Joint effects of air pollution and neighborhood socioeconomic status on cognitive decline - Mediation by depression, high cholesterol levels, and high blood pressure.

Air pollution and neighborhood socioeconomic status (N-SES) are associated with adverse cardiovascular health and neuropsychiatric functioning in older adults. This study examines the degree to which the joint effects of air pollution and N-SES on the cognitive decline are mediated by high cholesterol levels, high blood pressure (HBP), and depression. In the Emory Healthy Aging Study, 14,390 participants aged 50+ years from Metro Atlanta, GA, were assessed for subjective cognitive decline using the cognitive function instrument (CFI). Information on the prior diagnosis of high cholesterol, HBP, and depression was collected through the Health History Questionnaire. Participants' census tracts were assigned 3-year average concentrations of 12 air pollutants and 16 N-SES characteristics. We used the unsupervised clustering algorithm Self-Organizing Maps (SOM) to create 6 exposure clusters based on the joint distribution of air pollution and N-SES in each census tract. Linear regression analysis was used to estimate the effects of the SOM cluster indicator on CFI, adjusting for age, race/ethnicity, education, and neighborhood residential stability. The proportion of the association mediated by high cholesterol levels, HBP, and depression was calculated by comparing the total and direct effects of SOM clusters on CFI. Depression mediated up to 87 % of the association between SOM clusters and CFI. For example, participants living in the high N-SES and high air pollution cluster had CFI scores 0.05 (95 %-CI:0.01,0.09) points higher on average compared to those from the high N-SES and low air pollution cluster; after adjusting for depression, this association was attenuated to 0.01 (95 %-CI:-0.04,0.05). HBP mediated up to 8 % of the association between SOM clusters and CFI and high cholesterol up to 5 %. Air pollution and N-SES associated cognitive decline was partially mediated by depression. Only a small portion (<10 %) of the association was mediated by HBP and high cholesterol.

Alirocumab in Pediatric Patients With Heterozygous Familial Hypercholesterolemia: A Randomized Clinical Trial.

Importance: Many pediatric patients with heterozygous familial hypercholesterolemia (HeFH) cannot reach recommended low-density lipoprotein cholesterol (LDL-C) concentrations on statins alone and require adjunct lipid-lowering therapy (LLT); the use of alirocumab in pediatric patients requires evaluation. Objective: To assess the efficacy of alirocumab in pediatric patients with inadequately controlled HeFH. Design, Setting, and Participants: This was a phase 3, randomized clinical trial conducted between May 2018 and August 2022 at 43 centers in 24 countries. Pediatric patients aged 8 to 17 years with HeFH, LDL-C 130 mg/dL or greater, and receiving statins or other LLTs were included. Following consecutive enrollment into dosing cohorts, 25 of 99 patients screened for dosing every 2 weeks (Q2W) failed screening; 25 of 104 patients screened for dosing every 4 weeks (Q4W) failed screening. A total of 70 of 74 Q2W patients (95%) and 75 of 79 Q4W patients (95%) completed the double-blind period. Interventions: Patients were randomized 2:1 to subcutaneous alirocumab or placebo and Q2W or Q4W. Dosage was based on weight (40 mg for Q2W or 150 mg for Q4W if <50 kg; 75 mg for Q2W or 300 mg for Q4W if ≥50 kg) and adjusted at week 12 if LDL-C was 110 mg/dL or greater at week 8. After the 24-week double-blind period, patients could receive alirocumab in an 80-week open-label period. Main Outcomes and Measures: The primary end point was percent change in LDL-C from baseline to week 24 in each cohort. Results: Among 153 patients randomized to receive alirocumab or placebo (mean [range] age, 12.9 [8-17] years; 87 [56.9%] female), alirocumab showed statistically significant reductions in LDL-C vs placebo in both cohorts at week 24. Least squares mean difference in percentage change from baseline was -43.3% (97.5% CI, -56.0 to -30.7; P < .001) Q2W and -33.8% (97.5% CI, -46.4 to -21.2; P < .001) Q4W. Hierarchical analysis of secondary efficacy end points demonstrated significant improvements in other lipid parameters at weeks 12 and 24 with alirocumab. Two patients receiving alirocumab Q4W experienced adverse events leading to discontinuation. No significant difference in adverse event incidence was observed between treatment groups. Open-label period findings were consistent with the double-blind period. Conclusions and Relevance: The findings in this study indicate that alirocumab Q2W or Q4W significantly may be useful for reducing LDL-C and other lipid parameters and be well tolerated in pediatric patients with HeFH inadequately controlled with statins. Trial Registration: ClinicalTrials.gov Identifier: NCT03510884.

