Riesgo cardiovascular, dislipemias e indicación de estatinas en una población de obesos mórbidos

Introducción: La obesidad se relaciona con un riesgo cardiovascular (RCV) elevado. Esto nos obliga a tomar conductas terapéuticas y prevencionistas. El objetivo de este trabajo es evaluar el riesgo cardiovascular en una población de obesos mórbidos y valorar la correcta indicación de estatinas. Metodología: Estudio transversal, descriptivo, observacional, con la población obesos mórbidos del Programa de Obesidad y Cirugía Bariátrica (POCB) del Hospital Maciel, desde noviembre del 2014 a marzo del 2020. El RCV se valoró con la calculadora de la organización panamericana de la salud. La indicación de estatinas se consideró según RCV o diagnóstico de dislipemia. Resultados: Se analizaron 478 pacientes, el 84.3% fueron mujeres, la mediana para la edad fue de 44 años, y para el IMC 50 kg/m2. Se calculó un RCV bajo para el 57% de los pacientes; y alto o muy alto para un 37%. La prevalencia de las dislipemias fue 84,3%, a predominio de hipercolesterolemia (33,7%) y dislipemia aterogénica (19,5%). El 60.6% (290) de los pacientes presenta indicación de tratamiento con estatinas, solo el 38.9%. (113) las recibe. El 38.1% (43) alcanzan los objetivos terapéuticos. Conclusiones : La obesidad presenta múltiples comorbilidades que aumentan el RCV, aun así se encuentra subestimada por las calculadoras de riesgo. Queda en evidencia un infratratamiento farmacológico de estos pacientes, no logrando los objetivos terapéuticos propuestos.

Introduction: Obesity is related to a high cardiovascular risk (CVR). This forces us to take therapeutic and preventive behaviors. The objective of this work is to evaluate cardiovascular risk in a morbidly obese population and assess the correct indication of statins. Methodology: Cross-sectional, descriptive, observational study, with the morbidly obese population of the Obesity and Bariatric Surgery Program (POCB) of the Maciel Hospital, from November 2014 to March 2020. CVR was assessed with the calculator of the Pan-American health organization. The indication for statins was considered according to CVR or diagnosis of dyslipidemia. Results: 478 patients were analyzed, 84.3% were women, the median age was 44 years, and the BMI was 50 kg/m2. A low CVR was calculated for 57% of patients; and high or very high for 37%. The prevalence of dyslipidemia was 84.3%, with a predominance of hypercholesterolemia (33.7%) and atherogenic dyslipidemia (19.5%). 60.6% (290) of patients have an indication for treatment with statins, only 38.9%. (113) receives them. 38.1% (43) achieved therapeutic objectives. Conclusions: Obesity presents multiple comorbidities that increase CVR, yet it is underestimated by risk calculators. Pharmacological undertreatment of these patients is evident, not achieving the proposed therapeutic objectives.

Introdução : A obesidade está relacionada a um alto risco cardiovascular (RCV). Isso nos obriga a adotar comportamentos terapêuticos e preventivos. O objetivo deste trabalho é avaliar o risco cardiovascular em uma população com obesidade mórbida e avaliar a correta indicação de estatinas. Metodologia: Estudo transversal, descritivo, observacional, com a população com obesidade mórbida do Programa de Obesidade e Cirurgia Bariátrica (POCB) do Hospital Maciel, no período de novembro de 2014 a março de 2020. O RCV foi avaliado com a calculadora da organização pan-americana de saúde. A indicação de estatinas foi considerada de acordo com RCV ou diagnóstico de dislipidemia. Resultados: Foram analisados ​​478 pacientes, 84,3% eram mulheres, a mediana de idade foi de 44 anos e o IMC foi de 50 kg/m2. Um RCV baixo foi calculado para 57% dos pacientes; e alto ou muito alto para 37%. A prevalência de dislipidemia foi de 84,3%, com predomínio de hipercolesterolemia (33,7%) e dislipidemia aterogênica (19,5%). 60,6% (290) dos pacientes têm indicação de tratamento com estatinas, apenas 38,9%. (113) os recebe. 38,1% (43) alcançaram objetivos terapêuticos. Conclusões: A obesidade apresenta múltiplas comorbidades que aumentam o RCV, mas é subestimada pelas calculadoras de risco. É evidente o subtratamento farmacológico destes pacientes, não atingindo os objetivos terapêuticos propostos.

Association between 35 blood and urine biomarkers and oral leukoplakia: a two-sample Mendelian randomization study.

