Non-statin Lipid-lowering Therapy Research Articles

Abstract 4140116: Adherence to Lipid Lowering Therapy among US Veterans with Atherosclerotic Cardiovascular Disease

Introduction/Background: US Veterans experience a high burden of cardiovascular disease (CVD). Improved adherence to lipid-lowering therapy (LLT) is strongly associated with reducing low-density lipoprotein cholesterol (LDL-C), which has the potential to reduce morbidity and mortality among Veterans with atherosclerotic cardiovascular disease (ASCVD). Goals/Aims: To describe adherence to statin and non-statin LLT among US Veterans with ASCVD. Methods/Approach: Using Veterans’ Health Administration (VHA) electronic health records from January 1, 2003, to December 31, 2019, we identified regular users of the VHA who were on at least one LLT within 12-months after ASCVD diagnosis. ASCVD diagnosis was identified using ICD9/10 and Current Procedural Terminology codes. Medication possession ratio (MPR) was calculated as the sum of days’ supply for all fills of a given LLT during 12-, 24-, and 36-month follow-up, divided by the number of days in the follow-up period. Medication adherence was defined as MPR ≥ 0.80. Results/Data (descriptive and inferential statistics): The total number of Veterans on an LLT within 12-months after ASCVD diagnosis was 2,194,684 [mean (SD) age=68 (10) years, 98% male, and 75% white race]. Overall proportion of patients who were adherent to LLT was 68%, 64%, and 62%, at 12-, 24-, and 36-months post ASCVD diagnosis, respectively (Table). Conclusion(s): Suboptimal adherence to LLT was observed in one third of US Veterans with ASCVD. Adherence rates were highest in the first 12 months post ASCVD diagnosis. Future studies are needed to understand factors contributing to low and declining LLT adherence over time among Veterans.

Abstract 4136995: Veterans Affairs (VA) Lipid Optimization Reimagined Quality Improvement Program (VALOR-QI) in Veterans with Atherosclerotic Cardiovascular Disease (ASCVD) at the San Juan VA

ASCVD is the principal cause of morbidity and mortality for Veterans in the VA Healthcare System. San Juan VA is one of 50 VA sites participating in a national quality improvement initiative called the VALOR QI: VA Lipid Optimization Reimagined Quality Improvement Project. Is a collaborative project between the U.S. Department of Veterans Affairs (VA) and the American Heart Association (AHA) with the goal of positively impacting Veterans’ cardiovascular (CV) health. VA sites work with an AHA QI consultant to develop and deploy a local quality improvement plan to help overcome site specific barriers preventing Veterans from achieving optimal cholesterol levels. The program’s objectives include improving clinical pathways and processes to impact ASCVD management through a Learning Healthcare System model of quality improvement designed to improve the management of dyslipidemia among those with high-risk ASCVD. The hypothesis is that patients who are part of the VALOR QI program will be more successful in reaching LDL-C target. This will help to reduce the risk of ASCVD and mortality for the patients, promoting better management of lipid levels through medications, diet and regular monitoring. As part of the methodology, the patients are enrolled to the program using the criteria of Veterans > 18 years of age with diagnosis of ASCVD and LDL-C > 70 mg/dl or non-HDL > 100 mg/dl. The Healthcare Coach has a full track of their lipid medications, assists the patients with refills, provides educational materials, follows up with their clinical appointments, and emphasizes the importance of having a good compliance with therapy, appointments and diets to maintain the target of LDL-C. Once the patient starts with a new lipid medication, they are followed in 3 months with labs. After reaching the target the patient is followed up closely in 6 months with labs to prevent relapse. The VALOR QI Program started at VA San Juan in June 2023 and, as of May 30, 2024, had directly engaged 282 Hispanic patients. 111 (39.4%) achieved target LDL-C; 268 (95%) have any statin use; 117 (41.5%) are on any non-statin lipid-lowering therapy (LLT); 116 (41%) are on statin plus LLT; 25 (8.9%) are on PCSK9, and 133 (47.2%) received educational materials. In conclusion, this initiative led to target LDL levels in 39% of patients which represents a significant population. As this program is further implemented in our institution, we expect improvement in patient outcomes and prognosis.

