Cholesteryl Ester Transfer Protein Inhibitors Research Articles

Cholesteryl Ester Transfer Protein Inhibitors and Cardiovascular Outcomes: A Systematic Review and Meta-Analysis.

Atherosclerosis is a multi-factorial disease, and low-density lipoprotein cholesterol (LDL-C) is a critical risk factor in developing atherosclerotic cardiovascular disease (ASCVD). Cholesteryl-ester transfer-protein (CETP), synthesized by the liver, regulates LDL-C and high-density lipoprotein cholesterol (HDL-C) through the bidirectional transfer of lipids. The novelty of CETP inhibitors (CETPis) has granted new focus towards increasing HDL-C, besides lowering LDL-C strategies. To date, five CETPis that are projected to improve lipid profiles, torcetrapib, dalcetrapib, evacetrapib, anacetrapib, and obicetrapib, have reached late-stage clinical development for ASCVD risk reduction. Early trials failed to reduce atherosclerotic cardiovascular occurrences. Given the advent of some recent large-scale clinical trials (ACCELERATE, HPS3/TIMI55-REVEAL Collaborative Group), conducting a meta-analysis is essential to investigate CETPis' efficacy. We conducted a thorough search of randomized controlled trials (RCTs) that commenced between 2003 and 2023; CETPi versus placebo studies with a ≥6-month follow-up and defined outcomes were eligible. major adverse cardiovascular events (MACEs), cardiovascular disease (CVD)-related mortality, all-cause mortality. stroke, revascularization, hospitalization due to acute coronary syndrome, myocardial infarction (MI). Nine RCTs revealed that the use of a CETPi significantly reduced CVD-related mortality (RR = 0.89; 95% CI: 0.81-0.98; p = 0.02; I2 = 0%); the same studies also reduced the risk of MI (RR = 0.92; 95% CI: 0.86-0.98; p = 0.01; I2 = 0%), which was primarily attributed to anacetrapib. The use of a CETPi did not reduce the likelihood any other outcomes. Our meta-analysis shows, for the first time, that CETPis are associated with reduced CVD-related mortality and MI.

Discovery of novel cholesteryl ester transfer protein (CETP) inhibitors by a multi-stage virtual screening

Cholesteryl ester transfer protein (CETP) is a promising therapeutic target for cardiovascular diseases. It effectively lowers the low-density lipoprotein cholesterol levels and increases the high-density lipoprotein cholesterol levels in the human plasma. This study identified novel and highly potent CETP inhibitors using virtual screening techniques. Molecular docking and molecular dynamics (MD) simulations revealed the binding patterns of these inhibitors, with the top 50 compounds selected according to their predicted binding affinity. Protein–ligand interaction analyses were performed, leading to the selection of 26 compounds for further evaluation. A CETP inhibition assay confirmed the inhibitory activities of the selected compounds. The results of the MD simulations revealed the structural stability of the protein–ligand complexes, with the binding site remaining significantly unchanged, indicating that the five compounds (AK-968/40709303, AG-690/11820117, AO-081/41378586, AK-968/12713193, and AN-465/14952302) identified have the potential as active CETP inhibitors and are promising leads for drug development.Graphical

Obicetrapib on top of maximally tolerated lipid‐modifying therapies in participants with or at high risk for atherosclerotic cardiovascular disease: rationale and designs of BROADWAY and BROOKLYN

Obicetrapib, a novel, selective cholesteryl ester transfer protein (CETP) inhibitor, reduces low-density lipoprotein cholesterol (LDL-C), LDL particles, apolipoprotein (Apo) B, and lipoprotein(a) [Lp(a)] and increases high-density lipoprotein cholesterol (HDL-C) when added to statins with or without ezetimibe. By substantially reducing LDL-C, obicetrapib has the potential to lower atherogenic lipoproteins in patients with atherosclerotic cardiovascular disease (ASCVD) or heterozygous familial hypercholesterolemia (HeFH) whose LDL-C levels remain high despite treatment with available maximally tolerated lipid-modifying therapies, addressing an unmet medical need in a patient population at high risk for cardiovascular events. BROADWAY (NCT05142722) and BROOKLYN (NCT05425745) are ongoing placebo-controlled, double-blind, randomized Phase III trials designed to examine the efficacy, safety, and tolerability of obicetrapib as an adjunct to dietary intervention and maximally tolerated lipid-modifying therapies in participants with a history of ASCVD and/or underlying HeFH whose LDL-C is not adequately controlled. The primary efficacy endpoint was the percent change in LDL-C from baseline to day 84. Other endpoints included changes in Apo B, non-HDL-C, HDL-C, Apo A1, Lp(a) and triglycerides in addition to parameters evaluating safety, tolerability, and pharmacokinetics. BROADWAY also included an adjudicated assessment of major adverse cardiovascular events, measurements of glucose homeostasis, and an ambulatory blood pressure monitoring substudy. A total of 2532 participants were randomized in BROADWAY and 354 in BROOKLYN to receive obicetrapib 10 mg or placebo (2:1) for 365 days with follow-up through 35 days after the last dose. Results from both trials are anticipated in 2024. These trials will provide safety and efficacy data to support the potential use of obicetrapib among patients with ASCVD or HeFH with elevated LDL-C for whom existing therapies are not sufficiently effective or well-tolerated.

