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.
Background: Individuals with homozygous familial hypercholesterolemia (HoFH) have a severe clinical problem in their first decade of life, which is not usually present in heterozygous FH (HeFH) individuals. For this latter group of patients, FH diagnosis is mostly severely delayed with a significant increase in the risk of angina, myocardial infarction, peripheral artery disease, stroke, and cardiovascular and all-cause mortality. Methods: This study used various bioinformatics tools to analyze microarray data and identify critical miRNAs and their target genes associated with FH and its severity. Differentially expressed serum miRNAs from direct hybridization microarray data in three groups of subjects: healthy, HeFH, and HoFH. The differential expressed miRNAs were determined according to a log of fold-change (LFC) <-0.5 or >0.5 and of p < 0.05. Then, we assessed their target genes in silico. Gene ontology (GO) enrichment was applied by Cytoscape. The protein-protein interaction and co-expression network were analyzed by the STRING and GeneMANIA plugins of Cytoscape, respectively. Results: We identified increased expression of circulating hsa-miR-604, hsa-miR-652-5p, and hsa-miR-4451 as well as reduced expression of hsa-miR-3140-3p, hsa-miR-550a-5p, and hsa-miR-363-3p in both group of FH vs. healthy subjects. Higher levels of hsa-miR-1183, hsa-miR-1185-1-3p, hsa-miR-122-5p, hsa-miR-19a-3p, hsa-miR-345-3p, and hsa-miR-34c-5p were detected in HeFH in respect to HoFH when compared to healthy subjects. Most upregulated miRNAs mainly affected gene related to cardiac myofibrillogenesis, cholesterol synthesis, RNA editing for apolipoprotein B, and associated with LDL-cholesterol levels. In contrast, down-regulated miRNAs mainly affected gene related to plasma biomarker for coronary artery disease, lipids metabolism, cell adhesion and migration, genetic predictors of type 2 diabetes and cholesterol metabolism. The essential genes were primarily enriched in GO regarding biological regulation, intracellular nucleic acid binding, and the KEGG pathway of TGF-ß signaling. Conclusions: The case-control nature of this study precluded the possibility of assessing the predictive role of the identified differentially expressed miRNAs for cardiovascular events. Therefore, the signature of miRNAs reflecting the pathogenesis of both HeFH and HoFH.
Maturity-onset diabetes of the young (MODY) is a spectrum of clinically heterogenous forms of monogenic diabetes mellitus characterized by autosomal dominant inheritance, onset at a young age, and absence of pancreatic islets autoimmunity. This rare form of hyperglycemia, with clinical features overlapping with type 1 and type 2 diabetes mellitus, has 14 subtypes with differences in prevalence and complications occurrence which tailor therapeutic approach. MODY phenotypes differ based on the gene involved, gene penetrance and expressivity. While MODY 2 rarely leads to diabetic complications and is easily managed with lifestyle interventions alone, more severe subtypes, such as MODY 1, 3, and 6, require an individualized treatment approach to maintain a patient's quality of life and prevention of complications. This review summarizes current evidence on the presentation, diagnosis, and management of MODY, an example of a genetic cause of hyperglycemia that calls for a precision medicine approach.
