Current opinion in lipidology最新文献

Purpose of review: To summarize the recent literature on the effectiveness and safety of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) in reducing low-density lipoprotein cholesterol (LDL-C) and mitigating atherosclerotic cardiovascular disease (ASCVD) risk.

Recent findings: PCSK9i demonstrated considerable benefits in patients with acute myocardial infarction (AMI). Within an intensive lipid-lowering strategy ("strike early-strike strong"), these agents were associated with improved outcomes, primarily through LDL-C reductions and atheromatous plaque regression and stabilization, particularly in multivessel disease. In heterozygous familial hypercholesterolemia, significant LDL-C reductions were noted for alirocumab (-43.3%) and lerodalcibep (-58.6%), while in homozygous hypercholesterolemia, lerodalcibep (-4.9%) and inclisiran (-1.68%) were ineffective, with evolocumab demonstrating a superior -10.3% LDL-C reduction. PCSK9i exhibit a favorable safety profile and high adherence rates; nevertheless, concerns have been raised in patients with respiratory comorbidities and during pregnancy. Additionally, challenges like high costs and complex authorization procedures limit their widespread implementation. Clinicians should also be mindful of the potential discontinuation of concurrent lipid-lowering therapies following PCSK9i initiation.

Summary: PCSK9i remain integral in ASCVD risk reduction, given their potent LDL-C-lowering effects, all while maintaining a favorable safety profile. The greatest benefits are observed in patients with AMI, particularly in multivessel disease. Despite high adherence, broader utilization is hindered by persistent challenges, including costs and complex authorization processes.

Purpose of review: Small dense low-density lipoprotein cholesterol (sdLDL-C) is recognized for its strong atherosclerogenic potential. However, its direct measurement remains impractical in clinical settings due to its high cost, time constraints, and labor-intensive nature. This review discusses the benefits and limitations of estimating sdLDL-C using conventional lipid fractions, highlighting recent advancements in estimation methods.

Recent findings: Sampson et al. proposed a novel equation for estimating sdLDL-C based on conventional lipid parameters, offering a more accessible alternative to direct measurement. Recent studies, including ours, demonstrated that this estimation method achieves sufficiently high accuracy for overall application. However, its accuracy can be improved by incorporating machine learning. Furthermore, sdLDL-C estimated by Sampson's equation has been shown to be a superior risk marker for hypertension, an intermediate phenotype of atherosclerosis, and ischemic heart disease, a major cardiovascular event, compared to conventional lipid profiles alone, although further research is needed to determine whether estimated sdLDL-C is equivalent to directly measured sdLDL-C in risk assessment.

Summary: Estimated sdLDL-C presents a promising alternative to direct measurement. While estimated sdLDL-C levels can serve a risk marker for cardiovascular diseases, further research is needed to refine estimation models and explore their integration into clinical practice.

Purpose of review: As the primary guardians at the air-surface interface, the functional profile of alveolar macrophages (AM) is wide-ranging from establishment of the alveolar niche, homeostatic maintenance of surfactant levels, to pathogen clearance and resolution and repair processes. Alveolar lipid homeostasis is disturbed in chronic lung diseases and contributes to disease pathogenesis through extracellular localization in the alveolar lumen or intracellular accumulation in AM. This review aims to provide a focused overview of the state of knowledge of AM, their ontogeny and development during health and disease, and how dysregulated AM lipids play a key role in disease processes, from initiation to resolution.

Recent findings: While lipid-laden macrophages are observed across a broad spectrum of lung diseases, their occurrence has largely been considered consequential. Recent advances in lipidomic profiling of single cell types has revealed that disturbances to lipid homeostasis occur early in disease in tissue-resident cells. Comparisons between inflammatory and fibrotic injury models reveal specific alveolar macrophage subsets with different lipid utilization that contribute to the disease process.

Summary: Understanding the intricate web of AM population seeding and development and how this niche is perturbed by lipid disturbances may help provide leverage for new interventions.

