Cholesterol-lowering Treatment Research Articles

Overcoming therapeutic inertia in LDL cholesterol-lowering treatment with education and simplified treatment algorithms.

Overcoming therapeutic inertia in LDL cholesterol-lowering treatment with education and simplified treatment algorithms.

A Retrospective Study: The Effectiveness of Lipid-Lowering Medications in Individuals at High Risk for Cardiovascular Disease

Objective: The effective administration of lipid-lowering treatment is of utmost importance in mitigating cardiovascular (CV) risk in patients who are undergoing secondary prevention. High-dose statins, ezetimibe, and the relatively newer PCSK9 inhibitors (PCSK9i) have shown effectiveness in achieving low density lipoprotein cholesterol(LDL-C) treatment targets for these patients. However, despite substantial evidence supporting their efficacy, these interventions remain significantly underutilized, primarily due to poor levels of patient adherence. Moreover, there is limited data available on the overall effectiveness of cholesterol-lowering treatment and the proportion of secondary prevention patients who have achieved a well-regulated lipid profile. In light of these factors, the principal aim of this investigation was to evaluate the present status of lipid-lowering medication within this specific group of individuals. Methods: The study was conducted at Mardin Artuklu University, Mardin Training and Research Hospital between April 2021 and March 2023, focusing on patients with a history of secondary prevention of CVD. The study investigated prescribed cholesterol-lowering drugs, factors contributing to statin underuse, and lipid profile disclosure. Results: 872 patients were included. 86.8% received statins, 5.2% ezetimibe, and 3.4% fibrates, while 13.2% received no lipid-lowering therapy. 64% of those on statins were on high doses. LDL-C values were assessed in 452 patients, with only 30% below the recommended cutoff of 70 mg/dL. Conclusion: In this investigation involving secondary prevention patients, slightly over half of the participants received high-dose statins, while a negligible proportion received ezetimibe treatment. Alarmingly, over two-thirds of the patients demonstrated LDL-C values that deviated significantly from the therapeutic range, indicating a considerable gap between their lipid profiles and the recommendations set forth by clinical guidelines.

Improving cardiovascular control in a hypertensive population in primary care. Results from a staff training intervention

Objective A pilot study to evaluate a staff training intervention implementing a nurse-led hypertension care model. Design and setting Clinical and laboratory data from all primary care centres (PCCs) in the Swedish region Västra Götaland (VGR), retrieved from regional registers. Intervention started 2018 in 11 PCCs. A total of 190 PCCs served as controls. Change from baseline was assessed 2 years after start of intervention. Intervention Training of selected personnel, primarily in drug choice, team-based care, measurement techniques, and use of standardized medical treatment protocols. Patients Hypertensive patients without diabetes or ischemic heart disease were included. The intervention and control groups contained approximately 10,000 and 145,000 individuals, respectively. Main outcome measures Blood pressure (BP) <140/90 mmHg, LDL-cholesterol (LDL-C) <3.0 mmol/L, BP ending on −0 mmHg (digit preference, an indirect sign of manual measuring technique), choice of antihypertensive drugs, cholesterol lowering therapy and attendance patterns were measured. Results In the intervention group, the percentage of patients reaching the BP target did not change significantly, 56%–61% (control 50%–52%), non-significant. However, the percentage of patients with LDL-C < 3.0 mmol/L increased from 34%–40% (control 36%–36%), p = .043, and digit preference decreased, 39%−27% (control 41%−35%), p = 0.000. The number of antihypertensive drugs was constant, 1.63 − 1.64 (control 1.62 − 1.62), non-significant, but drug choice changed in line with recommendations. Conclusion Although this primary care intervention based on staff training failed to improve BP control, it resulted in improved cardiovascular control by improved cholesterol lowering treatment.