Characteristics of Coronary Atherosclerosis Related to Plaque Burden Regression During Treatment With Alirocumab: The ARCHITECT Study.

BACKGROUND: Intensive lipid-lowering therapy may induce coronary atherosclerosis regression. Nevertheless, the factors underlying the effect of lipid-lowering therapy on disease regression remain poorly characterized. Our aim was to determine which characteristics of atherosclerotic plaque are associated with a greater reduction in coronary plaque burden (PB) after treatment with alirocumab in patients with familial hypercholesterolemia. METHODS: The ARCHITECT study (Effect of Alirocumab on Atherosclerotic Plaque Volume, Architecture and Composition) is a phase IV, open-label, multicenter, single-arm clinical trial to assess the effect of the treatment with alirocumab for 78 weeks on the coronary atherosclerotic PB and its characteristics in subjects with familial hypercholesterolemia without clinical atherosclerotic cardiovascular disease. Participants underwent a coronary computed tomographic angiography at baseline and a final one at 78 weeks. Every patient received alirocumab 150 mg subcutaneously every 14 days in addition to high-intensity statin therapy. RESULTS: One hundred and four patients were enrolled. Median age was 53.3 (46.2-59.4) years and 54 were women (51.9%). The global coronary PB changed from 34.6% (32.5%-36.8%) at entry to 30.4% (27.4%-33.4%) at follow-up, which is -4.6% (-7.7% to -1.9%; P<0.001) reduction. A decrease in the percentage of unstable core (fibro-fatty+necrotic plaque; from 14.1 [7.9-22.3] to 8.0 [6.4-10.6]; -6.6%; P<0.001) was found. A greater PB (ß, 0.36 [0.13-0.59]; P=0.002) and a higher proportion of unstable core (ß, 0.15 [0.08-0.22]; P<0.001) were significantly related to PB regression. CONCLUSIONS: Treatment with alirocumab in addition to high-intensity statin therapy might produce a greater PB regression in patients with familial hypercholesterolemia with higher baseline PB and in those with larger unstable core. Further studies are needed to corroborate the hypothesis raised by these results. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05465278.

Safety and efficacy of bempedoic acid among patients with statin intolerance and those without: A meta-analysis and a systematic randomized controlled trial review.

OBJECTIVE: Bempedoic acid, an innovative oral medication, has garnered significant interest in recent times due to its potential as a therapeutic intervention for hypercholesterolemia. Nonetheless, the outcomes of the initial investigations might have been more definitive and coherent. Our objective was to perform a quantitative meta-analysis in order to evaluate bempedoic acid's safety and effectiveness. METHODS: A search was conducted on ClinicalTrials.gov, and PubMed from the time of inception until September 28, 2023. Randomized controlled trials comparing the safety and efficacy of bempedoic acid among patients with statin intolerance and those without were included in our analysis. The trial outcomes were summarized using a random effects model and were provided as mean differences or odds ratios (ORs) with a confidence interval of 95%. Additionally, trial heterogeneity and the possibility of bias were evaluated and investigated. RESULTS: Bempedoic acid treatment reduced low-density lipoprotein cholesterol levels more than placebo (mean difference -2.97%, 95% CI -5.89% to -0.05%), according to a pooled analysis of 16 eligible trials. The risk of death (OR 1.18, 95% CI 0.70 to 1.98) and muscle-associated occurrences (OR 1.00, 95% CI 0.77 to 1.31) was not impacted by bempedoic acid. In contrast, discontinuation of treatment was more frequently caused by adverse events in the bempedoic acid group (OR 1.13, 95% CI 1.01 to 1.27). CONCLUSIONS: In patients with statin intolerance as well as those without, bempedoic acid is a safe and efficacious lipid-lowering agent, according to findings from randomized controlled trials.