Background: Several existing studies have shown a correlation between some of the blood and urine biomarkers and oral leukoplakia (OLK). However, the causality of this relationship remains uncertain. Thus, this study aimed to examine the causal association between 35 blood and urine biomarkers and OLK. Methods: Single nucleotide polymorphisms (SNPs) associated with 35 blood and urine biomarkers were selected as instrumental variables (IVs) using a two-sample Mendelian randomization(MR) study to assess the causal relationship between the biomarkers and the risk of oral leukoplakia. We used the inverse variance weighted (IVW) method as the main analysis. Furthermore, several sensitivity analyses were performed to assess heterogeneity, horizontal pleiotropy, and stability. Results: Based on the selection criteria of the Inverse Variance Weighted (IVW) method, the analysis found that 5 blood and urine biomarkers were significantly associated with the development of leukoplakia, of which the results of IVW showed that abnormalities of Apolipoprotein B (Apo B), Cholesterol, Low-density Lipoprotein (LDL), Triglycerides (TG) promoted the development of oral leukoplakia, and Non Albumin Protein (NAP) had a protective effect on the development of oral leukoplakia. We then performed a Bonferroni correction for these results, and after correction Apo B was still causally associated with the development of oral leukoplakia (IVW P<0.0007), whereas the other four biomarkers could only provide some evidence of predisposition. Conclusion: Our two-sample Mendelian randomization study supports the existence of a causal relationship between these five blood and urine biomarkers and the occurrence of oral leukoplakia, and provides evidence for a number of risk and protective factors for the development of oral leukoplakia; however, the definitive mechanisms for the occurrence and development of oral leukoplakia still remain to be elucidated, and further studies on these relevant mechanisms are still needed.

Therapeutic Gene Editing in Dyslipidemias.

Dyslipidemia, characterized by abnormal lipid levels in the blood, significantly escalates the risk of atherosclerotic cardiovascular disease and requires effective treatment strategies. While existing therapies can be effective, long-term adherence is often challenging. There has been an interest in developing enduring and more efficient solutions. In this context, gene editing, particularly clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) technology, emerges as a groundbreaking approach, offering potential long-term control of dyslipidemia by directly modifying gene expression. This review delves into the mechanistic insights of various gene-editing tools. We comprehensively analyze various pre-clinical and clinical studies, evaluating the safety, efficacy, and therapeutic implications of gene editing in dyslipidemia management. Key genetic targets, such as low-density lipoprotein receptor (LDLR), proprotein convertase subtilisin/kexin type 9 (PCSK9), angiopoietin-like protein 3 (ANGPTL3), apolipoprotein C3 (APOC3), and lipoprotein (a) (Lp(a)), known for their pivotal roles in lipid metabolism, are scrutinized. The paper highlights the promising outcomes of gene editing in achieving sustained lipid homeostasis, discusses the challenges and ethical considerations in genome editing, and envisions the future of gene therapy in revolutionizing dyslipidemia treatment and cardiovascular risk reduction.

The mechanism of bile acid metabolism regulating lipid metabolism and inflammatory response in T2DM through the gut-liver axis.

Aims: The main objective of this study was to analyze the changes of intestinal microflora and how bile acid metabolic pathways affect lipid metabolism in T2DM through the gut-liver axis. Methods: Firstly, 16S rRNA sequencing, metabolomics and transcriptomic sequencing were performed on plasma and feces of clinical subjects to determine the changes of intestinal flora and its metabolites. Finally, T2DM mice model was verified in vivo. Results: T2DM patients have significant intestinal flora metabolism disorders. The differential fecal metabolites were mainly enriched in primary bile acid biosynthesis and cholesterol metabolism pathways in T2DM patients. After verification, the changes in gut microbiota and metabolites in T2DM patients (including up-regulated bacteria associated with BA metabolism, such as lactobacillus and bifidobacterial, and down-regulated bacteria capable of producing SCFAs such as Faecalibacterium, Bacteroides, Romboutsia and Roseburia); and the changes in the flora and metabolites that result in impairment of intestinal barrier function and changes of protein expression in the blood, intestine and liver of T2DM patients (including FGFR4↑, TRPM5↑ and CYP27A1↓, which are related to BA and lipid metabolism homeostasis, and TLR6↑, MYD88↑ and NF-κB↑, which are related to inflammatory response). These aspects together contribute to the development of further disorders of glucolipid metabolism and systemic inflammation in T2DM patients. Conclusions: Changes in intestinal flora and its metabolites may affect lipid metabolism and systemic inflammatory response in T2DM patients through the gut-liver axis mediated by bile acids.

Thymoquinone: A comprehensive review of its potential role as a monotherapy for metabolic syndrome.

