PCSK9 inhibitors: A new era of lipid lowering therapy

Chaudhary, Rahul; Garg, Jalaj; Shah, Neeraj; Sumner, Andrew D.

doi:10.4330/wjc.v9.i2.76

Cited by 227 publications

(203 citation statements)

References 93 publications

(103 reference statements)

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“…However, the European Medicines Agency (EMA) refused marketing authorization in 2012 citing safety concerns, such as injection site reactions, liver toxicity, and cardiovascular risk. Like pegaptanib, mipomersen did not achieve marketing success, and its future is unclear because of competition from small molecule and proprotein convertase subtilisin/kexin type 9‐inhibiting monoclonal antibodies …”

Section: Approved Oligonucleotide Therapeuticsmentioning

confidence: 99%

Targeting RNA: A Transformative Therapeutic Strategy

Yin

Rogge

2019

Clinical Translational Sci

109

103

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The therapeutic pathways that modulate transcription mechanisms currently include gene knockdown and splicing modulation. However, additional mechanisms may come into play as more understanding of molecular biology and disease etiology emerge. Building on advances in chemistry and delivery technology, oligonucleotide therapeutics is emerging as an established, validated class of drugs that can modulate a multitude of genetic targets. These targets include over 10,000 proteins in the human genome that have hitherto been considered undruggable by small molecules and protein therapeutics. The approval of five oligonucleotides within the last 2 years elicited unprecedented excitement in the field. However, there are remaining challenges to overcome and significant room for future innovation to fully realize the potential of oligonucleotide therapeutics. In this review, we focus on the translational strategies encompassing preclinical evaluation and clinical development in the context of approved oligonucleotide therapeutics. Translational approaches with respect to pharmacology, pharmacokinetics, cardiac safety evaluation, and dose selection that are specific to this class of drugs are reviewed with examples. The mechanism of action, chemical evolution, and intracellular delivery of oligonucleotide therapies are only briefly reviewed to provide a general background for this class of drugs.

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Section: Approved Oligonucleotide Therapeuticsmentioning

confidence: 99%

Targeting RNA: A Transformative Therapeutic Strategy

Yin

Rogge

2019

Clinical Translational Sci

109

103

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“…They do this by allowing LDL receptor recycling, thereby increasing their availability to remove LDL from the serum [16]. Data from the FOURIER study is promising in confirming that additional LDL reduction with PCSK9 inhibition results in further CVD risk reduction, especially in patients with diabetes [13∎∎].…”

Section: Combination Therapiesmentioning

confidence: 99%

Towards more specific treatment for diabetic dyslipidemia

Rodríguez

Newman

Schwartzbard

2018

Current Opinion in Lipidology

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Purpose of review Treatment of diabetic dyslipidemia is necessary because of its impact on cardiovascular disease, which is the leading cause of death in patients with diabetes. In the past, standard treatment of diabetic dyslipidemia focused only on correcting lipids. Although this remains the mainstay of treatment, because new antihyperglycemic treatments reduce cardiovascular events with minimal effect on dyslipidemia, a new approach is both timely and relevant. Recent findings LDL-lowering remains the focus of treatment for diabetic dyslipidemia, especially in patients with both diabetes and cardiovascular disease (CVD). Higher intensity statin therapy or lower LDL cholesterol goals are recommended in these patients. Combination therapy, especially with ezetimibe, fibrates, bile acid sequestrants, PCSK9 inhibitors and omega 3 fatty acids should be considered along with selected new agents to reduce glycemia. Summary As diabetic dyslipidemia plays a key role in CVD, aggressive treatment is indicated. New research targets include apo-CIII and lipoprotein(a) [Lp(a)]. In addition, new antihyperglycemic therapy is changing diabetes care and altering treatment guidelines. The most recent American Diabetes Association Standards of Care has expanded its recommendations for people with CVD and diabetes, suggesting that medications validated to improve cardiac health should be strongly considered.

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“…Monoclonal antibodies against proprotein‐convertase subtilisin/kexin type 9 (PCSK9) inhibitors are a newly‐introduced therapeutic approach against hypercholesterolemia . PCSK9 reduces low‐density lipoprotein (LDL) receptors by promoting their metabolism and degradation in the hepatocytes, thus inducing high plasma concentrations of low‐density lipoprotein C (LDL‐C) . It has been related to atherogenesis, by either altering endothelial repair or neovascularization mechanism, or by reducing LDL‐R expression in macrophages .…”

Section: Introductionmentioning

confidence: 99%

Gingival Ischemia and Petechiae in a Patient Medicated With PCSK9 Inhibitor for Hypercholesterolemia: An Adverse Drug Event?

Thermos

Tosios

2018

Clin Adv Periodontics

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Introduction Monoclonal antibodies against proprotein‐convertase subtilisin/kexin type 9 (PCSK9) inhibitors are a newly‐introduced therapeutic approach against hypercholesterolemia. Clinical trials have reported few adverse effects of PCSK9 inhibitors and there are no reports of oral adverse effects. We present the case of a patient that showed gingival discomfort on eating and toothbrushing, coupled with the presence of gingival ischemia and petechiae, 3 days after a subcutaneous abdominal injection of 75‐mg alirocumab for hypercholesterolemia, and contemplate on their possible pathogenesis. Case Presentation Αn 81‐year‐old male presented with gingival discomfort during eating and toothbrushing, 3 days after receiving a subcutaneous abdominal injection of alirocumab. Intraoral examination revealed that the anterior free and attached gingiva of both jaws appeared pale and the surrounding mucosa showed confluent petechiae that were more evident on the anterior palatal gingiva. The patient was asked to brush his teeth with a soft toothbrush and use a mouthwash containing hydrogen peroxide three times daily. At the 8‐day re‐examination he was symptom‐free, and the mucosa appeared totally normal. At the 5‐month follow‐up visit he reported having the same symptoms after each one of the 12 doses of alirocumab he received. Conclusions Adverse dugs effects associated with subcutaneous injection of alirocumab may manifest in the gingiva. Therefore, oral and periodontal examination should be included in the regular follow‐up of patients medicated with this drug.

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PCSK9 inhibitors: A new era of lipid lowering therapy

Cited by 227 publications

References 93 publications

Targeting RNA: A Transformative Therapeutic Strategy

Targeting RNA: A Transformative Therapeutic Strategy

Towards more specific treatment for diabetic dyslipidemia

Gingival Ischemia and Petechiae in a Patient Medicated With PCSK9 Inhibitor for Hypercholesterolemia: An Adverse Drug Event?

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