Bempedoic acid: a new player for statin-intolerant patients and beyond.

PURPOSE OF REVIEW: Low-density lipoproteins (LDL) cause atherosclerotic cardiovascular disease, a condition associated with significant morbidity and mortality. Statins represent the cornerstone for preventing cardiovascular events in patients with elevated LDL-cholesterol (LDL-C) levels, however, they are associated with frequent musculoskeletal adverse effects, which lead to drug discontinuation or limit their use to low (and less effective) doses. Bempedoic acid (BA) is a newly approved, safe, cholesterol-lowering agent that inhibits ATP-citrate lyase, an enzyme upstream to 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, the target of statins. Unlike statins, BA is not associated with musculoskeletal side effects, representing a promising drug for statin-intolerant patients. This review aims to summarize the current evidence on the efficacy, safety, and impact on clinical outcomes of BA, to review current indications for its use, and to highlight the ongoing clinical trials that will help deepen our knowledge of this promising compound. RECENT FINDINGS: BA improves clinical outcomes in statin-intolerant patients. Multiple ongoing studies are evaluating whether BA can be employed in other clinical settings. SUMMARY: BA safely and effectively reduces the levels of multiple atherogenic markers and can be employed to reach LDL-C targets independently from statin tolerance.

Resveratrol attenuates efavirenz-induced hepatic steatosis and hypercholesterolemia in mice by inhibiting pregnane X receptor activation and decreasing inflammation.

Efavirenz (EFV), a widely prescribed antiviral medication, has been implicated in dyslipidemia and can activate the pregnane X receptor (PXR), leading to hepatic steatosis and hypercholesterolemia in mice. Resveratrol (RES) can ameliorate hepatic steatosis and functions as a partial PXR agonist, capable of mitigating PXR expression induced by other PXR agonists. Therefore, we hypothesized that RES could attenuate EFV-induced hepatic steatosis and hypercholesterolemia by downregulating PXR expression and suppressing inflammatory cytokine production. Here, we conducted an in vivo study involving 6-week-old male mice, which were divided into 4 groups for a 7-day intervention: control (carrier solution), EFV (80 mg/kg), RES (50 mg/kg), and RES + EFV groups. Serum and hepatic tissue samples were collected to assess cholesterol and triglyceride concentrations. Hepatic lipid accumulation was evaluated through hematoxylin-eosin and oil red O staining. Polymerase chain reaction and western blot were performed to quantify hepatic inflammatory factors, lipogenic gene, and PXR expression. Our results indicated that hepatic lipid droplet accumulation was reduced in the RES + EFV group compared with the EFV group. Similarly, the expressions of hepatic inflammatory factors were attenuated in the RES + EFV group relative to the EFV group. Furthermore, RES counteracted the upregulation of hepatic lipid-metabolizing enzymes induced by EFV at both the transcriptional and protein levels. Importantly, PXR expression was downregulated in the RES + EFV group compared with the EFV group. Conclusively, our findings suggest that RES effectively mitigates EFV-induced hepatic steatosis and hypercholesterolemia by inhibiting PXR activation and decreasing inflammation.

Analysis of Adherence to anti-PCSK9 Antibody Therapy among Patients from Italy.

INTRODUCTION: Hypercholesterolemia is one of the main risk factors associated with atherosclerotic cardiovascular disease and coronary heart disease. Statins are the standard cholesterollowering treatment; however, they have shown, in clinical practice, a reduced adherence to therapy (<50%) and a modest achievement of the expected outcomes for treatment. This condition prompt scientific research to develop drugs with different mechanisms of action. In this regard, excellent results have been achieved with therapeutic use of monoclonal antibodies against PCSK9, enzyme involved in recycling of Low density lipoprotein receptors (LDLR) on the hepatocytes surface. Indeed, the reduction in receptor density caused by PCSK9 is associated with increased serum LDL levels. MATERIALS AND METHODS: After the data extraction of all Local Health Authority (ASL) of Foggia patients (302) who received, in 2021, at least one administration of Alirocumab or Evolocumab, the therapeutic adherence was calculated, for each individual patient, by indirect method (calculation of the Medication Possession Ratio - MPR). According to scientific literature, patients were classified into: adherents (MPR>80%), average adherents (MPR between 40% and 80%) and non-adherents (MPR<40%). Patients were then stratified by gender and age groups (0-18, 19-49, 50-64, >65). RESULTS: The results show that, for both drugs (Alirocumab and Evolocumab), women are more adherent than men and the group of young adults (19-49 years old) is the one with the lowest adherence to therapy, 69% for Alirocumab and 56% for Evolocumab. CONCLUSION: According to Italian Drug Agency (AIFA), poor therapeutic adherence is the main cause of ineffectiveness of drug therapies, and it is associated with increased hospitalizations, morbidity and mortality. Data obtained from this study allow to detect the categories of patients who need specific programs about the correct use of drugs, in order to increase therapeutic adherence and facilitate the achievement of the expected outcomes for treatment.

