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PubMed2026

Current and Future Perspectives of LDL-C Lowering Therapies 2026.

LDL cholesterol (LDL-C) is the central causal factor for atherosclerotic cardiovascular disease (ASCVD), and its reduction is a cornerstone of both primary and secondary prevention. Since the introduction of statins more than three decades ago, LDL-C-lowering therapy has expanded substantially, now encompassing ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9)-targeting agents, bempedoic acid, and other emerging modalities. This expanding therapeutic landscape has improved the feasibility of achieving guideline-recommended LDL-C targets, but it has also increased the complexity of clinical decision making. This review provides a contemporary and practical overview of the LDL-C-lowering strategies, beginning with the initial evaluation of patients with elevated LDL-C, including differentiation between primary and secondary causes and the identification of familial hypercholesterolemia (FH). We summarize the current treatment targets for primary and secondary prevention, highlight the optimal selection and use of statins, and discuss the assessment and management of statin intolerance, including the role of the nocebo effect. Non-statin therapies, including ezetimibe, bile acid sequestrants, PCSK9 inhibitors, inclisiran, and bempedoic acid, are reviewed with an emphasis on their mechanisms, efficacy, and clinical positioning. Advanced therapies for severe dyslipidemia, such as lipoprotein apheresis, lomitapide, and evinacumab, are also discussed in this review. Finally, we outline the future directions, including oral PCSK9 inhibitors, next-generation cholesteryl ester transfer protein (CETP) inhibitors, lipoprotein(a)-lowering agents, and genome-editing approaches. Collectively, these developments offer new opportunities to address unmet clinical needs, particularly in patients with FH, statin intolerance, and residual cardiovascular risk. A comprehensive understanding of these therapies is essential for further reducing the burden of ASCVD in the coming decades.

Humans↗

PubMed2026

Vitamin D Deficiency During Pregnancy Is Associated With Greater LDL-C Increase, Elevated β-Hydroxybutyrate and Altered Neonatal Metabolic Markers-A Secondary, Pooled Analysis of the Randomized, Controlled Vitamin D and Lifestyle for Gestational Diabetes Prevention Trial (DALI).

INTRODUCTION: Vitamin D (vitD) plays a role in metabolic regulation, including lipid metabolism and insulin sensitivity. During pregnancy, profound physiological changes in lipid handling and ketogenesis occur to support fetal development. However, the extent to which maternal vitamin D status influences these metabolic adaptations and fetal metabolic markers remains unclear. METHODS: In this secondary analysis, we examined lipid distribution throughout pregnancy-from before 20 weeks' gestation to delivery-in women with overweight or obesity, stratified by vitamin D status (deficiency, insufficiency, or sufficiency), assessing both maternal and cord blood. Main inclusion criteria were: age > =18 years, singleton pregnancy, < 20 weeks' gestation, BMI ≥ 29 kg/m2. Women with GDM < 20 weeks' gestation were excluded. In total, 962 pregnant women were divided into vitD deficient (< 30 nmol/L, n = 102), insufficient (30-50 nmol/L, n = 222) and sufficient (> 50 nmol/L, n = 638) groups. VitD levels and lipid concentrations were assessed at < 20, 24-28 and 35-37 weeks' gestation and in cord blood. RESULTS: Compared with vitD sufficient women, women with vitD deficiency had significantly larger increases in LDL-C throughout pregnancy and ß-OH-butyrate at 24-28 weeks' gestation, in adjusted analysis. VitD in cord blood was highest in offspring of mothers with vitD sufficiency. In cord blood, significantly higher ß-OH-butyrate was observed with vitD deficiency; lipid concentrations were similar between groups. CONCLUSIONS: Early vitamin D deficiency before 20 weeks of gestation was associated with altered metabolic trajectories during pregnancy, including greater increases in LDL cholesterol and ketone body concentrations in women with overweight or obesity, as well as higher cord blood ketone levels in their offspring. These findings suggest that early maternal vitamin D status may influence maternal and fetal metabolic adaptations, although causal relationships and clinical implications require further investigation. TRIAL REGISTRATION: Trial registered at ISRCTN registry (https://doi.org/10.1186/ISRCTN70595832) trial number ISRCTN70595832. Registration date 02/12/2011.

Humans↗

PubMed2026

Monogenic ALB Variants as Determinants of Severe Hypercholesterolemia: A Population-Based Cohort Study.

