The clinical significance of diabetes mellitus (DM) on the cardiovascular disease in the zero coronary artery calcium (CAC) group is not well studied. This study investigated the impact of DM in an asymptomatic population with zero CAC scores. Overall, 9269 adults who received coronary computed tomography angiography (CCTA) scans for coronary disease evaluation during a general medical checkup were initially selected. After excluding participants with CAC >0, 4139 were included in the analysis. Baseline characteristics, CCTA findings including significant stenosis ≥50%, and clinical outcomes were assessed, including all-cause death, cardiovascular death, myocardial infarction (MI), or revascularization. The average age was 51.8 years, and 2706 participants (65.3%) were male. DM group had a higher prevalence of noncalcified plaque (16.7% vs 11.6%), significant stenosis (3.4% vs 1.5%), and a greater atherosclerosis burden than the non-DM group. DM was identified as a significant predictor of significant stenosis (adjusted odds ratio 1.88 [1.07-3.33], p = 0.029). During the median follow-up of 5.3 years, participants with DM experienced a higher rate of revascularization (1.2% vs 0.3%, adjusted hazard ratio 3.64 [1.25-10.56], p = 0.018), with a remarkably low incidence of cardiovascular death (0% vs 0.1%) and MI (both 0%). The risk of significant stenosis and revascularization increased gradually according to the severity of DM. In conclusion, asymptomatic patients with DM and zero CAC scores may face an increased risk of coronary artery disease presence compared to non-DM individuals. Despite zero CAC suggesting a low risk of cardiovascular disease, patients with DM may still exhibit a demonstrable atherosclerotic burden.

Atherosclerosis (AS) is a major pathological factor contributing to the mortality associated with ischemic heart disease and is driven primarily by macrophage-mediated lipid accumulation and inflammatory processes. Conventional cardiovascular pharmacotherapies address these pathological mechanisms but often show limited efficacy, highlighting the need for innovative agents capable of effectively reducing lipid accumulation and inflammation with minimal toxicity. In this study, decursin, a monomer derived from traditional Chinese medicine, is shown to inhibit both lipid accumulation and inflammatory responses in macrophages through direct interaction with protein kinase Cδ (PKCδ), resulting in low cytotoxicity in vitro and negligible toxicity in vivo. To address the short half-life of decursin, a targeted cascade drug delivery system (ALD@EM), which is specifically designed to target AS pathophysiology, is developed. This system employs ICAM-1 and VCAM-1 antibodies for plaque localization and incorporates low-density lipoproteins (LDLs) to facilitate chemotaxis to lesion sites, with an inner layer of apoptotic endothelial cell membranes to increase macrophage internalization and drug release. As a result, ALD@EM nanovesicles significantly increased the accumulation and therapeutic efficacy of decursin within plaques, substantially reducing lipid deposition and plaque inflammation, thereby offering a novel strategy for targeted AS treatment.

Metabolic syndrome (MetS) is defined by the presence of at least three of five clinical parameters including abdominal obesity, insulin resistance, elevated triglycerides, reduced high-density lipoprotein (HDL) and hypertension. Major features describing MetS have been recognized risk factors for cancer onset, with an alarming impact on gastrointestinal (GI) tumors. Intriguingly, therapeutic administration of drugs to improve glycemic control and dyslipidemia (including metformin, statins) has been shown to have a preventive role in the development and in prognosis improvement of several cancer types. Overall, these observations highlight the key role of altered metabolism prevalently in cancer risk development and unveil anti-MetS agent repurposing potential beyond their conventional pharmacological action. The objective of this review is to summarize the current knowledge about the antitumor activity of anti-diabetic and anti-lipemic agents in GI cancer onset and progression. Here, pre-clinical evidence of their therapeutic potential and of their integration in novel compelling therapeutic strategies will be discussed. Possible clinical outcomes of these novel therapeutic combined protocols specifically dedicated to GI cancer patients will be put under the spotlight. In the future, these novel therapeutic options should be considered to improve conventional chemotherapy response and prognosis of this group of patients.

The intricate linking between the health of blood vessels and the functioning of neurons has attracted growing attention in the context of disorders that affect the neurological environment. Endothelial cells, forming the blood-brain barrier and blood-retinal barrier, play a fundamental role in maintaining the integrity of the brain-retina microenvironment connection. This review explores the molecular foundations of endothelial cell dysfunction and its implications for the brain-retina interaction. A comprehensive analysis of the complex factors contributing to endothelial dysfunction is presented, including oxidative stress, inflammation, reduced nitric oxide signaling, and disrupted vascular autoregulation. The significance of endothelial dysfunction extends to neurovascular coupling, synaptic plasticity, and trophic support. To our knowledge, there is currently no existing literature review addressing endothelial microvascular dysfunction and its interplay with the brain-retina microenvironment. The review also explains bidirectional communication between the brain and retina, highlighting how compromised endothelial function can disrupt this vital crosstalk and inhibit normal physiological processes. As neurodegenerative diseases frequently exhibit vascular involvement, a deeper comprehension of the interaction between endothelial cells and neural tissue holds promise for innovative therapeutic strategies. By targeting endothelial dysfunction, we may enhance our ability to preserve the intricate dynamics of the brain-retina microenvironment connection and ameliorate the progression of neurological disorders.

The widespread use of long-term pharmacological treatments for chronic conditions has led to polypharmacy, raising concerns about adverse effects and interactions. Deprescribing, the discontinuation of drugs with unfavorable benefit-risk ratios, is gaining attention. Studies evaluating the discontinuation of drugs have a broad methodological spectrum. The selection of outcomes poses a particular challenge. This scoping review addresses the methodological challenges of outcome selection in RCTs investigating drug discontinuation.

The scoping review includes RCTs that investigated the discontinuation of drugs whose efficacy and/or safety was in doubt. Data on study characteristics, the motivation for evaluating drug discontinuation, the number and type of primary endpoints, and the stated hypotheses were extracted and analyzed.

