2023 Update on European Atherosclerosis Society Consensus Statement on Homozygous Familial Hypercholesterolaemia: new treatments and clinical guidance

European Heart Journal, Journal Year: 2023, Volume and Issue: 44(25), P. 2277 - 2291

Published: May 2, 2023

Abstract This 2023 statement updates clinical guidance for homozygous familial hypercholesterolaemia (HoFH), explains the genetic complexity, and provides pragmatic recommendations to address inequities in HoFH care worldwide. Key strengths include updated criteria diagnosis of recommendation prioritize phenotypic features over genotype. Thus, a low-density lipoprotein cholesterol (LDL-C) >10 mmol/L (>400 mg/dL) is suggestive warrants further evaluation. The also state-of-the art discussion clinicians interpreting results testing family planning pregnancy. Therapeutic decisions are based on LDL-C level. Combination LDL-C-lowering therapy—both pharmacologic intervention apheresis (LA)—is foundational. Addition novel, efficacious therapies (i.e. inhibitors proprotein convertase subtilisin/kexin type 9, followed by evinacumab and/or lomitapide) offers potential attain goal or reduce need LA. To improve around world, recommends creation national screening programmes, education awareness, management guidelines that account local realities care, including access specialist centres, treatments, cost. crucial early diagnosis, better improved cardiovascular health patients with

Language: Английский

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International Atherosclerosis Society guidance for implementing best practice in the care of familial hypercholesterolaemia

Nature Reviews Cardiology, Journal Year: 2023, Volume and Issue: 20(12), P. 845 - 869

Published: June 15, 2023

Language: Английский

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World Heart Federation Cholesterol Roadmap 2022

Global Heart, Journal Year: 2022, Volume and Issue: 17(1), P. 75 - 75

Published: Oct. 14, 2022

Background: Atherosclerotic cardiovascular diseases (ASCVD) including myocardial infarction, stroke and peripheral arterial disease continue to be major causes of premature death, disability healthcare expenditure globally. Preventing the accumulation cholesterol-containing atherogenic lipoproteins in vessel wall is central any strategy prevent ASCVD. Advances current concepts about reducing cumulative exposure apolipoprotein B (apo B) emergence novel therapies provide new opportunities better The present update World Heart Federation Cholesterol Roadmap provides a conceptual framework for development national policies health systems approaches, so that potential roadblocks cholesterol management thus ASCVD prevention can overcome. Methods: Through review published guidelines research papers since 2017, consultation with committee composed experts clinical dyslipidaemias low-and-middle income countries (LMICs), this identifies (1) key principles effective (2) gaps implementation these interventions (knowledge-practice gaps); (3) system treatment elevated LMICs; (4) strategies overcoming these. Results: Reducing future burden will require diverse approaches throughout life-course. These include: greater focus on primordial prevention; availability affordable testing; universal screening inherited dyslipidaemias; risk stratification moving beyond 10-year look at lifetime adequate estimators; wider cholesterol-lowering which should include statins as essential medications globally; use doses potent statin regimens; combination ezetimibe or other order attain maintain robust reductions LDL-C those highest risk. Continuing efforts are needed literacy both public providers, utilising multi-disciplinary teams applications quantify benefits well increased adherence therapies. Conclusions: adverse effects LDL-cholesterol apo containing lipoprotein result preventable by different strategies, aimed efficiently tackling atherosclerosis stages human Preventive therefore updated implement policy, lifestyle changes when pharmacotherapies earlier investment in, shift towards, early preventive preserve rather than treat consequences

Language: Английский

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Unraveling the role of low‐density lipoprotein‐related genes in lung adenocarcinoma: Insights into tumor microenvironment and clinical prognosis

Environmental Toxicology, Journal Year: 2024, Volume and Issue: 39(10), P. 4479 - 4495

Published: March 15, 2024

The hypothesized link between low-density lipoprotein (LDL) and oncogenesis has garnered significant interest, yet its explicit impact on lung adenocarcinoma (LUAD) remains to be elucidated. This investigation aims demystify the function of LDL-related genes (LRGs) within LUAD, endeavoring shed light complex interplay LDL carcinogenesis.

