Search Results (1,667)

Background/Objectives: Cardiovasc{Citation}ular disease accounts for 50% of chronic kidney disease (CKD) mortality, yet fewer than 40% of patients achieve guideline LDL-cholesterol (LDL-C) targets on statins. Injectable lipid-lowering therapies (ILLTs)—PCSK9 inhibitors and inclisiran—offer 50–70% LDL-C reductions but lack comprehensive CKD-specific evidence synthesis. This systematic review evaluated ILLT efficacy, safety, and implementation across kidney function stages including dialysis. Methods: Following PROSPERO registration (CRD42024612594), we searched MEDLINE, Embase, Cochrane Library, CINAHL, and Google Scholar (1995–August 2025). Two reviewers independently screened studies using PICOS criteria: adults with CKD stages G3-G5, dialysis, or transplant recipients receiving injectable lipid therapies. Primary outcomes were LDL-C percentage change and major adverse cardiovascular events. Quality was assessed using NIH tools. Given heterogeneity, we performed narrative synthesis following SWiM guidance. Results: Eight studies (n = 28,013) met the criteria. The FOURIER trial demonstrated that evolocumab achieved 58–59% LDL-C reductions across kidney function strata (interaction p = 0.77) with preserved cardiovascular benefit (HR 0.82–0.89). Absolute risk reduction was greater in advanced CKD (2.5% vs. 1.7%), reflecting higher baseline rates. Pharmacokinetic studies showed no eGFR-exposure correlation requiring dose adjustment; evolocumab was not removed by haemodialysis. Inclisiran achieved a 67–80% PCSK9 reduction and a 35–58% LDL-C reduction across renal groups, with twice-yearly maintenance dosing. Both classes reduced non-HDL-C (45–50%), apoB (40–45%), and lipoprotein(a) (20–25%). Safety was favourable, with mild injection-site reactions (< 5%); no renal decline signals emerged. Conclusions: Evidence for injectable lipid-lowering therapies in CKD are driven largely by a single large post hoc subgroup analysis (FOURIER) and small phase 1–2 PK/PD studies, with minimal dialysis representation and no transplant data. These agents appear to provide substantial LDL-C reductions across CKD stages G3–G5 without dose adjustment, but cardiovascular and renal outcome data in advanced CKD and dialysis remain limited and should be interpreted cautiously. Full article

Background/Objectives: Metabolic alterations, including dyslipidemia, may influence tumor biology and treatment outcomes in neuroendocrine tumors. However, the clinical relevance of dyslipidemia and lipid-lowering therapy in bronchopulmonary neuroendocrine tumors (BP-NETs) treated with somatostatin analogues (SSAs) remains poorly defined. This translational proof-of-concept study evaluated progression-free survival (PFS) in patients with advanced BP-NETs receiving SSAs according to dyslipidemia and statin therapy and explored the effects of statin-SSA combination treatment in vitro. Methods: We retrospectively analyzed 24 patients with advanced well-differentiated BP-NETs treated with SSAs as first-line therapy. Fourteen patients (58.3%) had dyslipidemia, and 11 of them were receiving statins. In parallel, NCI-H727 cells were treated with atorvastatin (10 µM), lanreotide (5 or 10 µM), or their combination for 48–72 h. Cell viability, proliferation, cell death, apoptosis, DNA damage, and ATP production were assessed. Results: Median PFS was 22.5 months overall. A trend toward longer PFS was observed in non-dyslipidemic vs. dyslipidemic patients (70 vs. 36 months, p = 0.08). Among dyslipidemic patients, statin therapy was associated with a non-significant trend toward longer PFS compared with no statin therapy (36 vs. 18 months, p = 0.30). In vitro, combined atorvastatin–lanreotide treatment reduced cell viability and proliferation, increased cell death, enhanced cleaved caspase-3 and p-γH2AX expression, and reduced ATP production. Conclusions: These findings support the potential relevance of lipid metabolism modulation as an adjunct strategy in advanced BP-NETs while highlighting the need for larger prospective studies and dedicated biochemical investigation of the underlying lipid-related pathways. Full article