Purpose of review: Chylomicron biosynthesis plays a vital role in supplying essential lipids and lipid soluble vitamins to peripheral tissues for various functions. Despite this, the intracellular synthesis, trafficking, and secretion of chylomicrons remains only partly understood. The purpose of this review is to summarize the role of established proteins in this process and bring attention to recently identified proteins to provide an up-to-date model of chylomicron biosynthesis.

Recent findings: Recently, several proteins have been shown to play a role in the initial formation and lipidation of chylomicrons at the endoplasmic reticulum (ER), which include: TM6SF2, PLA2G12B, PRAP1, and SURF4. In addition, mitochondria have been implicated in chylomicron metabolism, but mechanistic insight is missing. The trafficking of chylomicrons from the ER to the Golgi, and the subsequent trafficking from the Golgi to the basolateral side of enterocytes, however, remains a mystery.

Summary: Progress in the chylomicron biosynthesis field is largely associated with findings in VLDL biosynthesis. In addition, increased insight in events after prechylomicrons leave the ER is needed. Given the important role of chylomicron biosynthesis in whole-body lipid metabolism, further research into the molecular mechanisms is warranted.

Purpose of review: Elevated lipoprotein(a) [Lp(a)] is a genetically determined independent risk factor for atherosclerotic cardiovascular disease (ASCVD). Current guidelines recommend universal testing of Lp(a) once in an individual's lifetime, with risk factor management intensification for those with elevated levels. However, there is a paucity of real-world data about how patients with elevated Lp(a) are managed and about their associated cardiovascular risk. The purpose of this review is to discuss recent progress in the establishment of registries of patients with elevated Lp(a).

Recent findings: Multiple registries that include patients with elevated Lp(a) have been established in various countries. These studies will provide a snapshot of the global burden of this condition and the current patterns of treatment of this patient population.

Summary: Elevated Lp(a) is a common but underdiagnosed risk factor for ASCVD. National and international registries are needed to expand our understanding and improve the treatment of this condition.

Purpose of review: To review the latest advances in lipoprotein(a) [Lp(a)] treatment, focusing on the impact of currently available lipid-lowering therapies and highlighting the highly anticipated and most developed RNA-based therapies.

Recent findings: Lp(a) is a key genetically determined cardiovascular risk modifier linked to myocardial infarction and calcific aortic stenosis development and progression. Conventional lipid-lowering therapies have no substantial effect on circulating Lp(a) levels, leading current guidelines to focus on managing traditional cardiovascular risk factors. New therapies, including antisense oligonucleotides and small interfering RNAs, target Lipoprotein(A) [LPA] gene translation to reduce apo(a) synthesis and Lp(a) particles formation. The most advanced candidates, pelacarsen, olpasiran, and lepodisiran, have shown promising Lp(a) reductions, ranging from -35% to -101% in Phase 1 and 2 trials. Phase 3 studies will clarify their effects on cardiovascular outcomes and address concerns about extremely low Lp(a) levels and safety.

Summary: The RNA-based agents pelacarsen, olpasiran, and lepodisiran represent the most advanced developments in this field. Ongoing Phase 3 trials, expected to be finalized between 2025 and 2029, will be crucial in determining their efficacy in improving cardiovascular outcomes and their safety profiles.

Purpose of review: Individuals with familial hypercholesterolemia (FH), particularly those with homozygous FH (HoFH) who have markedly elevated LDL-cholesterol (LDL-C) levels from birth, present with unique complications during pregnancy. This review explores the complexities of FH care during pregnancy.

Recent findings: The worldwide burden of FH is much greater than previously thought. Still, underdiagnosis and undertreatment are substantial, necessitating increased awareness, genetic screening efforts, and better access to diagnostic tools. Although there is guidance for implementing best practices in the care of FH, including pregnancy, currently, there are no evidence-based guidelines that address HoFH at the time of pregnancy planning or during pregnancy and lactation.

