Comparison of the efficacy and safety of Shanhuang Jiangzhi tablets and atorvastatin in the treatment of patients with hyperlipidaemia.

OBJECTIVES: To compare the efficacy and safety of Shanhuang Jiangzhi tablets and atorvastatin in reducing blood lipid levels. METHODS: Patients with hyperlipidaemia admitted to the cardiac centre between January 2019 and December 2020 were included in the study. A total of 1063 patients with hyperlipidaemia took either Shanhuang Jiangzhi tablets (n = 372) or atorvastatin (n = 691) and met the inclusion and exclusion criteria. Clinical data, including total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol, were retrospectively evaluated after propensity score matching (PSM) analysis. The adverse events were also recorded during the therapy process. RESULTS: Following PSM analysis, both groups were well matched across all parameters. Compared with the baseline, Shanhuang Jiangzhi tablets had greater effects on TC, TG and LDL-C, and the difference was statistically significant (p < 0.001). Furthermore, the results showed that Shanhuang Jiangzhi tablets are similar to atorvastatin in reducing TC and LDL-C, and all p-values were > 0.05. However, the decrease of TG was greater in the Shanhuang Jiangzhi group (p < 0.001). Clinical adverse reactions of Shanhuang Jiangzhi tablets are rare and have no statistical significance compared with atorvastatin (p = 0.682). CONCLUSIONS: Shanhuang Jiangzhi tablets have a higher hypotriglyceridaemic performance than atorvastatin and an equivalent ability to lower TC and LDL-C. In addition, Shanhuang Jiangzhi tablets are a low-risk option for lowering blood lipids.

Effect of Grape Seed Procyanidins Combined with Allicin on Lipid Levels in Hyperlipidemic Rats.

OBJECTIVES: To study the effects of grape seed proanthocyanidins (GSP) combined with allicin on serum lipids level and vascular damage in a rat model of hyperlipidemia. MATERIALS AND METHODS: SD rats(male, 170-220 gn= 40) were randomized into five groups (n = 8/group): modelhigh fat and cholesterol diet; controlnormal diet; model+low-dose (GSP+allicin )(GSP 45mg/kg, allicin 30mg/kg, orally); model+high-dose (GSP+allicin) (GSP180mg/kg, allicin 90mg/kg, orally) and positive control (model+simvastatin (4 mg/kg)). Normal control group was fed conventionally, and remaining four groups were fed high cholesterol and fat food to replicate the high fat model. After 9 weeks, the normal control group continued to receive regular feeding, while the other groups continued to receive high-fat feeding. At the same time, model and normal control groups were given equal volume of physiological saline by gavage, and the other treatment groups began to receive corresponding drugs by gavage once a day. After 4 weeks, serum levels of total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C) as well as high-density lipoprotein cholesterol (HDL-C) in rats were determined. And the body weight of rat, total antioxidant capacity (T-AOC), superoxide dismutase (SOD) and malondialdehyde (MDA)in serum were identified. The level of endothelin-1(ET-1) was quantitative analysis by ELISA assay. RESULTS: In comparison to normal controls, the model group displayed a marked rise in body weight, an increment in serum concentrations of LDL-C, TG and TC, as well as a decline in HDL (P<0.01), demonstrating successful model replication; All doses of GSP in combination with allicin resulted in a reduction in TG, LDL-C, and TC and an enhancement in HDL-C in contrast to the model control (all P<0.05). High-dose (GSP+allicin ) decreased MDA, and increased T-AOC and SOD activity(all P<0.01). All doses of GSP combined with allicin decreased ET-1 (all P<0.05). In addition, the protective effect of GSP combined with allicin was dose-dependent. CONCLUSIONS: Studies have shown that GSP combined with allicin can significantly improve blood lipids in hyperlipidemic rats, and this mechanism may be related to antioxidants and reduced endothelial damage.

Monocyte to high-density lipoprotein cholesterol ratio decreased in patients with psoriasis treated with ixekizumab.

