Management Of Hypercholesterolemia Research Articles

Effect of adding PCSK9 inhibitors to lipid-lowering interventions on arterial stiffness: A systematic review and meta-analysis.

Atherosclerosis, a leading cause of mortality, necessitates effective management of hypercholesterolemia, specifically elevated low-density lipoprotein cholesterol (LDL-C). The emergence of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) has revolutionised lipid-lowering. PCSK9i demonstrates substantial LDL-C reduction and cardiovascular benefits, particularly in statin-intolerant or nonresponsive individuals. However, the potential pleiotropic effects of PCSK9i, especially on arterial stiffness, remain a subject of investigation. This systematic review and meta-analysis seek to provide a nuanced understanding of the potential pleiotropic effects of PCSK9i, specifically on arterial health. The primary objective was to analyse the influence of PCSK9i on arterial stiffness, extending beyond traditional lipid-lowering metrics and contributing to a more comprehensive approach to cardiovascular risk reduction. A systematic search was conducted across major databases, clinical trial registries and grey literature. Inclusion criteria comprised adults in prospective cohort studies undergoing PCSK9i augmentation in lipid-lowering therapy, with a focus on arterial stiffness measured by pulse wave velocity (PWv). Random-effects meta-analyses, sensitivity analyses and meta-regression models were employed to assess the pooled effect of adding PCSK9i to lipid-lowering interventions on arterial stiffness. Five studies (158 participants) met the inclusion criteria, demonstrating a significant reduction in PWv (mean difference: -2.61 m/s [95% CI: -3.70, -1.52]; ES: -1.62 [95% CI: -2.53, -.71]) upon adding PCSK9i to lipid-lowering interventions. Subgroup analysis and meta-regression models suggested potential sex-based and baseline PWv-dependent variations, emphasising patient-specific characteristics. The meta-analysis provides robust evidence that adding PCSK9i to lipid-lowering interventions significantly improves arterial stiffness, indicating broader vascular benefits beyond LDL-C reduction.

A Comprehensive Review on Biological and Chemical Diversity in Aesculus L. Genus (Sapindaceae)

Abstract: Aesculus L. is a genus of 12 to 19 woody species, representing one of the most acclaimed examples of inter-continental incoherence of the plants native to temperate regions of the Northern Hemisphere. It is traditionally valued in Ayurveda and the Chinese system of medicine for its various species that possess antitumor, cardioprotective, anti-inflammatory and neuroprotective activities. Current studies on this genus have revealed the presence of specific saponins with a multispectrum of pharmacological actions and therapeutic applications. A repertoire of literature related to the biological, taxonomical, phytochemical and ethnopharmacological aspects of Aesculus genus and its uses in different indigenous populations was explored. An inventory of all the species of this genus that were found to be useful as per ethnopharmacological literature was prepared. The ethnobotany, phytochemistry and pharmacology of the individual species are outlined in this review. The extensive information cited here has adduced the likely areas where the important species of this genus can illustrate significant therapeutic intervention in the management of chronic disorders including diabetes, hypercholesterolemia and cancer. The wide range of its pharmacological actions is attributed to the distinct phytochemicals occurring in the species, especially the triterpenoidal saponins like aescin. This review amplifies the recent studies on phytochemical and pharmacological aspects, which alludes that these species have noteworthy therapeutic potential.

Hypercholesterolemia: a literature review on management using tafolecimab: a novel member of PCSK9 monoclonal antibodies.

Cardiovascular diseases (CVD) persist as the leading cause of mortality globally, with atherosclerotic cardiovascular disease (ASCVD), including hypercholesterolaemia, being a significant contributor. Hyperlipidemia management includes various lipid-lowering drugs, including statins, Bempedoic acid, inclisiran, Lomitapide, ANGPTL3 inhibitors, and PCSK9 inhibitors. Statins have traditionally dominated lipid management therapies; however, a subset of patients remains unresponsive or intolerant to this therapy, necessitating novel therapeutic approaches. Tafolecimab, a promising and novel PCSK9 monoclonal antibody, demonstrated significant LDL-C reduction and a favourable safety profile in clinical trials. This review aimed to discuss the role and efficacy of Tafolecimab in the management of hypercholesterolaemia. The authors searched online databases, including PubMed, Scopus, and Embase, for articles related to talofecimab. The efficacy of Tafolecimab in diverse patient populations, including those with comorbid conditions and various lipid disorders, has been explored. Ongoing trials, such as CREDIT-1, CREDIT-2, and CREDIT-4, have provided valuable insights into Tafolecimab's potential as a lipid-lowering agent. Moreover, the drug's extended dosing interval may enhance patient compliance and reduce treatment costs. It has also been found that Tafolecimab has more affinity for PCSK9 and a longer duration of LDL-C reduction than other monoclonal antibody drugs such as evolocumab. Thus, this review focuses on Tafolecimab, a novel PCSK9 monoclonal antibody, its mechanism of action, clinical trial outcomes, safety profile, and potential role in hypercholesterolaemia management. Despite its assuring potential, the long-term impact of Tafolecimab on cardiovascular outcomes remains to be fully elucidated, necessitating further research. Regulatory authorities like the FDA and EMA should also evaluate Tafolecimab's risks and benefits. In conclusion, Tafolecimab shows potential as an innovative therapeutic option for hypercholesterolaemia, particularly in patients with specific risk factors, but warrants additional research.

