Lower Plasma Low-density Lipoprotein Cholesterol Research Articles

Cost-effectiveness analysis of implementing the Nagasaki Acute Myocardial Infarction (AMI) secondary prevention clinical pathway

Abstract Background/Introduction Because of the poor prognosis associated with acute coronary syndromes (ACS), intensive low-density lipoprotein cholesterol (LDL-C) management therapy is recommended as early as possible after the onset of ACS, with the goal of lowering plasma LDL-C to <70 mg/dL. In Nagasaki City, a council was formed comprising all hospitals performing percutaneous coronary intervention along with general physicians, and an initiative to manage LDL-C using a region-wide LDL-C management clinical pathway (Figure 1) was launched in July 2022. The rate of intensive statin therapy at discharge increased from 34.5% to 79.8%, and the rate of patients achieving LDL-C <70 mg/dL at discharge increased from 37.2% to 54.6% following the implementation of the clinical pathway. However, the cost-effectiveness of implementing the clinical pathway remains to be determined. Purpose: The purpose of this study was to evaluate the cost-effectiveness of implementing the Nagasaki AMI Secondary Prevention Clinical Pathway. Methods: To evaluate the cost-effectiveness of implementing the clinical pathway compared with no implementation, a lifetime simulation was performed using mathematical models. The models consisted of a decision tree model to model the flow of the clinical pathway (Figure 2) and a Markov model to consider the risks of developing cardiovascular disease (CVD) events. The quality-adjusted life year (QALY) was used as the outcome. Drug costs and treatment costs for each CVD event were included. Drug costs were calculated from actual prescriptions. Treatment costs and utility scores for each event were based on the literature. The risk of each CVD event was calculated using baseline risks estimated using commercial claims data (DeSC Healthcare, Inc.) and patients' LDL-C levels at discharge and 1 month after discharge. LDL-C levels at each time point were set separately for the groups that achieved or did not achieve a discharge LDL-C < 70 mg/dL, for patients with and without implementing the clinical pathway. Results: Implementing the clinical pathway was evaluated as dominant, with an incremental gain of 0.079 QALYs per person and expected cost savings of JPY 103,124 per person. Implementing the clinical pathway was shown to not only provide additional health benefits by preventing CVD, but also to reduce future health care costs. In the analysis with a 10-year time horizon, the result remained dominant, and the same level of cost savings was expected. Conclusions: Implementing the Nagasaki AMI Secondary Prevention Clinical Pathway can be expected to reduce costs, in addition to increasing QALYs by preventing CVD. Further clinical and economic evaluation of long-term follow-up with a collaborative pathway to the general physician after discharge from the hospital is expected.

Statins, but not proprotein convertase subtilisin-kexin type 9 inhibitors, lower chemerin in hypercholesterolemia via low-density lipoprotein receptor upregulation.

Hypercholesterolemia is characterized by elevated low-density lipoprotein (LDL)-cholesterol levels and an increased risk of cardiovascular disease. The adipokine chemerin is an additional risk factor. Here we investigated whether cholesterol-lowering with statins or proprotein convertase subtilisin-kexin type 9 inhibitors (PCSK9i) affects chemerin. Both statins and PCKS9i lowered plasma LDL-cholesterol, triglycerides and total cholesterol in hypercholesterolemic patients, and increased high-density lipoprotein (HDL)-cholesterol. Yet, only statins additionally reduced chemerin and high-sensitivity C-reactive protein (hsCRP). Applying PCSK9i on top of statins did not further reduce chemerin. Around 20% of chemerin occurred in the HDL2/HDL3 fractions, while>75% was free. Statins lowered both HDL-bound and free chemerin. Pull-down assays revealed that chemerin binds to the HDL-component Apolipoprotein A-I (ApoA-I). The statins, but not PCSK9i, diminished chemerin secretion from HepG2 cells by upregulating LDL receptor mRNA. Furthermore, chemerin inhibited HDL-mediated cholesterol efflux via its chemerin chemokine-like receptor 1 in differentiated macrophages. In conclusion, statins, but not PCSK9i, lower circulating chemerin by directly affecting its release from hepatocytes. Chemerin binds to ApoA-I and inhibits HDL-mediated cholesterol efflux. Statins prevent this by lowering HDL-bound chemerin. Combined with their anti-inflammatory effect evidenced by hsCRP suppression, this represents a novel cardiovascular protective function of statins that distinguishes them from PCSK9i.