BACKGROUND: Hypoalbuminemia is associated with several risk factors for myocardial infarction, including hypercholesterolemia, liver disease, kidney disease, and diabetes. Homozygosity of loss-of-function (LoF) variants in the ALB gene, which encodes albumin, is a known cause of congenital hypoalbuminemia. Studies have also shown that heterozygous ALB LoF variants are associated with increases in low-density lipoprotein cholesterol (LDL-C), comparable to those seen in familial hypercholesterolemia. OBJECTIVES: This study examined the effect of ALB LoF variants and other causes of low albumin on LDL-C levels in 2 population biobanks. METHODS: This study used data from 2 large cohorts with linked electronic health record and genetic information: Geisinger's MyCode Community Health Initiative, a health care population based in Pennsylvania, USA; and the National Institutes of Health All of Us Research Program, a nationwide epidemiologic cohort. LDL-C values were adjusted for lipid-lowering medication use. Myocardial infarction diagnoses were extracted from electronic health records using International Classification of Diseases codes. A polygenic score for serum albumin was calculated for participants of European ancestry. Linear regression models were used to estimate associations, and results were meta-analyzed across cohorts using fixed-effects models. RESULTS: Among 155,530 MyCode and 405,701 All of Us adult participants, 77 individuals (1 of 7,289) carried an ALB LoF variant. Among noncarriers, a 1 g/dL decrease in serum albumin was associated with a 10.9 mg/dL (95% CI:, 10.4-11.4) decrease in LDL-C. In contrast, ALB LoF variants were associated with a 0.69 g/dL (95% CI: 0.60-0.78) reduction in serum albumin and a 38.3 mg/dL (95% CI: 28.2-48.5) increase in LDL-C. Paradoxically, whereas monogenic determinants of hypoalbuminemia were associated with increased LDL-C, polygenic determinants of lower albumin were associated with a 0.22 mg/dL (95% CI: 0.17-0.26) decrease in LDL-C per decile. CONCLUSIONS: ALB LoF variants represent a previously underrecognized monogenic cause of elevated LDL-C, with effect sizes slightly less than canonical familial hypercholesterolemia variants. The divergent effects of ALB-mediated vs polygenic or physiological reductions in albumin on LDL-C suggest distinct underlying mechanisms.

Humans↗

PubMed2026

Measurement of low-density lipoprotein cholesterol and other circulating lipids in Brazil: a systematic literature review.

Accurate laboratory assessment of circulating lipids underpins cardiovascular risk stratification, yet clinical interpretation depends not only on the assays but on the formula chosen to estimate low-density lipoprotein cholesterol (LDL-C). This review integrates the 2019-2025 evidence on laboratory methods for triglycerides (TG), total cholesterol (TC), and high-density lipoprotein cholesterol (HDLC), and on the formulas estimating LDL-C, VLDL-C, and non-HDL cholesterol, to determine how these should be measured, reported, and harmonized in Brazil, where lipid thresholds are adapted from international consensus. A PRISMA 2020 systematic search (PROSPERO CRD420251241064) of PubMed/MEDLINE, Scopus, SciELO, LILACS, Web of Science, and Embase retrieved 57,915 records; after removing 38,210 duplicates, 19,705 titles/abstracts were screened, 312 full texts assessed, and 25 sources included. Enzymatic colorimetric assays remain standard for TG, TC, and HDLC. For LDL-C, Martin/Hopkins classifies more accurately than Friedewald (89.6% vs 83.2% correct categorization in 5,051,467 patients), particularly at high TG and low LDL-C, while Sampson/NIH and modified Sampson/NIH extend reliable estimation into hypertriglyceridemia and very low LDL-C; direct measurement is reserved for TG beyond the validated range. Although the review centers on the Friedewald, Martin/Hopkins, and Sampson/NIH families that dominate guideline practice, other published equations exist and are addressed in context. In Brazil, atherogenic-lipid thresholds are risk-based decision limits rather than reference intervals; national surveys describe lipid distributions but were not designed to establish them. Analytical standardization through traceability programs, multicenter validation of formulas, and-where the distribution-based construct applies (HDLC, pediatrics)-nationally derived reference intervals are priorities for equitable cardiovascular risk assessment in Brazil.

Humans↗

PubMed2026

Effects of Moderate-Frequency Resistance Training on Cardiometabolic Risk Factors in Adults With Overweight or Obesity: A Systematic Review and Meta-Analysis.

