Review of Evolocumab for the Reduction of LDL Cholesterol and Secondary Prevention of Atherosclerotic Cardiovascular Disease.

Elevated low-density lipoprotein cholesterol (LDL-C) is a major causal factor for atherosclerotic cardiovascular disease (ASCVD), the leading cause of mortality worldwide. Statins are the recommended first-line lipid-lowering therapy (LLT) for patients with primary hypercholesterolemia and established ASCVD, with LLT intensification recommended in the substantial proportion of patients who do not achieve levels below guideline-recommended LDL-C thresholds with statin treatment alone. The proprotein convertase subtilisin/kexin type 9 inhibitor monoclonal antibody evolocumab has demonstrated significant LDL-C reductions of > 60% in the clinical trial and open-label extension settings, with LDL-C reductions observed early post-evolocumab initiation and maintained long term, during up to 8.4 years of follow-up. Evolocumab therapy, when added to a statin, also conferred a significant reduction in major cardiovascular (CV) events, including a 20% reduction in the composite of CV death, myocardial infarction (MI), or stroke. The absolute benefits were enhanced among various patient types at high and very high risk for secondary ASCVD (e.g., with recent MI, multiple events or peripheral artery disease). Importantly, evolocumab treatment resulted in incremental CV risk reductions during the extended follow-up, including a 23% reduction in CV mortality and no apparent LDL-C level below which there is no further CV risk reduction. Hence, the evolocumab clinical data support the need for early and significant LDL-C lowering, especially in vulnerable ASCVD patients, in order to derive the greatest benefit in the long term. Importantly, evolocumab had no impact on any treatment emergent adverse events apart from a small increase in local injection site reactions. A growing body of real-world evidence (RWE) for evolocumab in heterogeneous populations is consistent with the trial data, including robust LDL-C reductions below guideline-recommended thresholds, a favourable safety profile even at the lowest levels of LDL-C achieved, and a high treatment persistence rate of > 90%. Altogether, this review highlights findings from 50 clinical trials and RWE studies in > 51,000 patients treated with evolocumab, to demonstrate the potential of evolocumab to address the healthcare gap in LDL-C reduction and secondary prevention of ASCVD in a variety of high- and very high-risk patients.

Obicetrapib: Reversing the Tide of CETP Inhibitor Disappointments.

PURPOSE OF REVIEW: To discuss the history of cardiovascular outcomes trials of cholesteryl ester transfer protein (CETP) inhibitors and to describe obicetrapib, a next-generation, oral, once-daily, low-dose CETP inhibitor in late-stage development for dyslipidemia and atherosclerotic cardiovascular disease (ASCVD). RECENT FINDINGS: Phase 1 and 2 trials have evaluated the safety and lipid/lipoprotein effects of obicetrapib as monotherapy, in conjunction with statins, on top of high-intensity statins (HIS), and with ezetimibe on top of HIS. In ROSE2, 10 mg obicetrapib monotherapy and combined with 10 mg ezetimibe, each on top of HIS, significantly reduced low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B, total LDL particles, small LDL particles, small, dense LDL-C, and lipoprotein (a), and increased HDL-C. Phase 3 pivotal registration trials including a cardiovascular outcomes trial are underway. Obicetrapib has an excellent safety and tolerability profile and robustly lowers atherogenic lipoproteins and raises HDL-C. As such, obicetrapib may be a promising agent for the treatment of ASCVD.

Association between serum lipid and all-cause mortality in asthmatic populations: a cohort study.

BACKGROUND: Presently, the majority of investigations primarily evaluate the association between lipid profiles and asthma. However, few investigations explore the connection between lipids and mortality related to the disease. This study aims to explore the association of serum lipids with all-cause mortality within asthmatic adults. METHODS: The investigation included 3233 eligible patients with asthma from the NHANES (2011-2018). The potential associations were explored using three Cox proportional hazards models, restricted cubic splines (RCS), threshold effect models, and CoxBoost models. In addition, subgroup analyses were conducted to investigate these associations within distinct populations. RESULTS: After controlling all covariables, the Cox proportional hazards model proved a 17% decrease in the probability of death for each increased unit of low-density lipoprotein-cholesterol (LDL-C) (mmol/L). Yet, there was no association seen between blood high-density lipoprotein cholesterol (HDL-C), total cholesterol, or triglyceride and all-cause mortality in asthmatics. The application of RCS and threshold effect models verified an inverse and linear association of LDL-C with all-cause mortality. According to the results from the CoxBoost model, LDL-C exhibited the most substantial impact on the follow-up status of asthmatics among the serum lipids. CONCLUSION: Our investigation concluded that in American asthmatic populations, LDL-C levels were inversely and linearly correlated with mortality. However, no independent relationship was found between triglycerides, total cholesterol, or HDL-C and mortality.

