Prevalence and associated factors of non-adherence to antihyperlipidemic medication: a nationwide cross sectional survey in Pakistan.

Hyperlipidemia significantly contributes to the risk of developing cardiovascular diseases. However, about half of the patients do not adhere to their antihyperlipidemic medications, leading to healthcare costs and premature mortality. This study's objective was to determine the prevalence and associated factors of non-adherence to antihyperlipidemic medications. The study covered hypertensive patients (21,451) aged 21-75 years, presenting to the primary and secondary healthcare facilities across Pakistan (covering 21 divisions) from January 2022 to April 2023. The outcome intended was non-adherence to antihyperlipidemic medication, which was assessed by SEAMS and pill-counting methods (non-adherence < 80%). The study found overall non-adherence to antihyperlipidemic medication of 60.6% across Pakistan, with the highest non-adherence rates found in Azad Jammu and Kashmir (71.9%) and the lowest in Islamabad (47.7%). Multivariable logistic regression analysis revealed that female, no health card (Sehat Sahulat Program government insurance), < 5 years of illness, < 5 daily medications, and dose frequency of twice daily revealed a positively significant association with non-adherence. While monthly income 51,000-100,000, graduation level of education, Muhajir, and hyperlipidemia with one comorbid condition had a significant negative association with the non-adherence. Antihyperlipidemic non-adherence is a multifaceted, multifactorial, profound problem requiring a multipronged approach.

Evaluation of Anti-Hyperlipidemic Activity of the Seeds Extracts of Ficus carica: In Vitro and In Silico Approaches.

Obesity and hyperlipidemia have become major disorders predominantly causing prevailing cardiovascular diseases and ultimately death. The prolonged use of anti-obesity drugs and statins for reducing obesity and blood lipid levels is leading toward adverse effects of kidneys and muscles, specifically rhabdomyolysis. The objective of this study is to evaluate potential of seeds of Ficus carica against hyperlipidemia. Various extracts and isolated compounds from fig seeds were analyzed and evaluated for their anti-hyperlipidemic potential. Methanol extract and its ethyl acetate fraction showed maximum pancreatic lipase inhibition of 61.93% and 86.45% in comparison to reference drug Orlistat. Four compounds isolated by HPLC-PDA technique were determined as Gallic acid, Catechin, Epicatechin, and Quercetin also showed strong potential to inhibit enzyme pancreatic lipase comparable to Orlistat. These isolated compounds were further analyzed for molecular docking and MM-GBSA studies. Three ligands, namely Quercetin, Epicatechin, and Catechin were found more effective against pancreatic lipase as these possessed docking scores (-9.881, -9.741, -9.410) higher to that of the reference ligand Orlistat (-5.273). The binding free energies of these compounds were -55.03, -56.54, and 60.35 kcal/mol, respectively. The results have shown that Quercetin has the highest binding affinity correlating with the highest inhibition of pancreatic lipase enzyme 1LPB. Hence, it is suggested that seeds of F. carica have promising anti-hyperlipidemic potential and foremost in reducing obesity.

Hypertriglyceridemia Therapy: Past, Present and Future Perspectives.

Hypertriglyceridemia therapy is essential for preventing cardiovascular diseases. Fibrates belong to an important class of lipid-lowering drugs useful for the management of dyslipidaemia. By acting on the peroxisome proliferator-activated receptor (PPAR)-α, these drugs lower serum triglyceride levels and raise high-density lipoprotein cholesterol. Fibrate monotherapy is associated with a risk of myopathy and this risk is enhanced when these agents are administered together with statins. However, whereas gemfibrozil can increase plasma concentrations of statins, fenofibrate has less influence on the pharmacokinetics of statins. Pemafibrate is a new PPAR-α-selective drug considered for therapy, and clinical trials are ongoing. Apart from this class of drugs, new therapies have emerged with different mechanisms of action to reduce triglycerides and the risk of cardiovascular diseases.

2024 KSoLA consensus on secondary dyslipidemia.

Elevated blood cholesterol and triglyceride levels induced by secondary causes are frequently observed. The identification and appropriate handling of these causes are essential for secondary dyslipidemia treatment. Major secondary causes of hypercholesterolemia and hypertriglyceridemia include an unhealthy diet, diseases and metabolic conditions affecting lipid levels, and therapeutic side effects. It is imperative to correct secondary causes prior to initiating conventional lipid-lowering therapy. Guideline-based lipid therapy can then be administered based on the subsequent lipid levels.