Background: Monocyte to high-density lipoprotein cholesterol ratio (MHR) is a novel inflammatory biomarker which has been associated with cardiovascular diseases. Objective: To study MHR in patients with psoriasis treated with biological agents. Methods: Between April 2019 and August 2022, MHR was retrospectively evaluated in patients with psoriasis before and 3 months after treatment with infliximab, adalimumab, etanercept, ixekizumab, secukinumab, and ustekinumab in a university hospital in Ankara, Turkey. Results: This study included 128 patients, 53 females and 75 males. 39 (30.5%) patients were treated with infliximab, 26 (20.3%) with adalimumab, 8 (6.3%) with etanercept, 18 (14.1%) with ixekizumab, 12 (9.4%) with secukinumab, and 25 (19.5%) with ustekinumab. The median MHR was 0.0127 (0.0086-0.0165) in females and 0.0146 (0.0119-0.0200) in males (p = 0.011). The median MHR decreased after treatment with adalimumab, ixekizumab, secukinumab, and ustekinumab, whereas it increased after treatment with infliximab and etanercept (p = 0.790, p = 0.015, p = 0.754, p = 0.221, p = 0.276, p = 0.889, respectively). Conclusion: MHR significantly decreased in patients with psoriasis after treatment with ixekizumab. Since high MHR levels have been associated with poor clinical outcomes in patients with cardiovascular diseases, ixekizumab might have a positive impact in the treatment of psoriasis patients who had cardiovascular diseases. We suggest that MHR may be useful both in establishing appropriate biological agent treatment and in the follow-up of patients with psoriasis treated with biological agents.

[HDL - Quo vadis]. / HDL ­ Quo vadis.

Many epidemiological studies found low plasma levels of high-density lipoprotein (HDL) cholesterol (HDL-C) associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD). In cell culture and animal models, HDL particles show many anti-atherogenic actions. However, until now, clinical trials did not find any prevention of ASCVD events by drugs elevating HDL-C levels, at least not beyond statins. Also, genetic studies show no associations of HDL-C levels altering variants with cardiovascular risk. Therefore, the causal role and clinical benefit of HDL-C elevation in ASCVD are questioned. However, the interpretation of previous data has important limitations: First, the inverse relationship of HDL-C with the risk of ASCVD is limited to concentrations < 60 mg/dl (< 1.5 mmol/l). Higher concentrations do not reduce the risk of ASCVD events and are even associated with increased mortality. Therefore, neither the higher-the-better strategies of earlier drug developments nor the assumption of linear cause-and-effect relationships in Mendelian randomization trials are justified. Second, most of the drugs tested so far do not act specifically on HDL metabolism. Therefore, the futile endpoint studies question the clinical benefit of the investigated drugs, but not the importance of HDL in ASCVD. Third, the vascular functions of HDL are not exerted by its cholesterol content (i.e. HDL-C), but by a variety of other molecules. Comprehensive knowledge of the structure-function-disease relationships of HDL particles and their molecules is a prerequisite for testing their physiological and pathogenic relevance and possibly for optimizing the diagnosis and treatment of persons with HDL-associated risk of ASCVD, but also for other diseases, such as diabetes, chronic kidney disease, infections, autoimmune and neurodegenerative diseases.

A Systematic Review of Randomized Clinical Trials on the Efficacy and Safety of Pitavastatin.