We included 103 RCTs. Most studies were from Europe and the USA and mainly investigated antipsychotics/antidepressants, immunosuppressants, steroids and antiepileptics. The discontinuation studies were often conducted due to side effects of the treatment and doubts about the benefits of the drug. The primary endpoints reflected either the course of the disease ("justification of treatment") or the disadvantages of the drug ("justification of withdrawal"). Non-inferiority hypotheses were generally prevalent in justification of treatment studies, while superiority hypotheses were more commonly used in justification of withdrawal studies. However, due to methodological and practical challenges this was not always the case.

We present a framework to choose outcomes and specify hypotheses for discontinuation studies. With regard to this, both key challenges (justification of treatment and justification of withdrawal) must be met.

Heart failure (HF) often coexists with cancer. Beyond the known cardiotoxicity of some cancer treatments, HF itself has been associated with increased cancer incidence. The 2 conditions share common risk factors, mechanisms, and interactions that can worsen patient outcomes. The bidirectional relationship between HF and cancer presents a complex interplay of factors that are not fully understood. Recent preclinical evidence suggests that HF may promote tumor growth via the release of protumorigenic factors from the injured heart, revealing HF as a potentially protumorigenic condition. Our review discusses the biological crosstalk between HF and cancer, emphasizing the impact of HF on tumor growth, with inflammation, and modulating the immune system as central mechanisms. We further explore the clinical implications of this connection and propose future research directions. Understanding the mechanistic overlap and interactions between HF and cancer could lead to new biomarkers and therapies, addressing the growing prevalence of both conditions and enhancing approaches to diagnosis, prevention, and treatment.

Type 2 diabetes mellitus (T2DM) is a global health crisis, with cardiovascular disease (CVD) accounting for 75% of mortality in this population. Despite advances in managing traditional risk factors, such as low-density lipoprotein cholesterol (LDL) cholesterol reduction (IMPROVE-IT, FOURIER), antithrombotic therapies (PEGASUS, COMPASS), and triglyceride-lowering agents (REDUCE-IT), a substantial residual cardiovascular risk persists, driven in part by chronic low-grade systemic inflammation. Chronic low-grade inflammation is a central driver of cardiovascular-kidney-metabolic (CKM) syndrome in T2DM, perpetuating residual cardiovascular risk despite optimal management of traditional risk factors. This narrative review synthesizes evidence on how inflammation accelerates coronary heart disease (CHD), heart failure (HF), stroke, diabetic kidney disease (DKD), and peripheral artery disease (PAD). We evaluate the anti-inflammatory mechanisms of current therapies such as statins, sodium-glucose cotransporter 2 (SGLT2) inhibitors, and glucagon-like peptide 1 (GLP-1) receptor agonists, as well as emerging agents like colchicine and interleukin (IL)-1β/IL-6 inhibitors, emphasizing their differential efficacy across CKM traits. By integrating pathophysiological insights with clinical trial data, we propose biomarker-guided strategies to target inflammation as a modifiable risk factor, offering a roadmap to bridge the gap in diabetes-related cardiovascular care.

All commonly prescribed statins have been reported to cause reversible memory loss within weeks of therapy, though the exact molecular mechanism remains unknown. However, whether therapeutic concentrations of statins can directly regulate the contractility of resistance cerebral arteries that control cerebrovascular perfusion remains unexplored. Here, we examined the acute vascular effects of statins on rat cerebral arteries and the underlying molecular mechanisms. Our pressure myography data demonstrate that, at therapeutically-relevant nanomolar concentrations, statins produced a robust and rapid vasoconstriction, appearing within 2-3 min of drug application. Interestingly, such vasoconstriction was largely absent in female rat cerebral arteries. Endothelial denudation or mevalonate supplementation did not alter statin-induced vasoconstriction, suggesting an endothelium- and cholesterol-independent mechanism. In contrast, such vasoconstriction was abolished upon removal of extracellular Ca2+, pharmacological blockade of the smooth muscle cell voltage-gated Ca2+ channel, CaV1.2, or siRNA knockdown of CaV1.2 - all of which reduced [Ca2+]i, indicating that Ca2+ entry through CaV1.2 plays a critical role in cerebral artery vasoconstriction. Arterial biotinylation revealed that acute statin exposure did not alter the surface expression, distribution, or function of CaV1.2 channels. Altogether, our data unveil an unexpected role of statins in rapidly inducing constriction of resistance cerebral arteries by directly stimulating CaV1.2 in smooth muscle cells. These findings offer a plausible explanation for statin-associated reversible memory impairment, its mitigation by calcium channel blockers, and why such effects may not be observed in all subjects, particularly those concurrently taking antihypertensive agents.

This study aimed to compare the lipid-lowering effect and safety of low-intensity atorvastatin (5 mg) plus ezetimibe (10 mg) combination therapy (A5E10) with monotherapy regimens-atorvastatin 5 mg [A5], ezetimibe 10 mg [E10], and atorvastatin 10 mg [A10])-in dyslipidemia patients.

A randomized, double-blind, placebo-controlled trial involving 252 dyslipidemia patients was conducted at 25 centers in South Korea (NCT05970679). Participants aged ≥ 19 years were randomized into four groups: A5E10, A5, E10, and A10. The primary endpoint was the percentage change in low-density lipoprotein cholesterol (LDL-C) levels from baseline to 8 weeks. Secondary endpoints included changes in other lipid parameters, lipid ratios, LDL-C goal achievement rates and safety assessments.

The mean age of the patients was 63 years, and 51.2% were male. The A5E10 group showed significantly greater LDL-C reduction (47.6%) compared with A5 (33.4%), E10 (19.4%), and A10 (40.1%) at 8 weeks (p < 0.0001). A5E10 also significantly reduced triglyceride, non-high-density lipoprotein cholesterol, and apolipoprotein B levels. In addition, a significant reduction in LDL-C levels was observed over the 4 weeks, with a 46.7% reduction in LDL-C levels after 4 weeks of A5E10 administration. No severe adverse events were observed in the A5E10 group.

The combination of low-intensity atorvastatin and ezetimibe was more effective than moderate-intensity atorvastatin monotherapy in lowering LDL-C levels and improving other lipid parameters. It was well-tolerated and demonstrated rapid benefits within a month, offering a promising alternative for patients with low to moderate cardiovascular risk who do not achieve adequate control with statin monotherapy.