CETP inhibition enhances monocyte activation and bacterial clearance and reduces streptococcus pneumonia-associated mortality in mice.

Sepsis is a leading cause of mortality worldwide, and pneumonia is the most common cause of sepsis in humans. Low levels of high-density lipoprotein cholesterol (HDL-C) levels are associated with an increased risk of death from sepsis, and increasing levels of HDL-C by inhibition of cholesteryl ester transfer protein (CETP) decreases mortality from intraabdominal polymicrobial sepsis in APOE*3-Leiden.CETP mice. Here, we show that treatment with the CETP inhibitor (CETPi) anacetrapib reduced mortality from Streptococcus pneumoniae-induced sepsis in APOE*3-Leiden.CETP and APOA1.CETP mice. Mechanistically, CETP inhibition reduced the host proinflammatory response via attenuation of proinflammatory cytokine transcription and release. This effect was dependent on the presence of HDL, leading to attenuation of immune-mediated organ damage. In addition, CETP inhibition promoted monocyte activation in the blood prior to the onset of sepsis, resulting in accelerated macrophage recruitment to the lung and liver. In vitro experiments demonstrated that CETP inhibition significantly promoted the activation of proinflammatory signaling in peripheral blood mononuclear cells and THP1 cells in the absence of HDL; this may represent a mechanism responsible for improved bacterial clearance during sepsis. These findings provide evidence that CETP inhibition represents a potential approach to reduce mortality from pneumosepsis.

Synthesis and In-Silico Studies of Ortho-Fluorinated Benzenesulfonamides as Putative Anti-CETP Agents

Abstract: Cardiovascular disease is one of the primary causes of death. Atherosclerosis produces artery constriction or obstruction, which can lead to a heart attack or stroke. Cholesteryl Ester Transfer Protein (CETP) is a protein that aids in reverse cholesterol transport. It promotes cholesteryl ester transfer from HDL to LDL and VLDL. So, inhibition of CETP by drugs limits cardiovascular disease by decreasing LDL and increasing HDL cholesterol. In this study, ten ortho-fluoro substituted benzenesulfonamides 6a-6j were prepared, and their structure was fully determined using 1H NMR, 13C NMR, HR-MS, and IR. In vitro biological evaluation showed that compound 6d has the highest inhibitory activity with 100% inhibition, while compounds 6a-6c and 6e-6j had activities ranged from 29% - 83% at 10 μM concentration. Interestingly, para-substituted derivatives (6d, 6g, and 6j) were observed to have greater CETP inhibitory activities than their ortho- and meta- analogues irrespective to the nature of substituent, i.e., CH3, Cl, or NO2. Ligandfit docking experiment revealed the difference in the binding mode among the synthesized compounds, which is reflected in their CETP inhibitory activity. background: Cardiovascular disease is one of the primary causes of death. Atherosclerosis produces artery constriction or obstruction, which can lead to a heart attack or stroke. Cholesteryl ester transfer protein (CETP) is a protein that aids in reverse cholesterol transport. It promotes cholesteryl ester transfer from HDL to LDL and VLDL. So, inhibition of CETP by drugs limits cardiovascular disease by decreasing LDL and increasing HDL cholesterol. method: and their structure was fully determined using 1H-NMR, 13C-NMR, HR-MS, and IR. conclusion: Ligandfit docking experiment revealed the difference in the binding mode among the synthesized compounds which is reflected on their CETP inhibitory activity.

