Abstract 3699: Efficacy and Safety of Colesevelam HCl in Pediatric Patients with Heterozygous Familial Hypercholesterolemia

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Evan A Stein ◽  
David Marais ◽  
Tamas Szamosi ◽  
Frederick Raal ◽  
Daniel Schurr ◽  
...  
Keyword(s):  
Familial Hypercholesterolemia ◽  
Genetic Disorder ◽  
Genetic Diagnosis ◽  
Lipid Lowering ◽  
Controlled Study ◽  
Lipid Lowering Therapy ◽  
Efficacy And Safety ◽  
Degree Relative ◽  
Double Blind ◽  
Heterozygous Familial Hypercholesterolemia

Heterozygous familial hypercholesterolemia (heFH) is a genetic disorder resulting in elevated LDL-C, which confers a high risk for a coronary event. Colesevelam HCl (COL), a non-absorbable bile acid sequestrant, is approved to lower LDL-C in adults with primary hypercholesterolemia. This is the first data demonstrating the efficacy and safety of COL in pediatric pts with heFH. This 32wk multicenter, randomized, double-blind (DB), placebo (PLA)-controlled study included: a 4wk PLA run-in (to measure compliance); an 8wk DB period (pts randomized 1:1:1 to PLA, 1.875 g/d COL, or 3.75 g/d COL); an 18wk open-label (OL) treatment to goal (LDL-C <110 mg/dL) wherein all pts received COL 3.75 g/d (and were eligible to receive a statin); and a 2wk follow-up. Males and females, aged 10 –17yrs, with either genetic diagnosis of heFH or history of untreated LDL-C >160 mg/dL combined with familial dyslipidemia in a first degree relative, who had a baseline LDL-C >160 mg/dL (if naíve to lipid-lowering therapy) or >130 mg/dL (if on a statin [≥6wks]) and following a NCEP step 1 diet were included. Additional inclusion criteria were TG <250 mg/dL, ≥Tanner stage 2, and compliance ≥75% during the PLA run-in. Primary efficacy parameter was % change in LDL-C from baseline/Day 1 to Wk 8. The ITT population (randomized pts with a baseline and ≥1 post-baseline measurement) was used to evaluate efficacy parameters. Of the 194 pts randomized, 95.9% and 89.2% completed the DB and OL periods, respectively. Approximately 25% were on a statin at entry into the DB period; a further 10% added a statin during the OL period. At wk 8, LDL-C, TC, and apoB significantly decreased while HDL-C and apoA-I significantly increased with COL 3.75 g/d ( P <0.01 vs PLA for all; Table ). Adverse events were as expected; no choking was recorded. No effects were noted on growth, sexual maturation, hormone levels, absorption of fat-soluble vitamins, or clotting parameters. In summary, COL lowered LDL-C and was well tolerated in pediatric pts.

Lipid profile and genetic status in a familial hypercholesterolemia pediatric population: exploring the LDL/HDL ratio

2019 ◽  
Vol 57 (7) ◽  
pp. 1102-1110 ◽  
Author(s):  
Maria Donata Di Taranto ◽  
Renato de Falco ◽  
Ornella Guardamagna ◽  
Giulia Massini ◽  
Carola Giacobbe ◽  
...  
Keyword(s):  
Lipid Profile ◽  
Familial Hypercholesterolemia ◽  
Pediatric Population ◽  
Genetic Disorder ◽  
Genetic Diagnosis ◽  
Density Lipoprotein ◽  
Compound Heterozygous ◽  
Premature Coronary Artery Disease ◽  
Degree Relative ◽  
Genetic Status

