Cholesterol-lowering Medications Research Articles

Associations of omega-3 fatty acid subclasses with cardiovascular diseases in 500,000 individuals

Abstract Increased blood levels of omega-3 fatty acids have consistently been shown to be associated with reduced risk of cardiovascular diseases (CVD). However, large scale placebo-controlled trials of omega-3 supplementation have had discordant results: in 2018 REDUCE-IT reported a 25% risk reduction, whereas in 2020 STRENGTH reported no risk reduction. The two trials had both different placebos (mineral vs corn oil) and omega-3 formulations (EPA vs DHA+EPA). There is not yet a consensus on what explains these results. Here we describe the profiling of omega-3 fatty acid subclasses, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) with nuclear magnetic resonance (NMR), and test their associations with incident CVD in 500,000 individuals from UK Biobank. We utilized 500 MHz NMR spectrometers to analyze total omega-3 and its subclasses in EDTA plasma samples and employed biomarker-specific quantification algorithms to measure their absolute concentrations. In this study, we developed a novel algorithm to quantify EPA, complementing previously described algorithms for omega-3 and DHA. Correlation (r^2) of this novel NMR-based quantification and gas chromatography-based measurements was 0.77 for EPA. On average, DHA comprised 44.5% of the total omega-3 concentration, EPA accounted for 22.2%, and other subclasses constituted 34.3% in the cohort. We computed age and sex adjusted associations of omega-3, DHA, and EPA with 10-year risk of CVD among individuals who were not taking cholesterol lowering medication. We discovered protective associations: for DHA a hazard ratio of 0.85 (0.86-0.89, 95% confidence interval) per standard deviation versus 0.96 (0.95-0.98) for EPA, and 0.95 (0.93-0.97) for total omega-3 (Figure). Since DHA (used in the STRENGTH trial with a null result) has a significantly stronger epidemiological association than EPA, these results from a large-scale observational study do not support the hypothesis that the differential use of DHA and EPA in the REDUCE-IT and STRENGTH trials explains their divergent results.Figure

Use of cholesterol-lowering medications in relation to risk of primary liver cancer in the Clinical Practice Research Datalink.

Although the relation between statin use and liver cancer risk has been extensively examined, few studies have examined other cholesterol-lowering medications in relation to liver cancer risk. The authors examined five classes of nonstatin medications and liver cancer risk. A nested case-control including 3719 cases and 14,876 matched controls was conducted within the Clinical Practice Research Datalink. Additional matches on type 2 diabetes and chronic liver disease were also implemented. The medications examined included cholesterol absorption inhibitors, bile acid sequestrants, fibrates, niacin, and omega-3 fatty acids. Conditional logistic regression estimated odds ratios and 95% confidence intervals. Cholesterol absorption inhibitor use was associated with reduced liver cancer risk in the overall analysis (odds ratio, 0.69; 95% confidence interval, 0.50-0.96) and in analyses based on type 2 diabetes and chronic liver disease status. Although bile acid sequestrant use was associated with increased liver cancer risk in the overall analysis (odds ratio, 5.31; 95% confidence interval, 3.53-7.97), the results of the analyses based on type 2 diabetes and chronic liver disease status were inconsistent. [Correction added on 19 August 2024, after first online publication: In the preceding sentence, the value '3.534' has been changed to '3.54'.]. No associations were observed for the other medications. Cholesterol absorption inhibitors may be associated with reduced liver cancer risk. Whether bile acid sequestrant use was associated with increased risk was only partially supported in the current study.

Cholesterol and Cholesterol-Lowering Medications in COVID-19—An Unresolved Matter

Infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cause coronavirus disease 2019 (COVID-19), a disease with very heterogeneous symptoms. Dyslipidaemia is prevalent in at least 20% of Europeans, and dyslipidaemia before SARS-CoV-2 infection increases the risk for severe COVID-19 and mortality by 139%. Many reports described reduced serum cholesterol levels in virus-infected patients, in particular in those with severe disease. The liver is the major organ for lipid homeostasis and hepatic dysfunction appears to occur in one in five patients infected with SARS-CoV-2. Thus, SARS-CoV-2 infection, COVID-19 disease severity and liver injury may be related to impaired cholesterol homeostasis. These observations prompted efforts to assess the therapeutic opportunities of cholesterol-lowering medications to reduce COVID-19 severity. The majority of studies implicate statins to have beneficial effects on disease severity and outcome in COVID-19. Proprotein convertase subtilisin/kexin type 9 (PCSK9) antibodies have also shown potential to protect against COVID-19. This review describes the relationship between systemic cholesterol levels, liver injury and COVID-19 disease severity. The potential effects of statins and PCSK9 in COVID-19 are summarised. Finally, the relationship between cholesterol and lung function, the first organ to be affected by SARS-CoV-2, is described.