BACKGROUND: A subpopulation of statin users such as subjects with chronic kidney disease (CKD), Human Immune virus (HIV), acute coronary syndrome (ACS), revascularization, metabolic syndrome, and/or diabetes may particularly benefit from pitavastatin pharmacotherapy. AIM: The current systematic review aimed systematically to evaluate the effect of pitavastatin on primary cardiac events in subjects receiving pitavastatin in comparison to the other four statin members. METHODS: We conducted a systematic review on phases III and IV of randomized controlled trials (RCT-s, 11 trials) for subjects with primary cardiac events who received pitavastatin. Subjects diagnosed with any type of dyslipidemia (population 4804) and received pitavastatin (interventions) versus comparator (comparison) with the primary efficacy endpoint of minimization of LDL-C and non- HDL-C, had an increase in HDL-C and/or reduction in major adverse cardiac events (MACE, cardiovascular death, myocardial infarction (fatal/nonfatal), and stroke (fatal/nonfatal) and/or their composite (outcomes). The secondary safety endpoint was the development of any adverse effects. RESULTS: In the included trials (11), participants (4804) were randomized for pitavastatin or its comparators such as atorvastatin, pravastatin, rosuvastatin, simvastatin and followed up for 12 to 52 weeks. In terms of the primary outcome (reduction in LDL-C), pitavastatin 4 mg was superior to pravastatin 40 mg in three trials, while the 2 mg pitavastatin was comparable to atorvastatin 10 mg in four trials and simvastatin 20 and 40 mg in two 2 trials. However, rosuvastatin 2.5 mg was superior to pitavastatin 2 mg in two trials. Pitavastatin increased HDL-C and reduced non-HDL-C in eleven trials. Regarding the safety profile, pitavastatin has proved to be tolerated and safe. CONCLUSION: The FDA-approved indications for pitavastatin included primary dyslipidemia and mixed dyslipidemia as a supplementary therapy to dietary changes to lower total cholesterol, LDL-C, apolipoprotein B (Apo B), triglycerides (TG), and enhance HDL-C. Pitavastatin might be suitable for subjects with diabetes, ACS (reduced revascularization), metabolic syndrome, CKD, HIV, and subjects with low levels of HDL-C. We highly recommend rational individualization for the selection of statin.

Impact of red yeast rice supplementation on lipid profile: a systematic review and meta-analysis of randomized-controlled trials.

BACKGROUND: Dyslipidemia/hyperlipidemia are among the risk factors for chronic diseases, especially cardiovascular diseases. Red Yeast Rice (RYR) herbal supplement may be helpful in improving serum fat levels due to some mechanisms. Therefore, the aim of this study was to evaluate the effects of RYR consumption on total serum cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) and triglyceride (TG) levels in adults. RESEARCH DESIGN AND METHODS: Four comprehensive databases (SCOPUS, PubMed/MEDLINE, EMBASE, and Web of Science) were employed until 23 December 2021 RCTs, with 24 treatment arms included after screening 3623 articles. RESULTS: Pooled data showed significant effectiveness in lowering TC (WMD: -33.16 mg/dl, 95% CI: -37.69, -28.63, P < 0.001), LDL-C (WMD: -28.94 mg/dl, 95% CI: -32.90, -24.99, P < 0.001), and TG (WMD: -23.36 mg/dl, 95% CI: -31.30, -15.43, P < 0.001) concentration and increasing HDL-C concentration (WMD: 2.49 mg/dl, 95% CI: 1.48, 3.49, P < 0.001) following RYR supplementation. Furthermore, the effect of this herbal drug in doses less than 1200 mg and with an intervention duration of less than 12 weeks was more in individuals with dyslipidemia. CONCLUSION: In conclusion, this comprehensive article and meta-analysis showed that RYR significantly decreases TC, TG, and LDL-C as well as increases HDL-C.

Scavenging dicarbonyls with 5'-O-pentyl-pyridoxamine increases HDL net cholesterol efflux capacity and attenuates atherosclerosis and insulin resistance.

