Baseline LDL-C Levels Research Articles

Familial Hypercholesterolemia: Real-World Data of 1236 Patients Attending a Czech Lipid Clinic. A Retrospective Analysis of Experience in More than 50 years. Part I: Genetics and Biochemical Parameters.

Introduction: The cause of familial hypercholesterolemia (FH) is defect in LDL receptor or familial defect of apolipoprotein B-100 (FDB) or, rarely, defect in proprotein convertase subtilisin/kexin type 9. Identification and treatment of patients with FH improves their prognosis. Our data represent retrospective analysis of 50 years of specialised care in our center. Patients and Methods: A group of 1236 FH patients (841 women, 395 men; 993 study subjects and 243 relatives; mean age 44.8 ± 16.7 years) included 154 FDB patients followed at the Lipid Clinic of the General University Hospital in Prague since the mid-1960s to the present. Clinical diagnosis was based on the Dutch Lipid Clinic Network Criteria. Genetic analysis was performed using PCR-RFLP to detect FDB and apolipoprotein E (APOE) polymorphism. Biochemical data were collected and statistically analysed. Results: At baseline, mean LDL-C and total cholesterol (TC) levels of all FH patients combined were 6.49 ± 1.92 mmol/L and 8.95 ± 1.95 mmol/L, respectively. Their LDL-C levels decreased to 3.26 ± 1.57 mmol/L and TC levels to 5.43 ± 1.69 mmol/L during follow-up. In the subgroup of LDL receptor-mediated FH (non-FDB) patients, baseline LDL-C and TC levels of 6.61 ± 1.95 mmol/L and 9.09 ± 1.97 mmol/L declined to 3.21 ± 1.60 mmol/L and 5.39 ± 1.72 mmol/L, respectively, during follow-up. In the FDB subgroup of patients, baseline levels of LDL-C and TC were 5.57 ± 1.46 mmol/L and 7.88 ± 1.58 mmol/L decreasing to 3.45 ± 0.24 mmol/L and 5.58 ± 1.37 mmol/L, respectively, during follow-up. Differences were also found in the effects of various APOE isoforms on lipid lowering. A significant decrease in lipid parameters was observed with the E2E2 isoform whereas a minimal decrease was seen with the E4E4 and E3E3 isoforms. Conclusion: Whereas, overall, non-FDB patients had higher baseline lipid levels, these levels declined more appreciably compared with FDB patients during follow-up. Our retrospective analysis also found different effects of APOE isoforms on the decrease in lipid levels.

Real-world data on the prescription of proprotein convertase subtilisin/kexin type 9 inhibitors in high-risk patients in a tertiary medical center

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, alirocumab and evolocumab, are currently approved for clinical use by Taiwan National Health Insurance (NHI) in patients who had a recent atherosclerotic cardiovascular disease with persistent LDL-C levels >135mg/dL despite high-intensity statin (HIS) or maximally tolerated statin in combination with ezetimibe treatment. Since January 2020 to July 2020, total of 10 patients who had received coronary revascularization received NHI-approved alirocumab or evolocumab in our institution. The mean reduction of LDL-C following PCSK9 inhibitors treatment at 6-month and 12-month were respectively 62.5% and 60.2%. The patients in our study were younger, had more frequently received HIS/ezetimibe, and had higher baseline LDL-C levels with a greater LDL-C reduction following PCSK9 inhibitors treatment compared with those patients in previously studies. Our findings highlight that the NHI's regulation of PCSK9 inhibitors application should be re-evaluation to increase the use of NHI-approved PCSK9 inhibitors in high-risk patients.

Gradual increasing dyslipidemia in treatment-naive male patients with human immunodeficiency virus and treated with tenofovir plus lamivudine plus efavirenz for 3\xa0years

IntroductionSince the development of antiretroviral therapy (ART) with TDF plus 3TC plus EFV, this specific regimen has not been studied enough with long-term lipid and uric acid monitoring.MethodsA prospective follow-up cohort study was performed. Sixty-one treatment-naive male patients with human immunodeficiency virus (HIV) were divided into three groups based on their baseline CD4+ cell count (26, 12, and 23 patients in the < 200, 200 to 350, and > 350 groups, respectively). The lipid and purine metabolism parameters of the patients over 144 weeks were analyzed.ResultWithin 144 weeks, TG, LDL-c, TC and HDL-c gradually increased, especially TC and HDL-c (P = 0.001, 0.000, respectively). Moreover, the percentages of hyper-cholesterolemia, hyper LDL cholesterolemia, hyper-triglyceridemia and low HDL cholesterolemia also gradually increased, especially low HDL cholesterolemia significantly increased (P = 0.0007). The lower the baseline CD4+ cell counts were, the higher the TG levels and the lower the TC, LDL-c and HDL-c levels were. But there was significant difference of only baseline LDL-c levels between the three groups (P = 0.0457). No significant difference of the UA level and the percentages of hyperuricemia was found between the different follow-up time point groups or between the three CD4+ cell counts groups (all P > 0.05). The risk factors for dyslipidemia included age, anthropometric parameters and follow-up weeks, and for hyperuricemia was virus load.ConclusionsGradual increasing dyslipidemia was found in male patients with human immunodeficiency virus primarily treated with tenofovir plus lamivudine plus efavirenz for 3 years. There-fore lipid metabolism parameters should be closely monitored during long-term ART with the TDF plus 3TC plus EFV regimen.