Evaluating the effect of atorvastatin exposure and vitamin D levels on lipid outcomes in people with HIV-1 with suppressed HIV-1 RNA and LDL cholesterol <130 mg/dL.

INTRODUCTION: Cardiovascular disease (CVD) has become a leading cause of morbidity and mortality among people with HIV. Atorvastatin is known to reduce cardiovascular risk. We (1) compared atorvastatin concentrations between different boosted protease inhibitors (PIs) and with lipid outcomes and (2) compared pre-atorvastatin 25-OH vitamin D levels with atorvastatin concentrations and with lipid outcomes, in people with HIV with suppressed HIV-1 RNA and low-density lipoprotein cholesterol (LDL-C) <130 mg/dL. METHODS: A5275 was a randomized, double-blind, placebo-controlled crossover study of atorvastatin in virally suppressed people with HIV with fasting LDL-C <130 mg/dL. We analyzed results over the 20 weeks of active atorvastatin treatment. Atorvastatin was initiated at 10 mg daily and increased to 20 mg daily after 4 weeks if there were no findings of toxicity. Atorvastatin trough concentrations were measured at week 20. Participants took combination antiretroviral therapy (ART) that included a boosted PI throughout. RESULTS: Overall (n = 67), 70% of participants were male, and the median age was 51 years. There was no apparent association between atorvastatin trough concentrations and pre-atorvastatin vitamin D levels (r = 0.01, p = 0.9) or by boosted PI (p = 0.20). Median pre- to post-atorvastatin change was -39.0 mg/dL in fasting total cholesterol, -40.4 ng/mL in lipoprotein-associated phospholipase A2 (LP-PLA2), and -13.8 U/L in oxidized LDL, with all changes negatively correlated with atorvastatin trough concentrations (r = -0.19, -0.09, -0.21; p ≥ 0.096). CONCLUSIONS: No apparent associations between pre-atorvastatin vitamin D levels and outcomes were observed (all p > 0.70). In virologically suppressed people with HIV, higher atorvastatin concentrations were marginally associated with greater decreases in lipid outcomes.

Liposomal Phytosterols as LDL-Cholesterol-Lowering Agents in Diet-Induced Hyperlipidemia.

The high blood level of low-density lipoprotein cholesterol (LDL-C) is a primary risk factor for cardiovascular disease. Plant sterols, known as phytosterols (PSs), can reduce LDL-C in a range of 8-14%. The extent of LDL-C reduction depends on its formulation. Encapsulation into liposomes is one formulation strategy to enhance the efficiency of PSs. PSs (campesterol, stigmasterol, and ß-sitosterol) have frequently been assessed alone or in combination for their LDL-C-lowering ability. However, one naturally abundant PS, brassicasterol, has not yet been tested for its efficacy. We have previously developed a novel liposomal formulation containing the PS mixture present naturally in canola that is composed of brassicasterol, campesterol, and ß-sitosterol. In this work, the efficacy of our novel liposomal PS formulation that includes brassicasterol was assessed in a hamster model. Animals were divided into five groups: (i) liposomal PS in orange juice, (ii) liposomal PS in water, (iii) marketed PS in orange juice, (iv) control orange juice, and (v) control water. The animals were fed a high-fat, cholesterol-supplemented (0.5%) diet to induce hypercholesterolemia. The treatment was administered orally once daily for 4 weeks. Fasting blood samples were collected at baseline, week 2, and week 4. The extent of the reduction of total cholesterol, LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides was compared among the groups. Liposomal PSs in both orange juice and water significantly reduced LDL-C compared to their controls. Furthermore, the liposomal PS was as effective as a marketed PS-containing product in reducing LDL-C. Liposomal PSs in both orange juice and water showed similar efficacy in LDL-C reduction, highlighting that these vehicles/food matrices do not affect the efficacy of PSs. The liposomal formulation of a natural PS mixture extracted from canola oil, with brassicasterol as a major component, exhibited a significant LDL-C reduction in a hamster model.