Association of lipid-modifying therapy with risk of obstructive sleep apnea: A drug-target mendelian randomization study

BackgroundObstructive sleep apnea (OSA) is considered to be an important contributor of dyslipidemia. However, there lacks observational studies focusing on the potential effect of lipid management on OSA risk. Thus, we aimed to investigate the genetic association of lipid-modifying therapy with risk of OSA. MethodsA drug-target mendelian randomization (MR) study using both cis-variants and cis-expression quantitative trait loci (eQTLs) of lipid-modifying drug targets was performed. The MR analyses used summary-level data of genome wide association studies (GWAS). Primary MR analysis was conducted using inverse-variance-weighted (IVW) method. Sensitivity analysis was performed using weighted median (WM) and MR-pleiotropy residual sum and outlier (MR-PRESSO) methods. ResultsGenetically proxied low-density lipoprotein cholesterol (LDL-C)-lowering effect of cholesteryl ester transfer protein (CETP) was associated with reduced risk of OSA (odds ratio [OR] =0.75, 95% confidence interval [CI]: 0.60–0.94, false discovery rate [FDR] q value = 0.046). A significant MR association with risk of OSA was observed for CETP expression in subcutaneous adipose tissue (OR = 0.94, 95%CI: 0.89–1.00, FDR q value = 0.049), lung (OR = 0.94, 95%CI: 0.89–1.00, FDR q value = 0.049) and small intestine (OR = 0.96, 95%CI: 0.93–1.00, FDR q value = 0.049). No significant effects of high-density lipoprotein cholesterol (HDL-C)-raising effect of CETP inhibition, LDL-C-lowering and triglycerides-lowering effect of other drug targets on OSA risk were observed. ConclusionsThe present study presented genetic evidence supporting the association of LDL-C-lowering therapy by CETP inhibition with reduced risk of OSA. These findings provided novel insights into the role of lipid management in patients with OSA and encouraged further clinical validations and mechanistic investigations.

Lipid-lowering drug targets and lung related diseases: a Mendelian randomization study

ABSTRACT OBJECTIVES This genetics-based study aimed to evaluate the relationships of long-term lipid-lowering agents on lung-related diseases (LRD) outcomes. METHODS We extracted genetic variations of six drug target genes from a major genome-wide association study of low-density lipoprotein cholesterol (LDL-C) in individuals predominantly of European ancestry to represent the effects of LDL-C-lowering treatment. We conducted drug-targeted Mendelian randomization and utilized a range of outcomes to capture evidence of adverse side effects related to the inhibition of the gene. RESULTS Our study did not find any significant association between genetically proxied APOB, CETP, HMGCR, NPCIL, PCSK9, and LDLR inhibition (equivalent to a one standard deviation reduction in LDL-C) with the risk of Small Cell Lung Cancer, Non-Small Cell Lung Cancer, idiopathic pulmonary fibrosis, and Pneumonia (P > 0.05). However, long-term inhibition of NPC1L that mimics the use of statin drugs may have contradictory effects on pulmonary edema (OR = 0.508, 95%CI = 0.328–0.786,P = 0.002) and chronic obstructive pulmonary disease (OR = 1.524, 95%CI = 1.099–2.115, P = 0.012). A series of sensitivity analyses and positive control analyses have been conducted to confirm the reliability of the results. CONCLUSIONS In conclusion, this study reveals inconsistent associations between genetic proxy inhibition of APOB, CETP, HMGCR, NPCIL, PCSK9 and LDLR with LRD in specific populations.

Beyond Statins: Novel Lipid-Lowering Agents for Reducing Risk of Atherosclerotic Cardiovascular Disease

Although statins have served as the cornerstone for pharmacological lowering of lipid levels in atherosclerotic cardiovascular disease (ASCVD) risk reduction, many patients are unable to achieve target doses of statin medication due to side effects or target levels of cholesterol reduction on statin monotherapy. The landscape of lipid-lowering strategies has expanded in recent years, with the emergence of therapies that make use of small interfering RNA (siRNA) and antisense oligonucleotides, in addition to traditional small-molecule agents. Non-statin therapies that have shown promising results in randomized controlled trials include adenosine triphosphate-citrate lyase inhibitors, proprotein convertase subtilisin/kexin 9 (PCSK9)-inhibiting antibodies and siRNA, omega-3 polyunsaturated fatty acids, and lipoprotein(a) gene-inhibiting siRNA and ASOs, in addition to older therapies such as ezetimibe. In contrast, cholesteryl ester transfer protein (CETP) inhibitors have shown less promising results in randomized trials. The purpose of this narrative review is to summarize the evidence for these medications, with a focus on phase III randomized trials.

Circulating lipids, lipid-lowering drug targets, and breast cancer risk: Comprehensive evidence from Mendelian randomization and summary data-based Mendelian randomization.