Evinacumab (Evkeeza)

&#x0D; CADTH recommends that Evkeeza be reimbursed by public drug plans as an adjunct to diet and other low-density lipoprotein cholesterol (LDL-C)–lowering therapies for the treatment of adult and pediatric patients aged 5 years and older with homozygous familial hypercholesterolemia (HoFH) if certain conditions are met.&#x0D; Evkeeza should only be covered to treat patients aged 5 years and older with a diagnosis of HoFH and extremely high levels of LDL-C (sometimes referred to as bad cholesterol) despite receiving other cholesterol-lowering treatments.&#x0D; Evkeeza should only be reimbursed if prescribed by specialists with experience in managing HoFH and if the cost of Evkeeza is reduced. Evkeeza may only be prescribed for 24 weeks the first time it is used. To continue treatment with Evkeeza longer than 6 months, the treating physician must provide proof that the patient is responding to treatment, defined as reduction in LDL-C levels.&#x0D;

Higher prevalence of coronary microvascular dysfunction in asymptomatic individuals with high levels of lipoprotein(a) with and without heterozygous familial hypercholesterolaemia

Background and aimsMicrovascular dysfunction underlies many cardiovascular disease conditions; little is known regarding its presence in individuals with high levels of lipoprotein(a) [Lp(a)]. The aim of the present study was to determine the frequency of microvascular dysfunction among such subjects with and without concomitant familial hypercholesterolemia (FH). MethodsFour groups of asymptomatic individuals aged 30–59 years, without manifest cardiovascular disease, were recruited (n = 30 per group): controls with Lp(a) < 30 nmol/L, mutation-confirmed FH with Lp(a) < 30 nmol/L, or >125 nmol/L, and individuals with isolated Lp(a) > 125 nmol/L. Participants underwent evaluation of myocardial microvascular function by measuring coronary flow reserve (CFR) using transthoracic Doppler echocardiography, and of peripheral microvascular endothelial function by peripheral arterial tonometry. ResultsThe groups were balanced in age, sex, and body mass index. Each of the three dyslipoproteinaemic groups had a greater proportion of individuals with impaired coronary flow reserve, 30%, compared to 6.7% of controls (p = 0.014). The median CFR levels did not differ significantly between the four groups, however. Cholesterol-lowering treatment time was longer in the individuals with normal than in those with impaired CFR in the FH + Lp(a) > 125 group (p = 0.023), but not in the group with FH + Lp(a) < 30 (p = 0.468). There was no difference in peripheral endothelial function between the groups. ConclusionsCoronary microvascular dysfunction is more prevalent in asymptomatic individuals with isolated Lp(a) elevation and in heterozygous FH both with and without high Lp(a) compared to healthy controls. Cholesterol-lowering treatment could potentially prevent the development of microvascular dysfunction.

Prediction of Structure Activity Relationship (SAR) of Lactobacillus plantarum DA2 content for Cholesterol Reduction Treatment

Cholesterol is a chemical that is naturally created by the liver but can also be present in animal-based meals like meat and milk. Cholesterol is required by the body for the formation of healthy cells, the production of several hormones, and the production of vitamin D. Although cholesterol is necessary for the body, high levels can be harmful to one's health, hence therapy to lower cholesterol levels using natural products or the aid of bacterial metabolism is required. Lactobacillus plantarum 2DA is a lactic acid bacterium that has potential as a probiotic, so further analysis is needed on its ability as a therapy to reduce cholesterol through a bioinformatics approach. The method used in this research is to search for bacterial secondary metabolites by studying literature from published journals. Each compound is then searched in the PubChem database for its canonical structure and isomeric SMILE (simplified molecular-input line-entry system) and secondary metabolites in bacteria from the literature study were analyzed for potential using WAY2DRUG PASS prediction (http://www.pharmaexpert. ru/passonline/predict.php) as a cholesterol-lowering treatment. The results of the study based on the prediction of the SAR Way2 Drug Pass Server seen in the Probability To Be Active (Pa) values obtained 0.45, 0.49 and 0.37 for anti-hypercholesterolemic, cholesterol antagonist and cholesterol oxidase inhibitors. From the results obtained, it can be recommended that Lactobacillus plantarum 2DA can be further researched in vivo for cholesterol-lowering therapy.

