👤 Bailey B Banach

Whether lowering triglyceride-rich lipoproteins and remnant cholesterol favorably modifies coronary atherosclerosis is unclear. Olezarsen, an antisense oligonucleotide that targets apolipoprotein C-III, reduces triglycerides by ~60% and remnant cholesterol by ~70%, has a neutral effect on LDL cholesterol (LDL-C), and reduces apolipoprotein B (apoB) by ~15% in moderate hypertriglyceridemia. We investigated the effect of olezarsen on coronary plaque in adults with largely moderate hypertriglyceridemia. We conducted a coronary computed tomography angiography (CCTA) study within Essence-TIMI 73b, a randomized, placebo-controlled trial of olezarsen vs. placebo that enrolled patients between November 2022 and February 2024. Inclusion criteria were triglycerides ≥150 mg/dL (2.26 mmol/L), presence or high risk for cardiovascular disease, and non-calcified plaque on baseline CCTA. The primary endpoint was percent change from baseline to 12 months in non-calcified plaque volume (NCPV). Of 468 participants (349 olezarsen, 119 placebo), the median age was 63 years (IQR 56-70); 31% were women, and 97% received lipid-lowering therapy. Median baseline triglycerides were 249 mg/dL (IQR 197-331), and remnant cholesterol was 53 mg/dL (IQR 38-76). Median baseline NCPV was 125.3 mm Despite substantial triglyceride and remnant cholesterol lowering, treatment with olezarsen for 12 months on top of standard-of-care lipid-lowering therapy in patients with largely moderate hypertriglyceridemia did not affect noncalcified coronary plaque volume. Show less

Most patients with heterozygous familial hypercholesterolemia fail to achieve adequate low-density lipoprotein (LDL) cholesterol lowering. Here we carried out a randomized trial to test the safety and efficacy of obicetrapib, a highly selective cholesteryl ester transfer protein inhibitor that lowers LDL cholesterol levels in patients with heterozygous familial hypercholesterolemia and an LDL cholesterol level ≥70 mg dl Show less

Hyperlipidemia is the most prevalent cardiovascular (CV) risk factors. We aimed to analyze the distribution of lipid parameters and clinical variables associated with elevated and non-elevated selected lipid factors in a cohort of all consecutive patients whose lipid profile was assessed at a multi-specialist clinical center. This cross-sectional study analyzed electronic medical records of consecutive patients treated between March and November 2024. Lipid parameters measured included: total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), apolipoprotein B (apoB), and lipoprotein (a) [Lp(a)]. Non-high-density lipoprotein cholesterol (non-HDL-C) was calculated as TC-HDL-C. We used multivariate analysis to identify factors associated with LDL-C, TG, and Lp(a) concentrations. A total of 10,597 patients were included in the analysis. The median lipid concentrations (mg/dL) were: TC 162 (IQR 132-198), LDL-C 94 (IQR 69-129), non-HDL-C 112 (IQR 88-146), apoB 78 (IQR 63-99), and Lp(a) 11 (IQR 5-29). Elevated LDL-C > 100 mg/dL was observed in 45.7% of patients, non-HDL-C > 130 mg/dL in 35.1%, and apoB > 100 mg/dL in 23.2%. A discordance between LDL-C and apoB concentrations was present in 23.7% of patients (p < 0.001), while LDL-C/non-HDL-C and apoB/non-HDL-C discordance rates were 13% and 12.6%, respectively (p < 0.001). Patients at very high CV risk had lower TC, LDL-C, non-HDL-C, and apoB concentrations compared to those with low-to-moderate and high CV risk (p < 0.001) and showed the highest median Lp(a) concentration of 13 mg/dL (IQR 5-31; p = 0.01). Goal achievements of LDL-C < 100 mg/dL, TG < 150 mg/dL, and Lp(a) < 30 mg/dL were associated with lipid-lowering treatment [OR 1.32 (95% CI 1.12-1.52)], atrial fibrillation [OR 1.31 (95% CI 1.11-1.54)], chronic coronary syndromes [OR 1.27 (95% CI 1.05-1.52)], smoking [OR 0.78 (95% CI 0.65-0.95)], BMI [OR 0.98 (95% CI 0.96-0.99)], and age [OR 1.006 (95% CI 1.002-1.009)]. The highest proportion of patients with results within the normal range was observed for apoB and the lowest for LDL-C. The highest discordance was observed between apoB/LDL-C, with similar discordance rates between LDL-C/non-HDL-C and apoB/non-HDL-C. Lipid profile control was associated with BMI, atrial fibrillation, age, chronic coronary syndrome, aortic stenosis, diabetes, male gender, lipid-lowering therapy, and smoking. These findings highlight the complexity of lipid management. Show less

