Current opinion in lipidology最新文献

Purpose of review: Although therapies for hyperlipidemia and hypertension have been shown to be highly effective, they have not sufficiently mitigated overall cardiovascular disease risk. Endothelial cells (ECs) are an integral mediator in the development and progression of atherosclerotic cardiovascular disease. The purpose of this review is to provide an update on the current state of endothelial lipid metabolism research, with particular emphasis on atherosclerosis.

Recent findings: Although it has been known that elevated palmitic acid (PA) levels were linked to metabolic dysfunction, inflammation and cardiovascular diseases, more recent studies presented here elucidate the mechanisms behind the negative effects induced by PA. Palmitoylation was found to be detrimental in the case of pyruvate kinase isozyme M2 (PKM2) activity, but also vital for the normal functioning of endothelial ciliation and cell health. Endothelial cholesterol metabolism and hemodynamic forces have also been further confirmed to be key regulators in vessel development and endothelial homeostasis. Perturbations in these pathways promote endothelial dysfunction and maladaptive lipid accumulation.

Summary: Although atherosclerosis remains a complex, multifactorial disease that arises from the coordinated dysfunction across multiple vascular and immune cell types, substantial advances have been made in identifying mechanisms behind dysfunctional endothelial lipid metabolism. Despite this, further investigation is necessary to identify high impart therapeutic targets aimed at reducing overall cardiovascular disease risk.

Purpose of review: Elevated concentrations of both low-density lipoprotein (LDL)-cholesterol and lipoprotein(a) [Lp(a)] is probably the most detrimental lipid profile in terms of cardiovascular health. Our primary objective was to review the reports published before January 2026 pertaining to the metabolism of lipoprotein(a) and associated cardiovascular disease (CVD) risk specifically in familial hypercholesterolemia.

Recent findings: Lp(a) has consistently been found elevated in familial hypercholesterolemia (FH) cohorts. To a large extent, this results from the fact that elevated Lp(a) increases the likelihood for a patient to be clinically diagnosed as FH. For long, increases in Lp(a) concentrations observed in FH patients have been regarded as the consequence of impaired Lp(a) plasma clearance by the LDL receptor. However, recent studies strongly advocate against a significant role for the LDL receptor in mediating Lp(a) hepatic uptake. The molecular mechanisms by which Lp(a) is cleared from blood still remain elusive. Finally, mounting clinical evidence indicates that lowering LDL-C pharmacologically will not offset the specific cardiovascular risk stemming from elevated Lp(a) in FH.

Summary: It is highly recommended to systematically measure Lp(a) in FH patients. These patients should be treated with high-dose statins, when necessary, in combination with a proprotein convertase subtilisin/kexin type 9 inhibitor to reach LDL-C therapeutic goals. Hopefully, the Lp(a) lowering therapies currently under development will prove instrumental for adequate treatment of FH patients with concomitantly elevated Lp(a) in coming years.

Purpose of review: Advances in the management of lipid disorders have expanded therapeutic options for hypercholesterolemia and beyond. We review the current advances in RNA interference (RNAi) therapies as small interfering RNA (siRNA) drugs, critically assess their clinical positioning, and explore their potential role in reshaping lipid management over the next years.

Recent findings: RNAi enables targeted, durable suppression of key lipid-regulating proteins at the mRNA level. Inclisiran, the first approved RNAi therapy for hypercholesterolemia, achieves about 50% sustained LDL-c reduction with long-interval maintenance dosing, offering an alternative to monoclonal antibodies. Beyond LDL-c lowering, multiple RNAi drugs are in advanced development targeting lipoprotein(a), apolipoprotein C-III, and angiopoietin-like protein 3, aiming to address residual cardiovascular risk. Early safety and adherence data are encouraging, yet pivotal outcome trials and cost-effectiveness analyses are still pending.

Summary: RNAi is a naturally occurring gene-silencing mechanism that can be harnessed therapeutically through siRNA molecules. In lipidology, siRNA-based therapies represent a disruptive technology with the potential to transform both prevention and treatment of atherosclerotic cardiovascular disease. If ongoing trials confirm cardiovascular benefit and safety, RNAi agents could become foundational in personalized lipid management, moving the field toward long-acting, target-specific, and potentially combination-based regimens. The coming years will determine whether RNAi fulfills its promise as the future standard of care in lipid disorders.