Statin Use, Cholesterol Level, and Mortality Among Females With Breast Cancer

Several studies have reported an association between the use of statins and breast cancer (BC) mortality. However, most of these studies did not take into account the underlying cholesterol level. To investigate the association between serum cholesterol, statin use, and BC mortality. This cohort study included females with invasive BC that was newly diagnosed between January 1, 1995, and December 31, 2013, in Finland. The cohort had available hormone receptor data and at least 1 cholesterol measurement. All data were obtained from Finnish national registries. Statistical analyses were performed from January to May 2022. Use of statins; statin dose; and serum cholesterol, low-density lipoprotein, high-density lipoprotein, and triglyceride levels measured separately before and after BC diagnosis. Breast cancer mortality and overall mortality between date of BC diagnosis and December 31, 2015. A total of 13 378 female patients with BC (median [IQR] age, 62 [54-69] years) participated in the study. The median (IQR) follow-up was 4.5 (2.4-9.8) years after BC diagnosis, during which 16.4% of patients died and 7.0% died of BC. Prediagnostic statin use was a risk factor for BC death even after adjustment for total cholesterol level (hazard ratio [HR], 1.22; 95% CI, 1.02-1.46; P = .03). Reduced risk for BC death was seen for postdiagnostic statin use (HR, 0.85; 95% CI, 0.73-1.00; P = .05). The risk reduction was robust in participants whose cholesterol level decreased after starting statins (HR, 0.49; 95% CI, 0.32-0.75; P = .001) but was nonsignificant if cholesterol level did not subsequently decrease (HR, 0.69; 95% CI, 0.34-1.40; P = .30). Reduced BC mortality among statin users was also observed in females with estrogen receptor-positive tumors (HR, 0.82; 95% CI, 0.68-0.99; P = .03). Overall mortality was lower among statin users vs nonusers when adjusted for serum cholesterol level (HR, 0.80; 95% CI, 0.72-0.88; P < .001). Results of this cohort study showed that postdiagnostic use of statins was associated with reduced BC mortality compared with nonuse, and the risk was associated with subsequent change in serum cholesterol level. This finding suggests that cholesterol-lowering interventions with statins may be beneficial for patients with BC.

Myocardial microvascular dysfunction in asymptomatic patients with hereditary dyslipidemia

Abstract Introduction Microvascular dysfunction underlies the pathophysiology of many cardiovascular disease (CVD) conditions and is strongly associated with future cardiovascular events. Hereditary forms of dyslipidaemia such as familial hypercholesterolemia (FH) and high levels of lipoprotein(a) [Lp(a)] are associated with premature atherosclerotic CVD but the degree of microvascular dysfunction in asymptomatic individuals is not fully explored. Purpose To evaluate the presence of microvascular dysfunction in asymptomatic individuals with the hereditary dyslipidaemias FH and high Lp(a). Methods Asymptomatic individuals without manifest CVD were recruited to four groups with 30 subjects in each; 1) controls with Lp(a)&amp;lt;30 nmol/L, 2) FH+Lp(a)&amp;lt;30 nmol/L, 3) FH+Lp(a)&amp;gt;125 nmol/L, and 4) isolated Lp(a)&amp;gt;125 nmol/L without FH. FH diagnoses were confirmed by genetic analysis. Transthoracic doppler echocardiography was used to record coronary flow in the distal part of the left anterior descending artery at rest and during hyperaemia induced by intravenous infusion of adenosine. Coronary flow reserve (CFR) was calculated by dividing hyperaemic to basal flow. Peripheral microvascular endothelial function was determined by recording reactive hyperaemia index (RHI) by peripheral arterial tonometry in the index fingers of both hands. CFR and RHI were considered impaired if values were &amp;lt;2.5 and &amp;lt;1.67, respectively. Results The four groups were balanced in age (mean 42.6±8.4 years), sex (50% females), BMI (mean 25.0±4.7 kg/m2), and smoking status (5.0% current smokers). Low-density lipoprotein cholesterol was also similar across the four groups (mean 2.8±1.1 mmol/L) with the two FH groups being on cholesterol lowering treatment while the other two were pharmacologically naïve. The three groups with hereditary dyslipidaemia had a higher proportion of subjects with impaired CFR, 30.0% in each group compared to 6.6% in controls (p=0.014) (Figure 1A). The FH+Lp(a)&amp;lt;30 nmol/L and FH+Lp(a)&amp;gt;125 nmol/L groups had received cholesterol lowering treatment for a median (inter quartile range, IQR) of 4.0 (8.0) and 11.0 (11.0) years respectively (p&amp;lt;0.001). In the FH+Lp(a)&amp;gt;125 nmol/L group individuals with normal CFR had received significantly longer treatment (p=0.006) but not in the FH+Lp(a)&amp;lt;30 nmol/L group (p=0.568) (Figure 1B). There were no major differences in median CFR (p=0.550) (Figure 2A) or median RHI (p=0.341) (Figure 2B) levels between the four groups. Conclusion Asymptomatic individuals with the hereditary dyslipidaemias FH and/or high Lp(a) have a higher degree of coronary microvascular dysfunction compared to healthy controls. For individuals with combined traits FH and high Lp(a), the total treatment years of cholesterol lowering is associated with preserved coronary microvascular function suggesting CFR as a potential useful non-invasive tool for cardiovascular risk-stratification in patients with hereditary dyslipidaemias.Figure 1Figure 2