Clinical Deep Data Accumulation System (CLIDAS) reveals lipid paradox in guideline-defined high risk Japanese patients after PCI

Abstract Background Japanese clinical guidelines recommend a stratification of the risks and LDL-cholesterol (LDL-C) treatment goals for patients with coronary artery disease after percutaneous coronary intervention (PCI), i.e. &amp;lt;100 mg/dL for normal risk patients and &amp;lt;70 mg/dL for high risk patients; however, less is known about the association between baseline LDL-C values and long-term prognosis. Purpose To investigate the association between LDL-C goals and baseline LDL-C levels in relation to major adverse cardiovascular events (MACE) among high-risk patients after PCI, using a real-world database. Methods We developed the Clinical Deep Data Accumulation System (CLIDAS) that acquires clinical data directly from hospital information system, and implemented the system in 6 university hospitals and the national cardiovascular center in Japan. The CLIDAS database accumulates data regarding patient background, laboratory data, prescriptions, electrocardiogram, echocardiogram, PCI report, and long-term prognosis. We retrospectively analyzed 8540 consecutive patients who underwent PCI during April 2014 and March 2020 in participating hospitals, and classified them into the normal risk group (n=3712, 43%) and the high risk group [n=4828, 57%, with any of acute coronary syndrome (ACS), familial hypercholesterolemia (FH), or diabetes with additional risk factor(s)], for which LDL-C goals are &amp;lt;100 mg/dL and &amp;lt;70 mg/dL, respectively, according to the Japanese Atherosclerosis Society guidelines or the diagnosis and prevention of atherosclerotic cardiovascular diseases. The primary outcome was the time to first occurrence of MACE, a composite of cardiovascular death, stroke, myocardial infarction, and coronary revascularization in associations with baseline LDL-C levels and patient background. Results Proportion of male (77% vs. 77%) and age (71±11 vs. 70±11) were similar between 2 groups. The prevalence of ACS at the index PCI (0% vs. 62%), FH (0% vs. 2%), hypertension (61% vs. 86%), diabetes (11% vs. 67%), dyslipidemia (73% vs. 84%), hemodialysis (4% vs. 9%), peripheral artery disease (5% vs. 9%), smoking (16% vs. 30%), and prescription of statins (79% vs. 86%) were significantly higher in the high risk group. Among patients in the high risk group, but not in the normal risk group, baseline LDL-C &amp;lt;70 mg/dL was paradoxically associated with higher risk of MACE (P&amp;lt;0.0001 by Log-rank test) (Figure). The Cox proportional hazard model confirmed that the high risk group (risk ratio 1.54, 95% CI [1.31–1.81]), baseline LDL-C &amp;lt;70mg/dL (risk ratio 1.44, 95% CI [1.18–1.75]), baseline age (risk ratio 1.36, 95% CI [1.28–1.45] per 10 year), and prescription of statins (risk ratio 0.80, 95% CI [0.66–0.96]) were significantly associated with the risk of MACE in this population. Conclusion The CLIDAS real-world database revealed that baseline low LDL-C paradoxically associated with an increased risk of MACE among guideline-defined high risk patients after PCI. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Jichi Medical University, Tochigi, Japan, and Kowa

Cardiovascular benefit of lowering LDL-C below 1 mmol/L (40 mg/dl)

Abstract Background The 2019 ESC/EAS Dyslipidemia Guidelines recommend an LDL-C goal of &amp;lt;1.4 mmol/L (∼55 mg/dl) for patients with very high-risk ASCVD, and &amp;lt;1 mmol/L (∼40 mg/dl) for those with recurrent events within 2 years despite taking maximally tolerated statin therapy. The addition of PCSK9 inhibitors to statin therapy can achieve LDL-C levels well below 1 mmol/L in many patients, yet the clinical benefit of LDL-C lowering beyond this level has recently been questioned. Methods FOURIER was a cardiovascular outcomes trial comparing evolocumab vs. placebo in patients with stable ASCVD on optimized statin therapy with a median follow-up of 2.2 years. We performed an exploratory analysis to determine the consistency of CV risk reduction with LDL-C lowering below ∼1 mmol/L (40 mg/dl) with evolocumab. We modeled the achieved LDL-C at 48 weeks in the two treatment arms as well as the percentage of LDL-C difference between the two arms that was due to LDL-C below ∼1 mmol/L (40 mg/dl) as a function of baseline LDL-C. We then modeled the hazard ratio (HR) for the composite of CV death, MI or stroke (per 1 mmol/L reduction in LDL-C) with evolocumab vs. placebo as a function of baseline LDL-C. Results All 27,564 patients from FOURIER were included in this analysis. Patients with lower baseline LDL-C achieved lower LDL-C levels following evolocumab therapy, with achieved LDL-C typically being below 1 mmol/L (40 mg/dl) once the baseline LDL-C was below 2.4 mmol/L (94 mg/dl) and reaching levels approaching 0.5 mmol/L (∼20 mg/dl). Accordingly, the further baseline LDL-C levels were below 2.4 mmol/L (94 mg/dl), the greater the proportion of the difference in achieved LDL-C between the evolocumab and placebo arms was due to LDL-C levels below ∼1 mmol/L (40 mg/dl), reaching nearly 40% of the difference in LDL-C between treatment arms (Upper Panel). Despite this, the clinical benefit of LDL-C lowering was not attenuated (p=0.78) (and even appeared greater), with robust reductions in risk of CV death, MI or stroke even when LDL-C was lowered to nearly 0.5 mmol/L (∼20 mg/dl) and having close to 40% of the LDL-C difference between treatment arms due to LDL-C lowering below ∼1 mmol/L (40 mg/dl) (Lower Panel). Conclusion PCSK9 inhibitors added to statin therapy can achieve LDL-C well below 1 mmol/L (40 mg/dl). There is no evidence for attenuation of the clinical benefit of lowering LDL-C below this threshold. These data support lowering LDL-C to below 1 mmol/L (40 mg/dl) in patients with ASCVD. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Institute of Health

Evolocumab use in Europe: clinical guidelines vs. reimbursement thresholds – results from the HEYMANS study

