Lipid-lowering Agents Research Articles

CD36 inhibition reduces non-small-cell lung cancer development through AKT-mTOR pathway

Lung cancer is the most common cause of cancer-related deaths worldwide and is caused by multiple factors, including high-fat diet (HFD). CD36, a fatty acid receptor, is closely associated with metabolism-related diseases, including cardiovascular disease and cancer. However, the role of CD36 in HFD-accelerated non-small-cell lung cancer (NSCLC) is unclear. In vivo, we fed C57BL/6J wild-type (WT) and CD36 knockout (CD36−/−) mice normal chow or HFD in the presence or absence of pitavastatin 2 weeks before subcutaneous injection of LLC1 cells. In vitro, A549 and NCI-H520 cells were treated with free fatty acids (FFAs) to mimic HFD situation for exploration the underlying mechanisms. We found that HFD promoted LLC1 tumor growth in vivo and that FFAs increased cell proliferation and migration in A549 and NCI-H520 cells. The enhanced cell or tumor growth was inhibited by the lipid-lowering agent pitavastatin, which reduced lipid accumulation. More importantly, we found that plasma soluble CD36 (sCD36) levels were higher in NSCLC patients than those in healthy ones. Compared to that in WT mice, the proliferation of LLC1 cells in CD36−/− mice was largely suppressed, which was further repressed by pitavastatin in HFD group. At the molecular level, we found that CD36 inhibition, either with pitavastatin or plasmid, reduced proliferation- and migration-related protein expression through the AKT/mTOR pathway. Taken together, we demonstrate that inhibition of CD36 expression by pitavastatin or other inhibitors may be a viable strategy for NSCLC treatment.Graphical abstract1) Pitavastatin reduces NSCLC progression by inhibiting CD36.2) Inhibition of CD36 can improve HFD- or FFA-induced NSCLC.3) AKT/mTOR pathway is involved in CD36-regulated NSCLC.4) Inhibition of CD36 by pitavastatin or other inhibitors may be a strategy for NSCLC treatment.

Correlation Of Lipid Profile and Das28 Score of Early Rheumatoid Arthritis Patients on Conventional Synthetic Dmards

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation and a higher risk of cardiovascular diseases. The relationship between RA disease activity, lipid profiles, and the impact of disease-modifying antirheumatic drugs (DMARDs) on these parameters is an area of ongoing research. Objective: This study aimed to investigate the correlation between lipid profiles and the Disease Activity Score in 28 joints (DAS-28) in patients with early RA who were on conventional synthetic DMARDs. Methods: In this cross-sectional study, 30 RA patients from a rheumatology department were enrolled over six months. The study included adults aged 30-70 years, of both genders, who had been on DMARDs for at least 6 months. Exclusion criteria included fracture of the affected joint, pregnancy, use of steroids or lipid-lowering agents, and heavy smoking. Data on demographics, disease duration, type of DMARDs, and lipid profiles were collected. The DAS-28 score was calculated for each patient. Statistical analysis was performed using SPSS Version 25, with Pearson’s Correlation coefficient used to measure relationships between variables. Results: The cohort consisted of 53.3% males and 46.7% females, with a mean age of 48.23 years. The majority (76.7%) were rheumatoid factor positive. The most commonly used DMARD was Methotrexate (46.7%). The study found strong negative correlations between DAS-28 scores and lipid levels: total cholesterol (Pearson's r = -0.837), triglycerides (r = -0.759), LDL (r = -0.720), and HDL (r = -0.689). BMI showed a significant positive correlation with DAS-28 (r = 0.711). A notable negative correlation was observed between the duration of DMARD use and DAS-28 scores (r = -0.777). Conclusion: The study indicates a significant correlation between lipid profiles and disease activity in RA patients on DMARDs. The findings suggest that effective RA management with DMARDs could influence lipid metabolism and potentially reduce cardiovascular risks. These insights are crucial for developing comprehensive RA treatment strategies that encompass both joint health and cardiovascular considerations.