Does Genotype Affect the Efficacy of PCSK9 Inhibitors in the Treatment of Familial Hypercholesterolemia?

PURPOSE OF REVIEW: This review discusses whether patients' genotype affects the efficacy of PCSK9 inhibitors in treating familial hypercholesterolemia and how this might influence clinical management. RECENT FINDINGS: Currently, available evidence consistently demonstrates and is in good agreement that, in general, the LDL-C-lowering effect of PCSK9 inhibitors is similar across genotypes, except for compound heterozygous and homozygous familial hypercholesterolemia (FH). However, it remains to be seen whether the comparable therapeutic effect in lowering LDL-C level also leads to a comparable degree of cardiovascular risk reduction with different genotypes. Generally, the level of LDL-C reduction following PCSK9 inhibitor treatment is similar within different genotypes. Hence, genotype is a less reliable predictor for further LDL-C level reduction on PCSK9 inhibitor therapy, and attention should be given to other external influences, especially for heterozygous FH.

Physicians' perceptions and beliefs on the current dyslipidemia management practices within Saudi Arabia.

Background: Limited reports addressing physicians' understanding of the various low-density lipoprotein cholesterol (LDL-C) targets/statin intensity required for treating the various dyslipidemia patient populations in Saudi Arabia are available. Therefore, the current study assessed the perceptions and beliefs of practicing clinicians in Saudi Arabia regarding the current practice for management of dyslipidemia and potential perceived barriers to adherence to lipid guidelines encountered in their regular clinical practice. Knowledge of different clinical practices and beliefs could have a positive impact on improving the quality of future care provided by physicians. Methods: A survey questionnaire was designed to assess physicians' familiarity, usage, and adherence to seven different international guidelines and used to evaluate the management of dyslipidemia, practice of patient treatment, and perceived obstacles to adhering to lipid guidelines related to specific patients, doctors, and practice issues. Results: A total of 467 physicians were recruited for the study: (1) 57.2% were primary care physicians (PCPs) and (2) 42.8% were specialists. About 90.8% of them followed lipid guidelines of which the most common set were based on those by the American College of Cardiology/American Heart Association. The most utilized risk assessment tool was the atherosclerotic cardiovascular disease (ASCVD) risk calculator. About 60% of the physicians set an LDL-C target for their patients based on a combination of patients' risk factors and lipid profiles. In all, 42.1% of the physicians chose not to change existing therapy among patients with dyslipidemia to attain a non-high-density lipoprotein goal with controlled LDL-C level. Atorvastatin accounted for the greatest percentage of primary and secondary prevention choices (71.9% and 69.6%, respectively). Rosuvastatin was mostly preferred by physicians for patients with familial hypercholesterolemia. About two-thirds of the physicians (77.9%) prescribed statins to diabetic patients aged 40-75 years. Statin intolerance was encountered by 62.9% of the physicians in ≤ 10% of patients by 62.9%. Therapeutic strategies included switching to an alternative statin (40.1%) followed by reducing the statin dose (35.3%). Ezetimibe was prescribed by most physicians (77.9%) as an add-on to statin if the LDL-C target was not achieved. Fibrate was most preferred by physicians (62.7%) for hypertriglyceremia treatment followed by statins (28.7% of the physicians). Sixty-six percent reported not using proprotein convertase subtilisin/kexin type 9 serine protease inhibitors in their clinical practice due to unavailability at their institute (51.8%), high costs (26.3%), and/or lack of knowledge (20.6%). Perceived barriers to guideline adherence identified by physicians were lack of familiarity and knowledge of the guidelines, patient non-adherence, medication costs, and lack of timely follow-up appointments and educational tools. Multiple similarities and differences were observed after comparisons were made between specialists and PCPs in terms of guideline preference, clinical practice, and perceived barriers. Conclusion: Different perceptions and attitudes among physicians in Saudi Arabia were found due to variable recommendations by international lipid guidelines. Perceived barriers that included the patient, physician, and practice were identified by physicians at multiple levels. Multiple challenges and different action gaps were observed when comparing specialists to PCPs. It is recommended that standardized practices be followed by clinicians in Saudi Arabia, and actions to address the outlined barriers are essential for optimizing health outcomes and ASCVD prevention.

