scholarly journals Cholesteryl ester transfer protein (CETP) as a drug target for cardiovascular disease

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Amand F. Schmidt ◽  
Nicholas B. Hunt ◽  
Maria Gordillo-Marañón ◽  
Pimphen Charoen ◽  
Fotios Drenos ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Cholesteryl Ester ◽  
Cholesteryl Ester Transfer Protein ◽  
Drug Target ◽  
Mendelian Randomization ◽  
Age Related Macular Degeneration ◽  
Transfer Protein ◽  
Age Related

AbstractDevelopment 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.

scholarly journals Cholesteryl Ester Transfer Protein as a Drug Target for Cardiovascular Disease

2020 ◽  
Author(s):  
Amand Floriaan Schmidt ◽  
Nicholas B Hunt ◽  
Maria Gordillo-Maranon ◽  
Pimphen Charoen ◽  
Fotios Drenos ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiovascular Disease ◽  
Kidney Disease ◽  
Cholesteryl Ester ◽  
Cholesteryl Ester Transfer Protein ◽  
Drug Target ◽  
Transfer Protein ◽  
Age Related ◽  
Cetp Inhibitor ◽  
Cetp Inhibition

Background: Drug development of cholesteryl ester transfer protein (CETP) inhibition to prevent coronary heart disease (CHD) has yet to deliver licensed medicines. To distinguish compound from drug target failure, we compared evidence from clinical trials and Mendelian randomization (MR) results. Methods: Findings from meta-analyses of CETP inhibitor trials (≥ 24 weeks follow-up) were used to judge between-compound heterogeneity in treatment effects. Genetic data were extracted on 190+ pharmacologically relevant outcomes; spanning 480,698-21,770 samples and 74,124-4,373 events. Drug target MR of protein concentration was used to determine the on-target effects of CETP inhibition and compared to that of PCSK9 modulation. Results: Fifteen eligible CETP inhibitor trials of four compounds were identified, enrolling 79,961 participants. There was a high degree of heterogeneity in effects on lipids, lipoproteins, blood pressure, and clinical events. For example, dalcetrapib and evacetrapib showed a neutral effect, torcetrapib increased, and anacetrapib decreased cardiovascular disease (CVD); heterogeneity p-value < 0.001. In drug target MR analysis, lower CETP concentration (per ug/ml) was associated with CHD (odds ratio 0.95; 95%CI 0.91; 0.99), heart failure (0.95; 95%CI 0.92; 0.99), chronic kidney disease (0.94 95%CI 0.91; 0.98), and age-related macular degeneration (1.69; 95%CI 1.44; 1.99). Lower PCSK9 concentration was associated with a lower risk of CHD, heart failure, atrial fibrillation and stroke, and increased risk of Alzheimer's disease and asthma. Conclucion: Previous failures of CETP inhibitors are likely compound related. CETP inhibition is expected to reduce risk of CHD, heart failure, and kidney disease, but potentially increase risk of age-related macular disease.

scholarly journals Cholesteryl Ester Transfer Protein as a Drug Target for Cardiovascular Disease

2020 ◽  
Author(s):  
Amand Schmidt ◽  
Nicholas Hunt ◽  
Maria Gordillo-Maranon ◽  
Pimphen Charoen ◽  
Fotios Drenos ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiovascular Disease ◽  
Kidney Disease ◽  
Cholesteryl Ester ◽  
Cholesteryl Ester Transfer Protein ◽  
Drug Target ◽  
Transfer Protein ◽  
Age Related ◽  
Cetp Inhibitor ◽  
Cetp Inhibition

Abstract Drug development of cholesteryl ester transfer protein (CETP) inhibition to prevent coronary heart disease (CHD) has yet to deliver licensed medicines. To distinguish compound from drug target failure, we compared evidence from clinical trials and Mendelian randomization (MR) results. Findings from meta-analyses of CETP inhibitor trials (≥ 24 weeks follow-up) were used to judge between-compound heterogeneity in treatment effects. Genetic data were extracted on 190 + pharmacologically relevant outcomes; spanning 480,698 − 21,770 samples and 74,124-4,373 events. Drug target MR of protein concentration was used to determine the on-target effects of CETP inhibition and compared to that of PCSK9 modulation. Fifteen eligible CETP inhibitor trials of four compounds were identified, enrolling 79,961 participants. There was a high degree of heterogeneity in effects on lipids, lipoproteins, blood pressure, and clinical events. For example, dalcetrapib and evacetrapib showed a neutral effect, torcetrapib increased, and anacetrapib decreased cardiovascular disease (CVD); heterogeneity p-value < 0.001. In drug target MR analysis, lower CETP concentration (per \(\mu\)g/ml) was associated with CHD (odds ratio 0.95; 95%CI 0.91; 0.99), heart failure (0.95; 95%CI 0.92; 0.99), chronic kidney disease (0.94 95%CI 0.91; 0.98), and age-related macular degeneration (1.69; 95%CI 1.44; 1.99). Lower PCSK9 concentration was associated with a lower risk of CHD, heart failure, atrial fibrillation and stroke, and increased risk of Alzheimer’s disease and asthma. In conclusion, previous failures of CETP inhibitors are likely compound related. CETP inhibition is expected to reduce risk of CHD, heart failure, and kidney disease, but potentially increase risk of age-related macular disease.