Cardiometabolic benefits of fenofibrate in heart failure related to obesity and diabetes.

BACKGROUND: Heart failure (HF) is a serious and common condition affecting millions of people worldwide, with obesity being a major cause of metabolic disorders such as diabetes and cardiovascular disease. This study aimed to investigate the effects of fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARα) agonist, on the obese- and diabetes-related cardiomyopathy. METHODS AND RESULTS: We used db/db mice and high fat diet-streptozotocin induced diabetic mice to investigate the underlying mechanisms of fenofibrate's beneficial effects on heart function. Fenofibrate reduced fibrosis, and lipid accumulation, and suppressed inflammatory and immunological responses in the heart via TNF signaling. In addition, we investigated the beneficial effects of fenofibrate on HF hospitalization. The Korean National Health Insurance database was used to identify 427,154 fenofibrate users and 427,154 non-users for comparison. During the 4.22-year follow-up, fenofibrate use significantly reduced the risk of HF hospitalization (hazard ratio, 0.907; 95% CI 0.824-0.998). CONCLUSIONS: The findings suggest that fenofibrate may be a useful therapeutic agent for obesity- and diabetes-related cardiomyopathy.

Causal effects of lipid-lowering drugs on inflammatory skin diseases: Evidence from drug target Mendelian randomisation.

Clinical research has revealed that inflammatory skin diseases are associated with dyslipidaemia. Modulating lipids is also a rising potential treatment option. However, there is heterogeneity in the existing evidence and a lack of large-scale clinical trials. Observational research is prone to bias, making it difficult to determine causality. This study aimed to evaluate the causal association between lipid-lowering drugs and inflammatory skin diseases. A drug target Mendelian randomisation (MR) analysis was conducted. Genetic targets of lipid-lowering drugs, including proprotein convertase subtilis kexin 9 (PCSK9) and 3-hydroxy-3-methylglutaryl-assisted enzyme A reductase (HMGCR) inhibitor, were screened. Common inflammatory skin diseases, including psoriasis, allergic urticaria, rosacea, atopic dermatitis, systemic sclerosis and seborrhoeic dermatitis, were considered as outcomes. Gene-predicted inhibition of PCSK9 was causally associated with a decreased risk of psoriasis (ORIVW [95%CI] = 0.600 [0.474-0.761], p = 2.48 × 10-5) and atopic dermatitis (ORIVW [95%CI] = 0.781 [0.633-0.964], p = 2.17 × 10-2). Gene-predicted inhibition of HMGCR decreased the risk of seborrhoeic dermatitis (ORIVW [95%CI] = 0.407 [0.168-0.984], p = 4.61 × 10-2) but increased the risk of allergic urticaria (ORIVW [95%CI] = 3.421 [1.374-8.520], p = 8.24 × 10-3) and rosacea (ORIVW [95%CI] = 3.132 [1.260-7.786], p = 1.40 × 10-2). Among all causal associations, only PCSK9 inhibition demonstrated a robust causal effect on psoriasis after a more rigorous Bonferroni test (p < 4.17 × 10-3, which is 0.05/12). Modulating lipids via PCSK9 inhibition may offer potential therapeutic targets for psoriasis and atopic dermatitis. Given the potential cutaneous side effects associated with HMGCR inhibitors, PCSK9 inhibitors could be considered viable alternatives in lipid-lowering medication.

Development and Evaluation of Solidified Supersaturated SNEDDS Loaded with Triple Combination Therapy for Metabolic Syndrome.