Search for familial hypercholesterolemia patients in an Italian community: A real-life retrospective study.

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is a common inherited disorder of low-density lipoprotein (LDL) catabolism that causes elevated LDL-cholesterol (LDL-C) and premature atherosclerotic cardiovascular disease (ASCVD). Despite the availability of effective treatments, FH remains underdiagnosed and undertreated. The aims of the study were to identify putative FH subjects using data from laboratory and cardiology databases, genetically characterize suspected FH patients referred to the Lipid Clinic and monitor attainment of treatment goals in identified patients. METHODS AND RESULTS: We retrieved the electronic health records of 221,644 individuals referred to laboratory for routine assessment and of 583 ASCVD patients (age ≤65) who underwent percutaneous transluminal coronary angioplasty (PTCA). We monitored the lipid profiles of subjects with LDL-C ≥ 250 mg/dl identified by laboratory survey (LS-P), PTCA patients and patients from the Lipid Clinic (LC-P). The laboratory survey identified 1.46% of subjects with LDL-C ≥ 190 mg/dl and 0.08% with LDL-C ≥ 250 mg/dl. Probable/definite FH was suspected in 3% of PTCA patients. Molecularly-confirmed FH was found in 44% of LC-P subjects. Five new LDLR mutations were identified. The 50% LDL-C reduction target was achieved by 70.6% of LC-P patients. Only 18.5% of PTCA patients reached the LDL-C < 55 mg/dl target. CONCLUSION: By using a combined approach based on laboratory lipid profiles, documented ASCVD and Lipid Clinic data, we were able to identify subjects with a high probability of being FH. Attainment of LDL-C goals was largely suboptimal. Efforts are needed to improve FH detection and achievement of lipid targets.

Dietary diversity in primary schoolchildren of south-central Côte d'Ivoire and risk factors for non-communicable diseases.

BACKGROUND: A balanced nutrition is important for children's physical and cognitive development; yet, remains a challenge in many parts of low- and middle-income countries (LMICs). Early detection of nutritional deficiency and metabolic syndrome in school-aged children is necessary to prevent non-communicable diseases (NCDs) in later life. This study aimed at obtaining baseline data on health, nutritional status, and metabolic markers of NCDs among primary schoolchildren in Côte d'Ivoire. METHODS: A cross-sectional survey was conducted among 620 children from 8 public primary schools located in the south-central part of Côte d'Ivoire. Underweight and overweight were defined as a body mass index (BMI; kg/m2) < 5th and 85th up to 95th percentile for sex and age, respectively. Dietary diversity of children was calculated based on a 24-hour recall conducted with the primary caretaker according to the guideline of Food and Agriculture Organization. Anaemia, malaria, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and blood glucose levels (HbA1c) were assessed, using capillary blood samples. Logistic models were performed to identify risk factors associated with overweight, HDL-C, LDL-C, and HbA1c. RESULTS: Among the 620 children (330 girls, 290 boys; Mage 8.0 (± 1.7) years), 530 children attended school in a semi-urban and 90 in a rural area. Around 60% of children had a medium dietary diversity score (DDS). Children in peri-urban areas consumed more cereals (80.2% vs. 63.3%, p < 0.05). Most children were normal weight (n = 496), whereas 3.9% of children classified as prediabetic, 5% were underweight, and 15% overweight. LDL-C and HDL-C levels of children were associated with age, high DDS, and moderate anaemia. A significant association was found between prediabetes and malaria infection, as well as medium and high DDS. Overweight was associated with malaria infection and moderate anaemia. CONCLUSION: Overweight, prediabetes, low HDL-C, malaria, and anaemia are the main concerns of children's health in Taabo. Our findings highlight interactions between infectious diseases, particularly malaria, and NCD risk factors. Monitoring NCD risk and infectious disease comorbidity in LMIC paediatric populations simultaneously is essential to better understand the dual diseases burden and apply early prevention measures.

Association between preadmission low-density lipoprotein cholesterol concentration and risk of large intracerebral hemorrhage: Results from the Kailuan study.