Consensus document on diagnosis and management of familial hypercholesterolemia from the Italian Society for the Study of Atherosclerosis (SISA)

AimsFamilial Hypercholesterolemia (FH) is a genetic disorder of lipoprotein metabolism that causes an increased risk of premature atherosclerotic cardiovascular disease (ASCVD). Although early diagnosis and treatment of FH can significantly improve the cardiovascular prognosis, this disorder is underdiagnosed and undertreated. For these reasons the Italian Society for the Study of Atherosclerosis (SISA) assembled a Consensus Panel with the task to provide guidelines for FH diagnosis and treatment. Data synthesisOur guidelines include: i) an overview of the genetic complexity of FH and the role of candidate genes involved in LDL metabolism; ii) the prevalence of FH in the population; iii) the clinical criteria adopted for the diagnosis of FH; iv) the screening for ASCVD and the role of cardiovascular imaging techniques; v) the role of molecular diagnosis in establishing the genetic bases of the disorder; vi) the current therapeutic options in both heterozygous and homozygous FH. Treatment strategies and targets are currently based on low-density lipoprotein cholesterol (LDL-C) levels, as the prognosis of FH largely depends on the magnitude of LDL-C reduction achieved by lipid-lowering therapies. Statins with or without ezetimibe are the mainstay of treatment. Addition of novel medications like PCSK9 inhibitors, ANGPTL3 inhibitors or lomitapide in homozygous FH results in a further reduction of LDL-C levels. LDL apheresis is indicated in FH patients with inadequate response to cholesterol-lowering therapies. ConclusionFH is a common, treatable genetic disorder and, although our understanding of this disease has improved, many challenges still remain with regard to its identification and management.

An audit on the management of familial hypercholesterolaemia (FH) in the outpatient clinic setting

An audit on the management of familial hypercholesterolaemia (FH) in the outpatient clinic setting

Hypercholesterolemia Familial: Early Cardiovascular Complications, Treatment Challenges, and the Fatal Consequences of Delayed Diagnosis: an in-Depth Case Study

Familial Hypercholesterolemia (FH) is among the most common genetic disorders, present from birth. The transmission is mainly autosomal dominant. It is characterized by a exclusive increase in low-density lipoproteins (LDL). It is associated with a high risk of premature cardiovascular complications. The diagnosis of FH is generally based on the clinical presentation or genetic tests. The commonly used criteria are those of the Dutch Lipid Clinic Network. FH is a hereditary condition still largely underdiagnosed and undertreated. The prognosis of the disease is related to atheromatous cardiovascular complications, which, in the absence of treatment, lead to the patient's death in the first three decades, often due to myocardial infarction or sudden death. The management of familial hypercholesterolemia systematically involves two categories of measures: so-called hygienic-dietary measures associated with the treatment of other risk factors when they exist, and drug treatments. Familial hypercholesterolemia is still poorly detected. It is necessary to develop systematic approaches to identify patients with FH, conduct cascade screening of their relatives, and increase awareness and control of FH.

Prevalence and management of familial hypercholesterolaemia in patients with chest pain admitted to hospital: a retrospective observational study

ObjectivesPatients with familial hypercholesterolaemia (FH) are genetically burdened by a lifelong elevation of the low-density lipoprotein cholesterol (LDL-C) level, putting them at a very high risk of premature ischaemic heart...

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life. Pfizer, Amgen, Merck Sharp & Dohme, Sanofi-Aventis, Daiichi Sankyo, and Regeneron.