Background: Cardiovascular disease (CVD) represents the second leading cause of death among kidney transplant recipients (KTRs). CVD risks post-transplantation increase with aging, obesity, dyslipidemia, diabetes, hypertension, inactivity, sleep disturbances, immunosuppressant medications use, and graft dysfunction. This study assessed CVD prevalence and risk factors among KTRs. Methods: A cross-sectional study was conducted at National Guard Hospital, Jeddah between 2012–2022. Information was collected from the patients’ medical records. Physical activity, sleep, and adherence to immunosuppressant therapy were evaluated via interviews with adult KTRs using the International Physical Activity Scale, Jenkins Sleep Scale, and Immunosuppressant Therapy Barrier Adherence Scale, respectively. Results: Sixty-four KTRs were included: 67% were males, and the median age was 44.7 years. Eighteen patients (28.1%) had CVD, and 61.1% of them developed ischemic heart disease. KTRs with CVD were older, had lower estimated glomerular filtration rate (eGFR), and higher Hemoglobin A1c (HbA1c), but these differences were not statistically significant (p > 0.05). Patients with CVD had significantly lower LDL (p = 0.02) and more aspirin and statin use (p < 0.05). Forty-five patients (70.3%) completed the interview; most of them had few sleep disturbances and good adherence to immunosuppressant therapy. Low physical activity was reported by KTRs with CVD. Conclusions: CVD was present in over one-quarter of KTRs. Patients with CVD were older, less active, had lower GFR, higher HbA1c, and significantly lower LDL. More use of aspirin and statin improved the glycemic control, physical activity, and medication adherence, and may help in reducing CVD burden among KTRs. Full article

Background: Statins have been associated with a reduced risk of primary liver cancer (PLC), primarily hepatocellular carcinoma (HCC). However, the optimal use for effective protection and whether benefits vary by patient characteristics remain unclear. We evaluated the association between statin use and PLC risk in metabolic-dysfunction-associated steatotic liver disease (MASLD), considering cumulative exposure and potential effect modifiers. Methods: We conducted a retrospective cohort study using the Veteran Affairs electronic health records. Patients with chronically elevated liver enzymes and metabolic dysfunction, without other chronic liver diseases, were identified between 2007 and 2009 and followed through 2019 for incident PLC. Statin exposure was assessed at baseline and during the follow-up, with dose standardization by LDL-lowering potency (simvastatin-equivalent units). Time to PLC was analyzed using Cox models adjusted for covariates, considering potential interactions. Results: Among 329,577 patients (92% male; median age 62 years), 0.82% developed PLC (median follow-up of 9.7 years). Baseline statin use showed a significantly lower PLC risk (adjusted hazard ratio 0.64; 95% CI, 0.57–0.71; p < 0.0001). No significant interaction was observed with age, sex, metabolic syndrome, or cirrhosis. Higher cumulative statin exposure demonstrated a dose-dependent risk reduction, remaining significant at simvastatin-equivalent doses > 15,561 mg annually after accounting for incident cirrhosis. Atorvastatin/rosuvastatin use provided comparable protection, despite different lipophilicity, and demonstrated stronger effects than others. Conclusions: In MASLD, statin therapy was associated with a dose-dependent PLC risk reduction. High-intensity therapy (simvastatin-equivalent > 40 mg daily) conferred substantial protection regardless of age, sex, insulin resistance, or cirrhosis, supporting a potential statin-based PLC chemoprevention in MASLD. Full article

Despite the availability of numerous lipid-lowering agents, the treatment of lipid disorders remains a public health challenge. A substantial portion of patients, especially those with severe dyslipidemia or familial hypercholesterolemia (FH), fail to achieve the LDL-C goal. The leading causes of suboptimal LDL-C control include underprescription and poor adherence; however, in rare cases, it may result from an unusual biological response to treatment. In the presented case, a 78-year-old female with a history of transient ischemic attack and myocardial infarction was diagnosed with a heterozygous variant of FH and true statin intolerance following trials of simvastatin, rosuvastatin and pitavastatin. Initially, inclisiran was added to ezetimibe, leading to an unexpected increase in LDL-C. Due to the patient’s refusal of another statin re-challenge and the unavailability of bempedoic acid, nutraceuticals were introduced. After 6 months, inclisiran was discontinued because only a 22% reduction in LDL-C was achieved, likely attributable to the nutraceutical’s effect. Another PCSK9 inhibitor, evolocumab, was subsequently initiated. Shortly after the treatment onset, the patient complained of paraesthesia in the upper extremities and discontinued therapy. LDL-C levels increased by 7% after one month of treatment with evolocumab. The patient refused treatment with lipid apheresis. Possible causes of poor response to PCSK9 inhibitors include elevated lipoprotein(a) and FH. Full article