Abstract Background 2019 ESC/EAS guidelines recommend a 50% lowering in untreated LDL-C and use of PCSK9 inhibitors (PCSK9i) for patients (pts) at very high cardiovascular (CV) risk when LDL-C goals of &amp;lt;1.4mmol/L are not met despite maximally tolerated statins and ezetimibe. However, the LDL-C threshold at which PCSK9i are reimbursed are higher than the goals recommended in clinical guidelines. Purpose This prospective observational cohort study describes clinical characteristics and LDL-C control among pts initiating evolocumab across 12 EU countries. Methods Pts are followed from evolocumab initiation (baseline). Demographic/clinical characteristics, lipid lowering therapy (LLT) and lipid values are being collected from medical records (6 months before evolocumab up to 30 months post initiation). We report interim data from pts initiating evolocumab from August 2015 followed-up until July 2020. Results Of the 1,952 pts in whom evolocumab was initiated as per local reimbursement criteria, most (1844 [94%]) had 12 months follow-up, 785 (40%) had 24 months follow-up; mean follow-up: 20 months. Mean (SD) age was 60 (10.8) years; 85% of pts had a history of CV disease, 45% had familial hypercholesterolemia, 19% had type 2 diabetes, 65% were hypertensive, 7% had chronic kidney disease and 51% were prior/current smokers. At evolocumab initiation, 60% reported statin intolerance and 41% were on no background LLT. Fewer than half (846 [43%]) were receiving a statin (± ezetimibe); of these, most received a high/moderate intensity (68%/22%), with 13% receiving statin monotherapy. Median (Q1, Q3) baseline LDL-C was 3.98 (3.17, 5.07) mmol/L. Within 3 months of initiation median LDL-C fell by 58% to 1.63mmol/L. This reduction was maintained over time (Figure 1). Overall, 58% of pts achieved at least one LDL-C &amp;lt;1.4mmol/L during follow-up. Among pts receiving background statins ± ezetimibe at evolocumab initiation, 67% (710/1053) achieved at least one LDL-C &amp;lt;1.4mmol/L, versus 44% (317/714) of pts not receiving background statins/ezetimibe. During follow-up background oral LLT did not materially change; 40–45% pts received no LLT, 41–44% received statin ± ezetimibe, 12–14% received statin monotherapy. Conclusion In Europe, pts initiated on evolocumab had baseline LDL-C levels almost 3x higher than the present threshold for PCSK9i use recommended in guidelines reflecting disparities between local reimbursement criteria and guidelines. Although evolocumab led to a &amp;gt;50% reduction in LDL-C, only ∼50% pts achieved an LDL-C &amp;lt;1.4mmol/L, as approximately 41% received only evolocumab as monotherapy. LDL-C goal attainment was however higher among pts receiving evolocumab with background LLT. Therefore, lowering the LDL-C threshold for PCSK9i reimbursement, would result in more patients receiving combination therapy with oral LLT plus PCSK9i, thus increasing the likelihood of more pts achieving very-high risk LDL-C goals. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Amgen Europe GmbH

Association between baseline ldl-c and prognosis among patients with coronary artery disease and advanced kidney disease

Abstract Background Lower low-density lipoprotein cholesterol (LDL-C) is significantly associated with improved prognosis in patients with coronary artery disease (CAD). However, LDL-C reduction does not decrease all-cause mortality among CAD patients when renal function impairs. There are currently no studies examining the association of low baseline LDL-C concentration (&amp;lt;1.8 mmol/L) with mortality among patients with CAD and advanced kidney disease (AKD). We aimed to evaluate prognostic value of low baseline LDL-C level for all-cause death in these patients. Methods In this observational study, 803 CAD patients complicated with AKD (eGFR &amp;lt;30 mL/min/1.73 m 2) were enrolled between January 2008 to December 2018. Patients were divided into two groups (LDL-C &amp;lt;1.8 mmol/L, n=138; LDL-C ≥1.8 mmol/L, n=665). We used Kaplan-Meier methods and Cox regression analyses to assess the association between baseline low LDL-C levels and long-term all-cause mortality. Results Among 803 participants (mean age 67.4 years; 68.5% male), there were 315 incidents of all-cause death during a median follow-up of 2.7 years. Kaplan–Meier analysis showed that low LDL-C levels were associated with worse prognosis. After adjusting for full 24 confounders (e.g., age, diabetes, heart failure, and dialysis, etc.), multivariate Cox regression analysis revealed that lower LDL-C level (&amp;lt;1.8mmol/L) was significantly associated with higher risk of all-cause death (adjusted HR, 1.38; 95% CI, 1.01–1.89). Conclusions Our data demonstrated that among patients with CAD and AKD, a lower baseline LDLC level (&amp;lt;1.8mmol/L) did not present a higher survival rate but was related to a worse prognosis, suggesting a cautiousness of too low LDL-C levels among patients with CAD and AKD. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): This study was supported by the National Natural Science Foundation of China (Grant No. 81670339 and Grant No. 81970311), Cardiovascular Research Foundation Project of the Chinese Medical Doctor Association (SCRFCMDA201216) and Beijing Lisheng Cardiovascular Health Foundation (LHJJ20141751).