Multi-biobank Mendelian randomization analyses identify opposing pathways in plasma low-density lipoprotein-cholesterol lowering and gallstone disease

Plasma low-density lipoprotein (LDL)-cholesterol is positively associated with coronary artery disease risk while biliary cholesterol promotes gallstone formation. Different plasma LDL-cholesterol lowering pathways may have distinct effects on biliary cholesterol and thereby gallstone disease risk. We conducted a Mendelian randomization (MR) study using data from the UK Biobank (30,547 gallstone disease cases/336,742 controls), FinnGen (34,461 cases/301,383 controls) and Biobank Japan (9,305 cases/168,253 controls). We first performed drug-target MR analyses substantiated by colocalization to investigate the effects of plasma LDL-cholesterol lowering therapies on gallstone disease risk. We then performed clustered MR analyses and pathway analyses to identify distinct mechanisms underlying the association of plasma LDL-cholesterol with gallstone disease risk. For a 1-standard deviation reduction in plasma LDL-cholesterol, genetic mimics of statins were associated with lower gallstone disease risk (odds ratio 0.72 [95% confidence interval 0.62, 0.83]), but genetic mimics of PCSK9 inhibitors and targeting apolipoprotein B were associated with higher risk (1.11 [1.03, 1.19] and 1.23 [1.13, 1.35]). The association for statins was supported by colocalization (posterior probability 98.7%). Clustered MR analyses identified variant clusters showing opposing associations of plasma LDL-cholesterol with gallstone disease risk, with some evidence for ancestry-and sex-specific associations. Among variants lowering plasma LDL-cholesterol, those associated with lower gallstone disease risk were mapped to glycosphingolipid biosynthesis pathway, while those associated with higher risk were mapped to pathways relating to plasma lipoprotein assembly, remodelling, and clearance and ATP-binding cassette transporters. This MR study provides genetic evidence that different plasma LDL-cholesterol lowering pathways have opposing effects on gallstone disease risk.

Abstract 3071: Ras-related Protein 1a-mediated Regulation Of Proprotein Convertase Subtilisin/kexin Type 9

Background & Aims: Proprotein convertase subtilisin/kexin type 9 (PCSK9) has recently been identified as a therapeutic target to regulate plasma low-density lipoprotein cholesterol (LDL-C) levels. PCSK9 binds to the LDL receptor (LDLR) and targets it for lysosomal degradation, hindering LDL-C uptake from the circulation. Despite the use of anti-PCSK9 therapies, the molecular mechanisms by which PCSK9 gets regulated are not fully understood. In this regard, we recently discovered that activation of hepatic small GTPase, Ras-related protein 1a (Rap1a), decreases PCSK9 levels and subsequently lowers plasma LDL-C. In addition, the most widely used medicine to lower cholesterol, statins, have been shown to increase circulating PCSK9 levels, which limits their efficacy; however, our understanding of the link between statins and plasma PCSK9 is limited. Hypothesis & Aims: As statins block the synthesis of geranylgeranyl isoprenoids (GGPP), which are required for Rap1a activation, we explored the hypothesis that Rap1a is involved in statin-induced expression of PCSK9. We further explored the mechanisms of PCSK9 regulation by Rap1a. Methods: Mice were treated orally with statins and geranylgeraniol, the precursor of GGPP by daily oral gavage. Rap1a activator, 8-pCPT-2’-OMe-cAMP, was administered via i.p. injection. Hepatic PCSK9, plasma PCSK9, and LDL-C levels were assayed. For in vitro experiments, primary hepatocytes were isolated from wild-type mice and treated with vehicle, simvastatin, or simvastatin in combination with GGPP or 8-pCPT-2’-OMe-cAMP. PCSK9 levels were measured. Results: Statin treatment combined with GGOH lowered plasma PCSK9 and LDL-C in mice (174 ± 25 vs 109 ± 16 ng/mL and 24 ± 1.8 vs 19 ± 1.4 mg/dL, respectively, n=4-5, mean ± SEM, p < 0.05). Rap1a activator, 8-pCPT-2’-OMe-cAMP, also lowered statin-induced PCSK9 in vitro. Mechanistically, we found that Rap1a inhibits the downstream RhoA-ROCK pathway and regulates PCSK9 at the post-transcriptional level. Conclusions: In conclusion, our data reveal that Rap1a is a novel regulator of PCSK9 protein and blocking Rap1a prenylation through lowering geranylgeranyl levels contributes to statin-mediated induction of PCSK9.

ANGPTL3 and ApoC-III inhibitors for treating hypertriglyceridemia in context: horses for courses?

