👤 Veronica Nunez

Enlicitide decanoate, an oral proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor, was shown to reduce low-density lipoprotein (LDL) cholesterol levels in a phase 2 trial; longer-term data are needed. In this multinational, double-blind, randomized, placebo-controlled trial, we enrolled adults with a history of a major atherosclerotic cardiovascular disease event with an LDL cholesterol level of 55 mg per deciliter or higher and those who were at risk for a first atherosclerotic cardiovascular disease event with an LDL cholesterol level of 70 mg per deciliter or higher. Participants were assigned in a 2:1 ratio to receive enlicitide at a dose of 20 mg or placebo daily for 52 weeks. The primary end point was the mean percent change in LDL cholesterol level from baseline to week 24. Key secondary end points were the mean percent change in LDL cholesterol level at week 52 and the mean percent change in levels of non-high-density lipoprotein (non-HDL) cholesterol and apolipoprotein B and the percent change in lipoprotein(a) level at week 24. Of the 2909 participants in the intention-to-treat population, 1935 received enlicitide and 969 received placebo (5 did not receive enlicitide or placebo). The mean age of the participants was 63 years, and 39.3% were women. The mean (±SD) LDL cholesterol level at baseline was 96.1±38.9 mg per deciliter. The mean percent change in LDL cholesterol levels at week 24 was -57.1% (95% confidence interval [CI], -61.8 to -52.5) with enlicitide and 3.0% (95% CI, 0.9 to 5.1) with placebo, representing an adjusted between-group difference of -55.8 percentage points (95% CI, -60.9 to -50.7; P<0.001). The mean percent change in LDL cholesterol level at week 52, the mean percent changes in non-HDL cholesterol and apolipoprotein B levels at week 24, and the percent change in lipoprotein(a) levels at week 24 were significantly greater with enlicitide than with placebo (P<0.001 for all comparisons). The incidence of adverse events did not appear to differ between the groups. Among participants who had a history of or were at risk for a first atherosclerotic cardiovascular disease event, treatment with the oral PCSK9 inhibitor enlicitide resulted in significantly lower LDL cholesterol levels than placebo at 24 weeks. (Funded by MSD [Rahway, NJ]; CORALreef Lipids ClinicalTrials.gov number, NCT05952856.). Show less

The cavernous sinus (CS) has 4 compartments: superior, inferior, posterior, and lateral. Among these, the lateral compartment is the most common location for residual tumor, given the risk of neurovascular injury. The authors' study aimed to delineate the anatomical landmarks in this area and illustrate the technical nuances of the lateral transcavernous approach. Twenty-two colored silicone-injected specimens were dissected via an endoscopic endonasal approach to the lateral compartment of the CS. The anatomical landmarks and the internal carotid artery (ICA) mobilization technique were investigated. Two illustrative cases are provided. The lateral compartment of the CS is bounded by the carotid-oculomotor membrane (COM) and optic strut as the roof and the petrolingual ligament and lingual process as the floor. It is divided into 2 asymmetrical subcompartments: the upper, larger subcompartment, located superior to the abducens nerve, accommodates the lateral parasellar ligament (LPL), inferolateral trunk (ILT), and branches of the tentorial artery; and the lower, smaller subcompartment, inferior to the abducens nerve, accommodates only the sympathetic nerve branches as they join the abducens nerve. The LPL is a well-defined ligamentous band and was identified in 38 (86%) hemispheres with 2 distinct configurations: 1) robust LPL (59%), with highly compacted ligamentous bands tightly adherent to the ICA; and 2) dispersed LPL (27%), with less compaction and adherence to ICA. The main attachment of the LPL to the cavernous ICA was most commonly observed at the horizontal ICA segment (55%), followed by the anterior (18%) and posterior (14%) genua. The ILT, as the main vessel in the lateral compartment, was identified in 41 (93%) hemispheres and originated from the horizontal ICA segment (80%) or the anterior genu (14%), from either the lateral (52%) or inferior (41%) aspect of the cross-section of the ICA. In 64% of hemispheres, the LPL wrapped the ILT, abducens nerve, and sympathetic nerve to form a broad and firm neurovascular-ligamental complex. Transection of the LPL, ILT, and COM enables medial ICA mobilization and enhances access to the lateral compartment of the CS, potentially increasing the exposure width by 6 ± 1 mm. This study provides valuable insights into the anatomical intricacies of the lateral compartment of the CS and underscores the potential benefits of the endoscopic endonasal lateral transcavernous approach. Further clinical applications are essential for validating these findings and optimizing surgical outcomes. Show less

Glucose-dependent insulinotropic polypeptide (GIP) communicates nutrient intake from the gut to islets, enabling optimal levels of insulin secretion via the GIP receptor (GIPR) on β cells. The GIPR is also expressed in α cells, and GIP stimulates glucagon secretion; however, the role of this action in the postprandial state is unknown. Here, we demonstrate that GIP potentiates amino acid-stimulated glucagon secretion, documenting a similar nutrient-dependent action to that described in β cells. Moreover, we demonstrate that GIP activity in α cells contributes to insulin secretion by invoking paracrine α to β cell communication. Last, specific loss of GIPR activity in α cells prevents glucagon secretion in response to a meal stimulus, limiting insulin secretion and driving glucose intolerance. Together, these data uncover an important axis by which GIPR activity in α cells is necessary to coordinate the optimal level of both glucagon and insulin secretion to maintain postprandial homeostasis. Show less

Apolipoprotein A5 (APOA5) 1131 is one of the most investigated gene polymorphisms in association with cardiovascular diseases (CVD) for its roles in epigenetics pathways. The major objective of this metaprediction study was to comprehensively examine the association of polymorphism risk subtypes of APOA5 1131 gene and potential contributing factors of CVD risks in global populations. This study is a meta-analysis to determine APOA5 gene polymorphisms as risk factors for CVDs. Following the guidelines of meta-analyses, we applied big data analytics including the recursive partition tree, nonlinear association curve fit, and heat maps for data visualization-in addition to the conventional pooled analyses. A total of 17,692 CVD cases and 23,566 controls from 50 study groups were included. The frequency of APOA5 1131 CC and TC polymorphisms in Asian populations (22.2%-52.6%) were higher than that in other populations, including Caucasians and Eurasians (10.0%-25.0%). The homozygous CC and heterozygous TC genotypes (both p < .0001) were associated with increased risks for CVD and were higher in many Western nations, including Canada, Spain, the Czech Republic, Hungary, Turkey, Egypt, France, and Iran. The CC genotype was associated with greater risks (RR > 2.00, p < .0001) for dyslipidemia and myocardial infarction, whereas RR > 1.00 was associated with metabolic syndrome, coronary artery disease, and stroke. Air pollution was significantly associated with APOA5 1131 CC and TC polymorphisms. The findings of this study provided novel insight to further understand the associations among APOA5 1131 polymorphisms, air pollution, and the development of CVDs. Methylation studies are needed to examine epigenetic factors associated with APOA5 1131 polymorphisms and CVD and to suggest potential prevention strategies for CVD. Show less