Current Opinion in Lipidology

Current Issue Highlights

Lipoprotein(a): a unique lipoprotein at the crossroads of atherosclerosis and thrombosis
October 2026: 37(5):211-217
Purpose of review
Elevated plasma concentrations of lipoprotein(a) [Lp(a)] are a causal and independent risk factor for atherosclerotic cardiovascular disease and an emerging therapeutic target. However, despite Lp(a) being on the cusp of widespread clinical consideration, fundamental questions regarding the pathophysiology of Lp(a) remain, most notably its contribution to atherothrombosis. This review will summarize recent evidence for both indirect and direct prothrombotic roles of Lp(a).
Recent findings
Preclinical studies show that the proinflammatory properties of Lp(a) – largely attributable to its cargo of oxidized phospholipids – promote vulnerable plaques through effects on vascular and immune/inflammatory cells. Advanced imaging techniques show that elevated Lp(a) is associated with vulnerable plaque phenotypes in patients. Regarding thrombosis, previous assumptions that Lp(a) is antifibrinolytic have given way to an emerging picture that Lp(a) promotes a lysis-resistant clot architecture while stimulating the coagulation cascade and potentiating platelet responses. Indeed, clinical studies have demonstrated that patients with elevated Lp(a) specifically accrue clinical benefit from aspirin in the primary prevention setting.
Summary
That elevated Lp(a) is both directly and indirectly prothrombotic remains to be proven by additional clinical and animal model studies Nonetheless, the accumulating evidence indicates that considering the prothrombotic activities of Lp(a) will impact clinical management of Lp(a) and the deployment of Lp(a)-lowering therapies.
From smooth to ‘breaking bad’: vascular smooth muscle cell phenotypic switching at the heart of plaque vulnerability
October 2026: 37(5):201-210
Purpose of review
Atherosclerosis persists despite LDL-lowering therapies, highlighting lipid-independent drivers of disease. This review examines vascular smooth muscle cell (VSMC) plasticity as a central determinant of plaque progression and stability and evaluates emerging therapeutic strategies targeting VSMC phenotypic transitions.
Recent findings
VSMCs exhibit marked phenotypic plasticity, contributing to up to 50% of plaque foam cells and generating diverse states including macrophage-like, fibromyocyte, osteogenic, and intermediate populations. Key regulators such as Krüppel-like factor 4 (KLF4) and octamer-binding transcription factor 4 (OCT4) govern transitions between stabilising α-smooth muscle actin–positive (ACTA2⁺) cap-forming and destabilising lectin galactoside-binding soluble 3–positive (LGALS3⁺) inflammatory phenotypes. VSMC-derived foam cells display impaired cholesterol efflux and efferocytosis. Epigenetic reprogramming and oncogenic-like signalling, including nuclear factor kappa B (NF-κB), phosphoinositide 3-kinase/protein kinase B (PI3K/AKT), and mitogen-activated protein kinase (MAPK), underpin these changes. Emerging therapies include microRNA-based targeting of KLF4, chimeric antigen receptor regulatory T cells directed against oxidised LDL, nanoparticle systems targeting osteopontin, and fibroblast activation protein (FAP)-directed strategies.
Summary
VSMC plasticity integrates inflammatory and epigenetic signals to drive plaque evolution. Targeting specific VSMC states offers a precision medicine approach to stabilise plaques while preserving vascular integrity.
Sitosterolemia: evolving strategies for earlier diagnosis
October 2026: 37(5):196-200
Purpose of review
Sitosterolemia is a rare autosomal recessive lipid disorder caused by biallelic pathogenic variants in ABCG5 or ABCG8, resulting in excessive intestinal absorption and impaired biliary excretion of plant sterols. Although historically considered exceptionally rare, recent genetic studies suggest the disorder is substantially underdiagnosed, with marked phenotypic heterogeneity ranging from xanthomas and premature atherosclerosis to hematologic abnormalities, and frequently mimics familial hypercholesterolemia. This review summarizes recent advances in the clinical, biological, and genetic diagnosis of sitosterolemia, with a focus on strategies that may facilitate earlier detection.
