Baseline Low-density Lipoprotein Cholesterol Research Articles

Risk of Incident Diabetes Related to Lipoprotein(a), LDL Cholesterol, and Their Changes With Alirocumab: Post Hoc Analyses of the ODYSSEY OUTCOMES Randomized Trial

OBJECTIVE Previous genetic and clinical analyses have associated lower lipoprotein(a) and LDL cholesterol (LDL-C) with greater risk of new-onset type 2 diabetes (NOD). However, PCSK9 inhibitors such as alirocumab lower both lipoprotein(a) and LDL-C without effect on NOD. RESEARCH DESIGN AND METHODS In a post hoc analysis of the ODYSSEY OUTCOMES trial (NCT01663402), we examined the joint prediction of NOD by baseline lipoprotein(a), LDL-C, and insulin (or HOMA–insulin resistance [HOMA-IR]) and their changes with alirocumab treatment. Analyses included 8,107 patients with recent acute coronary syndrome on optimized statin therapy, without diabetes at baseline, assigned to alirocumab or placebo with median follow-up 2.4 years. Splines were estimated from logistic regression models. RESULTS Lower baseline lipoprotein(a) and higher baseline insulin or HOMA-IR independently predicted 782 cases of NOD; baseline LDL-C did not predict NOD. Alirocumab reduced lipoprotein(a) and LDL-C without affecting insulin or NOD risk (odds ratio [OR] vs. placebo 0.998; 95% CI 0.860–1.158). However, in logistic regression, decreased lipoprotein(a) and LDL-C on alirocumab were independent, opposite predictors of NOD. OR for NOD for 25% and 50% lipoprotein(a) reductions on alirocumab were 1.12 (95% CI 1.01–1.23) and 1.24 (1.02–1.52). OR for NOD for 25% and 50% LDL-C reductions on alirocumab were 0.88 (95% CI 0.80–0.97) and 0.77 (0.64–0.94). CONCLUSIONS Baseline lipoprotein(a) was inversely associated with risk of NOD. Alirocumab-induced reductions of lipoprotein(a) and LDL-C were associated with increased and decreased risk of NOD, respectively, without net effect on NOD. Ongoing trials will determine the impact of larger and longer lipoprotein(a) reductions on NOD.

Association of Cumulative Remnant Cholesterol with Kidney Function Decline in Chinese Population: A Prospective Cohort Study

Introduction: Limited data regarding the association between remnant cholesterol (RC), an emerging novel lipid marker, and chronic kidney disease (CKD). This study aims to investigate the association of baseline and cumulative exposure of RC (CumRC) with kidney function decline (KFD) risk in the general population of China. Methods: Using data from the physical examination database in the Third Xiangya Hospital of Central South University (Changsha, China). 22,702 participants (age ≥18 years) without KFD, who underwent 3 consecutive annual health examinations between 2012 and 2015, were included. KFD was recorded during the interval between the third examination and the end of follow-up through 2020. Results: The cumRC was classified into 4 groups according to these cut-off value: 0.92, 1.33 and 1.99 (mmol/L). During a median follow-up of 3.17 years, 1,085 new KFD events were confirmed. Participants in the highest quartile of cumRC had 43% higher risk of KFD (hazard ratio, 1.43 [95% confidence interval, 1.16–1.77]), compared with the lowest quartile. Similarly, restricted cubic spline analysis showed a significant dose–response relationship between cumRC and the risk of KFD (P non-linearity = 0.0314). However, baseline RC did not show any typical dose dependent positive relationship with KFD development. In the discordance analysis, high baseline RC/low baseline low-density lipoprotein cholesterol (LDL-C) or high cumRC/ low cumLDL-C were all associated with KFD in adjusted models. Conclusion: These data suggest a significant association between cumRC and risk of KFD independent of traditional CVD risk factors as well as LDL-C level. Therefore, consistent RC monitoring should be given to individuals for early KFD prevention, especially in population with normal LDL-C levels who are often overlooked.

Lerodalcibep and evolocumab for the treatment of homozygous familial hypercholesterolaemia with PCSK9 inhibition (LIBerate-HoFH): a phase 3, randomised, open-label, crossover, non-inferiority trial.

Lerodalcibep, a small binding anti-PCSK9 protein (adnectin), showed effective LDL cholesterol reduction in heterozygous familial hypercholesterolaemia. We aimed to assess the safety and efficacy of lerodalcibep and evolocumab in a globally diverse homozygous familial hypercholesterolaemia population. This phase 3, randomised, open-label, crossover, non-inferiority study consisted of two 24-week treatment periods separated by an 8-week washout. The study was conducted in 12 lipid clinics in six countries (India, Israel, Norway, South Africa, Türkiye, and the USA). Patients aged 10 years or older with genetically confirmed homozygous familial hypercholesterolaemia were randomly assigned by computer-generated randomisation scheme performed centrally via interactive response technology to either monthly lerodalcibep 300 mg (1·2 mL subcutaneous injection) or monthly evolocumab 420 mg (subcutaneous 9 min infusion of 3·5 mL) for 24 weeks (period A) followed by an 8-week washout and then crossed over to the alternate therapy for the next 24 weeks (period B). The trial was open label, but all efficacy parameters were masked to patients, study staff, and the sponsor from randomisation. The primary efficacy endpoint was the percent change from baseline (day 1 of period A) in LDL cholesterol concentration to week 24 for period A and B. The intention-to-treat (ITT) population, defined as all randomly assigned patients, was used for the primary analysis. The safety population included all patients who received any study medication. The margin used to establish non-inferiority was 6%. The trial is registered with ClinicalTrials.gov (NCT04034485) and EudraCT (2019-003611-62), and has now finished. Patients were enrolled from Nov 11, 2019, to July 2, 2021, and the final study visit took place on Aug 8, 2022. Of 82 patients screened, 66 entered period A (ITT population). The mean age was 28·7 years (SD 15·2); 20 (30%) of 66 were paediatric patients; 36 (55%) of 66 were female and 30 (45%) of 66 were male; and the mean baseline LDL cholesterol was 10·59 mmol/L (SD 4·37). Mean LDL cholesterol reduction by ITT analysis at week 24 was -4·9% (SE 3·5) on lerodalcibep compared with -10·3% (3·5) on evolocumab; the mean difference between treatments was 5·4% (95% CI -0·2 to 11·1), which did not show non-inferiority at the prespecified 6% margin. LDL cholesterol response varied considerably across the patient population but was generally similar in the same patients with both lerodalcibep and evolocumab. When averaged across all monthly visits, LDL cholesterol response was -9·1% (SE 3·2) on lerodalcibep and -10·8% (3·2) on evolocumab. Importantly, genotyping and free PCSK9 suppression were not predictive of response. Both drugs were well tolerated, with no treatment-related serious adverse events. Injection site reactions were reported in one (2%) of 65 patients on lerodalcibep and 15 (24%) of 62 patients on evolocumab. The LDL cholesterol response was highly variable, but generally similar in patients treated with both lerodalcibep and evolocumab. Importantly, the study showed the inability to predict response based on genotyping, reinforcing the rationale for PCSK9 inhibition in all patients with homozygous familial hypercholesterolemia and continuing its use in responders. LIB Therapeutics.