Aortic stenosis (AS) is the most common valvular disease, characterized by progressive fibro-calcific remodeling of the aortic leaflets, leading to increased morbidity and mortality. It is now well known that statins influence the production of proprotein convertase subtilisin/kexin type 9 (PCSK9), which in turn is linked to calcification. Here, we found that statins significantly increased, in a dose dependent manner, both PCSK9 secretion and valve interstitial cell (VIC) calcification, in vitro. These effects were blunted by PCSK9 genetic knock-down or by PCSK9 antibody neutralization. In AS patients, contrast-enhanced computed tomography evaluation showed a higher aortic valve calcium (AVC) content in patients on high-intensity statins compared to low-intensity ones, with no significant difference between low-intensity statin and non-users. At follow-up, high-intensity statin users exhibited a higher annual AVC accumulation compared to low-intensity statins and non-users. In a real-world scenario, high-intensity statin therapy was associated with a 30 % increased rate of hospitalization for non-rheumatic aortic valve disease. Our findings highlight the need for further investigation into the intricate relationship between statin therapy and aortic valve health to identify the optimal lipid-lowering strategy in the management of patients at risk of developing or afflicted by AS.

To identify pharmacological randomized controlled trials (RCTs) with "positive" outcomes driven by nonfatal myocardial infarction (MI) reductions and assess related guideline recommendations.

RCTs published between 2000 and 2024 focusing on mortality and nonfatal MI were identified through searches in PubMed and Web of Science. Citation tracking was used to find trials referenced in clinical guidelines. The levels of guideline recommendations based on the supporting trials were summarized. The impact of nonfatal MI on composite outcomes was assessed by using the leave-one-out method.

Of 21,005 records, 6 RCTs demonstrating positive outcomes due to nonfatal MI reduction were cited in current guidelines, including anti-thrombotic (3), intensive lipid-lowering (2), and anti-inflammatory (1) therapies. Intensive lipid-lowering trials (IMPROVE-IT, FOURIER; totaling 60 recommendations across 17 guidelines) were more frequently recommended in guidelines: 45% Class I, 33.3% Class IIa, and 21.7% Class IIb. Anti-thrombotic and anti-inflammatory trials had no Class I recommendations and higher Class IIb recommendations (66.7% and 100%). A meta-analysis including major intensive lipid-lowering RCTs on top of maximally tolerated statins (IMPROVE-IT, FOURIER, and ODYSSEY OUTCOMES) revealed no statistical difference in primary composite outcome after removing nonfatal MI events (relative risk 0.94, 95% confidence interval: 0.88-1.01).

In contemporary pharmacological RCTs with positive composite outcome driven by nonfatal MI reduction, intensive lipid-lowering trials are more frequently received strong guideline recommendations. This analysis underscores the need to evaluate whether these recommendations fully reflect the clinical significance of the observed benefits.

Background/aim: A growing body of evidence suggests a link between dyslipidemias and neurodegenerative diseases, highlighting the crucial role of lipid metabolism in the health of the central nervous system. The aim of our work was to provide an update on this topic, with a focus on clinical practice from an endocrinological point of view. Endocrinologists, being experts in the management of dyslipidemias, can play a key role in the prevention and treatment of neurodegenerative conditions, through precocious and effective lipid profile optimization. Methods: The literature was scanned to identify clinical trials and correlation studies on the association between dyslipidemia, statin therapy, and the following neurodegenerative diseases: Alzheimer's disease (AD), Parkisons's disease (PD), Multiple sclerosis (MS), and Amyotrophic lateral sclerosis (ALS). Results: Impaired lipid homeostasis, such as that frequently observed in patients affected by obesity and diabetes, is related to neurodegenerative diseases, such as AD, PD, and other cognitive deficits related to aging. AD and related dementias are now a real priority health problem. In the United States, there are approximately 7 million subjects aged 65 and older living with AD and related dementias, and this number is projected to grow to 12 million in the coming decades. Lipid-lowering therapy with statins is an effective strategy in reducing serum low-density lipoprotein cholesterol to normal range concentrations and, therefore, cardiovascular disease risk; moreover, statins have been reported to have a positive effect on neurodegenerative diseases. Conclusions: Several pieces of research have found inconsistent information following our review. There was no association between statin use and ALS incidence. More positive evidence has emerged regarding statin use and AD/PD. However, further large-scale prospective randomized control trials are required to properly understand this issue.

Introduction: Whether stroke survivors can meet risk factor recommendations set by guidelines is unknown. We investigated the proportion of stroke survivors that met the secondary prevention guideline recommendations, analyzed the trends over time, and assessed the impact on mortality. Methods: Using cross-sectional data on stroke survivors from the National Health and Nutrition Examination Survey (NHANES) from 1999-2018, we determined the proportion of stroke survivors who met guideline recommendations. We performed linear regression analyses to determine trends and performed Cox-proportional hazards models to assess mortality. Results: We included 2197 stroke survivors (51% female, mean age 68). Most patients met guidelines set for alcohol consumption (93% [95% CI 91-95]), while few met the thresholds for physical activity (18% [95% CI 15-30]) or BMI (25% [95% CI 22-27]). The proportion that met guidelines for blood pressure (+1.4% every 2 years) and LDL (+3.0%) increased, while the proportion that met physical activity guidelines decreased (-1.1%). Mortality was increased in those that did not meet recommendations regarding blood pressure (HR 1.24 [95% CI 1.04-1.48]) and smoking (HR 1.30 [95% CI 1.03-1.64]). Conclusion: More than half of stroke survivors do not meet recommendations set by prevention guidelines on BMI, physical activity and LDL.