The present study aimed to develop and optimize solidified supersaturated self-nanoemulsifying drug delivery systems (SNEDDS) for the combined administration of antihypertensive, antihyperglycemic, and antihyperlipidemic drugs to enhance their solubility and dissolution during the treatment of metabolic syndrome. Various SNEDDS formulations were prepared and subjected to pharmaceutical assessment. The solubility of candesartan (CC), glibenclamide (GB), and rosuvastatin (RC) in SNEDDS and supersaturated SNEDDS formulations was evaluated. The optimized formulation was solidified using Syloid adsorbent at different ratios. Pharmaceutical characterization of the formulations included particle size, zeta potential, in-vitro dissolution, PXRD, FTIR, and SEM analysis. The prepared optimized formulation (F6) was able to form homogeneous nanoemulsion droplets without phase separation, which is composed of Tween 20: PEG-400: Capmul MCM (4: 3: 3). It was mixed with 5% PVP-K30 to prepare a supersaturated liquid SNEDDS formulation (F9). In addition, it was found that the addition of PVP-K30 significantly increased solubility CC and GB from 20.46 ± 0.48 and 6.73 ± 0.05 to 27.67 ± 1.72 and 9.45 ± 0.32 mg/g, respectively. In-vitro dissolution study revealed that liquid and solid SNEDD formulations remarkably improved the dissolution rates of CC, GB, and RC compared to pure drugs. XRPD and FTIR analysis revealed that all drugs present in an amorphous state within prepared solidified supersaturated SNEDDS formulation. SEM images showed that liquid SNEDDS formulation was successfully adsorbed on the surface of Syloid. Overall, optimized F9 and solidified supersaturated SNEDDS formulations showed superior performance in enhancing drug solubility and dissolution rate. The present study revealed that the proposed triple combination therapy of metabolic syndrome holds a promising strategy during the treatment of metabolic syndrome. Further in-vivo studies are required to evaluate the therapeutic efficacy of prepared solidified supersaturated SNEDDS formulation.

Fenofibrate to prevent amputation and reduce vascular complications in patients with diabetes: FENO-PREVENT.

BACKGROUND: The potential preventive effect of fenofibrate on lower extremity amputation (LEA) and peripheral arterial disease (PAD) in patients with type 2 diabetes (T2D) is not fully elucidated. METHODS: We selected adult patients ≥ 20 years of age with T2D from the Korean National Health Insurance Service Database (2009-2012). The fenofibrate users were matched in a 1:4 ratio with non-users using propensity scores (PS). The outcome variables were a composite of LEA and PAD and the individual components. The risks of outcomes were implemented as hazard ratio (HR) with 95% confidence intervals (CI). For safety issues, the risks of acute kidney injury, rhabdomyolysis and resulting hospitalization were analyzed. RESULTS: A total of 114,920 patients was included in the analysis with a median follow-up duration of 7.6 years (22,984 and 91,936 patients for the fenofibrate user and non-user groups, respectively). After PS matching, both groups were well balanced. The fenofibrate group was associated with significantly lower risks of composite outcome of LEA and PAD (HR 0.81; 95% CI 0.70-0.94), LEA (HR 0.76; 95% CI 0.60-0.96), and PAD (HR 0.81; 95% CI 0.68-0.96). The risk of acute kidney injury, rhabdomyolysis, or hospitalization for these events showed no significant difference between the two groups. Subgroup analyses revealed consistent benefits across age groups, genders, and baseline lipid profiles. CONCLUSIONS: This nationwide population-based retrospective observational study suggests that fenofibrate can prevent LEA and PAD in patients with T2D who are on statin therapy.

Youth-derived Lactobacillus rhamnosus with prebiotic xylo-oligosaccharide exhibits anti-hyperlipidemic effects as a novel synbiotic.

Changes in dietary patterns and living habits have led to an increasing number of individuals with elevated cholesterol levels. Excessive consumption of high-cholesterol foods can disrupt the body's lipid metabolism. Numerous studies have firmly established the cholesterol-lowering effects of probiotics and prebiotics, with evidence showing that the synergistic use of synbiotics is functionally more potent than using probiotics or prebiotics alone. Currently, the screening strategy involves screening prebiotics for synbiotic development with probiotics as the core. However, in comparison to probiotics, there are fewer types of prebiotics available, leading to limited resources. Consequently, the combinations of synbiotics obtained are restricted, and probiotics and prebiotics are only relatively suitable. Therefore, in this study, a novel synbiotic screening strategy with prebiotics as the core was developed. The synbiotic combination of Lactobacillus rhamnosus S_82 and xylo-oligosaccharides was screened from the intestinal tract of young people through five generations of xylo-oligosaccharides. Subsequently, the cholesterol-lowering ability of the medium was simulated, and the two carbon sources of glucose and xylo-oligosaccharides were screened out. The results showed that synbiotics may participate in cholesterol-lowering regulation by down-regulating the expression of NPC1L1 gene, down-regulating ACAT2 and increasing the expression of ABCG8 gene in vitro through cell adsorption and cell absorption in vitro, and regulating the intestinal microbiota. Synbiotics hold promise as potential candidates for the prevention of hypercholesterolemia in humans and animals, and this study providing a theoretical foundation for the development of new synbiotic products.