Associations of different types of statins with the risk of open-angle glaucoma: a systematic review and network meta-analysis.

Previous studies implied that different types of statins may pose divergent impacts on the risk of glaucoma onset. This study aimed to comprehensively evaluate the effects of various statins on the risk of glaucoma occurrence. PubMed, Cochrane CENTRAL, Embase, and Web of Science were searched from February 1994 to February 2024. We included studies that investigated the effects of various types of statins, fibrates, ezetimibe, cholestyramine, niacin, PCSK9 inhibitors, omega-3 fatty acids, and any cholesterol-lowering medications on glaucoma onset or progression. The revised Cochrane risk-of-bias tool for randomized trials (RoB 2.0) and the Risk Of Bias In Non-randomized Studies-of Interventions (ROBINS-1) tool were used to assess the quality of randomized controlled trials (RCTs)and non-RCTs, respectively. The frequentist network meta-analysis framework was utilized to evaluate the comparative effectiveness, with the random effects model applied. This network meta-analysis comprised 12 studies, encompassing 262,217 individuals and including cholesterol-lowering medications such as statins, fibrates, ezetimibe, cholestyramine, niacin, and omega-3 fatty acids. Our findings demonstrate that comparing to the placebo, rosuvastatin (risk ratio [RR], 1.23; 95% confidence interval [CI], 1.03 to 1.46), simvastatin (RR, 1.21; 95% CI, 1.02 to 1.43), and pravastatin (RR, 1.20; 95% CI, 1.01 to 1.43) increased the risk of glaucoma onset with statistical significance. Rosuvastatin, simvastatin, and pravastatin were each associated with a significantly increased risk of glaucoma onset. We advise medical practitioners to exercise caution when prescribing these specific statins for patients who are at risk of developing glaucoma. What is known Previous studies have suggested a link between statins and the risk of developing glaucoma. However, there is still ongoing debate regarding the specific effects of each type of statin on the onset of glaucoma. What is new This network meta-analysis comprehensively evaluated the effects of various statins on the risk of glaucoma onset. Rosuvastatin, simvastatin, and pravastatin were associated with a significantly increased risk of glaucoma onset.

Atherosclerotic cardiovascular disease following a diagnosis of idiopathic inflammatory myopathy: analysis from a retrospective cohort in the TriNetX registry.

Idiopathic inflammatory myopathies (IIM) confer an increased risk of morbidity from atherosclerotic cardiovascular disease (ASCVD). While ASCVD risk has been studied in other countries, these results may not be applicable to patients with dermatomyositis (DM) and polymyositis (PM) in the United States. This retrospective analysis of a cohort of patients identified by ICD code from TriNetX investigated the incidence of ASCVD after International Classification of Disease (ICD) codes of DM, PM, dermatopolymyositis (DPM) or juvenile dermatomyositis (JDM). Patients were identified by entry of two ICD codes separated by at least 6months, according to their first diagnosis code; ASCVD was defined as first ICD code for myocardial infarction, ischemic stroke, transient ischemic attack, or peripheral arterial disease. Cox proportional hazards regression modeled time from first IIM ICD code to ASCVD event. A total of 35,554 patients were identified with the mean age at first IIM code of 54 and 26.1% were male. The most common comorbidity for all groups except JDM was hyperlipidemia (39.9%) though 79.2% of patients were on no cholesterol lowering medication. ASCVD occurred in 30.4% of patients with PM, 24.3% of patients with DM and 0.9% of patients with JDM. Patients with PM had a median time to event of 9.7years (95% Confidence interval (CI) 9.1, 10.7) and 14.3years (95% CI 12.6, 14.8) for DM. This study demonstrates that ASCVD is a comorbidity occurring after a median of 12.5years (95% CI 11.9, 13.6) in patients with IIM. ASCVD appears to be a long-term complication for IIM patients occurring in nearly a quarter of US patients without prior ASCVD with at least two ICD codes for IIM, with a median time to event of 12.5years. There appears to be a practice gap in the recognition and treatment of hyperlipidemia in these patients. Key Points • Hyperlipidemia was a common comorbidity identified in patients with IIM though most patients were not on cholesterol lowering medication. • Development of ASCVD appears to be a long-term complication for patients with IIM in the United States.