The risk of atherosclerotic cardiovascular disease increases with advancing age. Elevated LDL-cholesterol and non-HDL-cholesterol levels remain predictive of incident atherosclerotic cardiovascular events among individuals older than 75 years. Risk prediction among older individuals is less certain because most current risk calculators lack specificity in those older than 75 years and do not adjust for co-morbidities, functional status, frailty, and cognition which significantly impact prognosis in this age group. Data on the benefits and risks of lowering LDL-cholesterol with statins in older patients without atherosclerotic cardiovascular disease are also limited since most primary prevention trials have included mostly younger patients. Available data suggest that statin therapy in older primary prevention patients may reduce atherosclerotic cardiovascular events and that benefits from lipid-lowering with statins outweigh potential risks such as statin-associated muscle symptoms and incident Type 2 diabetes mellitus. While some evidence suggests the possibility that statins may be associated with incident cognitive impairment in older adults, a preponderance of literature indicates neutral or even protective statin-related cognitive effects. Shared decision-making which is recommended for all patients when considering statin therapy is particularly important in older patients. Randomized clinical trial data evaluating the use of non-statin lipid-lowering therapy in older patients are sparse. Deprescribing of lipid-lowering agents may be appropriate for select patients older than 75 years with life-limiting diseases. Finally, a patient-centered approach should be taken when considering primary prevention strategies for older adults.

Elevated remnant cholesterol and low-density lipoprotein (LDL) cholesterol both increase the risk of coronary artery disease (CAD), but it is not known if the same is true for peripheral artery disease (PAD).

This study tested the hypothesis that elevated remnant cholesterol and LDL cholesterol, each independent of the other, have causal effects on risk of PAD.

The authors constructed genetic scores from variants near genes known to directly affect levels of remnant cholesterol and LDL cholesterol, identified through a genome-wide association study of individuals in the UK Biobank. Univariable (remnant cholesterol and LDL cholesterol genetic scores separately) and multivariable (remnant cholesterol and LDL cholesterol genetic scores combined) Mendelian randomization were used to estimate the causal effects of higher remnant cholesterol and LDL cholesterol levels on ORs for PAD (n = 38,414 cases and 758,308 controls) and CAD (n = 221,445 cases and 770,615 controls).

Increments in remnant and LDL genetic scores corresponding to 1 mmol/L (39 mg/dL) higher remnant and LDL cholesterol, respectively, were associated with univariable ORs for PAD of 2.72 (95% CI: 2.10-3.52) and 1.37 (95% CI: 1.25-1.51); corresponding multivariable ORs were 2.16 (95% CI: 1.49-3.12) and 1.14 (95% CI: 1.00-1.30). For CAD, corresponding univariable ORs were 2.92 (95% CI: 2.34-3.64) and 1.67 (95% CI: 1.56-1.79), whereas multivariable ORs were 1.86 (95% CI: 1.39-2.47) and 1.44 (95% CI: 1.29-1.60). Scaled to 1 SD increments in remnant cholesterol and LDL cholesterol, corresponding univariable ORs were 1.37 (95% CI: 1.27-1.49) and 1.29 (95% CI: 1.20-1.39) for PAD, and 1.40 (95% CI: 1.31-1.51) and 1.51 (95% CI: 1.43-1.59) for CAD; corresponding multivariable ORs were 1.28 (95% CI: 1.14-1.43) and 1.11 (95% CI: 1.00-1.23) for PAD, and 1.22 (95% CI: 1.11-1.33) and 1.34 (95% CI: 1.23-1.46) for CAD.

Elevated remnant cholesterol had a causal effect on risk of PAD even after accounting for elevated LDL cholesterol, whereas most of the causal effect of elevated LDL cholesterol on risk of PAD was dependent on simultaneously elevated remnant cholesterol. These results indicate that remnant cholesterol may be the major cholesterol fraction responsible for increased risk of PAD. Future studies should investigate the biological mechanisms behind these findings to find improved therapies for prevention and treatment of PAD.

Atherosclerotic occlusive disease in developed nations, the primary causes of death and disability are atherosclerotic diseases, such as stroke and acute coronary syndromes. The most common acute vascular events are brought on by the rupture or erosion of hemodynamically insignificant atherosclerotic plaques. The most frequent cause of both carotid and coronary steno-occlusive disease is atherosclerosis. The atherosclerotic plaque starts progressing when the foam cells break down and release lipids into the extracellular space when the stimulus for atherogenesis is intensified. Thus, creating a lipid pool that is primarily acellular. At the same time, activated smooth muscle cells go into the intimal layer and multiply, dramatically improving their capacity to make collagen and maintain the fibrous cap. As the plaque thickens, its deeper layers may become hypoxic, causing angiogenesis and microvessel multiplication from the adventitial vasa vasorum. Since the middle of the 20 th century, there have been significant drops in the incidence and mortality from ischemic heart disease and ischemic stroke in high-income countries. Blood tests are typically performed to measure cholesterol and blood sugar levels and are used as diagnostic tests for atherosclerosis. Cardiograms and exercise stress tests are also used for diagnosis. Risk factors of atherosclerosis include high blood pressure, smoking, diabetes mellitus, high blood pressure, obesity, diet, sedentary lifestyle, and high total cholesterol and low-density lipoprotein cholesterol. The cornerstones of managing atherosclerotic are still medical care and lifestyle changes. A growing number of atherosclerotic types can benefit greatly from endovascular therapy. When compared to normal surgical procedures, it is linked with much lower morbidity and mortality, as well as a quicker recovery time. This article aims to provide a brief introduction, risk factors, epidemiology, diagnostic tests, prevention, and good practice management advice for atherosclerosis.

Peripheral arterial disease (PAD) is a major complication in individuals with diabetes and is increasingly prevalent in those with diabetic foot ulcers (DFUs). Despite this, the characterisation of PAD in diabetic patients remains insufficiently refined, leading to suboptimal management and outcomes. This review underscores the necessity for a more nuanced understanding of PAD's anatomical and biological aspects in diabetic patients. The distribution of atherosclerotic plaques varies significantly among individuals, influencing prognosis and treatment efficacy. We describe three key patterns of PAD in diabetes: pattern 1 PAD-below-the-knee (BTK) disease (with infrageniculate disease where present); pattern 2-below-the-ankle (BTA) disease; and pattern 3-small artery disease (SAD), each presenting unique challenges and require tailored therapeutic approaches. BTK PAD, characterised by occlusions in the anterior tibial, posterior tibial, and peroneal arteries, necessitates targeted revascularisation to improve foot perfusion. BTA PAD, involving the pedal and plantar arteries, is associated with higher risks of amputation and requires advanced revascularisation techniques. SAD, affecting the small arteries of the foot, remains an enigma and is challenging to treat with the current mechanical methods, highlighting the potential of autologous cell therapy as a promising alternative. A refined characterisation of PAD in diabetes is crucial for developing effective, individualised treatment strategies, ultimately improving patient outcomes, and reducing the burden of diabetic foot complications. In light of these complexities, it is incredulous that we often use a single term, "peripheral arterial disease", to describe such a diverse array of disease patterns. This oversimplification can be perilous, as it may lead to inadequate therapeutic approaches and suboptimal patient care.