When using traditional approaches, such as pharmacokinetics and pharmacodynamics, the entire cellular or molecular response to drugs in the body cannot be fully ascertained or established. The oral medication process involves pharmacokinetics, followed by oral microbiomics and then gut microbiomics and pharmacodynamics. Recently, there has been increasing interest in the role of genetics (pharmacogenetics and pharmacogenomics) in both humans and microbiomes, as well as omics alterations (e.g., epigenetic, transcriptomic, proteomic, and metabolomic alterations as a consequence of drug exposure), which can help to ascertain the cellular responses to medications. Both the efficacy and toxicity of a drug are influenced by these factors. To assess these at an individual level, an integrative Personalized Medicine Model may be needed to help with medication management. Two example application cases for SSRIs and statins demonstrate the clinical usefulness of such a model, which can guide clinicians during drug selection and dosing to reduce reliance on trial-and-error, thus potentially improving patient outcomes and safety. Integrating this framework into practical clinical workflows requires the capture, analysis, and translation of multi-omics data in order to realize decision support protocols and actionable drug recommendations. This review also discusses IT requirements and different stakeholder roles. Although the proposed model can guide the treatment of diseases at the individual patient level, further research is still needed before it can be implemented as part of drug development research, clinical care, and healthcare delivery systems. Full article

Background/Objectives: The study’s goal is to assess the association between long-term statin therapy and influenza incidence, influenza severity, and all-cause mortality. Methods: Two population-based dynamic cohorts (exposed and unexposed to statins) were followed from 2010 to 2019. Participants were 60 years or older; frail patients were excluded. The primary outcomes were influenza incidence, influenza-related intensive care unit (ICU) admission as a proxy for severity, and all-cause mortality. The exposed cohort comprised new statin users with a minimum of two pharmacy invoices within 90 days of enrollment. Adjusted risk ratios (aRRs) for influenza incidence, ICU admission, and mortality rate were calculated using Poisson regression. Results: The initial study population of 639,564 individuals was evenly split into exposed (319,782) and unexposed (319,782) cohorts; mean age was 71 years (standard deviation: 8 years), and 57% were women. Compared to non-users, new statin users showed a higher influenza incidence [9.39 (95% confidence interval: 9.36–9.42) vs. 7.64 (7.61–7.66) per 1000 person-years], ICU admission [1.65 (1.65–1.66) vs. 1.36 (1.35–1.36) per 1000 person-years], and overall mortality rate [97.09 (96.75–97.43) vs. 94.15 (93.82–94.47) per 1000 person-years]. Adjusted analysis revealed no significant association between statin use and influenza incidence [aRR: 1.04 (0.98–1.10)] or influenza-related ICU admission [aRR: 1.03 (0.89–1.19)] and shifted the effect on mortality from harmful to beneficial [aRR: 0.88 (0.87–0.89)]. Conclusions: Despite new users’ greater vulnerability at the start of treatment, our findings indicate that statins do not influence influenza incidence or severity but reduce all-cause mortality, warranting further exploration of their anti-inflammatory properties. Full article

Pancreatic ductal adenocarcinoma (PDAC) has limited effective therapeutic strategies. Statins inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and may affect tumor cell fitness via the mevalonate pathway, mitochondrial function, and redox homeostasis. We systematically compared seven statins in patient-derived PDAC cell lines and related viability effects to mitochondrial, redox, cell-cycle, apoptotic, and metabolic responses. Statins were tested in three PDAC cell lines (PDAC-1/2/3) using MTT assays (5–20 µM; 24–120 h). Based on MTT responses, mechanistic profiling was performed after 72 h at 20 µM concentration using lipophilic statins, including apoptosis (Annexin V/7-AAD), cell-cycle distribution, mitochondrial membrane potential (Δψm), intracellular ROS, and ¹H-NMR quantification of intracellular and extracellular metabolites. Statins reduced viability in a concentration- and time-dependent manner, with lipophilic statins more active than hydrophilic. PDAC-1 was highly sensitive, PDAC-3 intermediate, and PDAC-2 comparatively resistant. PDAC-1 and PDAC-3 showed G0/G1 accumulation, Δψm depolarization, reactive oxygen species (ROS) elevation, and Annexin V–positive apoptosis, whereas PDAC-2 (high basal ROS) showed ROS reduction and limited apoptosis despite Δψm loss. Metabolomics indicated reduced glucose and amino-acid utilization and lactate secretion while preserving line-specific metabolic fingerprints. PDAC cell lines display marked inter-tumoral heterogeneity in statin responses, supporting evaluation of statins as chemosensitizing adjuvants in functionally guided PDAC treatment strategies. Full article