Hypertriglyceridemia (HTG) is an independent and casual risk factor for atherosclerotic cardiovascular disease (ASCVD). There is an unmet need for more effective treatments for patients with HTG. Angiopoietin-like protein 3 (ANGPTL3) and apolipoprotein C-III (apoC-III) are key regulators of triglyceride-rich lipoprotein (TRL) metabolism. We review recent clinical trials targeting ANGPTL3 and apoC-III with monoclonal antibody and nucleic acid therapies, including antisense oligonucleotides and small interfering RNA. ANGPTL3 and apoC-III inhibitors are effective in lowering plasma triglycerides and TRLs, with possibly greater efficacy with the inhibition of apoC-III. By contrast to ANGPTL3 inhibition that has the advantage of greater lowering of plasma low-density lipoprotein (LDL)-cholesterol and apoB levels, apoC-III inhibition only has a modest or no effect in lowering plasma LDL-cholesterol and apoB concentrations. Therapeutic inhibition of ANGPTL3 and apoC-III can correct HTG possibly by reducing production and increasing catabolism of TRL particles, but this remains to be formally investigated in patients with HTG. Novel agents targeting ANGPTL3 and apoC-III can correct HTG and potentially lower risk of ASCVD in patients with HTG. The long-term safety and cost-effectiveness of these agents await confirmation in ongoing and future studies.

Fenugreek Leaves and Lemon are Mild to Moderately Effective Hypolipidemic Herbs to Lower Total Plasma Cholesterol, Triglycerides, and LDL Cholesterol in Primary and Secondary Hyperlipidemic Patients

In recent decades, some researchers assert that other newer lipid measurements, including non-HDL-C, apolipoprotein (apo) A-I, apoB, and lipid ratios, are superior to traditional LDL-C in predicting adverse outcomes in general population. Some researchers even suggest that apoB can replace the standard “lipid profile” as a target for motoring and therapy in at-risk patients. High plasma lipids interact with free radicals in human body leading to develop coronary artery disease. We in this study have compared hypolipidemic effects of Fenugreek, Curcuma longa, and Lemon. Study was conducted at Jinnah Hospital Lahore-Pakistan from January 2022 to May 2022. Ninety hyperlipidemic patients of age group 19 to 70 were included in the study. Exclusion criteria were diabetic, alcoholic additives, hypertensive patients and those whose kidney or liver functions were impaired. Consent was taken from all participants. Their base line lipid profile was taken in biochemistry laboratory of the hospital. They were divided in three groups i.e. 30 patients in each group. Group-I was advised to take 500 mg of Curcuma longa (haldi) mixed in fresh milk without cream, thrice daily for two months. Group-II patients were advised to take 100 grams of Fenugreek leaves mixed with salad in each meal (thrice daily) for the period of two months. Group-III patients were advised to take 40 ml of fresh lemon juice mixed with 40 ml mineral water thrice daily for two months. They all were advised not to take heavy meal rich with any type of fat like junk food etc. One hour daily brisk walk was advised to all participants. 15 days follow up visit was scheduled for them. After two months their lipid profile was re-determined. When results were compiled and statistically analyzed by applying paired ‘t’ test, it revealed that Curcuma longa decreased total cholesterol, TG, LDL cholesterol 16.10, 20.01, and 17.59 mg/dl respectively. Fenugreek decreased total cholesterol, TGs, and LDL cholesterol 14.70, 17.33, and 17.06 mg/dl respectively. Lemon in two months therapy decreased total cholesterol, TGs, and LDL cholesterol 15.45, 10.13, and 11.97 mg/dl respectively. None of the above mentioned herbs raised HDL cholesterol significantly. It was concluded from this research work that Curcuma longa, Fenugreek leaves and Lemon are mild to moderately effective hypolipidemic herbs to lower total plasma cholesterol, triglycerides, and LDL cholesterol but have no potential to raise HDL cholesterol when analyzed biostatistically.

Targeting Allosteric Site of PCSK9 Enzyme for the Identification of Small Molecule Inhibitors: An In Silico Drug Repurposing Study.