Abstract 18219: J-Shaped Association Between LDL-Cholesterol Level and Cardiovascular Events: A Longitudinal Follow-Up Study Over 2.4 Million Nationwide Primary Prevention Cohort

Introduction: Low-density lipoprotein (LDL)-cholesterol lowering treatment showed benefits in patients with high atherosclerotic cardiovascular disease (ASCVD) risk. Hypothesis: Although high LDL-cholesterol level is known to increase ASCVD risks, prognostic implications of low LDL-cholesterol level remain elusive. Methods: Using the data from a Korean Nationwide Cohort, we included 2,432,471 subjects without previous ASCVD. From 2009, subjects were followed for myocardial infarction (MI) and ischemic stroke until 2018. Subjects were stratified according to 10-year ASCVD risks (&lt;5%, 5 to &lt;7.5%, 7.5 to &lt;20%, and ≥20%) and LDL-cholesterol level (&lt;70, 70-99, 100-129, 130-159, 160-189, and ≥190 mg/dL). Results: In the overall population (median follow-up: 9.3 years), the relationship between LDL-C level and cardiovascular events showed J-shaped curve. Subjects with LDL-cholesterol &lt;70mg/dL showed increased risk of myocardial infarction compared to those with LDL-cholesterol 70 to &lt;100mg/dL after adjusting covariates in low ASCVD risk group. Similarly, subjects with LDL-cholesterol 70-99 mg/dL and 100-129 mg/dL had lower stroke risks than those with LDL-cholesterol &lt;70mg/dL in low ASCVD risk group. In contrast, LDL-cholesterol level and risks of MI and stroke showed linear association in high ASCVD risk group. Conclusions: High LDL-cholesterol level is associated with increased risk of MI or stroke, while low LDL-cholesterol level does not warrant safety from ASCVD in the primary prevention setting.

Improved arterial inflammation with high dose omega-3 fatty acids in patients with elevated lipoprotein(a): Selective effect of eicosapentaenoic acid?

Elevated lipoprotein(a) [Lp(a)] is a causal risk factor for atherosclerotic cardiovascular disease. However, there are no approved and effective treatments for lowering Lp(a) and the associated cardiovascular risks. Omega-3 fatty acids (ω-3FAs), primarily eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have both triglyceride-lowering and anti-inflammatory properties. This pilot study investigated the effect of high dose ω-3FAs (3.6 g/day) on arterial inflammation in 12 patients with elevated Lp(a) (> 0.5 g/L) and stable coronary artery disease (CAD) receiving cholesterol-lowering treatment. Arterial inflammation was determined using 18F-fluorodexoyglucose positron emission tomography/computed tomography before and after 12-weeks intervention. ω-3FAs significantly lowered plasma concentrations of triglycerides (–17%, p < 0.01), Lp(a) (-5%, p < 0.01) as well as aortic maximum standardized uptake value (SUVmax) (–4%, p < 0.05). The reduction in SUVmax was significantly inversely associated with average on-treatment EPA (r = -0.750, p < 0.01), but not DHA and triglyceride, concentrations. In conclusion, high dose ω-3FAs decrease arterial inflammation in patients with elevated Lp(a) and stable CAD, which may involve a direct arterial effect of EPA.