Effect of Financial Incentives for Process, Outcomes, or Both on Cholesterol Level Change

Financial incentives may improve health behaviors. It is unknown whether incentives are more effective if they target a key process (eg, medication adherence), an outcome (eg, low-density lipoprotein cholesterol [LDL-C] levels), or both. To determine whether financial incentives awarded daily for process (adherence to statins), awarded quarterly for outcomes (personalized LDL-C level targets), or awarded for process plus outcomes induce reductions in LDL-C levels compared with control. A randomized clinical trial was conducted from February 12, 2015, to October 3, 2018; data analysis was performed from October 4, 2018, to May 27, 2021, at the University of Pennsylvania Health System, Philadelphia. Participants included 764 adults with an active statin prescription, elevated risk of atherosclerotic cardiovascular disease, suboptimal LDL-C level, and evidence of imperfect adherence to statin medication. Interventions lasted 12 months. All participants received a smart pill bottle to measure adherence and underwent LDL-C measurement every 3 months. In the process group, daily financial incentives were awarded for statin adherence. In the outcomes group, participants received incentives for achieving or sustaining at least a quarterly 10-mg/dL LDL-C level reduction. The process plus outcomes group participants were eligible for incentives split between statin adherence and quarterly LDL-C level targets. Change in LDL-C level from baseline to 12 months, determined using intention-to-treat analysis. Of the 764 participants, 390 were women (51.2%); mean (SD) age was 62.4 (10.0) years, 310 (40.6%) had diabetes, 298 (39.0%) had hypertension, and mean (SD) baseline LDL-C level was 138.8 (37.6) mg/dL. Mean LDL-C level reductions from baseline to 12 months were -36.9 mg/dL (95% CI, -42.0 to -31.9 mg/dL) among control participants, -40.0 mg/dL (95% CI, -44.7 to -35.4 mg/dL) among process participants, -41.6 mg/dL (95% CI, -46.3 to -37.0 mg/dL) among outcomes participants, and -42.8 mg/dL (95% CI, -47.4 to -38.1 mg/dL) among process plus outcomes participants. In exploratory analysis among participants with diabetes and hypertension, no spillover effects of incentives were detected compared with the control group on hemoglobin A1c level and blood pressure over 12 months. In this randomized clinical trial, process-, outcomes-, or process plus outcomes-based financial incentives did not improve LDL-C levels vs control. ClinicalTrials.gov Identifier: NCT02246959.

Target Populations and Treatment Cost for Bempedoic Acid and PCSK9 Inhibitors: A Simulation Study in a Contemporary CAD Cohort

The lowered LDL-C treatment goal of the 2019 European Society of Cardiology dyslipidemia guidelines results in a significant increase in the projected need for cost-intensive proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. Addition of bempedoic acid (BA) to established oral lipid-lowering medication (LLM) has the potential to enable affordable LDL-C goal attainment, particularly in patients with statin intolerance (SI). The goal of this study was to quantify the target populations for BA and PCSK9 inhibitors as well as the related treatment costs to achieve the LDL-C goal of <55 mg/dL and a ≥50% reduction assuming the addition of BA to LLM. This study included 1922 patients with coronary artery disease (CAD) from the contemporary observational cohort study INTERCATH. A Monte Carlo simulation incorporating an algorithm adding sequentially a statin, ezetimibe, optionally BA, and a PCSK9 inhibitor was applied to achieve the LDL-C treatment goal, with consideration of both partial and total SI. Two scenarios were simulated for both a moderate (2% full and 10% partial) and a high (12% full) rate of SI: (1) without BA; and (2) with BA. Patients' mean age was 69.3 years, and the median baseline LDL-C level was 86.0 mg/dL. The need for a PCSK9 inhibitor would be 41.4% for a moderate rate of SI and 46.1% for a high rate of SI. Addition of BA would: (1) reduce the need for a PCSK9 inhibitor to 25.3% and 29.4%, thus lowering the annual overall treatment cost incurred through PCSK9 inhibitor ± BA per 1 million patients with CAD by 13.3% and 10.5%; (2) lower the cost per prevented event in the entire cohort (-5.0% and -6.3%), although at the price of fewer prevented events (-8.7% and -4.5%); and (3) reduce the cost per prevented event (-6.8% for both rates of SI) while preventing more events (7.6% and 6.9%) in the subpopulation of patients with full SI. Use of BA is projected to reduce the need for PCSK9 inhibitors as well as the treatment cost for add-on LLM. The subpopulation of patients with full SI might profit particularly.

The relationship between genotype of familial hypercholesterolemia and the efficacy of PCSK9 inhibitors

Objective: This study intends to explore the difference in the efficacy of PCSK9 inhibitors in patients with different FH phenotypes by analyzing the level of blood lipids before and after treatment with PCSK9 inhibitors in patients with familial hypercholesterolemia (FH) with different allele grades. Methods: Patients with FH phenotype, who admitted to Beijing Anzhen Hospital from January 2019 to October 2020, were enrolled. Age, sex and other clinical information were collected from enrolled, and the pathogenic genes were detected by the second generation sequencing technique. The patients were divided into five groups according to the number of alleles involved and the degree of gene damage: single allele-null mutation group, single allele-defect mutation group, multi-allele-null mutation group, multi-allele-defect mutation group and no major pathogenic gene mutation group. The results of blood lipids were collected before medication, 4-6 weeks of intensive statin treatment and one month after combined treatment with PCSK9 inhibitor (PCSK9i). The LDL-C level were compared among groups. ASCVD risk stratification was performed in all patients, and the proportion of LDL-C level reaching the corresponding risk stratification target value of each genotype group after treatment was analyzed. Results: A total of 66 patients with FH phenotype were included, including 47 males (71.2%) and 19 females (28.8%),the mean age was(43.1±13.4 years). There were 7 cases in single allele-null mutation group (10.6%), 25 cases in single allele-defect mutation group (37.9%), 8 cases in multi-allele-null mutation group (12.1%), 18 cases in multi-allele-defect mutation group (27.3%) and 8 cases in no major pathogenic mutation group (12.1%). The degree of LDL-C reduction post combined PCSK9 inhibitor therapy was as follows: single allele mutation group>no major pathogenic mutation group>multi-allele mutation group, general distribution was in the range of 0-90.0%. Two groups of single allele mutation and no major pathogenic mutation group>50.0%>multi-allele mutation group. Under the combined treatment of PCSK9 inhibitors, the further decrease of LDL-C was in the order of single allele mutation group>non-major pathogenic mutant group>multi-allele mutation group. The efficacy of combined therapy on reducing LDL-C at 1 month after treatment decreased with the increase of baseline LDL-C level (r = 0.46, P<0.001) in patients with FH phenotype. In addition, the further decrease of LDL-C level post high-intensity statin therapy combined with PCSK9 inhibitors decreased with the increase of baseline LDL-C levels (r = 0.40, P<0.001). The degree of LDL-C decrease was high and stable by statin combined with PCSK9 inhibitor therapy in single allele mutation group. In the single allele-defect mutant group, the decrease of LDL-C increased with the increase of baseline LDL-C level post intensive statin treatment and combined PCSK9 inhibitor treatment ((r=0.54, P=0.009); r=0.45,P=0.030), and the further decrease of LDL-C level decreased with the increase of baseline LDL-C level in single allele-defect mutant group post combined therapy with PCSK9 inhibitor (r=0.43, P=0.040). The decrease of LDL-C in patients with the multi-allele mutation group varied with different pathogenic gene loci and combinations post combined therapy with PCSK9 inhibitor. There was no significant difference in the level of blood lipids between the group without major pathogenic gene mutation and the group with single allele mutation before and after treatment. The percentage of patients achieving LDL-C goals with different genotypes of phenotypic FH were as follows: single allele mutation group (86.7%), non-major pathogenic mutant group (75.0%) and multi-allele mutation grou (<5.0%). Conclusions: All patients with different FH phenotypes could benefit from the intensive lipid-lowering therapy with statins and PCSK9 inhibitors, however, there are significant differences in the efficacy of lowering LDL-C in Chinese patients with FH phenotype with different molecular etiologies. Therefore, the pathogenic gene analysis may suggest the lipid-lowering effect of PCSK9 inhibitors in patients with FH.

