Browsing by Author "Nora Franceschini"

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    Cholesteryl ester transfer protein (CETP) as a drug target for cardiovascular disease
    (2021-12-01) Amand F. Schmidt; Nicholas B. Hunt; Maria Gordillo-Marañón; Pimphen Charoen; Fotios Drenos; Mika Kivimaki; Deborah A. Lawlor; Claudia Giambartolomei; Olia Papacosta; Nishi Chaturvedi; Joshua C. Bis; Christopher J. O’Donnell; Goya Wannamethee; Andrew Wong; Jackie F. Price; Alun D. Hughes; Tom R. Gaunt; Nora Franceschini; Dennis O. Mook-Kanamori; Magdalena Zwierzyna; Reecha Sofat; Aroon D. Hingorani; Chris Finan; Faculty of Tropical Medicine, Mahidol University; Bristol Medical School; NIHR Bristol Biomedical Research Centre; Edinburgh Medical School; VA Boston Healthcare System; Istituto Italiano di Tecnologia; British Heart Foundation; Utrechts Instituut voor Farmaceutische Wetenschappen; University Medical Center Utrecht; University of Washington School of Medicine; The University of North Carolina at Chapel Hill; University College London; University of Bristol; Brunel University London; Medical Research Council; Leids Universitair Medisch Centrum; Mahidol University; Harvard Medical School; Health Data Research UK
    Development of cholesteryl ester transfer protein (CETP) inhibitors for coronary heart disease (CHD) has yet to deliver licensed medicines. To distinguish compound from drug target failure, we compared evidence from clinical trials and drug target Mendelian randomization of CETP protein concentration, comparing this to Mendelian randomization of proprotein convertase subtilisin/kexin type 9 (PCSK9). We show that previous failures of CETP inhibitors are likely compound related, as illustrated by significant degrees of between-compound heterogeneity in effects on lipids, blood pressure, and clinical outcomes observed in trials. On-target CETP inhibition, assessed through Mendelian randomization, is expected to reduce the risk of CHD, heart failure, diabetes, and chronic kidney disease, while increasing the risk of age-related macular degeneration. In contrast, lower PCSK9 concentration is anticipated to decrease the risk of CHD, heart failure, atrial fibrillation, chronic kidney disease, multiple sclerosis, and stroke, while potentially increasing the risk of Alzheimer’s disease and asthma. Due to distinct effects on lipoprotein metabolite profiles, joint inhibition of CETP and PCSK9 may provide added benefit. In conclusion, we provide genetic evidence that CETP is an effective target for CHD prevention but with a potential on-target adverse effect on age-related macular degeneration.