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

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. 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). 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. 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.

J-shaped association between LDL cholesterol and cardiovascular events: A longitudinal primary prevention cohort of over 2.4 million people nationwide

IntroductionLow-density lipoprotein (LDL) cholesterol-lowering treatment is beneficial for the secondary or primary prevention of high-risk atherosclerotic cardiovascular disease (ASCVD). However, the prognostic implications of low LDL cholesterol levels in patients without previous ASCVD and without statin use remain elusive. MethodsFrom a nationwide cohort, 2,432,471 participants without previous ASCVD or statin use were included. For myocardial infarction (MI) and ischemic stroke (IS), participants were followed-up from 2009 to 2018. They were stratified according to 10-year ASCVD risk (<5 %, 5 %–<7.5 %, 7.5 %–<20 %, and ≥20 %) and LDL cholesterol level (<70, 70–99, 100–129, 130–159, 160–189, and ≥190 mg/dL). ResultsThe relationship between LDL cholesterol levels and ASCVD events exhibited a J-shaped curve for both MI and IS. After classification according to the ASCVD risk, this J-shaped relationship was consistently observed for the composite of MI and IS. Participants with an LDL cholesterol level <70 mg/dL showed a higher MI risk than those with a level of 70–99 mg/dL or 100–129 mg/dL in the low-ASCVD risk group. The J-shaped curve between LDL cholesterol levels and MI risk was attenuated across ASCVD risk groups. For IS, participants with an LDL cholesterol level <70 mg/dL demonstrated increased risks compared with those with a level of 70–99 mg/dL, 100–129 mg/dL, or 130–159 mg/dL in the borderline, intermediate, and high ASCVD risk groups, respectively. In contrast, a linear association was observed in participants taking statins. Interestingly, a J-shaped association was observed between LDL cholesterol and high-sensitivity C-reactive protein (hs-CRP) levels; the mean hs-CRP level and the proportion of individuals with increased hs-CRP levels were relatively high among individuals with an LDL cholesterol level <70 mg/dL. ConclusionsAlthough high LDL cholesterol levels increase the risk of ASCVD, low LDL cholesterol levels do not warrant safety from ASCVD. Therefore, individuals with low LDL cholesterol levels should be carefully monitored.

Recurrent Atherosclerotic Cardiovascular Disease Events Potentially Prevented with Guideline-Recommended Cholesterol-Lowering Therapy following Myocardial Infarction.

Many adults with atherosclerotic cardiovascular disease (ASCVD) who are recommended to take a statin, ezetimibe and/or a proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) by the 2018 American Heart Association/American College of Cardiology cholesterol guideline do not receive these medications. We estimated the percentage of recurrent ASCVD events potentially prevented with guideline-recommended cholesterol-lowering therapy following a myocardial infarction (MI) hospitalization. We conducted simulations using data from US adults with government health insurance through Medicare or commercial health insurance in the MarketScan database. We used data from patients with an MI hospitalization in 2018-2019 to estimate the percentage receiving guideline-recommended therapy. We used data from patients with an MI hospitalization in 2013-2016 to estimate the 3-year cumulative incidence of recurrent ASCVD events (i.e., MI, coronary revascularization or ischemic stroke). The low-density lipoprotein cholesterol (LDL-C) reduction with guideline-recommended therapy was derived from trials of statins, ezetimibe and PCSK9i, and the associated ASCVD risk reduction was estimated from a meta-analysis by the Cholesterol-Lowering Treatment Trialists Collaboration. Among 279,395 patients with an MI hospitalization in 2018-2019 (mean age 75years, mean LDL-C 92mg/dL), 27.3% were receiving guideline-recommended cholesterol-lowering therapy. With current cholesterol-lowering therapy use, 25.3% (95%CI: 25.2%-25.4%) of patients had an ASCVD event over 3years. If all patients were to receive guideline-recommended therapy, 19.8% (95%CI: 19.5%-19.9%) were estimated to have an ASCVD event over 3years, representing a 21.6% (95%CI: 20.5%-23.6%) relative risk reduction. Implementation of guideline-recommended cholesterol-lowering therapy could prevent a substantial percentage of recurrent ASCVD events.