Association Between Xanthelasma Palpebrarum with Cardiovascular Risk and Dyslipidemia: A Case Control Study

ObjectiveTo determine whether Xanthelasma palpebrarum (XP) is associated with dyslipidemia, cardiovascular disease (CVD) and other systemic conditions in a large population. DesignCase-control study conducted at a single tertiary care center. ParticipantsIndividuals who were examined at a medical screening institute from 2001 to 2020. MethodsMedical records were reviewed to extract data on ophthalmic evaluations, blood tests, and systemic diagnoses. Patients identified with XP in at least one eye comprised the study group. A control group without XP was established matched by age and sex at a 10:1 ratio to allow robust statistical analysis. Main Outcome MeasuresAssociations between XP and dyslipidemia and CVD. Lipid profiles, diagnosis of dyslipidemia and CVD were compared between the case and control groups. ResultsThe database included 35,452 individuals, 24,287 males (69%), mean age 52.2±12.2 years. The study population included 203 XP patients (0.6%) and 2030 matched controls. The prevalence of dyslipidemia diagnosis and the usage rates of statins, fibrates, or other cholesterol-lowering medications was similar between the two groups. Lipid profiles were similar between the groups, including median total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglyceride levels (187 controls vs. 192 XP, 48 controls vs. 47 XP, 120 controls vs. 125 XP, 111 controls vs. 105 XP, respectively, P>0.05 for all). The rate of CVD was similar as well (10% controls vs. 8.9%, XP P=0.56). The prevalences of related conditions, including hypertension, diabetes mellitus, and history of cerebrovascular accident, were similar between groups (24% controls vs. 23% XP, 14% controls vs. 10% XP, 1.3% controls vs. 1% XP, respectively P>0.05). ConclusionsXP was not associated with increased rates of dyslipidemia or CVD. This questions the extent to which XP serves as an indicative marker for heightened systemic risk.Introduction

Causal association between triglycerides and cholesterol-lowering medication with non-rheumatic valve disease: A 2-sample Mendelian randomization study.

Previous studies have found a possible causal relationship between triglycerides and lipid-lowering drugs and valvular disease. The aim of this study was to explore the potential causal relationship between triglycerides and lipid-lowering drugs and valvular disease using Mendelian randomization (MR) analysis. Data sets associated with triglycerides (441,016 participants and 12,321,875 single nucleotide polymorphisms [SNPs]) and cholesterol-lowering drugs (209,638 participants and 9851,867 SNPs) were retrieved from the Genome-Wide Association Study (GWAS) database. A total of 297 and 49 SNPs significantly associated with triglycerides and cholesterol-lowering drugs, respectively (P < 5 × 10-8), were identified. Similarly, data sets for non-rheumatic valve diseases (NVDs) (361,194 participants and 10,080,950 SNPs) were obtained from the GWAS database. Inverse variance weighting was used as the primary method for calculating the odds ratio (OR) and 95% confidence intervals (CI). The MR-Egger, weighted median, and weighted mode analyses were also used to test the robustness of the main results. The MR-Egger intercept test and the MR-PRESSO test were used to evaluate horizontal pleiotropy. Inverse variance weighted (IVW) results showed that both triglyceride and cholesterol-lowering medication were positively associated with NVDs (OR = 1.001, 95% CI 1.000-1.0012, P = 0.006; OR = 1.007, 95% CI 1.003-1.010; P = 0.002). This study suggests that both triglyceride and cholesterol-lowering medications are positively associated with NVDs, suggesting that lowering triglyceride levels or the use of cholesterol-lowering medications may reduce the incidence of NVDs. However, larger samples are required for further validation.

Community Pharmacists Identification of Gaps in Care - Statin Utilization for Primary Prevention.

Background: Statins are a highly effective lipid-lowering therapy associated with significant reductions in atherosclerotic cardiovascular disease (ASCVD) events and death. Despite these benefits, statins are underutilized. Pharmacist-led interventions to increase statin prescribing are effective. To our knowledge, no prior studies implemented a comprehensive cardiovascular risk assessment utilizing point-of-care (POC) testing in community pharmacies. Objectives: The primary objective was to determine if community pharmacists can be utilized to identify gaps in care regarding appropriate use of statin therapy for prevention of ASCVD events in HPSAs. Secondary objectives were to assess public interest in ASCVD risk assessment and statin prescribing by the pharmacist, and to identify factors associated with statin gaps in care. Methods: A cross-sectional study was conducted at three independent community pharmacies. Participants were identified based on age and medication history and were scheduled at their pharmacy to receive a comprehensive ASCVD risk screening consisting of POC measurement of a complete lipid panel, blood glucose or A1C, and blood pressure. Participants were informed of their statin candidacy at the screening. Participants completed a survey regarding perceptions of the services provided and opinions of statin prescribing by pharmacists. Results: Of the 57 participants, 43 (75.4%) were possible statin candidates. Most indicated trusting their pharmacist to prescribe a cholesterol-lowering medication and felt insurance should pay for these screenings. Conclusion: ASCVD risk assessment conducted within the community pharmacy setting for can be utilized to identify treatment gaps in status use. Participants indicated trusting pharmacists to provide this service and found the service valuable.