PCSK-9-inhibitor therapy improves endothelial function in high-risk patients with cardiovascular disease.

Impaired endothelial function predicts cardiovascular events. The aim of this study was to analyze the effect of evolocumab on endothelial function in patients with cardiovascular disease. This was a prospective, double-blinded, randomized, controlled, single center study including patients with cardiovascular disease and treated with statins. Patients were consecutively randomized (1:1) to either evolocumab treatment or placebo. All patients underwent examination of endothelial function at baseline, and after 1, 4 and 8weeks of treatment by a semi-automatic high-resolution ultrasound system (UNEX EF 18G). Parameters of endothelial function were flow-mediated vasodilation (FMD), low flow-mediated vasoconstriction (L-FMC) and vasoactive range (VAR). Hundred three patients with a mean age of 66.2 ± 7.7years and a mean LDL-cholesterol of 98 ± 19.1mg/dl completed the study. The change in VAR from baseline to week 8 was significantly different with evolocumab compared to placebo (p = 0.045). Moreover, VAR increased after 8weeks of treatment with evolocumab compared to baseline (p = 0.034). No change has been noticed in FMD and L-FMC after 8weeks of treatment with evolocumab. In subgroup analyses, VAR improved in patients with age ≤ 67years, lower systolic blood pressure (≤ 125mmHg) and higher baseline LDL-cholesterol (> 95mg/dl), (p = 0.006, p = 0.049 and p = 0.042, respectively) after 8weeks of evolocumab treatment. No serious adverse event related to study medication occurred during the study. Our data indicate that endothelial function improved with evolocumab treatment in high-risk patients on statin therapy with preexisting cardiovascular disease. Our results contribute to the mechanistic explanation why lower incidence of the cardiovascular composite endpoint has been demonstrated in the FOURIER study.

Abstract 4144577: Temporal Trends in Attainment of LDL-c Goals Post Coronary Artery Bypass Grafting (CABG): Data From a Large Integrated Healthcare System

Introduction: Multisociety guidelines in secondary atherosclerotic cardiovascular disease (ASCVD) cholesterol goals have evolved over time. We aim to identify temporal trends in low density lipoprotein cholesterol (LDL-c) and statin use in a post coronary artery bypass grafting (CABG) population. Methods: This is a retrospective study of Kaiser Permanente Northern California members who underwent CABG from 2008 to 2019. Patients were stratified according to three time frames (2008-2013, 2014-2018, 2019) based on the release of multisociety guidelines in 1999, 2013 and 2018. LDL-c goal was defined as a last available value less than 70 mg/dL at 1 year follow up. Lipid lowering therapies were identified through pharmacy records. Cox proportional hazard modeling was used to identify major adverse cardiovascular event (MACE) free survival at up to 12 years follow up. Results: The cohort included 6422 patients, mean age 64.9 years, 83% male, with baseline LDL-c 95.9 mg/dL. Of the cohort, 47% of patients achieved an LDL-c < 70 mg/dL at 1-year follow up. Of the stratified groups, the 2019 cohort demonstrated the highest attainment of LDL-c goal (65%, N=392) compared to 2008-2013 cohort (41%, N=1197) and 2014-2018 cohort (57%, N=1406) (Table 1). A relative increase in high dose statin monotherapy and a decrease in low/moderate dose statin monotherapy was temporally demonstrated in recent cohorts. There was a positive correlation between increasing year and attainment of LDL-c goal (R2=0.916) (Figure 1). Attainment of LDL-c <70 at 1 year post CABG was associated with higher MACE free survival (log-rank p=0.057). Conclusions: Recent cholesterol guidelines post ASCVD have a stronger emphasis on specified LDL-c goals which is associated with increased attainment of LDL-c <70 and improved MACE free survival in our post CABG patients.