Effective enhancement of the ability of Monascus pilosus to produce lipid-lowering compound Monacolin K via perturbation of metabolic flux and histone acetylation modification.

Monacolin K (MK), also known as lovastatin, is a polyketide compound with the ability to reduce plasma cholesterol levels and many other bio-activities. Red yeast rice (also named Hongqu) rich in MK derived from Monascus fermentation has attracted widespread attention due to its excellent performance in reducing blood lipids. However, industrial Monascus fermentation suffers from the limitations such as low yield of MK, long fermentation period, and susceptibility to contamination. In this study, we firstly blocked the competitive pathway of MK biosynthesis to create polyketide synthase gene pigA (the key gene responsible for the biosynthesis of Monascus azaphilone pigments) deficient strain A1. Then, based on the strategies to increase precursor supply for MK biosynthesis, acetyl-CoA carboxylase gene acc overexpression strains C1 and C2 were constructed with WT and A1 as the parent, respectively. Finally, histone deacetylase gene hos2 overexpression strain H1 was constructed by perturbation of histone acetylation modification. HPLC detection revealed all these four strains significantly increased their abilities to produce MK. After 14 days of solid-state fermentation, the MK yields of strains A1, C1, C2, and H1 reached 2.03 g/100 g, 1.81 g/100 g, 2.45 g/100 g and 2.52 g/100 g, which increased by 28.5 %, 14.7 %, 43.9 % and 36.1 % compared to WT, respectively. RT-qPCR results showed that overexpression of hos2 significantly increased the expression level of almost all genes responsible for MK biosynthesis after 5-day growth. Overall, the abilities of these strains to produce MK has been greatly improved, and MK production period has been shortened to 14 days from 20 days, providing new approaches for efficient production of Hongqu rich in MK.

Innovative Applications of Pectin in Lipid Management: Mechanisms, Modifications, Synergies, Nanocarrier Systems, and Safety Considerations.

Pectin, a natural polysaccharide predominantly sourced from the cell walls of terrestrial plants, is widely regarded for its gelling, thickening, and stabilizing properties, which have extensive applications in the food, pharmaceutical, and biotechnological industries. This review discusses the mechanistic pathways by which pectin mediates its lipid-lowering properties, such as pectin's antioxidant activity, the modulation of gut microbiota, its anti-inflammatory properties, its capacity to bind bile acids and cholesterol, and its impact on the expression of genes associated with lipid metabolism. To enhance its hypolipidemic properties, chemical, physical, and enzymatic modification techniques are explored. Additionally, the synergistic effects of pectin in combination with other bioactive compounds such as phytosterols and polyphenols, as well as its potential in nanocarrier-mediated delivery systems for lipid-lowering agents, are highlighted. The review also conducts a critical analysis of the safety and regulatory considerations associated with pectin use, emphasizing the necessity for comprehensive toxicological evaluations and adherence to regulatory standards. This paper underscores the growing potential of pectin not only as a dietary fiber but also as a multifaceted agent for ameliorating hyperlipidemia, catalyzing a shift toward more targeted and efficacious lipid-lowering strategies.

Characteristics of Patients With Atherosclerotic Cardiovascular Disease in Belgium and Current Treatment Patterns for the Management of Elevated LDL-C Levels.

BACKGROUND: Dyslipidemia remains the major cause of atherosclerotic cardiovascular disease (ASCVD). Lipid management in patients with increased cardiovascular (CV) risk needs improvement across Europe, and data gaps are noticeable at the country level. HYPOTHESIS: We described the current treatment landscape in Belgium, hypothesizing that lipid management in patients with ASCVD remains inadequate and aiming to understand the reasons. METHODS: Using data from an anonymized primary care database in Belgium derived from 494 750 individuals, we identified those with any CV risk factor between November 2019 and October 2022 and described the clinical features of patients with ASCVD. The main outcomes were the proportion of patients (i) receiving lipid-lowering therapies (LLTs), (ii) per low-density lipoprotein cholesterol (LDL-C) threshold, stratified per LLT, (iii) reaching the 2021 ESC recommended LDL-C goals, and (iv) LDL-C reduction per type of LLT was also determined. RESULTS: Among 40 888 patients with very high CV risk, 24 859 had established ASCVD. Most patients with ASCVD were either receiving monotherapy (59.6%) or had no documented LLT (25.1%). Further, 64.2% of those with no documented LLT exhibited LDL-C levels ≥ 100 mg/dL. Among common treatment options, one of the greatest improvements in LDL-C levels was achieved with combination therapy of statin and ezetimibe, reducing LDL-C levels by 41.5% (p < 0.0001). Yet, in this group, 24.8% of patients had still LDL-C levels ≥ 100 mg/dL and only 20.7% were at goal. CONCLUSION: Our study emphasizes the importance of developing strategies to help patients achieve their LDL-C goals, with a focus on supporting the implementation of combination LLT in routine clinical practice.