OBJECTIVE: Oxidative stress contributes to the development of insulin resistance (IR) and atherosclerosis. Peroxidation of lipids produces reactive dicarbonyls such as Isolevuglandins (IsoLG) and malondialdehyde (MDA) that covalently bind plasma/cellular proteins, phospholipids, and DNA leading to altered function and toxicity. We examined whether scavenging reactive dicarbonyls with 5'-O-pentyl-pyridoxamine (PPM) protects against the development of IR and atherosclerosis in Ldlr-/- mice. METHODS: Male or female Ldlr-/- mice were fed a western diet (WD) for 16 weeks and treated with PPM versus vehicle alone. Plaque extent, dicarbonyl-lysyl adducts, efferocytosis, apoptosis, macrophage inflammation, and necrotic area were measured. Plasma MDA-LDL adducts and the in vivo and in vitro effects of PPM on the ability of HDL to reduce macrophage cholesterol were measured. Blood Ly6Chi monocytes and ex vivo 5-ethynyl-2'-deoxyuridine (EdU) incorporation into bone marrow CD11b+ monocytes and CD34+ hematopoietic stem and progenitor cells (HSPC) were also examined. IR was examined by measuring fasting glucose/insulin levels and tolerance to insulin/glucose challenge. RESULTS: PPM reduced the proximal aortic atherosclerosis by 48% and by 46% in female and male Ldlr-/- mice, respectively. PPM also decreased IR and hepatic fat and inflammation in male Ldlr-/- mice. Importantly, PPM decreased plasma MDA-LDL adducts and prevented the accumulation of plaque MDA- and IsoLG-lysyl adducts in Ldlr-/- mice. In addition, PPM increased the net cholesterol efflux capacity of HDL from Ldlr-/- mice and prevented both the in vitro impairment of HDL net cholesterol efflux capacity and apoAI crosslinking by MPO generated hypochlorous acid. Moreover, PPM decreased features of plaque instability including decreased proinflammatory M1-like macrophages, IL-1ß expression, myeloperoxidase, apoptosis, and necrotic core. In contrast, PPM increased M2-like macrophages, Tregs, fibrous cap thickness, and efferocytosis. Furthermore, PPM reduced inflammatory monocytosis as evidenced by decreased blood Ly6Chi monocytes and proliferation of bone marrow monocytes and HSPC from Ldlr-/- mice. CONCLUSIONS: PPM has pleotropic atheroprotective effects in a murine model of familial hypercholesterolemia, supporting the therapeutic potential of reactive dicarbonyl scavenging in the treatment of IR and atherosclerotic cardiovascular disease.

Effect Of Tamoxifen On Plasma Lipid Profile In Patients Of Breast Cancer.

BACKGROUND: To evaluate the effect of Tamoxifen on plasma lipid profile in breast cancer patients presenting at tertiary care hospitals. METHODS: It was a longitudinal study conducted at the Department of Oncology of Jinnah Postgraduate Medical Center from December 2018 to November 2019. Eighty-eight females aged 26-66 years diagnosed with breast cancer were included in the study using a non-probability consecutive sampling technique. Detailed gynaecological and clinical investigations and detailed history were taken. The blood samples of all the patients were collected and the plasma lipid profile was measured before initiation of Tamoxifen treatment and three- and six-months post-treatment at the clinical laboratory. The plasma lipid profile includes the measurement of Total cholesterol (mg/dl), Triglyceride(mg/dl), High-density Lipoprotein (mg/dl) & Low-density Lipoprotein (mg/dl). SPSS version 23 was used to analyse data. RESULTS: After treatment, there was a significant reduction in serum cholesterol & Low-density Lipoprotein level by 20.54 mg/dl & 16.46 mg/dl at 3 months (p<0.05), moreover there was a significant increase in Triglyceride by 22.14 at 3 months (p<0.05). No significant difference was observed in High density lipoprotein level at 3 months after using Tamoxifen. At 6 months there was a significant reduction in serum cholesterol and low-density lipoprotein by 32.29mg/dl and 24.11 mg/dl at 6 months (p<0.05), moreover there was a significant increase in Triglyceride level by 42.19 mg/dl at 6 months (p<0.05). No significant difference was observed in High-density lipoprotein level at 6 months after using Tamoxifen. CONCLUSIONS: Total cholesterol and Low-density Lipoprotein levels showed significant reduction over the period of six months from the baseline with the use of Tamoxifen. Hence Tamoxifen should be considered to have an added advantage on lipid metabolism and therefore, can reduce the risk of cardiovascular events.

Utilizing the Probation Office as an Opportunity to Screen for Cardiometabolic Outcomes: A Feasibility Study.

This cross-sectional study examined whether the probation office setting was feasible to screen adults on probation for cardiometabolic risk factors, measure risk profiles, and estimate the prevalence of obesity, hypertension, hypercholesterolemia, and diabetes. During June and August 2019, screening included blood pressure, anthropometrics, total and high-density lipoprotein (HDL) cholesterol, and glucose. A survey included demographics, medical history, and current medication. The participation rate was 36% (N = 202). The screening identified 5% had hypercholesterolemia, 38% of men and 50% of women had low HDL cholesterol, 70% had overweight/obesity, 31% of men and 55% of women had elevated waist circumferences, and 26.7% had Stage 1 hypertension. Of individuals with a history of hypertension (n = 74), 77% had elevated blood pressure. Of those with a history of diabetes (n = 27), 22% had hyperglycemia, independent of whether they reported being prescribed medication. The screening identified 11% with Stage 2 hypertension, 27% with Stage 1 hypertension, 22% with elevated blood pressure, and 5% with hyperglycemia. Our findings suggest it is feasible to identify individuals at high risk for cardiometabolic disorders during routine probation office visits. These data can then be used to provide referrals for treatment to improve long-term health outcomes.