Investigating layer-by-layer chitosan-dextran sulfate-coated mesoporous silica as a pH-sensitive drug delivery system

Mesoporous silica nanoparticles (MSNPs) coated by chitosan (CS) were shown to be a proper candidate as a carrier for drug delivery purposes. However, choosing the suitable drug-containing complexes to be applied on MSNPs-CS is of much greater importance to evaluate the possible candidate for an efficient combination of cell viability, drug release kinetics, and atherosclerosis prevention. In this regard, this study concentrates on the synthesis and assessment of coated MSNPs-CS designed for drug delivery purposes. The MSNPs are coated with polyelectrolyte complexes (PEC) composed of CS and dextran sulfate (MSNPs-CS-DX), serving as a versatile drug carrier with favorable biological characteristics. CS-DX is applied to MSNPs without requiring complex or multi-step synthesis procedures. Rosuvastatin, a cholesterol-lowering medication, is chosen for its therapeutic relevance. Additionally, CS-DX is found to relatively impede the uptake of low-density lipoproteins (LDLs) by macrophages, enhancing their potential therapeutic utility. FTIR pattern, FESEM, and TEM images prove MSNPs-CS-DX formation. DLS measurement demonstrates the average particle size of 110 nm for MSNPs, with the combined thickness of CS and DX layers ranging from 10 to 15 nm. BET test is carried out to evaluate the pore size and porosity of structure, showing outstanding results that cause an entrapment efficiency of 57% for MSNPs-CS-DX. Furthermore, the findings demonstrate the pH sensitivity of MSNPs-CS-DX on drug release kinetics. Notably, the CS-DX layer exhibits a significant enhancement in cell viability of human umbilical vein endothelial cells (HUVEC) by approximately 24% within a 24 h timeframe compared to MSNPs lacking CS-DX.Graphical

#843 Methylation of HMGCR gene promoter in patients on hemodialysis

Abstract Background and Aims Patients with chronic kidney disease (CKD) exhibit a pronounced risk for cardiovascular mortality; the most vulnerable group enrolls patients on hemodialysis. Unfortunately no meaningful decrease of cardiovascular risk after cholesterol lowering medication – inhibitors of HMGCR - was demonstrated in hemodialysed patients. The incidence of complications in CKD patients correlates with changed epigenetic mechanisms, the most studied epigenetic phenomenon is DNA methylation. The aim of this study was to elucidate the methylation status of HMGCR gene and evaluate its impact on cardiovascular morbidity and mortality in patients receiving hemodialysis. Method We analyzed DNA in plasma of 21 hemodialyzed patients before and after dialysis. Then bisulfite conversion was carried out to distinguish methylated and unmethylated form of DNA. The primers of HMGCR genes promoters were designed, after that methylation specific PCR and sequential analysis of PCR products were performed. Results Although the methylation rate of HMGCR gene dropped 9 patients during the hemodialysis session, no statistical significance of this demethylation was confirmed. No correlation of methylation status of HMGCR gene and cholesterol or phosphorus was confirmed. Hypomethylated promoter of HMGCR gene was found in 6 patients, who either underwent amputation of lower extremity due to arterial ischemia or has deceased due to cardiovascular event during next 6 month of follow-up period. Conclusion This study suggests that both DNA demethylation and consecutive increased expression of HMGCR gene could be predictors of high risk of cardiovascular morbidity and mortality in hemodialyzed diabetic patients.

Abstract PO4-20-04: A Randomized Window of Opportunity Study of Preoperative Letrozole and Simvastatin Versus Letrozole Alone in Stage I-III Hormone Receptor Positive, HER2 Negative Breast Cancer