BACKGROUND: To examine the association between low-density lipoprotein cholesterol (LDL-C) concentrations and the risk of a large hematoma volume after intracerebral hemorrhage (ICH). METHODS: Patients from the Kailuan study (Tangshan, China) who were hospitalized with ICH during 2006 and 2020 were included in this study. The concentration of lipid concentrations, hematoma volume and other clinical characteristics were retrospectively collected and analyzed. Hematoma volumes were measured on the first available brain scan using the ABC/2 method. LDL-C concentrations were obtained from the last physical examination before the occurrence of ICH. LDL-C concentration was categorized into four groups in accordance with the quartiles. Logistic regression was used to assess the association between LDL-C concentrations and the risk of a large hematoma volume of ≥30 ml. A generalized linear regression model was used to analyze the dose-response relationship between LDL-C concentration and hematoma volume. RESULTS: A total of 836 patients with ICH were evaluated. In the Multivariate logistic regression, compared to the second quartile of LDL_C, the first quartile of LDL_C had a significantly higher risk of a large hematoma volume (OR 2.49 [95% CI 1.54-4.01]), and the higher quartile of LDL_C is not associated with higher odds of large hematoma volume. In the generalized linear regression model, the adjusted ß for the association between LDL-C concentration and hematoma volume was 9.46 (95% confidence interval 2.87-16.04), whereas higher LDL-C concentration was not associated with a large hematoma volume. CONCLUSIONS: This study confirmed that low LDL-C concentrations prior to ICH are associated with a higher risk of a large hematoma volume.

Nutrient patterns and cardiometabolic risk factors among Iranian adults: Tehran lipid and glucose study.

BACKGROUND: The present study aimed to assess the relation between nutrient patterns and changes in adult anthropometric and cardiometabolic factors. METHODS: This study was conducted on 1637 adults participating in the Tehran Lipid and Glucose Study (2005-2008), who were free of cardiovascular diseases and cancer and had completed dietary data. They were followed to the next survey (2008-2011). Dietary intakes were collected and nutrient patterns were obtained. Three year changes in anthropometric and cardiometabolic factors were measured. RESULTS: Five nutrient patterns were extracted. The first pattern was characterized by "plant protein, thiamine, niacin, and minerals including phosphorus, zinc, copper, magnesium, manganese, and selenium". Animal protein, lactose, vitamin D, riboflavine, pantothenic acid, vitamin B12, calcium, phosphorus, and zinc" were loaded in the second pattern. The third and fourth patterns were characterized by "vitamin K, fiber, calcium, iron, manganese, and potassium", and "high correlation with starch, thiamine and folate, and negative correlation with mono and poly unsaturated fatty acids and vitamin E", respectively. The fifth pattern was high in Fructose, vitamins A, C, pyridoxine, and potassium. There was no association between nutrient patterns and 3-year changes in blood pressure and fasting blood glucose; whereas, per each quartile increment of the fifth pattern adjusted for potential confounders, triglyceride change was decreased [ß = - 3.66, 95% CI (- 6.57, - 0.57); P for trend = 0.014]. CONCLUSION: Present study indicates that nutrient patterns may have an association with cardiometabolic factors, particularly a pattern rich in fructose, vitamins A, C, pyridoxine, and potassium which decreases triglyceride level.

Association between the -11377 C/G and -11391 G/A polymorphisms of adiponectin gene and adiponectin levels with susceptibility to type 1 and type 2 diabetes mellitus in population from the west of Iran, correlation with lipid profile.

Adipose tissue, an endocrine organ, secretes bioactive factors including adiponectin. Adiponectin is a protein hormone that enhances insulin sensitivity through increased fatty acid oxidation and inhibition of hepatic glucose production. We assessed the association of the adiponectin promoter region polymorphisms -11391 G/A and -11377 C/G with susceptibility to type 1 (T1DM) and type 2 (T2DM) diabetes mellitus in the population of west Iran. Also, we investigated the effect of adiponectin level and lipid profile on T1DM and T2DM development. In this case-control study, we recruited 189 patients with diabetes (100 T2DM and 89 T1DM) and 161 sex and age-matched unrelated healthy controls. Adiponectin mutations were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), and the protein level was measured by the enzyme-linked immunosorbent assay. Other biochemical parameters were determined by routine laboratory methods. The G allele of adiponectin gene at -11377 position (C/G) significantly increased the risk of T1DM. With respect to genotype models, codominant (2.97 times), dominant (3.6-fold), and over-codominant (2.9-fold) patients with T1DM who carried -11377 C > G single-nucleotide polymorphisms were significantly susceptible to the development of the disease. A significantly higher level of adiponectin in T1DM was oberved compared with the control group. In contrast, patients with T2DM had lower adiponectin levels compared with healthy controls. The genotype distributions of -11391 G/A polymorphisms were the same for patients with diabetes and control groups. The presence of G allele at -11377 C/G adiponectin gene significantly increased serum adiponectin level and may be a risk factor for T1DM susceptibility among the western Iranian population.