[Effects of moderate dose rosuvastatin on carotid plaque in patients with diabetes mellitus evaluated by magnetic resonance imaging].

Objective: To observe the effect of lipid regulating therapy on carotid atherosclerotic plaque in diabetic patients. Methods: The REACH study, conducted between March 2009 and February 2012, enrolled asymptomatic patients with magnetic resonance imaging (MRI) confirmed carotid atherosclerotic plaque, who had never taken lipid-lowering drugs. Patients were treated with a moderate dose of rosuvastatin for 24 months. Blood lipid levels were measured and carotid MRI was performed at baseline, 3 and 24 months after treatment. The volume of carotid wall and lipid-rich necrotic core (LRNC) were measured by image analysis software. This study retrospectively analyzed patients in the REACH study. Patients were divided into diabetes group and non-diabetic group. The changes of blood lipid level and MRI parameters of carotid atherosclerotic plaque were compared between the two groups and their correlation was analyzed. Results: A total of 38 patients with carotid atherosclerotic plaque were included in this study, including 13 patients (34.2%) in the diabetic group and 25 patients (65.8%) in the non-diabetic group. Baseline parameters were comparable between the two groups, except higher HbA1c level in diabetes group (P<0.05). Compared with baseline, the total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) and triglyceride (TG) levels were significantly decreased at 3 and 24 months in both two groups (P<0.05). The change of high-density lipoprotein cholesterol (HDL-C) in diabetes group was not obvious, while it was significantly increased in non-diabetic group at 24 months ((1.38±0.33) mmol/l vs. (1.26±0.26) mmol/l, P<0.05). MRI results showed that the volume and percentage of LRNC remained unchanged at 3 months, slightly decreased at 24 months (64.86 (45.37, 134.56) mm3 vs. 75.76 (48.20, 115.64) mm3, P>0.05) and (15.84% (11.47%, 24.85%) vs. 16.95% (11.64%, 22.91%), P>0.05) in diabetic group. In non-diabetic group, the volume and percentage of LRNC were significantly decreased at 3 months (63.01 (44.25, 188.64) mm3 vs. 72.49 (51.91, 199.59) mm3, P<0.05) and (13.76% (8.81%, 27.64%) vs. 16.04% (11.18%, 27.05%), P<0.05) respectively. Both parameters further decreased to (55.63 (27.18, 179.40) mm3) and (12.71% (8.39%, 24.41%)) at 24 months (both P<0.05). Wall volume, lumen volume and percent wall volume (PWV) were not affected post therapy in both two groups(P>0.05). There were no correlations between the changes of plaque parameters including volume and percentage of LRNC, wall volume, lumen volume, PWV and the changes of blood lipid parameters (TC, LDL-C, HDL-C and TG) in 3 and 24 months (P>0.05). Conclusion: Lipid-lowering therapy possesses different effects on carotid atherosclerotic plaque in diabetic and non-diabetic patients, and the LRNC improvement is more significant in non-diabetic patients as compared to diabetic patients.

Dyslipidemia Secondary to the Use of HAART in Adults: A Systematic Review.