Abstract Background Familial hypercholesterolemia (FH) is a genetic disorder caused by mutations in genes involved in low-density lipoprotein (LDL) uptake (LDLR, APOB and PCSK9). Genetic diagnosis is particularly useful in asymptomatic children allowing for the detection of definite FH patients. Furthermore, defining their genetic status may be of considerable importance as the compound heterozygous status is much more severe than the heterozygous one. Our study aims at depicting the genetic background of an Italian pediatric population with FH focusing on the correlation between lipid profile and genetic status. Methods Out of 196 patients with clinically suspected FH (LDL-cholesterol [LDL-C] levels above 3.37 mmol/L, cholesterol level above 6.46 mmol/L in a first-degree relative or the presence of premature cardiovascular acute disease in a first/second-degree relative), we screened 164 index cases for mutations in the LDLR, APOB and PCSK9 genes. Results Patients with mutations (129/164) showed increased levels of LDL-C, 95th percentile-adjusted LDL-C and LDL/high-density lipoprotein (HDL) ratio and decreased levels of HDL-C, adjusted HDL-C. The association of the LDL/HDL ratio with the presence of mutations was assessed independently of age, (body mass index) BMI, parental hypercholesterolemia, premature coronary artery disease (CAD), triglycerides by multivariate logistic regression (odds ratio [OR]=1.701 [1.103–2.621], p=0.016). The LDL/HDL ratio gradually increased from patients without mutations to patients with missense mutations, null mutations and compound heterozygotes. Conclusions In conclusion, the LDL/HDL ratio proved to be a better parameter than LDL-C for discriminating patients with from patients without mutations across different genetic statuses.

Abstract 14407: The Longer-term Efficacy and Safety of Evinacumab in Patients With Homozygous Familial Hypercholesterolemia

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Frederick J Raal ◽  
Robert S Rosenson ◽  
Laurens F Reeskamp ◽  
G. Kees Hovingh ◽  
John J Kastelein ◽  
...  
Keyword(s):  
Familial Hypercholesterolemia ◽  
Treatment Period ◽  
Lipid Lowering ◽  
Efficacy And Safety ◽  
Homozygous Familial Hypercholesterolemia ◽  
Pcsk9 Inhibitors ◽  
Open Label ◽  
Phase 3 ◽  
Double Blind ◽  
Term Efficacy

Background: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic lipid disorder characterized by markedly elevated LDL-C and premature ASCVD. For HoFH patients (pts) with complete loss of low-density lipoprotein receptor (LDLR) function in both copies of the LDLR gene (null mutations) and some other HoFH pts, statins and PCSK9 inhibitors have limited to no efficacy, presenting a great unmet medical need. The efficacy and safety of evinacumab (EVIN; an angiopoietin-like protein 3 inhibitor) in HoFH pts was assessed during the double-blind treatment period (DBTP) of a phase 3 trial (NCT03399786). Objective: To examine longer-term efficacy and safety of EVIN in pts with HoFH who participated in the subsequent open-label treatment period (OLTP) of this phase 3 study. Methods: Patients with HoFH on stable lipid-lowering therapies (± lipoprotein apheresis) and screening LDL-C ≥70 mg/dL who completed the 24-week DBTP entered the 24-week OLTP and received IV EVIN 15 mg/kg every 4 weeks. Results: In total, 64 pts completed the DBTP and received open-label EVIN. Mean (standard deviation [SD]) baseline LDL-C at DBTP entry was 250.5 (162.3) mg/dL. From baseline to Week 48, EVIN reduced mean LDL-C by 46.3% (mean [SD] reduction of 134.3 [117.3] mg/dL). At Week 48, mean LDL-C reductions with open-label EVIN were 42.7% and 55.8% for pts who received EVIN (n=44) vs placebo (n=20) during the DBTP, respectively ( Figure ). LDL-C reduction observed at Week 48 was similar for pts with null/null mutations (n=19; 47.2%) versus non-null/null mutations (n=39; 45.9%). Adverse events (AEs) occurred in 47 pts (73.4%) during the OLTP; the most common were nasopharyngitis (9.4%) and headache (9.4%). During the OLTP, serious AEs occurred in 7 pts (10.9%; all pts received EVIN during the DBTP); none were considered related to study treatment. Conclusions: In pts with HoFH, EVIN showed substantial and sustained LDL-C reduction regardless of LDLR function and was generally well tolerated.

scholarly journals Familial hypercholesterolemia: case series of a rare condition

2021 ◽  
Vol 26 (3S) ◽  
pp. 4610
Author(s):  
O. P. Ishevskaia ◽  
A. M. Namitokov ◽  
S. V. Kruchinova ◽  
E. D. Kosmacheva
Keyword(s):  
Familial Hypercholesterolemia ◽  
Cardiovascular Events ◽  
Genetic Disorder ◽  
Positive Family History ◽  
Genetic Research ◽  
Case Series ◽  
Young Age ◽  
Diagnostic Methods ◽  
Lipid Lowering ◽  
Lipid Lowering Therapy