Language: Английский

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Evinacumab in homozygous familial hypercholesterolaemia: long-term safety and efficacy

European Heart Journal, Journal Year: 2024, Volume and Issue: 45(27), P. 2422 - 2434

Published: June 10, 2024

Abstract Background and Aims Homozygous familial hypercholesterolaemia (HoFH) is a rare genetic disorder characterized by severely elevated LDL cholesterol (LDL-C) premature atherosclerotic cardiovascular disease. In the pivotal Phase 3 HoFH trial (NCT03399786), evinacumab significantly decreased LDL-C in patients with HoFH. This study assesses long-term safety efficacy of adult adolescent Methods this open-label, single-arm, (NCT03409744), aged ≥12 years who were evinacumab-naïve or had previously received other trials (evinacumab-continue) intravenous 15 mg/kg every 4 weeks stable lipid-lowering therapy. Results A total 116 (adults: n = 102; adolescents: 14) enrolled, whom 57 (49.1%) female. Patients treated for median (range) duration 104.3 (28.3–196.3) weeks. Overall, treatment-emergent adverse events (TEAEs) serious TEAEs reported 93 (80.2%) 27 (23.3%) patients, respectively. Two (1.7%) deaths (neither was considered related to evinacumab). Three (2.6%) discontinued due (none From baseline Week 24, mean 43.6% [mean (standard deviation, SD), 3.4 (3.2) mmol/L] overall population; reduction adults adolescents 41.7% (SD), 3.2 (3.3) 55.4% 4.7 (2.5) mmol/L], Conclusions large cohort HoFH, generally well tolerated markedly irrespective age sex. Moreover, sustained over long term.

Language: Английский

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Lerodalcibep and evolocumab for the treatment of homozygous familial hypercholesterolaemia with PCSK9 inhibition (LIBerate-HoFH): a phase 3, randomised, open-label, crossover, non-inferiority trial

The Lancet Diabetes & Endocrinology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

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Efficacy, Safety, and Tolerability of Inclisiran in Patients With Homozygous Familial Hypercholesterolemia: Results From the ORION-5 Randomized Clinical Trial

Circulation, Journal Year: 2023, Volume and Issue: 149(5), P. 354 - 362

Published: Oct. 18, 2023

BACKGROUND: Homozygous familial hypercholesterolemia is a genetic disease characterized by extremely high levels of low-density lipoprotein cholesterol (LDL-C) and risk premature cardiovascular events. The proof-of-concept study ORION-2 (A Study Inclisiran in Participants With Familial Hypercholesterolemia) showed that inclisiran, small interfering RNA prevents production the hepatic PCSK9 protein (proprotein convertase subtilisin/kexin type 9), could lead to durable reductions LDL-C when added statins ezetimibe patients with homozygous hypercholesterolemia. METHODS: ORION-5 was phase 3, 2-part, multicenter 56 elevated despite maximum tolerated doses LDL-C–lowering therapies or without apheresis. Patients eligible for part 1 (double-blind, 6 months) were randomized 2:1 receive either 300 mg inclisiran sodium (equivalent 284 inclisiran) placebo. Placebo-treated from transitioned 2 (open-label, 18 months). primary end point percentage change baseline day 150. RESULTS: mean age 42.7 years, 60.7% women. 294.0 mg/dL 356.7 placebo groups, respectively. placebo-corrected level 150 −1.68% (95% CI, −29.19% 25.83%; P =0.90), difference not statistically significant between groups. −60.6% treatment ( <0.0001); this sustained throughout study, confirming effect on its biological target PCSK9. No differences groups observed other lipids lipoproteins (apolipoprotein B, total cholesterol, non−high-density cholesterol). Adverse events serious adverse did differ study. CONCLUSIONS: reduce substantial lowering levels. well-tolerated, safety findings consistent previously reported studies overall profile. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03851705.