Purpose of review: To critically examine the emerging evidence linking ultra-processed food (UPF) consumption to chronic kidney disease (CKD), with a particular focus on prevention strategies, biological mechanisms, and implications for dietary guidelines and public health policy.

Recent findings: Recent systematic reviews and meta-analyses consistently report a positive association between high UPF consumption and CKD risk. Mechanistic insights suggest roles for food additives, altered nutrient bioavailability, and inflammatory pathways, while omics-based studies offer preliminary biomarker candidates. The KDIGO 2024 guidelines now emphasize dietary interventions, including reduced UPF consumption, as a core component of CKD management.

Summary: The findings support limiting UPF consumption as part of CKD prevention strategies. Nonetheless, the evidence base is largely derived from overlapping observational studies, with limited original research published in the considered timeframe. Moreover, the scarcity of recent original studies, methodological inconsistencies in UPF classification and CKD outcome definitions, highlight the urgent need for further research and standardization of approaches. Integrating precision nutrition and validated biomarkers into nephrology could enhance individualized dietary recommendations and public health interventions.

Purpose of review: Type 2 diabetes (T2D) is a heterogeneous, progressive metabolic disease and a major contributor to cardiovascular disease worldwide. Current prevention strategies, centred on population-level lifestyle recommendations, have had limited success, highlighting the need for more comprehensive approaches that account for interindividual variation in intervention response.

Recent findings: Although discrete T2D subtypes using genomics or clinical variables have been proposed for targeted diabetes prevention and care strategies, emerging evidence supports a more dynamic view of heterogeneity as a continuous spectrum of metabolic dysfunction. Continuous glucose monitoring and multiomics profiling have shown promises in detecting early metabolic dysfunction in individuals with normal glycemia.

Summary: In this review, we synthesize advances in modelling T2D phenotypic continuum and highlight how emerging technologies, including continuous glucose monitoring and multiomics profiling, can detect early metabolic dysregulation. We also discuss methodological challenges, such as the need for standardized deep phenotyping, robust analytic frameworks, and inclusion of diverse populations to ensure equity in translation. Finally, we outline future directions for translating these insights into scalable, mechanism-informed interventions that address glycaemic progression from subclinical changes to more advanced forms of the disease.

Purpose of review: Well conducted, prospective, blood-based biomarker studies on dementia risk are growing, providing valuable insights into disease mechanisms that precede clinical symptoms. These investigations are crucial for advancing our understanding of dementia pathology and identifying early biological changes.

Recent findings: Emerging evidence shows that proteins detected in peripheral tissues and the circulatory system can also play a role in neurological diseases. Both neuronal and nonbrain-specific proteins have been associated with dementia prior to symptom onset, highlighting the complex and multisystem nature of disease development. Of the 11 studies included in this review that focused on prospective studies of dementia that applied plasma proteomics, 36 proteins were identified in at least two independent cohorts, suggesting that blood-based proteomics detects consistent protein levels that may be altered years before dementia diagnosis.

Summary: Blood-based biomarkers hold promise for early diagnosis, patient stratification, and mechanistic research in dementia. The observed overlap in protein profiles across studies suggests we are beginning to uncover systemic biological differences that contribute to disease progression.

Purpose of review: Elevated plasma lipoprotein(a) [Lp(a)] is a causal and independent risk factor for atherosclerotic cardiovascular disease and an emerging therapeutic target. Over the past 15 years, many medical bodies from around the world have released scientific statements and clinical guidelines regarding Lp(a). This review tracks how recommendations on Lp(a) have evolved over this timeframe.

Recent findings: Powerful studies demonstrating the independent association of elevated Lp(a) in large numbers of patients have been published. The data allowed a more precise formulation of risk categories for Lp(a) levels and of models for how a given level of Lp(a) in a moderate-risk to high-risk primary prevention patient might inform management of modifiable risk factors such as LDL cholesterol. Guidelines and statements have increasingly recommended universal screening for elevated Lp(a) and have identified elevated Lp(a) as a risk-enhancing or amplifying factor. However, some gaps and inconsistencies remain.