Despite major improvements in primary and secondary prevention, a flattening in the improvement of survival curves of patients with or at risk of acute myocardial infarction has been reached in recent years. Pharmacological therapies that reduce LDL cholesterol (LDL-C) levels have shown incremental clinical and vascular benefits according to the achieved LDL-C levels. However, a non-negligible rate of events still occurs in patients achieving very low LDL-C levels. In addition to risk factors related to inflammatory pathways, emerging lipid-related factors seem to account for this residual atherothrombotic burden, with accumulative evidence establishing lipoprotein (a) (Lp(a)) as the single greatest emerging risk factor. Ongoing trials will evaluate whether the pharmacological reduction of Lp(a) levels reduces the incidence of cardiac events, and therefore may represent a novel therapeutic target. In addition, implementing atherosclerosis imaging may help improve traditional clinical scores to identify better patients at high risk of cardiovascular events who may benefit more from early and effective treatment strategies. In the era of tailored medicine, direct imaging of atherosclerosis can play a crucial role in helping clinicians better stratify patient risk and patients better understand the burden of their disease, ultimately improving medication adherence and goal attainment.

Statins reduce recurrent stroke and cardiovascular events in patients with non-cardioembolic stroke. The benefits of statins in patients with AF and recent IS remain unclear. We aimed to investigate the benefits of statins in patients with AF and recent IS.

This retrospective, cohort study was conducted using deidentified electronic medical records within TriNetX platform. Patients with AF and recent IS, who received statins within 28 days of their index stroke were propensity score-matched with those who did not. Patients were followed up for up to 2 years. Primary outcomes were the 2-year risk of recurrent IS, all-cause mortality and the composite outcome of all-cause mortality, recurrent IS, transient ischaemic attack (TIA), and acute myocardial infarction (MI). Secondary outcomes were the 2-year risk of TIA, intracranial haemorrhage (ICH), acute MI, and hospital readmission. Cox regression analyses were used to calculate hazard ratios (HRs) with 95% confidence intervals (95%CI).

Of 20,902 patients with AF and recent IS, 7500 (35.9%) received statins within 28 days of their stroke and 13,402 (64.1%) did not. 11,182 patients (mean age 73.7 ± 11.5; 5277 (47.2%) female) remained after propensity score matching. Patients who received early statins had significantly lower risk of recurrent IS (HR: 0.45, 95%CI: 0.41-0.48, p < 0.001), mortality (HR: 0.75, 95%CI: 0.66-0.84, p < 0.001), the composite outcome (HR: 0.48, 95%CI: 0.45-0.52, p < 0.001), TIA (HR: 0.37, 95%CI: 0.30-0.44, p < 0.001), ICH (HR: 0.59, 95%CI: 0.47-0.72, p < 0.001 ), acute MI (HR: 0.35, 95%CI: 0.30-0.42, p < 0.001) and hospital readmission (HR: 0.46, 95%CI: 0.42-0.50, <0.001). Beneficial effects of early statins were evident in the elderly, different ethnic groups, statin dose intensity, and AF subtypes, large vessel occlusion and embolic strokes and within the context of statin lipophilicity, optimal LDL-cholesterol levels, various cardiovascular comorbidities, treatment with intravenous thrombolysis or endovascular thrombectomy, and NIHSS 0-5 and NIHSS > 5 subgroups.

Patients with AF and recent IS, who received early statins, had a lower risk of recurrent stroke, death, and other cardiovascular outcomes including ICH, compared to those who did not.

Statins may reduce the risk of recurrent gallstone disease by decreasing bile cholesterol saturation and pathogenicity. However, limited studies have investigated this issue. This study aimed to assess whether statin doses and serum cholesterol levels were associated with a decreased risk of recurrent biliary stone diseases after the first event index, with a follow-up time of 15 years.

Based on the Chang Gung Research Database (CGRD) between January 1, 2001, and December 31, 2020, we enrolled 68,384 patients with the International Classification of Diseases, Ninth and Tenth Revision codes of choledocholithiasis. After exclusions, 32,696 patients were divided into non-statin (<28 cDDD, cumulative defined daily doses) (n = 27,929) and statin (≥28 cDDD) (n = 4767) user groups for analysis. Serum cholesterol trajectories were estimated using group-based trajectory modeling (n = 8410).

The statin users had higher Charlson Comorbidity Index (CCI) scores than the non-statin users. Time-dependent Cox regression analysis showed that statin use >365 cDDD was associated with a significantly lower risk of recurrent biliary stones (adjusted hazard ratio [aHR] = 0.28, 95% CI, 0.24-0.34; p < 00.0001), acute pancreatitis (aHR = 0.24, 95% CI, 0.17-0.32, p < 00.0001), and cholangitis (aHR = 0.28, 95% CI, 0.25-0.32, p < 00.0001). Cholecystectomy was also a protective factor for recurrent biliary stones (aHR = 0.41, 95% CI, 0.37-0.46; p < 00.0001). The higher trajectory serum cholesterol group (Group 3) had a lower risk trend for recurrent biliary stones (aHR = 0.79, p = 0.0700) and a lower risk of cholangitis (aHR = 0.79, p = 0.0071).

This study supports the potential benefits of statin use and the role of cholecystectomy in reducing the risk of recurrent biliary stone diseases.