State of the Art Comprehensive Review of Individual Statins, Their Differences, Pharmacology, and Clinical Implications.

Statins are currently the primary treatment for hyperlipidemia, particularly for the treatment of high levels of low-density lipoprotein cholesterol (LDL-C), as many studies have proven benefit in a variety of populations. The benefits of statin treatment for high cholesterol have been proven in many trials. Forefront among different adverse events is statin-induced myopathy, which still eludes complete understanding, and may range anywhere from muscle soreness or fatigue to potentially extremely rare occurrence of rhabdomyolysis.As most adverse events are rare and not life-threatening, in high-risk patients, a high-dose statin should be started initially as data suggests that clinicians rarely up titrate statin therapy after initial prescription leading to under-treatment of many patients requiring high-dose statin therapy. As we will discuss in this paper, musculoskeletal side effects are the main concern and reason for discontinuing statin therapy. The occurrence and true association of other adverse events in patients on statin such as new onset of diabetes, hepatic toxicity, or cognitive impairment are rare, controversial, and not proven. In placebo-controlled studies, abnormal liver function occurs to a similar degree in statin- and placebo-treated patients. This led to FDA removal of the requirement to monitor liver function tests in patients on statin therapy.The combination of statins with other compounds such as ezetimibe or PCSK9 inhibitors has shown some additional benefits in the treatment of hypercholesterolemia. The goal of this manuscript is to conduct a comprehensive review about most commonly used statins and compare data on their history, structures, benefits, adverse effects, and clinical outcomes.

A Clinical Guide to Combination Lipid-Lowering Therapy.

PURPOSE OF REVIEW: We provide an overview of our current understanding of combination lipid-lowering therapies intended for dyslipidemia treatment and cardiovascular disease prevention. First, we analyze recent statin and non-statin combination therapy guidelines and clinical studies since the publication of 2013 American College of Cardiology Cholesterol Guidelines. Second, we examine the clinical utility of non-statin agents alone and in combination in terms of LDL-C lowering and ASCVD risk reduction. RECENT FINDINGS: Medical societies, including the American College of Cardiology (ACC), National Lipid Association (NLA), and American Association of Clinical Endocrinologists (AACE), have released guidelines to address the appropriate use of non-statin therapies. The guidelines incorporated new evidence, including the IMPROVE-IT and FOURIER clinical trials, which demonstrate that the combination of statin therapy with other non-statin agents such as ezetimibe and PCSK9 inhibitors has a significant clinical benefit. Increasing evidence that aggressive low-density lipoprotein cholesterol (LDL-C) lowering leads to lower cardiovascular disease risk supports the need for continued exploration of the role of combination lipid-lowering therapies. A review of guidelines and clinical trials evaluating non-statin agents illuminates the growing base of evidence and expert opinion supporting the use of combination lipid-lowering therapies. While the majority of clinical trial data utilizes dyslipidemia monotherapy, especially statins, combination therapies represent an opportunity for individualized, patient-centered approach to LDL-C lowering and atherosclerotic cardiovascular disease (ASCVD) risk reduction. The overview provides a perspective on lipid management intended for clinicians who seek additional information and guidance on the use of combination therapies.

Genetic variants of SLC12A3 modulate serum lipid profiles in a group of Mongolian pedigree population.