Measuring Costs of Cardiovascular Disease Prevention for Patients with Familial Hypercholesterolemia in Administrative Claims Data.

Familial hypercholesterolemia is a common genetic condition that significantly increases an individual's risk of cardiovascular events such as heart attack, stroke, and cardiac death and is a candidate for population-wide screening programs. Economic analyses of strategies to identify and treat familial hypercholesterolemia are limited by a lack of real-world cost estimates for screening services and medications for reducing cardiovascular risk in this population. We estimated the cost of lipid panel testing in patients with hyperlipidemia and the cost of statins, ezetimibe, and PCKS9 inhibitors in patients with familial hypercholesterolemia from a commercial claims database and report costs and charges per panel and prescription by days' supply. The mean cost for a 90-day supply for statins was $183.33, 2.3 times the mean cost for a 30-day supply at $79.35. PCSK9 inhibitors generated the highest mean costs among medications used by patients with familial hypercholesterolemia. Lipid testing and lipid-lowering medications for cardiovascular disease prevention generate substantial real-world costs which can be used to improve cost-effectiveness models of familial hypercholesterolemia screening and care management.

A Narrative Review of Diabetic Macroangiopathy: From Molecular Mechanism to Therapeutic Approaches.

Diabetic macroangiopathy, a prevalent and severe complication of diabetes mellitus, significantly contributes to the increased morbidity and mortality rates among affected individuals. This complex disorder involves multifaceted molecular mechanisms that lead to the dysfunction and damage of large blood vessels, including atherosclerosis (AS) and peripheral arterial disease. Understanding the intricate pathways underlying the development and progression of diabetic macroangiopathy is crucial for the development of effective therapeutic interventions. This review aims to shed light on the molecular mechanism implicated in the pathogenesis of diabetic macroangiopathy. We delve into the intricate interplay of chronic inflammation, oxidative stress, endothelial dysfunction, and dysregulated angiogenesis, all of which contribute to the vascular complications observed in this disorder. By exploring the molecular mechanism involved in the disease we provide insight into potential therapeutic targets and strategies. Moreover, we discuss the current therapeutic approaches used for treating diabetic macroangiopathy, including glycemic control, lipid-lowering agents, and vascular interventions.

Top 5 Research Studies of the month for Italian Primary Care Physicians: January 2024.

This monthly article provides a collection of summaries of the most relevant studies identified as POEMs (patient-oriented evidence that matters) for Italian primary care physicians. 1) A recent high-quality systematic review (SR) of 76 SRs found that, compared to all other lipid-lowering medications, for overall, primary, and secondary prevention the best balance of benefits, harms, and costs is provided by statins. 2) To our surprise, a network meta-analysis of 12 randomized controlled trials (RCTs) concluded that acetaminophen and ketorolac were more effective than morphine in alleviating pain from renal colic and were less likely than morphine to cause adverse effects and the need for rescue analgesia. 3) Proton pump inbibitors (PPI) use in children is associated with an increased risk of developing serious infections as compared with the use other acid-suppressing therapy. It seems prudent to use antacids and histamine 2 receptor antagonists first and reserve PPIs for nonresponders. 4) Overdiagnosis - the identification of, in this case, breast cancer, that would not have caused symptoms in a person's lifetime - seems to increase with age. In a study including more than 50.000 women aged above 70 who underwent mammography screening, the overdiagnosis rate was 31%, 47% and 51% for women aged 70 to 74 years, 75 to 84 years and over age 85, respectively. 5) An RCT among community-dwelling adults conducted in the US found that using a regular cuff on larger-than-average arms can falsely raise blood pressure readings by almost 5 mmHg, and a regular cuff on an especially thin arm can lower readings by 3.6 mmHg.

Genetic association of lipid-lowering drugs with aortic aneurysms: a Mendelian randomization study.