Metabolic syndrome (MetS) is a widespread global epidemic that affects individuals across all age groups and presents a significant public health challenge. Comprising various cardio-metabolic risk factors, MetS contributes to morbidity and, when inadequately addressed, can lead to mortality. Current therapeutic approaches involve lifestyle changes and the prolonged use of pharmacological agents targeting the individual components of MetS, posing challenges related to cost, compliance with medications, and cumulative side effects. To overcome the challenges associated with these conventional treatments, herbal medicines and phytochemicals have been explored and proven to be holistic complements/alternatives in the management of MetS. Thymoquinone (TQ), a prominent bicyclic aromatic compound derived from Nigella sativa emerges as a promising candidate that has demonstrated beneficial effects in the treatment of the different components of MetS, with a good safety profile. For methodology, literature searches were conducted using PubMed and Google Scholar for relevant studies until December 2023. Using Boolean Operators, TQ and the individual components of MetS were queried against the databases. The retrieved articles were screened for eligibility. As a result, we provide a comprehensive overview of the anti-obesity, anti-dyslipidaemic, anti-hypertensive, and anti-diabetic effects of TQ including some underlying mechanisms of action such as modulating the expression of several metabolic target genes to promote metabolic health. The review advocates for a paradigm shift in MetS management, it contributes valuable insights into the multifaceted aspects of the application of TQ, fostering an understanding of its role in mitigating the global burden of MetS.

Effectiveness of conversional metabolic and bariatric surgery on dyslipidemia and the cost of lipid-lowering medications over 4 years: a French nationwide study.

BACKGROUND: The need for conversional metabolic and bariatric surgery (CMBS) is still growing. No large-scale prospective cohort studies have assessed changes in lipid-lowering treatment (LLT) after CMBS. OBJECTIVES: This study assesses and compares the effectiveness of the 4 main CMBS sequences after sleeve gastrectomy (SG) and adjustable gastric banding (AGB) on reimbursement and cost of LLT. SETTING: France. METHODS: This nationwide observational population-based cohort study analyzed data from the French National Health Insurance database. It included all patients who had undergone primary SG and AGB in France between January 1, 2012, and December 31, 2014, and followed until December 31, 2020. The study assessed LLT reimbursement evolution and costs across 4 different CMBS sequences. RESULTS: During follow-up, 6396 patients underwent the 4 CMBS sequences: SG-RYGB (Roux-en-Y gastric bypass) (n = 2400), AGB-SG (n = 2277), AGB-RYGB (n = 1173), and SG-SG (n = 546), with a rate of LLT reimbursement of 9.8%, 3.6%, 6.6%, and 7.9%, respectively, in the year before CMBS. The rates of discontinuation of treatment at 2 and 4 years were 41.9%, 35.4%, 45.6%, 20.5% and 45.6%, 31.3%, 64.3%, 31.6%, respectively. At 4 years, the median [interquartile range] annual costs (euros) per patient were significantly lower (P < .01) than the costs in the year before CMBS for each sequence: 86.8 [57.3; 136.1] versus 38.0 [.0; 64.6], 79.1 [50.5; 120.1] versus 50.4 [15.6; 64.1], 89.0 [66.5; 139.6] versus .0 [.0; 58.8], and 89.8 [66.1; 121.4] versus 63.1 [.0; 93.4]. CONCLUSIONS: Our study underlines the effectiveness of CMBS in significantly reducing the need and associated costs of LLT for patients with dyslipidemia over a 4-year period.

Increased oxidative stress biomarkers in central serous chorioretinopathy.

Current data suggest that oxidative stress may play an important role in the occurrence of acute central serous chorioretinopathy (CSC), as chorioretinal integrity may be affected by disruption of the patient's metabolic redox balance, indicating the need for biomarkers. In addition to oxidative stress, high-density lipoprotein (HDL) dysfunction due to dyslipidemia can also lead to many types of physical discomfort. However, little is known about the pathophysiology of the disease resulting from oxidative stress and HDL dysfunction in CSC. The aim of this study was to investigate whether serum oxidative stress and HDL functionality markers have an impact on CSC disease. The case series of this study included 33 consecutive patients with treatment-naïve acute CSC. Thirty-five healthy volunteers of similar age were included in this study as non-CSC controls. Serum samples of the participants were taken and routine lipid values, serum Total Antioxidant Status (TAS), Total Oxidant Status (TOS), Oxidized Low Density Lipoprotein (ox-LDL), and Paraoxonase (PON1) levels were measured quantitatively. Serum oxidative stress index (OSI) was then calculated. Serum Ox-LDL, TOS and OSI levels in the acute CSC group, consisting of patients who had never been treated before and had no other disease, were statistically significantly higher than the control group. Conversely, serum PON1 and TAS levels were lower in CSC than in the control group. The relationship between CSC and deterioration in serum redox balance and decrease in PON1 activity, an important marker of HDL functionality, was demonstrated for the first time through this study. According to the literature, serum levels of these biomarkers, which identify acute/chronic inflammation and oxidative stress, have not been measured before in CSC disease. Finally, it is conceivable that redox balance and HDL functionality may be important in the diagnosis and treatment of the acute phase of CSC.