BACKGROUND: Resistance training (RT) effectively manages cardiometabolic risk factors in adults, but the specific effects of moderate-frequency RT (2-3 sessions/week) in adults with overweight or obesity are understudied. OBJECTIVE: This study aimed to evaluate moderate-frequency RT's effects on cardiometabolic risk factors in this population and quantify effect sizes. DATA SOURCES: PubMed, Web of Science, EMBASE, and Cochrane Library searched up to July 2025. ELIGIBILITY: English randomized controlled trials (RCTs) comparing RT (≥ 7 weeks) to nonexercise control; nonathletic adults ≥ 18 years with BMI ≥ 25 kg/m2. PARTICIPANTS: 454 participants across 12 RCTs (mean age 58.93 ± 12.87 years; mean BMI 31.2 ± 3.5 kg/m2; ~50% female). RESULTS: RT significantly reduced diastolic blood pressure (MD = -1.53 mmHg; 95% CI: -2.16 to -0.91; p < 0.01), LDL-C (MD = -0.25 mmol/L; 95% CI: -0.41 to -0.08; p < 0.01), and triglycerides (MD = -0.17 mmol/L; 95% CI: -0.30 to -0.04; p = 0.01). No significant effects on systolic blood pressure, mean arterial pressure, waist circumference, glycemic markers, total cholesterol, or HDL-C. Subgroup analyses showed larger LDL-C/triglyceride improvements with concurrent dietary control. CONCLUSION: Moderate-frequency RT inconsistently improves cardiometabolic risk factors, benefiting diastolic blood pressure, LDL-C, and triglycerides but not glycemic or other parameters. Combining with dietary control may enhance benefits, supporting RT as a complementary strategy in multimodal lifestyle interventions. TRIAL REGISTRATION PROSPERO: CRD42022343167.

Humans↗

PubMed2026

LDLR Variant Classification Through Activity-Normalized Prime Editing Screening.

BACKGROUND: Inherited variants in the LDL (low-density lipoprotein) receptor (LDLR) gene are the most common cause of familial hypercholesterolemia, significantly increasing coronary artery disease risk. Early identification of pathogenic LDLR variants enables prompt lipid-lowering therapy and cascade testing of at-risk relatives; however, most LDLR variants observed in the population have uncertain or absent clinical classifications, leaving many patients without actionable information. METHODS: We developed the first activity-normalized prime editing screening pipeline to measure the impact of 5184 LDLR coding variants on LDL-cholesterol (LDL-C) uptake. Each prime editing guide RNA is paired with a genotypic outcome reporter to correct for variable editing efficiency, overcoming a key limitation of previous pooled genome editing screens. A statistical framework further improves variant effect estimates by jointly analyzing all missense variants at each amino acid position. RESULTS: We show that prime editing of the reporter construct correlates with endogenous variant installation frequency, validating the activity normalization approach. The resulting scores capture a continuous spectrum of functional effects, robustly separate pathogenic versus benign ClinVar variants, and show concordance with LDL-C levels in UK Biobank participants. We calibrate functional evidence strengths to the ACMG/AMP variant interpretation framework, enabling integration into a clinical variant classification workflow. By combining functional, computational, population, and contextual evidence, 322 of 434 LDLR variants currently classified as variants of uncertain significance, conflicting, or absent from ClinVar appear to meet evidence thresholds for reclassification and can be prioritized for expert review, substantially expanding the pool of actionable variant classifications. The screen also reveals a cluster of gain-of-function variants in LDLR class A repeat 5, at least some of which enhance LDL-C uptake through increased apolipoprotein B interaction, with implications for therapeutic genome editing. Last, prime editing uniquely detects splice-altering coding variants missed by cDNA-based screens and pathogenicity predictors, revealing an advantage of endogenous variant installation. CONCLUSIONS: Altogether, activity-normalized prime editing provides a scalable framework for LDLR variant classification that substantially expands the proportion of variants with evidence for genetic diagnosis and reveals novel biology with therapeutic relevance.

CRISPR screening↗

PubMed2026

Clinical outcomes stratified by CYP2C19 phenotypes in intracranial artery stenting patients with genotype-guided antiplatelet regimens: a real-world single-center retrospective cohort study.