The lack of effective pharmacotherapies for aortic aneurysms (AA) is a persistent clinical challenge. Lipid metabolism plays an essential role in AA. However, the impact of lipid-lowering drugs on AA remains controversial. The study aimed to investigate the genetic association between lipid-lowering drugs and AA. Our research used publicly available data on genome-wide association studies (GWASs) and expression quantitative trait loci (eQTL) studies. Genetic instruments, specifically eQTLs related to drug-target genes and SNPs (single nucleotide polymorphisms) located near or within the drug-target loci associated with low-density lipoprotein cholesterol (LDL-C), have been served as proxies for lipid-lowering medications. Drug-Target Mendelian Randomization (MR) study is used to determine the causal association between lipid-lowering drugs and different types of AA. The MR analysis revealed that higher expression of HMGCR (3-hydroxy-3-methylglutaryl coenzyme A reductase) was associated with increased risk of AA (OR = 1.58, 95% CI = 1.20-2.09, P = 1.20 × 10-03) and larger lumen size (aortic maximum area: OR = 1.28, 95% CI = 1.13-1.46, P = 1.48 × 10-04; aortic minimum area: OR = 1.26, 95% CI = 1.21-1.42, P = 1.78 × 10-04). PCSK9 (proprotein convertase subtilisin/kexin type 9) and CETP (cholesteryl ester transfer protein) show a suggestive relationship with AA (PCSK9: OR = 1.34, 95% CI = 1.10-1.63, P = 3.07 × 10-03; CETP: OR = 1.38, 95% CI = 1.06-1.80, P = 1.47 × 10-02). No evidence to support genetically mediated NPC1L1 (Niemann-Pick C1-Like 1) and LDLR (low-density lipoprotein cholesterol receptor) are associated with AA. This study provides causal evidence for the genetic association between lipid-lowering drugs and AA. Higher gene expression of HMGCR, PCSK9, and CETP increases AA risk. Furthermore, HMGCR inhibitors may link with smaller aortic lumen size.

Correlations between genetically predicted lipid-lowering drug targets and inflammatory bowel disease

BackgroundMillions of individuals globally suffer from Inflammatory bowel diseases (IBDs). There is a dearth of large population-based investigations on lipid metabolism and IBDs, and it is unclear whether lipid-lowering drugs target IBDs causally. Consequently, the aim of this study was to investigate the effects of lipid-lowering medication targets on the occurrence and progression of IBDs.MethodsAmong the more than 400,000 participants in the UK Biobank cohort and the more than 170,000 participants in the Global Lipids Genetics Consortium, a total of nine genes linked to lipid-lowering drug targets were obtained (ABCG5/ABCG8, APOB, APOC3, LDLR, LPL, HMGCR, NPC1L1, PCSK9, and PPARA). IBD data were acquired from de Lange et al. (patients/sample size of IBDs: 25042/59957; ulcerative colitis (UC): 12366/45,975; Crohn's disease (CD): 12194/40,266) and the FinnGen cohort (patients/total sample size of IBDs: 4420/176,899; CD: 1520/171,906; UC: 3325/173,711). All four datasets were cross-combined for validation via Mendelian randomization analysis, and potential mediating factors were explored via mediation analysis.ResultsGenetically proxied APOC3 inhibition was related to increased IBD risk (odds ratio (95% confidence interval): 0.87 (0.80–0.95); P < 0.01) and UC risk (0.83 (0.73–0.94); P < 0.01). IBD and CD risk were reduced by genetic mimicry of LDLR and LPL enhancements, respectively (odds ratioLDLR: 1.18 (1.03–1.36); P = 0.018; odds ratioCD: 1.26 (1.11–1.43); P = 2.60E-04). Genetically proxied HMGCR inhibition was associated with increased CD risk (0.68 (0.50–0.94); P = 0.018). These findings were confirmed through Mendelian analysis of the cross-combination of four separate datasets. APOC3-mediated triglyceride levels may contribute to IBDs partly through mediated triglycerides, Clostridium sensu stricto 1, Clostridiaceae 1, or the Lachnospiraceae FCS020 group. LDLR enhancement may contribute to IBDs partly through increasing Lactobacillaceae.ConclusionVigilance is required to prevent adverse effects on IBDs (UC) for patients receiving volanesorsen (an antisense oligonucleotide targeting ApoC3 mRNA) and adverse effects on CD for statin users. LPL and LDLR show promise as candidate drug targets for CD and IBD, respectively, with mechanisms that are potentially independent of their lipid-lowering effects.