Breast cancer (BC) is the most common and fatal cancer among women, yet the causal relationship between circulating lipids, lipid-lowering drugs, and BC remains unclear. Mendelian randomization (MR) and summary data-based MR (SMR) analysis are used to explore the causal relationship between plasma lipids, lipid-lowering drug targets, and BC. The result of MR suggested that per mg/dL higher levels of LDL-C (OR = 1.045, FDR = 0.023), HDL-C (OR = 1.079, FDR = 0.003), TC (OR = 1.043, FDR = 0.026), and APOA-I (OR = 1.085, FDR = 2.64E-04) were associated with increased BC risk, while TG was associated with reduced BC risk (OR = 0.926, FDR = 0.003). Per mg/dL higher levels of HDL-C (OR = 1.080, FDR = 0.011) and APOA-I (OR = 1.083, FDR = 0.002) were associated with increased ER+BC risk, while TG was associated with reduced ER+BC risk (OR = 0.909, FDR = 0.002). For every per 1mg/dL decrease in LDL, HMGCR (OR: 0.839; FDR = 0.016), NPC1L1 (OR: 0.702; FDR = 0.004), and PCSK9 (OR: 0.916; FDR = 0.026) inhibition were associated with reduced BC risk, whereas CETP inhibition (OR: 1.194; FDR = 0.026) was associated with increased BC risk. For every per 1mg/dL decrease in LDL, HMGCR (OR: 0.822; FDR = 0.023), NPC1L1 (OR: 0.633; FDR = 2.37E-03), and APOB inhibition (OR: 0.816; FDR = 1.98E-03) were associated with decreased ER-BC risk, while CETP inhibition (OR: 1.465; FDR = 0.011) was associated with increased ER-BC risk. SMR analysis indicated that HMGCR was associated with increased BC risk (OR: 1.112; p = 0.044). Lipids are associated with the BC risk, and lipid-lowering drugs targets HMGCR, NPC1L1, PCSK9, and APOB may be effective strategies for preventing BC. However, lipid-lowering drugs target CETP may potentially increase BC risk.

Chemical Synthesis, Biological Evaluation, and Cheminformatics Analysis of a Group of Chlorinated Diaryl Sulfonamides: Promising Inhibitors of Cholesteryl Ester Transfer Protein.

Hyperlipidemia is characterized by an abnormally elevated serum cholesterol, triglycerides, or both. The relationship between an elevated level of LDL and cardiovascular diseases is well-established. Cholesteryl ester transfer protein (CETP) is an enzyme that moves cholesterol esters and triglycerides between LDL, VLDL, and HDL. CETP inhibition leads to a reduction in cardiovascular disease by raising HDL and minimizing LDL. This study synthesized ten meta-chlorinated benzene sulfonamides 6a-6j and explored their structure-activity relationship. The synthesized molecules were characterized using 1H-NMR, 13C-NMR, IR, and HR-MS. Moreover, cheminformatics analyses included pharmacophore mapping, LibDock studies, and cheminformatics characterization using 2-dimensional (2D) molecular descriptors and principal component analysis. Based on in vitro functional CETP assays, compounds 6e, 6i, and 6j demonstrated the strongest inhibitory activities against CETP, reaching 100% inhibition. The inhibitory activity of compounds 6a-6d and 6f-6h ranged from 47.5% to 96.5% at 10 μM concentration. Pharmacophore mapping results suggested CETP inhibitory action, while the docking scores and calculated binding energies predicted favoring binding at the CETP active site. Best-scoring docking poses predicted critical hydrophobic features corresponding to key interactions with His232 and Cys13. Cheminformatics analysis using 2D molecular descriptors indicated that the synthesized compounds span various physicochemical properties and drug-likeness. It was found that a chloro moiety at the ortho-position, or a nitro group at the meta and para-positions, improves the CETP inhibitory activity of synthesized analogs. Computational studies suggest the formation of stable ligand-protein complexes between compounds 6a- 6j and CETP.

Effect of lipid-lowering therapies on C-reactive protein levels: a comprehensive meta-analysis of randomized controlled trials.