The risk of atherosclerotic cardiovascular disease increases with advancing age. Elevated low-density lipoprotein (LDL)-cholesterol and non-high-density lipoprotein (non-HDL)-cholesterol levels remain predictive of incident atherosclerotic cardiovascular events among individuals older than 75 years. Risk prediction among older individuals is less certain because most current risk calculators lack specificity in those older than 75 years and do not adjust for co-morbidities, functional status, frailty, and cognition which significantly impact prognosis in this age group. Data on the benefits and risks of lowering LDL-cholesterol with statins in older patients without atherosclerotic cardiovascular disease are also limited since most primary prevention trials have included mostly younger patients. Available data suggest that statin therapy in older primary prevention patients may reduce atherosclerotic cardiovascular events and that benefits from lipid-lowering with statins outweigh potential risks such as statin-associated muscle symptoms and incident type 2 diabetes mellitus. While some evidence suggests the possibility that statins may be associated with incident cognitive impairment in older adults, a preponderance of literature indicates neutral or even protective statin-related cognitive effects. Shared decision-making which is recommended for all patients when considering statin therapy is particularly important in older patients. Randomized clinical trial data evaluating the use of non-statin lipid-lowering therapy in older patients are sparse. Deprescribing of lipid-lowering agents may be appropriate for select patients older than 75 years with life-limiting diseases. Finally, a patient-centered approach should be taken when considering primary prevention strategies for older adults.

Vascular dementia (VaD) is a second most common type of dementia subsequent to Alzheimer disease (AD). VaD is characterized by cognitive impairment and memory loss that may progress due to the development of cerebral amyloid angiopathy (CAA) a hallmark of AD. CAA triggers the progression of ischemic and hemorrhagic strokes with the subsequent the development of VaD and mixed dementia. Early diagnosis of patients with appropriate use of anti-inflammatory can prevent CAA-related inflammation and VaD development. Currently, there are no effective drugs in the management of VaD. Of note, cholesterol-lowering agent statins which are commonly used in patients with vascular diseases and dyslipidemia may affect the progression of VaD. Many previous studies highlighted the potential therapeutic efficacy of statins in treating VaD. Though, the underlying mechanisms of statins in prevention and treatment of VaD are not fully clarified. Consequently, this review aims to discuss the mechanistic role of statins in the management of VaD, and how statins may adversely affect the cognitive function in VaD patients.

Low-density lipoprotein cholesterol (LDL-C) is an important factor in the development of cardiovascular disease, making its management a key aspect of cardiovascular health. While high-dose statin therapy is often recommended for LDL-C reduction, careful consideration is needed due to patient-specific factors and potential side effects. This study aimed to develop a machine learning (ML) model to estimate the likelihood of achieving target LDL-C levels in patients hospitalized for coronary artery disease and treated with moderate-dose statins. The predictive performance of three ML models, including Extreme Gradient Boosting (XGBoost), Random Forest, and Logistic Regression, was evaluated using electronic medical records from the Asan Medical Center in Seoul across six performance metrics. Additionally, all three models achieved an average AUROC of 0.695 despite reducing features by over 43%. SHAP analysis was conducted to identify key features influencing model predictions, aiming insights into patient characteristics associated with achieving LDL-C targets. This study suggests that ML-based approaches may help identify patients likely to benefit from moderate-dose statins, potentially supporting personalized treatment strategies and clinical decision-making for LDL-C management.

Cholesterol is an essential element for the development and normal function of the central nervous system. While peripheral cholesterol is influenced by liver metabolism and diet, brain cholesterol metabolism takes place in an isolated system due to the impermeability of the blood-brain barrier (BBB). However, cross-talk occurs between the brain and periphery, specifically through metabolites such as oxysterols that play key roles in regulating cholesterol balance. Several neurodegenerative conditions such as Alzheimer's disease or Parkinson's disease are considered to be affected by the loss of this balance. Also, the treatment of hypercholesterolemia needs to consider these discrete interferences between brain and peripheral cholesterol and the possible implications of each therapeutic approach. This is particularly important because of 27-hydroxycholesterol and 24-hydroxycholesterol, which can cross the BBB and are involved in cholesterol metabolism. This paper examines the metabolic pathways of cholesterol metabolism in the brain and periphery and focuses on the complex cross-talk between these metabolisms. Also, we emphasize the regulatory role of the BBB and the need for an integrated approach to cholesterol management.

With the improvement of living standards, an increasing number of patients are presenting with mixed hyperlipidemia. In addition to cholesterol reduction, it is imperative to lower triglyceride levels. The combination of statin and fibrate for reducing lipid levels has commonly been applied in clinical therapy. However, the combination of drugs also increases the risk of adverse events (AEs). In this study, we analyzed the safety signals of rosuvastatin-fenofibrate combination by assessing the publicly available US Food and Drug Administration Adverse Event Reporting System (FAERS), so as to provide a reference for rational clinical use of rosuvastatin and fenofibrate, and reduce the occurrence of related AEs.

Reports to the FAERS from 1 January 2004 to 19 March 2020 were analyzed. The proportional report ratio (PRR), reporting odds ratio (ROR), and Bayesian Confidence Propagation Neural Network (BCPNN) analysis were used to extract data from FAERS for suspected signals referring to the combination of rosuvastatin and fenofibrate.

A total of 68 safety signals were detected from the top 250 AEs in 3,587 reports, of which 28 signals were not included in the drug labels. All the detected AEs were associated with 12 System Organ Classes (SOC), such as gastrointestinal, musculoskeletal and connective tissue, general diseases, investigations and nervous system. The most frequent AEs were analyzed, and it was found that women generally have a higher susceptibility to experiencing AEs, including pain, nausea, fatigue, myalgia, diarrhea, dyspnea, headache, weakness, and dizziness.

Clinicians should pay more attention to the AEs of gastrointestinal and muscular system during combination therapy, and it is recommended to strengthen pharmaceutical care during clinical application.

Empiric antibiotics active against Pseudomonas aeruginosa are recommended by professional societies for certain infections and are commonly prescribed for hospitalized patients. The effect of this practice on mortality is uncertain.

A systematic literature search was conducted using Embase, Medline, PubMed, Web of Science, Cochrane, Scopus and Google Scholar from earliest entry through 9 October 2023. We included studies of patients hospitalized with P. aeruginosa infections that compared mortality rates depending on whether patients received active empiric antibiotics.