Abstract Hormone receptor positive (HR+), HER2 negative (HER2-) breast cancers are poor responders to immunotherapy. There is a need for innovative approaches to improve immune responses in these tumors. The combination of statins and aromatase inhibitors have demonstrated antiproliferative and immunomodulatory properties. However, this combination has never been studied in the preoperative setting; thus, our ongoing study represents an opportunity to investigate this approach. We designed a randomized two-arm presurgical “window of opportunity” trial to evaluate the effects of letrozole and simvastatin versus letrozole alone 14 days prior to surgery. Tissue and blood will be obtained at baseline and 14 days after completion of therapy at the time of surgery. Inflammatory markers in the blood and multiplex immunohistochemistry (IHC) in tissue will be assessed. To be eligible for the trial, participants must be postmenopausal women with histologically confirmed stage I-III HR+, HER2- invasive breast cancer with baseline ki-67 ≥10% that have not received prior chemotherapy, endocrine therapy, and/or immunotherapy within 3 months prior to trial enrollment. They should also not have received any cholesterol lowering medication within 3 months prior to trial enrollment. The primary objective is to determine if the addition of simvastatin to letrozole compared to letrozole alone will result in a decrease in geometric mean % change in ki-67 from pre-surgical baseline to 14 days following preoperative therapy. Ki-67 is a validated surrogate marker for disease-free survival in HR+, HER2- breast cancer. The main secondary objective is to determine if the addition of simvastatin to letrozole compared to letrozole alone will result in increased immune activation from pre- to post-treatment based on the evaluation of the immune subtype composition in tissue via multiplex immunofluorescence. We aim to enroll 16 patients in each arm to achieve 90% power and detect a minimum difference of 7.5% in ki-67 using a two-sided Mann-Whitney U or Wilcoxon Rank-Sum test. After accounting for a possible drop off rate of 20%, the study’s target accrual will be 40 participants. Statistical analyses will be performed using SAS 9.4. the significance level will be set at alpha = 0.1. Descriptive statistics will be applied to tissue and blood biomarkers of interest at 2 designated time points, prior to preoperative therapy and following completion of preoperative therapy. The absolute change or percentage change of those biomarkers will also be calculated and compared between the 2 arms using the nonparametric Mann-Whitney U test. The correlation among biomarkers will be described by Pearson correlation coefficient with 95% confidence interval. The p-value will be adjusted by Benjamini-Hochberg procedure to control the false discovery rate. All adverse events experienced data will be described by summary statistics and will be assessed according to CTCAE version 5.0. Currently, the study has accrued 2 participants. After completing accrual, we will assess whether the tumor-immune milieu has undergone modulation, resulting in a more immunogenic environment. If an immunogenic effect is demonstrated, this will provide rationale for a future multi-center trial assessing the combination of letrozole, simvastatin, and immunotherapy. Citation Format: Ruth Sacks, Elizabeth Haas, Jade Jones, Manali Bhave, Keerthi Gogineni, Jane Meisel, Demetria Smith-Graziani, Suchi Pakkala, Sarah Friend, Cletus Arciero, Lauren Postlewait, Clara Farley, Cathy Graham, Toncred Styblo, Monica Rizzo, Rhonda Pickett, Nicholas Crasta, Lori Brown, Xiaoxian Li, Sunil Badve, Madhav Dhodapkar, Kevin Kalinsky. A Randomized Window of Opportunity Study of Preoperative Letrozole and Simvastatin Versus Letrozole Alone in Stage I-III Hormone Receptor Positive, HER2 Negative Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-20-04.

Measuring the Influence of Side Effect Expectations, Beliefs, and Incident Side Effects on the Risk for Drug Discontinuation Among Individuals Starting New Medications, a Cross-sectional Study.

To measure the impact of beliefs, expectations, side effects, and their combined effects on the risk for medication nonpersistence. Using a cross-sectional design, individuals from Saskatchewan, Canada who started a new antihypertensive, cholesterol-lowering, or antihyperglycemic medication were surveyed about risk factors for nonpersistence including: (a) beliefs measured by a composite score of three questions asking about the threat of the condition, importance of the drug, and harm of the drug; (b) incident side effects attributed to treatment; and (c) expectations for side effects before starting treatment. Descriptive statistics and logistic regression models were used to quantify the influence of these risk factors on the outcome of nonpersistence. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated. Among 3,029 respondents, 5.8% (n=177) reported nonpersistence within four months after starting the new drug. After adjustment for numerous covariates representing sociodemographics, health-care providers, medication experiences and beliefs, both negative beliefs (OR: 7.26, 95%CI: 4.98-10.59) and incident side effects (OR: 8.00, 95%CI: 5.49-11.68) were associated with the highest odds of nonpersistence with no evidence of interaction. In contrast, expectations for side effects before starting treatment exhibited an important interaction with incident side effects following treatment initiation. Among respondents with incident side effects (n=741, 24.5%), the risk for early nonpersistence was 11.5% if they indicated an expectation for side effects before starting the medication compared to 23.6% if they did not (adjusted OR: 0.38, 95%CI: 0.25-0.60). Expectations for side effects may be a previously unrecognized but important marker of the probability to persist with treatment. A high percentage of new medication users appeared unprepared for the possibility of side effects from their new medication making them less resilient if side effects occur.