Recent findings
Phytosterol quantification, particularly sitosterol, campesterol, and stigmasterol, remains indispensable for accurate diagnosis. Hematologic abnormalities, including hemolytic anemia, stomatocytosis, and macrothrombocytopenia, are increasingly recognized as valuable diagnostic clues complementing the biochemical approach. Expanded variant catalogs for ABCG5/ABCG8 and genome-wide association studies have revealed potentially polygenic contributions to phytosterol metabolism extending beyond these two genes. However, no specific guidelines have yet been established for cascade screening.
Summary
Earlier diagnosis requires integration of clinical, biochemical, hematologic, and genetic data. Plasma phytosterol measurement remains the diagnostic cornerstone. Improved disease awareness, broader access to sterol testing, and expanded genetic screening may reduce diagnostic delays and enable timely management, including ezetimibe and dietary phytosterol restriction.
HDL-associated proteins affecting CVD and systemic inflammation
October 2026: 37(5):191-195
Purpose of review
It has become clear that elevated HDL-C is not a reliable marker of protection against inflammation and cardiovascular disease (CVD). This review summarizes recent advances in understanding how HDL function is affected by its associated proteins, demonstrating that this is a more appropriate lens through which to assess HDL's protective capacity.
Recent findings
Recent publications have demonstrated an inverse relationship between ApoM and clinical outcomes in chronic kidney disease and its concomitant cardiovascular indications. Mechanistic studies show that ApoM's regulation of mitochondrial function and autophagy are likely contributors to this effect. Additionally, ApoA-I, serum amyloid albumin (SAA), and SR-B1 have recently been highlighted as key regulators of atherogenesis through their ability to prevent LDL transcytosis and arterial entrapment by proteoglycans. Lastly, a novel mechanism is described wherein HDL-bound endotoxin is degraded through the endosome–lysosome pathway in an SR-B1-dependent manner, attenuating IL-1β activation. In the same study, inhibition of CETP (cholesterol ester transfer protein) increased HDL and improved mortality in a mouse model of sepsis, highlighting this pathway's importance and therapeutic potential of CETP inhibition, which is currently in key clinical trials.
Summary
HDL regulates inflammation and CVD through a variety of mechanisms independent of reverse cholesterol transport, including autophagy, LDL deposition, endotoxin clearance.
Lipids and lipoproteins in calcific aortic valve disease
October 2026: 37(5):185-190
Purpose of review
Lipids and lipoproteins have established roles in calcific atherosclerosis, but there is less awareness of their role in calcific aortic valve disease (CAVD). Clinical studies link CAVD with severe hypercholesterolemia, and genetic studies consistently link it with lipoprotein little (a) [Lp(a)], a major carrier of oxidized phospholipids. Given the remarkable similarities between calcific atherosclerotic plaques and calcific aortic valves, lipids are incriminated. Hence, lipid-lowering therapies used for atherosclerosis have been tested in CAVD, but results have been inexplicably disappointing. New evidence for the importance of lipids, despite failure of lipid-lowering, and new concepts in diagnostic and therapeutic approaches are discussed.
Recent findings
Evidence supports a key role of Lp(a) levels in CAVD. Potential diagnostic advances include pH-sensitive-fluorescence probes for visualizing lipid droplets in valves and identification of natural antibodies to modified LDL that associate inversely with CAVD. Potential therapeutic advances include Lp(a) lowering, SGLT2 inhibition, and reactivation of soluble guanylate cyclase. Trial outcomes currently remain mixed.
Summary
Recent studies clarify the mechanisms by which lipids, lipoproteins, and Lp(a) contribute to CAVD. New potential diagnostic techniques include screening for natural antibodies and visualizing lipid deposits. New therapeutic agents include oligonucleotides and nanoparticles. New clinical trials are underway.