Intensive cholesterol-lowering treatment reduces synovial inflammation during early collagenase-induced osteoarthritis, but not pathology at end-stage disease in female dyslipidemic E3L.CETP mice

The association between metabolic syndrome (MetS) and osteoarthritis (OA) development has become increasingly recognized. In this context, the exact role of cholesterol and cholesterol-lowering therapies in OA development has remained elusive. Recently, we did not observe beneficial effects of intensive cholesterol-lowering treatments on spontaneous OA development in E3L.CETP mice. We postulated that in the presence of local inflammation caused by a joint lesion, cholesterol-lowering therapies may ameliorate OA pathology. Female ApoE3∗Leiden.CETP mice were fed a cholesterol-supplemented Western type diet. After 3 weeks, half of the mice received intensive cholesterol-lowering treatment consisting of atorvastatin and the anti-PCSK9 antibody alirocumab. Three weeks after the start of the treatment, OA was induced via intra-articular injections of collagenase. Serum levels of cholesterol and triglycerides were monitored throughout the study. Knee joints were analyzed for synovial inflammation, cartilage degeneration, subchondral bone sclerosis and ectopic bone formation using histology. Inflammatory cytokines were determined in serum and synovial washouts. Cholesterol-lowering treatment strongly reduced serum cholesterol and triglyceride levels. Mice receiving cholesterol-lowering treatment showed a significant reduction in synovial inflammation (P=0.008, WTD: 95% CI: 1.4- 2.3; WTD+AA: 95% CI: 0.8- 1.5) and synovial lining thickness (WTD: 95% CI: 3.0-4.6, WTD+AA: 95% CI: 2.1-3.2) during early-stage collagenase-induced OA. Serum levels of S100A8/A9, MCP-1 and KC were significantly reduced after cholesterol-lowering treatment (P=0.0005, 95% CI:-46.0 to-12.0; P=2.8×10-10, 95% CI:-398.3 to-152.1; P=2.1×10-9,-66.8 to-30.4, respectively). However, this reduction did not reduce OA pathology, determined by ectopic bone formation, subchondral bone sclerosis and cartilage damage at end-stage disease. This study shows that intensive cholesterol-lowering treatment reduces joint inflammation after induction of collagenase-induced OA, but this did not reduce end stage pathology in female mice.

Plain language summary of results from ORION-10 and ORION-11: two studies to learn how well inclisiran works in people with high cholesterol.

This is a summary of the article describing the results of the ORION-10 and ORION-11 studies, which was published in the New England Journal of Medicine in April 2020. The studies included adult participants with atherosclerotic cardiovascular disease (ASCVD). ASCVD happens when the blood vessels that carry blood from the heart to other areas of the body are blocked by fatty build-up (plaque) causing a heart attack, stroke, or other problems. High levels of low-density lipoprotein cholesterol (LDL cholesterol) in the blood can cause this fatty build-up. ORION-11 also included participants who were at high risk for ASCVD due to other conditions or high cholesterol that runs in the family. To help researchers understand whether a medicine called inclisiran could help to lower LDL (bad) cholesterol in participants with ASCVD, or at risk of having ASCVD, who had high cholesterol and were taking the highest dose of statins recommended for them. In the ORION-10 and ORION-11 studies, around half of the participants received inclisiran and around half received a placebo (a placebo looks like the study treatment but has no medicine in it) in addition to their usual cholesterol-lowering treatment. Participants in each study received 4 injections of their assigned treatment: at the start, at 3months, and then every 6months. LDL cholesterol was lowered by about 50% more in the inclisiran group compared with the placebo group. This lowering of LDL cholesterol was consistent throughout both studies. Adverse events (medical problems) were similar between treatment groups. Participants in the inclisiran group had more reactions where the injections were given than the placebo group, but these were mostly mild and only lasted a few days. Based on the results of these studies, inclisiran was approved by the United States Food and Drug Administration (FDA) as a treatment option for use with statins to reduce LDL cholesterol in people with ASCVD. Clinical Trial Registration: NCT03399370 (ORION-10), NCT03400800 (ORION-11) (ClinicalTrials.gov).