Predictors of cardiovascular disease in individuals with dysbetalipoproteinemia: a prospective study in the UK Biobank.

BACKGROUND: Dysbetalipoproteinemia (DBL) is a disorder of remnant cholesterol metabolism associated with a severe risk of atherosclerotic cardiovascular disease (ASCVD). OBJECTIVE: The objective of this study was to investigate the univariate and multivariate predictors of ASCVD in individuals with DBL. METHODS: Data from 2,699 individuals with ε2/ε2 genotypes from the UK Biobank were included in this study. DBL was defined as having an ε2ε2 genotype with evidence of dyslipidemia, defined as total cholesterol ≥ 200 mg/dL [5.2 mmol/L] and TG ≥ 175 mg/dL [2.0 mmol/L]) or lipid-lowering therapy use (n=964). RESULTS: Age, hypertension, waist circumference and a polygenic risk score for coronary artery disease (PRSCAD) were independent predictors of ASCVD among individuals with DBL. Cumulative ASCVD-free survival was lower in the ε2/ε2 DBL group (84%) compared to the ε2/ε2 non-DBL group (94%) (p<0.0001), and for DBL individuals with a PRSCAD ≥ median (79%) compared to those with a PRSCAD < median (89%) (p=0.001). CONCLUSION: We show in a large prospective cohort that a PRSCAD predicts the ASCVD risk among individuals with DBL. The findings of the present study highlight the need for better risk stratification in ε2/ε2 carriers to identify high risk individuals that would need aggressive cardiovascular management despite their low apolipoprotein B value.

Association of remnant cholesterol with sarcopenia in Korean adults: a nationwide population-based study using data from the KNHANES.

Background: Mounting evidence indicates the importance of the interplay between skeletal muscles and lipid metabolism. Remnant cholesterol (remnant-C) is considered one of the principal residual risk factors for cardiovascular disease and metabolic disorders; however, there are limited studies on the impact of remnant-C on sarcopenia. Methods: Data from the Korea National Health and Nutrition Examination Surveys (KNHANES) between 2008 and 2011 were used in this nationwide population-based study. In total, 17,408 participants were enrolled in this study. The subjects were categorized into four groups according to the quartile of remnant-C values. We conducted multivariable logistic regression analysis to evaluate the association between remnant-C and muscle mass measured using dual-energy X-ray absorptiometry. Results: A total of 1,791 participants (10.3%) presented low muscle mass, and there was a sequential increase in the percentage of low muscle mass across remnant-C quartiles (Q1, 5.2%; Q2, 8.7%; Q3, 11.5%; Q4, 15.7%). In the full adjusted model, those in the highest remnant-C quartile group showed significantly increased odds ratio (OR) for low muscle mass compared with those in the lowest remnant-C group after adjusting for various confounding factors (OR = 1.33, 95% confidence interval (CI) = 1.06-1.68, P <0.05). A wide range of subgroups and sensitivity analyses showed consistent results, supporting the robustness of our findings. Conclusions: Increased remnant-C value was associated with a high risk of low muscle mass in the Korean population. Remnant-C may be a novel marker for the prediction and management of sarcopenia in aging societies.

Association between vitamin D deficiency and serum lipid levels in a group of Romanian patients.

Background and aims: Vitamin D deficiency is widespread across the globe. Numerous reports have linked vitamin D deficiency to certain non-skeletal diseases such as cardiovascular diseases. According to recent studies, there is evidence indicating a possible link between 25-hydroxyvitamin D deficiency and dyslipidemia. The main aim of this study is to investigate the relationship between vitamin D levels and lipid profile and to identify people who may benefit from vitamin D supplementation. Methods: In this observational study, a total of 154 patients were included, 98 women and 56 men, aged between 19 and 82 years, in which serum vitamin D levels, total cholesterol, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triglycerides (TG) and blood sugar were analyzed. Results: The serum levels of vitamin D showed some differences, being lower in patients with dyslipidemia, with a positive correlation between vitamin D levels and total cholesterol (F ratio = 7.3247, p=0.008), and also with LDL cholesterol (F ratio = 5.0023, p=0.027). The HDL-C fraction and triglycerides showed no significant correlation with the serum levels of vitamin D. Further on, we divided the patients according to the fraction that had pathological values and compared the levels of vitamin D between these categories. We observed that the lowest levels of vitamin D were present in patients with all lipid parameters modified (HIGH-TC/LOW-HDL/HIGH-LDL/HIGH-TG), and also the highest levels of low HDL-C and high LDL-C. Conclusion: Our research provides additional evidence to the unfavorable lipid profile found in people with vitamin D deficiency.