Association Between BMI and Cardiovascular Benefits After More Intensive LDL-C Lowering Strategy: A Systematic Review and Meta-Analysis

Objective: To assess the influencing factors, especially BMI level contributing to the cardiovascular benefits of more intensive LDL-C lowering strategy. Methods: We systematically searched MEDLINE, Cochrane Central Register of Controlled Trials, Web of Science, ClinicalTrials and Embase for randomized controlled trials of statins, ezetimibe, proprotein convertase subtilisin-kexin type 9 inhibitors, ATP Citrate Lyase inhibitors published before April, 2021. Results: A total of 263787 participants from 33 trials were included. BMI level, baseline LDL-C level and type of lipid-lowering agents are the main factors affecting the cardiovascular benefits from more intensive LDL-C lowering strategies. Among them, the influence of BMI is more prominent. Each 1kg/m2 increase in BMI level reduced the benefit of cardiovascular mortality by 8% (RR 1.08, 95% CI 1.03-1.13), and this effect still exists when only statins are used as the LDL-C lowering strategy. The same trend was also found in myocardial infarction (RR 1.06, 95% CI 1.01-1.11) and revascularization events (RR 1.06, 95% CI 1.02-1.10) by 6%, respectively. Compared to 44% reduction of cardiovascular mortality when the BMI level was less than 25kg/m2 (RR 0.56, 95%CI 0.36-0.86), the reduction gradually vanished as the BMI increased, no benefit of cardiovascular mortality was found when the BMI was higher than 28kg/m2, this cut point is 29kg/m2 in myocardial infarction and 30kg/m2 in revascularization events. Conclusions: With the increase of BMI level, some cardiovascular benefits of intensive LDL-C lowering strategy gradually vanished. Funding Information: This work was partially supported by the National Natural Science Foundation of China (No. 81570732, Shaohua Wang and No. 81870568, Shaohua Wang). Declaration of Interests: The authors declare that they have no competing interests.

Abstract 13200: Relationship Between Baseline Low-Density Lipoprotein Cholesterol and Percent Low-Density Lipoprotein Cholesterol Reduction With Evolocumab in the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk) Trial

Introduction: The FOURIER trial demonstrated that the PCSK9 inhibitor evolocumab robustly reduced LDL-C amongst patients on moderate or high intensity statins. We investigated whether the magnitude of the percentage LDL-C reduction is consistent across baseline LDL-C levels. Methods: FOURIER enrolled 27,564 patients with ASCVD and an LDL-C ≥70 mg/dl or a non-HDL-C ≥100 mg/dl on optimized statin therapy at the time of enrollment. The % LDL-C reduction from baseline to 12 wks was examined in patients on study drug through 12 wks (N=25,847) using a quadratic regression model including terms for treatment (evolocumab vs. placebo), baseline LDL-C and [LDL-C] 2 , and interaction terms. Stratified analyses were done for patients on high vs. moderate intensity statin. Results: Overall, compared with placebo, evolocumab reduced LDL-C by 61% (95% CI 61-62%). Patients with lower baseline LDL-C had significantly greater % LDL-C reductions (Figure top; P&lt;0.001 for interaction between baseline LDL-C and % LDL-C reduction with evolocumab). Among patients with a baseline LDL-C of 70 mg/dL, LDL-C reduction was 68% (95% CI 67-69%) vs. 54% (95% CI 53-55%) in patients with a baseline LDL-C of 130 mg/dl. When stratified by concomitant statin intensity, similar relationships were observed (Figure middle &amp; bottom). Conclusions: The magnitude of % LDL-C reduction with evolocumab is greater in patients with lower baseline LDL-C levels. These data are encouraging for the use of PCSK9 inhibition even for patients at the lower end of LDL-C.