Value of the clinical pharmacist interventions in the application of the American College of Cardiology (ACC/AHA) 2018 guideline for cholesterol management.

OBJECTIVES: The study aims to examine the extent to which the updated ACC/AHA management of blood cholesterol guideline (2018) is implemented in practice and to assess the value of the clinical pharmacist interventions in improving physicians' adherence the guidelines recommendations. METHODS: We utilized in this study an interventional before-after design. The study was conducted on 272 adult patients who visited the study site internal medicine clinics and were candidates for statin therapy based on the 2018 ACC/AHA guidelines for cholesterol management. Adherence to guideline recommendations was measured before and after clinical pharmacists' interventions by calculating the percentage of patients receiving statin therapy as per guideline recommendation, the type and intensity (moderate or high intensity) of statin therapy used, and the need for additional non-statin therapy. RESULTS: Adherence with guideline recommendations was significantly improved from 60.3% to 92.6% (X2 = 79.1, p = 0.0001) after clinical pharmacist interventions. Among patients who were on statin therapy, the percentage of those who were on proper statin intensity increased significantly from 47.6% to 94.4% (X2 = 72.5, p = 0.0001). The combination of statins with non-statin therapies such as ezetimibe and PCSK9 inhibitors increased from 8.5% to 30.6% (X2 = 95, p<0.0001) and from 0.0% to 1.6% (X2 = 6, p = 0.014), respectively. The use of other lipid-lowering agents was diminished from 14.6% to 3.2% (X2 = 19.2, p<0.0001). CONCLUSION: Collaboration between physicians and clinical pharmacists is a crucial strategy to improve patients' treatment and hence, achieve better health outcomes among patients suffering from dyslipidemia.

Xenosterolemia in clinical practice: what is in a name?

PURPOSE OF REVIEW: The aim of this study was to assess the potential value of the measurement of plasma xenosterols (or phytosterols) concentrations in clinical practice. RECENT FINDINGS: Recent genetic studies suggest that individuals with elevated plasma phytosterol concentrations due to monogenic and polygenic variants are at an increased risk of coronary artery disease. This supports early observations that elevated plasma phytosterol concentrations are per se atherogenic. SUMMARY: Measurement of plasma phytosterols can identify individuals with xenosterolemia (or phytosterolemia). This may be clinically useful in four ways: Establishing a diagnosis and informing management of patients with homozygous phytosterolemia; Providing a comprehensive differential diagnosis for familial hypercholesterolemia; Providing an index of cholesterol absorption that may inform personalized pharmacotherapy; and Informing more precise assessment of risk of cardiovascular disease.

Prevalence of adverse events varies with the different oral isotretinoin brands in acne treatment: a retrospective observational study.