BACKGROUND: The serum lipid profile, including LDL-C level, is associated with hypertension which is the major cause of cerebrovascular disease (CVD) amounting 30% of global death rate. Previous work also demonstrated important roles of genetic variants of SLC12A3 gene on human CVD, hypertension and other diseases in Mongolian population. However, the relationship between SLC12A3 gene polymorphisms on individuals' lipid profile is still unknown. METHODS: A panel of 15 SNPs of SLC12A3 gene was genotyped within a 424 Mongolians pedigree cohort. The associations between SLC12A3 polymorphisms and four lipid profiles were analyzed by family-based association test (FBAT) and confirmed with haplotype analysis. RESULTS: From both single site and haplotype analyses, the results demonstrated a close relationship between SLC12A3 polymorphisms and LDL-C level. Two SNPs, rs5803 and rs711746 showed significant associations with individuals' serum LDL-C level (z = - 2.08, P -e = 0.038; z = 2.09, P -e = 0.023, respectively), and distribution of haplotypes constructed by two SNPs also associated with participants' serum LDL-C level, significantly (Global Chi2 = 9.06 df = 3, P = 0.028). CONCLUSION: Our results demonstrated the importance of SLC12A3 polymorphisms in individuals' difference about their serum lipid profiles, thereby providing evidence that the genetic variants may contribute to CVD development via modulating person's LDL-C level and blood pressure, in certain contexts.

The Association of Statin Therapy with Incident Diabetes: Evidence, Mechanisms, and Recommendations.

PURPOSE OF REVIEW: Recent studies have demonstrated a higher risk of incident diabetes associated with statin use, causing concern among patients and clinicians. In this review, we will assess the evidence and proposed mechanisms behind statin therapy and its association with incident diabetes. We will then review the current recommendations for statin use in light of this association and suggest next steps for clinicians managing these patients and researchers exploring this phenomenon. RECENT FINDINGS: The annual risk of developing new-onset diabetes with statin treatment is approximately 0.1%. In comparison, the absolute risk reduction of major coronary events with statin use is approximately 0.42% annually. Statins are associated with the development of incident diabetes, particularly among those with predisposing risk factors for diabetes. However, the benefit of statin use among these patients in preventing major coronary events strongly favors statin use despite its risk of incident diabetes.

Role of Non-Statins, LDL-C Thresholds, and Special Population Considerations: A Look at the Updated 2016 ACC Consensus Committee Recommendations.

PURPOSE OF REVIEW: The 2013 ACC/AHA Cholesterol guidelines was a major paradigm shift in the management and treatment of dyslipidemia. The new guidelines outlined "statin benefit groups," highlighted weighing the benefit versus risks of statin therapy ("net benefit"), and discussed the importance of shared decision making between patients and providers in primary prevention. While there was widespread agreement on the main groups benefiting from statin therapy, there was significant controversy regarding LDL-C goals and thresholds, the role of non-statin therapy, and the use of statins in specific populations. The goal of this review is to understand the rationale for the updated 2016 ACC Expert Consensus on Non-Statins and to contrast it with the 2015 NLA Recommendations on the Management of Dyslipidemia. RECENT FINDINGS: The findings of the ACC Expert Consensus Panel were largely influenced by the results of several new clinical trials using non-statin therapy in combination with moderate to high intensity statin therapy. The IMPROVE-IT trial demonstrated that ezetimibe on top of statin therapy lowered ASCVD risk in patients with acute coronary syndromes whose LDL was driven below the previous LDL-C target of <70 mg/dL. In addition, preliminary data assessing the safety of evolocumab and alirocumab on top of statin therapy suggested possible large reductions in ASCVD risk in post hoc analysis. Both the 2016 ACC Consensus Recommendations and the 2015 NLA Recommendations emphasize the importance of maximally tolerated statin therapy, the use of adjunctive non-statin LDL lowering therapy, and the use of LDL-C goals and thresholds to guide intensification of LDL lowering therapy. Although there are some important differences between the ACC Consensus and NLA recommendations in terms of treatment of special populations (i.e., CHF) and on the use of non-HDL-C goals and thresholds, both guidelines support a role for ezetimibe, bile acid sequestrants, and PCSK-9 inhibitors in patients on maximum tolerated statin therapy. The recent positive results of the FOURIER trial gives additional support to the non-statin recommendations of both the ACC and NLA.

Effects of atorvastatin on renal function in patients with dyslipidemia and chronic kidney disease: assessment of clinical usefulness in CKD patients with atorvastatin (ASUCA) trial.