Abstract 14267: Evinacumab Lowers LDL-C in Patients With Homozygous Familial Hypercholesterolemia Irrespective of Background Lipid-lowering Medication

Background: Homozygous familial hypercholesterolemia (HoFH) is characterized by very premature atherosclerotic cardiovascular disease due to profoundly elevated levels of LDL-C. Attempts to lower LDL-C in patients with HoFH often require multiple lipid-lowering medications (LLMs). Evinacumab, an angiopoietin-like protein 3 inhibitor, has been shown to reduce LDL-C in patients with HoFH by approximately 50% when added to maximally tolerated background LLMs. Objective: In this post-hoc analysis we assessed efficacy of evinacumab in patients with HoFH according to background LLM type. Methods: This was a double-blind, placebo-controlled, 24-week phase 3 trial (NCT03399786) that randomized patients 2:1 to receive intravenous (IV) evinacumab 15 mg/kg (n=43) or IV placebo (n=22) every 4 weeks. The effect of background LLMs on the efficacy of evinacumab to lower LDL-C was assessed for the following subgroups: high intensity-statin, low-intensity statins, lomitapide, triple therapy (ezetimibe + PCSK9 inhibitor + statin), and quadruple therapy (triple therapy + lomitapide). Primary endpoint was % LDL-C reduction from baseline to week 24. Results: At baseline, 55.4% (evinacumab, 58.1%; placebo, 50.0%) of HoFH patients were on triple therapy. Overall, 93.8% were on statins (76.9% on high intensity statins). Across LLM subgroups, mean baseline LDL-C levels ranged from 166.8 mg/dL to 281.8 mg/dL (Table). From baseline to week 24, marked reductions in LDL-C occurred with evinacumab treatment, which were observed in all groups: quadruple therapy (66.8%), triple therapy (56.0%), lomitapide (49.6%), high-intensity statins (48.6%) and low-intensity statins (41.0%). Evinacumab was generally well-tolerated. Conclusions: Evinacumab substantially lowers LDL-C levels in patients with HoFH irrespective of background LLM.

Abstract 13588: Cardiovascular Outcomes in Patients With Established Atherosclerosis and LDLR Loss of Function: Results From the FOURIER Trial

Introduction: Patients with loss of function (LoF) mutations of the LDL receptor gene (LDLR) have lifelong elevations in LDL-C. We investigated their risk of cardiovascular (CV) events compared with patients with intact LDLR function. Methods: We performed a prospective genetic cohort analysis from the FOURIER trial including all 14,297 patients who consented for genetic testing, passed QC, and were of European ancestry. All patients had established ASCVD and were on moderate or high intensity statin therapy. Whole exome sequencing was performed and LoF mutations in LDLR were identified using LOFTEE, a tool for detecting protein-truncating variants. Polygenic risk for CAD was also calculated for each patient using a previously validated 27-SNP genetic risk score, with high and low risk defined as above and below the median. The primary endpoint was a composite of CV death, myocardial infarction, stroke, unstable angina, or coronary revascularization. Results: There were 111 (0.8%) patients identified with an LDLR LoF mutation, representing an approximately 4-fold enrichment compared to the general population. These patients had mean baseline LDL-C levels 62 mg/dl higher than those without an identified LDLR LoF mutation (160 vs. 98 mg/dl, p&lt;0.0001) and a 70% increased risk of CV events (HR 1.70 [1.04-2.79], p=0.03) ( Figure, a ). When polygenic risk for CAD was combined with LDLR mutation status there was a significant gradient of risk identified (p-trend=0.001). Patients without a monogenic LDLR mutation or high polygenic risk had a 2.5-year KM event rate of 8.6%; those with either one had a 10.0-12.9% event rate; those with both had a 17.1% event rate ( Figure, b ). Conclusion: ASCVD patients with LDLR LoF mutations have persistently elevated LDL-C and increased CV risk despite intensive statin therapy. The combination of a monogenic LDLR mutation with high polygenic risk for CAD appears additive in this secondary prevention cohort.

Abstract 13826: Lipoprotein (a) Levels Among Children Diagnosed With a Primary Hypercholesterolemia

Introduction: The American Academy of Pediatrics (AAP) recommends universal lipid screening in all children beginning at nine years of age. Although not a component of the lipid profile, an elevated lipoprotein (a) (Lp(a)) (≥30 mg/dL) is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD) in adults. Plasma Lp(a) levels are a product of the Lp (a) gene, which is fully expressed by 5 years of age, and remains relatively unchanged into adulthood. Limited number of studies have examined Lp(a) levels in children diagnosed with a primary hypercholesterolemia. Hypothesis: To determine the frequency of Lp(a) excess, defined as ≥30 mg/dL, among children diagnosed with a primary hypercholesterolemia (i.e., Familial Hypercholesterolemia (FH), Familial Combined Hyperlipidemia (FCH), Polygenic Hypercholesterolemia (PH). Methods: We reviewed the Ascension St. John Children’s Center Lipid Clinic database between 8/1/2012 and 12/31/2019. Only children diagnosed with a primary hypercholesterolemia and having a baseline Lp(a) assessment were included. FH was diagnosed using the Dutch Lipid Score. PH was diagnosed as an elevated LDL-C level not associated with a monogenic mutation or a secondary cause. FCH was diagnosed as an elevated LDL-C in combination with any triglyceride elevation in the absence of secondary causes. Results: One-hundred and twenty patients were evaluated (mean age: 12.1 ± 2.0 years). Seventy-eight percent (93) of the children were white and 52% (62) were male. The frequency of an Lp(a) excess was 44% (53) in this group. The frequencies of Lp(a) excess by diagnosis, and the median Lp(a) and mean LDL-C levels are displayed in Table 1. Conclusions: Lp(a) excess is relatively frequent among children diagnosed with a primary hypercholesterolemia. Since an Lp(a) excess is an ASCVD risk factor, it should be considered clinically relevant when determining the baseline LDL-C level at which a lipid-lowering agent is initiated in children.