The primary cause of atherosclerotic cardiovascular disease (ASCVD) is elevated levels of low-density lipoprotein cholesterol (LDL-C). Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in this process by binding to the LDL receptor (LDL-R) domain, leading to reduced influx of LDL-C and decreased LDL-R cell surface presentation on hepatocytes, resulting higher circulating levels of LDL-C. As a consequence, PCSK9 has been identified as a crucial target for drug development against dyslipidemia and hypercholesterolemia, aiming to lower plasma LDL-C levels. This research endeavors to identify promising inhibitory candidates that target the allosteric site of PCSK9 through an in silico approach. To start with, the FDA-approved Drug Library from Selleckchem was selected and virtually screened by docking studies using Glide extra-precision (XP) docking mode and Smina software (Version 1.1.2). Subsequently, rescoring of 100 drug compounds showing good average docking scores were performed using Gnina software (Version 1.0) to generate CNN Score and CNN binding affinity. Among the drug compounds, amikacin, bestatin, and natamycin were found to exhibit higher docking scores and CNN affinities against the PCSK9 enzyme. Molecular dynamics simulations further confirmed that these drug molecules established the stable protein-ligand complexes when compared to the apo structure of PCSK9 and the complex with the co-crystallized ligand structure. Moreover, the MM-GBSA calculations revealed binding free energy values ranging from -84.22 to -76.39 kcal/mol, which were found comparable to those obtained for the co-crystallized ligand structure. In conclusion, these identified drug molecules have the potential to serve as inhibitors PCSK9 enzyme and these finding could pave the way for the development of new PCSK9 inhibitory drugs in future in vitro research.

Extracellular vesicle-mediated delivery of CRISPR/Cas9 ribonucleoprotein complex targeting proprotein convertase subtilisin-kexin type 9 (Pcsk9) in primary mouse hepatocytes.

The loss-of-function of the proprotein convertase subtilisin-kexin type 9 (Pcsk9) gene has been associated with significant reductions in plasma serum low-density lipoprotein cholesterol (LDL-C) levels. Both CRISPR/Cas9 and CRISPR-based editor-mediated Pcsk9 inactivation have successfully lowered plasma LDL-C and PCSK9 levels in preclinical models. Despite the promising preclinical results, these studies did not report how vehicle-mediated CRISPR delivery inactivating Pcsk9 affected low-density lipoprotein receptor recycling in vitro or ex vivo. Extracellular vesicles (EVs) have shown promise as a biocompatible delivery vehicle, and CRISPR/Cas9 ribonucleoprotein (RNP) has been demonstrated to mediate safe genome editing. Therefore, we investigated EV-mediated RNP targeting of the Pcsk9 gene ex vivo in primary mouse hepatocytes. We engineered EVs with the rapamycin-interacting heterodimer FK506-binding protein (FKBP12) to contain its binding partner, the T82L mutant FKBP12-rapamycin binding (FRB) domain, fused to the Cas9 protein. By integrating the vesicular stomatitis virus glycoprotein on the EV membrane, the engineered Cas9 EVs were used for intracellular CRISPR/Cas9 RNPdelivery, achieving genome editing with an efficacy of ±28.1% in Cas9 stoplight reporter cells. Administration of Cas9 EVs in mouse hepatocytes successfully inactivated the Pcsk9 gene, leading to a reduction in Pcsk9 mRNA and increased uptake of the low-density lipoprotein receptor and LDL-C. These readouts can be used in future experiments to assess the efficacy of vehicle-mediated delivery of genome editing technologies targeting Pcsk9. The ex vivo data could be a step towards reducing animal testing and serve as a precursor to future in vivo studies for EV-mediated CRISPR/Cas9 RNP delivery targeting Pcsk9.

Insights into the current management of dyslipidemia from a clinical pharmacological perspective

The low-density lipoprotein cholesterol (LDL-C) is established as a causative agent of atherosclerotic cardiovascular disease (ASCVD) and lowering plasma LDL-C levels represents the main approach to reduce the risk of cardiovascular events. Statins remain the cornerstone of drug therapy for dyslipidemia. Although moderate- to high- intensity statin therapy has demonstrated consistent benefits for secondary prevention of cardiovascular events, statin monotherapy is insufficient to achieve the guideline-recommended LDL-C levels for high- and very high-risk patients. Some patients cannot tolerate statins, especially when taking long-term high doses. Several non-statin drugs that have a complementary mechanism of action to statins are now available, including ezetimibe, monoclonal antibodies targeted to proprotein convertase subtilisin/kexin type 9 (PCSK9 mAb), and, more recently, inclisiran, bempedoic acid, and evinacumab. Considering the recommendations from guidelines by domestic and international cardiovascular associations, combining these drugs should be contemplated to attain treatment goals for patients. Key words: dyslipidemia, atherosclerotic cardiovascular disease, lipid-lowering drugs, familial hypercholesterolemia, hypertriglyceridaemia, nonstatin therapies.