Traditional Chinese medicine and plant-derived natural products in regulating triglyceride metabolism: Mechanisms and therapeutic potential.

The incidence of cardiometabolic disease is increasing globally, with a trend toward younger age of onset. Among these, atherosclerotic cardiovascular disease is a leading cause of mortality worldwide. Despite the efficacy of traditional lipid-lowering drugs, such as statins, in reducing low-density lipoprotein cholesterol levels, a significant residual risk of cardiovascular events remains, which is closely related to unmet triglyceride (TG) targets. The clinical application of current TG-lowering Western medicines has certain limitations, necessitating alternative or complementary therapeutic strategies. Traditional Chinese medicine (TCM) and plant-derived natural products, known for their safety owing to their natural origins and diverse biological activities, offer promising avenues for TG regulation with potentially fewer side effects. This review systematically summarises the mechanisms of TG metabolism and subsequently reviews the regulatory effects of TCM and plant-derived natural products on TG metabolism, including the inhibition of TG synthesis (via endogenous and exogenous pathways), promotion of TG catabolism, regulation of fatty acid absorption and transport, enhancement of lipophagy, modulation of the gut microbiota, and other mechanisms. In conclusion, through a comprehensive analysis of recent studies, this review consolidates the multifaceted regulatory roles of TCM and plant-derived natural products in TG metabolism and elucidates their potential as safer, multi-target therapeutic agents in managing hypertriglyceridemia and mitigating cardiovascular risk, thereby providing a basis for new drug development.

Treating Hypercholesterolemia in Older Adults for Primary Prevention of Cardiovascular Events.

As the population ages, the demographic of adults aged 75 years and older in the U.S. is projected to grow to 45 million by 2050. Hypercholesterolemia is directly linked to atherosclerotic cardiovascular disease (ASCVD), which remains the leading cause of death in older adults. However, primary prevention of ASCVD through lipid-lowering agents remains unclear among older adults owing to limited involvement of older adults in current trials, lack of dedicated trials, and evidence primarily derived from secondary and retrospective analyses. Therefore, this article aims to (1) review key updates from the latest guidelines on treatment of hypercholesterolemia in older adults, (2) highlight limitations of the current ASCVD risk scores in the geriatric population, (3) present outcomes from key studies on the use of lipid-lowering agents and associated side effects, including a brief review of novel agents such as bempedoic acid, although very few adults over age 75 were included in these trial, and (4) finally, highlight upcoming dedicated trials of statins in older adults for the primary prevention of important geriatric outcomes as well as ASCVD.

Exploring the causal effect between lipid-modifying drugs and idiopathic pulmonary fibrosis: a drug-target Mendelian randomization study.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a respiratory disorder of obscure etiology and limited treatment options, possibly linked to dysregulation in lipid metabolism. While several observational studies suggest that lipid-lowering agents may decrease the risk of IPF, the evidence is inconsistent. The present Mendelian randomization (MR) study aims to determine the association between circulating lipid traits and IPF and to assess the potential influence of lipid-modifying medications for IPF. METHODS: Summary statistics of 5 lipid traits (high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglyceride, apolipoprotein A, and apolipoprotein B) and IPF were sourced from the UK Biobank and FinnGen Project Round 10. The study's focus on lipid-regulatory genes encompassed PCSK9, NPC1L1, ABCG5, ABCG8, HMGCR, APOB, LDLR, CETP, ANGPTL3, APOC3, LPL, and PPARA. The primary effect estimates were determined using the inverse-variance-weighted method, with additional analyses employing the contamination mixture method, robust adjusted profile score, the weighted median, weighted mode methods, and MR-Egger. Summary-data-based Mendelian randomization (SMR) was used to confirm significant lipid-modifying drug targets, leveraging data on expressed quantitative trait loci in relevant tissues. Sensitivity analyses included assessments of heterogeneity, horizontal pleiotropy, and leave-one-out methods. RESULTS: There was no significant effect of blood lipid traits on IPF risk (all P＞0.05). Drug-target MR analysis indicated that genetic mimicry for inhibitor of NPC1L1, PCSK9, ABCG5, ABCG8, and APOC3 were associated with increased IPF risks, with odds ratios (ORs) and 95% confidence intervals (CIs) as follows: 2.74 (1.05-7.12, P = 0.039), 1.36 (1.02-1.82, P = 0.037), 1.66 (1.12-2.45, P = 0.011), 1.68 (1.14-2.48, P = 0.009), and 1.42 (1.20-1.67, P = 3.17×10-5), respectively. The SMR method identified a significant association between PCSK9 gene expression in whole blood and reduced IPF risk (OR = 0.71, 95% CI: 0.50-0.99, P = 0.043). Sensitivity analyses showed no evidence of bias. CONCLUSIONS: Serum lipid traits did not significantly affect the risk of idiopathic pulmonary fibrosis. Drug targets MR studies examining 12 lipid-modifying drugs indicated that PCSK9 inhibitors could dramatically increase IPF risk, a mechanism that may differ from their lipid-lowering actions and thus warrants further investigation.