Despite advancements in early diagnosis and effective medications in last decade, most heterozygous familial hypercholesterolemia (heFH) patients still fail to achieve their low-density lipoprotein cholesterol (LDL-C) goals and remain at residual cardiovascular disease risk. We present recent data from the regional FH registry in Poland, highlighting the challenges and real-life clinical management of FH patients. The registry is held at the Regional Centre for Rare Diseases, founded in 2016, at the 2nd largest, supraregional hospital in Poland, where >80 different rare diseases in patients from all over Poland are diagnosed and treated, including phenotypically or genetically diagnosed FH patients. Our analysis focused on both children and adult FH patients, excluding those treated with inclisiran due to a small sample size (n = 5). We studied 173 consecutive heFH patients, median age for adult population was 40 years (range: 27-57), of whom 56.14 % were women. Among the population, 82.1 % were adults (n = 142), and 31 were children (17.92 %; median age 9 (8-13), females 58.16 %). Children exhibited lower total cholesterol and triglyceride levels compared to adults, with no significant differences in LDL-C and high-density lipoprotein cholesterol (HDL-C) levels. Molecular diagnosis in the whole population revealed that 76.6 % had an LDL receptor (LDLR) mutation, while 23.4 % had an apolipoprotein B (APOB) mutation. Risk assessment categorized patients into high (70.7 %), very high (22.1 %), and extremely high (7.1 %) risk groups. Triple therapy achieved treatment goals in 61.76 % of adults and 70.97 % of children. At baseline, 36.62 % of adult patients were not using statins. High-intensity statin therapy combined with ezetimibe was initiated for the remaining patients. Only 3.33 % of patients avoided statins due to complete intolerance. Ezetimibe was used in 57.27 % of patients (mostly in combination therapy), and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors were prescribed for 28.17 % FH patients. In adults receiving statin and ezetimibe therapy, median achieved LDL-C was 141 mg/dl (107-184). For triple therapy, median achieved LDL-C was 52.5 mg/dL (32-86.5). Overall median achieved LDL-C in the study population was 99.5 mg/dl (57.5-145.4). PCSK9 inhibitors reduced LDL-C by 165.6 mg/dl. Combination therapy did not significantly alter baseline lipoprotein(a) (Lp(a)) levels (p = 0.134), and PCSK9 inhibitors led to a mean Lp(a) reduction of 18.66 mg/dl (45 % reduction; p = 0.013). Multivariable regression analysis identified key factors for achieving LDL-C targets in FH patients: DLCN total score, DLCN category, ezetimibe use, and PCSK9 inhibitors. In Poland, FH patients are often diagnosed too late (usually over 40 years of age), and many still do not reach their LDL-C goals. Combination LLT double or triple therapy significantly increases the likelihood of achieving LDL-C targets - even up to fivefold. Therefore, unrestricted access to PCSK9 inhibitors for all FH patients is crucial, without the current limitations imposed by drug reimbursement programs like B101. Show less

Highly effective therapies to reduce triglyceride levels are lacking. Olezarsen is an In this phase 3, international, double-blind, randomized, placebo-controlled trial, we enrolled patients with moderate hypertriglyceridemia (triglyceride level, 150 to 499 mg per deciliter) and elevated cardiovascular risk or with severe hypertriglyceridemia (triglyceride level, ≥500 mg per deciliter) and randomly assigned them in a 1:3 ratio to a 50-mg or 80-mg cohort. The patients were then randomly assigned in a 3:1 ratio to receive monthly subcutaneous olezarsen or matching placebo within each cohort. The primary outcome was the least-squares mean percent change in triglyceride level from baseline to 6 months among the patients with moderate hypertriglyceridemia, reported as the difference between each olezarsen dose group and the placebo group (the placebo-adjusted change). A total of 1349 patients (254 in the olezarsen 50-mg group, 766 in the olezarsen 80-mg group, and 329 in the placebo group) were included in the primary efficacy analysis. The median age was 64 years, 40% of the patients were women, and the median triglyceride level at baseline was 238.5 mg per deciliter (interquartile range, 190.5 to 307.5). At 6 months, the placebo-adjusted least-squares mean change in triglyceride level was -58.4 percentage points (95% confidence interval [CI], -65.1 to -51.7; P<0.001) in the olezarsen 50-mg group and -60.6 percentage points (95% CI, -67.1 to -54.0; P<0.001) in the olezarsen 80-mg group. The incidence of serious adverse events appeared to be similar across the trial groups. Among patients with moderate hypertriglyceridemia and elevated cardiovascular risk, treatment with olezarsen resulted in significantly greater reduction in triglyceride levels at 6 months than placebo. (Funded by Ionis Pharmaceuticals; ESSENCE-TIMI 73b ClinicalTrials.gov number, NCT05610280.). Show less