Safety and efficacy of bempedoic acid among patients with statin intolerance and those without: A meta-analysis and a systematic randomized controlled trial review.

Bempedoic acid, an innovative oral medication, has garnered significant interest in recent times due to its potential as a therapeutic intervention for hypercholesterolemia. Nonetheless, the outcomes of the initial investigations might have been more definitive and coherent. Our objective was to perform a quantitative meta-analysis in order to evaluate bempedoic acid's safety and effectiveness. A search was conducted on ClinicalTrials.gov, and PubMed from the time of inception until September 28, 2023. Randomized controlled trials comparing the safety and efficacy of bempedoic acid among patients with statin intolerance and those without were included in our analysis. The trial outcomes were summarized using a random effects model and were provided as mean differences or odds ratios (ORs) with a confidence interval of 95%. Additionally, trial heterogeneity and the possibility of bias were evaluated and investigated. Bempedoic acid treatment reduced low-density lipoprotein cholesterol levels more than placebo (mean difference -2.97%, 95% CI -5.89% to -0.05%), according to a pooled analysis of 16 eligible trials. The risk of death (OR 1.18, 95% CI 0.70 to 1.98) and muscle-associated occurrences (OR 1.00, 95% CI 0.77 to 1.31) was not impacted by bempedoic acid. In contrast, discontinuation of treatment was more frequently caused by adverse events in the bempedoic acid group (OR 1.13, 95% CI 1.01 to 1.27). In patients with statin intolerance as well as those without, bempedoic acid is a safe and efficacious lipid-lowering agent, according to findings from randomized controlled trials.

In vitro and In vivo Assessment of the Effect of Okra Gum Solid Dispersion in Atorvastatin Solubility

Background: Atorvastatin is BCS class II drug; it is lipid-lowering medication. Okra gum (OKG), from the pods of Abelmoschus esculentus, is natural product contain polymers having advantages over synthetic ones as it is safe, chemically inert, nonirritant, biodegradable, and does not require toxicological studies. Aim: This study aimed to assess the effect of okra gum solid dispersion in atorvastatin solubility. Method: The gum was extracted by hot water extraction and the dry extract was evaluated for percentage practical yield, flow properties, pH values and FTIR spectroscopy. Then solid dispersions with different drug to polymer ratios were prepared from OKG, and hydroxy propyl methyl cellulose (HPMC) by solvent evaporation method. Saturation solubility was tested for the solid dispersions prepared, the physical mixtures and atorvastatin. Tablets were prepared from solid dispersions with the highest saturation solubility, then tablets were tested and evaluated. Finally, in vivo test was done using Swiss albino mice and data were analyzed using one way Anova test followed by T test. Results: The content percent of atorvastatin in the solid dispersion prepared were 99,9- 100.1%, the tablets showed satisfactory physicochemical properties as 1.29% RSD in tablet weight variation, 24 min disintegration time, 5.24±0.457 Hardness and OKGSD tablets showed sustained release manner and 87% of drug released in 6 hrs. Lipid profile results showed significant decrease in total cholesterol level with marked decrease in LDL when using OKGSD tablets. Conclusion: It was concluded that OKG is promising excipient that can be used in dosage forms formulation to enhance solubility of low soluble drugs.