We found 27 studies of 12 522 patients that reported adjusted OR of active empiric antibiotics on mortality. The pooled adjusted OR was 0.40 (95% CI, 0.32-0.50), favouring active empiric antibiotics. In practice, the mortality effect of empiric antibiotics against P. aeruginosa depends on the prevalence of P. aeruginosa and baseline mortality. The estimated absolute mortality benefit was 0.02% (95% CI, 0.02-0.02) for soft tissue infections, 0.12% (95% CI, 0.10-0.13) for urinary tract infections and community-acquired pneumonia, 0.3% (0.25-0.34) for sepsis without shock, 1.1% (95% CI, 0.9-1.4) for septic shock and 2.4% (95% CI, 1.9-2.8) for nosocomial pneumonia.

The mortality effect for empiric antibiotics against P. aeruginosa depends crucially on the prevalence of P. aeruginosa and baseline mortality by type of infection. For soft tissue infections, urinary tract infections and community-acquired pneumonia, the mortality benefit is low. Meaningful benefit of empiric antibiotics against P. aeruginosa is limited to patients with approximately 30% mortality and 5% prevalence of P. aeruginosa, which is largely limited to patients in intensive care settings.

Poor adherence to lipid-lowering drugs in diabetic patients with dyslipidemia increases has been linked with an increased cardiovascular risk. A better understanding of the determinants of adherence to lipid-lowering drugs and treatment satisfaction among people with diabetes and dyslipidemia is crucial.

We aimed to assess the prevalence of adherence to lipid-lowering drugs, identify its determinant factors, and evaluate treatment satisfaction among users of lipid-lowering drugs who have diabetes and dyslipidemia.

We surveyed 398 adult patients with diabetes and dyslipidemia, using a validated medication adherence survey (Adherence to Refills and Medications Scale) and a validated treatment satisfaction survey (Treatment Satisfaction Questionnaire for Medication, TSQM). Sociodemographic and medical history data were collected through questionnaires.

The prevalence of poor medication adherence was 36%. Factors associated with poor adherence included adverse reactions to medications, lack of medication availability, and lack of family support. Adherent patients reported lower low-density lipoprotein-cholesterol (LDL-C) and total cholesterol levels, higher treatment satisfaction, and a higher prevalence of cardiovascular disease and comorbidities. Having a family history of dyslipidemia was negatively associated with adherence, while the number of comorbidities positively influenced it. The scores of TSQM components such as effectiveness, global satisfaction, and convenience were significantly higher in people who were adherent or achieved the LDL-C target.

Our findings highlight the need for interventions targeting several factors impacting adherence to lipid-lowering drugs in patients with diabetes and dyslipidemia. Managing adverse effects, leveraging family support, and ensuring medication access represent crucial aspects of improving adherence and potentially mitigating cardiovascular risks in this high-risk population.

Stroke is one of the most common causes of disability in older adults. It remains a common cause of death and permanent functional limitation in individuals who are older than 80 years. Approximately 50% of all strokes occur in people over the age of 75, and 30% in those over 85. Top priorities in primary stroke prevention include the treatment of hypertension, anticoagulation for patients with atrial fibrillation, and lifestyle modifications such as smoking cessation.

Complete blood count (CBC)-derived indices have been proposed as reliable inflammatory biomarkers to predict outcomes in the context of coronary artery disease. These indices have yet to be thoroughly validated in patients with intermediate coronary stenosis. Our study included 1527 patients only with intermediate coronary stenosis. The examined variables were neutrophil-lymphocyte ratio (NLR), derived NLR, monocyte-lymphocyte ratio (MLR), platelet-lymphocyte ratio (PLR), systemic immune inflammation index (SII), system inflammation response index (SIRI), and aggregate index of systemic inflammation (AISI). The primary endpoint was the composite of major adverse cardiovascular events (MACEs), including all-cause death, non-fatal myocardial infarction, and unplanned revascularization. Over a follow-up of 6.11 (5.73-6.55) years, MACEs occurred in 189 patients. Receiver operator characteristic curve analysis showed that SIRI outperformed other indices with the most significant area under the curve. In the multivariable analysis, SIRI (hazard ratio [HR] 1.588, 95% confidence interval [CI] 1.138-2.212) and AISI (HR 1.673, 95% CI 1.217-2.300) were the most important prognostic factors among all the indices. The discrimination ability of each index was strengthened in patients with less burden of modifiable cardiovascular risk factors. SIRI also exhibited the best incremental value beyond the traditional cardiovascular risk model.

This meta-analysis aimed to investigate the effect of statins on the prognosis of patients with intracerebral hemorrhage (ICH).

We conducted a systematic search using the keywords "statin" and "intracerebral hemorrhage" across four electronic databases (PubMed, Cochrane Library, Web of Science, and Embase) from their inception to October 31, 2023, to identify studies comparing the effects of statins on the prognosis of patients with ICH. The primary outcome was total mortality after ICH. This meta-analysis was registered online (PROSPERO ID: CRD42023493063).

Our initial search identified 5,543 studies. After applying inclusion criteria, 30 studies with a total of 42,298 patients were included in the final analysis. Our meta-analysis showed that statins significantly reduced overall mortality in patients with ICH (OR: 0.61; 95% CI: 0.51-0.73; I 2 = 87%; p < 0.01). Subgroup analyses further demonstrated lower mortality in ICH patients treated with statins compared to those not treated, including in the propensity score matching (PSM) group (OR: 0.59; 95% CI: 0.48-0.74; I 2 = 90%; p < 0.01), the prospective cohort study (PCS) group (OR: 0.56; 95% CI: 0.40-0.77; I 2 = 89%, p < 0.01), and the retrospective cohort study (RCS) group (OR: 0.64; 95% CI: 0.51-0.81; I 2 = 87%, p < 0.01).

Our meta-analysis of 30 studies suggests that statin use may be associated with improved mortality and functional outcomes in patients with intracerebral hemorrhage (ICH).

https://www.crd.york.ac.uk/PROSPERO/, CRD42023493063.