Summary: FH management in pregnancy requires a reasonable balance between fetal safety and maternal LDL-C control. Discontinuing lipid-lowering medication during pregnancy and the postpartum period needs to be considered, and in severe cases, lipoprotein apheresis may be an appropriate substitute. Comprehensive patient care requires coordination by genetic counselors, cardiologists, lipidologists, and obstetricians. The management of HoFH in pregnancy requires further research efforts, enhancement of public knowledge, and worldwide cooperation. By focusing on these areas, we can make significant progress in diagnostics and develop efficient management plans for improving outcomes among pregnant women with HoFH.

Purpose of review: The study of naturally occurring genetic variation in human populations has laid the foundation for proprotein converts subtilisin/kexin type 9 inhibitors, and more recently new classes of lipid-lowering drugs such as lipoprotein(a) inhibitors and lipoprotein lipase pathway activators. These emerging therapies lower plasma lipoprotein-lipid levels that are not adequately managed by traditional low-density lipoprotein (LDL) cholesterol-lowering medications. By targeting different risk factors, these therapies could help manage the important residual cardiovascular risk of LDL cholesterol medications.

Recent findings: We review the latest insights into the pharmacological and genetic modulation of these new therapeutic targets. We highlight that the drugs remarkably recapitulate the lipid effects observed in genetic studies. In addition to lowering lipoprotein-lipid levels, robust genetic evidence support that these drugs may prevent cardiometabolic outcomes.

Summary: Emerging lipid-lowering therapies could launch a new era for preventive medicine in which treatments are optimally tailored to patient's lipoprotein-lipid profiles.

Purpose of review: Hypertriglyceridemia (HTG), which arises from defects in triglyceride-rich lipoprotein (TRL) metabolism, is associated with increased morbidity and mortality from pancreatitis and atherosclerotic cardiovascular disease. Traditional therapies, including fibrates and omega-3 fatty acids, have shown limited efficacy in controlling triglyceride (TG) levels and cardiovascular risk. This review explores the role of emerging therapies that target TG and TRL metabolism via novel biochemical pathways.

Recent findings: Apolipoprotein C-III inhibitors appear most effective for patients with variants of severe HTG, particularly multifactorial and familial chylomicronemia syndromes, by enhancing TRL metabolism through both lipoprotein lipase-dependent and independent mechanisms. Angiopoeitin-like proteins 3 and 4 inhibitors appear most useful for mixed hyperlipidemia, with favorable effects across the entire spectrum of apoB-containing atherogenic lipoproteins. For patients with HTG and concomitant complications of insulin resistance, including metabolic associated steatotic liver disease and type 2 diabetes mellitus, fibroblast growth factor-21 analogs may provide significant benefit.

Summary: HTG is a diverse condition. Apolipoprotein C-III inhibitors, angiopoeitin-like proteins 3 and 4 inhibitors, and fibroblast growth factor-21 analogs represent significant advancements in the treatment of HTG, offering new hope for effectively managing this condition across its full spectrum of disease.

Purpose of review: Cognitive decline and late-onset dementia pose significant challenges in aging societies, and many dementia cases could be prevented or delayed through modification of associated risk factors, many of which are tied to cardiovascular and metabolic dysfunction. As individuals age, the blood-brain barrier becomes more permeable, easing the exchange of molecules between the bloodstream and the brain. Consequently, blood-based biological markers (so-called biomarkers) provide a minimally invasive and accessible means of accessing molecular changes associated with aging and neurodegeneration.

Recent findings: Circulating free fatty acids, also called nonesterified fatty acids (NEFAs), and sphingolipids are associated with cardiovascular disease, insulin resistance, and diabetes; thus, could be promising candidates as biomarkers for cognitive decline and dementia.

Summary: The opportunity to study such minimally invasive biomarkers further opens up potential new avenues for improved understanding of the underlying biology of diseases of the brain.