Chronic low-degree inflammation is a hallmark of atherosclerotic cardiovascular (CV) disease. To assess the effect of lipid-lowering therapies on C-reactive protein (CRP), a biomarker of inflammation, we conducted a meta-analysis according to the PRISMA guidelines. Databases were searched from inception to July 2023. Inclusion criteria were: (i) randomized controlled trials (RCTs) in human, Phase II, III, or IV; (ii) English language; (iii) comparing the effect of lipid-lowering drugs vs. placebo; (iv) reporting the effects on CRP levels; (v) with intervention duration of more than 3 weeks; (vi) and sample size (for both intervention and control group) over than 100 subjects. The between-group (treatment-placebo) CRP absolute mean differences and 95% confidence intervals were calculated for each drug class separately. A total of 171 668 subjects from 53 RCTs were included. CRP levels (mg/L) were significantly decreased by statins [-0.65 (-0.87 to -0.43), bempedoic acid; -0.43 (-0.67 to -0.20), ezetimibe; -0.28 (-0.48 to -0.08)], and omega-3 fatty acids [omega3FAs, -0.27 (-0.52 to -0.01)]. CRP was reduced by -0.40 (-1.17 to 0.38) with fibrates, although not statistically significant. A slight increase of CRP concentration was observed for proprotein convertase subtilisin/kexin type 9 inhibitors [0.11 (0.07-0.14)] and cholesteryl-ester transfer protein inhibitors [0.10 (0.00-0.21)], the latter being not statistically significant. Meta-regression analysis did not show a significant correlation between changes in CRP and LDL cholesterol (LDL-C) or triglycerides. Statins, bempedoic acid, ezetimibe, and omega3FAs significantly reduce serum CRP concentration, independently of LDL-C reductions. The impact of this anti-inflammatory effect in terms of CV prevention needs further investigation.

Type 2 Diabetes and HDL Dysfunction: A Key Contributor to Glycemic Control.

High-density lipoproteins (HDL) have been shown to exert multiple cardioprotective and antidiabetic functions, such as their ability to promote cellular cholesterol efflux and their antioxidant, anti-inflammatory, and antiapoptotic properties. Type 2 diabetes (T2D) is usually associated with low high-density lipoprotein cholesterol (HDL-C) levels as well as with significant alterations in the HDL composition, thereby impairing its main functions. HDL dysfunction also negatively impacts both pancreatic β-cell function and skeletal muscle insulin sensitivity, perpetuating this adverse self-feeding cycle. The impairment of these pathways is partly dependent on cellular ATP-binding cassette transporter (ABC) A1-mediated efflux to lipid-poor apolipoprotein (apo) A-I in the extracellular space. In line with these findings, experimental interventions aimed at improving HDL functions, such as infusions of synthetic HDL or lipid-poor apoA-I, significantly improved glycemic control in T2D patients and experimental models of the disease. Cholesteryl ester transfer protein (CETP) inhibitors are specific drugs designed to increase HDLC and HDL functions. Posthoc analyses of large clinical trials with CETP inhibitors have demonstrated their potential anti-diabetic properties. Research on HDL functionality and HDL-based therapies could be a crucial step toward improved glycemic control in T2D subjects.

HDL as a Treatment Target: Should We Abandon This Idea?

High-density lipoproteins (HDL) have long been regarded as an antiatherogenic lipoprotein species by virtue of their role in reverse cholesterol transport (RCT), as well as their established anti-inflammatory and antioxidant properties. For decades, HDL have been an extremely appealing therapeutic target to combat atherosclerotic cardiovascular diseases (ASCVD). Unfortunately, neither increasing HDL with drugs nor direct infusions of reconstituted HDL have convincedly proven to be positive strategies for cardiovascular health, raising the question of whether we should abandon the idea of considering HDL as a treatment target. The results of two large clinical trials, one testing the latest CETP inhibitor Obicetrapib and the other testing the infusion of patients post-acute coronary events with reconstituted HDL, are still awaited. If they prove negative, these trials will seal the fate of HDL as a direct therapeutic target. However, using HDL as a therapeutic agent still holds promise if we manage to optimize their beneficial properties for not only ASCVD but also outside the cardiovascular field.

Comparing the drug target effects of Cholesteryl ester transfer protein (CETP) on cardiovascular diseases in East Asian and European populations