BACKGROUND: HIV infection affects millions of people globally. Currently, although several drugs have brought an improvement in the quality and life expectancy of these individuals, they are accompanied by several adverse effects. OBJECTIVE: To conduct a systematic review of studies examining the relationship between antiretroviral therapy (ART) uses and secondary dyslipidemia. METHODS: The review followed the criteria defined by PRISMA. Only articles that completely evaluated the lipid profile were included, which consisted of total cholesterol (TC), triglycerides (TG), and LDL cholesterol (LDL-c), HDL cholesterol (HDL-c). RESULTS: It was observed that the use of nucleoside and non-nucleoside reverse transcriptase inhibitor (NNRTI and NNRTI respectively) drugs and protease inhibitors are the most used in ART and are associated with changes in lipid profiles. The main changes observed were increases in TC, TG, and LDL-c in addition to a decrease in HDL-c. These patients had a higher risk of developing cardiovascular disease not only due to the use of therapy, but also due to the presence of other comorbidities evaluated in these studies, such as obesity, diabetes, and hypertension. The increase in age, the difference between genders, CD4 T-cell count, and viral load, were observed as risk factors for worsening dyslipidemia. CONCLUSION: According to the findings of this study, anti-HIV therapy is linked to dyslipidemia, which may or may not be the primary cause, and is frequently connected with a number of metabolic problems that can exacerbate the illness.

Pretreatment HDL-C and ApoA1 are predictive biomarkers of progression-free survival in patients with EGFR mutated advanced non-small cell lung cancer treated with TKI.

BACKGROUND: We aimed to explore the correlation between blood lipids (high density lipoprotein cholesterol [HDL-C] and apolipoprotein A1 [ApoA1]) and epidermal growth factor receptor (EGFR) T790M mutation, as well as its predictive role in clinical efficacy and progression-free survial (PFS) in advanced non-small cell lung cancer (NSCLC) patients treated with EGFR tyrosine kinase inhibitors (EGFR-TKI). METHODS: We retrospectively collected information of 153 patients with advanced NSCLC harboring exon EGFR mutation and receiving EGFR-TKI. RESULTS: The best cutoff value for HDL-C and ApoA1 was determined to be 1.15 and 1.14 mmol/l. The overall response rate (ORR) was 67.7% in the high HDL-C group and 46.6% in the low HDL-C group, respectively. The ORR of the high ApoA1 group showed a significant increase than that of the low ApoA1 group (68.1% vs. 38.5%). The mean ApoA1 level of the EGFR T790M mutation-positive group was significantly higher than that of the EGFR T790M mutation-negative group (1.13 g/l vs. 1.01 g/l). Patients with high ApoA1 levels were related to the EGFR T790M mutation (r = 0.324). (3) The median progression-free survival (PFS) of the high HDL-C group and low HDL-C group were 13.00 months and 10.20 months. The median PFS of the high ApoA1 group and the low ApoA1 group were 12.10 and 10.00 months, respectively. Multivariate Cox stepwise regression model analysis demonstrated ECOG PS, pathological type and HDL-C were confirmed as critical and independent predictors of PFS. CONCLUSIONS: Patients with EGFR T790M mutations often show higher ApoA1 levels. Peripheral serum HDL-C and ApoA1 before treatment can be used as potential significant factors for predicting clinical efficacy and PFS in advanced NSCLC patients treated with EGFR-TKI.

High-density lipoproteins: A promising tool against cancer.

High-density lipoproteins (HDL) are well known for their protective role against the development and progression of atherosclerosis. Atheroprotection is mainly due to the key role of HDL within the reverse cholesterol transport, and to their ability to exert a series of antioxidant and anti-inflammatory activities. Through the same mechanisms HDL could also affect cancer cell proliferation and tumor progression. Many types of cancers share common alterations of cellular metabolism, including lipid metabolism. In this context, not only fatty acids but also cholesterol and its metabolites play a key role. HDL were shown to reduce cancer cell content of cholesterol, overall rewiring cholesterol homeostasis. In addition, HDL reduce oxidative stress and the levels of pro-inflammatory molecules in cancer cells and in the tumor microenvironment (TME). Here, HDL can also help in reverting tumor immune escape and in inhibiting angiogenesis. Interestingly, HDL are good candidates for drug delivery, targeting antineoplastic agents to the tumor mass mainly through their binding to the scavenger receptor BI. Since they could affect cancer development and progression per se, HDL-based drug delivery systems may render cancer cells more sensitive to antitumor agents and reduce the development of drug resistance.

Pharmacokinetic/Pharmacodynamic Modelling to Describe the Cholesterol Lowering Effect of Rosuvastatin in People Living with HIV.