The potential of Myrmecodia pendans in preventing complications of diabetes mellitus as an antidiabetic and antihyperlipidemic agent.

Background: Hyperglycemia in diabetes mellitus (DM) can lead to dyslipidemia, which is a risk factor for macrovascular complications such as heart disease and stroke. Aside from administering antidiabetic medications, DM treatment can also be achieved through the use of natural components, such as Myrmecodia pendans, commonly known as the ant nest plant (ANP). Aim: This study aimed to investigate the impact of administering the ANP on the lipid profile of Wistar rats. Methods: A group of 20 rats was divided into two categories: 6 rats served as healthy controls (H), while the remaining 14 rats were subjected to a high-lipid diet and streptozotocin to generate a model of type 2 diabetes mellitus (T2DM). The diabetic rats were divided into two groups: the DM group consisted of rats that did not receive any treatment, while the ANP group was administered the herb orally. Results: The results revealed significant variations in triglyceride, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) levels among the three groups (p < 0.05). The post hoc test revealed disparities in triglyceride and LDL between those in the DM group and the ANP group (p < 0.05). Conclusion: Myrmecodia pendans demonstrated the ability to decrease triglyceride and LDL, while increasing HDL levels in rats with T2DM.

Lipids, lipid-modified drug target genes, and the risk of male infertility: a Mendelian randomization study.

Background: Previous observational studies have reported a possible association between circulating lipids and lipid-lowering drugs and male infertility (MIF), as well as the mediating role of circulating vitamin D. Then, due to issues such as bias, reverse causality, and residual confounding, inferring causal relationships from these studies may be challenging. Therefore, this study aims to explore the effects of circulating lipids and lipid-lowering drugs on MIF through Mendelian randomization (MR) analysis and evaluate the mediating role of vitamin D. Method: Genetic variations related to lipid traits and the lipid-lowering effect of lipid modification targets are extracted from the Global Alliance for Lipid Genetics Genome-Wide Association Study. The summary statistics for MIF are from the FinnGen 9th edition. Using quantitative expression feature loci data from relevant organizations to obtain genetic variations related to gene expression level, further to explore the relationship between these target gene expression levels and MIF risk. Two-step MR analysis is used to explore the mediating role of vitamin D. Multiple sensitivity analysis methods (co-localization analysis, Egger intercept test, Cochrane's Q test, pleiotropy residuals and outliers (MR-PRESSO), and the leave-one-out method) are used to demonstrate the reliability of our results. Result: In our study, we observed that lipid modification of four lipid-lowering drug targets was associated with MIF risk, the LDLR activator (equivalent to a 1-SD decrease in LDL-C) (OR=1.94, 95% CI 1.14-3.28, FDR=0.040), LPL activator (equivalent to a 1-SD decrease in TG) (OR=1.86, 95% CI 1.25-2.76, FDR=0.022), and CETP inhibitor (equivalent to a 1-SD increase in HDL-C) (OR=1.28, 95% CI 1.07-1.53, FDR=0.035) were associated with a higher risk of MIF. The HMGCR inhibitor (equivalent to a 1-SD decrease in LDL-C) was associated with a lower risk of MIF (OR=0.38, 95% CI 0.17-0.83, FDR=0.39). Lipid-modifying effects of three targets were partially mediated by serum vitamin D levels. Mediation was 0.035 (LDLR activator), 0.012 (LPL activator), and 0.030 (CETP inhibitor), with mediation ratios of 5.34% (LDLR activator), 1.94% (LPL activator), and 12.2% (CETP inhibitor), respectively. In addition, there was no evidence that lipid properties and lipid modification effects of six other lipid-lowering drug targets were associated with MIF risk. Multiple sensitivity analysis methods revealed insignificant evidence of bias arising from pleiotropy or genetic confounding. Conclusion: This study did not support lipid traits (LDL-C, HDL-C, TG, Apo-A1, and Apo-B) as pathogenic risk factors for MIF. It emphasized that LPL, LDLR, CETP, and HMGCR were promising drug targets for improving male fertility.

