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Clinical Efficacy of Proprotein Convertase Synthase Kexin Type 9 Inhibition in Persons with Diabetes Mellitus

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Lipoproteins in Diabetes Mellitus

Part of the book series: Contemporary Diabetes ((CDI))

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Abstract

Diabetes mellitus (DM) is associated with atherogenic dyslipidemia and heightened systemic inflammatory, oxidative, and thrombotic tones. These metabolic abnormalities greatly increase the risk for atherosclerotic cardiovascular disease (ASCVD) in both coronary and peripheral arterial trees. The primary approach to attenuating increased risk for ASCVD attributable to dyslipidemia is to lower serum levels of low-density lipoprotein cholesterol (LDL-C) in a risk-stratified manner. Treatment with statins constitutes first-line therapy. For patients unable to achieve their risk-stratified LDL-C target, adjuvant therapies are used to facilitate appropriate levels of incremental LDL-C reduction. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a major regulator of LDL receptor (LDL-R) expression along the hepatocyte surface. The role of PCSK9 in LDL-R expression is to promote its destruction. PCSK9 chaperones internalized LDL-R into lysosomes for proteolytic destruction, thereby reducing their cell surface expression. This reduces hepatic LDL-C clearance capacity. PCSK9 is produced and secreted by the liver into the extracellular milieu. In the extracellular space, PCSK9 can be therapeutically neutralized by monoclonal antibodies (evolocumab and alirocumab). Alternatively, intracellular messenger ribonucleic acid (mRNA) for PCSK9 can be silenced using a silencing oligonucleotide (inclisiran) that promotes RNase-dependent hydrolysis of the mRNA, reducing PCSK9 production. Both approaches result in significant reductions in LDL-C as well as other atherogenic apo B-containing lipoproteins. The use of monoclonal antibodies (mAbs) and mRNA silencing purposed for the reduction of PCSK9 production is safe and to date is not associated with disturbances in insulin sensitivity or in serum levels of glucose or glycated hemoglobin. The PCSK9 mAbs have demonstrated a clear capacity to reduce the risk for acute cardiovascular events in prospective randomized clinical trials. A prospective randomized trial with inclisiran is fully randomized and underway.

Prepared for Lipoproteins in Diabetes (2nd edition), Jenkins A., and Toth, P.P., eds. Springer Pub, New York.

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Authors and Affiliations

  1. CGH Medical Center, Sterling, IL, USA

    Peter P. Toth

  2. Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Peter P. Toth

  3. University of Palermo, School of Medicine, Palermo, Italy

    Manfredi Rizzo

  4. Department of Preventive Cardiology and Lipidology, Medical University of Lodz, Lodz, Poland

    Maciej Banach

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  1. NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia

    Alicia J. Jenkins

  2. Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Peter P. Toth

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Toth, P.P., Rizzo, M., Banach, M. (2023). Clinical Efficacy of Proprotein Convertase Synthase Kexin Type 9 Inhibition in Persons with Diabetes Mellitus. In: Jenkins, A.J., Toth, P.P. (eds) Lipoproteins in Diabetes Mellitus. Contemporary Diabetes. Humana, Cham. https://doi.org/10.1007/978-3-031-26681-2_27

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