Background: The prevalence of long-COVID (LC) presents a significant challenge to healthcare systems globally. There are still some discrepancies on the role of sex as an independent risk factor of LC complications. Thus, we aimed to determine the differences in clinical and cardiovascular complications between males and females without comorbidities after COVID-19. Methods: Clinical data on the course of the disease with the accompanying symptoms and post-COVID-19 symptoms were compiled from both male and female subjects with a minimum 12-week interval after COVID-19 recovery. Next, the patients were followed for 12 months. ECG, echocardiography, 24 h ECG monitoring, 24 h ambulatory blood pressure monitoring (ABPM), and selected biochemical tests were performed. LC was diagnosed based on the World Health Organization (WHO) definition. To reduce the impact of confounders, i.e., body mass index (BMI) and age, on the results of the study, the nearest neighbour (NN) propensity score matching (PSM) method with a 1:1 ratio was used. Results: The results were obtained following the removal of cases with comorbidities from the database consisting of 1237 males and 2192 females, and PSM of the new database included 886 cases (443 males and 443 females). At both the 3-month and 1-year post-recovery marks, females consistently reported a higher frequency of LC symptoms compared to males (p < 0.001 for both comparisons). Moreover, after 1 year of follow-up, females exhibited a higher prevalence of LC compared to males, with rates of 14% versus 8.3%, respectively (p = 0.013). The symptoms that significantly differed between females and males in the 12-month follow-up were hair loss (5.4 vs. 0.7%, p < 0.001), memory and concentration disturbances (8.4 vs. 4.3%, p = 0.013), and headaches (4.3 vs. 1.4%, p = 0.008). Females presented lower mean arterial pressure (MAP) [89 (83-95) mmHg versus (vs.) 94 (89-100); p < 0.001] and lower pulse pressure (PP) [46 (42-52) mmHg vs. 51 (48-57); p < 0.001] in 24 h ABPM and more elevated heart rates (HRs) in 24 h ECG monitoring as well as arrhythmia (p < 0.001 and p = 0.018, respectively). Males had a higher occurrence of ECG abnormalities such as QRS >= 120 ms, ST-T changes, T inversion, arrhythmia, and QRS fragmentation (27.3% vs. 19.2%; p = 0.004). No significant differences were observed between males and females concerning physical activity levels, stress, fatigue, alcohol consumption, and smoking habits. Conclusions: One year post-COVID-19 recovery, regardless of age and BMI, healthy females more often suffered from LC symptoms than males. They had lower MAP and PP in 24 h ABPM, more often had higher HRs and arrhythmia in 24 h ECG monitoring, and fewer ECG abnormalities than males.
BACKGROUND: Cardiovascular disease is a leading cause of mortality worldwide and is likely to rise. Acute coronary syndrome (ACS) is consequent on inflammation. As a common and cost-effective inflammatory biomarker, the neutrophil-to-lymphocyte ratio (NLR) may be beneficial in cardiovascular medicine. AIMS: This meta-analysis examines the diagnostic and prognostic performance of the NLR in ACS. METHODS: We systematically searched PubMed Central, Medline, Scopus, EMBASE, Cochrane Central Register of Controlled Trials, and Clinicaltrial.gov databases. The search spanned from databases inception to January 10, 2024. The findings were aggregated into normalized mean differences with 95% confidence intervals. RESULTS: Ninety articles, with 45 990 participants, were included. Pooled analysis of the NLR varied and was higher in ST-segment elevation myocardial infarction (STEMI) vs. non-ST-segment elevation myocardial infarction patients (4.94 ± 3.24 vs. 3.24 ± 2.74), acute myocardial infarction vs. unstable angina (4.47 ± 3.43 vs. 2.97 ± 1.58), ACS vs. stable angina (SA) (5.45 ± 4.28 vs. 2.46 ± 2.15), and ACS vs. controls (5.31 ± 4.01 vs. 2.46 ± 2.45). The NLR also was associated with ACS mortality, with survivors having lower results (3.67 ± 2.72 vs. 5.56 ± 3.93). Subanalysis showed that differences in the NLR were observed in STEMI survivors (4.28 ± 3.24 vs. 6.79 ± 3.98). Of ACS patients with major cardiovascular events (MACE) vs. without MACE, the NLR was 6.29 ± 4.89 vs. 3.82 ± 4.12. In STEMI patients, the NLR differed between those with and without MACE (6.99 ± 5.27 vs. 4.99 ± 4.12). CONCLUSIONS: The NLR is an effective tool for differentiating between different types of ACS. A high NLR is associated with ACS and increased MACE at 30 days. The NLR also appears to be a good predictor of MACE risk, at least in STEMI patients.
Acute Coronary Syndrome , Myocardial Infarction , Non-ST Elevated Myocardial Infarction , Percutaneous Coronary Intervention , ST Elevation Myocardial Infarction , Humans , Prognosis , Acute Coronary Syndrome/diagnosis , ST Elevation Myocardial Infarction/diagnosis , Neutrophils , Lymphocytes
Cystatins, a family of proteins known for their inhibitory role against cysteine proteases, have garnered significant attention in the field of neurodegeneration. Numerous genetic, experimental, and clinical studies concerning cystatin C suggest it plays an important role in the course of neurodegenerative diseases. Its beneficial effects are associated with cysteine protease inhibition, impact on ß-amyloid aggregation, as well as regulation of cell proliferation, autophagy, and apoptosis. Cystatin isolated from chicken egg white, called ovocystatin, has been widely used in medical and pharmaceutical research due to its structural and biological similarities to human cystatin C. This article focuses on the potential use of cystatins, with special emphasis on easily obtained ovocystatin, in the treatment of neurodegenerative diseases, such as dementia. The current evidence on cystatin use has shed light on its mechanisms of action and therapeutic implications for neuroprotection and maintenance of cognitive functions.