Background: Sortilin (SORT1), linked to the 1p13.3 coronary risk locus, is implicated in lipid trafficking and atherogenesis; however, clinical studies of circulating SORT1 have produced inconsistent results. We evaluated whether circulating SORT1 is associated with angiographic burden and lesion localization in patients with premature or early clinical debut coronary atherosclerosis. Methods: This single-center, cross-sectional study analyzed a dataset collected from January to May 2023. Participants were classified as coronary atherosclerosis cases if the dataset contained an age of clinical debut of clinically significant atherosclerosis (n = 101). Controls had no recorded debut age and 0% stenosis in all assessed coronary segments (n = 27). Blood was collected in clot activator tubes; serum was stored at −40 °C until analysis. SORT1 (ng/mL) was measured using an Aviscera Bioscience ELISA. Coronary stenoses were recorded as percent diameter stenosis for left main (LM), proximal/mid/distal LAD, proximal/mid/distal LCx, and proximal/mid/distal RCA. Burden metrics included the number of segments with any stenosis (>0%), the number of obstructive segments (≥50%), the number of diseased vessels, and maximum stenosis. The prespecified primary endpoint was obstructive proximal LAD stenosis (≥50%). Nonparametric tests and Spearman correlations were used. Logistic regression evaluated the association between log2-transformed SORT1 and proximal LAD obstruction, adjusted for age, sex, LDL-C, statin use, and smoking/diabetes/hypertension durations. Results: SORT1 was higher in cases than controls (8.60 [2.60–17.10] vs. 2.30 [1.25–10.65] ng/mL; p = 0.0058). Within cases, SORT1 did not correlate with global angiographic burden (any-stenosis segments: ρ = −0.066, p = 0.513; obstructive segments: ρ = −0.060, p = 0.552; diseased vessels: ρ = −0.045, p = 0.652; maximum stenosis: ρ = −0.084, p = 0.403). Obstructive proximal LAD stenosis occurred in 44/101 (43.6%) and was associated with higher SORT1 (12.25 [4.18–17.45] vs. 4.10 [2.20–11.60] ng/mL; p = 0.0093). Each doubling of SORT1 was independently associated with proximal LAD obstruction (adjusted OR 1.48, 95% CI 1.12–1.95; p = 0.005). Conclusions: In this cross-sectional cohort, circulating SORT1 was associated with obstructive proximal LAD stenosis but not with global angiographic burden metrics. These findings are hypothesis-generating and warrant validation in independent cohorts with standardized preanalytics and prospective designs to assess temporal relationships and clinical utility. Full article

Background: Statins are central to primary and secondary prevention of atherosclerotic cardiovascular disease but are often underutilized due to myopathy and intolerance. While individual pharmacogenetic (PGx) variants, particularly in SLCO1B1, are linked to statin-associated muscle symptoms, the real-world impact of both clinical and cumulative PGx burden on regimen modification and adverse outcomes remains unclear. We aimed to evaluate the existing uncertainty regarding whether combined PGx scores can effectively guide statin dose titration and regimen modification, thereby filling a key clinical gap. Methods: A retrospective cohort study of 911 statin-treated patients with coronary artery disease was conducted from the Qatar Cardiovascular Biorepository with available whole-genome sequencing data. Variants in SLCO1B1, ABCG2, and CYP2C9 were combined into a functional PGx burden score, and their associations with statin regimen modification, intolerance, myopathy, liver injury, adherence, and composite adverse events were evaluated. The composite adverse events were defined as the occurrence of any statin-related adverse event, including statin-associated myopathy, liver injury, or poor medication adherence, during the follow-up period. Patients were classified as having experienced the composite outcome if at least one of these events occurred. Results: Over 12 months following statin initiation, 10.2% of patients underwent dose escalation, 11.4% de-escalation, and 78.4% remained on the same regimen. PGx burden is not statistically significantly associated with statin intolerance (OR 1.14; 95% CI: 0.73–1.76), composite adverse outcome (OR 1.08; 95% CI 0.82–1.42), or time to regimen change (HR 1.02; 95% CI 0.77–1.35). However, higher PGx burden showed a directional tendency toward dose de-escalation (RRR 1.18, 95% CI 0.76–1.84) and lower likelihood of escalation (RRR 0.93, 95% CI 0.56–1.54). Conclusions: Clinical factors, particularly statin intensity and myopathy, were the primary determinants of regimen modification. The PGx burden contributes to vulnerability to statin-related adverse effects in a context-dependent manner but does not independently drive statin regimen modification in routine clinical practice. Prospective studies are warranted to assess the clinical utility of PGx-guided workflows in statin therapy. Full article