Abstract 4136584: The Association of De Novo Niacin Use with Long-Term Mortality

Introduction: Niacin is a non-statin lipid-lowering therapy that has been shown to lower triglycerides and improve other risk factors for cardiovascular diseases. However, previous studies have reported inconsistent effects of niacin on mortality, and its effect on long-term prognosis has not been well studied. Goals: The aim of this study is to examine the association of niacin therapy with long-term all-cause mortality. Methods: In a nationwide historical cohort of 1,139,630 US Veterans with normal baseline kidney function, we examined the association of de novo niacin prescription from 2004 to 2006 with all-cause mortality during a 14-year follow-up. Associations were examined in Cox proportional hazard models adjusted for demographics, major comorbidities, and laboratory measurements. Prescription time-distribution matching was used to control for survival bias. Results: We identified 133,450 new users of niacin. Overall, patients had a mean (standard deviation) age of 60 (13) years, with 6% female, 78% White, 16% Black, and 6% Hispanic. Niacin users were more likely to be male, White, current, or former smokers and had higher frequencies of comorbidities. Niacin use (vs. non-use) was associated with a lower risk of death (Hazard ratio: 0.89, 95% confidential interval: 0.88-0.90) in the fully adjusted model (Model 4, Figure). Conclusion: In a large national cohort of US Veterans, niacin use was associated with a lower risk of death. Further studies are needed to corroborate the potential benefits of niacin on survival.

Lipoprotein (a) Testing in Patients With Atherosclerotic Cardiovascular Disease in 5 Large US Health Systems.

Lipoprotein (a) is an independent risk factor for atherosclerotic cardiovascular disease. However, lipoprotein (a) testing remains variable and it is unclear what factors influence testing and if testing changes clinical management. A retrospective study using electronic medical record data from 5 health systems identified an atherosclerotic cardiovascular disease cohort divided into those with and without a lipoprotein (a) test between 2019 and 2021. Baseline characteristics and lipid-lowering therapy patterns were assessed. Multivariable regression modeling was used to determine factors associated with lipoprotein (a) testing. Among 595 684 patients with atherosclerotic cardiovascular disease, only 2587 (0.4%) were tested for lipoprotein (a). Those who were older or Black individuals were less likely to have lipoprotein (a) testing, while those with familial hypercholesterolemia, ischemic stroke/transient ischemic attack, peripheral artery disease, prior lipid-lowering therapy, or low-density lipoprotein cholesterol ≥130 mg/dL were more likely to be tested. Those with a lipoprotein (a) test, regardless of the lipoprotein (a) value, were more frequently initiated on any statin therapy (30.3% versus 10.6%, P < 0.001), ezetimibe (7.65% versus 0.8%, P < 0.001), or proprotein convertase substilisin/kexin type 9 inhibitor (6.7% versus 0.3%, P < 0.001) compared with those without a test. Those with an elevated lipoprotein (a) level more frequently initiated ezetimibe (11.5% versus 5.9%, P < 0.001) or proprotein convertase substilisin/kexin type 9 inhibitor (10.9% versus 4.8%, P < 0.001). Lipoprotein (a) testing in patients with atherosclerotic cardiovascular disease is infrequent, with evidence of disparities among older or Black individuals. Testing for lipoprotein (a), regardless of level, is associated with greater initiation of any lipid-lowering therapy, while elevated lipoprotein (a) is associated with greater initiation of nonstatin lipid-lowering therapy. There is a critical need for multidisciplinary and inclusive approaches to raise awareness for lipoprotein (a) testing, and its implications on management.

Lipid lowering therapy and the unmet targets in Indian patients with angiographically proven coronary artery disease: results from the OLS registry