Cardiovascular Disease Burden in Persons with Mental Illness: Comparison between a U.S. Psychiatry Outpatient Sample and a U.S. General Population Sample

Background. Cardiovascular disease (CVD) and depression are the leading causes of disability in the U.S. Using electronic health record data, we describe the CVD burden among persons with mental illness enrolled in the Penn State Psychiatry Clinical Assessment and Rating Evaluation System (PCARES) Registry between 2015 and 2020. Methods. CVD burden assessment included prevalence of CVD conditions (any major CVD or individual CVD risk factors), indicated medication prescriptions for CVD risk factors, and mean levels of body mass index (BMI, kg/m2), glycosylated hemoglobin (HbA1C, %), glucose (mg/dl), and lipids (mg/dl). We compared the CVD burden between the PCARES sample to a representative sample of adults from the U.S. general population (NHANES 2013-2016) using one-sample chi-square/t-tests for proportions/means. The CVD burden in NHANES participants was adjusted to PCARES age, race, and sex statistics. Results. The PCARES sample (N=3556) had a mean (SE) age of 42.4 (0.3) years and comprised 63.0% women, 85.0% non-Hispanic Caucasians, and 41.0% with major depressive disorder. CVD burden was higher in the PCARES sample compared to NHANES participants for any major CVD (8.6% vs. 4.6%), diabetes (18.4% vs. 10.4%), BMI (30.3 vs. 28.3), HbA1C (6.1 vs. 5.6), cholesterol (185.6 vs. 181.7), triglycerides (153.3 vs. 136.1), and indicated antihypertensive (94.3% vs. 76.9%) and cholesterol-lowering (49.5% vs. 36.7%) medications (Bonferroni-corrected p=0.03 for each outcome). The CVD burden was lower in the PCARES sample compared to NHANES participants for hypertension (45.9% vs. 50.4%), dyslipidemia (43.2% vs. 61.9%), HDL-C (48.4 vs. 41.4), and LDL-C (107.9 vs. 112.0) (Bonferroni-corrected p=0.03 for each outcome). Glucose levels (110.9 vs. 111.9) and indicated antidiabetic medications (87.4% vs. 86.6%) were similar in the two samples (p&gt;0.05). Conclusions. The CVD burden was higher in persons with mental illness compared to the U.S. general population. Integrated mental and physical healthcare services could reduce long-term disability among persons with mental illness.

Abstract 4429: Plasma metabolic profiles in association with subsequent risk of colorectal cancer in the UK Biobank cohort

Abstract Background: Dysregulation of metabolic processes contributes to colorectal cancer (CRC) etiology. We aimed to comprehensively evaluate the prospective associations between pre-diagnostic metabolic biomarkers and CRC risk in 230,420 UK Biobank participants. Methods: A total of 249 metabolic biomarkers were measured by nuclear magnetic resonance spectroscopy from baseline plasma samples. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of metabolic biomarkers with CRC risk after adjusting for potential confounders. Subgroup analyses were performed by sex and CRC subsites (i.e., proximal colon, distal colon, rectum). We also conducted factor analyses to identify latent factors and examined their associations with CRC risk. Results: During a median follow-up time of 9.7 years, 2,410 incident primary CRC cases were identified after excluding participants diagnosed with CRC within two years after blood collection. After correcting for multiple testing, 50 metabolic biomarkers, including lipids and lipoproteins, fatty acids, ketone bodies, and inflammation, were significantly associated with incident CRC risk. No statistically significant differences were observed for the biomarker-CRC associations by sex and CRC subsite. In the sensitivity analysis, excluding cholesterol-lowering medication users did not alter the main findings. In factor analyses, we identified a significant association of CRC risk (HR = 1.08; 95% CI = 1.04-1.13; P-value = 6.89×10-5) with a metabolite pattern which was positively correlated with triglycerides and inversely correlated with relative concentrations of omega-6 fatty acids and polyunsaturated fatty acids. Conclusion: We identified multiple metabolic biomarkers and a metabolite pattern associated with CRC risk in a large prospective cohort. These findings suggest lipid metabolism may contribute to carcinogenesis of the colorectum. Citation Format: Fangcheng Yuan, Guochong Jia, Wanqing Wen, Wei Zheng. Plasma metabolic profiles in association with subsequent risk of colorectal cancer in the UK Biobank cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4429.