Virgin Coconut Oil-based Nanostructured Lipid Carrier Improves the Hypolipidemic Effect of Rosuvastatin.

Background: Monitoring noncommunicable diseases is regarded as a critical concern that has to be managed in order to avoid a wide variety of complications such as increasing blood lipid levels known as dyslipidemia. Statin drugs, mostly, Rosuvastatin (RSV) was investigated for its effectiveness in treating dyslipidemia. However, reaching the most efficient treatment is essential and improving the effect of RSV is crucial. Therefore, a combination therapy was a good approach for achieving significant benefit. Although RSV is hydrophobic, which would affect its absorption and bioavailability following oral administration, overcoming this obstacle was important. Purpose: To that end, the purpose of the present investigation was to incorporate RSV into certain lipid-based nanocarriers, namely, nanostructured lipid carrier (NLC) prepared with virgin coconut oil (CCO). Methods: The optimized RSV-NLC formula was selected, characterized and examined for its in vitro, kinetic, and stability profiles. Eventually, the formula was investigated for its in vivo hypolipidemic action. Results: The optimized NLC formulation showed a suitable particle size (279.3±5.03 nm) with PDI 0.237 and displayed good entrapment efficiency (75.6±1.9%). Regarding in vitro release, it was efficiently prolonged for 24 h providing 93.7±1.47%. The optimized formula was established to be stable after 3 months storage at two different conditions; 4°C and 25°C. Importantly, including CCO in the development of RSV-NLC could impressively enhance lowering total cholesterol level in obese rat models, which endorse the potential synergistic action between RSV and CCO. Conclusion: The study could elucidate the impact of developing NLC using CCO for improving RSV anti-hyperlipidemic activity.

Lipids, Apolipoproteins, Lipid-Lowering Drugs, and the Risk of Cerebral Small Vessel Disease: A Mendelian Randomization Study.

BACKGROUND: Serum lipids are causally involved in the occurrence of atherosclerosis, but their roles in cerebral small vessel disease remain unclear. This study aimed to investigate the causal roles of lipid or apolipoprotein traits in cerebral small vessel disease and to determine the effects of lipid-lowering interventions on this disease. METHODS AND RESULTS: Data on genetic instruments of lipids/apolipoproteins, as well as characteristic cerebral small vessel disease manifestations, including small vessel stroke (SVS) and white matter hyperintensity (WMH), were obtained from publicly genome-wide association studies. Through 2-sample Mendelian randomization analyses, it was found that decreased levels of high-density lipoprotein cholesterol (odds ratio [OR], 0.85, P=0.007) and apolipoprotein A-I (OR, 0.83, P=0.005), as well as increased level of triglycerides (OR, 1.16, P=0.025) were associated with a higher risk of SVS. A low level of high-density lipoprotein cholesterol (OR, 0.93, P=0.032) was associated with larger WMH volume. Specifically, the genetically determined expressions of lipid fractions in various size-defined lipoprotein particles were more closely related to the risk of SVS than WMH. Moreover, it was found that the hypertension trait ranked at the top in mediating the causal effect of hyperlipidemia on SVS and WMH by using Mendelian randomization-based mediation analysis. For drug-target Mendelian randomization, the low-density lipoprotein cholesterol-reducing genetic variation alleles at HMGCR and NL1CL1 genes and the high-density lipoprotein cholesterol-raising genetic variation alleles at the CETP gene were predicted to decrease the risk of SVS. CONCLUSIONS: The present Mendelian randomization study indicates that genetically determined hyperlipidemia is closely associated with a higher risk of cerebral small vessel disease, especially SVS. Lipid-lowering drugs could be potentially considered for the therapies and preventions of SVS rather than WMH.