Abstract Introduction The Lipid Association of India (LAI) 2020 guidelines classify patients with established atherosclerotic cardiovascular disease in either very high-risk or extreme-risk groups and recommend that intensive lipid-lowering therapy (LLT) should be administered to such patients to achieve a target low-density lipoprotein cholesterol (LDL-C) level below 50 mg/dl at least (preferably &amp;lt; 30 mg/dl in extreme risk groups). Purpose This study aimed to assess the achievement of the LAI-recommended LDL-C goals in patients with angiographically proven coronary artery disease (CAD). Methods The Optimization of LDL-C in the Stable CAD (OLS) registry started in August 2023 in 10 interventional cardiology centers across Northern India. Interventional cardiologists (ICs) were treating all enrolled patients with angiographically proven stable CAD, and data were collected at a single visit, including the most recent LDL-C and the LLT in the preceding three months of that LDL-C reading. The primary outcome was achieving the LAI-recommended LDL-C goal of &amp;lt;50 mg/dl. The achievement of the American College of Cardiology (ACC) recommended goal of &amp;lt;70 mg/dl was also assessed. Results A total of 1860 patients with angiographically proven CAD were enrolled in this ongoing registry over four months (August 2023- November 2023). The mean age of the study population was 60.2 + 9.2 years, and 79% were males. 30.3% of patients had Diabetes mellitus (DM), 36.1% had hypertension (HTN), 42.3% were obese (body mass index &amp;gt; 25kg/m2), and 17.8% of patients were current smokers. 74.2% of patients had a history of myocardial infarction, while 76.7% had undergone prior percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). Rosuvastatin was the statin prescribed in 59.4% of patients, while atorvastatin was prescribed in 37.2%. 1270 (68.3%) of patients were taking high-intensity statin (HIS) therapy (either 20-40 mg rosuvastatin or 40-80 mg atorvastatin). Only 22 (1.2%) patients took other lipid-lowering agents, including ezetimibe, bempedoic acid, and fibrates. None of the patients were using PCSK9 Inhibitors. Only 482(25.9%) patients achieved their LAI recommended goal of LDL-C &amp;lt;50 mg/dl, 113(6.1%) achieved LDL-C &amp;lt; 30 mg/dl, while 863(46.4%) achieved ACC goal of &amp;lt;70 mg/dl. Notably, only 62(3.3%) patients were not taking any lipid-lowering treatment. Conclusion Results of the OLS study demonstrate the high-risk status of CAD in Indian patients with a high prevalence of DM, HTN, and obesity. Most patients were post-PCI/CABG, mainly because ICs did enrolments. More than two-thirds of patients were taking HIS and very few were not taking any treatment. Despite this, only one-fourth of patients achieved the target LDL-C goals. Greater and early utilization of combination LLT, including HIS and non-statin LLT, is likely needed to reduce these gaps for patients at the highest risk.

Sex Differences in Low-Density Lipoprotein Cholesterol Treatment Among Young Israeli Patients Following Premature Acute Coronary Syndrome.

Introduction: Effective management of dyslipidemias is crucial for reducing morbidity and mortality among patients after acute coronary syndrome (ACS). Sex differences in dyslipidemia management after premature ACS in Israeli patients have not been extensively studied. This study aimed to investigate potential disparities between men and women in managing dyslipidemia, considering current guidelines. Methods: This retrospective cohort study examined patients who were 55 years old or younger and admitted to Meir Medical Center for ACS from January 2018 to February 2019. The study aimed to evaluate the use of lipid-lowering therapy (LLT), measure the achievement of target low-density lipoprotein cholesterol (LDL-C) levels, and analyze the occurrence of major adverse cardiovascular and cerebrovascular events (MACCE) in both male and female patients. Results: The study included a total of 687 participants, of which 23.3% were identified as females. Upon discharge, ∼80% of the patients were prescribed high-intensity statins. After 1 year, it was observed that females had higher levels of LDL-C and lower rates of achieving target LDL-C levels (<70 and 55 mg/dL) as compared with males (45% vs. 54.6% and 30% vs. 42.2%, respectively). The use of non-statin LLT at the 1-year mark was minimal in both groups. Finally, it was found that the occurrence of MACCE was similar between males and females. Conclusion: Sex disparities in dyslipidemia management after a premature ACS were apparent, with females having higher LDL-C levels and lower rates of target achievement. Intervention is necessary to address these disparities and encourage greater use of non-statin LLT.

CO1 Comparative Efficacy of Non-Statin Lipid-Lowering Therapies in Patients With Hypercholesterolemia at Increased Cardiovascular Risk: An Updated Network Meta-Analysis

CO1 Comparative Efficacy of Non-Statin Lipid-Lowering Therapies in Patients With Hypercholesterolemia at Increased Cardiovascular Risk: An Updated Network Meta-Analysis

Age- and sex-based heterogeneity in coronary artery plaque presence and burden in familial hypercholesterolemia: A multi-national study

