Current opinion in lipidology最新文献

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.

Purpose of review: The causal role of LDL in atherosclerotic cardiovascular disease (ASCVD) is well established, but the contribution of HDL has proven more complex. CETP inhibitors were originally developed to increase HDL-cholesterol (HDL-C), but the failure of clinical trials and genetic evidence have changed our understanding of CETP biology. With the development of obicetrapib, a next-generation CETP inhibitor, there has been renewed interest in its therapeutic potential. This review summarizes the latest findings on CETP inhibition and highlights the evolving perspectives from lipid modulation to broader clinical applications.

Recent findings: Clinical trials and Mendelian randomisation consistently show that increasing HDL-C alone does not reduce cardiovascular risk, while lowering apoB-containing lipoproteins is associated with benefit. Off-target effects, modest efficacy or insufficient follow-up limited previous CETP inhibitors. Obicetrapib, in contrast, achieves a significant LDL-C and apoB reduction, a marked HDL-C increase and favourable safety. Beyond ASCVD, CETP inhibition may also have an impact on diabetes risk, cognitive function and possibly other conditions, although data are still preliminary.

Summary: The therapeutic focus has shifted from HDL-C elevation to apoB lowering as the determinant of cardiovascular benefit. Obicetrapib shows promise, with ongoing trials designed to define its role in ASCVD management.

Purpose of review: The review focusses on the role of liver transplantation, and rarely combined liver and heart transplantation, in the current management of homozygous familial hypercholesterolaemia (HoFH).

Recent findings: The review features world-wide reports published during the past 10 years describing the rationale and outcomes of liver transplantation for children and adults with HoFH. It also provides information on the scale of liver and heart transplantation for a variety of other disorders.

Summary: Liver transplantation provides a more effective means of lowering LDL than currently available alternatives such as apheresis and lomitapide but carries with it an unacceptably high risk of posttransplant morbidity and mortality. This is mainly due to the adverse effects of life-long immunosuppressive drug therapy, which restricts the use of liver transplantation to those HoFH patients in whom optimal medical therapy has failed.

Purpose of review: In 1994, the 4S trial was revolutionary by showing that cholesterol lowering with simvastatin reduced, not only atherosclerotic vascular disease (ASCVD) events, but also all-cause mortality as compared to placebo. During the following 30 years, statins have proved to be well tolerated and effective and also paved way for new innovations in the field of dyslipidaemia therapy.

Recent findings: The aim of this review is to summarize current knowledge about statins and effects of cholesterol-lowering accumulated in the wake of 4S trial: both vascular and nonvascular benefits, adverse effects, adherence, and statin intolerance. While secondary prevention of ASCVD has emphasized 'the lower the better' in LDL-cholesterol lowering, emerging topic is 'the longer the better' to reduce lifetime LDL burden and achieve full potential of ASCVD prevention. With statins as backbone therapy, new treatment innovations are in trials to better manage all atherosclerotic lipoproteins and residual risk.

Summary: After becoming generic, statins are inexpensive and well tolerated therapy with potential to substantially reduce the burden of atherosclerotic vascular disease world-wide. To achieve these goals, both accessibility and adherence are fundamental issues.

Purpose of review: Lipid metabolism and de-novo lipogenesis (DNL) is broadly controlled by the SREBP transcription factors. These transcription factors are matured from membrane-anchored precursor proteins by the proteolytic actions of the proteases S1P and S2P. In this review, we summarize the current understanding of SPRING, a recently identified activator of S1P.

Recent findings: Recent studies of SPRING using animal, cellular, biochemical, and biophysical methods have established SPRING as a core component of the SREBP machinery. Deletion of SPRING in cells and animal livers specifically reduces SREBP activity yet leaves other S1P substrates intact, demonstrating an SREBP-specific role for SPRING in licensing S1P activity. Mechanistic biochemical and structural studies revealed that SPRING activates S1P by competitively displacing its inhibitory pro-domain and elucidated how small molecule inhibition of S1P can be accomplished.

Summary: Current studies have shown how SPRING activates S1P and uncovered a critical role for SPRING in the SREBP pathway. Further studies are warranted to understand this emerging, connection between SPRING and the regulation of DNL through SREBP.

Purpose of review: To identify the opportunity of targeting patients with elevated lipoprotein(a) [Lp(a)] in patients with peripheral arterial disease (PAD).

Recent findings: Lp(a) plays a causal role in atherosclerotic cardiovascular disease. Cohort studies demonstrate that elevated Lp(a) levels independently associate with an increased risk of developing PAD. Patients with manifest PAD have a high residual cardiovascular risk, despite use of traditional lipid lowering. The current approach to treatment of patients with high Lp(a) levels involves intensification of management of conventional cardiovascular risk factors and consideration of use of aspirin. In recent years, therapeutic programs have developed injectable RNA targeted agents and a small molecule Lp(a) assembly disrupter that are well tolerated and produce effective Lp(a) lowering. Many of these agents are being evaluated in large cardiovascular outcomes trials. Advances have also looked to develop gene/base editing and epigenetic treatments to lower Lp(a).

Summary: These studies demonstrate that Lp(a) plays an important role in cardiovascular disease, including PAD. However, it remains to be determined if more effective Lp(a) lowering will translate to cardiovascular benefit. If this does prove to be the case, integration of Lp(a) testing and therapeutics has the potential to transform clinical outcomes in people living with PAD.

Purpose of review: Cardiovascular diseases (CVDs) are a leading cause of death worldwide. While it is well known that obesity, dyslipidemia and diabetes are major risk factors of CVD, observational clinical studies have shown that variability in body weight, circulating LDL-cholesterol (LDL-C) or glucose levels further increase this risk. The underlying mechanisms, however, leading to increased risk of CVD due to metabolic cycling are not well understood.

Recent findings: Recent studies have shown that metabolic cycling can cause reprogramming of immune cells and their progenitors. Weight, LDL-C, or glucose cycling induced myelopoiesis, monocytosis and/or altered immune cell functions. This resulted in a heightened immune response, ultimately worsening atherosclerosis.

Summary: Even though there are differences in how metabolic cycling is measured in clinical and basic research studies, the conclusion remains the same: metabolic cycling increases CVD severity. Some studies have highlighted the role of reprogramming of myeloid cells and their progenitors in progression of atherosclerosis due to metabolic cycling, but further research is required to better understand the mechanisms behind it.

Purpose of review: This review integrates recent structural and biochemical insights into apolipoprotein B (apoB) containing lipoproteins to highlight how factors beyond cholesterol levels contribute to atherosclerosis.

Recent findings: Emerging evidence demonstrates that the atherogenic potential of apoB-containing lipoproteins varies substantially both between and within lipoprotein classes. Recent studies using high-resolution cryo-electron microscopy, crosslinking mass spectrometry, and computational modeling reveal that even subtle differences in lipoprotein composition, particle size, and lipid spatial organization can significantly alter the conformation and dynamic behavior of apoB on the particle surface. These conformational shifts influence a variety of lipoprotein characteristics such as the stability of the particle, their ability to interact with receptors and enzymes, and their proatherogenic potential as measured by the propensity of lipoproteins to bind to proteoglycans of the arterial wall or to undergo modification and aggregation.

Summary: In this review, we discuss how novel structural and functional information can refine our understanding of the distinct properties of apoB-containing lipoproteins and their role in atherosclerosis and lipid accumulation. Understanding of the specific features related to the proatherogenic behavior of the lipoproteins helps in understanding the complexities of atherogenesis and cardiovascular risk beyond cholesterol.