OBJECTIVES: Clinical trial evidence is scarce for optimal antiplatelet strategies in patients undergoing intracranial artery stenting with CYP2C19 loss‑of‑function alleles, especially regarding the efficacy‑safety balance. METHODS: This single‑center retrospective study enrolled patients receiving genotype‑guided antiplatelet regimens for intracranial stenting between January and December 2023, with 6‑month follow‑up. Clinical outcomes were compared across CYP2C19 phenotypes. RESULTS: Among 205 patients, 46.8% were normal metabolizers, 40.5% intermediate metabolizers, and 12.7% poor metabolizers. Aspirin-clopidogrel was prescribed for all normal metabolizers, 80.7% intermediate metabolizers, and 19.2% poor metabolizers. No intergroup differences were observed in risks of ischemic stroke/transient ischemic attack (TIA), cardiovascular events, intracerebral hemorrhage (ICH), or any bleeding (all P > 0.05). In intermediate metabolizers and poor metabolizer subgroups, ischemic stroke/TIA rates were 11.1% in the aspirin-clopidogrel group and 9.68% in the aspirin-ticagrelor group, with no significant difference compared to normal metabolizers (4.17%). ICH rates were 1.39% in the aspirin-clopidogrel group and 6.45% in the aspirin-ticagrelor group, showing no significant difference versus normal metabolizers (1.04%). Multivariate logistic analysis found the number of stents (odds ratio [OR] = 2.70; 95% confidence interval [CI] = 0.89-6.95; P = 0.043) was a risk factor for ischemic stroke/TIA. Ticagrelor-based dual antiplatelet therapy (DAPT; OR = 10.57; 95% CI = 1.00-111.7; P = 0.05) and baseline l ow-density lipoprotein cholesterol (LDL-C; OR = 7.22; 95% CI = 1.80-29.01; P = 0.005) were associated with ICH risk. CONCLUSION: Antiplatelet regimens were adjusted for a subset of intermediate metabolizers and poor metabolizers prior to stenting, and the 6-month clinical outcomes were comparable across normal metabolizers, intermediate metabolizers, and poor metabolizers. The stent number was associated with ischemic stroke/TIA risk; baseline LDL-C and ticagrelor-based DAPT with ICH risk. These exploratory findings need validation in adequately powered studies.

CYP2C19↗

PubMed2026

Genetically Proxied Inhibition of Cholesterol-Lowering Drug Targets and Survival in HPV-Positive and Non-HPV-Driven Head and Neck Cancer: A Multicentre MR Study.

BACKGROUND: Cholesterol pathways may influence head and neck squamous cell carcinoma (HNSCC) progression, but evidence on prognosis is inconsistent. We used Mendelian randomization (MR) to test whether genetically proxied inhibition of major low-density lipoprotein cholesterol (LDL-C)-lowering drug targets and circulating lipid traits affects overall survival (OS) in HPV-positive and non-HPV-driven HNSCCs. METHODS: We proxied lifelong LDL-C lowering using 55 cis-acting single-nucleotide polymorphisms in HMGCR, NPC1L1, PCSK9, and LDL-receptor (LDLR) from the updated 2021 Global Lipids Genetics Consortium and instrumented circulating lipid traits. Two-sample MR estimated effects on OS in 4,869 multicentre HNSCC cases (1,291 HPV-positive; 3,578 non-HPV-driven) using minimally adjusted Cox models. Sensitivity analyses additionally adjusted for tumor stage and treatment, assessed collider bias using an external HNSCC incidence genome-wide association study, and examined between-center heterogeneity and colocalization. RESULTS: Using the updated Global Lipids Genetic Consortium 2021 instruments, genetically proxied HMGCR inhibition showed a directionally protective but nonsignificant association with OS in HPV-positive oropharyngeal HNSCC in the primary analysis [inverse variance weighted (IVW) HR = 0.19; 95% confidence interval (CI), 0.03-1.18; P = 0.08], with directionally concordant weighted median results. No corresponding protective association was observed for HMGCR in non-HPV-driven disease (IVW HR = 1.68; 95% CI, 0.78-3.63; P = 0.19). No clear evidence of association was observed for NPC1L1, PCSK9, LDLR, or circulating lipid traits in either HPV stratum. Colocalization did not support a shared causal variant. CONCLUSIONS: These analyses provide suggestive evidence that genetically proxied HMGCR inhibition may influence survival in HPV-positive oropharyngeal HNSCC. IMPACT: HMGCR-related pathways may be relevant to prognosis in HPV-positive oropharyngeal HNSCC, whereas clear survival effects of other cholesterol-lowering targets were not supported.

Humans↗

PubMed2026

Comparison of Traditional Chinese Exercise and Equipment-Based Exercise on Glycaemic Control and Vitamin D Levels in Middle-Aged and Elderly Patients With Prediabetes: A Randomised Controlled Trial.