Infections May Cause Arterial Inflammation, Atherosclerosis, Myocarditis and Cardiovascular Disease

Effective prevention and treatment of atherosclerosis and cardiovascular disease (CVD), the commonest cause of death in most countries, is still lacking. For many years we have studied the cholesterol hypothesis and found that there are many contradictions to this hypothesis. For instance, no trial has shown exposure response; the lipid values are not associated with degree of atherosclerosis, and people with high LDL-C live just as long or longer than people with low LDL-C. These facts together with the observation that inflammation is a common finding in atherosclerotic arteries have probably contributed to the hypothesis that CVD may be caused by inflammation. However, several trials with anti-inflammatory drugs have shown that such treatment increases the risk of CVD. Therefore, a relevant hypothesis is whether it is infections which cause the inflammation and whether CVD may be caused by infections because many human observations and animal experiments are in accordance with this idea. As cholesterol-lowering treatment is ineffective and may cause serious side effects, we believe that future research should elucidate the importance of infections in the etiology of CVD. A relevant method would be to perform a blood culture on all patients with an acute AMI and if it is positive, to treat the patient with an appropriate antibiotic.

Targeting Redox Enzymes of Cholesterol Biosynthesis: A Step in the Right Direction Towards Ending Cardiovascular Disease

Global occurrence of cardiovascular diseases is a serious health concern resulting in over 2 million deaths annually. A major cause of cardiovascular disease is elevated levels of blood plasma cholesterol which leads to the precipitation of lipoproteins and arterial plaque formation. This review details treatment of hypercholesterolemia that target redox enzymes involved in the biosynthesis of the lipid. It begins with a brief discussion of both high- and low-density lipoproteins that are the vehicles for cholesterol transport in humans. An overview of the five stages of cholesterol anabolism in the liver is then provided focusing on the two rate-limiting redox enzymes involved in the pathway. These enzymes are 3-hydroxy-3-methylglutyl CoA reductase (HMGR) and squalene monooxygenase (SMO). The structure and catalytic mechanisms are presented in great detail to lay the foundation for a presentation of common cholesterol lowering drugs. The first of these are the statins that competitively inhibit HMGR and have shown the greatest success in both the treatment and prevention of cardiovascular diseases. An inhibitor of SMO called terbinafine is then discussed. This drug molecule is a fairly effective anti-fungal but is not currently approved in the U.S. to treat high cholesterol. However, it has been shown to lower low-density lipoproteins and exhibits promise to provide the framework for the development of new cholesterol lowering treatments to target SMO. It is hoped that this review article will raise awareness and spur future research into the treatment of hypercholesterolemia to treat and/or prevent cardiovascular disease.

Preclinical toxicity assessment of a peptide-based antiPCSK9 vaccine in healthy mice

BackgroundProprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition is a novel cholesterol-lowering treatment for decreasing the risk of atherosclerosis. We have previously shown that active immunization using the antiPCSK9 vaccine could decrease hypercholesterolemia and impede the development of atherosclerotic lesions in the experimental model of atherosclerosis. Here, we evaluated the toxicity of the vaccine in healthy mice. MethodsForty male and female albino mice were divided into 4 experimental groups, including vaccine female (10 mice) and male (10 mice) groups receiving the antiPCSK9 vaccine as well as the corresponding control female (10 mice) and male (10 mice) groups receiving the phosphate buffer. Vaccination was planned based on 4 subcutaneous injections of the vaccine formulation (10 µg/mouse) in bi-weekly intervals. The toxicity study was performed by the subacute protocol, 28 days after the last vaccine injection. To this end, the plasma levels of lipid indexes, urea, creatinine, AST, ALT, ALP, and fasting plasma glucose (FPG), as well as the CBC test were measured. To evaluate histopathological alterations, various tissues including the heart, liver, kidney, spleen, and brain were studied using hematoxylin & eosin (H&E) staining by an expert pathologist. The severity of damage to the tissue was considered based on the standard classification; grade 1 as light damage, grade 2 as moderate damage, grade 3 as near intense damage, and grade 4 as intense damage. ResultsThe results showed non-significant changes of total cholesterol, LDL-C, triglyceride, HDL-C, FBS, creatinine, urea, AST, ALP, ALT, and PAB in the vaccinated mice when compared with control mice. The CBS test indicated that there were no significant changes in the levels of WBC, RBC, HGB, HCT, MCH, MCHC, PLT, LYM, NEUT, MCV, RDW-S, PDW, and MPV in the vaccinated mice when compared with control mice. Evaluating histopathological alterations in various tissues indicated no significant adverse effects in vaccinated mice when compared to control mice. ConclusionThe findings of the present study indicate that antiPCSK9 is safe and exerts no adverse effects on the function of different organs and blood levels of cellular and biochemical biomarkers in healthy mice.