Abstract P540: Sleep Duration, Rapid Eye Movement Sleep, and Subclinical Myocardial Damage

Introduction: Sleep is strongly linked to clinical cardiovascular disease and was added in 2022 to the AHA’s Life’s Essential 8. Optimizing sleep duration and quality may reduce the risk of cardiovascular disease. Few studies have examined self-reported sleep duration and percent time in rapid eye movement (REM) sleep measured by single night in-home polysomnography with high sensitivity cardiac troponin T (hs-troponin T), a biomarker of subclinical cardiovascular disease. Methods: We conducted a cross-sectional study of adults without a history of cardiovascular disease who participated in both the Atherosclerosis Risk in Communities (ARIC) Study and the Sleep Heart Health Study (SHHS) in 1995-1998. We used linear regression with sleep duration and percentage time of REM sleep modeled as predictors with restricted cubic splines and examined associations with the outcome, hs-troponin T. We adjusted for age, sex, body mass index, waist-to-hip ratio, alcohol intake, smoking status, systolic blood pressure, hypertension medication use, diabetes, HDL- and LDL-cholesterol, and cholesterol-lowering medication use. Results: Among 1,587 participants (mean age 63, 54% female), the mean sleep duration was 7.3 hours, and mean % REM time was 20.7. Sleep duration was not associated with hs-troponin T ( Figure, Panel A ). However, percentage REM sleep was negatively associated with hs-troponin T, but with a threshold effect; there was a negative linear association of hs-troponin T with % REM sleep but only at values &lt;15% ( Figure, Panel B ). Conclusion: While self-reported sleep duration was not associated with TnT levels, there was evidence that low % REM sleep, a specific neurophysiological sleep state, was associated with subclinical cardiovascular disease. These findings suggest that multiple sleep dimensions should be considered in efforts to optimize cardiovascular health.

Discovery and Exploration of Lipid-Modifying Drug Targets for ALS by Mendelian Randomization.

Observational studies have faced challenges in identifying replicable causes for amyotrophic lateral sclerosis (ALS). To address this, we employed an unbiased and data-driven approach to discover and explore potential causal exposures using two-sample Mendelian randomization (MR) analyses. In the phenotype discovery stage, we assessed 3948 environmental exposures from the UK Biobank and utilized ALS summary statistics (Europeans, 20,806 cases, 59,804 controls) as the outcome within a phenome-wide MR pipeline. Through a range of sensitivity analyses, two medication traits were identified to be protective for ALS. In the target exploration stage, we further conducted drug target MR analyses using the latest and trans-ethnic summary data on lipid-related traits and ALS (Europeans, 27,205 cases, 110,881 controls; East Asians, 1234 cases, 2850 controls). Our aim was to explore potential causal drug targets through six lipid-modifying effects. These comprehensive analyses revealed significant findings. Specifically, "cholesterol-lowering medication" and "atorvastatin" survived predefined criteria in the phenotype discovery stage and exhibited a protective effect on ALS. Further in the target exploration stage, we demonstrated that the therapeutic effect of APOB through LDL-lowering was associated with reduced ALS liability in Europeans (OR = 0.835, P = 5.61E - 5). Additionally, the therapeutic effect of APOA1 and LDLR through TC-lowering was associated with reduced ALS liability in East Asians (APOA1, OR = 0.859, P = 5.38E - 4; LDLR, OR = 0.910, P = 2.73E - 5). Overall, we propose potential protective effects of cholesterol-lowering drugs or statins on ALS risk from thousands of exposures. Our research also suggests APOB, APOA1, and LDLR as noveltherapeutic targets for ALS and supports their potential protective mechanisms may be mediated by LDL-lowering or TC-lowering effects.

Identification of patients at risk of cardiovascular disease in greater Manchester in the VICTORION-Spirit study

Background: Inclisiran is a cholesterol-lowering small interfering RNA treatment licensed in the UK for lowering low-density lipoprotein cholesterol (LDL-C). VICTORION-Spirit (NCT04807400) is an implementation science study designed to provide evidence for inclisiran implementation within the National Health Service. The aim was to describe the process of patient identification employed in VICTORION-Spirit. Methods: A Phase IIIb, multicentre, randomised controlled study, VICTORION-Spirit is evaluating inclisiran implementation in participants with atherosclerotic cardiovascular disease (ASCVD) or ASCVD-risk equivalents and elevated LDL-C. Feasibility Assessment and Recruitment System for Improving Trial Efficiency (FARSITE) software utilising natural language search functions identified patients who may benefit from inclisiran. FARSITE searches were performed within Salford, Manchester, Trafford and Bury Clinical Commissioning Groups to identify individuals with elevated LDL-C or total cholesterol and pre-existing cardiovascular disease (CVD) or at risk of ASCVD. Results: FARSITE used ‘total cholesterol &gt;4 mmol/l’ terminology rather than ‘LDL-C’; the former yielded &gt;3 times the number of eligible patients. The search for individuals with pre-existing CVD identified 24,196 people in a population of 560,969 (4.3%); including ‘total cholesterol &gt;4 mmol/l’ identified 10,431 individuals with pre-existing CVD and elevated total cholesterol. Searches for individuals at risk of ASCVD identified 65,457 people, narrowing to 26,580 at risk of ASCVD plus elevated total cholesterol. The most discriminatory SNOMED concept codes and their prevalence within the dataset can inform national approaches to develop similar searches. Conclusions: FARSITE searches employed in VICTORION-Spirit identified a population at risk of ASCVD in Greater Manchester, England, who may benefit from a cholesterol-lowering medication such as inclisiran.