BACKGROUND: Prediabetes is a critical window for preventing progression to type 2 diabetes mellitus (T2DM). Both vitamin D deficiency and physical inactivity are associated with impaired glucose metabolism. This study compared the effects of Traditional Chinese Exercise (TCE) and Kuanle Equipment Exercise (KEE) on glycaemic measures, lipid profiles, body composition and serum 25-hydroxyvitamin D3 [25(OH)D3] in middle-aged and elderly adults with prediabetes. METHODS: We conducted a 12-week, single-centre, randomised controlled trial involving 62 participants with prediabetes (mean age 55.2 ± 8.4 years; 88.7% female). Participants were randomly assigned to control (usual care, n = 21), TCE (n = 20), or KEE (n = 21). Primary outcomes included fasting plasma glucose (FPG), 2-h OGTT glucose, glycated haemoglobin (HbA1c) and serum 25(OH)D3. Secondary outcomes comprised triglycerides, total cholesterol, LDL-C, HDL-C and body composition. RESULTS: At baseline, mean serum 25(OH)D3 was 21.53 ± 3.90 nmol/L. At 12 weeks, both TCE and KEE improved FPG, 2-h OGTT glucose, HbA1c and 25(OH)D3 versus control (all p ≤ 0.001). Relative changes in FPG were -9.4% (TCE) and -15.2% (KEE) versus -1.5% (control); corresponding changes were -14.6% and -21.2% for 2-h OGTT glucose, -6.7% and -12.9% for HbA1c, and +60.6% and +81.9% for 25(OH)D3. Direct TCE-KEE comparisons were not significant (all p > 0.05). In an exploratory analysis, change in 25(OH)D3 was inversely associated with change in 2-h OGTT glucose (partial r = -0.358, p = 0.006), but not with FPG, HbA1c, or triglycerides. CONCLUSIONS: Both TCE and KEE improved glycaemic outcomes and increased serum 25(OH)D3 compared with usual care in middle-aged and elderly adults with prediabetes. Although KEE produced numerically larger estimates, direct between-group comparisons were not significant, and the superiority of KEE over TCE was not established. These vitamin D findings require confirmation in trials that quantify sunlight exposure and dietary vitamin D intake.

Aged↗

PubMed2026

Effects of 12 weeks of resistance and concurrent training with graded protein intakes on lipid profile, kidney and liver biomarkers in middle-aged to older women.

PURPOSE: To examine secondary lipid, kidney-related, and liver-enzyme responses to three protein intakes during resistance training (RT) alone or the same RT plus cycling (CT) in middle-aged to older women. METHODS: In this randomized 2×3 factorial trial, 108 women aged 40-77 years were assigned to RT or CT and 0.8, 1.6, or 2.2 g kg-1 d-1 protein for 12 weeks. This complete-case secondary analysis included 83 participants. Linear mixed-effects models tested Time × Training, Time × Protein, and Time × Training × Protein effects, with false-discovery-rate-adjusted omnibus tests and Holm-adjusted contrasts. RESULTS: Triglycerides, total cholesterol, LDL-C, and apolipoprotein B decreased and HDL-C increased in all conditions. Lipid changes differed by protein condition, and several were more favorable with CT; however, CT comprised RT plus additional cycling and greater exercise exposure. Urea, blood urea nitrogen, creatinine, the blood urea nitrogen-to-creatinine ratio, and cystatin C increased, whereas three eGFR estimates decreased. Responses differed mainly between 0.8 and the two higher protein conditions, with little evidence of differences between 1.6 and 2.2 g kg-1 d-1. ALT, AST, and GGT differed by protein condition; AST and GGT also showed training-dependent responses. CONCLUSIONS: The dietary and exercise interventions modified lipid and clinical-chemistry responses. Because energy and food composition were not fully matched and CT added cycling to RT, the findings do not isolate protein dose or exercise modality. Changes in eGFR estimates and liver enzymes do not establish organ injury or long-term safety.

Humans↗

PubMed2026

Multimodal intervention benefits: Responder analysis of J-MINT PRIME Kanagawa trial.

INTRODUCTION: The J-MINT PRIME Kanagawa trial was an 18-month multimodal intervention (incorporating exercise, nutrition, and metabolic management) for dementia prevention. Because the primary analysis showed no significant benefits, we performed an exploratory responder analysis to identify responsive subpopulations. METHODS: We analyzed the Full Analysis Set comprising 188 participants. Classification and regression tree (CART) analysis, applied to the intervention arm, identified baseline predictors of cognitive improvement. These rules were then applied to the entire cohort to evaluate treatment effects on the Mini-Mental State Examination (MMSE) using fully adjusted mixed-effects models for repeated measures (MMRM). RESULTS: CART identified a "Target Group" (N = 108) characterized by baseline profiles such as an MMSE score < 28 or specific metabolic ranges (e.g., LDL-C < 135 mg/dL). Within this target group, the intervention significantly preserved MMSE trajectories compared with the control group (group × time interaction, P = 0.022). In contrast, the Non-Target Group (N = 80), consisting of high-functioning individuals (MMSE ≥ 28), exhibited no significant group × time interaction. DISCUSSION: Multimodal interventions may effectively preserve global cognition in older adults with sub-threshold cognitive decline. Careful targeting of appropriate populations, while considering potential longitudinal measurement artifacts (e.g., practice effects), is essential. These findings provide a hypothesis-generating framework that warrants external validation in future prevention trials.