Epidemiological evidence suggests the presence of common risk factors for the development and prognosis of both cardio- and cerebrovascular diseases, including stroke, Alzheimer's disease, vascular dementia, heart, and peripheral vascular diseases. Accumulation of harmful blood signals may induce organotypic endothelial dysfunction affecting blood-brain barrier function and vascular health in age-related diseases. Genetic-, age-, lifestyle- or cardiovascular therapy-associated imbalance of amyloid-beta (Aβ) peptide metabolism in the brain and periphery may be the missing link between age-related neurocardiovascular diseases. Genetic polymorphisms of genes related to Aβ metabolism, lifestyle modifications, drugs used in clinical practice, and Aβ-specific treatments may modulate Aβ levels, affecting brain, vascular, and cardiac diseases. This narrative review elaborates on the effects of interventions on Aβ metabolism in the brain, cerebrospinal fluid, blood, and peripheral heart or vascular tissues. Implications for clinical applicability, gaps in knowledge, and future perspectives of Aβ as the link among age-related neurocardiovascular diseases are also discussed.

The efficacy and safety of statins for secondary prevention in patients who have experienced a cardioembolic stroke are not well-defined. However, previous observational data reported hyperlipidemia as a risk factor for both ischemic and bleeding complications in patients with AF and previous stroke. Based on these premises, we conducted a sub-analysis of the RAF and RAF-NOAC studies to evaluate the efficacy and safety of statins in secondary prevention in patients with acute ischemic stroke and AF.

We combined patient data from the RAF and RAF-NOAC studies, prospective observational studies conducted across Stroke Units in Europe, the United States, and Asia from January 2012 to June 2016. We included consecutive patients with AF who suffered an acute ischemic stroke with a follow-up of 90 days. Our outcomes were the combined endpoint, including stroke, transient ischemic attack, systemic embolism, symptomatic intracerebral hemorrhage, and major extracranial bleeding. Furthermore, both ischemic and hemorrhagic outcomes were evaluated separately.

A total of 1742 patients were included (46% male), and 898 (52%) received statins after the index event, of whom 436 (48.6%) were already taking statins before the index event, 462 (51.4%) started treatment after. At multivariable analysis, statin use was statistically associated with age (OR 0.92, 95% CI 0.97-0.99, p = 0.001), male sex (OR 1.35, 95% CI 1.07-1.70, p = 0.013), anticoagulation (OR 2.53, 95% CI 1.90-3.36, p < 0.0001), hyperlipidemia (OR 5.52, 95% CI 4.28-7.12, p < 0.0001), paroxysmal AF (OR 1.40, 95% CI 1.12-1.75, p = 0.003), leukoaraiosis (OR 1.39, 95% CI 1.11-1.75, p = 0.004) and heart failure (OR 0.72, 95% CI 0.53-0.98, p = 0.034). Statin use was not associated with the combined outcome event (OR 0.84, 95% CI 0.58-1.23, p = 0.3) and ischemic outcome event (OR 1.17, 95% CI 0.73-1.88, p = 0.5) while was associated with a lower risk of hemorrhagic outcome event (OR 0.51, 95% CI 0.28-0.91, p = 0.02).

Statins protect cerebral arterial vessels (particularly small vessels) from subacute damage due to hypertension, diabetes, and other harmful agents (such as reactive oxygen species, proinflammatory cytokines, etc.) due to their systemic anti-inflammatory and endothelium-protective effects.

Our data show that statins seem to protect against global bleeding events in cardioembolic stroke patients; this may be due to the pleiotropic effect of statins. More data are warranted to confirm these findings.

Cardiovascular drug use may help prevent dementia; however, current evidence is mixed. Using a case-control design, we investigated the association between duration and combination of multiple cardiovascular drug classes and incident dementia.

From the Swedish national registers, we included 88,065 incident dementia cases aged ≥ 70 at diagnosis between 2011 and 2016 and 880,650 age- and sex-matched controls. Cardiovascular drug use was ascertained from the Prescribed Drug Register.

Long-term users (≥ 5 years) of antihypertensives, diuretics, lipid-lowering drugs (LLDs), and oral anticoagulants (OACs) had statistically significantly fewer dementia diagnoses (odds ratio [OR] 0.75-0.91) than non-users. Antiplatelets use was associated with more dementia diagnoses (OR 1.13-1.25). Use of antihypertensives in combination with diuretics, LLDs, and OACs for ≥ 5 years was associated with fewer dementia diagnoses (OR 0.66-0.84).

Preventing dementia via cardiovascular drug pathways may be possible. It is however important to consider the potential long-term negative cognitive effect of antiplatelets.

Use ≥ 5 years of common cardiovascular drugs was associated with lower dementia risk. Common cardiovascular drug combination use was associated with lower dementia risk. Anti-platelet use of any duration was associated with higher dementia risk.

Statin-associated muscle symptoms (SAMS) are a major cause of treatment discontinuation. Clinical Pharmacogenetics Implementation Consortium (CPIC) recommend dose adjustment for statin treatment according to known SLCO1B1 genotype to reduce SAMS. We hypothesized that the association between SLCO1B1 genotype and SAMS is misestimated because of publication bias.

We searched published systematic reviews on the association between SLCO1B1 genotype and SAMS. To assessed publication bias, we used funnel plot visual inspection, Egger's test, and the Bayes Factor (BFPublication-bias) from Robust Bayesian Meta-Analysis (RoBMA). We compared the odds ratios (ORUncorrected) from meta-analyses before and after correcting for publication bias using trim-and-fill (ORTrim&Fill) and RoBMA (ORRoBMA) methods.

We included 8 cohort and 11 case-control studies, totaling 62 OR of three SLCO1B1 genotypes and six statin drugs. In the primary analysis, the funnel plot was suggestive of publication bias, confirmed by Egger's test (p=0.001) and RoBMA (BFPublication-bias = 18). Correcting the estimate for publication bias resulted in loss of the association, from a significant ORUncorrected (1.31 95%CI [1.13-1.53]) to corrected ORs suggesting no difference: ORTrim&Fill (1.07 95%CI [0.89-1.30]) and ORRoBMA (1.02 95%CI [1.00-1.33]). This suggested that publication bias overestimated the association by 18 % and 23 %, respectively. Similar results were found for genotype rs4149056, simvastatin and atorvastatin.

The effect of the SLCO1B1 genotype on the risk of developing SAMS is overestimated in the published literature, especially rs4149056. This could lead prescribers to incorrectly decreasing statin doses or even avoiding statin use, leading to a loss of the potential cardiovascular benefit of statins.