BACKGROUND: Rosuvastatin is a lipid-lowering agent widely prescribed in people living with HIV, which is actively transported into the liver, making it a potential victim of drug-drug interactions with antiretroviral agents. OBJECTIVES: The aims of this study were to characterise the pharmacokinetic profile of rosuvastatin and to describe the relationship between rosuvastatin concentrations and non-high-density lipoprotein (HDL)-cholesterol levels in people living with HIV. METHODS: A population pharmacokinetic model (NONMEM) was developed to quantify the influence of demographics, clinical characteristics and comedications on rosuvastatin pharmacokinetics. This model was combined with an indirect effect model to describe non-HDL-cholesterol measurements. RESULTS: A two-compartment model with sequential zero- and first-order absorption best fitted the 154 rosuvastatin concentrations provided by 65 people living with HIV. None of the tested covariates significantly influenced rosuvastatin pharmacokinetics. A total of 403 non-HDL cholesterol values were available for pharmacokinetic-pharmacodynamic modelling. Baseline non-HDL cholesterol decreased by 14% and increased by 12% with etravirine and antiretroviral drugs with a known impact on the lipid profile (i.e. protease inhibitors, efavirenz, cobicistat), respectively. The baseline value was surprisingly 43% lower in people living with HIV aged 80 years compared with those aged 40 years. Simulations based on the covariate-free model predicted that, under standard rosuvastatin dosages of 5 mg and 20 mg once daily, 31% and 64% of people living with HIV would achieve non-HDL-cholesterol targets, respectively. CONCLUSIONS: The high between-subject variability that characterises both rosuvastatin pharmacokinetic and pharmacodynamic profiles remained unexplained after the inclusion of usual covariates. Considering its limited potential for drug-drug interactions with antiretroviral agents and its potent lipid-lowering effect, rosuvastatin prescription appears safe and effective in people living with HIV with hypercholesterolaemia. CLINICAL TRIAL REGISTRATION NO: NCT03515772.

Beneficial Effects of Reconstituted High-Density Lipoprotein (rHDL) on Circulating CD34+ Cells in Patients after an Acute Coronary Syndrome.

BACKGROUND: High-density lipoproteins (HDL) favorably affect endothelial progenitor cells (EPC). Circulating progenitor cell level and function are impaired in patients with acute coronary syndrome (ACS). This study investigates the short-term effects of reconstituted HDL (rHDL) on circulating progenitor cells in patients with ACS. METHODS AND FINDINGS: The study population consisted of 33 patients with recent ACS: 20 patients from the ERASE trial (randomized to receive 4 weekly intravenous infusions of CSL-111 40 mg/kg or placebo) and 13 additional patients recruited as controls using the same enrolment criteria. Blood was collected from 16 rHDL (CSL-111)-treated patients and 17 controls at baseline and at 6-7 weeks (i.e. 2-3 weeks after the fourth infusion of CSL-111 in ERASE). CD34+ and CD34+/kinase insert domain receptor (KDR+) progenitor cell counts were analyzed by flow cytometry. We found preserved CD34+ cell counts in CSL-111-treated subjects at follow-up (change of 1.6%), while the number of CD34+ cells was reduced (-32.9%) in controls (p = 0.017 between groups). The level of circulating SDF-1 (stromal cell-derived factor-1), a chemokine involved in progenitor cell recruitment, increased significantly (change of 21.5%) in controls, while it remained unchanged in CSL-111-treated patients (p = 0.031 between groups). In vitro exposure to CSL-111 of early EPC isolated from healthy volunteers significantly increased CD34+ cells, reduced early EPC apoptosis and enhanced their migration capacity towards SDF-1. CONCLUSIONS: The relative increase in circulating CD34+ cells and the low SDF-1 levels observed following rHDL infusions in ACS patients point towards a role of rHDL in cardiovascular repair mechanisms.

Inhibition of arthritis in the Lewis rat by apolipoprotein A-I and reconstituted high-density lipoproteins.