Abstract 4114461: Low-density lipoprotein cholesterol, prevalence of cardiovascular disease risk factors, and predicted cardiovascular disease risk among young adults: National Health and Nutrition Examination Survey 2015-2020

Introduction: It is unclear if young adults with hyperlipidemia are also more likely to have non-lipid cardiovascular disease (CVD) risk-factors or higher long-term CVD risk. As such, we assessed associations between low-density lipoprotein cholesterol (LDL-C) levels and non-lipid CVD risk factors as well as 10- and 30-year risk of CVD in young adults. Methods: We included a nationally representative sample of adults 20-<40 years from the National Health and Nutrition Examination Survey (January 2015-March 2020). We described sociodemographic characteristics and CVD risk factors by LDL-C level. We used simple logistic regression to determine associations between LDL-C level and each CVD risk factor. We then calculated the median 10- and 30-year CVD risk by LDL-C category for each participant using the PREVENT risk estimating equations. Results: Among 2,133 (weighted estimation: 90.3 million) young adults, 51.0%, 32.6%, 12.5%, and 3.9% had an LDL-C <100 mg/dL, 100-<130 mg/dL, 130-<160 mg/dL, and 160-<190 mg/dL, respectively. Compared to participants with an LDL-C <100mg/dL, those with an LDL-C 100-<130 mg/dL, 130-<160 mg/dL, and 160-189 mg/dL were more likely to have metabolic syndrome, an enlarged waist, hypertension, elevated glucose, diabetes mellitus, high triglycerides, and high hs-CRP (Table). The median 10-year risk of CVD was approximately 1% across all baseline LDL-C levels. Over a 30-year time horizon, the median risk of incident CVD exceeded 5% only in the 130-<160mg/dL and 160-189mg/dL LDL-C categories (6.0% and 7.6%, respectively). LDL-C and the interaction between LDL-C and CVD risk enhancing factors were independently associated with 30-year predicted risk of CVD (p=0.006 and p=0.005, respectively). Discussion: Many young adults with an elevated LDL-C have concomitant high-risk CVD characteristics. The risk/benefit calculous for addressing this modifiable risk factor in these patients should be further explored.

Abstract 4131775: Effectiveness of Lipid-lowering therapy with Bempedoic Acid plus Ezetimibe in a Real-world Cohort

Introduction: Bempedoic acid and the combination with ezetimibe (BA+EZE) have demonstrated low-density lipoprotein cholesterol (LDL-C) lowering in clinical trials of adults with primary hyperlipidemia at high risk for or with cardiovascular disease. The impact of BA+EZE on LDL-C outcomes in a real-world cohort has not been studied. Aim: To evaluate the effectiveness of BA+EZE on LDL-C reduction and goal achievement using real-world data. Methods: This was a retrospective cohort study using deidentified electronic health records and linked claims data. Adult patients were included if they had a pharmacy claim for BA+EZE from March 1, 2020 to March 15, 2024 (date of first pharmacy claim = index date ), had ≥1 baseline LDL-C lab result on or within 6 months prior to the index date, and ≥2 LDL-C lab results post-index, including 1 lab result 12 months post-index (±60 days). Patients with documented use of ezetimibe on or within 6 weeks prior to index were excluded. For all patients with available valid lab results, LDL-C was determined at baseline (the value closest to but not after the index date), 3 months (±30 days), 6 months (±60 days) and 12 months (±60 days). Results: A total of 615 BA+EZE patients were identified (mean age 62±11 years, 52% women). At baseline, 64% had evidence of statin use in the prior 12 months and the mean LDL-C was 131±52 mg/dl. Figure 1 shows the change in the proportion of patients achieving LDL-C control at index, 3-, 6-, and 12-months post-index. The proportion of patients achieving LDL-C <100 mg/dL more than doubled from index (30%) to 3 months (67%), and was sustained through 12 months (55%). At 12 months, there were fewer patients with LDL-C ≥130 mg/dL (24% vs 47% at index). The mean LDL-C reduction was 28% at 3 months (to 94±47 mg/dL), 27% at 6 months (96±44 mg/dL), and 22% at 12 months (102±47 mg/dL) (p<0.0001 for all vs index). Conclusion: Patients who initiated BA+EZE showed early and sustained improvements in LDL-C. Future research should consider the impact of time on therapy and adherence on LDL-C control.

Independence of Lipoprotein(a) and Low-Density Lipoprotein Cholesterol-Mediated Cardiovascular Risk: A Participant-Level Meta-Analysis.

Low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) (Lp[a]) levels are independently associated with atherosclerotic cardiovascular disease (ASCVD). However, the relationship between Lp(a) level, LDL-C level, and ASCVD risk at different thresholds is not well defined. A participant-level meta-analysis of 27 658 participants enrolled in 6 placebo-controlled statin trials was performed to assess the association of LDL-C and Lp(a) levels with risk of fatal or nonfatal coronary heart disease events, stroke, or any coronary or carotid revascularization (ASCVD). The multivariable-adjusted association between baseline Lp(a) level and ASCVD risk was modeled continuously using generalized additive models, and the association between baseline LDL-C level and ASCVD risk by baseline Lp(a) level by Cox proportional hazards models with random effects. The joint association between Lp(a) level and statin-achieved LDL-C level with ASCVD risk was evaluated using Cox proportional hazards models. Compared with an Lp(a) level of 5 mg/dL, increasing levels of Lp(a) were log-linearly associated with ASCVD risk in statin- and placebo-treated patients. Among statin-treated individuals, those with Lp(a) level >50 mg/dL (≈125 nmol/L) had increased risk across all quartiles of achieved LDL-C level and absolute change in LDL-C level. Even among those with the lowest quartile of achieved LDL-C level (3.1-77.0 mg/dL), those with Lp(a) level >50 mg/dL had greater ASCVD risk (hazard ratio, 1.38 [95% CI, 1.06-1.79]) than those with Lp(a) level ≤50 mg/dL. The greatest risk was observed with both Lp(a) level >50 mg/dL and LDL-C level in the fourth quartile (hazard ratio, 1.90 [95% CI, 1.46-2.48]). These findings demonstrate the independent and additive nature of Lp(a) and LDL-C levels for ASCVD risk, and that LDL-C lowering does not fully offset Lp(a)-mediated risk.