HIV infection can promote persistent immune activation and endothelial dysfunction, contributing to atherosclerosis. Carotid intima–media thickness (cIMT) is an established marker of subclinical atherosclerosis. We evaluated the association between cIMT severity and two routinely available markers of immune dysregulation (CD4/CD8 ratio and nadir CD4+ cell count) in people living with HIV (PLWH). We conducted an Italian multicenter cross-sectional study including 1148 PLWH who underwent carotid color Doppler ultrasound. We classified cIMT as ≤0.9, 1.0–1.4, or >1.4 mm and analyzed these categories using multinomial logistic regression, reporting adjusted odds ratios (aORs) with 95% confidence intervals (CIs). We adjusted models for age, sex, BMI, HIV acquisition risk factor, hypertension, diabetes, dyslipidemia/statin use, triglycerides, integrase inhibitor use, and ART duration. cIMT was ≤0.9 mm in 615 (53.6%) participants, 1.0–1.4 mm in 379 (33.0%), and >1.4 mm in 154 (13.4%). Using nadir CD4+ ≥ 200 cells/µL and CD4/CD8 ≥ 1.0 as reference, PLWH with nadir CD4+ < 200 and CD4/CD8 ≥ 1.0 had higher odds of cIMT 1.0–1.4 mm (aOR 1.66, 95% CI 1.02–2.69) and >1.4 mm (aOR 3.45, 95% CI 1.68–7.07). In conclusion, CD4+ nadir and this combined pattern were associated with greater cIMT severity, supporting a role for immune dysregulation in subclinical atherosclerosis. Full article

Background/Objectives: Many patients with acute coronary syndrome (ACS) fail to achieve adequate low-density lipoprotein-cholesterol (LDL-C) reduction, despite receiving high-intensity statin therapy. Identifying patients requiring early combination therapy remains a challenging task. This study aimed to determine the prevalence of statin hyporesponsiveness in patients with ACS and investigate the predictive role of baseline LDL-C and albumin levels. Methods: This retrospective study enrolled 366 patients with ACS treated with high-intensity statins (atorvastatin 40–80 mg). Hyporesponsiveness was defined as LDL-C reduction of <50% at 21–28 d. The baseline parameters were analyzed using logistic regression and receiver operating characteristic (ROC) curve analysis. Results: Hyporesponsiveness was observed in 63.1% of patients. Hyporesponders had significantly lower baseline albumin (41.7 vs. 43.3 g/L, p = 0.0002) and LDL-C (126.6 vs. 147.3 mg/dL, p < 0.0001) levels. Categorical analysis revealed that the combination of baseline LDL-C < 100 mg/dL and albumin < 40 g/L predicted hyporesponsiveness in 95.7% of cases. ROC curve analysis identified optimal predictive cut-offs of 128.50 mg/dL for LDL-C (area under the curve (AUC): 0.652) and 41.15 g/L for albumin (AUC: 0.618). The combined LDL-C + albumin model demonstrated superior predictive performance with an AUC of 0.670 (95% CI: 0.615–0.725). Conclusions: Low baseline LDL-C and low albumin are strong predictors of statin hyporesponsiveness in patients with ACS. These routinely obtained biomarkers can identify very high-risk patients who may benefit from proactive combination lipid-lowering therapy from hospital discharge, supporting the “strike early and strike strong” strategy and challenging the traditional stepwise approach. Full article