Abstract Introduction Cholesteryl ester transfer protein (CETP) is a drug target originally evaluated for raising HDL-C, for efficacy against coronary heart disease (CHD). Previous attempts to develop a licensed drug compound inhibiting CETP have heterogeneous CHD effects, which are likely attributable to the developed compound rather than CETP itself. Currently, novel CETP inhibitors are being pursued for the treatment of CHD. Drug target Mendelian randomization studies, leveraging genetic evidence, have shown that on-target CETP inhibition reduces CHD risk in individuals of European ancestries. However, similar MR studies conducted in East Asian ancestries have failed to show a CHD effect, questioning the value of pharmacological inhibition of CETP in this population. Purpose In this study, we compared drug target MR effects of CETP inhibition in Europeans and East Asians, focusing on cardiovascular efficacy outcomes, and relevant safety outcomes. Methods We used ancestry-specific GWAS summary statistics for Europeans (n=1,320,016) and East Asians (n=146,492) from the Global Lipids Genetics Consortium, taking variants from within and around ±50 kbp of the CETP locus. Colocalization was employed to determine potential trans-ancestry signals between CETP variants for HDL-C and LDL-C. Subsequently, drug target MR was used to estimate ancestry-specific effects of on-target CETP inhibition on 11 plasma biomarkers and 15 clinical outcomes between East Asian and European populations. Differences between ancestries were evaluated using interaction tests. Results There was strong support (posterior probability: 99.8%) of a shared causal CETP variant affecting HDL-C in both populations. Given the absence of a LDL-C signal in East Asians, similar colocalization was not observed for LDL-C. Employing drug target MR scaled to a standard deviation increase in HDL-C, we found that lower CETP had more pronounced decreasing effects in Europeans on LDL-C, LP[a], systolic blood pressure and pulse pressure (interaction p-values >1.9×10-3). Nevertheless, lower CETP protected against CHD, angina, intracerebral haemorrhage, and heart failure in both ancestries, for example for CHD (OR, 0.89; 95%CI, 0.84-0.94) in East Asians, compared to Europeans (OR, 0.95; 95%CI, 0.92-0.99, interaction p-value: 0.05). Exploring potential safety outcomes, lower CETP was protective against pneumonia in Europeans and East Asians (interaction p-value=0.53) and had a potential harmful effect on asthma and chronic kidney disease in East Asians (interaction p-value > 1.9×10-3). Conclusion In conclusion, on-target and sufficiently potent CETP inhibition is anticipated to prevent cardiovascular diseases in both European and East Asian populations.

Abstract 14019: Comparing the Effect Profile of CETP in Individuals of East Asian and European Ancestries

Introduction: Cholesteryl ester transfer protein (CETP) is a lipid drug target under development for CHD in both European and East Asian populations.Previous drug target Mendelian randomization (MR) studies conducted in East Asians failed to show a CHD effect, which has been interpreted as lack of effectiveness of CETP inhibition for CHD prevention in this population. Hypothesis: In this study, we inferred the effect of CETP inhibition in individuals of European and East Asian ancestries using drug target Mendelian randomization. Methods: We leveraged genetic associations of CETP variants with major blood lipid fractions for individuals of European (n=1,320,016) and East Asian (n=146,492) ancestries. Colocalization was employed to identify potential cross-ancestry signals of CETP variants for plasma concentrations of LDL-C or HDL-C. Drug target MR was used to estimate ancestry-specific effects of on-target CETP inhibition. Differences between ancestries were evaluated using interaction tests, applying a multiplicity corrected alpha of 1.9х10 -3 based on the 26 considered traits. Results: There was strong support (posterior probability=1.00) of a shared causal CETP variant affecting HDL-C in both populations, which was not observed for LDL-C. Employing drug target MR scaled to a standard deviation increase in HDL-C, we found that lower CETP was associated with lower LDL-C, Lp[a], systolic blood pressure and pulse pressure in both groups, but the effects were more pronounced in European individuals (interaction p-values < 1.9х10-3). Lower CETP was protective against CHD, angina, intracerebral haemorrhage and heart failure in both ancestries, for example for CHD in East Asians (OR 0.89, 95%CI 0.84;0.94) compared to Europeans (OR 0.95, 95%CI 0.92;0.99, interaction p-value=0.05). Conclusions: In conclusion, on-target inhibition of CETP is anticipated to decrease cardiovascular disease in individuals of both European and East Asian ancestries.

Abstract 15201: Obicetrapib as an Adjunct to Stable Statin Therapy Significantly Lowers LDL-C, Non-HDL-C, and Apolipoprotein B in Japanese Patients: Results From the Japan Phase 2 Study