The use of statins and inhibitors of proprotein convertase subtilisin-kexin type 9 (PCSK 9) in patients with dyslipidemia

Scientific relevance. According to the WHO data, cardiovascular diseases rank first as the cause of human death. In 2022, 18,601,923 people died from cardiovascular diseases, which amounted to 33 % of the total mortality in the world. Malignant neoplasms rank second with 9,958,133 deaths, representing 17.6 % of total mortality. Among cardiovascular diseases, ischemic heart disease (IHD), the pathogenesis of which is associated with impaired cholesterol and lipoprotein metabolism, is leading. The use of statin drugs is recommended as a first-line lipid-lowering therapy. As an alternative to HMG-CoA reductase inhibitors (statins), proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9) were discovered in 2003, however, they are less popular due to insuf ficient data on these drugs and their costliness. Purpose of the work: to study the safety of using proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in patients with dyslipidemia and compare the advantages and disadvantages in relation to the ef fects of HMG-CoA reductase (statins). Discussion: The analysis of literature data has shown that the most frequent manifestations of intolerance to statins are muscle symptoms. The main mechanisms of statin-associated complications are mediated by inhibition of HMG-CoA reductase, as well as by the effect of drugs on cellular and subcellular processes, skeletal muscles and genetic features of patients. PCSK9 inhibitors have a fundamentally different mechanism of action — they bind and inactivate PCSK9, which leads to a decrease of low-density lipoprotein cholesterol in the blood level. A small number of undesirable reactions have been identified for drugs of this group, the most important of which is immunogenicity. However, even if patients have antibodies to PCSK9 inhibitor, the efficacy of the drug in reducing the level of low-density lipoproteins remains high.Conclusion. In medical studies, PCSK9 inhibitors have been shown to perform better compared to HMG-CoA reductase inhibitors; meanwhile, patients continue to use statins as lipid-lowering medications.

The therapeutic potential of probucol and probucol analogues in neurodegenerative diseases.

Neurodegenerative disorders present complex pathologies characterized by various interconnected factors, including the aggregation of misfolded proteins, oxidative stress, neuroinflammation and compromised blood-brain barrier (BBB) integrity. Addressing such multifaceted pathways necessitates the development of multi-target therapeutic strategies. Emerging research indicates that probucol, a historic lipid-lowering medication, offers substantial potential in the realm of neurodegenerative disease prevention and treatment. Preclinical investigations have unveiled multifaceted cellular effects of probucol, showcasing its remarkable antioxidative and anti-inflammatory properties, its ability to fortify the BBB and its direct influence on neural preservation and adaptability. These diverse effects collectively translate into enhancements in both motor and cognitive functions. This review provides a comprehensive overview of recent findings highlighting the efficacy of probucol and probucol-related compounds in the context of various neurodegenerative conditions, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and cognitive impairment associated with diabetes.

The association between water intake and future cardiometabolic disease outcomes in the Malmö Diet and Cancer cardiovascular cohort.

The aim of this study was to explore the longitudinal association between reported baseline water intake and incidence of coronary artery disease (CAD) and type 2 diabetes in the Malmö Diet and Cancer Cohort (n = 25,369). Using cox proportional hazards models, we separately modelled the effect of plain and total (all water, including from food) water on CAD and type 2 diabetes risk, whilst adjusting for age, sex, diet collection method, season, smoking status, alcohol intake, physical activity, education level, energy intake, energy misreporting, body mass index, hypertension, lipid lowering medication, apolipoprotein A, apolipoprotein B, and dietary variables. Sensitivity analyses were run to assess validity. After adjustment, no association was found between tertiles of plain or total water intake and type 2 diabetes risk. For CAD, no association was found comparing moderate to low intake tertiles from plain or total water, however, risk of CAD increased by 12% (95% CI 1.03, 1.21) when comparing high to low intake tertiles of plain water, and by 17% (95% CI 1.07, 1.27) for high versus low tertiles of total water. Sensitivity analyses were largely in agreement. Overall, baseline water intake was not associated with future type 2 diabetes risk, whilst CAD risk was higher with higher water intakes. Our findings are discordant with prevailing literature suggesting higher water intakes should reduce cardiometabolic risk. These findings may be an artefact of limitations within the study, but future research is needed to understand if there is a causal underpinning.