Abstract 14943: Trans-Biobank Mendelian Randomization Analyses Identify Distinct and Opposing Pathways in the Association of Lower Plasma Low-Density Lipoprotein-Cholesterol With Risk of Gallstone Disease

Background: Higher plasma LDL-cholesterol increases coronary artery disease risk, while biliary cholesterol promotes gallstone formation. Trial evidence suggests that lowering plasma LDL-cholesterol with bempedoic acid increases gallstone risk. Hypothesis: Different plasma LDL-cholesterol lowering pathways have distinct effects on biliary cholesterol and thereby gallstone disease risk. Methods: We conducted a Mendelian randomization (MR) study using data from the UK Biobank (30,547 gallstone disease cases/336,742 controls), FinnGen (34,461 cases/301,383 controls) and Biobank Japan (9,305 cases/168,253 controls). We firstly performed drug-target MR analyses substantiated by colocalization to investigate the effects of plasma LDL-cholesterol lowering therapies on gallstone risk. We then performed clustered MR analyses followed by pathway analyses to identify distinct pathways in the association of lower plasma LDL-cholesterol with gallstone risk. Results: Genetic mimics of statins were associated with lower gallstone risk, but genetic mimics of PCSK9 inhibitors, mipomersen and bile acid sequestrants were associated with higher gallstone risk. The association for statins was supported by colocalization (posterior probability 98.7%). Clustered MR analyses consistently identified clusters showing opposing associations of lower plasma LDL-cholesterol with gallstone risk. Among variants predicting lower plasma LDL-cholesterol, those associated with lower gallstone risk were mapped to glycosphingolipid biosynthesis pathway, while those associated with higher gallstone risk were mapped to pathways relating to ATP-binding cassette transporters and plasma lipoprotein assembly, remodelling, and clearance. Conclusions: Genetic evidence suggests that different plasma LDL-cholesterol lowering pathways may have opposing effects on gallstone disease risk. Specifically, statins may reduce gallstone disease risk.

FRI570 Repatha Induced Thyroid Storm

Abstract Disclosure: L.R. Sepulveda-Garcia: None. L.N. Madera Marin: None. L. El Musa Penna: None. W. Medina-Torres: None. M.A. Ortiz-Rivera: None. A. Rosado-Burgos: None. M. Alvarado: None. M. Ramirez: None. L.A. Gonzalez-Rodriguez: None. Introduction: Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors are an effective medical therapy for lowering plasma LDL-cholesterol and enhancing the LDL-cholesterol ability of statins. In 2020, a case of transient hyperthyroidism secondary to evolocumab was reported. We present a case of impending thyroid storm after a patient received evolocumab. Patient description: 60 y/o female patient with medical history remarkable for hyperlipidemia, anti-TPO positive non-toxic multinodular goiter, hypertension, fibromyalgia, and coronary artery disease who presented with heat intolerance, palpitations, tremors, and insomnia after second dose of evolocumab. At physical exam found with tachycardia, hypertension, anxious mood, tremors, leg pitting edema +1 bilateral, and deep tendon reflexes +3 in lower extremities, although no palpable or painful goiter. Laboratories compatible with hyperthyroidism [TSH < 0.008 uIU/mL (0.3 – 3.0 uIU/mL), Free T4 4.29 ng/dL (0.89 – 1.76 ng/dL), Total T4 20.03 ug/dL (4.5-12 ug/dL)] and clinically with severe thyrotoxicosis. Patient was sent to ED for further evaluation and management. Case outcomes: Upon admission patient presented with a tonic-clonic seizure with short post ictal state. Burch-Wartofsky scale Point Scale 35, consistent with impending thyroid storm. Thyrotoxicosis management given requiring high doses of PTU, hydrocortisone and propranolol, including the need to add cholestyramine to the regime. By day 9 of therapy, patient was transitioned to methimazole 30mg daily with discontinuation of hydrocortisone and cholestyramine. Upon discharge, 2 weeks later, thyroid function tests had normalized to a FT4 of 1.39 ng/dL and a Total T4 of 9.6 ug/dL. Case discussion: A case of transient hyperthyroidism with PCSK9 inhibitor was previously reported requiring only symptomatic treatment. In this case a patient presented with severe thyrotoxicosis after she received her second dose of evolocumab. PCSK9 inhibitor therapy immunological influence on thyroid remains unknown. This case shows the importance of thyroid function test follow up in patients on PCSK9 inhibitor therapy and the possibility of immunological influence on the thyroid. Presentation: Friday, June 16, 2023

Orally Bioavailable Macrocyclic Peptide That Inhibits Binding of PCSK9 to the Low Density Lipoprotein Receptor.

Inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9)-low density lipoprotein receptor interaction with injectable monoclonal antibodies or small interfering RNA lowers plasma low density lipoprotein-cholesterol, but despite nearly 2 decades of effort, an oral inhibitor of PCSK9 is not available. Macrocyclic peptides represent a novel approach to target proteins traditionally considered intractable to small-molecule drug design. Novel mRNA display screening technology was used to identify lead chemical matter, which was then optimized by applying structure-based drug design enabled by novel synthetic chemistry to identify macrocyclic peptide (MK-0616) with exquisite potency and selectivity for PCSK9. Following completion of nonclinical safety studies, MK-0616 was administered to healthy adult participants in a single rising-dose Phase 1 clinical trial designed to evaluate its safety, pharmacokinetics, and pharmacodynamics. In a multiple-dose trial in participants taking statins, MK-0616 was administered once daily for 14 days to characterize the safety, pharmacokinetics, and pharmacodynamics (change in low density lipoprotein cholesterol). MK-0616 displayed high affinity (Ki = 5pM) for PCSK9 in vitro and sufficient safety and oral bioavailability preclinically to enable advancement into the clinic. In Phase 1 clinical studies in healthy adults, single oral doses of MK-0616 were associated with >93% geometric mean reduction (95% CI, 84-103) of free, unbound plasma PCSK9; in participants on statin therapy, multiple-oral-dose regimens provided a maximum 61% geometric mean reduction (95% CI, 43-85) in low density lipoprotein cholesterol from baseline after 14 days of once-daily dosing of 20 mg MK-0616. This work validates the use of mRNA display technology for identification of novel oral therapeutic agents, exemplified by the identification of an oral PCSK9 inhibitor, which has the potential to be a highly effective cholesterol lowering therapy for patients in need.

Curcumin from turmeric is an extremely efficient agent in increasing cholesterol uptake by the liver cells

Medicinal plants have a long history of usage and today, they are being extensively used for various diseases. There are several reasons for increasing the use of medicinal plants. Many plants from different parts of the world have been investigated for hypolipidemic effects. Based on strong epidemiological evidence on the relationship between high LDL-C and an increased risk of CVD, treatment and control of elevated LDL-C are as primary goals of CVD prevention in guidelines. In the meantime, both epidemiological and experimental studies confirm the protective effect of high-density lipoprotein cholesterol (HDL-C) on the onset of CAD despite LDL-C level, owing to the reverse cholesterol transport process of HDL-C. However, in recent decades, some researchers assert that other newer lipid measurements, including non-HDL-C, apolipoprotein (apo)A-I, apoB, and lipid ratios, are superior to traditional LDL-C in predicting adverse outcomes in general population. Some researchers even suggest that apoB can replace the standard “lipid profile” as a target for motoring and therapy in at-risk patients. High plasma lipids interact with free radicals in human body leading to develop coronary artery disease. We in this study have compared hypolipidemic effects of Fenugreek, Curcuma longa, and Lemon. Study was conducted at Jinnah Hospital Lahore-Pakistan from January 2018 to May 2018. Ninety hyperlipidemic patients of age group 19 to 70 were included in the study. Exclusion criteria were diabetic, alcoholic additives, hypertensive patients and those whose kidney or liver functions were impaired. Consent was taken from all participants. Their base line lipid profile was taken in biochemistry laboratory of the hospital. They were divided in three groups i.e. 30 patients in each group. Group-I was advised to take 500 mg of Curcuma longa (haldi) mixed in fresh milk without cream, thrice daily for two months. Group-II patients were advised to take 100 grams of Fenugreek leaves mixed with salad in each meal (thrice daily) for the period of two months. Group-III patients were advised to take 40 ml of fresh lemon juice mixed with 40 ml mineral water thrice daily for two months. They all were advised not to take heavy meal rich with any type of fat like junk food etc. One hour daily brisk walk was advised to all participants. 15 days follow up visit was scheduled for them. After two months their lipid profile was re-determined. When results were compiled and statistically analyzed by applying paired ‘t’ test, it revealed that Curcuma longa decreased total cholesterol, TG, LDL cholesterol 16.10, 20.01, and 17.59 mg/dl respectively. Fenugreek decreased total cholesterol, TGs, and LDL cholesterol 14.70, 17.33, and 17.06 mg/dl respectively. Lemon in two months therapy decreased total cholesterol, TGs, and LDL cholesterol 15.45, 10.13, and 11.97 mg/dl respectively. None of the above-mentioned herbs raised HDL cholesterol significantly. It was concluded from this research work that Curcuma longa, Fenugreek leaves and Lemon are mild to moderately effective hypolipidemic herbs to lower total plasma cholesterol, triglycerides, and LDL cholesterol but have no potential to raise HDL cholesterol when analyzed biostatistically.