Recaticimab as Add-On Therapy to Statins for Nonfamilial Hypercholesterolemia: The Randomized, Phase 3 REMAIN-2 Trial

BackgroundCurrently available antiproprotein convertase subtilisin/kexin type 9 monoclonal antibodies can effectively decrease low-density lipoprotein cholesterol (LDL-C) levels, but require frequent dosing. Recaticimab is a novel humanized monoclonal antibody against proprotein convertase subtilisin/kexin type 9. In a phase 1b/2 trial, recaticimab as add-on to stable statins showed robust LDL-C reduction with a dosing interval up to every 12 weeks (Q12W) in patients with hypercholesterolemia. ObjectivesREMAIN-2 (REcaticiMab Add-on therapy In patients with Nonfamilial hypercholesterolemia) aimed to assess the efficacy and safety of 48-week treatment with recaticimab as add-on therapy to statins in nonfamilial hypercholesterolemia. MethodsREMAIN-2 was a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial. During the run-in period, patients received stable moderate or high-intensity statin, with or without cholesterol absorption inhibitors (ezetimibe) or fenofibrate, for ≥4 weeks. Patients with an LDL-C of ≥1.8 mmol/L (if with atherosclerotic cardiovascular disease [ASCVD]) or ≥2.6 mmol/L (if without ASCVD) were then randomized (2:2:2:1:1:1) to receive recaticimab 150 mg every 4 weeks (Q4W), 300 mg every 8 weeks (Q8W), or 450 mg Q12W, or matching placebo injections (Q4W, Q8W, or Q12W) for 48 weeks. The primary efficacy endpoint was percentage change from baseline to week 24 in LDL-C level. ResultsA total of 689 randomly assigned patients received treatment (mean age, 55.8 years; male, 64.4%; ASCVD history, 69.5%; concomitant ezetimibe, 11.2%; mean baseline LDL-C, 2.8 mmol/L). Percentage change in LDL-C from baseline to week 24 was significantly more pronounced with recaticimab vs placebo (P < 0.0001), with least-squares mean differences of −62.2% (95% CI: −67.0% to −57.4%), −59.7% (95% CI: −65.0% to −54.4%), and −53.4% (95% CI: −58.7% to −48.2%) for the 150 mg Q4W, 300 mg Q8W, and 450 mg Q12W regimens, respectively. The decreases in LDL-C with recaticimab were maintained through week 48. Secondary lipid variables, including non–high-density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a) also favored the recaticimab groups. During the treatment period, the incidence of treatment-related adverse events (28.5% vs 26.6%) and serious treatment-related adverse events (0.4% vs 0.4%) was similarly low in both the recaticimab and placebo groups. ConclusionsRecaticimab as add-on to stable statin therapy significantly decreased LDL-C levels at week 24 and sustained the decreases through week 48, providing a novel therapeutic alternative with a dosing interval of up to every 12 weeks in patients with nonfamilial hypercholesterolemia.

Risk of recurrent ischaemic events in ACS patients with baseline LDL-C below guideline-recommended thresholds: insights from the prospective SPUM-ACS study

Abstract Introduction The 2023 European Society of Cardiology (ESC) guidelines recommend intensive low-density lipoprotein cholesterol (LDL-C) reduction for patients with acute coronary syndromes (ACS), adding ezetimibe and/or proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) to achieve recommended target goals (LDL-C&amp;lt;55 mg/dL). Purpose This population-based, real-world study aimed to examine cardiovascular (CV) events in ACS patients with baseline LDL-C levels below current guideline thresholds. Methods ACS patients admitted to four Swiss University Hospitals and enrolled in the multicenter SPUM registry (NCT 01000701) between 2009 and 2017 were followed prospectively until 1 year. The composite primary endpoint was major adverse cardiac and cerebrovascular events (MACCE); i.e., non-fatal stroke, myocardial infarction (MI), and death) at 1 year. Multivariable-adjusted Cox proportional hazard regression models were fit to estimate ischaemic risk among those with LDL-C&amp;lt;55 mg/dL. Results Out of 4’787 ACS patients, 226 patients (4.7%) had baseline LDL-C&amp;lt;55 mg/dL. These patients were older (69.7±11.3 vs 63.4±12.4, p&amp;lt;0.001), more frequently male (20.8%vs 15.9%, p&amp;lt;0.001), had more often traditional CV risk factors (all p&amp;lt;0.001) and were more likely to have a complex history of CV disease, such as previous MI (37.2% vs 10.9%, p&amp;lt;0.001), prior percutaneous (47.8% vs 13.2%, p&amp;lt;0.001) or surgical (15.0% vs 3.5%, p&amp;lt;0.001) coronary revascularization. Inflammatory biomarkers were also higher (hs-CRP, 30.1±63.6 vs 10.7±25.8 mg/L), with most patients being on high-dose statin therapy (82.4% vs 38.7%, p&amp;lt;0.001). At 1 year, patients with LDL-C&amp;lt;55 mg/dL had a higher rate of MACCE (16.4% vs 7.0%, p&amp;lt;0.001), with individual components of the primary endpoint occurring more frequently among these patients (all p&amp;lt;0.001), except for a numerical increase in CE (2.7% vs 1.7%, p=n.s.), as shown in the figure (Panel A). The enhanced MACCE risk persisted after adjustment for potential differences in baseline characteristics, with a 51% (adj. HR 1.51, CI95% 1.05-2.17, p=0.026) increase in MACCE (Panel B). Diabetes, low eGFR and high hs-CRP levels remained independent predictors of MACCE in patients with low baseline LDL-C (all p&amp;lt;0.001). Conclusions Our real-world data confirm that even ACS-patients reaching currently recommended LDL-C thresholds have a substantial incidence of recurrent CV events. These findings reinforce the opportunity for lipid-lowering therapy intensification in high-risk patients to levels below guideline-recommended threshold in order to further reduce CV risk.Event-risk according to baseline LDL-C