Sex Differences in the Primary Prevention of Cardiovascular Diseases in a Dutch Primary Care Setting.

Sex differences in the primary prevention of cardiovascular diseases (CVD) have been shown, but the evidence is mixed and fragmented. In this study, we assessed sex differences in cardiovascular risk factors assessment, risk factor levels, treatment, and meeting of treatment targets, within a Dutch primary care setting. Data were obtained from individuals aged 40 to 70 years old, without prior CVD, registered during the entire year in 2018 at one of the 51 general practices participating in the Julius General Practitioner's Network (JGPN). History of CVD was defined based on the International Classification of Primary Care (ICPC). Linear and Poisson regressions were used to investigate sex differences in risk factor assessment, risk factor levels, treatment, and meeting of treatment targets. We included 83,903 individuals (50% women). With the exception of glycated hemoglobin (HbA1c), all risk factors for CVD were more often measured in women than in men. Lipid measurements and body mass index values were higher in women, while blood pressure (BP) and HbA1c levels were higher in men, along with estimated glomerular filtration rate (eGFR) levels. Among individuals with elevated BP or cholesterol levels, no sex difference was observed in the prescription of antihypertensive medications (RR 1.00, 95% CI: 0.94-1.06) but women were less likely than men to receive lipid-lowering medications (RR 0.87, 95% CI: 0.79-0.95). Among treated individuals, women were more likely than men to meet adequate levels of blood pressure (RR 1.17, 95% CI: 1.09-1.25) and less likely to meet target levels of cholesterol (RR 0.90, 95% CI: 0.83-0.98). While women were more likely to have their CVD risk factors measured, they were less likely to be prescribed lipid-lowering medications and to meet target levels. When treated, men were less likely to achieve adequate blood pressure control.

De-escalating treatment indications for patients who achieve metabolic goals

IntroductionRobust evidence exists regarding initiation, intensification or modification of treatments. Recommendations to de-escalate therapy are lacking, specifically in diabetes. A successful treatment de-intensification reduces overtreatment, polypharmacy, and risk of adverse effects. ObjectiveTo encompass current recommendations for deprescribing common drugs and create a consensus among health professionals. MethodsWe reviewed four databases for deprescribing approaches published between 2010 and 2022. Articles were divided into different groups of drugs (for uric-acid, hypoglycemic, lipid-lowering, and psychotropic drugs). ResultsHypoglycemic agents: strategies were limited to newer agents and insulin regimens for elderly individuals. Reducing insulin was associated with 1.1% reduction of A1c over time. SGLT2i and GLP-1RAs dose reduction depends on adverse events. Lipid-lowering agents: studies show that patients with very low cholesterol have fewer cardiovascular events without associated increased risk. Antihypertensive agents: Younger patients, lower systolic blood pressure, and few comorbidities are ideal characteristics for discontinuation. Uric acid therapy: we found no recommendation for dose de-escalation. Poor treatment adherence is associated with episodes of gout and deforming arthritis in the long term. ConclusionDeprescribing hypoglycemic, statins, antihypertensives, and urate-lowering agents may be feasible in selected patients, but periodic surveillance is important. More evidence is necessary to support this decision entirely.

Association of metformin use with abdominal aortic aneurysm: A systematic review and meta-analysis.