Oral isotretinoin remains the most effective treatment for acne. The aim of this retrospective single-center cohort study was to estimate the prevalence of adverse events with the different oral isotretinoin brands used in acne treatment. The population consisted of all patients who consulted for acne between January 2015 and January 2020. The inclusion criterion was the initiation of treatment with oral isotretinoin. The exclusion criteria were the use of two or more brands during the same course of treatment and previous treatment with oral isotretinoin. Statistical analysis was carried out using Chi-square and Mann-Whitney tests. We analyzed 468 patients of whom 68.6% were female. The median age was 21 years. The median weight was 65 kg. The treatment was Roaccutane®, Curacné®, Acnotren®, Isosupra®, Contracné®, or Acnogen® in 44.2%, 28%, 14.5%, 10.5%, 1.7% and 0.4% of cases, respectively. Xerosis was the most frequently reported side effect regardless of the brand. The highest frequencies of hypercholesterolemia (25.6%) and eczema (13%) were noted with Roaccutane®; hypertriglyceridemia (16.8%), epistaxis (9.9%) and fatigue (3.1%) with Curacné®; excessive sweating (4.1%) and headache (4.1%) with Isosupra®; and abnormal liver function tests (11%) with Acnotren®. We found a significant correlation mainly between abnormal ASAT and Acnotren® (p = 0.009), hypercholesterolemia and Roaccutane® [OR = 1.652 (95% CI 1.056-2.585)], hypertriglyceridemia and higher body weight (p = 0.004). Factors related to the drug brand and to characteristics of acne patients could explain the variability in the prevalence of some adverse events.

Lipid-lowering efficacy and safety of alirocumab in a real-life setting in France: Insights from the ODYSSEY APPRISE study.

BACKGROUND: Recently, a multicentre, prospective, single-arm, phase 3b, open-label trial was conducted to determine the safety and efficacy of alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, in a real-life setting. This study enrolled patients at high cardiovascular risk, with heterozygous familial hypercholesterolaemia (HeFH) or non-familial hypercholesterolaemia (non-FH). Results showed that alirocumab was well tolerated and resulted in a clinically significant reduction in low-density lipoprotein cholesterol (LDL-C). AIM: This ancillary analysis aimed to describe the characteristics of the French patients enrolled in the study, the main results observed in this population according to their familial hypercholesterolaemia status, and adherence to treatment. METHODS: French data were analysed separately from the original dataset of the study. RESULTS: Among 215 French patients in the ODYSSEY APPRISE trial, 63.7% had non-FH, with a mean LDL-C concentration of 5.0±1.8mmol/L at baseline. The mean duration of alirocumab exposure was 72.4±42.5 weeks, with only 48.4% of patients receiving statins concomitantly. At week 12, a mean reduction in LDL-C of 56.5±17.8% was observed: 51.2±22.8% in HeFH; 59.5±13.2% in non-FH. This improvement in LDL-C started from week 4 and remained stable and sustained until week 120 in both populations. The overall incidence of severe treatment-emergent adverse events (TEAEs) was 33.5%. The most frequent TEAEs were myalgia (15.8%) and asthenia (15.3%). No tolerance or efficacy differences were observed between patients with or without established coronary artery disease or other cardiovascular disease, whatever the age of these events or considering the concomitant use of other lipid-lowering therapies. CONCLUSIONS: In the French setting, alirocumab was well tolerated, safe and highly effective at reducing LDL-C. These findings support the use of alirocumab to manage hypercholesterolaemia in patients at high cardiovascular risk.

Facts and ideas on statins with respect to their lipophilicity: a focus on skeletal muscle cells and bone besides known cardioprotection.

Statins are known to block cholesterol synthesis in the liver. They also exhibit non-lipid pleiotropic effects due to the inhibition of protein prenylation, thereby modulating various signaling pathways of cellular homeostasis and integrity. Both lipid control and pleiotropic action of statins are clinically used, mainly for treatment of hypercholesterolemia and primary and secondary prevention of cardiovascular diseases. Because the prescription of statins is increasing and statin therapy is often lifelong, in particular in patients with other risk factors, safety issues being associated with polymorbidity and polypragmasia as well as the persistence with and adherence to statins are specific points of attention of clinicians and clinical pharmacologists. Furthermore, because skeletal myocytes have a cholesterol inhibitory sensitivity greater than hepatocytes, a choice of an appropriate statin based on its lipophilicity and the associated likelihood of its side effects on skeletal muscle cells and bone is warranted in such polymorbid patients. These approaches can effectively modulate the risk: benefit ratio and highlight a need for personalized therapy as much as possible, thereby minimizing risk of discontinuation of therapy and poor compliance.

MiR-133a-3p/Sirt1 epigenetic programming mediates hypercholesterolemia susceptibility in female offspring induced by prenatal dexamethasone exposure.