Language: Английский

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Evinacumab for Pediatric Patients With Homozygous Familial Hypercholesterolemia

Circulation, Journal Year: 2023, Volume and Issue: 149(5), P. 343 - 353

Published: Oct. 20, 2023

BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by severely elevated low-density lipoprotein cholesterol (LDL-C) levels due to profoundly defective LDL receptor (LDLR) function. Given that LDL-C starts in utero, atherosclerosis often presents during childhood or adolescence, creating largely unmet need for aggressive LDLR-independent lipid-lowering therapies young patients with HoFH. Here we present the first evaluation of efficacy and safety evinacumab, novel therapy, pediatric HoFH from parts A B 3-part study. METHODS: The phase 3, part B, open-label study treated 14 5 11 years age genetically proven (true homozygotes compound heterozygotes) >130 mg/dL, despite optimized therapy (including apheresis lomitapide), intravenous evinacumab 15 mg/kg every 4 weeks. RESULTS: Evinacumab treatment rapidly durably (through week 24) decreased profound reduction week, mean (SE) −48.3% (10.4%) baseline 24. ApoB (mean [SE], –41.3% [9.0%]), non–high-density (–48.9% [9.8%]), total (–49.1% [8.1%]) were similarly decreased. Treatment-emergent adverse events reported 10 (71.4%) patients; however, only 2 (14.3%) considered be treatment-related (nausea abdominal pain). One serious treatment-emergent event tonsillitis occurred (n=1), but this was not treatment-related. CONCLUSIONS: constitutes new inadequately controlled lowering nearly half these extremely high-risk difficult-to-treat individuals. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04233918.

Language: Английский

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Contemporary Homozygous Familial Hypercholesterolemia in the United States: Insights From the CASCADE FH Registry

Journal of the American Heart Association, Journal Year: 2023, Volume and Issue: 12(9)

Published: April 29, 2023

Background Homozygous familial hypercholesterolemia (HoFH) is a rare, treatment‐resistant disorder characterized by early‐onset atherosclerotic and aortic valvular cardiovascular disease if left untreated. Contemporary information on HoFH in the United States lacking, extent of underdiagnosis undertreatment uncertain. Methods Results Data were analyzed from 67 children adults with clinically diagnosed CASCADE (Cascade Screening for Awareness Detection) FH Registry. Genetic diagnosis was confirmed 43 patients. We used clinical characteristics genetically patients to query Family Heart Database, US anonymized payer health database, estimate number similar lipid profiles “real‐world” setting. Untreated low‐density lipoprotein cholesterol levels lower than (533 versus 776 mg/dL; P =0.001). At enrollment, supravalvular valve stenosis present 78.4% 43.8% 25.5% 18.8% children, respectively. most recent follow‐up, despite multiple lipid‐lowering treatment, goals achieved only minority children. Query Database identified 277 individuals HoFH. Advanced treatments prescribed 18%; 40% no treatment; reported 20%; uncommon. Conclusions Only severe phenotypes are early. remains challenging treat. indicate systemically underdiagnosed undertreated. Earlier screening, aggressive treatments, guideline implementation required reduce burden

Language: Английский

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Sex Differences in Diagnosis, Treatment, and Cardiovascular Outcomes in Homozygous Familial Hypercholesterolemia

JAMA Cardiology, Journal Year: 2024, Volume and Issue: 9(4), P. 313 - 313

Published: Feb. 14, 2024

Homozygous familial hypercholesterolemia (HoFH) is a rare genetic condition characterized by extremely increased low-density lipoprotein (LDL) cholesterol levels and premature atherosclerotic cardiovascular disease (ASCVD). Heterozygous (HeFH) more common than HoFH, women with HeFH are diagnosed later undertreated compared to men; it unknown whether these sex differences also apply HoFH.

Language: Английский

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