Humans↗

PubMed2026

Effects of phytosterols supplementation on hepatic lipid metabolism and metabolic outcomes in obese rodent models: a systematic review and meta-analysis.

This study aimed to synthesize and quantitatively assess the available evidence on the effects of phytosterol supplementation on hepatic lipid metabolism and obesity-related metabolic outcomes in obese rodent models, integrating biochemical, histological, and molecular evidence. A systematic search was conducted in electronic databases (PubMed, EMBASE, and Web of Science). Data on study design, population, intervention, outcomes, and risk of bias were extracted and analyzed. A quantitative meta-analysis was performed. Meta-analysis showed reductions in body weight, serum triglycerides, total cholesterol, LDL-C, VLDL-C, glucose, liver weight, hepatic cholesterol, hepatic triglycerides, and nonalcoholic fatty liver disease activity score. No significant changes were observed for adiposity index, HDL-C, insulin, or hepatic expression of PPARα, FAS, and SREBP1c. Conversely, CPT1A expression was significantly increased following PS supplementation. Subgroup analyses indicated that the beneficial effects on lipid and hepatic outcomes were generally consistent across rodent species (mice, rats, and hamsters), obesity induction models, and routes of administration, although the magnitude of responses varied between strains, with C57BL/6 mice showing more pronounced metabolic improvements. Additional analyses suggested that treatment duration and phytosterol composition may modulate specific outcomes, whereas dose-response meta-regression identified dose-dependent associations for serum and hepatic cholesterol, and PPARα expression in dietary supplementation studies. Overall, the available preclinical evidence suggests that phytosterol supplementation may improve several metabolic and hepatic outcomes in rodent models of obesity. However, the substantial heterogeneity across studies highlights the need for standardized experimental protocols and future clinical studies before these findings can be translated to human health.

Animals↗

PubMed2026

Association of lipoprotein-associated phospholipase A2 with recurrence risk and its predictive value in large artery atherosclerotic stroke.

OBJECTIVE: To investigate the association of lipoprotein-associated phospholipase A2 (Lp-PLA2) with large artery atherosclerotic (LAA) stroke and its predictive value for recurrence. METHODS: We consecutively enrolled 412 acute LAA stroke patients. Using a cutoff of 200 ng/mL, patients were divided into high and low Lp-PLA2 groups, and into recurrence and non‑recurrence groups based on 1‑year follow‑up. Baseline characteristics, lipid profiles, National Institutes of Health Stroke Scale (NIHSS) scores, and vascular stenosis degree were compared. Binary logistic regression and Receiver Operating Characteristic (ROC) analysis were used to identify independent risk factors and evaluate predictive value. RESULTS: The high Lp-PLA2 group had significantly higher low-density lipoprotein cholesterol (LDL-C), small dense low-density lipoprotein cholesterol (sdLDL-C), prevalence of severe stenosis (≥70%), and proportion of NIHSS > 15 (all P < 0.05). The recurrence group showed elevated Lp-PLA2, higher LDL‑C and sdLDL-C, more severe neurological deficits, and more severe stenosis (all P < 0.001). Multivariable regression identified elevated Lp-PLA2 (per 10 ng/mL: OR = 1.139, 95% CI: 1.089-1.191), moderate (OR = 3.145) and severe (OR = 11.663) neurological deficits, and severe stenosis (OR = 9.390) as independent risk factors for recurrence (all P < 0.05). The Area Under the Curve (AUC) of Lp-PLA2 was 0.75 (95% CI: 0.69-0.82), with an optimal cutoff of 208.95 ng/mL. CONCLUSION: Elevated Lp-PLA2 is associated with adverse lipid profiles, more severe neurological deficits, and greater vascular stenosis in LAA stroke patients, and independently predicts 1‑year recurrence. Lp-PLA2 shows moderate predictive value, supporting its potential for risk stratification.

Humans↗

PubMed2026

A GRADE-assessed systematic review and meta-analysis of randomized controlled trials evaluating the effects of olive leaf or olive pomace supplementation on cardiometabolic and anthropometric health markers.