Summary: Ongoing cardiovascular outcomes trials of potent Lp(a)-lowering therapies will inform clinical use of Lp(a) in the future. Presently, consensus is building for measurement of Lp(a) in all adults and for incorporation of Lp(a) levels into clinical decision-making for prevention of cardiovascular disease. However, caution is warranted as the evidence base underlying this consensus has several important missing pieces.

Purpose of review: Low-grade systemic inflammation, as determined by high-sensitivity C-Reactive Protein (hsCRP), plays a significant role in the progression and development of atherosclerotic cardiovascular disease (ASCVD) and is recognized as a risk enhancer for increased incidence of major adverse cardiovascular events (MACE). (In 2024, the US Food and Drug Administration approved colchicine, as the first anti-inflammatory agent for secondary cardiovascular prevention. While this step signified a translational milestone, recent neutral colchicine trials such as CLEAR- SYNERGY, have reignited controversy regarding the overall efficacy of colchicine, and the need for alternative anti-inflammatory therapies. As the understanding of inflammation's role in atherosclerosis grows, questions persist about the best management strategies and future therapeutic options. This review aims to provide an updated summary that includes insights from recent key trials, explores investigational anti-inflammatory treatments, and discusses considerations for future trial designs.

Recent findings: This review will encompass recent trials involving colchicine, IL-1 antagonists, and interluekin-6 Inhibitors.

Summary: In this review, we will discuss mechanisms of inflammation as they pertain to ASCVD, significant contemporary trials, novel anti-inflammatory therapies, and considerations for future trial designs.

Purpose of review: Triglyceride-rich lipoproteins (TRLs) and LDL remain major drivers of atherosclerotic cardiovascular disease, and angiopoietin-like protein 3 (ANGPTL3) has emerged as a promising target to lower both triglycerides and LDL cholesterol (LDL-C). This review provides an overview on ANGPTL3 inhibition, including genetic insights and clinical evidence, and examines patient groups in which therapies may be particularly well suited to reduce residual cardiovascular risk.

Recent findings: Genetic studies have shown that carriers of ANGPTL3 loss-of-function variants exhibit lower levels of triglycerides and LDL-C, and a reduced cardiovascular risk. Evinacumab, a monoclonal antibody targeting ANGPTL3, lowers LDL-C by approximately 50% in patients with homozygous familial hypercholesterolemia (HoFH), in whom traditional lipid-lowering therapies are largely ineffective. In patients with mixed dyslipidemia, small interfering RNAs (e.g. zodasiran and solbinsiran) and antisense oligonucleotides (e.g. vupanorsen) achieve approximately 60% triglyceride and 20% LDL-C lowering, with the small interfering RNAs having a generally favorable safety profile.

Summary: ANGPTL3 inhibition offers an LDL receptor-independent means to lower atherogenic particles spanning from TRLs to LDL, complementing traditional lipid-lowering therapies. Evinacumab is practice-changing in HoFH, and RNA agents may soon broaden applicability to patients with mixed dyslipidemia and residual cardiovascular risk, pending cardiovascular outcomes trials.

Purpose of review: This review explores the evolving understanding of efferocytosis - the clearance of dead or dying cells by phagocytes - in the context of atherosclerosis. It highlights recent discovers in cell death modalities, impaired clearance mechanisms and emerging therapeutic strategies aimed at restoring efferocytosis to stabilize plaques and resolve inflammation.

Recent findings: Recent studies have expanded the scope of efferocytosis beyond apoptotic cells to include other pro-inflammatory cell death modes, including pyroptosis, necroptosis and ferroptosis, revealing context-dependent clearance efficiency and immunological outcomes. Novel mechanisms of impaired efferocytosis have been identified, including CD47- or CD147-mediated inhibition, efferocyte metabolic reprogramming and age-related MerTK cleavage. Therapeutic advances include nanoparticle-mediated delivery of SHP-1 inhibitors, engineered efferocytotic receptors, and treatment with resolvin D1 to enhance efferocytosis and reduce inflammation.

Summary: Efferocytosis is a critical process in maintaining vascular homeostasis and preventing plaque rupture in atherosclerosis. Its impairment contributes to necrotic core expansion and chronic inflammation. Advances in understanding the molecular regulation of efferocytosis and its therapeutic modulation offer new avenues for intervention. Targeting efferocytosis may complement lipid-lowering and/or anti-inflammatory therapies, representing a promising strategy for cardiovascular disease management.