascular disease receiving maximally tolerated statins, the addition of bempedoic acid compared with placebo resulted in a significant lowering of LDL-C level over 12 weeks. Further research is needed to assess the durability and clinical effect as well as long-term safety. Trial Registration: ClinicalTrials.gov Identifier: NCT02991118.

Lipid management in contemporary community practice: Results from the Provider Assessment of Lipid Management (PALM) Registry.

BACKGROUND: The latest cholesterol guidelines have shifted focus from achieving low-density lipoprotein cholesterol (LDL-C) targets toward statin use and intensity guided by atherosclerotic cardiovascular disease (ASCVD) risk. METHODS: Statin use and intensity were evaluated in 5,905 statin-eligible primary or secondary prevention patients from 138 PALM Registry practices. RESULTS: Overall, 74.7% of eligible adults were on statins; only 42.4% were on guideline-recommended intensity. Relative to primary prevention patients, ASCVD patients were more likely to be on a statin (83.6% vs 63.4%, P<.0001) and guideline-recommended intensity (47.3% vs 36.0%, P<.0001). Men were more likely than women to be prescribed recommended intensity for primary (odds ratio [OR] 1.87, 95% CI 1.49-2.34) and secondary (OR 1.47, 95% CI 1.26-1.70) prevention. In primary prevention, increasing age, diabetes, obesity, hypertension, and lower 10-year ASCVD risk were associated with increased odds of receiving recommended intensity. Among ASCVD patients, those with coronary artery disease were more likely to be on recommended intensity than cerebrovascular or peripheral vascular disease patients (OR 1.71, 95% CI 1.41-2.09), as were those seen by cardiologists (OR 1.43, 95% CI 1.12-1.83). Median LDL-C levels were highest among patients not on statins (124.0 mg/dL) and slightly higher among those on lower-than-recommended intensity compared with recommended-therapy recipients (88.0 and 84.0 mg/dL, respectively; P≤.0001). CONCLUSIONS: In routine contemporary practice, 1 in 4 guideline-eligible patients was not on a statin; less than half were on the recommended statin intensity. Untreated and undertreated patients had significantly higher LDL-C levels than those receiving guideline-directed statin treatment.

Design and rationale for the Patient and Provider Assessment of Lipid Management (PALM) registry.

BACKGROUND: Despite improvements in diagnosis and treatment, the prevalence of hyperlipidemia among adults in the United States remains high. Data are limited on treatment patterns and patient perceptions of cardiovascular disease risk since the release of new lipid guidelines. OBJECTIVES: The objectives of the PALM registry are to assess contemporary patterns of lipid-lowering therapy use among adults receiving care in a nationally representative cohort of community clinics, determine consistency of treatment with varying lipid guidelines, identify factors affecting use of lipid-lowering therapy including patient-reported statin intolerance, and assess patient and provider knowledge of cardiovascular risk reduction goals. STUDY DESIGN: The PALM registry will enroll 7,500 patients likely to be considered for lipid-lowering therapy from 175 cardiology, primary care, and endocrinology practices across the United States. In this cross-sectional, observational registry, a novel tablet-based platform will be used to collect patient-reported knowledge, attitudes, and beliefs regarding cardiovascular risk reduction and lipid management. Chart abstraction and core laboratory lipid levels will describe current lipid management. Provider surveys will assess perception of current lipid-lowering goals and barriers to optimal cardiovascular risk reduction. CONCLUSION: The PALM registry will allow for better understanding of current practice patterns, patient experiences, and patient and provider attitudes toward cholesterol management for cardiovascular disease risk reduction. These data can be used to better understand gaps in care and design targeted interventions to improve uptake of lipid-lowering therapies for cardiovascular risk reduction.

Efficacy and safety of bempedoic acid in patients with heterozygous familial hypercholesterolemia: analysis of pooled patient-level data from phase 3 clinical trials.

BACKGROUND: Patients with heterozygous familial hypercholesterolemia (HeFH) often cannot reach guideline-recommended low-density lipoprotein cholesterol (LDL-C) goals despite multidrug therapy. OBJECTIVE: To evaluate the efficacy and safety of bempedoic acid as an add-on therapy for lowering LDL-C in patients with HeFH. METHODS: 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. RESULTS: 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%). CONCLUSION: 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.

Identification of people with heterozygous familial hypercholesterolemia.

PURPOSE OF REVIEW: Familial hypercholesterolemia is an underdiagnosed autosomal codominant genetic condition associated with significantly increased risk of early cardiovascular disease when untreated. Early diagnosis and treatment decrease the excess risk, and strategies for identification of affected individuals are being developed worldwide. This review will discuss, from a clinician's perspective, some of the issues involved in identifying people with familial hypercholesterolemia. RECENT FINDINGS: Several sets of recommendations have been published outlining the strategies for identification of people with familial hypercholesterolemia in various countries and regions. These include Australasia, Europe, and the USA. SUMMARY: Continuing efforts to find the best methods for identification of people with familial hypercholesterolemia are needed to ensure that this very treatable inherited condition is diagnosed early enough to prevent the development of atherosclerotic vascular disease.

Management of patients with statin intolerance.

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.

Evaluation of the efficacy and safety of bempedoic acid in women and men: Pooled analyses from phase 3 trials.