BACKGROUND: Dyslipidemia is a risk factor for the progression of chronic kidney disease (CKD). While conventional lipid lowering therapy provides a benefit to CKD management, the effect of statins on eGFR remains unclear. METHODS: A prospective, multi-center, open-labeled, randomized trial. Total of 349 CKD patients with hyperlipidemia were randomized into 2 groups, and followed for 2 years. Group A included patients who were treated with atorvastatin. Group C were treated with conventional lipid lowering drugs other than statin. Primary endpoint was changes in eGFR. Secondary endpoints included changes in urinary albumin excretion, serum LDL-C, serum triglyceride, cardio-vascular events and all-cause mortality. RESULTS: As the primary endpoint, eGFR decreased by 2.3 ml/min/1.73 m2 in Group A and by 2.6 ml/min/1.73 m2 in Group C, indicating that there was no difference in change of eGFR between the two groups. As secondary endpoints, atorvastatin succeeded to reduce serum LDL-C level significantly and rapidly, but conventional therapy did not. In fact, mean LDL-C level did not reach the target level of 100 mg/dl in Group C. Serum triglyceride was lowered only by atorvastatin, but not conventional drugs. The number of cardiovascular events and all-cause mortality did not differ between in two groups. CONCLUSION: The ASUCA (Assessment of Clinical Usefulness in CKD Patients with Atorvastatin) trial demonstrated that atorvastatin failed to exhibit reno-protections compared to conventional therapy in Japanese patients with dyslipidemia and CKD. It would be due in part to the ability of atorvastatin to more potently reduce serum LDL and triglycerides compared to conventional therapy.

SLC12A3 variants modulate LDL cholesterol levels in the Mongolian population.

BACKGROUND: Abnormalities in lipid metabolism are crucial factors in the pathogenesis of cardiovascular disease (CVD). Variants of many genes have been verified to confer risk for lipid metabolism abnormalities. However, the relationship between genetic variants of the NCC-encoding SLC12A3 gene and lipid metabolism in the Mongolian population remains unclear. In the present study, we aimed to elucidate the effects of SLC12A3 variants on Mongolian lipid metabolism, including total cholesterol (TCHO), triglycerides (TG), low-density lipoprotein cholesterol (LDL-c), and high-density lipoprotein cholesterol (HDL-c). METHODS: A randomly selected population of Mongolians (n = 331) from China underwent clinical testing. An ANOVA test, Kruskal-Wallis H test (K-W test) and haplotype analysis were used to evaluate the association between the levels of lipids (TCHO, TG, LDL-c, and HDL-c) and polymorphisms in SLC12A3 loci. RESULTS: We identified three single nucleotide polymorphisms (SNPs) rs5803, rs2010501 and rs711746 in the SLC12A3 gene that were significantly associated with an individual's serum LDL-c level. Haplotypes combining these SNPs also showed the same trend (all p values < 0.01). Furthermore, the influence of SLC12A3 genetic polymorphisms on differences in individual serum LDL-c levels remained significant, even after we controlled gender, and demographic and other non-genetic factors. CONCLUSION: These results suggest that variants of the SLC12A3 gene confer susceptibility to the abnormal serum LDL-c level in the Mongolian population.

Short-term treatment with a 2-carba analog of cyclic phosphatidic acid induces lowering of plasma cholesterol levels in ApoE-deficient mice.

Plasma cholesterol levels are associated with an increased risk of developing atherosclerosis. An elevated low-density lipoprotein cholesterol (LDL-C) level is a hallmark of hypercholesterolemia in metabolic syndrome. Our previous study suggested that when acetylated LDL (AC-LDL) was co-applied with a PPARγ agonist, rosiglitazone (ROSI), many oil red O-positive macrophages could be observed. However, addition of cyclic phosphatidic acid (cPA) to ROSI-stimulated macrophages completely abolished oil red O-stained cells, indicating that cPA inhibits PPARγ-regulated AC-LDL uptake. This study aimed to determine whether metabolically stabilized cPA, in the form of a carba-derivative of cPA (2ccPA), could reduce plasma cholesterol levels and affect the expression of genes related to atherosclerosis in apolipoprotein E-knockout (apoE(-/-)) mice. 2ccPA reduced LDL-C levels in these mice (n = 3) from 460 to 330 mg/ml, from 420 to 350 mg/ml, and 420 to 281 mg/ml under a western-type diet. 2ccPA also reduced expression of lipid metabolism-related genes, cytokines, and chemokines in ApoE-deficient mice on a high-fat diet. Taken together, these results suggest that 2ccPA governs anti-atherogenic activities in the carotid arteries of apoE-deficient mice.