Isoflavones obtained from red clover improve both dyslipidemia and menopausal symptoms in menopausal women: a prospective randomized placebo-controlled trial.

OBJECTIVE: This study aimed to investigate the effects of red clover isoflavones on menopausal symptoms and the lipid profile in menopausal females. METHODS: This study included postmenopausal women with dyslipidemia. The red clover group (n = 39) received 40 mg isoflavone red clover capsule twice daily for 6 months, while placebo (n = 36) was 40 mg starch capsule twice daily. Data were collected at baseline, 3 months and 6 months. The Menopause Rating Scale (MRS) was applied to calculate subdimension and total scores. RESULTS: The two groups were similar in terms of age, MRS and lipid profile at baseline. In the red clover group, MRS scores decreased significantly at both 3 and 6 months. Similarly, total cholesterol, low-density lipoprotein cholesterol (LDL-C) and triglyceride levels decreased at both 3 months and 6 months. High-density lipoprotein cholesterol increased significantly from baseline to 3 months and 6 months. Except for LDL-C and MRS urogenital score at 3 months, the improvements were significantly in favor of red clover isoflavone treatment. CONCLUSIONS: Red clover treatment for 3-6 months demonstrated significant improvements in lipid profiles and menopausal symptoms. While promising, further research is crucial to ascertain long-term safety and recommend the use of red clover isoflavones during menopause.

Combined impact of elevated C-reactive protein levels and dyslipidemia on stroke: a CHNS prospective cohort study.

Background: The objective of this study was to examine whether the combination of elevated levels of C-reactive protein (CRP) and dyslipidemia increased the risk of stroke among middle-aged and older adult individuals in China. Methods: This study utilized longitudinal data from the China Health and Nutrition Survey (CHNS) collected in 2009, 2015, and 2018. A total of 8,023 participants aged ≥40 years (3,595 males and 4,428 females) were included. The Generalized Estimating Equation (GEE) method was employed to examine the association between inflammation, dyslipidemia, their combined effects, and stroke in the Chinese population. Results: A total of 174 stroke events occurred during follow-up. Compared with those with normal CRP levels (CRP ≤ 3 mg/L), the adjusted ORs and 95%CI were 2.13 (1.25, 3.64) for the female with elevated CRP level. Compared with those with non-dyslipidemia, the adjusted ORs and 95%CI were 1.56 (1.03, 2.37) for the individuals with high LDL cholesterol, 1.93 (1.12, 3.33) for the male with high LDL cholesterol. Compared with those with normal CRP levels and non-dyslipidemia, the adjusted ORs and 95%CI were 1.74 (1.08, 2.78) for the individuals with elevated CRP levels and dyslipidemia, 2.41 (1.29, 4.49) for the male with elevated CRP levels and dyslipidemia. People with the coexistence of elevated CRP levels and dyslipidemia had the highest risk of stroke among male. Conclusion: In females, higher levels of inflammation are associated with an increased incidence of stroke. In males, individuals with dyslipidemia characterized by high LDL cholesterol levels are more susceptible to stroke. In the general population, the joint effect of inflammation and dyslipidemia predisposes individuals to a higher risk of stroke, particularly among males.

Physician preferences for treatment of low-density lipoprotein cholesterol among patients with atherosclerotic cardiovascular disease (ASCVD)-A discrete choice experiment.

Objective: Approximately 80 % of patients with atherosclerotic cardiovascular disease (ASCVD) do not achieve the guideline-based target for low-density lipoprotein (LDL-C) levels in current clinical practice, particularly the 95 % of ASCVD patients receiving oral statin monotherapy. The objective was to determine physician prescribing preferences for LDL-C lowering therapies beyond statins for patients with ASCVD. Methods: A discrete choice experiment (DCE) survey was administered to cardiologists and primary care physicians in the United States, presenting a series of treatment choices systematically varied across 8 treatment attributes: % LDL-C reduction, myalgias, other side effects, route and frequency of administration, time to prior authorization, patient monthly out-of-pocket cost (mOOP), and adherence. Data were analyzed using logistic regression to estimate preference weights for each attribute. Results: A total of 200 cardiologists and 50 primary care physicians (PCPs) completed the survey. Both exhibited similar prescribing preferences, highly valuing efficacy in reducing LDL-C levels and minimization of patients OOP cost. Each additional 10 % reduction in LDL-C was associated with a 69 % relative increase in physician preference. By contrast, a 10 % relative decrease in preference was observed for each $10 additional monthly mOOP. Compared to PCPs, cardiologists tended to place more emphasis on LDL-C reduction, being more willing to accept higher mOOP or side effects. Although oral therapies were preferred, injectable therapies, like the PCSK9 siRNA-like drug, administered less frequently that allowed for greater LDL-C reduction were seen as having considerable utility, especially among patients with a history of medication nonadherence. Conclusion: These results document considerable preference similarities among cardiologist and PCP prescribers of LDL-C lowering therapies for ASCVD. Broad availability of several therapies with varying administration frequencies and product profiles are likely of great value to prescribing physicians aiming to achieve target LDL-C concentrations. Considering all aspects of treatment, most participants preferred a PCSK9 siRNA-like drug.