AIMS: Cardiometabolic diseases (CMDs) are major contributors to global morbidity and mortality, and dietary bioactives such as polyphenols may modulate key risk factors. Olive by-products, particularly olive leaves (OL) and olive pomace (OP), are rich in phenolic compounds with antioxidant, anti-inflammatory, and cardiometabolic effects demonstrated across in vitro, preclinical, and clinical studies. DATA SYNTHESIS: This GRADE-assessed systematic review and meta-analysis included 30 randomized controlled trials (n = 1726) evaluating OL or OP supplementation on 21 standardized biomarkers, encompassing inflammatory markers, lipid profile, glycemic control, insulin sensitivity, anthropometric measures, and blood pressure. Meta-analyses were conducted using random-effects models, with effect sizes calculated as mean differences (or standardized mean differences for oxLDL). Between-study heterogeneity was assessed with I2 statistics, and sensitivity and subgroup analyses explored potential sources of variability. Publication bias was evaluated using Begg's test and funnel plots where appropriate. OL supplementation significantly improved lipid parameters (total cholesterol, triglycerides, LDL-C, ApoB, oxLDL) and increased ApoA1, while reducing TNF-α, systolic and diastolic blood pressure, body weight, and BMI. No significant effects were observed on glycemic markers. OP supplementation showed no consistent cardiometabolic benefits and was associated with an increase in IL-8. Certainty of evidence ranged from very low to high, with several outcomes downgraded due to imprecision, heterogeneity, or limited study numbers. CONCLUSION: These findings support the targeted use of OL as an adjunctive strategy for cardiometabolic risk management. Evidence for OP supplementation remains limited, underscoring the need for well-powered, high-quality RCTs to clarify its clinical effects.

Humans↗

PubMed2026

Probiotic supplementation improves body composition, lipid profiles, and fatty acid metabolism in combat sports athletes during the weight reduction phase.

PURPOSE: Pre-competition weight control for combat sports athletes may alter body composition and fatty acid metabolism. Probiotics have shown potential to regulate overall metabolism; however, their specific effects on fatty acid metabolism during weight control in athletes remain unclear. METHODS: Thirty-two combat sports athletes participating in the 4-week weight reduction period were assigned to either the probiotic group (Group E) or the placebo group (Group C). Body composition, lipid profiles, and fatty acid metabolism were measured before and after the 4-week weight reduction phase. RESULTS: All the athletes experienced a decrease in body weight, body mass index (BMI), body fat percentage, and muscle mass following the 4-week weight loss intervention. Notably, a more significant reduction in body fat percentage (p < 0.05) was observed, along with lower levels of triglycerides (TG) and low-density lipoprotein cholesterol (LDL-C), specifically in Group E. Weight loss intervention resulted in increased levels of short-chain fatty acids (SCFAs), specifically acetic acid, propionic acid, and butyric acid. Notably, Group E exhibited higher mean values for SCFAs compared to Group C (p < 0.05). Additionally, the serum levels of γ-linolenic acid and 8,11,14-eicosatrienoic acid were significantly reduced in Group E (p < 0.05). In contrast, the majority of free fatty acids (FFAs) showed significant increases, with greater magnitudes of change observed in Group C (p < 0.05). CONCLUSION: Probiotic supplementation can improve body composition, enhance SCFAs levels, and decrease circulating FFAs in combat sports athletes, suggesting that probiotics may have a beneficial impact on pre-competition weight management. TRIAL REGISTRATION NUMBER: chiCTR2400079908 (Reg Date:2024-01-16).

Humans↗

PubMed2026

X chromosome-wide association studies for quantitative trait loci based on the mixture of general pedigrees and additional unrelated individuals.

Genome-wide association studies have successfully identified many genetic variants associated with complex traits. However, most existing methods target autosomes rather than X chromosome, and several existing X chromosome-wide association studies (XWAS) at quantitative trait loci (QTL) largely focus on unrelated individuals, with limited attention to general pedigrees or mixture of general pedigrees and additional unrelated individuals (called the mixed data for brevity). In this study, we propose nine novel methods for XWAS at QTL in the mixed data (${\mathrm{MQX}}_{\mathrm{cat}}$, ${\mathrm{MQZ}}_{\mathrm{max}}$, ${\mathrm{MT}}_{\mathrm{plinkw}}$, ${\mathrm{MT}}_{\mathrm{chenw}}$, $\mathrm{MwM}3\mathrm{VNA}$, ${\mathrm{MQMVX}}_{\mathrm{cat}}$, ${\mathrm{MQMVZ}}_{\mathrm{max}}$, $\mathrm{MpMV}$, and $\mathrm{McMV}$), also applicable to general pedigrees alone. The first four methods test for mean differences across genotypes; the latter four test for differences in both means and variances; $\mathrm{MwM}3\mathrm{VNA}$ tests for variance differences only. All mean-based and mean-variance-based methods incorporate X chromosome inactivation information, and all nine methods consider genetic relatedness in pedigrees. Simulation studies confirm well-controlled type I error rates, and inclusion of pedigrees significantly improves statistical power. Note that there has been no study focusing on X chromosome for the mixed data or general pedigrees from UK Biobank database, so we apply our proposed methods to this dataset, which identify five total cholesterol (TC)-associated and 13 low-density lipoprotein cholesterol (LDL-C)-associated single nucleotide polymorphisms (SNPs). Linkage disequilibrium (LD) analysis reveals that these SNPs fall into three distinct LD blocks. Functional annotation and gene ontology enrichment analysis reveal 16 and 28 enriched pathways for TC-associated and LDL-C-associated genes, respectively. These methods provide robust and powerful tools for XWAS at QTL in both mixed data and general pedigrees.