Introduction. Cardiovascular events at a young age are often the first manifestation of a genetic disorder such as familial hypercholesterolemia. High cholesterol levels, xanthomas and xanthelasmas, as well as a positive family history of cardiovascular disease, make it possible to identify a group of patients subject to genetic research. The identification of a specific mutation helps to determine further strategy not only for a patient, but also to his or her immediate relatives, thereby effectively conducting both secondary and primary prevention of atherosclerosis complications.Brief description. Using the example of patients from the Krasnodar Lipid Center, the relevance of genetic testing and cascade screening is demonstrated. We show problems of delayed diagnosis and low medical adherence, as well as the ways to optimize care for patients with genetic lipid metabolism disorders.Discussion. The rise in the incidence of cardiovascular events at a young age in developed countries prompts the search for more improved screening and diagnostic methods for familial hypercholesterolemia. The optimal age of initiation of lipid-lowering therapy in children with established familial hypercholesterolemia is also discussed. While secondary prevention appears to be clearer, there is still insufficient achievement of low-density lipoprotein cholesterol targets in patients with a previous cardiovascular event.

scholarly journals Statins for Children with Familial Hypercholesterolemia

2021 ◽  
Author(s):  
Dinara Sadykova ◽  
Liliia Galimova ◽  
Evgeniia Slastnikova ◽  
Zulfiia Khabibrakhmanova ◽  
Natalya Guseva
Keyword(s):  
Familial Hypercholesterolemia ◽  
World Literature ◽  
Genetic Disorder ◽  
Cumulative Effect ◽  
Lipid Lowering ◽  
Lipid Lowering Therapy ◽  
Arterial Walls ◽  
Lowering Therapy ◽  
The World ◽  
Initiation Of Therapy

Familial hypercholesterolemia (FH) is the most common genetic disorder in the world. It is characterized by increased level of total cholesterol (TC), low-density lipoproteins (LDL-C) since childhood. The diagnosis and initiation of therapy are optimal in childhood before complications (aortic stenosis, atherosclerotic changes in the arterial walls) appear. The initiation of lipid-lowering therapy in FH since childhood is important to reduce the cumulative effect of LDL-C, to increase patient’s life expectancy. Statins are recommended as first-line drugs for treatment with monitoring of the recommended clinical, biochemical markers under the supervision of a physician. However, due to limited experience, there are differing opinions among clinicians regarding the age of initiation of lipid-lowering therapy. This review is an attempt to critically study the available data from the world literature concerning the use of statins in children with FH, their effectiveness, safety. It is important to determine the endpoints for determining the effectiveness of statins, such as lowering LDL-C, assessing the thickness of the intima-media complex. The frequency of occurrence of possible side effects in children is considered - diabetes mellitus, hepatotoxicity, muscle pain and others. There is a need to continue randomized trials to prove the lifelong benefit of low LDL-C in patients with FH.

Abstract 15576: Cardiovascular Disease in Elderly Familial Hypercholesterolemia Individuals Attending a Cascade Screening Program

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
elaine coutinho ◽  
Marcio H Miname ◽  
Viviane Z Rocha ◽  
Marcio S Bittencourt ◽  
Cinthia Jannes ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Familial Hypercholesterolemia ◽  
High Intensity ◽  
Screening Program ◽  
Coronary Revascularization ◽  
Genetic Diagnosis ◽  
Lipid Lowering ◽  
Lipid Lowering Therapy ◽  
Cvd Risk ◽  
Cascade Screening