Relationship between the atherogenic index of plasma and the prevalence of kidney stones: insights from a population-based cross-sectional study.

OBJECTIVE: To investigate the association between atherogenic index of plasma (AIP) and kidney stones (KS) occurrence and recurrence. METHODS: Data were obtained from the National Health and Nutrition Examination Survey (NHANES) 2007-2014. Non-pregnant adults who provided complete information on AIP and KS were included in the analyses. AIP was calculated as log (triglyceride/high-density lipoprotein cholesterol). KS was ascertained with questionnaires. Weighted multivariable logistic regression model and restricted cubic spline (RCS) were applied to examine the associations between AIP and KS occurrence and recurrence. RESULTS: A total of 6488 subjects (weighted mean age 43.19 years and 49.26% male) with a weighted mean AIP of 0.66 were included in this study. The multivariable-adjusted OR for nephrolithiasis occurrence across consecutive tertiles was 1.00 (reference), 1.21 (95% CI: 0.90-1.62), and 1.85 (95% CI: 1.39-2.48), respectively. Moreover, each SD increment of AIP was associated with a 50% (OR:1.50, 95% CI: 1.25-1.81) higher risk of nephrolithiasis recurrence. RCSs showed significant and linear dose-response relationships between AIP and nephrolithiasis occurrence (p-overall = 0.006, p-nonlinear = 0.689) and recurrence (p-overall = 0.001, p-nonlinear = 0.848). The positive associations between AIP and nephrolithiasis occurrence and recurrence persisted in sensitivity analyses, suggesting the robustness of the results. CONCLUSION: In the current US nationally representative cross-sectional study, AIP was positively associated with KS occurrence and recurrence.

Genetic association of lipid traits and lipid-related drug targets with normal tension glaucoma: a Mendelian randomization study for predictive preventive and personalized medicine.

Background: Glaucoma is the leading cause of irreversible blindness worldwide. Normal tension glaucoma (NTG) is a distinct subtype characterized by intraocular pressures (IOP) within the normal range (< 21 mm Hg). Due to its insidious onset and optic nerve damage, patients often present with advanced conditions upon diagnosis. NTG poses an additional challenge as it is difficult to identify with normal IOP, complicating its prediction, prevention, and treatment. Observational studies suggest a potential association between NTG and abnormal lipid metabolism, yet conclusive evidence establishing a direct causal relationship is lacking. This study aims to explore the causal link between serum lipids and NTG, while identifying lipid-related therapeutic targets. From the perspective of predictive, preventive, and personalized medicine (PPPM), clarifying the role of dyslipidemia in the development of NTG could provide a new strategy for primary prediction, targeted prevention, and personalized treatment of the disease. Working hypothesis and methods: In our study, we hypothesized that individuals with dyslipidemia may be more susceptible to NTG due to a dysregulation of microvasculature in optic nerve head. To verify the working hypothesis, univariable Mendelian randomization (UVMR) and multivariable Mendelian randomization (MVMR) were utilized to estimate the causal effects of lipid traits on NTG. Drug target MR was used to explore possible target genes for NTG treatment. Genetic variants associated with lipid traits and variants of genes encoding seven lipid-related drug targets were extracted from the Global Lipids Genetics Consortium genome-wide association study (GWAS). GWAS data for NTG, primary open angle glaucoma (POAG), and suspected glaucoma (GLAUSUSP) were obtained from FinnGen Consortium. For apolipoproteins, we used summary statistics from a GWAS study by Kettunen et al. in 2016. For metabolic syndrome, summary statistics were extracted from UK Biobank participants. In the end, these findings could help identify individuals at risk of NTG by screening for lipid dyslipidemia, potentially leading to new targeted prevention and personalized treatment approaches. Results: Genetically assessed high-density cholesterol (HDL) was negatively associated with NTG risk (inverse-variance weighted [IVW] model: OR per SD change of HDL level = 0.64; 95% CI, 0.49-0.85; P = 1.84 × 10-3), and the causal effect was independent of apolipoproteins and metabolic syndrome (IVW model: OR = 0.29; 95% CI, 0.14-0.60; P = 0.001 adjusted by ApoB and ApoA1; OR = 0.70; 95% CI, 0.52-0.95; P = 0.023 adjusted by BMI, HTN, and T2DM). Triglyceride (TG) was positively associated with NTG risk (IVW model: OR = 1.62; 95% CI, 1.15-2.29; P = 6.31 × 10-3), and the causal effect was independent of metabolic syndrome (IVW model: OR = 1.66; 95% CI, 1.18-2.34; P = 0.003 adjusted by BMI, HTN, and T2DM), but not apolipoproteins (IVW model: OR = 1.71; 95% CI, 0.99-2.95; P = 0.050 adjusted by ApoB and ApoA1). Genetic mimicry of apolipoprotein B (APOB) enhancement was associated with lower NTG risks (IVW model: OR = 0.09; 95% CI, 0.03-0.26; P = 9.32 × 10-6). Conclusions: Our findings supported dyslipidemia as a predictive causal factor for NTG, independent of other factors such as metabolic comorbidities. Among seven lipid-related drug targets, APOB is a potential candidate drug target for preventing NTG. Personalized health profiles can be developed by integrating lipid metabolism with life styles, visual quality of life such as reading, driving, and walking. This comprehensive approach will aid in shifting from reactive medical services to PPPM in the management of NTG. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-024-00373-5.