Inclisiran-A Revolutionary Addition to a Cholesterol-Lowering Therapy.

Hypercholesterolemia plays a crucial role in the development of atherosclerosis, but it remains an undertreated and underdiagnosed disease. Taking into consideration the high prevalence of lipid disorders, long duration of the asymptomatic course of the disease, life-threatening complications resulting from inaccurate therapy, and stringent treatment goals concerning LDL cholesterol level in the prevention of cardiovascular events, novel lipid-lowering therapies have been introduced in the last few years. In this article, a drug belonging to the group of small interfering RNA (siRNA) called inclisiran is described. It is a novel molecule that increases the number of LDL receptors (LDLRs) on the surface of hepatic cells by preventing the formation of proprotein convertase subtilisin/kexin type 9 (PCSK9) responsible for the degradation of LDLRs. With great potential for lowering plasma LDL cholesterol level, high liver specificity, comfortable dosing regimen, and good tolerance without significant adverse effects, it could play an important part in future hypolipemic therapies.

A cVLP-Based Vaccine Displaying Full-Length PCSK9 Elicits a Higher Reduction in Plasma PCSK9 Than Similar Peptide-Based cVLP Vaccines.

Administration of PCSK9-specific monoclonal antibodies, as well as peptide-based PCSK9 vaccines, can lower plasma LDL cholesterol by blocking PCSK9. However, these treatments also cause an increase in plasma PCSK9 levels, presumably due to the formation of immune complexes. Here, we utilize a versatile capsid virus-like particle (cVLP)-based vaccine platform to deliver both full-length (FL) PCSK9 and PCSK9-derived peptide antigens, to investigate whether induction of a broader polyclonal anti-PCSK9 antibody response would mediate more efficient clearance of plasma PCSK9. This head-to-head immunization study reveals a significantly increased capacity of the FL PCSK9 cVLP vaccine to opsonize and clear plasma PCSK9. These findings may have implications for the design of PCSK9 and other vaccines that should effectively mediate opsonization and immune clearance of target antigens.

Targeting PCSK9 With Antibodies and Gene Silencing to Reduce LDL Cholesterol.

The discovery of PCSK9 and its role in regulating the low-density lipoprotein (LDL) receptor, and the effect of loss-of-function mutations of its gene, identified it as a therapeutic target in 2006. Fully humanized monoclonal antibodies to PCSK9 (alirocumab and evolocumab) proved effective for lowering LDL cholesterol and subsequently for reducing atherosclerotic events in large outcome trials. Suppressing PCSK9 synthesis via gene silencing using inclisiran, a small interfering RNA, is another approach that effectively reduces LDL cholesterol, and a cardiovascular outcome trial is in progress. These treatments are given subcutaneously on a background of maximally tolerated statin treatment and are long-lasting: dosing is once or twice a month, self-administered, for alirocumab and evolocumab, and every 6 months for inclisiran, in the clinic, with an extra dose at 3 months in the initial year of therapy. These 3 agents produce mean LDL reductions of about 55% with no important adverse effects detectable to date. They are indicated in patients with atherosclerotic vascular disease or familial hypercholesterolemia who cannot achieve LDL cholesterol targets with maximally tolerated statin treatment. Such therapy can produce very low plasma LDL cholesterol and PCSK9, but there is no evidence this is harmful. Introduction into clinical practice has been impeded by economic considerations. The barrier to their use has not been scientific or medical, but rather the impact on healthcare resources. Prices have been reduced, but whether they are now cost-effective varies from country to country.

ANGPTL3 as a Drug Target in Hyperlipidemia and Atherosclerosis.

Elevated low-density lipoprotein cholesterol (LDL-C) and triglyceride-rich lipoproteins (TRLs) or remnants are important risk factors for the development of atherosclerotic cardiovascular disease (ASCVD). The ongoing challenge of not being able to achieve recommended LDL-C targets despite maximally tolerated lipid-lowering therapy (LLT) has led to the development of novel therapeutic agents including angiopoietin-like 3 (ANGPTL3) inhibitors. ANGPTL3 is a glycoprotein produced by the liver that inhibits lipoprotein lipase and endothelial lipase. Data from genetic and clinical studies have shown that a lower ANGPTL3 level is associated with lower plasma LDL-C, triglyceride (TG), and other lipoproteins. Pharmacological inactivation of ANGPTL3 with the monoclonal antibody, evinacumab, results in a 50% reduction in LDL-C, even in patients with homozygous familial hypercholesterolemia (HoFH). The safe and effective targeted delivery of nucleic acid-based therapies will shape the future of the lipid arena. ANGPTL3 is a novel target in lipoprotein metabolism, targeting not only LDL-C via an LDL-receptor (LDLR) independent mechanism but also TRLs and carries a significant promise for further ASCVD risk reduction.