ObjectivesIndividuals with familial hypercholesterolemia (FH) are at an increased risk for coronary artery disease (CAD). While prior research has shown variability in coronary artery calcification (CAC) among those with FH, studies with small sample sizes and single-center recruitment have been limited in their ability to characterize CAC and plaque burden in subgroups based on age and sex. Understanding the spectrum of atherosclerosis may result in personalized risk assessment and tailored allocation of costly add-on, non-statin lipid-lowering therapies. We aimed to characterize the presence and burden of CAC and coronary plaque on computed tomography angiography (CTA) across age- and sex-stratified subgroups of individuals with FH who were without CAD at baseline. MethodsWe pooled 1,011 patients from six cohorts across Brazil, France, the Netherlands, Spain, and Australia. Our main measures of subclinical atherosclerosis included CAC ranges (i.e., 0, 1–100, 101–400, >400) and CTA-derived plaque burden (i.e., no plaque, non-obstructive CAD, obstructive CAD). ResultsNinety-five percent of individuals with FH (mean age: 48 years; 54% female; treated LDL-C: 154 mg/dL) had a molecular diagnosis and 899 (89%) were on statin therapy. Overall, 423 (42%) had CAC=0, 329 (33%) had CAC 1–100, 160 (16%) had CAC 101–400, and 99 (10%) had CAC >400. Compared to males, female patients were more likely to have CAC=0 (48% [n = 262] vs 35% [n = 161]) and no plaque on CTA (39% [n = 215] vs 26% [n = 120]). Among patients with CAC=0, 85 (20%) had non-obstructive CAD. Females also had a lower prevalence of obstructive CAD in CAC 1–100 (8% [n = 15] vs 18% [n = 26]), CAC 101–400 (32% [n = 22] vs 40% [n = 36]), and CAC >400 (52% [n = 16] vs 65% [n = 44]). Female patients aged 50–59 years were less likely to have obstructive CAD in CAC >400 (55% [n = 6] vs 70% [n = 19]). ConclusionIn this large, multi-national study, we found substantial age- and sex-based heterogeneity in CAC and plaque burden in a cohort of predominantly statin-treated individuals with FH, with evidence for a less pronounced increase in atherosclerosis among female patients. Future studies should examine the predictors of resilience to and long-term implications of the differential burden of subclinical coronary atherosclerosis in this higher risk population.

Clinical characteristics and treatment patterns in patients with atherosclerotic cardiovascular disease with hypercholesterolemia: a retrospective analysis of a large US real-world database cohort

Objective Guidelines developed by the American College of Cardiology/American Heart Association (ACC/AHA) recommend lipid-lowering therapies (LLTs) to reduce low-density lipoprotein cholesterol (LDL-C) and atherosclerotic cardiovascular disease (ASCVD) risk. This study described LLT utilization patterns and LDL-C goal achievement (to <70 mg/dL) among patients with ASCVD in the United States. Methods This retrospective study was conducted using Optum’s de-identified Clinformatics Data Mart Database (CDM). Patients with their first ASCVD diagnosis (index date) in the CDM database between July 1, 2015, and December 31, 2018, were followed for ≥12 months to assess LLT utilization patterns and change in LDL-C. LLTs included were statins and non-statin LLTs (ezetimibe, fibrates, and proprotein convertase subtilisin/kexin type 9 inhibitors). Adherence was measured as the proportion of days covered (PDC), defined as the number of days with drug on-hand (or number of days exposed to drug) divided by the 12-month follow-up period. Patients with PDC ≥0.8 were considered adherent. Results Among the patients with ASCVD (N = 1,424,893) included in this study, only 621,978 (43.7%) had at least one LDL-C measurement at baseline (6 months prior to and 3 months after the index date). The mean age was 71.5 years, and almost half of the patients were female. Patients were followed for a mean (standard deviation [SD]) duration of 30.6 (11.4) months (median of 29.9 months). During the follow-up, about one-quarter of the patients did not receive any LLT. Among treated patients, 89.5% received statins and 10.5% received non-statin LLT. Less than half (47.6%) of the patients were adherent to the index treatment during the 12-month follow-up. Even in patients receiving combination therapy (statin + non-statin LLT), a sizable proportion (35.8%) showed an increase in LDL-C over the follow-up period. Conclusions This retrospective study highlighted limited LDL-C monitoring in patients with ASCVD, and unmet need in terms of suboptimal utilization of non-stain LLTs, limited adherence to LLTs, and inadequate lipid control after treatment (among those with LDL-C measurements during the follow-up period) need to be addressed to improve outcomes in this patient cohort.

Therapeutic gaps in low-density lipoprotein cholesterol management have narrowed over time but remain wide: a wide study of 40,141 acute coronary syndrome patients from 2016 to 2021