Mounting evidence indicates that adverse intrauterine conditions increase offspring's hypercholesterolemia susceptibility in adulthood. This study aimed to confirm prenatal dexamethasone exposure (PDE)-induced hypercholesterolemia susceptibility in female adult offspring rats, and elucidate its intrauterine programming mechanism. Pregnant Wistar rats were injected with dexamethasone subcutaneously (0, 0.1 and 0.2 mg/kg·d) from gestational day (GD) 9 to 20. Serum and liver of the female offspring were collected at GD21 and postnatal week (PW) 12 and 28. PDE offspring showed elevated serum total cholesterol (TCH) levels and a cholesterol phenotype of high cardiovascular disease risk at PW12 and PW28. The histone acetylation levels of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (Hmgcr) and its expression were consistently increased in the PDE offspring both in utero and after birth. Moreover, PDE promoted glucocorticoid receptor (GR) nuclear translocation and miR-133a-3p expression and inhibited sirtuin-1 (Sirt1) expression in the fetal liver. In vitro, dexamethasone increased intracellular and supernatant TCH levels and miR-133a-3p expression, decreased SIRT1 expression, and promoted HMGCR histone acetylation and expression in bone marrow mesenchymal stem cells (BMSCs) hepatoid differentiated cells and HepG2 cell line. GR siRNA, miR-133a-3p inhibitor or SIRT1 overexpression reversed dexamethasone-induced downstream molecular and phenotypic changes. Furthermore, elevated TCH levels in umbilical cord blood and increased HMGCR expression in peripheral blood mononuclear cells (PBMCs) were observed in human female neonates who had received dexamethasone treatment during pregnancy. In conclusion, PDE can cause persistent enhancement of hepatic cholesterol synthesis function before and after birth through GR/miR-133a-3p/Sirt1 pathway, eventually leading to increased hypercholesterolemia susceptibility in female offspring rats.

Lipid profile of patients treated with evolocumab in Spanish hospital nephrology units (RETOSS NEFRO).

BACKGROUND AND OBJECTIVE: To describe the clinical characteristics, the reasons for initiating therapy and the effects of treatment in the initial phase of evolocumab availability in the Nephrology Units of Spain. MATERIAL AND METHODS: Retrospective, observational and multicentric study that included patients initiating treatment with evolocumab (from February 2016 to August 2018), in 15 Nephrology Units in Spain. The demographic and clinical characteristics of the patients, the lipid lowering treatment and the evolution of the lipid profiles between 24 weeks pre-initiation and 12±4 weeks post-initiation of evolocumab were reviewed. RESULTS: 60 patients were enrolled: 53.3% women; mean (SD) age, 56.9 (12.8) years, 45.0% with familial hypercholesterolemia (FH) (5.0% homozygous and 40.0% heterozygous) and 65.0% with atherosclerotic cardiovascular disease. The mean (SD) eGFR was 62.6 (30.0) ml/min/1.73m2 (51.7% of patients had eGFR <60ml/min/1.73m2 [CKD stage>2]), 50.0% had proteinuria (>300mg/g) and 10.0% had nephrotic syndrome. Other CV risk factors were hypertension (75.0%), diabetes (25.0%), and smoking (21.7%). A 40.0% of patients were statin intolerant. At evolocumab initiation, 41.7% of patients were on a high intensity statin, 18.3% on moderate intensity statin and 50.0% were receiving ezetimibe. Mean (SD) LDL-c at evolocumab initiation was 179.7 (62.9) mg/dL (53.4% of patients with LDL-c ≥160mg/dL and 29.3% ≥190mg/dL). After 12 weeks, evolocumab resulted in LDL-c reductions of 60.1%. At week 12, 90.0% of patients reached LDL-c levels <100mg/dL, 70.0% <70mg/dL, and 55.0% <55mg/dL, while mean eGFR levels and statin use remained stable. CONCLUSION: In Nephrology Units of Spain, evolocumab was predominantly prescribed in patients with FH, chronic renal disease (CRD>2) and secondary prevention, with LDL-c levels above those recommended by the guidelines. Evolocumab used in clinical practice significantly reduced the LDL-c levels in all patients included in the study.

Evidence for intensive LDL-C lowering for acute coronary syndrome: Recommendations from the Lipid Association of India.