Abdominal aortic aneurysm (AAA) is a cardiovascular disease characterized by a high mortality rate when ruptured. Some studies suggest a potential inverse correlation between AAA and diabetes patients, especially those undergoing metformin treatment. However, this relationship remains unclear. This paper offers a systematic review and meta-analysis with the objective of clarifying the influence of metformin on AAA. A search for relevant articles was performed across multiple databases including PubMed, ScienceDirect, Cochrane and Scopus. The focus was on studies that examined the comparative effects of metformin and non-metformin treatments on AAA patients. Data from appropriate studies were consolidated to estimate the effects. Our study encompassed 11 articles, comprising 13 cohorts that compared metformin (n = 32,250) with a control group (n = 116,339). The random effects meta-analysis revealed that metformin was associated with a slower growth rate (weighted mean difference (WMD) -0.86 mm; 95% CI: -1.21 to -0.52; p < 0.01; I2: 81.4%) and fewer AAA-related events (OR: 0.54; 95% CI: 0.34 to 0.86; p = 0.01; I2: 60.9%). The findings suggest that metformin may be linked to a reduced risk of aortic aneurysm. A meta-regression analysis indicated that the association between metformin and AAA growth was significantly influenced by male gender (p = 0.027), but not by age (p = 0.801), hypertension (p = 0.256), DM (p = 0.689), smoking history (p = 0.786), use of lipid-lowering agents (p = 0.715), or baseline diameter (p = 0.291). These results hint at a potential role for metformin in limiting annual AAA growth, AAA-related events, and the risk of AAA.

Low Handgrip Strength (Possible Sarcopenia) With Insulin Resistance Is Associated With Type 2 Diabetes Mellitus.

Older adults with sarcopenic obesity are at high risk for type 2 diabetes mellitus (T2DM). However, few East Asians have sarcopenic obesity. Since many East Asians have insulin resistance (IR) without obesity, it is possible that older East Asians with sarcopenia and IR might be at high risk for T2DM. However, this relationship has not been studied. This cross-sectional study included 1629 older adults aged 65 to 84 years registered in the Bunkyo Health Study. All underwent a 75-g oral glucose tolerance test and handgrip strength measurement. Participants were classified into 4 groups by possible sarcopenia (handgrip strength <28 kg in men and <18 kg in women) and IR status (triglyceride glucose [TyG] index ≥8.79 for men and ≥8.62 for women [third quartile]). Modified Poisson regression was used to estimate relative risk (RR) and 95%CIs for T2DM with adjustment for confounding factors. The mean age was 73.1 ± 5.4 years. T2DM was diagnosed in 212 (13.0%) participants. After adjusting for age, sex, body mass index, use of lipid-lowering medications, hypertension, and cardiovascular disease, possible sarcopenia and IR were associated with T2DM, with their coexistence showing a notably stronger association (control: RR, 1.00 [Reference]; possible sarcopenia: RR, 1.55 [95% CI, 1.04-2.30]; IR: RR, 2.69 [95% CI, 1.99-3.65]; and IR possible sarcopenia: RR, 4.76 [95% CI, 3.34-6.79]). Possible sarcopenia based on low handgrip strength and IR based on the TyG index are independently associated with T2DM in older Japanese individuals. Their coexistence shows a particularly strong association with T2DM.

Unlocking the mysteries of VLDL: exploring its production, intracellular trafficking, and metabolism as therapeutic targets

Reducing circulating lipid levels is the centerpiece of strategies for preventing and treating atherosclerotic cardiovascular disease (ASCVD). Despite many available lipid-lowering medications, a substantial residual cardiovascular risk remains. Current clinical guidelines focus on plasma levels of low-density lipoprotein (LDL). Recent attention has been given to very low-density lipoprotein (VLDL), the precursor to LDL, and its role in the development of coronary atherosclerosis. Preclinical investigations have revealed that interventions targeting VLDL production or promoting VLDL metabolism, independent of the LDL receptor, can potentially decrease cholesterol levels and provide therapeutic benefits. Currently, methods, such as mipomersen, lomitapide, and ANGPTL3 inhibitors, are used to reduce plasma cholesterol and triglyceride levels by regulating the lipidation, secretion, and metabolism of VLDL. Targeting VLDL represents an avenue for new lipid-lowering strategies. Interventions aimed at reducing VLDL production or enhancing VLDL metabolism, independent of the LDL receptor, hold promise for lowering cholesterol levels and providing therapeutic benefits beyond LDL in the management of ASCVD.

PCSK-9 inhibitors: a new direction for the future treatment of ischemic stroke.