Abstract Background There are significant therapeutic gaps in ‘real-word’ low-density lipoprotein cholesterol (LDL-C) management in very-high risk patients. Understanding these gaps is important for developing strategies to bridge these gaps. Purpose We aimed to evaluate trends and identify therapeutic gaps in LDL-C management in very-high risk patients. Methods We retrospectively analyzed consecutive patients admitted with a diagnosis of acute coronary syndrome (ACS) to 16 public hospitals in between 2016 and 2021. Baseline and 12-month lipid-lowering therapy (LLT) including statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor and LDL-C levels were recorded. We evaluated trends-over-time in percentage achievement of guideline Class I recommendations including (i) in-hospital initiation of high-intensity LLT; (ii) lipid-profile at follow-up post discharge; (iii) achieve at least 50% reduction in LDL-C from baseline with a goal of (iv) LDL-C &amp;lt;1.4 mmol/L. Results Of 40,141 ACS patients (mean age 71, male 66.5%), 61.2% were statin-naïve on admission. Baseline average LDL-C was 2.35 mmol/L (IQR 1.74 to 3.13 mmol/L). LLT prescription on discharge increased over time from 63.8% in 2016 to 96.2% in 2021. The use of high-intensity statins on discharge also increased over time from 24.7% to 53.7% but still suboptimal. The use of high-intensity statins increased significantly at 12-months (29.4% in 2016 and 59% in 2021) compared to on discharge (44.1% vs. 40.9% overall, p&amp;lt;0.001). The use of combination LLT was very low (1.3%-3.8%). Up to 22% of patients did not have repeated lipid profile after discharge. Of patients who had follow-up lipid profile, the median LDL-C was 1.74 mmol/L with a median LDL-C reduction of 29%. Only 27.5% reached the LDL-C goal of &amp;lt;1.4 mmol/L and 22.5% achieved at least 50% of LDL-C reduction. LDL-C reduction improved over time from 25.8% in 2016 to 31% in 2021, proportion of patients who reached LDL-C goal of &amp;lt;1.4 mmol/L improved over time from 20.8% in 2016 to 28.7% in 2021, and proportion of patients who achieved at least 50% of LDL-C reduction improved over time from 18.5% in 2016 to 24.6% in 2021, respectively. Conclusion Despite an increasing trend in the use of high-intensity statins and combination LLT over time, most patients did not reach guideline-recommended LDL-C target. Early up-titration of statin and addition of non-statin LLT may be required in the majority of patients.

Abstract 16164: Lipoprotein (a) Testing in Patients With Atherosclerotic Cardiovascular Disease in Five Large U.S. Health Systems

Introduction: Lipoprotein (a) [Lp(a)] is an independent, causal risk factor for atherosclerotic cardiovascular disease (ASCVD). Screening patterns remain variable and it is unclear what factors are associated with Lp(a) testing, and whether knowing the Lp(a) value changes management. Research Question: To better understand the proportion of Lp(a) testing, factors predicting Lp(a) testing, and impact on management in ASCVD patients. Methods: A retrospective study using electronic medical record data from five health systems in the CardioHealth Alliance and PCORnet® identified a cohort with an ASCVD diagnosis in 5 years prior to the index date. The index date was defined as the date of the first Lp(a) test result in 2019-2021 for those with a Lp(a) test, or the date of a randomly selected outpatient encounter in 2019-2021 for those without a Lp(a) test. Initiation of lipid lowering therapy (LLT) was assessed within 6 months after the index date. Multivariable regression modeling was used to determine factors associated with Lp(a) testing. Results: Among 595,685 ASCVD participants, only 2,588 (0.4%) were tested for Lp(a). In adjusted models, those who were older, Black, or Hispanic were less likely to have Lp(a) testing, while those with familial hypercholesterolemia, ischemic stroke/TIA, PAD, prior LLT, or LDL-C ≥130mg/dL were more likely to be tested (table). Those with elevated Lp(a) (&gt;50mg/dL or &gt;125 nmol/L) were more likely to initiate any LLT (43.9% vs 34.6%, p=0.03), particularly PCSK9i (10.9% vs 4.8%, p&lt;0.01) and ezetimibe (11.5% vs 5.9%, p &lt;0.01) compared to those without elevated Lp(a). Statin initiation remained similar between those with and without elevated Lp(a) (32.1% vs 29.5%, p=0.47). Conclusion: Lp(a) testing in ASCVD patients is infrequent, with evidence of disparities by race and ethnicity. Having elevated Lp(a) was associated with higher initiation of non-statin LLT. However, overall initiation of any LLT after an elevated Lp(a) test was low.

Gaps in Guideline-Based Lipid-Lowering Therapy for Secondary Prevention in the United States: A Retrospective Cohort Study of 322 153 Patients.