Introduction: Worldwide, there has been an increase in the incidence of metabolic syndrome. The search for genetic markers of this syndrome is ongoing. The leptin receptor has recently received attention. One of the polymorphisms (Gln223Arg) is possibly associated with the development of obesity and insulin resistance. However, the results of studies on this polymorphism remain equivocal. Gln223Arg polymorphism has not been studied previously in the Kyrgyz population. Thus, we aimed to investigate the possible association of the Gln223Arg polymorphism of the leptin receptor gene with metabolic syndrome components in the Kyrgyz population. Material and methods: 237 Kyrgyz subjects, aged 35-70 years, were studied. For the analysis anthropometric data, glucose, insulin, lipid spectrum, leptin were obtained. The genotype of the Gln223Arg leptin polymorphism was evaluated using TaqMan real-time PCR. Results: The distribution of genotypes was as follows: Gln223Gln 46.4%, Gln223Arg 40.1%, Arg223Arg 13.5%. In the study no association was found with abdominal obesity, arterial hypertension, hypertriglyceridemia or low-density cholesterol levels. Relationships of Gln223Arg and Arg223Arg genotypes with insulin resistance (p < 0.03) were found. Gln223Arg polymorphism was associated with a higher level of glycemia (5.54 vs. 5.39 mmol/l, p < 0.05) and insulinemia (8.3 vs. 7.1 µIU/ml, p < 0.05). Correlation analysis showed that carriers of the Arg223 allele demonstrated a higher risk of insulin resistance (odds ratio (OR) = 1.83, 95% CI: 1.03-3.24; p < 0.03) than carriers of the Gln223 allele. Conclusions: Gln223Arg polymorphism of the leptin receptor gene may be a marker of predisposition to insulin resistance in the Kyrgyz population. Further studies are necessary to confirm these results in populations from other regions.
Lipoprotein(a) [Lp(a)] is made up of a low-density lipoprotein (LDL) particle and a specific apolipoprotein(a). The blood concentration of Lp(a) is approximately 90% genetically determined, and the main genetic factor determining Lp(a) levels is the size of the apo(a) isoform, which is determined by the number of KIV2 domain repeats. The size of the apo(a) isoform is inversely proportional to the blood concentration of Lp(a). Lp(a) is a strong and independent cardiovascular risk factor. Elevated Lp(a) levels ≥ 50 mg/dl (≥ 125 nmol/l) are estimated to occur in more than 1.5 billion people worldwide. However, determination of Lp(a) levels is performed far too rarely, including Poland, where, in fact, it is only since the 2021 guidelines of the Polish Lipid Association (PoLA) and five other scientific societies that Lp(a) measurements have begun to be performed. Determination of Lp(a) concentrations is not easy due to, among other things, the different sizes of the apo(a) isoforms; however, the currently available certified tests make it possible to distinguish between people with low and high cardiovascular risk with a high degree of precision. In 2022, the first guidelines for the management of patients with elevated lipoprotein(a) levels were published by the European Atherosclerosis Society (EAS) and the American Heart Association (AHA). The first Polish guidelines are the result of the work of experts from the two scientific societies and their aim is to provide clear, practical recommendations for the determination and management of elevated Lp(a) levels.
Lipid disorders, primarily hypercholesterolemia, are the most common cardiovascular (CV) risk factor in Poland (this applies even 3/4 of people). The low-density lipoprotein cholesterol (LDL-C) serum level is the basic lipid parameter that should be measured to determine CV risk and determines the aim and target of lipid-lowering treatment (LLT). Lipid-lowering treatment improves cardiovascular prognosis and prolongs life in both primary and secondary cardiovascular prevention. Despite the availability of effective lipid-lowering drugs and solid data on their beneficial effects, the level of LDL-C control is highly insufficient. This is related, among other things, to physician inertia and patients' fear of side effects. The development of lipidology has made drugs available with a good safety profile and enabling personalisation of therapy. Pitavastatin, the third most potent lipid-lowering statin, is characterised by a lower risk of muscle complications and new cases of diabetes due to its being metabolised differently. Thus, pitavastatin is a very good therapeutic option in patients at high risk of diabetes or with existing diabetes, and in patients at cardiovascular risk. This expert opinion paper attempts at recommendation on the place and possibility of using pitavastatin in the treatment of lipid disorders.