Background: Obicetrapib is a selective CETP inhibitor that has been shown to reduce LDL-C, non-HDL-C, lipoprotein particles, and apolipoproteins when used as monotherapy, and in combination with ezetimibe, on background high-intensity statins. Previous studies of obicetrapib were conducted in predominantly Caucasian participants. There is a lack of clinical experience with obicetrapib when used in combination with stable statin therapy among Asian population. Objectives: This study was designed to fill the gap in clinical experience and to characterize the safety, efficacy profile of obicetrapib within the Asian population. Methods: The Phase 2 study is a trial of Japanese participants who had not achieved treatment goal in accordance with the 2022 Japan Atherosclerosis Society Guidelines and with LDL-C >70 mg/dL or non-HDL-C > 100 mg/dL and TG < 400 mg/dL, while receiving stable statin background therapy. Participants were randomized 1:1:1:1 to obicetrapib 2.5 mg (n=25), obicetrapib 5 mg (n=25), obicetrapib 10 mg (n=26), or placebo (n=26). The primary endpoint was percent change in LDL-C from baseline to week 8. Key secondary endpoints included changes in ApoB, non-HDL-C, and HDL-C. Standard safety assessments were conducted. Results: Obicetrapib produced significant lowering of median LDL-C (45.8%, P<0.0001), ApoB (29.7%, P<0.0001), non-HDL-C (37.0%, P<0.0001) and raising of HDL-C (158.9%, P<0.0001). Placebo demonstrated median change of -0.9%, -0.4%, -0.4% and +5.2% for these parameters respectively. Obicetrapib was well tolerated with similar treatment emergent adverse events compared to placebo. There were no clinically significant changes in laboratory parameters, vital signs, or physical examinations in any treatment group. Conclusions: Similar to previous studies, obicetrapib 2.5 mg, 5 mg, and 10 mg resulted in significant reductions in LDL-C, ApoB, and non-HDL-C in the Asian population. All doses of obicetrapib were safe and well tolerated.

CETP Expression in Bone-Marrow-Derived Cells Reduces the Inflammatory Features of Atherosclerosis in Hypercholesterolemic Mice.

CETP activity reduces plasma HDL-cholesterol concentrations, a correlate of an increased risk of atherosclerotic events. However, our recent findings suggest that CETP expression in macrophages promotes an intracellular antioxidant state, reduces free cholesterol accumulation and phagocytosis, and attenuates pro-inflammatory gene expression. To determine whether CETP expression in macrophages affects atherosclerosis development, we transplanted bone marrow from transgenic mice expressing simian CETP or non-expressing littermates into hypercholesterolemic LDL-receptor-deficient mice. The CETP expression did not change the lipid-stained lesion areas but decreased the macrophage content (CD68), neutrophil accumulation (LY6G), and TNF-α aorta content of young male transplanted mice and decreased LY6G, TNF-α, iNOS, and nitrotyrosine (3-NT) in aged female transplanted mice. These findings suggest that CETP expression in bone-marrow-derived cells reduces the inflammatory features of atherosclerosis. These novel mechanistic observations may help to explain the failure of CETP inhibitors in reducing atherosclerotic events in humans.

Fluorinated Diaryl Sulfonamides: Molecular Modeling, Synthesis, and In Vitro Validation as New CETP Inhibitors.

Hyperlipidemia, a cardiovascular disease risk factor, is characterized by a rise in low-density lipoprotein (LDL), triglycerides and total cholesterol, and a decrease in high-density lipoprotein (HDL). Cholesteryl ester transfer protein (CETP) enables the transfer of cholesteryl ester from HDL to LDL and very low-density lipoprotein. CETP inhibition is a promising approach to prevent and treat cardiovascular diseases. By inhibiting lipid transport activity, it increases HDL levels and decreases LDL levels. Herein, diaryl sulfonamides 6a-6g and 7a-7g were prepared, and the structure of these compounds was fully determined using different spectroscopic techniques. These compounds underwent biological evaluation in vitro and showed different inhibitory activities against CETP; 100% inhibitory activity was observed for compounds 7a-7g, while activities of compounds 6a-6g ranged up to 42.6% at 10 µM concentration. Pharmacophore mapping agreed with the bioassay results where the four aromatic ring compounds 7a-7g possessed higher fit values against Hypo4/8 and the shape-complemented Hypo4/8 in comparison to compounds 6a-6g. Docking of the synthesized compounds using libdock and ligandfit engines revealed that compounds 7a-7g formed п-п stacking and hydrophobic interactions with the binding pocket, while compounds 6a-6g missed these hydrophobic interactions with amino acids Leu206, Phe265, and Phe263.

Lipoprotein(a) as a Risk Factor for Cardiovascular Diseases: Pathophysiology and Treatment Perspectives.