Changes in lipid lowering therapy one year after percutaneous coronary intervention: data from the large contemporary ZON-HR registry

Abstract Background Patients who underwent percutaneous coronary intervention (PCI) should receive at least high-intensity statin therapy according to current ESC guidelines to prevent ischemic events. However, previous studies have shown that about 80% of the patients using high-intensity statin monotherapy are not reaching the low density lipoprotein- cholesterol (LDL-C) target value of below 1.4 mmol/L. This means that additional lipid lowering therapy is necessary in most patients. The ‘Zuid-Oost Netherlands Heart Registry’ (ZON-HR) is a multicentre, prospective registry designed to improve secondary prevention after PCI by a patient-tailored approach. Purpose To describe changes in lipid lowering therapy one year after PCI in the ZON-HR. Methods Since November 2020 data from all patients who underwent PCI in one of the four participating ZON-HR hospitals were included. In 4811 patients one year follow-up was completed. Patients with known discharge medication and medication at one year after PCI were included in the analyses (n=3487). Combination therapy was defined as having at least two different lipid lowering medications prescribed. The association between predefined variables and combination therapy at one year post PCI was assessed with multivariable logistic regression to adjust for baseline differences. Results The mean age of the patients was 67.7 ± 10.7 years, 72.4% was male and the baseline LDL-C value was 2.7 ± 1.1 mmol/L. While patients with an acute coronary syndrome (ACS) had higher LDL-C values at baseline, they received combination of lipid lowering therapy at discharge less often compared to patients with a chronic coronary syndrome (CCS) (7.9% vs 11.5%, p&amp;lt;0.001) (table 1). After one year, both ACS and CCS patients were treated more often with combination therapy (20.1% vs 23.3%, p=0.047). However, still only about 20% of the patients were receiving combination therapy one year after PCI. In the ACS population, younger patients with higher LDL-C values at baseline and previous myocardial infarction had a higher chance of receiving combination lipid lowering therapy one year after PCI (table 2). Conclusion Additional lipid lowering medication is needed, besides high-intensity statins, in order to reach the strict LDL-C target values in very high risk patients. However, the step-up from mono- to combination lipid lowering therapy only occurs in about 10% of the patients. Lipid lowering combination therapy is prescribed more often in CCS patients compared to ACS patients, both at discharge and one year after PCI.Baseline values and combination therapyPredictors combination therapy at 1 year

Global burden of high-risk cardiovascular patients without prior myocardial infarction or stroke: VESALIUS-REAL - preliminary results from Germany

Abstract Background Clinical trial data has shown that low-density lipoprotein cholesterol (LDL-C) lowering with PCSK9-inhibitors reduced cardiovascular (CV) endpoints in patients with established atherosclerotic cardiovascular disease (ASCVD). Intervening early in patients with high CV risk prior to myocardial infarction (MI) or stroke, while perceived to be less urgent, may result in larger public health benefits. The effect of evolocumab in this population is investigated in a phase-3 clinical trial (NCT03872401: Effect of Evolocumab in Patients at High Cardiovascular Risk Without Prior Myocardial Infarction or Stroke [VESALIUS-CV]). This observational study examines the global burden of VESALIUS-CV-like population in the REAL-World ("VESALIUS-REAL") in eight regions (Germany, Hong Kong, Japan, South Korea, Sweden, Taiwan, UK and US) using a unified protocol across multiple databases. The multi-database study is ongoing, and the current analysis focuses on characteristics of VESALIUS-CV like patients in Germany. Methods Eligibility criteria are shown in the Figure. Data were obtained from the German Disease Analyzer (2013-2022), a representative claims database from Germany. Criteria were aligned with the clinical trial, and real-world definitions were created using diagnosis and procedure codes. Results A total of 195,621 patients were included in the present analysis (Table). At baseline, the median age was 71 years (Q1-Q3: 64-79) and 48% of patients were women. Approximately two-thirds of patients had atherosclerosis (48.5% had coronary artery disease, 13.8% had cerebrovascular disease and 13.8% had peripheral artery disease) and 33.7% had high-risk diabetes mellitus (DM), defined as DM with microvascular complications or chronic insulin use. The median baseline LDL-C was 139 (Q1-Q3: 113-166) mg/dL [3.6 (2.9 - 4.3) mmol/L] and 110,867 patients (57%) had an LDL-C ≥130 mg/dL (≥3.4 mmol/L). Overall, 69% of VESALIUS-CV like patients were receiving no background LLT. Conclusions Despite having atherosclerosis and/or high-risk DM and LDL-C exceeding target thresholds, a large proportion of VESALIUS-CV like patients were not on any LLT in Germany. Final results from VESALIUS-REAL will be able to report if this treatment gap is also observed in other countries.

Physician disagreement with treatment guidelines as a critical barrier to achieving low-density lipoprotein cholesterol targets in very high-risk patients: an implementation science study