OBJECTIVE: This study questions whether high-density lipoproteins (HDLs) and apolipoprotein A-I inhibit joint inflammation in streptococcal cell wall peptidoglycan-polysaccharide (PG-PS)-induced arthritis in female Lewis rats. APPROACH AND RESULTS: Administration of PG-PS to female Lewis rats caused acute joint inflammation after 4 days, followed by remission by day 8. The animals subsequently developed chronic joint inflammation that persisted until euthanasia at day 21. Treatment with apolipoprotein A-I 24 hours before and 24 hours after PG-PS administration reduced the acute and chronic joint inflammation. Treatment with apolipoprotein A-I at days 7, 9, and 11 after PG-PS administration reduced the chronic joint inflammation. Treatment with apolipoprotein A-I or reconstituted HDLs consisting of apolipoprotein A-I complexed with phosphatidylcholine 24 hours before and at days 1, 7, 9, and 11 after PG-PS administration reduced acute and chronic joint inflammation. Treatment with apolipoprotein A-I also reduced the inflammatory white blood cell count, synovial fluid proinflammatory cytokine levels, synovial tissue macrophage accumulation, as well as toll-like receptor 2, and inflammatory cytokine expression. At the molecular level, preincubation of human monocyte-derived macrophages with apolipoprotein A-I or reconstituted HDLs before PG-PS stimulation inhibited the PG-PS-induced increase in toll-like receptor 2 and myeloid differentiation primary response gene (88) mRNA levels, nuclear factor-κB activation, and proinflammatory cytokine production. The effects of apolipoprotein A-I and reconstituted HDLs were abolished by transfecting the human monocyte-derived macrophages with ATP-binding cassette transporter A1 or G1 siRNA. CONCLUSIONS: Apolipoprotein A-I and reconstituted HDLs attenuate PG-PS-induced arthritis in the rat. Studies in human monocyte-derived macrophages indicate that this benefit may be because of the inhibition of toll-like receptor 2 expression and decreased nuclear factor-κB activation in macrophages.

HDL-C levels and cardiovascular disease: more is not always better!

HMG-CoA reductase inhibitors have consistently demonstrated a relative risk reduction of death and myocardial infarction ranging between 29 and 35%. Nevertheless, in spite of significant improvement in prevention, cardiovascular disease remains the main cause of morbidity and mortality in industrialized countries. This significant residual risk observed in approximately 70% of patients under optimal anti-atherosclerotic therapies, warrants the exploration and development of alternative cardiovascular drugs. Specifically, HDL-C levels have been inversely correlated with the incidence of cardiovascular disease and an estimated 1 mg/dl higher HDL-C is associated with a 2% lower risk for men and a 3% lower risk for women. However, HDL-C-C pharmacological induced increases presented contradicting results regarding atherosclerotic development and in some cases increased cardiovascular mortality. In this review, we will focus on the structure and metabolism of HDL-C and patents related to HDL-C levels and cardiovascular disease along with the possible role of HDL-C increasing therapies in the future primary and secondary prevention of cardiovascular disease.

Recombinant high-density lipoprotein formulations.

High-density lipoprotein cholesterol (HDL-C) has emerged as a biomarker of residual cardiovascular disease (CVD) risk in high-risk patients treated with low-density lipoprotein cholesterol (LDL-C)-lowering therapies inclusive of inhibitors of 3-hydroxy-3-methyl-glutaryl-CoA reductase. The evidence for increasing low levels of HDL-C is sparse, and the available data are confounded by metabolic interactions between elevated very low-density lipoprotein (VLDL) and LDL particle concentrations. Despite these limitations, there has been widespread interest in novel strategies that target HDL. One such path has been the development of recombinant HDL formulations that mimic the pre-beta fraction of native HDL, which is the main HDL subclass that mediates cholesterol efflux from lipid-laden macrophages. Various recombinant HDL formulations (apolipoprotein A-1 [apoA-1]-bound phospholipid disks or delipidated HDL particles, mutant apoA-1 proteins, and apoA-1 mimetic peptides) have been investigated in animal studies and some human trials. However, these HDL-modifying therapies require evaluation in clinical trials of atherosclerosis and CVD events. This review presents our current knowledge on novel recombinant therapies, and their future prospects to mitigate atherosclerotic CVD events.