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death in Poland. Lipoprotein(a) [Lp(a)] constitutes an independent, causal risk factor for ASCVD and aortic valve stenosis. Elevated Lp(a) is found in approximately 20% of the Polish population. Lp(a) measurements have been recommended in all adult patients to improve cardiovascular risk stratification. As the testing rate remains insufficient, there is a need to facilitate the incorporation of Lp(a) into routine patient care. This clinically oriented review outlines (i) up-to-date evidence on the role of Lp(a) in cardiovascular diseases, (ii) recent real-world data on the characteristics of Polish patients with elevated Lp(a), and (iii) strategies for Lp(a) testing and management in light of the current national recommendations and the latest 2025 Focused Update of the 2019 ESC/EAS Guidelines for the management of dyslipidemias. Show less

Lipoprotein (a) (Lp(a)) is a largely genetically determined (70-90%) independent risk factor for cardiovascular disease (CVD). However, clinicians often encounter adults/elder adults with elevated Lp(a), who are otherwise healthy and asymptomatic for atherosclerosis. We aimed to identify additional risk factors and conditions, apart from elevated Lp(a), which lead to atherosclerosis progression and CVD, and whether any protective factors mitigate Lp(a)-related risk. In the STAR (Specialist Care Patients) Lp(a) study, we prospectively enrolled 2,594 consecutive patients aged over 50 years, who had elevated Lp(a), referred to two outpatient cardiology clinics. These patients were either healthy, or had established CVD or three or more cardiovascular risk factors. Lp(a) concentration was measured by enzyme-linked immunosorbent assay. Among adults > 50 years with Lp(a) ≥ 30 mg/dl (75 nmol/l) (mean Lp(a), 65.4 vs. 72.7 mg/dl, In adults > 50 years with elevated Lp(a), Lp(a) - related risk of atherosclerosis progression can be substantially mitigated by addressing modifiable CVD risk factors, such as obesity, diabetes, inflammation, and dyslipidemia, preferably by early preventive measures. In our study cohort, Lp(a) was independently associated with atherosclerosis progression in the patient group only. Show less

Cardiovascular diseases (CVDs) remain a leading global cause of mortality and disability, with significant disparities observed across countries. This is particularly true in Central and Eastern Europe (CEE), where populations are primarily at high and very high CVD risk. Highlighting modifiable risk factors underscores the urgent need for effective prevention programs. This paper introduces the European Program for Prevention (EPP), an initiative by the International Lipid Expert Panel (ILEP), designed to address these challenges. The EPP aims to enhance awareness and knowledge of validated preventive healthcare solutions implemented in CEE countries, showcase the region's potential for innovative strategies, and evaluate the adaptability of successful programs for broader implementation. The EPP strongly supports the EU Cardiovascular Health Plan, as well as initiatives by the World Heart Federation (WHF) and World Health Organization (WHO), by promoting best practices, early detection, integrated prevention frameworks, training, cross-border cooperation, and policy development. It advocates shifting healthcare priorities towards pre-disease prevention, thus reducing reliance on resource-intensive treatments. The program proposes an optimal CVD prevention system that includes mandatory health education, screening programs for familial hypercholesterolemia and universal Lp(a) screening, and comprehensive check-ups, notably integrated, comprehensive care programs. By leveraging existing validated programs and fostering collaboration, the EPP seeks to reduce the burden of CVD, improve outcomes, and promote cardiovascular health across Europe and beyond. Show less