Dyslipidaemia is a modifiable risk factor commonly associated with diabetes mellitus and prediabetes, with a major impact on the early development of atherosclerotic cardiovascular disease. Various studies have tried to identify the key treatment targets, their optimal values according to patients' CV risk, and the most efficient yet safe therapeutic agents which, alongside lifestyle changes, would improve lipid levels and reduce cardiovascular mortality and morbidity. Currently, there are multiple pharmacologic options that can be used in the management of dyslipidaemia, such as statins, ezetimibe, bempedoic acid, PCSK9 inhibitors, n-3 polyunsaturated fatty acids or fibrates, to name only a few, while many other are under development. In the current setting of a continuously increasing population of patients with metabolic disorders, this review aims to summarise current knowledge regarding lipid disorders and the recommendations of recent guidelines in treating dyslipidaemia in patients with diabetes mellitus or prediabetes.
BACKGROUND: Patients with heterozygous familial hypercholesterolemia (HeFH) often cannot reach guideline-recommended low-density lipoprotein cholesterol (LDL-C) goals despite multidrug therapy. OBJECTIVE: To evaluate the efficacy and safety of bempedoic acid as an add-on therapy for lowering LDL-C in patients with HeFH. METHODS: Pooled data from two 52-week phase 3 clinical trials of patients with atherosclerotic cardiovascular disease and/or HeFH receiving maximally tolerated statin therapy (randomized 2:1 to bempedoic acid or placebo) were analyzed by HeFH status. Endpoints included changes from baseline to week 12 (and up to week 52) in LDL-C and other lipid parameters, achievement of LDL-C goals, and safety. RESULTS: A total of 217 (bempedoic acid, 146; placebo, 71) patients with HeFH and 2,792 (bempedoic acid, 1,864; placebo, 928) without HeFH were included (mean baseline LDL-C, 172.8 mg/dL and 102.6 mg/dL, respectively). Bempedoic acid significantly lowered LDL-C at week 12 vs. placebo regardless of HeFH status (with HeFH, -21.2%; without HeFH, -18.2% [both P<0.0001]). Bempedoic acid significantly reduced other lipid parameters and high-sensitivity C-reactive protein vs. placebo regardless of HeFH status (all P≤0.01). Among patients with HeFH treated with bempedoic acid, 32% and 27% achieved LDL-C <100 mg/dL at weeks 12 and 52, respectively. Overall treatment-emergent adverse event incidence was comparable across all four groups (74.7-77.5%). CONCLUSION: Bempedoic acid significantly lowered LDL-C levels vs. placebo and was generally well tolerated in all patients, with no new safety findings in patients with HeFH, despite more intensive lipid-lowering therapy in patients with vs. without HeFH.
Cholesterol, LDL , Dicarboxylic Acids , Fatty Acids , Heterozygote , Hyperlipoproteinemia Type II , Humans , Dicarboxylic Acids/therapeutic use , Dicarboxylic Acids/adverse effects , Hyperlipoproteinemia Type II/drug therapy , Male , Cholesterol, LDL/blood , Fatty Acids/therapeutic use , Fatty Acids/adverse effects , Middle Aged , Female , Adult , Treatment Outcome , Clinical Trials, Phase III as Topic , Aged
BACKGROUND: The long-terms outcomes of out of hospital cardiac arrest (OHCA) survivors are not well known. METHODS: Using the Myocardial Ischaemia National Audit Project (MINAP) registry, linked to Office for National Statistics (ONS) mortality data, we analysed 661 326 England, Wales and Northern-Ireland AMI patients; 14 127 (2%) suffered OHCA and survived beyond thirty-days of hospitalisation. Patients dying within thirty-days of admission were excluded. Mean follow-up for patients included was 1 500 days. Cox regression models were fitted, adjusting for demographics and management strategy. RESULTS: OHCA survivors were younger (in years) (64 (interquartile range [IQR] 54-72) vs. 70 (IQR 59-80), P < 0.001), more often underwent invasive coronary angiography (88% vs. 71%, P < 0.001) and percutaneous coronary intervention (72% vs. 45%, P < 0.001). Overall, risk of mortality for OHCA patients that survived past 30-days was lower than patients that did not suffer cardiac arrest (adjusted hazard ratio [HR] 0.91; 95% CI; 0.87-0.95, P < 0.001). 'Excellent care' according to the mean opportunity-based quality indicator (OBQI) score compared to 'Poor care', predicted reduced risk of long-term mortality post OHCA, for all-patients (HR: 0.77, CI; 0.76-0.78, P < 0.001), more for STEMI patients (HR: 0.73, CI; 0.71-0.75, P < 0.001), but less significantly in NSTEMI patients (HR: 0.79, CI; 0.78-0.81, P < 0.001). CONCLUSIONS: Out of hospital cardiac arrest (OHCA) patients remain at significant risk of mortality in-hospital. However, if surviving over thirty-days post arrest, OHCA survivors have good longer-term survival up to ten-years compared to the general AMI population. Higher quality inpatient care appears to improve long-term survival in all OHCA patients, more so in STEMI.
