TY - JOUR
T1 - Cholesteryl ester transfer protein (CETP) as a drug target for cardiovascular disease
AU - Schmidt, Amand F.
AU - Hunt, Nicholas B.
AU - Gordillo-Marañón, Maria
AU - Charoen, Pimphen
AU - Drenos, Fotios
AU - Kivimaki, Mika
AU - Lawlor, Deborah A.
AU - Giambartolomei, Claudia
AU - Papacosta, Olia
AU - Chaturvedi, Nishi
AU - Bis, Joshua C.
AU - O’Donnell, Christopher J.
AU - Wannamethee, Goya
AU - Wong, Andrew
AU - Price, Jackie F.
AU - Hughes, Alun D.
AU - Gaunt, Tom R.
AU - Franceschini, Nora
AU - Mook-Kanamori, Dennis O.
AU - Zwierzyna, Magdalena
AU - Sofat, Reecha
AU - Hingorani, Aroon D.
AU - Finan, Chris
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85115675591&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/34561430
U2 - https://doi.org/10.1038/s41467-021-25703-3
DO - https://doi.org/10.1038/s41467-021-25703-3
M3 - Article
C2 - 34561430
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 5640
ER -