Heart failure (HF) and atherosclerosis represent two major cardiovascular diseases that are intricately linked, both contributing significantly to global morbidity, mortality, and healthcare burden. Despite substantial progress in diagnostic methods and therapeutic strategies, the overall impact of these conditions remains considerable. This is largely due to their complex and overlapping pathophysiological mechanisms, persistent residual atherosclerotic risk, and the ongoing challenges associated with implementing guideline-directed medical therapy for HF in routine clinical practice. Recent advancements in the management of diverse HF phenotypes, lipid abnormalities, atherosclerotic cardiovascular disease (ASCVD), and obesity have facilitated the adoption of multidrug regimens. These include β-blockers, renin-angiotensin-aldosterone system inhibitors, sodium-glucose cotransporter 2 (SGLT2) inhibitors, and glucagon-like peptide-1 (GLP-1), which have collectively improved outcomes in HF populations. Lipid-lowering therapy, particularly statins, has demonstrated significant efficacy in reducing ASCVD events and slowing HF progression, as well as lowering the risk of HF-related hospitalizations. Elevated lipoprotein(a) [Lp(a)] has emerged as an independent risk factor for both ASCVD and HF, being associated with increased risk of incident HF, disease progression, hospitalization, and adverse outcomes. However, there remains a lack of conclusive evidence as to whether targeted reduction of Lp(a) leads to a decrease in major adverse cardiovascular events or improves HF incidence or outcomes. In parallel, contemporary therapeutic advances in coronary and peripheral artery revascularization, along with novel pharmacologic treatments for obesity such as GLP-1 receptor agonists including semaglutide and tirzepatide have shown beneficial effects in reducing cardiovascular mortality, HF progression, and body weight, irrespective of HF status. These converging therapeutic strategies underscore the close interrelationship between HF and atherosclerosis. This review aims to elucidate the shared pathophysiological mechanisms linking these conditions and to examine their clinical overlap with ischemic heart disease, cerebrovascular disease, peripheral arterial disease, dyslipidemia, and obesity. A comprehensive understanding of these interrelated cardiovascular entities may offer valuable insights to inform future research directions and optimize the clinical management of patients affected by both HF and atherosclerotic disease. Show less

On average, LDL particles are the most populous lipoprotein in serum under fasting conditions. For many reasons, it has been the primary target of lipid-lowering guidelines around the world. In the past 30 years, we have witnessed remarkable changes in each iteration of dyslipidaemia guidelines, with LDL-cholesterol (LDL-C) targets becoming lower and lower among patients at high and very high risk for atherosclerotic cardiovascular disease (ASCVD). The world over, goal attainment rates are low, and hence, ASCVD prevalence remains unacceptably high. Inadequate LDL-C lowering is a major issue in contemporary cardiovascular (CV) medicine. Another issue that vexes even the most astute clinician is that of 'residual risk', meaning the excess risk that remains even after LDL-C is appropriately reduced. In recent years, an important new component of residual risk has emerged: triglyceride-enriched lipoproteins or remnant lipoproteins. These precursors to LDL particles can assume outsized importance among patients with derangements in triglyceride metabolism (e.g. genetic variants, insulin resistance, and diabetes mellitus) and may be more atherogenic than LDL species. Consequently, to reduce total risk for acute CV events, the time has come to include the entire spectrum of apoB-containing lipoproteins in approaches to both risk evaluation and treatment. Show less

Obicetrapib, a novel, selective cholesteryl ester transfer protein (CETP) inhibitor, reduces low-density lipoprotein cholesterol (LDL-C), LDL particles, apolipoprotein (Apo) B, and lipoprotein(a) [Lp(a)] and increases high-density lipoprotein cholesterol (HDL-C) when added to statins with or without ezetimibe. By substantially reducing LDL-C, obicetrapib has the potential to lower atherogenic lipoproteins in patients with atherosclerotic cardiovascular disease (ASCVD) or heterozygous familial hypercholesterolemia (HeFH) whose LDL-C levels remain high despite treatment with available maximally tolerated lipid-modifying therapies, addressing an unmet medical need in a patient population at high risk for cardiovascular events. BROADWAY (NCT05142722) and BROOKLYN (NCT05425745) are ongoing placebo-controlled, double-blind, randomized Phase III trials designed to examine the efficacy, safety, and tolerability of obicetrapib as an adjunct to dietary intervention and maximally tolerated lipid-modifying therapies in participants with a history of ASCVD and/or underlying HeFH whose LDL-C is not adequately controlled. The primary efficacy endpoint was the percent change in LDL-C from baseline to day 84. Other endpoints included changes in Apo B, non-HDL-C, HDL-C, Apo A1, Lp(a), and triglycerides in addition to parameters evaluating safety, tolerability, and pharmacokinetics. BROADWAY also included an adjudicated assessment of major adverse cardiovascular events, measurements of glucose homeostasis, and an ambulatory blood pressure monitoring substudy. A total of 2,532 participants were randomized in BROADWAY and 354 in BROOKLYN to receive obicetrapib 10 mg or placebo (2:1) for 365 days with follow-up through 35 days after the last dose. Results from both trials are anticipated in 2024. These trials will provide safety and efficacy data to support the potential use of obicetrapib among patients with ASCVD or HeFH with elevated LDL-C for whom existing therapies are not sufficiently effective or well-tolerated. Show less

