Familial Hypercholesterolemia

Klose, Gerald; Laufs, Ulrich; März, Winfried; Windler, E.

doi:10.3238/arztebl.2014.0523

Cited by 38 publications

(17 citation statements)

References 81 publications

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“…A limitation of this study is the unknown status of LLT therapy for enrolled patients because of an unclear patient questionnaire that resulted in inconsistencies specifically and exclusively in the respective data. Other limitations could include the 24-week study duration for the long-term efficacy and safety assessment of alirocumab in a real-world setting as well as the confirmation of FH status that was based on an algorithm and criteria used in Germany [33]. Furthermore, the open-label treatment of alirocumab might have introduced a bias by study participants and physicians [34].…”

Section: Discussionmentioning

confidence: 99%

PEARL: A Non-interventional Study of Real-World Alirocumab Use in German Clinical Practice

Parhofer

Stritzky

Pietschmann

et al. 2019

Drugs - Real World Outcomes

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Background Several lipid guidelines recommend that proprotein convertase subtilisin/kexin type 9 inhibitors should be considered for patients with atherosclerotic cardiovascular disease who are inadequately treated with maximally tolerated lipid-lowering treatment. Objectives The PEARL study assessed the efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab in patients with hypercholesterolemia in a real-world setting. Methods PEARL was an open, prospective, multicenter, non-interventional study conducted in Germany. Patients ( n = 619) for whom treating physicians decided to use alirocumab 75 or 150 mg every 2 weeks according to German guidelines (low-density lipoprotein cholesterol > 1.8/2.6 mmol/L [> 70/100 mg/dL], depending on cardiovascular risk, despite maximally tolerated statin therapy with/without other non-alirocumab lipid-lowering therapy) were enrolled and followed for 24 weeks. Physicians could adjust the alirocumab dose based on their clinical judgment. The primary efficacy endpoint was low-density lipoprotein cholesterol reduction from baseline (prior to alirocumab therapy) to week 24. Results Overall, 72.8% of patients reported complete or partial statin intolerance. Mean low-density lipoprotein cholesterol was 4.7 mmol/L (180.5 mg/dL) and 2.3 mmol/L (89.8 mg/dL) at baseline and week 24, respectively. Least-squares mean percentage change from baseline to week 24 in low-density lipoprotein cholesterol was − 48.6%. Initial alirocumab dose was 75 mg in 72.9% of patients and 150 mg in 24.5% of patients; 19.6% of patients received an alirocumab dose increase (75 to 150 mg) and 1.6% of patients received a dose decrease. Adverse events were reported in 10.3% of patients, with myalgia being the most common. Conclusions In a real-world setting in Germany, alirocumab was used in patients who had high baseline low-density lipoprotein cholesterol levels with/without statin intolerance. Efficacy and safety were consistent with findings observed in the ODYSSEY Phase III program. Electronic supplementary material The online version of this article (10.1007/s40801-019-0158-0) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

PEARL: A Non-interventional Study of Real-World Alirocumab Use in German Clinical Practice

Parhofer

Stritzky

Pietschmann

et al. 2019

Drugs - Real World Outcomes

View full text Add to dashboard Cite

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“…They usually present with interdigital planar xanthomas, cutaneous xanthomas, tendon xanthomas, and familial clustering. One of their parents will have severe hypercholesterolemia, and 50% of the patient’s siblings will also be heterozygous because the gene for FH is dominant [ 7 ].…”

Section: Discussionmentioning

confidence: 99%

A Case of Premature Triple Vessel Coronary Artery Disease and Valvular Degeneration: A Rare Presentation of Familial Hypercholesterolemia

Gull

Rashid

Aleem

et al. 2020

Cureus

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Familial hypercholesterolemia (FH) is one of the inherited causes of coronary artery disease (CAD) and causes calcific valvular degeneration in rare cases. A 13-year-old boy with multiple xanthomas presented with severe chest pain, shortness of breath, and sweating. He was diagnosed with premature CAD leading to non-ST-elevation myocardial infarction, secondary to early-onset FH [severely raised low-density lipoprotein (LDL) and triglycerides (TG) on lipid profile]. CT angiogram showed triple vessel disease, and echocardiogram revealed tight aortic stenosis. Percutaneous coronary angioplasty was done, and valvuloplasty was planned on the follow-up assessment. Early diagnosis and prompt management could have prevented these complications.

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“…Another late symptom is the manifestation of xanthelasmata as well as corneal arcus. Also, coronary manifestations in HoFH appear in their second and third decades ( Klose et al, 2014 ) though fatal myocardial infarctions (MIs) are possible even in early childhood ( Wiegman et al, 2015 ). On the other hand, the clinical manifestations in heterozygous FH patients are possible from early adulthood onward and premature CAD in the second or third decade of life.…”

Section: Introductionmentioning

confidence: 99%

“…On the other hand, the clinical manifestations in heterozygous FH patients are possible from early adulthood onward and premature CAD in the second or third decade of life. Sometimes symptoms may remain clinically hidden ( Klose et al, 2014 ). If left untreated, approximately 50% heterozygous males and 15% females have a fatal MI by the age of 60 ( Henderson et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Proteostasis Regulation in the Endoplasmic Reticulum: An Emerging Theme in the Molecular Pathology and Therapeutic Management of Familial Hypercholesterolemia

et al. 2020

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Familial hypercholesterolemia (FH) is an autosomal genetic disease characterized by high serum low-density lipoprotein (LDL) content leading to premature coronary artery disease. The main genetic and molecular causes of FH are mutations in low-density lipoprotein receptor gene ( LDLR ) resulting in the non-clearance of LDL from the blood by hepatocytes and consequently the formation of plaques. LDLR is synthesized and glycosylated in the endoplasmic reticulum (ER) and then transported to the plasma membrane via Golgi. It is estimated that more than 50% of reported FH-causing mutations in LDLR result in misfolded proteins that are transport-defective and hence retained in ER. ER accumulation of misfolded proteins causes ER-stress and activates unfolded protein response (UPR). UPR aids protein folding, blocks further protein synthesis, and eliminates misfolded proteins via ER-associated degradation (ERAD) to alleviate ER stress. Various studies demonstrated that ER-retained LDLR mutants are subjected to ERAD. Interestingly, chemical chaperones and genetic or pharmacological inhibition of ERAD have been reported to rescue the transport defective mutant LDLR alleles from ERAD and restore their ER-Golgi transport resulting in the expression of functional plasma membrane LDLR. This suggests the possibility of pharmacological modulation of proteostasis in the ER as a therapeutic strategy for FH. In this review, we picture a detailed analysis of UPR and the ERAD processes activated by ER-retained LDLR mutants associated with FH. In addition, we discuss and critically evaluate the potential role of chemical chaperones and ERAD modulators in the therapeutic management of FH.

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Familial Hypercholesterolemia

Abstract: Familial hypercholesterolemia is a common disease that can be diagnosed simply and reliably on clinical grounds and by molecular genetic testing. Timely diagnosis and appropriate treatment can lower the risk of atherosclerosis in heterozygous patients to that of the general population.

Cited by 38 publications

References 81 publications

PEARL: A Non-interventional Study of Real-World Alirocumab Use in German Clinical Practice

PEARL: A Non-interventional Study of Real-World Alirocumab Use in German Clinical Practice

A Case of Premature Triple Vessel Coronary Artery Disease and Valvular Degeneration: A Rare Presentation of Familial Hypercholesterolemia

Proteostasis Regulation in the Endoplasmic Reticulum: An Emerging Theme in the Molecular Pathology and Therapeutic Management of Familial Hypercholesterolemia

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