BACKGROUND AND AIMS: Sex-specific differences in the response to lipid-lowering therapies have been reported. Here, we assessed the effect of bempedoic acid in women and men using pooled, patient-level data from four phase 3 clinical trials of bempedoic acid. METHODS: Patients were grouped into two pools: 1) atherosclerotic cardiovascular disease (ASCVD) and/or heterozygous familial hypercholesterolemia (HeFH) "on statins" and 2) "low-dose or no statin". Percent changes from baseline to at least week 12 in low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), apolipoprotein B (Apo B), and high-sensitivity C-reactive protein (hsCRP), as well as safety, were analyzed by statin pool and sex. RESULTS: Overall, 3623 patients were included (bempedoic acid, 2425; placebo, 1198). Significant reductions in lipid parameters and hsCRP were observed with bempedoic acid vs. placebo in both sexes in the ASCVD and/or HeFH on statins (n = 3009) and the low-dose or no statin (n = 614) pools (p ≤ 0.002). Compared with men, women had significantly greater placebo-corrected reductions in LDL-C (-21.2% vs. -17.4%; p = 0.044), non-HDL-C (-17.3% vs. -12.1%; p = 0.003), TC (-13.8% vs. -10.5%; p = 0.012), and Apo B (-16.0% vs. -11.3%; p = 0.004) in the ASCVD and/or HeFH on statins pool. Women had similar reductions to men in lipid parameters in the low-dose or no statin pool and hsCRP in both pools. The safety of bempedoic acid was comparable between sexes. CONCLUSIONS: In this pooled analysis, women experienced significant improvements in levels of LDL-C and other lipid parameters with bempedoic acid.

Sex-related differences in premature cardiovascular disease in familial hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia (FH) is associated with an increased prevalence of premature atherosclerotic cardiovascular disease (ASCVD), however, little is known about sex-specific differences in premature ASCVD and its risk factors. OBJECTIVE: The present study seeks to assess the burden and risk factors for premature ASCVD among men and women with FH. METHODS: In this study we retrospectively examined sex-specific differences in ASCVD prevalence, risk factor burdens, and lipid treatment outcomes in 782 individuals with clinically or genetically confirmed FH treated in 5 U.S. lipid and genetics clinics. A generalized linear model using Binomial distribution with random study site effect and sex-stratified analysis was used to determine the strongest predictors of premature ASCVD, and lipid treatment outcomes. Covariates included age, sex, diabetes mellitus (DM), hypertension, and current smoking. RESULTS: Among the cohort, 98/280 men (35%) and 89/502 women (18%) had premature ASCVD (defined as <55 years in men and <65 years in women). Women with premature ASCVD had higher mean treated total cholesterol (216 vs. 179 mg/dl, p=<0.001) and LDL-C (135 vs. 109 mg/dl, p= 0.005). CONCLUSION: These data confirm that high percentages of women and men with FH develop premature ASCVD, and suggest that FH may narrow the observed sex difference in premature ASCVD onset. These data support more aggressive prevention and treatment strategies in FH, including in women, to reduce non-lipid risk factors and residual hypercholesterolemia.

Designing implementation strategies to improve identification, cascade testing, and management of families with familial hypercholesterolemia: An intervention mapping approach.

Introduction: Familial hypercholesterolemia (FH) is a common inherited cholesterol disorder that, without early intervention, leads to premature cardiovascular disease. Multilevel strategies that target all components of FH care including identification, cascade testing, and management are needed to address gaps that exist in FH care. We utilized intervention mapping, a systematic implementation science approach, to identify and match strategies to existing barriers and develop programs to improve FH care. Methods: Data were collected utilizing two methods: a scoping review of published literature, related to any component of FH care, and a parallel mixed method study using interviews and surveys. The scientific literature was searched using key words including "barriers" or "facilitators" and "familial hypercholesterolemia" from inception to December 1, 2021. The parallel mixed method study recruited individuals and families with FH to participate in either dyadic interviews (N = 11 dyads/22 individuals) or online surveys (N = 98 respondents). Data generated from the scoping review, dyadic interviews, and online surveys were used in the 6-step intervention mapping process. Steps 1-3 included a needs assessment, development of program outcomes and creation of evidence-based implementation strategies. Steps 4-6 included program development, implementation, and evaluation of implementation strategies. Results: In steps 1-3, a needs assessment found barriers to FH care included underdiagnosis of the condition which led to suboptimal management due to a myriad of determinants including knowledge gaps, negative attitudes, and risk misperceptions by individuals with FH and clinicians. Literature review highlighted barriers to FH care at the health system level, notably the relative lack of genetic testing resources and infrastructure needed to support FH diagnosis and treatment. Examples of strategies to overcome identified barriers included development of multidisciplinary care teams and educational programs. In steps 4-6, an NHLBI-funded study, the Collaborative Approach to Reach Everyone with FH (CARE-FH), deployed strategies that focused on improving identification of FH in primary care settings. The CARE-FH study is used as an example to describe program development, implementation, and evaluation techniques of implementation strategies. Conclusion: The development and deployment of evidence-based implementation strategies that address barriers to FH care are important next steps to improve identification, cascade testing, and management.