Latest Articles

Current, novel and emerging lipid-lowering therapies in pediatric familial hypercholesterolemia
Current Opinion in Lipidology. September 19, 2026
Purpose of review
Over the past decade, pharmacological treatment options for children with familial hypercholesterolemia (FH) have expanded considerably. The recent European Atherosclerosis Society consensus recommends more stringent LDL cholesterol (LDL-C) targets than previously advocated. Consequently, more children with FH are expected to become eligible for novel therapeutic options. This review summarizes established and emerging lipid-lowering therapies (LLT) evaluated in children, focusing on recent and ongoing clinical trials.
Recent findings
Conventional LLT remains the cornerstone of FH treatment, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are approved for pediatric use and achieve significant LDL-C reductions; however, injectable administration and high costs limit their widespread use. Novel oral PCSK9 inhibitors are currently under investigation in clinical trials, and fixed-dose combinations may offer a more practical and cost-effective approach. Additionally, angiopoietin-like protein 3 inhibitors and microsomal triglyceride transfer protein inhibitors lower LDL-C in dependently of LDL receptor activity, making them particularly suitable for homozygous FH patients.
Summary
The management of FH is entering a new therapeutic era. As therapeutic options expand and agents with greater LDL-C reductions become available, personalized treatment strategies will become increasingly important to achieve LDL-C targets and may ultimately shift from stepwise intensification approaches toward early intensive treatment.
CRISPR therapy for dyslipidemia
Current Opinion in Lipidology. September 18, 2026
Purpose of review
Several lipid and lipoprotein risk factors play an important role in the causality of atherosclerotic cardiovascular disease. Many therapies are limited by suboptimal long-term adherence. This narrative review summarizes the potential for gene editing and epigenetic therapy for the management of dyslipidemia.
Recent findings
Recent advances in genomic engineering permit the ability to develop gene editing, base editing and epigenomic editing of specific regions of DNA in humans. These therapies have advanced to early phase clinical evaluation with initial reports demonstrating favorable reductions in ANGPTL3 and proprotein convertase subtilisin kexin type 9, with consequent decreases in levels of low-density lipoprotein cholesterol and triglycerides. Apart from mild-moderate infusion reactions, the early experience with these therapies appears to be well tolerated.
Summary
Advances in genomic engineering have developed a number of agents with the potential for robust and durable changes to atherosclerotic lipid and lipoprotein risk factors. How these agents will enter clinical practice will require further evaluation in clinical trials.
Oral PCSK9 inhibitors: closing the gap between potency and practicality
Current Opinion in Lipidology. September 18, 2026
Purpose of review
Oral proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors represent a new generation of lipid-lowering therapies that combine the potency of injectable PCSK9 inhibitors with the convenience of oral administration. This review examines the mechanisms, trial evidence, and implementation considerations for oral PCSK9 inhibitors that have reached phase 2 or later clinical development.
Recent findings
Two oral PCSK9 inhibitors, enlicitide and laroprovstat, have demonstrated that oral PCSK9 inhibition is pharmacologically viable through distinct mechanisms of action. Enlicitide, a macrocyclic peptide that competitively blocks the PCSK9–LDL receptor interaction, achieved placebo-corrected LDL-C reductions of ~60% across three phase 3 trials, with high adherence and a favorable safety profile over 52weeks. Laroprovstat, a small molecule that inhibits PCSK9-mediated lysosomal trafficking of the LDL receptor, produced dose-dependent LDL-C reductions of up to 51% in a phase 2 trial and is advancing through phase 3 evaluation. Large cardiovascular outcomes trials remain underway for both agents.
Summary
Oral PCSK9 inhibitors have the potential to improve the convenience and acceptability of PCSK9-targeted therapy. Whether these advantages translate into greater real-world uptake will depend on affordability, payer coverage, clinician adoption, and long-term adherence.