Associations of cholesteryl ester transfer protein (CETP) gene variants with predisposition to age-related macular degeneration

Gene ◽  
2017 ◽  
Vol 636 ◽  
pp. 30-35 ◽  
Author(s):  
Rasa Liutkeviciene ◽  
Alvita Vilkeviciute ◽  
Greta Streleckiene ◽  
Loresa Kriauciuniene ◽  
Romanas Chaleckis ◽  
...  
Keyword(s):  
Cholesteryl Ester ◽  
Macular Degeneration ◽  
Cholesteryl Ester Transfer Protein ◽  
Age Related Macular Degeneration ◽  
Gene Variants ◽  
Transfer Protein ◽  
Age Related

Associations Between Chronic Kidney Disease and Age-Related Macular Degeneration

2009 ◽  
Vol 16 (3) ◽  
pp. 181-186 ◽  
Author(s):  
Dorothea Nitsch ◽  
Jennifer Evans ◽  
Paul J. Roderick ◽  
Liam Smeeth ◽  
Astrid E. Fletcher
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Macular Degeneration ◽  
Age Related Macular Degeneration ◽  
Age Related

scholarly journals Cholesteryl Ester Transfer Protein Genetic Variants Associated with Risk for Type 2 Diabetes and Diabetic Kidney Disease in Taiwanese Population

Genes ◽  
2019 ◽  
Vol 10 (10) ◽  
pp. 782 ◽  
Author(s):  
Huang ◽  
Chen ◽  
Liu ◽  
Lin ◽  
Lin ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Kidney Disease ◽  
Cholesteryl Ester ◽  
Cholesteryl Ester Transfer Protein ◽  
Diabetic Kidney Disease ◽  
Density Lipoprotein ◽  
Diabetic Kidney ◽  
Transfer Protein ◽  
Low Levels

Cholesteryl ester transfer protein (CETP) plays an important role in lipid metabolism. Low levels of high-density lipoprotein cholesterol (HDL-C) increase the risk of type 2 diabetes (T2D). This study investigated CETP gene variants to assess the risk of T2D and specific complications of diabetic kidney disease (DKD) and diabetic retinopathy. Towards this, a total of 3023 Taiwanese individuals (1383 without T2D, 1640 with T2D) were enrolled in this study. T2D mice (+Leprdb/+Leprdb, db/db) were used to determine CETP expression in tissues. The A-alleles of rs3764261, rs4783961, and rs1800775 variants were found to be independently associated with 2.86, 1.71, and 0.91 mg/dL increase in HDL-C per allele, respectively. In addition, the A-allele of rs4783961 was significantly associated with a reduced T2D risk (odds ratio (OR), 0.82; 95% confidence interval (CI), 0.71‒0.96)), and the A-allele of rs1800775 was significantly related to a lowered DKD risk (OR, 0.78; 95% CI, 0.64‒0.96). CETP expression was significantly decreased in the T2D mice kidney compared to that in the control mice (T2D mice, 0.16 0.01 vs. control mice, 0.21 0.02; p = 0.02). These collective findings indicate that CETP variants in the promoter region may affect HDL-C levels. Taiwanese individuals possessing an allele associated with higher HDL-C levels had a lower risk of T2D and DKD.

Age-Related Macular Degeneration in Chronic Kidney Disease: A Meta-Analysis of Observational Studies

2018 ◽  
Vol 48 (4) ◽  
pp. 278-291 ◽  
Author(s):  
Yi-Ju Chen ◽  
Ling Yeung ◽  
Chi-Chin Sun ◽  
Chien-Chieh Huang ◽  
Kuo-Su Chen ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Macular Degeneration ◽  
Observational Studies ◽  
Meta Analysis ◽  
Positive Association ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
Statistical Heterogeneity ◽  
Risk Ratios

Background: Age-related macular degeneration (AMD) is an important cause of blindness in aged people. Chronic kidney disease (CKD) was reported to be associated with a higher risk of AMD. However, supporting evidence was inconsistent between studies. This work intends to examine whether a positive association exists between CKD and AMD by systematic review and meta-analysis. Methods: A systematic search of electronic databases (Medline, PubMed, Cochrane and EMBASE) and reference lists on June 2017. The key inclusion criteria were controlled trials that investigated the relationship between AMD and CKD. The outcome measures included risk ratios and/or occurrence rates of AMD in CKD vs. non-CKD population. Data were pooled according to the type of AMD by random effect model. Results: Twelve observational studies (3 cohorts, 2 case controls, and 7 cross-sectionals) with a total 335,601 participants were included. Eleven studies reported risk ratios and 9 reported occurrence rates. Pooled prevalence for early, advanced, and any AMD were all higher in the CKD population than in the non-CKD population. The pooled multivariate adjusted OR of CKD vs. non-CKD was 1.49 (95% CI 1.11–2.02) for early, 1.55 (95% CI 1.05–2.27) for exudative, 1.58 (95% CI 1.12–2.23) for advanced, and 1.35 (95% CI 1.05–1.73) for any AMD. However, high statistical heterogeneity and methodological diversity existed. Moreover, results were inconsistent between different study designs. Conclusions: The overall results support a positive association between CKD and AMD, although some limitations exist. Given the risk that AMD is increased in CKD, regular eye screenings for the CKD population is recommended for an early detection and intervention.

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