Background/Objectives: Species of the Sporothrix genus were used as a biological model to identify potential antifungal compounds within the NIH Clinical Collection library. Methods: A total of 707 compounds were screened for antifungal activity using in vitro susceptibility assays. Compounds exhibiting significant inhibitory effects (growth inhibitions greater than 80%) were further evaluated by determining their minimum inhibitory concentrations (MICs). As cerivastatin demonstrated the highest activity after itraconazole, it was selected for further evaluation, either alone or in combination with itraconazole, using susceptibility assays, electron microscopy, and flow cytometry analyses. Results: Among the screened compounds, twenty-six showed significant inhibition of yeast growth (≥80%). Compounds with previously reported antifungal activity or not used as oral treatment were excluded from further analysis. MIC determination of eleven selected compounds revealed that cerivastatin inhibited the growth of Sporothrix brasiliensis, Sporothrix schenckii, and Sporothrix globosa at concentrations of 1.25 µM and 0.6 µM. Combination treatment with cerivastatin and itraconazole resulted in greater inhibition of Sporothrix growth than either agent alone. Flow cytometry and microscopic analyses revealed more pronounced morphophysiological alterations in yeast cells following combination treatment. Conclusions: These findings highlight the potential of cerivastatin as an antifungal agent when used in combination with itraconazole. Furthermore, the chemical scaffold of cerivastatin warrants further investigation as a basis for the development of novel statins with antifungal activity. Full article

This review presents an innovative and timely exploration of how cytoprotection can serve as a cohesive therapeutic approach by which to address the hemorrhage–thrombosis paradox. Presenting counteraction of both hemorrhage and thrombosis as phase-dependent outcomes of vascular dysregulation, the manuscript synthesizes conceptual, experimental, and clinical evidence into a unified systems-level model focused on the stable gastric pentadecapeptide BPC 157, which acts as a cytoprotective mediator. In rodents, BPC 157 can simultaneously counteract hemorrhage and thrombosis without directly affecting the coagulation cascade (aggregometry, thromboelastometry). This cytoprotective framework (decreased hemorrhage, decreased thrombosis) stands with presentation of both hemorrhage and thrombosis in the wound, arrhythmias, and Virchow triad, and resolution of these disturbances. As proof of the concept (full cytoprotective effect), a vasoprotective cytoprotective mediator capable of bidirectional regulation, BPC 157, is effective for wound healing, arrhythmia control, and normalization of Virchow’s triad (i.e., following major injuries, occlusion/occlusion-like syndromes). As a comparison from a cytoprotective (partial vs. full) standpoint, conventional agents—anticoagulants, antiplatelet drugs, and fibrinolytics—provide only partial protection by targeting isolated components of hemostasis. Beta blockers, calcium channel blockers, prostaglandins, NO modulators, ACE inhibitors, and statins each exert broader cytoprotective effects; however, these actions remain incomplete and context-dependent, typically unidirectional, dose-limited, or are achieved at the expense of opposing pathological risks. Contrarily, for BPC 157, decreased hemorrhage (including both anticoagulants and antiplatelet agents), decreased thrombosis, effective wound healing, arrhythmia control, and normalization of Virchow’s triad involve preservation of endothelial integrity, normalization of microcirculation, modulation of the NO system, stabilization of hemostatic balance, and recruitment of adaptive collateral pathways. Nevertheless, reliance on preclinical models necessitates further clinical validation. Full article

This critical integrative review reassesses the lipid paradigm by systematically mapping 380 influential trials and cohort studies on cholesterol, saturated fats, and statins in relation to cardiovascular and cognitive outcomes. The evidence base reveals a nearly even split between studies supporting and challenging LDL-centric causality, alongside pervasive methodological flaws, including reliance on surrogate lipid markers, ecological inferences, residual confounding, and industry-related reporting biases. Trial-generation comparisons and structured risk-of-bias assessment (ROB 2, ROBINS-I) repeatedly show that substantial pharmacological LDL reductions do not consistently yield proportional reductions in myocardial infarction, stroke, or all-cause mortality. Integrating Mendelian randomization with clinical and metabolomic data, the review advances a Critical Window Hypothesis in which LDL is necessary but not sufficient for atherogenesis, exerting dominant causal influence during early and midlife plaque initiation, while inflammatory, oxidative, and hemodynamic factors become primary drivers in advanced disease. Metabolomic studies of extreme longevity and late-life cohorts demonstrate that bile acids, steroid metabolites, and low-glycemic metabolic profiles—not total cholesterol—better predict survival and cognitive preservation, and that higher LDL in the oldest-old often associates with lower mortality and dementia risk. These findings challenge universal LDL-centric policies and support lifestyle medicine strategies prioritizing systemic metabolic optimization over isolated cholesterol targets. Full article