Red yeast rice (RYR) has a cholesterol-lowering effect due to the presence of bioactive components (monacolins, mainly monacolin K) that act by inhibiting the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. The European Food Safety Authority (EFSA) assessed the use of RYR and, while pointing out several uncertainties regarding the available data, raised a warning related to the safety of RYR when used as a food supplement at a dose of monacolin as low as 3 mg/day. In their decision in June 2023, EFSA approved the use of monacolins from RYR at doses less than 3 mg/day. We therefore decided to interrogate the different adverse event reporting systems (FAERS and CAERS) and analyse the characteristics of the cases reported to be associated with RYR supplements, and we reviewed the most recent meta-analyses with a focus on the occurrence of muscle symptoms and liver dysfunction. In terms of all musculoskeletal disorders from September 2013 (when the first case related to RYR consumption was recorded) to 30 September 2023, 363,879 cases were reported in the FAERS, with the number of cases related to RYR consumption being very small and accounting for 0.008% of cases. In the same time frame, 27,032 cases of hepatobiliary disorders were reported, and the cases attributable to RYR ingestion accounted for 0.01% of all cases. A low rate of muscle symptoms and liver dysfunction attributed to RYR ingestion was also observed in the CAERS database, where only 34 cases of adverse muscle events and 10 cases of adverse liver events reported RYR as the suspect product, while 19 cases of both muscle events and 10 cases of adverse liver events reported it as a concomitant product. This profile mirrors that of meta-analyses of randomised clinical trials of RYR, in which RYR use was not associated with either liver dysfunction or muscular adverse symptoms.
Biological Products , Liver Diseases , Humans , Lovastatin , Dietary Supplements/adverse effects , Dietary Supplements/analysis , Biological Products/adverse effects , Muscles/chemistry , Liver Diseases/epidemiology , Liver Diseases/etiology , Liver Diseases/drug therapy , Plant Extracts
PURPOSE OF REVIEW: Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of premature death. Lipid disorders, particularly elevated serum low-density lipoprotein cholesterol (LDL-C), contribute significantly to ASCVD. The risk of developing ASCVD is influenced by the duration of exposure to elevated LDL-C concentrations (cholesterol-years concept). Implementing lipid-lowering treatments based on the principles of "the earlier the better," "the lower the better," and "the longer the better" has been shown to reduce cardiovascular risk and significantly extend lifespan. Despite the availability of numerous lipid-lowering drugs, achieving satisfactory control of lipid disorders remains very challenging. Therefore, there is a need for novel approaches to improve treatment adherence. RECENT FINDINGS: One promising solution under investigation is the development of an anti-PCSK9 vaccine, which could be administered annually to provide long-term control over LDL-C concentrations. Experimental studies and the sole clinical trial conducted thus far have demonstrated that the anti-PCSK9 vaccine induces a durable immune response associated with lipid-lowering and anti-atherosclerotic effects. Furthermore, it has exhibited good tolerability and a satisfactory safety profile. However, we still need data from phase 2, 3, and cardiovascular outcome trial to confirm its safety and efficacy and add value in the armamentarium of available and perspective lipid-lowering drugs. This article highlights the significance of developing an anti-PCSK9 vaccine and provides an overview of the current knowledge on various anti-PCSK9 vaccines.
Anticholesteremic Agents , Atherosclerosis , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Vaccines , Humans , Cholesterol, LDL , Hypolipidemic Agents/therapeutic use , Atherosclerosis/drug therapy , Cholesterol , Proprotein Convertase 9 , Vaccines/therapeutic use , Anticholesteremic Agents/therapeutic use , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use