Aggressive low-density lipoprotein (LDL) lowering for primary prevention: still an elusive goal.

Cardiovascular disease (CVD) is the leading cause of mortality globally. Low-density lipoprotein (LDL) plays an important role in CVD pathophysiology. Research has shown the safety and efficacy of keeping LDL at very low levels for CVD prevention. Therefore, experts recommend intense LDL-lowering approaches starting at young ages, promoting the mantras "the lower, the better" and "the earlier, the better." This commentary discusses the challenges regarding applying aggressive LDL-lowering approaches in the general population, including pharmacological efficacy and side effects, the cost-effectiveness of interventions, and patient adherence to treatment regimens.

Peripheral serotonin controls dietary fat absorption and chylomicron secretion via 5-HT4 receptor in males.

Postprandial dyslipidemia is commonly present in people with type II diabetes and obesity and is characterized by overproduction of apolipoproteinB48 (apoB48)-containing chylomicron particles from the intestine. Peripheral serotonin is emerging as a regulator of energy homeostasis with profound implications for obesity, however, its role in dietary fat absorption and chylomicron production is unknown. Chylomicron production was assessed in Syrian golden hamsters by administering an olive oil gavage and i.p. poloxamer to inhibit lipoprotein clearance. Administration of serotonin or selective serotonin reuptake inhibitor, fluoxetine, increased postprandial plasma triglyceride (TG) and TG-rich lipoproteins (TRLs). Conversely, inhibiting serotonin synthesis pharmacologically by p-chlorophenylalanine (PCPA) led to a reduction in both the size and number of TRL particles, resulting in lower plasma TG and apoB48 levels. The effects of PCPA occurred independently of gastric emptying and vagal afferent signaling. Inhibiting serotonin synthesis by PCPA led to increased TG within the intestinal lumen and elevated levels of TG and cholesterol in the stool when exposed to a high-fat/high-cholesterol diet. These findings imply compromised fat absorption, as evidenced by reduced lipase activity in the duodenum and lower levels of serum bile acids, which are indicative of intestinal bile acids. During the postprandial state, mRNA levels for serotonin receptors (5HTRs) were upregulated in the proximal intestine. Administration of cisapride, a 5HT4 receptor agonist, alleviated reductions in postprandial lipemia caused by serotonin synthesis inhibition, ind---icating that serotonin controls dietary fat absorption and chylomicron secretion via 5HT4 receptor.

Exploring the glycation association with dyslipidaemia: Novel approach for diabetic nephropathy.