Introduction: Familial hypercholesterolemia (FH) is associated with early onset of cardiovascular disease (CVD) and mortality. Lipid lowering treatment (LLT) may change the natural history of FH, however there is scant information about elderly individuals (older than 60 years) with FH. This study describes characteristics of elderly FH individuals presenting or not CVD. Hypothesis: Monogenic defects are important markers of CVD risk and initiation and long-term use of lipid lowering therapy (LLT) is relevant to minimize this risk. Methods: Cross-sectional analysis of clinical and laboratory of molecularly proven elderly FH (FH+) and non-affected (FH-) individuals attending a cascade screening program. FH+ were divided in those presenting or not CVD (defined as previous myocardial infarction or ischemic stroke, carotid or coronary revascularization and angina with stenosis ≥50% on angiography). Results: From 4,111 genotyped individuals, 462 (11.2%) elders were included (198 FH+ and 264 FH-). There was predominance of females in either groups, however with more men in FH+ 37.4% vs. 24.2%, p=0.002. No differences were seen between FH+ and FH- regarding age, [median (%25;75%)] 66 (62;71) and 66 (63;71) years, p=0.68; use of LLT 88.5% vs. 91.5%, p=0.29 and high intensity LLT 61.7 % vs. 55.8%, p=0.20, respectively. Despite longer LLT duration in FH+ 11(7;20) vs. 7 (3;13) years, p<0.001, in either groups LLT was started late, at 54 (47;61) and 59 (52;64) years, p <0.001, respectively in FH+ and FH-. FH+ had higher LDL-C at diagnosis, 243 (179;302) vs. 228 (209;251) mg/dL, p=0.013, as well as greater frequencies of previous CVD 40.9% vs. 27.3%, p=0.002, and early CVD 22.2% vs. 9.0%, p<0.001. In FH+, male sex [OR (95%CI)] 5.29 (2.25-12.45), p<0.001, and use of high intensity LLT 2.51 (1.08-5.87), p=0.03, were independently associated with CVD. Conclusions: The genetic diagnosis of FH was associated with higher rates of CVD and early CVD vs. FH- hypercholesterolemics. Elders with FH+ who survived despite late LLT initiation have a worse CVD history than FH- elders, emphasizing the relevance of a monogenic defect as cause of long-lasting hypercholesterolemia and CVD risk, particularly in men.

Abstract 682: Lapaqistat Acetate Monotherapy: Effects of a Novel Squalene Synthase Inhibitor on LDL-C Levels and Other Lipid Parameters in Patients with Primary Hypercholesterolemia

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Harold E Bays ◽  
Robert J Weiss ◽  
James M Rhyne ◽  
Yinzhong Chen ◽  
Claudia Lopez ◽  
...  
Keyword(s):  
Study Drug ◽  
Squalene Synthase ◽  
Phase Iii ◽  
Lipid Lowering ◽  
Controlled Study ◽  
Lipid Lowering Therapy ◽  
Double Blind ◽  
Apo B ◽  
Primary Hypercholesterolemia ◽  
Hs Crp

Background: Lapaquistat acetate (LAPA) inhibits squalene synthase, an important enzyme in the cholesterol biosynthetic pathway. Early studies showed that LAPA reduced LDL-C and improved lipid profiles in animals and humans. Methods: This multicenter, phase III, randomized, double-blind, parallel-group, placebo-controlled study assessed LAPA monotherapy in nondiabetic patients ≥ 18 yrs old with primary hypercholesterolemia (mean LDL-C > 130 mg/dL and < 220 mg/dL; mean triglyceride [TG] ≤400 mg/dL). Treatment-naïve patients or patients discontinuing previous lipid-lowering therapy underwent a 6-wk dietary stabilization period, then were randomized to 100 mg LAPA (n = 241) or Placebo (n = 120) once daily for 12 wks. The primary endpoint was percent (%) change from baseline compared with Placebo in direct LDL-C at Wk 12 or last on-treatment value. Secondary endpoints included: % change in calculated LDL-C, non-HDL-C, total cholesterol (TC), Apo B, HDL-C, VLDL-C, Apo A1, TG, and hs-CRP. Safety was monitored using clinical and laboratory examinations. Results: LAPA significantly reduced LDL-C levels (see Table ) within 2– 4 wks of treatment initiation that were maintained throughout the study. LDL-C remained relatively unchanged in the Placebo group. Compared with Placebo, LAPA lowered LDL-C levels 20.09% by end of study (p < 0.001). Non-HDL-C, TC, Apo B, VLDL-C, Apo A1, TG, and hs-CRP were also significantly reduced vs Placebo. Both the overall adverse event (AE) profile and the rate of AEs considered potentially related to study drug (~24%), were similar between treatment groups. Two serious AEs occurred in each group; the 2 SAEs in lapaquistat-treated patients were considered not related to study drug. Conclusion: LAPA (100 mg/day) monotherapy provided significant improvements in LDL-C, non-HDL-C, TC, Apo B, VLDL-C, TG, and hs-CRP levels, was generally safe and well tolerated, and potentially represents a novel treatment for hypercholesterolemic patients.

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