Bempedoic Acid: A New Tool for LDL-Cholesterol Control in Patients with Coronary Artery Disease.

Nowdays a small proportion of patients with high/very high/extreme atherosclerotic cardiovascular disease risk achieves the optimal target of LDL-cholesterol, because of drug intolerance, poor adherence to the therapy, or inapplicability of the stepwise strategy in lipid lowering therapy, recommended by the current guidelines. The new oral agent bempedoic acid lowers plasma LDL-cholesterol by inhibiting adenosine triphosphate-citrate lyase, an enzyme involved in the synthesis of cholesterol, and, ultimately, by up-regulating the LDL receptors. Several clinical trials in patients with atherosclerotic cardiovascular disease or familial heterozygous hypercholesterolemia demonstrated that bempedoic acid alone or combined with statins and/or ezetimibe significantly reduced LDL-cholesterol and high-sensitivity C-reactive protein. Bempedoic acid is well tolerated with no significant increase in muscle-related symptoms, since it can be activated only in the liver but not in the skeletal muscles. Bempedoic acid provides an effective tool to further reduce LDL-cholesterol as add on therapy in patients unable to reach the target despite maximally tolerated lipid lowering therapy.

Antihyperlipidemic Activity of Gut-Restricted LXR Inverse Agonists.

Hyperlipidemia and increased circulating cholesterol levels are associated with increased cardiovascular disease risk. The liver X receptors (LXRs) are regulators of de novo lipogenesis and cholesterol transport and have been validated as potential therapeutic targets for the treatment of atherosclerosis. However, efforts to develop LXR agonists to reduce cardiovascular diseases have failed due to poor clinical outcomes-associated increased hepatic lipogenesis and elevated low-density lipoprotein (LDL) cholesterol (C). Here, we report that LXR inverse agonists are effective in lowering plasma LDL cholesterol and triglycerides in several models of hyperlipidemia, including the Ldlr null mouse model of atherosclerosis. Mechanistic studies demonstrate that LXR directly regulates the expression of Soat2 enzyme in the intestine, which is directly responsible for the re-uptake or excretion of circulating lipids. Oral administration of a gut-specific LXR inverse agonist leads to reduction of Soat2 expression in the intestine and effectively lowers circulating LDL cholesterol and triglyceride levels without modulating LXR target genes in the periphery. In summary, our studies highlight the therapeutic potential of the gut-restricted molecules to treat hyperlipidemia and atherosclerosis through the intestinal LXR-Soat2 axis.

Impact of Low-density Lipoprotein Cholesterol Levels on Outcomes in Nonvalvular Atrial Fibrillation: Results from the China Atrial Fibrillation Registry Study.

BackgroundLow-density lipoprotein cholesterol (LDL-C) reduction improves cardiovascular outcomes. This study investigates the relationship between lipid levels and outcomes in patients with nonvalvular atrial fibrillation by LDL-C quarters.Material/MethodsPatients with atrial fibrillation were enrolled from 31 typical hospitals in China. Of 19 515 patients, 6775 with nonvalvular atrial fibrillation (NVAF) were followed for 5 years or until an event occurred.ResultsHyperlipidemia was not an independent risk factor for stroke/thromboembolism and cardiovascular mortality among patients with NVAF (hazard ratio 0.82, 95% CI 0.7–0.96, P=0.82). When patients were divided into quartiles according to LDL-C levels at the time of enrollment (Q1, <1.95; Q2, 1.95–2.51; Q3, 2.52–3.09; and Q4, >3.09 mmol/L), as LDL-C increased, events tapered off according to Kaplan-Meier curves for patients who were without oral anticoagulants and off statins (non-OAC; log-rank=8.3494, P=0.0393) and for those with oral anticoagulants (OAC; log-rank=6.7668 P=0.0797). This relationship was stronger for patients who were without OAC treatment and off statins than for those with OAC treatment. The relationship was not significant in patients with or without OAC and on statins (log-rank=2.5080, P=0.4738). This relationship also existed in patients with CHA2DS2-VASc scores <2 (log-rank=5.893, P=0.1167). For those with CHA2DS2-VASc scores ≥2 (log-rank=6.6163, P=0.0852), the relationship was stronger.ConclusionsIn patients with NVAF using standard or no lipid-lowering medication, low plasma LDL-C levels were related to an increased risk of stroke/thromboembolism and cardiovascular mortality.