Abstract Background/Introduction The challenges that physicians face in implementing evidence-based lipid-lowering therapy in patients at high risk of atherosclerotic cardiovascular disease (ASCVD) are relatively undocumented. Purpose This study aimed to provide insights into the challenges that Korean physicians face in assisting their high-risk ASCVD patients in achieving guideline-recommended low-density lipoprotein cholesterol (LDL-C) levels. Methods We enrolled 704 patients from 10 tertiary hospitals in South Korea, between November 2020 and November 2022. These patients were at very high risk of ASCVD, with baseline LDL-C levels ≥70mg/dL (1.8 mmol/L) while receiving maximally tolerated statins and/or ezetimibe. We measured the proportion of participants achieving LDL-C levels &amp;lt;70mg/dL at visit 1(0)/ visit 2(6-16)/ visit 3 (18-30 weeks), and recorded physician feedback on lipid-lowering treatment strategies. Results Out of the 704 enrolled patients (mean [IQR] age, 66.0 [59–72] years; 580 men [82.4%]), the median (IQR) baseline LDL-C level was 82.0 (74.0–94.5) mg/dL. Lipid-lowering therapy at baseline included statins in 99.0% (with 1.0% statin intolerant) or statins and ezetimibe in 56.4%. The proportion of participants achieving LDL-C levels &amp;lt;70mg/dL at each visit were 0%, 56.3%, and 58.7%, respectively. Among 307 patients on maximally tolerated statins at baseline, physicians did not have an intention to intensify the lipid-lowering treatment regimen in 171 (55.7%) of those patients. (Figure 1) Physician disagreement with the guidelines was the major reason for not using the recommended therapy (70.8%), followed by the patient’s refusal for reasons other than the cost (8.2%), medical limitations such as comorbidities (7.0%), and drug costs (6.4%). Among 397 patients on maximally tolerated statins and ezetimibe at baseline, physicians did not have an intention to intensify the lipid-lowering treatment regimen in 299 (75.3%) of those patients. (Figure 2) Physician disagreement with the guidelines was the major reason for not using the recommended therapy (46.2%), followed by the patient’s refusal for reasons other than the cost (15.7%), medical limitations such as comorbidities (14.4%), and drug costs (12.7%). Conclusion In this implementation science study, the proportion of patients at very high risk of ASCVD who achieved LDL-C levels &amp;lt;70mg/dL via lipid-lowering therapy was less than 60%. Physician disagreement with the guidelines was the main reason for not adopting the recommended intensified LDL-C lowering therapy.Figure 1Figure 2

Sex differences in management of LDL-cholesterol in patients with chronic coronary syndrome

Abstract Background Effective management of low-density lipoprotein cholesterol (LDL-C) is crucial for preventing recurrent cardiovascular (CV) events in patients with chronic coronary syndrome (CCS). Sex may impact the LDL-C management, by gender bias and/or sex-specific responses to pharmacological interventions. Purpose We examined sex-specific LDL-C management in CCS patients, assessing target achievement rates and their implications for CV outcomes. Methods In the international CLARIFY registry, we included 22,134 CCS patients with baseline LDL-C measurements. LDL-C levels were monitored annually over the 5-year follow-up period. Target LDL-C was set at 100 mg/dL, in line with prevailing recommendations at that time. Sex-specific differences in LDL-C were adjusted for age, geographical region and indication for lipid lowering drugs (stroke, MI, PAD). The primary endpoint was the incidence of MACE, defined as CV death or MI during the 5-year follow-up, evaluated using multivariable analysis adjusted for known predictors of recurrent CV events in CCS patients. Results Of 22,134 patients, 21.6% were women. Upon inclusion (6.5 ± 6.3 years after CCS diagnosis), women were more likely than men to have LDL-C levels above the recommended threshold (45.6% vs. 37.4%; aOR 1.47, 95%CI 1.38-1.58, p&amp;lt;0.001) and less likely to receive statin treatment (82.7% vs. 85.4%, p&amp;lt;0.001). Although women and men had comparable numbers of LDL-C measurements during follow-up, the discrepancies endured over the 5-year observation period, with women consistently showing lower likelihoods of achieving LDL-C targets at 1, 2, 3, 4, and 5 years post-inclusion (p&amp;lt;0.001 for all time points). Overall, women were less likely than men to have all available LDL-C concentrations within the target range (37.8% vs. 44.6%; aOR 0.70, 95% CI 0.64-0.76, p&amp;lt;0.001) and more likely to never reach the target LDL-C goal during follow-up (22.6% vs. 17.5%; aOR 1.43, 95% CI 1.32-1.55, p&amp;lt;0.001). Failing to achieve at least one LDL-C concentration below 100 mg/dL was associated with an increased risk of subsequent MACE (adjusted HR 1.57, 95%CI 1.38-1.77, p&amp;lt;0.001), with similar associations observed in both men (aHR 1.66, 95% CI 1.44-1.91, p&amp;lt;0.001) and women (aHR 1.31, 95% CI 1.01-1.70, p=0.05). Conclusion In patients with CCS, women consistently showed lower likelihood of reaching LDL-C targets throughout follow-up compared to men, even after adjusting for age, geographical region and other statin indications. Notably, women were more likely to have no LDL-C concentration within recommended range during follow-up, which is particularly concerning given its association with an increased risk of CV events. A contributing factor to this sex disparity in LDL-C control is women's lower likelihood of receiving lipid-lowering drugs than men. These results highlight the need for tailored interventions to address sex-related disparities in LDL-C management and improve cardiovascular outcomes in CCS patients.

Clinical impact of systemic inflammation across the spectrum of different high-sensitivity CRP values in patients undergoing percutaneous coronary intervention

