2026-08-01 | Lipoprotein apheresis: still needed in many patients, or soon a historical practice?
Abstract Lipoprotein apheresis (LA) has long been used as an ultima ratio therapy for patients with extreme lipid-driven cardiovascular risk. One perspective maintains that, despite major advances in lipid-lowering pharmacology and the emergence of gene-silencing therapies, LA remains indispensable for selected patients with homozygous familial hypercholesterolemia (HoFH), severe hypercholesterolemia refractory to maximal therapy, and isolated lipoprotein(a) [Lp(a)]–mediated progressive cardiovascular disease. An opposing view argues that modern and emerging pharmacological agents—PCSK9 inhibitors, inclisiran, bempedoic acid, evinacumab, and targeted Lp(a)-lowering antisense and small interfering RNA (siRNA) agents—have already rendered LA obsolete in almost all patients, with its remaining niche closing rapidly as outcome data accumulate. This combined manuscript juxtaposes the two positions in a streamlined form and concludes with a balanced conclusion of the future role of LA.
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2026-07-18 | Precise hepatic base editing of ASGR1 enables robust and durable LDLR-independent lipid lowering in vivo.
Familial hypercholesterolemia (FH), most frequently caused by LDLR loss-of-function variants, is a common autosomal-dominant disorder that leads to early-onset, life-threatening cardiovascular disease. Therapeutic options for LDLR-deficient homozygous FH (HoFH) are very limited, motivating the development of durable, effective, and LDLR-independent gene therapies. Human genetic studies have linked ASGR1 loss-of-function variants with low serum cholesterol levels and significantly reduced cardiovascular risk, yet in vivo ASGR1 editing has not been explored as a therapeutic strategy for HoFH. Here, using an optimized hepatocyte-specific delivery platform, we achieved 57.6% liver-wide Asgr1 base editing in Ldlr-/- mice, yielding ∼95% reduction of hepatic ASGR1 expression and sustained 40%-50% reductions in serum LDL-cholesterol (LDL-C), total cholesterol (TC), and triglyceride levels, with a favorable safety profile. Importantly, moderate Asgr1 editing (32.0%) with partial protein suppression (58%) also conferred significant and durable lipid lowering, thereby defining a therapeutically relevant editing window aligned with ASGR1 suppression level in carriers of ASGR1 loss-of-function variants. Benchmarking against Angptl3 editing revealed comparable reductions in LDL-C and TC, while combined Asgr1/Angptl3 editing further enhanced serum cholesterol lowering, suggesting potential benefits of combined editing. Together, these findings establish hepatic ASGR1 base editing as a potent, durable, and LDLR-independent gene-therapy strategy for severe HoFH.
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2026-07-12 | The Angiopoietin-like Protein (ANGPTL) Axis in Dyslipidemia: Mechanisms, Cardiovascular Risk, and Emerging Therapies.
The angiopoietin-like protein (ANGPTL) 3-4-8 axis has emerged as a central regulator of lipoprotein lipase and lipid metabolism. This review examines the mechanistic basis of ANGPTL pathway modulation and therapeutic implications for cardiovascular risk reduction across diverse phenotypes of dyslipidemia. Genetic studies demonstrate that loss-of-function variants in ANGPTL3 and ANGPTL4 are associated with lower triglycerides and decreased coronary artery disease risk. Pharmacologic inhibition of ANGPTL3 with monoclonal antibodies and RNA-based therapies reduces triglycerides, remnant cholesterol, low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B (apoB) through mechanisms predominantly independent of the LDL receptor. Clinical trials with ANGPTL3 inhibitors have demonstrated marked LDL-C reductions in patients with homozygous familial hypercholesterolemia (HoFH), as well as broad lipid-lowering effects in patients with mixed dyslipidemia. Emerging strategies targeting the ANGPTL3/8 complex and ANGPTL4 further refine lipid-lowering effects, while early genome-editing data suggest the potential for durable ANGPTL3 suppression. Modulation of the ANGPTL-lipoprotein lipase axis is a novel strategy to address residual atherosclerotic risk beyond traditional LDL receptor-dependent therapies. ANGPTL3 inhibitors have been practice-changing in HoFH, and more broadly, ANGPTL-directed therapies hold promise for patients with mixed dyslipidemia to mitigate cardiovascular risk.
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2026-07-02 | Homozygous familial hypercholesterolemia, experience with Evinacumab treatment in two Mexican pediatric patients: case report
Homozygous familial hypercholesterolemia (HoFH) is a rare and life-threatening genetic disorder characterized by extremely elevated low-density lipoprotein cholesterol (LDL-C) levels from birth, leading to accelerated atherosclerotic cardiovascular disease and premature mortality. Conventional lipid-lowering therapies often provide insufficient LDL-C reduction, particularly in patients with minimal or absent LDL receptor (LDLR) function. Evinacumab, an angiopoietin-like protein 3 (ANGPTL3) inhibitor, lowers LDL-C independently of LDLR activity and represents a major therapeutic advance. Here we report two Mexican pediatric patients with HoFH who demonstrated profound LDL-C reductions following initiation of Evinacumab (59% and 68% within the first month of treatment), exceeding reductions observed in pivotal clinical trials. Both patients maintained sustained LDL-C reductions during long-term follow-up (up to 22 months). Importantly, temporary treatment interruption in both cases due to administrative and supply related difficulties limited access to Evinacumab was associated with marked rebound hypercholesterolemia. Reinitiation of therapy led to rapid and substantial lipid reduction, demonstrating a clear dechallenge–rechallenge effect and confirming the relevance of a continuous pharmacologic treatment with ANGPTL3 inhibition. Serial vascular imaging in one patient revealed partial regression of subclavian and carotid artery stenosis, as well as reduced aortic wall thickening following sustained LDL-C reduction; adding evidence to the recently described vascular improvement associated with Evinacumab therapy in pediatric HoFH. Both patients also experienced clinically meaningful improvements in quality of life, and treatment was well tolerated without serious adverse events.
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2026-06-26 | Women with Homozygous Familial Hypercholesterolemia and Impact on Reproductive Life from Menarche to Menopause: Long-Term Case Series Observational Study
Homozygous familial hypercholesterolemia (HoFH) is a genetic disease in which LDL-C is high at birth, causing cardiovascular disease. Reproductive issues in women are also caused by lipid-lowering therapies (LLTs) that must be interrupted during pregnancy and breastfeeding. The only safe choice during pregnancy is lipoprotein apheresis (LA), although there are limited data regarding fertility, pregnancy, and menopause. This long-term case series observational study examined 23 genetically confirmed HoFH women in a tertiary health facility, obtaining clinical, cardiovascular, biochemical, and reproductive information through medical records and structured interviews. Cardiovascular disease and aortic valve disease were found in 48% and 52%, respectively; four women died prematurely. Menarche (12.1 years) and menopause (52.0 years) were in the normal range. The majority of these had regular menstrual cycles; there was one case of polycystic ovary syndrome. Twelve women became spontaneously pregnant. Obstetric complications included preterm delivery, gestational diabetes, hypertension, and fetal growth restriction. This study showed that continuous LA during pregnancy was associated with better lipid control and maternal-fetal outcomes, but cardiovascular impairment was observed in the case of interruption of LLT. LLT interruption affects the inherited lipid disorder, and a very short period of breastfeeding is recommended. HoFH in women under treatment has no impact on the menstrual cycle or on the timing of menopause. Pregnancy is a high-risk condition that needs the care of a multidisciplinary team. The need to ensure continuous LA, systematic reproductive counseling, early cardiovascular examination, and aligned lifelong care is critical in maximizing the outcome of HoFH women.
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