Patients with acute coronary syndrome (ACS) have a high risk of subsequent adverse cardiovascular outcomes, particularly within the first 30 days. Although it is well documented that initiation of statin therapy in the setting of ACS improves short- and long-term cardiovascular outcomes, and achievement of lower levels of low density lipoprotein cholesterol (LDL-C) incrementally improves outcomes, many patients with ACS have persistent hypercholesterolemia after discharge from the hospital. This is a missed opportunity that prompted the Lipid Association of India to develop recommendations for earlier initiation of more aggressive LDL-C lowering treatment, particularly for patients of South Asian descent who are well-documented to have earlier onset of more aggressive atherosclerotic cardiovascular disease. The Lipid Association of India recommends individualized aggressive LDL-C goals after ACS, which can be rapidly achieved with high intensity statin therapy and subsequent goal-directed adjunctive treatment with ezetimibe and PCSK9 inhibitors. Improved treatment of hypercholesterolemia achieved within weeks after ACS has the potential to reduce the high rate of morbidity and mortality in these high risk patients.

Effectiveness and safety of red yeast rice predominated by monacolin K ß-hydroxy acid form for hyperlipidemia treatment and management.

OBJECTIVE: To assess the lipid-lowering activity and safety of a dietary supplement containing monacolin K ß-hydroxy acid form (MKA), Heye (), and Cangzhu (), compared to lifestyle modifications. METHODS: Totally 117 subjects with moderate to severe dyslipidemia (according to Chinese guidelines) and low CV risk were randomly assigned into three treatment groups: lifestyle modification (LM), LM plus a low dosage of MKA, LM plus a high dosage of MKA, and treated for 60 d. The primary endpoint was the reduction of low density lipoprotein cholesterol (LDL-C) and total cholesterol (TC). Safeties along with Traditional Chinese Medicine Syndromes were assessed through the study. RESULTS: A low dosage of MKA along with lifestyle modifications caused a significant decrease in LDL-C by 15.6% on average (95% , 9.6% to 21%) with, a decrease in TC by 15.3% on average (95% CI, 9.26% to 21.4%), and a decrease in non-HDL-C by 35.4% (95% CI, 25.76% to 41.34%). Weak evidence of a reduction of triglycerides but an increment of HDL-C was observed in patients with severe hyperlipidemia. No severe adverse events occurred during the study. CONCLUSION: Our results confirm the LDL-C and TC lowering properties of MKA is clinically meaningful. It also produces a significant reduction of non-HDL-C, and slightly effects on TG and HDL-C as well.

Effect of PCSK9 inhibition with evolocumab on lipoprotein subfractions in familial dysbetalipoproteinemia (type III hyperlipidemia).

BACKGROUND AND AIMS: Familial dysbetalipoproteinemia (FDBL) is a rare inborn lipid disorder characterized by the formation of abnormal triglyceride- and cholesterol-rich lipoproteins (remnant particles). Patients with FDBL have a high risk for atherosclerotic disease. The effect of PCSK9 inhibition on lipoproteins and its subfractions has not been evaluated in FDBL. METHODS: Three patients (65±7 years, 23±3 kg/m2, 2 females) with FDBL (diagnosed by isoelectrofocusing) and atherosclerosis (coronary and/or cerebro-vascular and/or peripheral arterial disease) resistant or intolerant to statin and fibrate therapy received evolocumab (140mg every 14 days). In addition to a fasting lipid profile (preparative ultracentrifugation), apoB and cholesterol concentrations were determined in 15 lipoprotein-subfractions (density gradient ultracentrifugation; d 1.006-1.21g/ml) before and after 12 weeks of evolocumab treatment. Patients with LDL-hypercholesterolemia (n = 8, 56±8 years, 31±7 kg/m2) and mixed hyperlipidemia (n = 5, 68±12 years, 30±1 kg/m2) also receiving evolocumab for 12 weeks were used for comparison. RESULTS: All patients tolerated PCSK9 inhibition well. PCSK9 inhibitors reduced cholesterol (29-37%), non-HDL-cholesterol (36-50%) and apoB (40-52%) in all patient groups including FDBL. In FDBL, PCSK9 inhibition reduced VLDL-cholesterol and the concentration of apoB containing lipoproteins throughout the whole density spectrum (VLDL, IDL, remnants, LDL). Lipoprotein(a) was decreased in all patient groups to a similar extent. CONCLUSIONS: This indicates that the dominant fraction of apoB-containing lipoproteins is reduced with PCSK9 inhibition, i.e. LDL in hypercholesterolemia and mixed hyperlipidemia, and cholesterol-rich VLDL, remnants and LDL in FDBL. PCSK9 inhibition may be a treatment option in patients with FDBL resistant or intolerant to statin and/or fibrate therapy.