Dyslipidemia and the preventive potential in the Greenlandic population

BackgroundLow-density lipoprotein cholesterol (LDL-C) is a well-established risk factor for development of cardiovascular diseases. Based on available clinical data, we aimed to investigate the plasma lipid profile in the Greenlandic population, the proportion on cholesterol-lowering treatment and the adherence to local indications for cholesterol-lowering therapy. MethodsThis is an observational cross-sectional study of the adult (≥21 years) Greenlandic population with focus on clinically determined lipid levels from 2017 to early 2022. We investigated levels of dyslipidemia and assessed cholesterol-lowering medication usage in individuals with an indication according to current Greenlandic guidelines, which include a) LDL-C >5 mmol/l, b) diabetes, c) diagnosed atherosclerotic disease and 4) a SCORE2 >7.5%. ResultsIn the adult Greenlandic population of 40,565 individuals a lipid profile was available in 13,895 with a mean LDL-C of 3.0 mmol/L and 976 (7%) had a LDL-C >5 mmol/l. One or more indications for cholesterol-lowering medication was present in 3988 individuals and a total of 5464 adult Greenlanders either fulfilled local criteria for statin therapy or received a statin (some without current indication) and among these, 2232 (41%) individuals received no statin. ConclusionThese findings indicate that clinically significant dyslipidemia is common in the adult Greenlandic population and that the cardiovascular preventive potential of cholesterol-lowering therapy is currently underutilized.

Familial Hypercholesterolemia Patients with COVID-19-Effective Cholesterol-Lowering Therapy is Urgent both during and after Infection.

Heterozygous familial hypercholesterolemia (HeFH) patients are the prime example of subjects who are at high risk for both acute myocardial infarction (AMI) and ischemic stroke during, and post, SARS-CoV-2 infection. HeFH per se, if left untreated, results in premature clinical atherosclerosis often presenting in the fourth or fifth decade of life. The other concern in HeFH is endothelial dysfunction which is already evident from early childhood. In untreated HeFH patients, the severe hypercholesterolemia causes endothelial dysfunction from an early age, and as a result thereof, atherosclerotic lesions develop prematurely, particularly in the coronary arteries, and result in further endothelial dysfunction and inflammation in these critical segments of the arterial tree. As the pre-existing endothelial dysfunction in HeFH patients is most likely sensitive to further direct and indirect SARS-CoV-2 virus-dependent damage, we can infer that HeFH serves as an example of a comorbidity that predicts a poorer prognosis with COVID-19 infection. Indeed, a large US national database study showed that patients diagnosed with HeFH and SARS-CoV-2 infection had significantly increased Annualized Incidence Density Rates (AIDRs) of AMI when compared to matched HeFH controls not having been diagnosed with SARS-CoV-2 infection. Effective cholesterol lowering is essential for the prevention, or at least alleviation, of the detrimental effects of SARS-CoV-2 infection among HeFH patients. Due to the pre-existing subclinical or even clinical atherosclerotic cardiovascular disease in subjects with HeFH, cholesterol-lowering treatment needs to be continued or, better still, intensified during, and for an extended period post, SARS-CoV-2 infection.