Quantitative Trait Loci↗

PubMed2026

Comparative efficacy of LDL-C-lowering therapies in first-time vs. recurrent myocardial infarction prevention: a meta-analysis of large-scale randomized controlled trials.

AIMS: Reducing elevated low-density lipoprotein cholesterol (LDL-C) is central to global efforts to prevent myocardial infarction (MI). While many studies have evaluated LDL-C-lowering therapies in first-time and recurrent MI prevention, direct comparisons of their relative efficacy are lacking. Therefore, we conducted a systematic review and meta-analysis to compare the efficacy of LDL-C-lowering therapies in first-time vs. recurrent MI prevention. METHODS AND RESULTS: We searched three databases until 30 November 2024, for randomized controlled trials (RCTs) with at least 1000 patient-years of follow-up. Efficacy was quantified as relative risk (RR) with 95% confidence intervals (CIs). Differences in benefit magnitude were assessed using Cochran's Q test. Data were pooled with a random-effects model, and heterogeneity was measured using the I2 statistic. Additionally, we applied the Cochrane Risk of Bias Tool to evaluate study quality and utilized the GRADE method to assess the certainty of the evidence. This study included 22 large-scale RCTs involving 180 304 participants. In first-time MI prevention, LDL-C-lowering therapies achieved a remarkable 38% reduction in MI risk [12 RCTs; 79 604 participants; RR, 0.62 (95% CI, 0.55-0.69); P < 0.001]. In recurrent MI prevention, these therapies were associated with a more modest but significant 16% risk reduction [11 RCTs; 100 700 participants; RR, 0.84 (95% CI, 0.80-0.88); P < 0.001]. Importantly, the benefit magnitude between the two groups was significantly different (Q = 22.63; P < 0.001), highlighting the greater relative benefit in first-time MI prevention. Furthermore, the robustness of our findings was consistently supported by leave-one-out analyses, the absence of publication bias, high-quality GRADE evidence, and subgroup and sensitivity analyses. CONCLUSION: Our findings suggest that LDL-C-lowering therapies may offer a greater benefit in preventing first-time MI compared with recurrent MI.

Humans↗

PubMed2026

Efficacy and Safety of Ultra-Low Starting Dose Febuxostat Titration in Male Patients With Primary Gout.

BACKGROUND: Since gout is a common metabolic arthritis caused by urate crystal deposition, urate-lowering therapy (ULT) is clearly indicated, but the initiation of ULT frequently causes paradoxical acute flares that in turn impair patient adherence. OBJECTIVE: This study sought to assess the effectiveness and safety of an ultra-low-dose initiation strategy for febuxostat (10 mg/day) compared to the standard starting dose (20 mg/day) in reducing initiation-related flares while maintaining long-term urate control. METHODS: 120 male patients with primary gout presenting with acute arthritis were randomly assigned to initiate febuxostat at 10 mg/day (Group A) or 20 mg/day (Group B), with protocol-mandated biweekly titration. The primary outcomes were gout flare frequency over 24 weeks (assessed using Poisson regression), serum uric acid (SUA) target attainment, and the incidence of adverse events. RESULTS: Although both groups achieved comparable target SUA levels by week 24, Group A demonstrated a significantly lower overall flare incidence (36.7% vs. 70.0%; p < 0.001), along with a greater percentage of flare-free patients (70.0% vs. 46.7%; p = 0.016). Multivariable Poisson regression revealed that Group B had an approximately twofold higher risk of flares compared to Group A (Incidence Rate Ratio = 1.95; p = 0.012), with obese patients deriving the most pronounced benefit from the ultra-low-dose approach. To avert one additional flare, the calculated number needed to treat was 4.3. Additionally, the occurrence of clinically significant liver injury (ALT/AST > 3× ULN) was low in both groups, with 3.3% in Group A and 1.7% in Group B. Multivariable regression analysis confirmed that LDL-C is an independent predictor of ALT (β = 12.90, p = 0.009), while febuxostat dosage was not linked to hepatotoxicity. CONCLUSION: Initiating febuxostat at a dose of 10 mg/day with gradual titration demonstrates a superior safety profile by effectively reducing early acute flares without compromising long-term urate control, which is particularly advantageous for high-risk cohorts, including obese patients.

Humans↗