Abstract Background Systemic inflammation enhances atherosclerosis progression and is a well-established determinant of cardiovascular risk. High-sensitivity C-reactive protein (hsCRP), the most widely available biomarker of inflammation, has indeed been associated with the occurrence of major adverse cardiovascular and cerebrovascular events (MACCE) in patients undergoing percutaneous coronary intervention (PCI). However, some heterogeneity exists in the threshold to define high hsCRP associated with increased cardiovascular risk, with the 2 and 3 mg/L cut-offs being used more commonly. Purpose We aimed to evaluate the clinical impact of systemic inflammation in patients undergoing PCI across the spectrum of baseline hsCRP values. Methods We retrospectively evaluated consecutive patients undergoing PCI with drug-eluting stent implantation from 2012 to 2022 at Mount Sinai Hospital (NY, USA). We excluded patients presenting with acute myocardial infarction or active cancer and those for whom baseline hsCRP was not available or was above 10 mg/L. Patients were stratified into three groups according to baseline hsCRP levels: &amp;lt;2.0, 2.0 to 3.0, and &amp;gt;3.0 mg/L. We estimated the risk of 12-month adverse events using the lowest hsCRP group (&amp;lt;2.0 mg/L) as reference. The primary endpoint was MACCE, defined as the composite of all-cause death, myocardial infarction (MI), or stroke. Secondary endpoints were MACCE individual components, target vessel revascularization (TVR), stent thrombosis and bleeding. Results A total of 10,811 patients were included in the analysis. Of these, 6,210 (57.4%) had hsCRP &amp;lt;2.0 mg/L, 1,624 (15.0%) between 2 and 3 mg/L and 2,977 (27.6%) &amp;gt;3.0 mg/L. Incidence of anemia, diabetes mellitus, peripheral and cerebrovascular artery disease, atrial fibrillation and chronic kidney disease increased stepwise across hsCRP groups. Moreover, patients with higher hsCRP tended to present more frequently with unstable angina and higher baseline LDL cholesterol levels. As regards procedural variables, coronary artery disease severity and PCI complexity did not differ significantly across groups. When compared with patients with hsCRP &amp;lt; 2, hsCRP &amp;gt; 3 mg/L was associated with a greater adjusted risk of MACCE (4.9% vs 2.4%; HR 1.75 % CI 1.35 - 2.28), all-cause death (2.5% vs 0.9%, HR 2.34, 95%CI 1.57-3.47) and MI (2.5% vs 1.3%; HR 1.58 95%CI 1.11-2.26) (Figure 1). Risks of stroke, TVR, stent thrombosis and bleeding did not significantly differ across hsCRP groups (Table 1) Conclusions In patients undergoing PCI, elevated hsCRP values exceeding 3 mg/L exhibit a more robust association with the risk of MACCE and all-cause mortality, as compared with both hsCRP &amp;lt; 2.0 and between 2.0 and 3.0 mg/L. In this context, the use of hsCRP might improve the stratification of patients associated with higher inflammatory burden.

Efficacy of combination therapy with statin and ezetimibe versus high dose statin monotherapy in secondary prevention in high-risk patients

Abstract Background Secondary prevention in patients with acute coronary syndrome focuses on lowering low-density lipoprotein (LDL) cholesterol below 55 mg/dL. In all statin-naïve patients at high risk (LDL-cholesterol target &amp;lt;55 mg/dL), initiation of high-intensity statin monotherapy is recommended by ESC guidelines. Nonetheless, at one month, a significant proportion of patients do not reach their LDL-cholesterol target. Purpose The aim of this study was to compare lipid-lowering therapy with statin monotherapy versus statin with ezetimibe in secondary prevention in patients at high risk. Methods The current prospective study included 264 consecutive patients admitted with acute ST elevation myocardial infarction who underwent percutaneous coronary intervention. None of the patients had taken lipid-lowering drugs in the previous 12 months. Patients were randomly assigned to one of two treatment groups: Group 1 - rosuvastatin 40 mg (n= 144) and Group 2 - rosuvastatin 40 mg and ezetimibe 10 mg (n= 120). All patients' lipid profiles were assessed upon admission and after one month of lipid-lowering treatment. Results At baseline, no patient had LDL cholesterol level lower than 55 mg/dL. There was no significant difference in lipid profile at baseline between the two groups (all p &amp;gt; 0.05). No differences were observed between the two groups in terms of baseline LDL-cholesterol deviation from the target (103.4% versus 99.70%; p= 0.66). As expected, the combination therapy reduced LDL-cholesterol at one month significantly higher compared to high-dose statin monotherapy (-59.65% versus -37.54%; p&amp;lt; 0.0001). After one month of treatment, only 47.92% of patients in Group 1 reached the LDL-cholesterol target (&amp;lt;55 mg/dL) compared to 90.00% of the patients in Group 2 (p&amp;lt;0.0001; R.R.= 0.53). Conclusion(s) Our findings show that statin and ezetimibe combination therapy is more effective in reduction in LDL-cholesterol levels and reaching targets compared to statin monotherapy alone. In statin-naïve patients at high risk, early initiation of the statin and ezetimibe combination instead of statin monotherapy should be taken into account in secondary prevention, for an earlier reach of the LDL-cholesterol target and to reduce the overall cardiovascular risk.

Asia-Pacific Real-World Evolocumab Use, LDL-C Reduction, Physician Goals, and Patient Perceptions: HALES Observational Study.

Real-world data are needed to understand the effectiveness of new therapeutic options for low-density lipoprotein cholesterol (LDL-C) reduction in Asia-Pacific clinical practice. Description of evolocumab use among adults with establisHed Atherosclerotic cardiovascuLar diseasE or hypercholesterolemia in ASia-Pacific region (HALES) was performed to better understand characteristics of and clinical decision-making for adults with established atherosclerotic cardiovascular disease/hypercholesterolemia after local evolocumab approval. The HALES observational study, conducted at 33 sites (Hong Kong, Thailand, South Korea, Singapore, Taiwan, and Australia) comprised (1) chart review of patients who received evolocumab, a proprotein convertase subtilisin/kexin type9 inhibitor (PCSK9i), and (2) physician/patient survey and one-time data collection of patients with high cardiovascular risk initiating evolocumab or initiating/continuing non-PCSK9i lipid-lowering therapy. Patients could only enroll in (1) or (2). Chart review included 724 very high-risk patients initiating evolocumab from regulatory approval to 2021. From median baseline LDL-C of 3.2mmol/L (123.7mg/dL), patients had a median percent change in LDL-C of - 60.8% at 1-6months. Goal achievement increased from 7.9% to 69.8% for < 1.8mmol/L (< 70mg/dL) and 4.4% to 57.8% for < 1.4mmol/L (< 55mg/dL) from baseline to 12months. In the one-time data collection, more patients had ≥ 1.8mmol/L (≥ 70mg/dL) baseline LDL-C in the evolocumab vs non-PCSK9i group (95.2% and 48.5%, respectively). Surveys found that physicians applied guideline-recommended treatment targets, and patients demonstrated gaps in understanding cardiovascular risk. Real-world, Asia-Pacific data showed that LDL-C reduction after initiating evolocumab was consistent with that observed in other clinical trials and patient populations. Graphical abstract available for this article.·.