Hypercholesterolemia aggravates sevoflurane-induced cognitive impairment in aged rats by inducing neurological inflammation and apoptosis.

We aimed to explore the effects of hypercholesterolemia on sevoflurane-induced cognitive impairment in aged rats and the underlying mechanism(s). Aged rats were administrated with high-fat diet, sevoflurane, or both. Thereafter, the plasma levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) were evaluated. The Morris water maze task was performed to evaluate the spatial learning and memory ability of rats. Moreover, Nissl and Evans blue staining were conducted to test nerve damage and detect the blood-brain barrier permeability, respectively. The percentage of apoptotic cells was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling assay. The messenger RNA expression of inflammatory factors and protein expression of microglial activation markers and apoptosis-related proteins were tested by real-time polymerase chain reaction, enzyme-linked immunosorbent assay, or western blot analysis, respectively. High-fat diet induced high levels of TC, TG, and LDL but decreased levels of HDL. However, sevoflurane had no effects on these levels. In contrast, sevoflurane significantly induced the impairment of learning and memory, nerve damage, neuroinflammatory damage, and neuronal apoptosis. Hypercholesterolemia exacerbated the sevoflurane-induced impairment in aged rats. These results suggested that hypercholesterolemia aggravates sevoflurane-induced cognitive impairment in aged rats, possibly by inducing neurological inflammation and apoptosis.

Nuclear Receptor PXR in Drug-Induced Hypercholesterolemia.

Atherosclerosis is a major global health concern. The central modifiable risk factors and causative agents of the disease are high total and low-density lipoprotein (LDL) cholesterol. To reduce morbidity and mortality, a thorough understanding of the factors that influence an individual's cholesterol status during the decades when the arteria-narrowing arteriosclerotic plaques are forming is critical. Several drugs are known to increase cholesterol levels; however, the mechanisms are poorly understood. Activation of pregnane X receptor (PXR), the major regulator of drug metabolism and molecular mediator of clinically significant drug-drug interactions, has been shown to induce hypercholesterolemia. As a major sensor of the chemical environment, PXR may in part mediate hypercholesterolemic effects of drug treatment. This review compiles the current knowledge of PXR in cholesterol homeostasis and discusses the role of PXR in drug-induced hypercholesterolemia.

New insights into the role of bempedoic acid and ezetimibe in the treatment of hypercholesterolemia.

PURPOSE OF REVIEW: A number of new cholesterol-lowering drugs have been recently developed and approved, enriching the pharmacological armamentarium beyond and above statins. Ezetimibe, available since two decades, and bempedoic acid, a new drug inhibiting the same biosynthetic pathway targeted by statins but at an early step, represent valuable tools for the treatment of hypercholesterolemia, particularly in specific groups of patients. RECENT FINDINGS: Bempedoic acid, either alone or in combination with ezetimibe, appears to reduce significantly LDL-C levels, an effect that has been observed also in patients with statin intolerance. A Mendelian randomization study has anticipated a protective cardiovascular effect of bempedoic acid; a randomized clinical trial is currently assessing whether the pharmacological control of hypercholesterolemia with bempedoic acid translates into a clinical benefit. Bempedoic acid, as well as ezetimibe, does not appear to induce adverse events in muscles; moreover, whereas statins are associated with a modest, although significant, increased risk of new-onset diabetes, bempedoic acid does not, at least based on the available evidence. SUMMARY: On the basis of available data, and while awaiting the results of the outcome trial, bempedoic acid appears to represent a valuable approach for the treatment of hypercholesterolemia, either alone or in combination in ezetimibe.