The prevalence of hypertriglyceridemia has been increasing worldwide. Attention is drawn to the fact that the frequency of a special hypertriglyceridemia entity, named chylomicronemia syndrome, is variable among its different forms. The monogenic form, termed familial chylomicronemia syndrome, is rare, occuring in 1 in every 1 million persons. On the other hand, the prevalence of the polygenic form of chylomicronemia syndrome is around 1:600. On the basis of the genetical alterations, other factors, such as obesity, alcohol consumption, uncontrolled diabetes mellitus and certain drugs may significantly contribute to the development of the multifactorial form. In this review, we aimed to highlight the recent findings about the clinical and laboratory features, differential diagnosis, as well as the epidemiology of the monogenic and polygenic forms of chylomicronemias. Regarding the therapy, differentiation between the two types of the chylomicronemia syndrome is essential, as well. Thus, proper treatment options of chylomicronemia and hypertriglyceridemia will be also summarized, emphasizing the newest therapeutic approaches, as novel agents may offer solution for the effective treatment of these conditions. Show less

Curcumin, a bioactive polyphenol, is a yellow pigment of the Curcuma longa (turmeric) plant. Curcumin has many pharmacologic effects including antioxidant, anti-carcinogenic, anti-obesity, anti-angiogenic and anti-inflammatory properties. Recently, it has been found that curcumin affects lipid metabolism, and subsequently, may alleviate hyperlipidemia and atherosclerosis. Plasma HDL cholesterol (HDL-C) is an independent negative risk predictor of cardiovascular disease (CVD). However, numerous clinical and genetic studies have yielded disappointing results about the therapeutic benefit of raising plasma HDL-C levels. Therefore, research efforts are now focused on improving HDL functionality, independent of HDL-C levels. The quality of HDL particles can vary considerably due to heterogeneity in composition. Consistent with its complexity in composition and metabolism, a wide range of biological activities is reported for HDL, including antioxidant, anti-glycation, anti-inflammatory, anti-thrombotic, anti-apoptotic and immune modulatory activities. Protective properties of curcumin may influence HDL functionality; therefore, we reviewed the literature to determine whether curcumin can augment HDL function. In this review, we concluded that curcumin may modulate markers of HDL function, such as apo-AI, CETP, LCAT, PON1, MPO activities and levels. Curcumin may subsequently improve conditions in which HDL is dysfunctional and may have potential as a therapeutic drug in future. Further clinical trials with bioavailability-improved formulations of curcumin are warranted to examine its effects on lipid metabolism and HDL function. Show less

Juvenile neuronal ceroid lipofuscinosis (JNCL) is a childhood neurodegenerative disease with early-onset, severe central vision loss. Affected children develop seizures and CNS degeneration accompanied by severe motor and cognitive deficits. There is no cure for JNCL, and patients usually die during the second or third decade of life. In this study, independent lines of induced pluripotent stem cells (iPSCs) were generated from two patients with molecularly confirmed mutations in CLN3, the gene mutated in JNCL. Clinical-grade adeno-associated adenovirus serotype 2 (AAV2) carrying the full-length coding sequence of human CLN3 was generated in a U.S. Food and Drug Administration-registered cGMP facility. AAV2-CLN3 was efficacious in restoring full-length CLN3 transcript and protein in patient-specific fibroblasts and iPSC-derived retinal neurons. When injected into the subretinal space of wild-type mice, purified AAV2-CLN3 did not show any evidence of retinal toxicity. This study provides proof-of-principle for initiation of a clinical trial using AAV-mediated gene augmentation for the treatment of children with CLN3-associated retinal degeneration. Show less