Impact of Implementation of a Region-Wide Low-Density Lipoprotein Cholesterol Management Clinical Pathway for the Secondary Prevention of Acute Myocardial Infarction

Aggressive lipid-lowering therapy is important for secondary prevention of acute myocardial infarction (AMI). The recommended target for low-density lipoprotein cholesterol (LDL-C) of <70 mg/dL is often not achieved. To address this gap, we implemented a clinical pathway in all hospitals that perform percutaneous coronary interventions (PCI) with primary care physicians in Nagasaki and aimed to validate the effectiveness of this pathway in an acute setting. This retrospective cohort study included medical records extracted from 8 hospitals in Nagasaki, Japan, where PCI was performed for patients with AMI. The index date was defined as the date of hospitalization for AMI between July 1, 2021, and February 28, 2023. The primary outcome was the rate of achieving LDL-C <70 mg/dL at discharge. The median baseline LDL-C level at admission was 121 mg/dL (n=226) in the pre-implementation group and 116 mg/dL (n=163) in the post-implementation group. In the post-implementation group, 131 patients were treated using the clinical pathway. The rate of achieving LDL-C <70 mg/dL at discharge increased significantly from 37.2% before implementation to 54.6% after implementation. Logistic regression analysis revealed a positive correlation between the implementation of the clinical pathway and achieving LDL-C <70 mg/dL. Implementation of a region-wide clinical pathway for LDL-C management significantly improved the rate of intensive lipid-lowering therapy and the achievement of LDL-C targets.

Efficacy of Food Industry By-Product β-Glucan/Chitin–Chitosan on Lipid Profile of Overweight and Obese Individuals: Sustainability and Nutraceuticals

Fat-binding nutraceutical supplements have gained considerable attention as potential cholesterol-lowering strategies to address dyslipidemia in overweight and obese individuals. This study aimed to evaluate the effects of a polysaccharide-rich compound containing β-glucan/chitin–chitosan (βGluCnCs) on lipid profiles and lipoprotein function. In a prospective, two-arm clinical trial, 58 overweight and obese individuals were randomized to receive either 3 g/day of βGluCnCs or a placebo (microcrystalline cellulose) for 12 weeks. Serum lipids and lipoprotein functions were assessed at baseline and at 4-week intervals throughout the study. The administration of βGluCnCs led to a significant increase in HDL cholesterol (HDLc) levels and improved HDLc/non-HDLc and HDLc/total cholesterol (TC) ratios, while reducing apolipoprotein B (ApoB) levels (p &lt; 0.05). However, the intervention did not affect HDL particle diameter, particle number, or lipoprotein functionality. Women demonstrated greater sensitivity to changes in HDLc during βGluCnCs supplementation, whereas men exhibited a significant reduction in ApoB levels. When stratified by baseline LDL cholesterol (LDLc) levels (cut-off: 130 mg/dL), the increase in HDLc and the ApoA1/ApoB ratio was found in the low-LDL group. In contrast, the high-LDL group experienced a significant reduction in atherogenic non-LDLc and LDLc, along with an improvement in HDL’s antioxidant capacity after βGluCnCs intervention. These changes were not statistically significant in the placebo group. In conclusion, our study demonstrated that daily supplementation with βGluCnCs significantly improved lipid profiles, with effects that varied based on sex and baseline LDLc levels.

Long-term effectiveness and safety of lomitapide in patients with homozygous familial hypercholesterolemia: an observational case series

BackgroundWe assessed long-term real-world effectiveness and safety of lomitapide in patients with homozygous familial hypercholesterolemia (HoFH).MethodsRetrospective case series of six patients with HoFH treated with lomitapide in an Italian clinic. Changes in low-density lipoprotein cholesterol (LDL-C) during lomitapide treatment were assessed. The effect on LDL-C of PCSK9 inhibitors, apheresis and lomitapide was evaluated. Additionally, high-density lipoprotein cholesterol (HDL-C), gastrointestinal tolerability, hepatic steatosis/elasticity, transaminases, and cardiovascular events and symptoms were assessed.ResultsMedian age at HoFH clinical and molecular diagnoses was 25 (range 2–49) and 40 (29–71) years, respectively. Five (83.3%) had prior cardiovascular events. One patient received apheresis, which was subsequently discontinued. All patients received PCSK9 inhibitors but discontinued due to minimal effectiveness. Median (range) age at lomitapide initiation was 44 (28–73) years, with a median 47 (18–85) months’ treatment (mean dose 17.5 [5–40] mg/day). Mean (SD) baseline LDL-C was 263.2 (148.1) mg/dL, which decreased by 80% at nadir (52.8 [19.2] mg/dL) and 69% at last follow-up (81.3 [30.5] mg/dL). Four patients (66.7%) achieved LDL-C < 70 mg/dL sometime during follow-up, all of whom also achieved LDL-C < 55 mg/dL. Adverse events (AEs) were generally mild to moderate, hepatic steatosis was either absent or mild/moderate and hepatic elasticity remained normal in all but two patients (> 70 years old). All patients with reported cardiovascular symptoms had improvements in symptoms, and all patients reported stabilization or regression of intima-media thickness and atheromatous plaques.ConclusionsThese long-term, real-world data demonstrate that lomitapide substantially reduced LDL-C for up to seven years. Most patients achieved LDL-C goal at some point, consistent with published Phase III trial and real-world evidence data. No patient discontinued lomitapide treatment. Further long-term follow-up in a larger patient population will be important to determine cardiovascular and other outcomes.