Association between chronic viral infection-related hospitalization and risk of cardiovascular disease: Apopulation-based cohort study.

Chronic viral infection induces immunosenescence and systemic low-grade inflammation, leading to worsened long-term outcomes. We sought to explore the short- and long-term effects of chronic viral infection on cardiovascular disease (CVD). Based on UK Biobank data, exposed group was identified as individuals who had chronic virus infection-related hospitalization (IRH). Unexposed group was randomly selected, matched by 5-year age interval, sex, and Charlson comorbidity index at a ratio up to 1:10. Restricted cubic splines were used to model time-varying effects of IRH in nonproportional Cox models. A cut-off value of 5 years was recorded and used in piecewise Cox proportional hazards models as we estimated short- and long-term effects of IRH on CVD. A total of 2826 exposed participants and 28 212 matched unexposed participants were included. Chronic viral IRH was associated with increased risk of CVD (0-5 years: hazard ratio, 1.57 [95% confidence interval: 1.32, 1.87] and 5+ years: 1.31 [1.06, 1.61]). Elevated risk of stroke was only observed within the initial 5-year follow-up (0-5 years: 1.91 [1.30, 2.81]). The short- and long-term associations were observed in herpes or hepatitis virus IRH with risk of CVD (all p < 0.05). Subgroup analysis revealed long-term association between chronic viral IRH and CVD among female (5+ years: 1.68 [1.27, 2.22]) but not among male. The association between chronic viral infection and elevated CVD risk appeared to be stronger among individuals who did not take cholesterol-lowering medication, antithrombotic medication, or certain antihypertensive medications (all p for interaction < 0.05). The risk of CVD event remained persistently higher within and over 5 years following chronic viral IRH, especially in individuals infected with herpes and hepatitis virus.

Genetically Linked Cognitive Dysfunction Induced by Cholesterol-Lowering Medications: A Two-Case Report

Genetically Linked Cognitive Dysfunction Induced by Cholesterol-Lowering Medications: A Two-Case Report

Ezetimibe Lowers Risk of Alzheimer's and Related Dementias over Sevenfold, Reducing Aggregation in Model Systems by Inhibiting 14-3-3G::Hexokinase Interaction.

Numerous factors predispose to progression of cognitive impairment to Alzheimer's disease and related dementias (ADRD), most notably age, APOE(ε4) alleles, traumatic brain injury, heart disease, hypertension, obesity/diabetes, and Down's syndrome. Protein aggregation is diagnostic for neurodegenerative diseases, and may be causal through promotion of chronic neuroinflammation. We isolated aggregates from postmortem hippocampi of ADRD patients, heart-disease patients, and age-matched controls. Aggregates, characterized by high-resolution proteomics (with or without crosslinking), were significantly elevated in heart-disease and ADRD hippocampi. Hexokinase-1 (HK1) and 14-3-3G/γ proteins, previously implicated in neuronal signaling and neurodegeneration, are especially enriched in ADRD and heart-disease aggregates vs. controls (each P<0.008), and their interaction was implied by extensive crosslinking in both disease groups. Screening the hexokinase-1::14-3-3G interface with FDA-approved drug structures predicted strong affinity for ezetimibe, a benign cholesterol-lowering medication. Diverse cultured human-cell and whole-nematode models of ADRD aggregation showed that this drug potently disrupts HK1::14-3-3G adhesion, reduces disease-associated aggregation, and activates autophagy. Mining clinical databases supports drug reduction of ADRD risk, decreasing it to 0.14 overall (P<0.0001; 95% C.I. 0.06-0.34), and <0.12 in high-risk heart-disease subjects (P<0.006). These results suggest that drug disruption of the 14-3-3G::HK1 interface blocks an early "lynchpin" adhesion, prospectively reducing aggregate accrual and progression of ADRD.