Ischemic stroke, the most prevalent and serious manifestation of cerebrovascular disease, is the main cause of neurological problems that require hospitalization, resulting in disability and death worldwide. Currently, clinical practice focuses on the effective management of blood lipids as a crucial approach to preventing and treating ischemic stroke. In recent years, a great breakthrough in ischemic stroke treatment has been witnessed with the emergence and use of a novel lipid-lowering medication, Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor. And its remarkable potential for reducing the occurrence of ischemic stroke is being acknowledged. This article aims to provide a comprehensive review, encompassing the association between PCSK9 and the heightened risk of ischemic stroke, the mechanisms, and the extensive evidence supporting the proven efficacy of PCSK9 inhibitors in clinical practice. Through this present study, we can gain deeper insights into the utilization and impact of PCSK9 inhibitors in treating ischemic stroke.

Genetically proxied therapeutic inhibition of lipid-lowering drug targets and risk of rheumatoid arthritis disease: a Mendelian randomization study.

To evaluate the potential impact of consistent use of similar treatments over a long period; it is essential to investigate the potential correlation between genetic variations that influence the expression or function of pharmacological targets for reducing lipid levels and the risk of developing rheumatoid arthritis. We used variants in the following genes to conduct Mendelian randomization analyses: HMGCR (encoding the target for statins), PCSK9 (encoding the target for PCSK9 inhibitors, such as evolocumab and alirocumab), and NPC1L1 (encoding the target for ezetimibe). Data from lipid genetics consortia (173,082 sample size) were used to weight variations according to their correlations with low-density lipoprotein cholesterol (LDL-C). In two large datasets (total n = 19,562 cases, 501,655 controls). We conducted a meta-analysis of Mendelian randomization estimates, weighted by LDL-C levels, on the regional differences in the risk of rheumatoid arthritis using data from two large databases. We approached SMR and IVW-MR analyses to examine the relationship between target gene expression (including HMGCR, PCSK9, and NPC1L1) and LDL-C levels mediated by these genes with RA. The IVW-MR analysis revealed no significant association between genetically predicted LDL-C concentration and the risk of RA (OR = 0.88, 95% CI = 0.59-1.29; OR = 0.91, 95% CI = 0.67-1.23; OR = 0.81, 95% CI = 0.49-1.36; all p > 0.05). Similarly, our findings from the SMR approach provided no evidence to suggest that gene expression of HMGCR, PCSK9, and NPC1L1 was associated with the risk of RA (OR = 0.91, 95% CI = 0.79-1.05, p = 0.207; OR = 0.96, 95% CI = 0.85-1.09, p = 0.493). Our results do not provide evidence to support the hypothesis that reducing LDL-C levels with statins, alirocumab, or ezetimibe effectively prevents the risk of developing RA. However, our study provides valuable insights into the assessment of lipid-lowering agents in RA, which can enhance our understanding of the condition and assist in clinical practice by aiding in the determination and monitoring of RA status to clinical response.

Aspirin for Primary Prevention of Cardiovascular Disease: What We Now Know

Cardiovascular disease (CVD), including coronary artery disease and stroke, is the leading cause of death worldwide. Advances in primary and secondary prevention of CVD have improved patient prognoses and outcomes, however, it is imperative that the clinician and patient engage in early risk factor screening and preventive management of modifiable risk factors for CVD. In addition to blood lipid and blood pressure lowering medications, aspirin has been a long-standing therapy targeted to the prevention of CVD based on its antiplatelet and anti-inflammatory activity. However, recent articles and reports on updates to clinical guidelines for the primary prevention of CVD have resulted in confusion about aspirin recommendations. This review aims to assess the latest guidance on aspirin in CVD prevention and how to identify appropriately at-risk patients who may benefit from low-dose aspirin therapy as part of their CVD preventive healthcare choices. Additionally, this review will provide practical application guidance about clinician-patient conversations to clearly explain the benefits and risks of aspirin use and ensure a patient-centric decision to initiate aspirin therapy.