Many patients with atherosclerotic cardiovascular disease (ASCVD) are not on guideline-recommended statin therapy. We evaluated utilization of statins and other lipid-lowering therapy (LLT), and changes in low-density lipoprotein cholesterol (LDL-C), among patients with ASCVD over a 1-year period. LLT and LDL-C levels at the first outpatient visit (January 1, 2017-December 31, 2018) and 1-year follow-up were evaluated using data from Cerner Real-World Data, an electronic health record-derived data set from 92 US health systems. Logistic regression was used to evaluate factors associated with high-intensity statin use. We identified 322 153 patients with ASCVD (median age 69 years, 58.8% men, 81.8% White). Overall, 76.1% of patients were on statins, with only 39.4% on high-intensity statins. Men were more likely to receive high-intensity statins than women (multivariable-adjusted odds ratio, 1.34 [95% CI, 1.30-1.38]). Increasing age was associated with lower odds of statin use (odds ratio, 0.79 per 5-year increase at 60 years [95% CI, 0.78-0.81]). Patients with peripheral artery disease (odds ratio, 0.40 [95% CI, 0.37-0.42]) and cerebrovascular disease (odds ratio, 0.75 [95% CI, 0.70-0.80]) had lower odds of using high-intensity statins than those with coronary artery disease. At baseline, most patients (61.3%) had elevated LDL-C (≥70 mg/dL), including 59.8% of those on low/moderate-intensity statins and 76.1% on no statin; only 45.3% achieved an LDL-C <70 mg/dL at 1 year. Nonstatin LLT use was low (ezetimibe, 4.4%; proprotein convertase subtilisin/kexin type 9 inhibitors, 0.7%). Among patients on no statin or low/moderate-intensity statin at baseline, 14.8% and 13.4%, respectively, were on high-intensity statins at 1 year. Among patients with ASCVD in routine care, high-intensity statins are underutilized, and uptitration and use of nonstatin therapy are uncommon. Women, older adults, and individuals with noncardiac ASCVD are particularly undertreated. Concerted efforts are needed to address therapeutic inertia for lipid management in patients with ASCVD.

Hypercholesterolemia and cardiovascular risk

Pharmacological reduction of LDL-cholesterol (LDL-C) is a major treatment strategy in limiting atherosclerotic cardiovascular (ASCVD) risk. Statins remain the primary therapeutic cornerstone in ASCVD prevention. Furthermore, ezetimibe, bempedoic acid, and PCSK9 inhibition have recently also shown to reduce cardiovascular risk. Unfortunately, a treatment gap remains between guideline-recommended LDL-C goals and what is achieved in real-world practice. An important reason for this is the limited use of novel and effective non-statin lipid-lowering therapies. In order to achieve LDL-C treatment goals and, ultimately, reduction of cardiovascular events, a combination lipid-lowering therapy needs to be considered as the standard of care for patients at very high cardiovascular risk.

Evolving Management of Low-Density Lipoprotein Cholesterol: A Personalized Approach to Preventing Atherosclerotic Cardiovascular Disease Across the Risk Continuum.

Management of elevated low-density lipoprotein cholesterol (LDL-C) is central to preventing atherosclerotic cardiovascular disease (ASCVD) and key to reducing the risk of ASCVD events. Current guidelines on the management of blood cholesterol recommend statins as first-line therapy for LDL-C reduction according to an individual's ASCVD risk and baseline LDL-C levels. The addition of nonstatin lipid-lowering therapy to statins to achieve intensive LDL-C lowering is recommended for patients at very high risk of ASCVD events, including patients with familial hypercholesterolemia who have not achieved adequate LDL-C lowering with statins alone. Despite guideline recommendations and clinical trial evidence to support the use of lipid-lowering therapies for ASCVD risk reduction, most patients at high or very high risk do not meet LDL-C thresholds. This review explores the challenges associated with LDL-C lowering in contemporary clinical practice and proposes a framework for rethinking the binary definition of ASCVD, shifting from "primary" versus "secondary" prevention to a "continuum of risk." The approach considers the role of plaque burden and progression in subclinical disease and emphasizes the importance of early risk assessment and treatment for preventing first cardiovascular events. Patients at high risk of ASCVD events who require significant LDL-C lowering should be considered for combination therapies comprising statin and nonstatin agents. Practical guidance for the pharmacological management of elevated LDL-C, both now and in the future, is provided.

