👤 Nadia Jaber

Cholesteryl ester transfer protein (CETP) inhibitors, specifically anacetrapib and obicetrapib, have shown strong lipid-modifying effects by lowering low-density lipoprotein cholesterol (LDL-C) and altering other lipid parameters. However, comparative evidence on their relative efficacy and safety is limited. To compare the efficacy and safety of anacetrapib and obicetrapib. We systematically searched PubMed, Scopus, Web of Science, Cochrane Central Register, and ClinicalTrials.gov. The protocol was registered at OSF ( https://doi.org/10.17605/OSF.IO/VRP8Y ). The primary outcome was change in LDL-C; secondary outcomes included high-density lipoprotein cholesterol (HDL-C), non-HDL-C, total cholesterol, triglycerides, lipoprotein (a), apolipoprotein B (ApoB), apolipoprotein AI (ApoAI), apolipoprotein E (ApoE), incidence of adverse events, serious adverse events, and discontinuation. A frequentist random-effects network meta-analysis was performed using the netmeta package in R, with placebo as reference. Ten randomized controlled trials (2,937 patients) were included. Obicetrapib showed the most significant reduction in LDL-C (MD -33.63 mg/dL; 95% CI [-44.10, -23.16]) and the most significant increase in HDL-C (MD 154.33 mg/dL; 95% CI [132.73, 175.93]), outperforming anacetrapib. Both drugs comparably reduced non-HDL-C, ApoB, and Lp(a). Obicetrapib was associated with greater increases in ApoA1 and ApoE, while anacetrapib lowered triglycerides more effectively. Obicetrapib had the lowest risk of overall adverse events (RR 0.69; 95% CI [0.49, 0.99]) and ranked favorably for serious adverse events and discontinuation. Both agents effectively reduced LDL-C levels, with obicetrapib demonstrating superior efficacy compared to anacetrapib. Additionally, both treatments demonstrated favorable safety profiles. These findings underscore the potential of CETP inhibitors as promising therapeutic options for patients with dyslipidemia. Show less

BackgroundAlzheimer's disease (AD) is the most common form of dementia, marked by progressive cognitive decline. Low-density lipoprotein cholesterol (LDL-C) has been implicated in AD pathology, but findings remain inconsistent. Apolipoprotein E4 (APOE4) status and sex may contribute to this variability.ObjectiveTo examine how LDL-C association with neurodegeneration in AD patients, differ according to APOE4 status and gender.MethodsWe stratified 106 AD patients by APOE4 status and sex into four subgroups: male APOE4+, female APOE4+, male APOE4-, and female APOE4-. Longitudinal cortical thickness changes were assessed using magnetic resonance imaging (MRI). We examined the association between LDL-C levels and cortical thinning within each subgroup.ResultsIn APOE4-positive females, higher LDL-C levels were significantly associated with accelerated cortical thinning in several regions, including the parahippocampal (β = -0.0075, p = 0.017), medial orbitofrontal (β = -0.0025, p = 0.028), fusiform (β = -0.0047, p = 0.034), posterior cingulate (β = -0.0097, p = 0.006), and inferior temporal cortices (β = -0.0085, p = 0.019). This subgroup also showed a significant association between LDL-C and MMSE decline (β = -1.409, p = 0.014) as well as longitudinal increases in cerebrospinal fluid phosphorylated tau181 (β = 0.014, p = 0.039). These effects were not observed in other subgroups.ConclusionsElevated LDL-C is associated with increased neurodegeneration and cognitive decline in female AD patients carrying the APOE4 allele. These exploratory findings highlight a subgroup-specific vulnerability to lipid-related neurodegeneration in AD and underscore the importance of considering both sex and genetic background in future studies. Show less

The class III phosphoinositide 3-kinase (PI3K) Vps34 (also known as PIK3C3 in mammals) produces phosphatidylinositol 3-phosphate [PI(3)P] on both early and late endosome membranes to control membrane dynamics. We used Vps34-deficient cells to delineate whether Vps34 has additional roles in endocytic trafficking. In Vps34 Show less

PIK3C3/Vps34 is the class III PtdIns3K that is evolutionarily conserved from yeast to mammals. Its central role in mammalian autophagy has been suggested through the use of pharmacological inhibitors and the study of its binding partners. However, the precise role of PIK3C3 in mammals is not clear. Using mouse strains that allow tissue-specific deletion of PIK3C3, we have described an essential role of PIK3C3 in regulating autophagy, and liver and heart function. Show less

A critical regulator of autophagy is the Class III PI3K Vps34 (also called PIK3C3). Although Vps34 is known to play an essential role in autophagy in yeast, its role in mammals remains elusive. To elucidate the physiological function of Vps34 and to determine its precise role in autophagy, we have generated Vps34(f/f) mice, in which expression of Cre recombinase results in a deletion of exon 4 of Vps34 and a frame shift causing a deletion of 755 of the 887 amino acids of Vps34. Acute ablation of Vps34 in MEFs upon adenoviral Cre infection results in a diminishment of localized generation of phosphatidylinositol 3-phosphate and blockade of both endocytic and autophagic degradation. Starvation-induced autophagosome formation is blocked in both Vps34-null MEFs and liver. Liver-specific Albumin-Cre;Vps34(f/f) mice developed hepatomegaly and hepatic steatosis, and impaired protein turnover. Ablation of Vps34 in the heart of muscle creatine kinase-Cre;Vps34(f/f) mice led to cardiomegaly and decreased contractility. In addition, while amino acid-stimulated mTOR activation was suppressed in the absence of Vps34, the steady-state level of mTOR signaling was not affected in Vps34-null MEFs, liver, or cardiomyocytes. Taken together, our results indicate that Vps34 plays an essential role in regulating functional autophagy and is indispensable for normal liver and heart function. Show less