Does Evolocumab use in Europe match 2019 ESC/EAS lipid guidelines? Results from the HEYMANS study

Abstract Background 2019 ESC/EAS dyslipidaemia guidelines recommend a 50% lowering in untreated LDL-C and use of PCSK9 inhibitors (PCSK9i) for patients at very-high cardiovascular (CV) risk when LDL-C target goals of &amp;lt;1.4 mmol/L or &amp;lt;1.0 mmol/L (for those with 2 CV events within two-years) are not met despite maximally tolerated statins and ezetimibe. Purpose This observational study describes a cohort of patients initiating evolocumab across 10 EU countries. Methods Patients are followed from evolocumab initiation (baseline). Demographic/clinical characteristics, lipid modifying therapy (LLT) and lipid values were collected from medical records (6 months prior to evolocumab initiation through 30 months post initiation). We report interim data from patients initiating evolocumab from August 2015 with follow-up through October 2019. Results 1896 patients initiated on evolocumab as per local reimbursement criteria were included in this interim analysis (planned sample size: N=2,000). Most (1663 [88%]) had 12 months follow-up, 665 (35%) had 18 months follow-up; mean follow-up, 16.3 months. Mean (SD) age was 60.0 (10.8) years; 85% of patients had a history of CV disease (CVD), 44% had a diagnosis of familial hypercholesterolemia (FH), 19% had type 2 diabetes, 66% were hypertensive, 7% had renal impairment and half (51%) were prior or current smokers. The majority (60%) reported statin intolerance and 42% were not receiving any LLT at evolocumab initiation. Fewer than half (805 [43%]) were receiving a statin (±ezetimibe) at evolocumab initiation; of these, most were on a high/moderate intensity (68%/22%). 12% of patients were receiving statin monotherapy. Median (Q1, Q3) baseline LDL-C was 3.98 (3.16, 5.06) mmol/L. Within 3 months of evolocumab initiation median LDL-C fell by 58% to 1.62 mmol/L. This reduction was maintained over time (Figure). Overall, 58% of patients achieved at least one LDL-C &amp;lt;1.4 mmol/L during follow-up. Among patients receiving background statins and/or ezetimibe at evolocumab initiation, 67% (667/990) achieved at least one LDL-C &amp;lt;1.4 mmol/L, compared with 43% (295/679) of patients not receiving background statins/ezetimibe. During follow-up, 39–46% patients received no background LLT, 40–44% received statin ±ezetimibe, 11–14% received statin monotherapy. Conclusion In Europe, patients initiated on evolocumab had baseline LDL-C levels almost 3 times higher than the present threshold for PCSK9i use, reflecting local reimbursement criteria. Evolocumab resulted in a more than 50% reduction in LDL-C; however, only approximately half of all patients achieved an LDL-C &amp;lt;1.4 mmol/L. LDL-C goal attainment was higher among patients receiving evolocumab with background LLT, suggesting that achievement of EAS/ESC LDL-C goals requires multiple LLTs and a lower threshold for PCSK9i initiation. LDL-C levels after evolocumab initiation Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Amgen

REDUCE-IT: total ischemic events reduced across the full range of baseline LDL cholesterol and other key subgroups

Abstract Background REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial), a study of 8,179 randomized statin-treated patients with elevated triglycerides (TG) and increased cardiovascular (CV) risk followed for a median of 4.9 years, demonstrated robust results. Icosapent ethyl (IPE), a pure and stable prescription form of eicosapentaenoic acid, 4g/day reduced both time-to-first and total primary endpoint ischemic events (CV death, nonfatal myocardial infarction [MI], nonfatal stroke, coronary revascularization, or hospitalization for unstable angina) by 25% (HR 0.75; 95% CI 0.68–0.83; p&amp;lt;0.0001) and 30% (rate ratio 0.70; 95% CI 0.62–0.78; p&amp;lt;0.0001), respectively. Similar substantial reductions in first and total key secondary endpoint ischemic events (composite of CV death, nonfatal MI, or nonfatal stroke) were also observed. Demographic and baseline disease characteristics were generally balanced across treatment groups. Time-to-first event analyses showed robust and generally consistent benefit across subgroups. Previous total event analyses by baseline TG demonstrated large, consistent, statistically significant reductions across tertiles, suggesting the CV benefit of IPE is tied primarily to non-TG factors. Purpose Further explore the extent to which IPE reduced total primary and key secondary events across prespecified baseline demographic, disease, treatment, and lipid/lipoprotein/inflammatory biomarker subgroups. Methods Total events across subgroups were assessed with the prespecified negative binomial regression method. Main outcomes were total (first and subsequent) primary and key secondary composite endpoint events. Results Median baseline LDL-C levels in ascending tertiles were 58, 76, and 96 mg/dL; there were large, significant relative reductions in total primary endpoint events with IPE across tertiles (35%, 28%, and 27%, respectively; interaction p=0.62), with parallel substantial absolute risk reductions. Similar, significant relative reductions of 33%, 28%, and 24% in total key secondary endpoint events were observed, along with substantial absolute risk reductions. Total events analyses of prespecified subgroups also demonstrated robust and generally consistent findings for the primary and key secondary composite endpoints. Conclusion REDUCE-IT demonstrated substantial reductions in first and total primary and key secondary endpoint ischemic events, with robust and generally consistent results across baseline TG and LDL-C levels, as well as other prespecified baseline biomarker, demographic, disease, and treatment subgroups. These analyses provide useful insights for clinicians considering the range of patients who may benefit from IPE therapy and suggest that mechanisms beyond the lipid/lipoprotein/inflammatory pathways tested, including mechanisms beyond the LDL receptor pathways, may contribute to the observed substantial reductions in total ischemic burden with IPE therapy. Funding Acknowledgement Type of funding source: Other. Main funding source(s): The study was funded by Amarin Pharma, Inc.