Management of Statin Intolerant Patients in the Era of Novel Lipid Lowering Therapies: A Critical Approach in Clinical Practice

Statins are the cornerstone of lipid-lowering therapies effective for cardiovascular risk reduction. Although they are generally well tolerated, statin intolerance (SI) is frequent in clinical practice, and it is usually related to the onset of muscle symptoms, which are defined under the acronym SAMS (Statin-Associated Muscle Side Effects). These side effects are responsible for statin treatment discontinuation that results in increased cardiovascular risk. The National Lipid Association (NLA) has recently provided an updated definition of statin intolerance, and a distinction between complete and partial statin intolerance has been reported. The evaluation of symptom severity and the presence of muscle damage biomarker alterations make it essential to adopt a patient-centered approach aimed at obtaining a personalized therapeutic strategy. Firstly, it could be useful to administer a different statin, reduce the dosage or adopt an alternate dosage regimen. However, some patients are unable to tolerate any statin at every dosage, or despite taking statins at the maximum tolerated dose, they fail to achieve the recommended LDL-C target, and thus it is necessary to introduce a non-statin hypolipidemic treatment. Ezetimibe, proprotein-convertase subtilisin/kexin type 9 (PCSK9) inhibitors such as monoclonal antibodies (alirocumab and evolocumab) or RNA messenger silencing (inclisiran), bempedoic acid or nutraceuticals are non-statin lipid-lowering therapies that could be used as an alternative or in addition to statins to achieve an early and sustained LDL-C reduction in clinical practice. In this review, we evaluated SI management focusing on non-statin lipid lowering therapies and their implications in lipid lowering approaches in clinical practice.

Uptake of non-statin lipid-lowering therapies for secondary prevention in community practice

Nearly two-thirds of individuals with atherosclerotic cardiovascular disease (ASCVD) do not reach target low-density lipoprotein cholesterol despite statin therapy. Three novel lipid-lowering therapies have proven to further reduce ASCVD beyond statins, including: ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i), and icosapent ethyl. This study evaluated the use of these three agents in 728,423 individuals with ASCVD from 89 US health systems from 01/2018 through 03/2021 using the electronic health record. As of 2021, only 6.0% of ASCVD patients were on ezetimibe, 1.6% were on a PCSK9i, and 1.3% on icosapent ethyl, with utilization only marginally increasing over the study period. Addressing the underutilization of non-statin lipid-lowering therapy for secondary prevention is a critical step in improving the treatment gap of patients with residual risk of ASCVD.

Inclisiran: A Review in Hypercholesterolemia.

Inclisiran (Leqvio®) is a first-in-class, subcutaneously administered, small interfering RNA (siRNA) that prevents hepatic synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9), thereby decreasing circulating low-density lipoprotein cholesterol (LDL-C). In the EU, inclisiran is indicated in adults with primary hypercholesterolemia or mixed dyslipidemia, as an adjunct to diet. It is intended for use in patients unable to reach LDL-C goals on maximally tolerated statin therapy, with or without other lipid-lowering therapies (LLTs). In patients who are statin intolerant or for whom a statin is contraindicated, it can be used with or without other LLTs. In clinical trials, twice-yearly injections of inclisiran (after initial doses at days 1 and 90) approximately halved LDL-C levels in patients with, or at high risk of developing, atherosclerotic cardiovascular disease (ASCVD) who had hypercholesterolemia, irrespective of whether or not their existing treatment included a statin. The safety and tolerability profile of the drug was similar to placebo, although mild to moderate, transient injection-site adverse reactions were more frequent with inclisiran. Pending confirmation of the expected reduction in cardiovascular (CV) events with inclisiran, it is a valuable additional/alternative antihyperlipidemic agent to a statin, as its infrequent maintenance dosing regimen confers a convenience advantage over other non-statin LLTs.

Current Insights on Dyslipidaemia Management for Prevention of Atherosclerotic Cardiovascular Disease: A Malaysian Perspective.

Dyslipidaemia is highly prevalent in the Malaysian population and is one of the main risk factors for atherosclerotic cardiovascular disease (ASCVD). Low-density lipoprotein cholesterol (LDL-C) is recognised as the primary target of lipid-lowering therapy to reduce the disease burden of ASCVD. Framingham General CV Risk Score has been validated in the Malaysian population for CV risk assessment. The Clinical Practice Guidelines (CPG) on the management of dyslipidaemia were last updated in 2017. Since its publication, several newer randomised clinical trials have been conducted with their results published in research articles and compared in meta-analysis. This underscores a need to update the previous guidelines to ensure good quality care and treatment for the patients. This review summarises the benefits of achieving LDL-C levels lower than the currently recommended target of < 1.8mmol/L without any safety concerns. In most high and very high-risk individuals, statins are the first line of therapy for dyslipidaemia management. However, certain high-risk individuals are not able to achieve the LDL-C goal as recommended in the guideline even with high-intensity statin therapy. In such individuals, lower LDL-C levels can be achieved by combining the statins with non-statin agents such as ezetimibe and PCSK9 inhibitors. Emerging non-statin lipid-lowering therapies and challenges in dyslipidaemia management are discussed in this article. The review also summarises the recent updates on local and international guidelines for dyslipidaemia management.