Cardiovascular disease (CVD) is still a leading cause of morbidity and mortality, despite all the progress achieved as regards to both prevention and treatment. Having high levels of lipoprotein(a) [Lp(a)] is a risk factor for cardiovascular disease that operates independently. It can increase the risk of developing cardiovascular disease even when LDL cholesterol (LDL-C) levels are within the recommended range, which is referred to as residual cardiovascular risk. Lp(a) is an LDL-like particle present in human plasma, in which a large plasminogen-like glycoprotein, apolipoprotein(a) [Apo(a)], is covalently bound to Apo B100 via one disulfide bridge. Apo(a) contains one plasminogen-like kringle V structure, a variable number of plasminogen-like kringle IV structures (types 1-10), and one inactive protease region. There is a large inter-individual variation of plasma concentrations of Lp(a), mainly ascribable to genetic variants in the Lp(a) gene: in the general po-pulation, Lp(a) levels can range from <1 mg/dL to >1000 mg/dL. Concentrations also vary between different ethnicities. Lp(a) has been established as one of the risk factors that play an important role in the development of atherosclerotic plaque. Indeed, high concentrations of Lp(a) have been related to a greater risk of ischemic CVD, aortic valve stenosis, and heart failure. The threshold value has been set at 50 mg/dL, but the risk may increase already at levels above 30 mg/dL. Although there is a well-established and strong link between high Lp(a) levels and coronary as well as cerebrovascular disease, the evidence regarding incident peripheral arterial disease and carotid atherosclerosis is not as conclusive. Because lifestyle changes and standard lipid-lowering treatments, such as statins, niacin, and cholesteryl ester transfer protein inhibitors, are not highly effective in reducing Lp(a) levels, there is increased interest in developing new drugs that can address this issue. PCSK9 inhibitors seem to be capable of reducing Lp(a) levels by 25-30%. Mipomersen decreases Lp(a) levels by 25-40%, but its use is burdened with important side effects. At the current time, the most effective and tolerated treatment for patients with a high Lp(a) plasma level is apheresis, while antisense oligonucleotides, small interfering RNAs, and microRNAs, which reduce Lp(a) levels by targeting RNA molecules and regulating gene expression as well as protein production levels, are the most widely explored and promising perspectives. The aim of this review is to provide an update on the current state of the art with regard to Lp(a) pathophysiological mechanisms, focusing on the most effective strategies for lowering Lp(a), including new emerging alternative therapies. The purpose of this manuscript is to improve the management of hyperlipoproteinemia(a) in order to achieve better control of the residual cardiovascular risk, which remains unacceptably high.

Novel Pharmacological Therapies for the Management of Hyperlipoproteinemia(a).

Lipoprotein(a) [Lp(a)] is a well-established risk factor for cardiovascular disease, predisposing to major cardiovascular events, including coronary heart disease, stroke, aortic valve calcification and abdominal aortic aneurysm. Lp(a) is differentiated from other lipoprotein molecules through apolipoprotein(a), which possesses atherogenic and antithrombolytic properties attributed to its structure. Lp(a) levels are mostly genetically predetermined and influenced by the size of LPA gene variants, with smaller isoforms resulting in a greater synthesis rate of apo(a) and, ultimately, elevated Lp(a) levels. As a result, serum Lp(a) levels may highly vary from extremely low to extremely high. Hyperlipoproteinemia(a) is defined as Lp(a) levels > 30 mg/dL in the US and >50 mg/dL in Europe. Because of its association with CVD, Lp(a) levels should be measured at least once a lifetime in adults. The ultimate goal is to identify individuals with increased risk of CVD and intervene accordingly. Traditional pharmacological interventions like niacin, statins, ezetimibe, aspirin, PCSK-9 inhibitors, mipomersen, estrogens and CETP inhibitors have not yet yielded satisfactory results. The mean Lp(a) reduction, if any, is barely 50% for all agents, with statins increasing Lp(a) levels, whereas a reduction of 80-90% appears to be required to achieve a significant decrease in major cardiovascular events. Novel RNA-interfering agents that specifically target hepatocytes are aimed in this direction. Pelacarsen is an antisense oligonucleotide, while olpasiran, LY3819469 and SLN360 are small interfering RNAs, all conjugated with a N-acetylgalactosamine molecule. Their ultimate objective is to genetically silence LPA, reduce apo(a) production and lower serum Lp(a) levels. Evidence thus so far demonstrates that monthly subcutaneous administration of a single dose yields optimal results with persisting substantial reductions in Lp(a) levels, potentially enhancing CVD risk reduction. The Lp(a) reduction achieved with novel RNA agents may exceed 95%. The results of ongoing and future clinical trials are eagerly anticipated, and it is hoped that guidelines for the tailored management of Lp(a) levels with these novel agents may not be far off.