LDL-cholesterol decrease by anti-PCSK9 monoclonal antibodies: systematic review, meta-analysis and meta-regression of randomized controlled trials

Abstract Background PCSK9 antibodies are novel potent and expansive lipid lowering agents that demonstrated clinical benefit in high risk patients. We hypothesized that optimization of dose and administration schedule, ideally adapted to the target population, could reduce costs while maintaining the clinical benefit. Objective To explore the relationship between LDL-Cholesterol (LDL-C) decrease by anti-PCSK9 monoclonal antibodies and several covariates such as drug dose, administration schedule, baseline LDL-C, population and statins. Methods We performed systematic review, meta-analysis and meta-regression of randomized controlled trials that compared alirocumab or evolocumab to placebo or no treatment and reported LDL-C decrease, with a minimum follow-up of 12 weeks and with a sample size of 30 patients or more. Electronic searches of MEDLINE, EMBASE, CENTRAL and ClinicalTrials.gov from inception to March 2019. We evaluated the quality of included studies and extracted aggregate data. We used random effect models and multivariate multilevel meta-regression to explore factors influencing LDL-C decrease. All analyses were performed with R. Results From 1479 references identified and screened on title/abstract, the full texts of 72 articles were screened. We included 32 studies (31 references.) Anti-PCSK9 mAbs decreased LDL-C by 53%, 95% CI (−56% to −50%), with no significant difference between the two drugs (p=0.07). In univariate meta-regressions, higher baseline LDL-C level, monthly administration, higher percentage of patients with high-dose statins were associated with a lower LDL-C decrease (p&amp;lt;0.0001, p=0.02 and p=0.006 respectively). Drug dose and population did not influence LDL-C decrease in univariate analysis, but with a significant statistical interaction between drug dose and administration schedule (p=0.03). In multivariate meta-regression, LDL-C decrease remained significantly and negatively influenced by baseline LDL-C level (p&amp;lt;0.0001) and the percentage of patients with high-dose statins (p=0.0009), and was significantly and positively influenced by drug dose (p&amp;lt;0.0001). Conclusion Alirocumab and evolocumab showed substantial LDL-C reductions in clinical trials, without significant differences in their biological efficacies. A higher baseline LDL-C, higher intensity of statin co-treatment and a lower dose seemed to negatively influence LDL-C decrease. Funding Acknowledgement Type of funding source: None

Major Lipids and Future Risk of Pneumonia: 20-Year Observation of the Atherosclerosis Risk in Communities (ARIC) Study Cohort

BackgroundCirculating lipids have been implicated as important modulators of immune response, and altered lipid levels correlate with the severity of infection. However, long-term prognostic implications of lipid levels regarding future infection risk remain unclear. The current project aims to explore whether baseline lipid levels are associated with risk of future serious infection, measured by hospitalization for pneumonia. MethodsA retrospective analysis was performed in 13,478 participants selected from the Atherosclerosis Risk in Communities (ARIC) study, a large community-based longitudinal cohort in the United States with a median follow-up time of >20 years. First incident of hospitalization for pneumonia was identified through hospital discharge records. Cox proportional hazard models were used to assess the association of baseline major lipid levels (total cholesterol, low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], triglycerides) with time to first pneumonia hospitalization. ResultsA total of 1969 (14.61%) participants had a pneumonia hospitalization during a median follow-up time of 21.5 years. The hazard ratio (HR) for pneumonia hospitalization was 0.90 (95% confidence interval, 0.87-0.92) for every 10-mg/dL increase in baseline HDL-C, and 1.02 (95% confidence interval, 1.02-1.03) for every 10-mg/dL increase in baseline triglycerides. HDL-C and triglycerides both remained significant predictors of pneumonia hospitalization after multivariable adjustment. Such associations were not seen with baseline LDL-C or total cholesterol levels. ConclusionLower baseline HDL-C and higher triglyceride levels were strongly associated with increased risk of long-term pneumonia hospitalization in a large longitudinal US cohort.

Efficacy of more intensive lipid-lowering therapy on cardiovascular diseases: a systematic review and meta-analysis

BackgroundCardiovascular disease is the leading cause of morbidity and mortality with incidence rates of 5–10 per 1000 person-years, according to primary prevention studies. To control hyperlipidemia—a major risk factor of cardiovascular disease—initiation of lipid-lowering therapy with therapeutic lifestyle modification or lipid-lowering agent is recommended. Few systematic reviews and meta-analyses are available on lipid-lowering therapy for the primary prevention of cardiovascular diseases. In addition, the operational definitions of intensive lipid-lowering therapies are heterogeneous. The aim of our study was to investigate whether intensive lipid-lowering therapies reduce greater cardiovascular disease risks in primary prevention settings.MethodsMEDLINE, EMBASE, and Cochrane Library databases were searched from inception to March 2019 for randomized controlled trials. We used random effects model for overall pooled risk ratio (RR) estimation with cardiovascular events of interest and all-cause mortality rate for the intensive lipid-lowering group using the standard lipid-lowering group as the reference. The Cochrane Risk of Bias Tool was used for quality assessment.ResultsA total of 18 randomized controlled trials were included. The risk reductions in cardiovascular outcomes and all-cause mortality associated with more intensive vs. standard lipid-lowering therapy across all trials were 24 and 10%, respectively (RR 0.76, 95% confidence interval 0.68–0.85; RR 0.90, 95% confidence interval 0.83–0.97); however, the risk reduction varied by baseline LDL-C level in the trial. A greater risk reduction was noted with higher LDL-C level. Intensive lipid-lowering for coronary heart disease protection was more pronounced in the non-diabetic populations than in the diabetic populations.ConclusionsMore intensive LDL-C lowering was associated with a greater reduction in risk of total and cardiovascular mortality in trials of patients with higher baseline LDL-C levels than less intensive LDL-C lowering. Intensive lipid-lowering was associated with a significant risk reduction of coronary heart disease and must be considered even in the non-diabetic populations.