Bempedoic Acid: Lipid Lowering for Cardiovascular Disease Prevention.

The management of low-density lipoprotein cholesterol (LDL-C) levels is a central strategy for the prevention of atherosclerotic cardiovascular disease. Current United States (2018 American Heart Association/American College of Cardiology/Multisociety) and European (2019 European Society of Cardiology/European Atherosclerosis Society) guidelines endorse statin therapy as the first-line therapy for pharmacologic LDL-C lowering. However, in clinical practice up to 30% of patients report partial or complete intolerance to statin therapy. While the nocebo effect with statins is well described, perceived statin intolerance prevents many patients from achieving LDL-C thresholds associated with clinical benefit. Bempedoic acid is a novel, oral, non-statin lipid-l owering therapy that works by inhibiting adenosine triphosphate-citrate lyase, an enzymatic reaction upstream of 3-hydroxy-3-methylglutaryl coenzyme A reductase in the hepatic cholesterol synthesis pathway. Bempedoic acid confers reduction in LDL-C of ~18% on background statin therapy,~21% in patients with statin intolerance, and ~38% when given in fixed-dose combination with ezetimibe. The CLEAR Outcomes trial, which enrolled high-risk primary and secondary prevention patients with reported statin intolerance and LDL-C levels ≥100 mg/dL, showed that bempedoic acid compared with placebo reduced 4-component major adverse cardiovascular events (MACE) by 13% (hazard ratio 0.87, 95% confidence interval 0.79-0.96). Bempedoic acid also reduced 3-component MACE by 15%, myocardial infarction by 23% and coronary revascularization by 19%. The benefit was even greater in the primary prevention cohort (hazard ratio 0.70, 95% confidence interval 0.55-0.89) for 4-component MACE. Bempedoic acid was associated with increases in uric acid levels and cholelithiasis, but numerically fewer events of myalgia and new-onset diabetes. These findings confirm that bempedoic acid is an effective approach to reduce cardiovascular outcomes in high-risk patients with statin intolerance who require further reduction in LDL-C.

2360. Serum Cholesterol Variability and Mortality in PLWH On Lipid-Lowering Therapy

Abstract Background In people living with HIV (PLWH), consistent use of lipid lowering therapy (LLT) is associated with lower all-cause mortality and use of tenofovir disoproxil fumarate (TDF) with reduced serum cholesterol (C). In the general population, high cholesterol variability (CV) is independently associated with all-cause mortality. We explored the relationship between consistency of LLT/TDF exposure, cholesterol variability, and mortality in PLWH. Methods In a cohort of 15,860 PLWH who achieved undetectable viremia on ART between 2001 and 2011 we used multivariable Cox modeling, stratified by prevalent cardiovascular disease (CVD) to identify predictors of mortality and built multi-level marginal structural models for different LLT/TDF exposure levels based on percentage of days covered (PDC) over the past year, categorizing exposures into low (PDC &amp;lt; 50%), high (50–93%), and consistent (≥94%). The latter two were further subdivided into single and dual exposures for a composite LLT model where we explored effect sizes before and after inclusion of time-updated absolute C values and its 1-year coefficient of variation (CoV). We also examined the relationship between consistency of LLT/TDF use and C variability in a mixed linear model. Results During a median follow-up (f/u) of 4.3 years, there were 2,269 deaths. For 43% of f/u time patients were exposed to TDF, for 13% to non-statin LLT, and for 17% to statins. The hazard ratio (HR) of death for consistent use was 0.38, 95% confidence interval (CI) 0.32–0.45 for TDF, 0.40 (CI:0.28–0.58) for non-statin LLT, and 0.50 (CI:0.40–0.63) for statins (Fig 1). In the composite model, increasing LLT intensity was inversely associated with mortality risk but low C and high CV remained strong independent predictors of death. High HDL C values were protective (Table). The effect sizes for high LLT intensity and high HDL-CV moderately decreased when they were modeled jointly. Compared to unexposed patients, HDL CoV was significantly lower during consistent LLT exposures but higher for patients with low LLT exposure (Fig 2). Conclusion In PLWHA, intensity of LLT exposure is inversely related with all-cause mortality. The highest LLT intensity levels were associated with the lowest HDL-CV. This could serve as a partial explanation for the lower mortality. Disclosures Roger Bedimo, MD, Gilead Sciences: Advisor/Consultant|Janssen: Advisor/Consultant|Merck &amp; Co.: Advisor/Consultant|Merck &amp; Co.: Grant/Research Support|ViiV Healthcare: Advisor/Consultant.