The transcription factor known as sterol regulatory element-binding protein (SREBP) and the glycation pathways, specifically the formation of Advanced Glycation End Products (AGEs), have a significant and deleterious impact on the kidney. They alter renal lipid metabolism and promote glomerulosclerosis, mesangial cell expansion, tubulointerstitial fibrosis, and inflammation, leading to diabetic nephropathy (DN) progression. Although several pieces of scientific evidence are reported for potential causes of glycation and lipotoxicity in DN, the underlying mechanism of renal lipid accumulation still needs to be fully understood. We provide a rationalized view on how AGEs exert multiple effects that cause SREBP activation and inflammation, contributing to DN through Receptor for AGEs (RAGE) signaling, AGE-R1-dependent downregulation of Sirtuin 1 (SIRT-1), and increased SREBP Cleavage Activating Protein (SCAP) glycosylation. This review emphasizes the association between glycation and the SREBP pathway and how it affects the onset of DN associated with obesity. Finally, we discuss the correlation of glycation and the SREBP pathway with insulin resistance (IR), oxidative stress, endoplasmic reticulum stress, inflammation, and existing and emerging therapeutic approaches toward better controlling obesity-related DN.

Pharmacokinetics and Safety of Pemafibrate in Patients with both Dyslipidemia and Severe Renal Impairment: A Phase 4 Study.

AIMS: Per the package insert, pemafibrate was contraindicated for use in patients with severe renal impairment despite its biliary excretion. To validate this, we evaluated the pharmacokinetics and safety of pemafibrate for 12 weeks in patients with hypertriglyceridemia and renal impairment. METHODS: In this phase 4, multicenter, placebo-controlled, double-blind, parallel-group, comparative study, 21 patients were randomly assigned to pemafibrate 0.2 mg/day or placebo within Groups A (estimated glomerular filtration rate [eGFR] ＜30 mL/min/1.73m2 without hemodialysis; pemafibrate n=4; placebo, n=2), B (hemodialysis; pemafibrate, n=4; placebo, n=1), and C (eGFR ≥ 30 and ＜60 mL/min/1.73m2 without hemodialysis; pemafibrate, n=8; placebo, n=2) for 12 weeks. Area under the concentration vs time curve within the dosing interval (τ) (AUCτ) of pemafibrate was measured after 12-week administration. RESULTS: The AUCτ (geometric mean) of pemafibrate was 7.333 and 7.991 ng·h/mL in Groups A+B and C, respectively; in Groups A+B to C at 12 weeks, the geometric mean ratio of pemafibrate AUCτ was 0.92 (90% confidence interval [CI]: 0.62, 1.36). The upper limit of the 90% CI was ≤ 2.0 (predetermined criterion). There was no consistent trend in the AUCτ and maximum plasma concentration of pemafibrate with/without statin use. Renal impairment degree did not affect the incidence of adverse events. No safety concerns were observed. CONCLUSION: Pemafibrate repeated administration in patients with severe renal impairment did not increase pemafibrate exposure.

Glycemic Control and Cardiometabolic Risk in Black Zimbabweans with Type 2 Diabetes Mellitus.

Purpose: Type 2 diabetes mellitus (T2DM) frequently presents with modified cardiometabolic risk profiles, indicative of an elevated susceptibility to cardiovascular disease (CVD). Cardiometabolic risk factors such as obesity, hyperglycemia, hypertension, insulin resistance and dyslipidemia are known contributors to increased CVD hazard in individuals with T2DM. This study evaluated the glycemic control-based cardiometabolic risk profiles of black Zimbabweans with T2DM. Patients and Methods: A cross-sectional study of 116 T2DM patients recruited from diabetic clinics at Parirenyatwa and Sally Mugabe Hospitals, Harare, Zimbabwe, was conducted. Blood samples were collected for glycated hemoglobin (HbA1c) and lipid profile assessment. The Framingham risk scores (FRS) based on body mass index (BMI) and lipid profile were used to determine CVD risk. Parametric variables were analyzed using one-way analysis of variance (ANOVA) with post hoc Bonferroni correction, while non-parametric variables were compared using the Kruskal-Wallis test with post hoc Dunn test for multiple comparisons. Results: The overall frequency of dyslipidemia was 83.6% (n=97) and hypoalphalipoproteinemia was the most prevalent dyslipidemia (79.3%). Median HDLC levels were significantly lower in participants with poor glycemic control (1.12 mmol/L) compared to those with good glycemic control group (1.37 mmol/L) (p=0.011). Despite lack of significant variations in Framingham Risk Scores, there was a trend towards lower FRS-BMI in the good control group (29.8%) compared to the inadequate control (35.4%) and poor control (32.7%) groups (p=0.078). Conclusion: Duration since DM diagnosis was observed to be an important risk factor for poor glycemic control being significantly shorter in those with good glycemic control compared to those with inadequate and poor control. Overall, there was no significant difference in HbA1c status by age but individuals with poor glycemic control were significantly older than those with good control. The most prevalent dyslipidemia among the study participants was hypoalphalipoproteinemia which is reportedly associated with genetic predisposition, warranting further investigations.