Familial Hypercholesterolemia and Type 2 Diabetes: Diagnostic and Therapeutic Challenges

Familial hypercholesterolemia (FH) is a largely underdiagnosed and undertreated disease. Findings regarding the coexistence and interplay between FH and type 2 diabetes (T2D) are conflicting. Epidemiological data suggest an approximately halved prevalence of T2D in FH and an approximately doubled cardiovascular disease (CVD) risk, dependent on mutation type, age, sex, lifestyle, associated pathologies and therapy.For conference attending physicians involved in hypercholesterolemia management, a FH survey was developed including diagnostic-screening situations, severity assessment, while for hypercholesterolemia patients with premature CVD, a web-based tool was prepared for identification of familial cases. For diagnosis, the Simon Broome, DLCN and MEDPED criteria were used.Physicians showed difficulties in FH identification and risk stratification, overestimating the role of associated metabolic changes and underestimating identified mutations characterized by increased CVD risk at any LDL-C level. In children, neither universal nor early lipid screening in strong family history was recommended, unlike in cases with associated metabolic disturbances. In patients, 21.73% presented definite and/or probable FH diagnosis by at least two scoring systems, 3.84% manifesting also T2D. The case of a 45-year-old patient with gestational diabetes and PCOS, conflicting algorhithms-based FH diagnosis and no means for genetic testing, good cholesterol response to statins but aggravating aorta stenosis exemplifies management challenges.In conclusion, FH identification and individual risk assessment may be assisted by targeting selected patients for diagnosis and physicians for raising awareness, but limited access to mutation analysis and novel non-diabetogenic lipid lowering therapies incumber management of FH and the reduced number of cases with coexisting T2D.

Association Between Hypercholesterolemia and Lumbar Degenerative Back Pain: A Medicare Expenditure Panel Survey (MEPS) Study.

Introduction Hypercholesterolemia is known to be a major contributor to the morbidity associated with cardiovascular disease and has been hypothesized to result in degenerative changes to the spine through atherosclerosis of segmental lumbar vessels.The purpose of this study is to determine the relationship between hypercholesterolemia and degenerative lumbar spine conditions in a U.S. cohort. Methods A total of 30,461 participated in the 2018 Medicare Expenditure Panel Survey (MEPS).Of those, 1,063 subjects responded to whether a diagnosis of lumbar disorders with low back pain was present. Odds ratios (OR) were calculated, and logistic regression analyses were adjusted for demographic, education, occupation, cardiovascular and mental health conditions. Results Of the 1,063 respondents, 455 (43%) reported back pain. Mean age of the respondents was 62.7±16.1. Men and women reported back pain at similar rates (43% vs 45%, p=0.664). Age, race, education level and occupation were similar between those with and without back pain (p>0.05). Those with a diagnosis of depression had higher odds of having back pain (p<0.05). Prevalence of back pain in subjects who responded to the back pain diagnosis item on the survey was 42.6%. On univariate analysis, diagnosis of total cholesterol levels was significantly higher in those with a diagnosis of back pain (OR 1.36, 95% CI [1.20-1.54], p<.0001). Multivariable analysis showed that hypercholesterolemia was independently associated with back pain (adjusted OR 1.32, 95% CI [1.04-1.68], p=0.021) after controlling for covariates. Conclusions In this study, subjects with hypercholesterolemia were 34% more likely to have back pain after controlling for confounders which presents as a recent discovery amongst U.S. populations.Further studies should be performed to investigate the management of hypercholesterolemia in the development and progression of degenerative lumbar back pain.

Comorbidity in lipoprotein apheresis: Their role in the era of new lipid-lowering therapies.

Despite advance in pharmacotherapy of lipid disorders, lipoprotein apheresis (LA) plays a leading role in the management of severe hypercholesterolemia and in atherosclerosis prevention. Aim of this study was to retrospectively evaluate Charlson Comorbidity Index (CCI), presence of major comorbidity, and/or concomitant polypharmacy (definite as 5+ drugs daily) in patients with inherited dyslipidemias on chronic LA. Since 1994, we performed more than 500 LA treatment/year and followed a total of 83 patients (age 56 [47-65] years, male 75%). In subjects with more than 5 years of LA treatment (38 patients, age 54 [45-62] years, male 66%), at the end of the observation time (9 [7-16] years), patients had higher CCI, polypharmacy, anemia, heart failure, peptic ulcer disease, and benign prostatic hyperplasia. Even in the era of new lipid-lowering therapies, the LA treatment established itself as a safe and lifesaving intervention. Patients on chronic LA require a multidisciplinary approach to address their comorbidity and the apheresis unit's medical staff (doctors and nurses) play a pivotal role creating a bridge toward the general practitioner and other specialists for overcoming clinical issues.

PCSK9 Targeting in the Management of Hypercholesterolaemia

It has long been established that elevated plasma concentrations of low-density lipoprotein cholesterol (LDL-C) are among the prominent contributors leading to the development of atherosclerotic plaques and, ultimately, cardiovascular disease. In the current era of optimal risk factor modification, proprotein convertase subtilisin/kexin type 9 (PCSK9) targeting has emerged as a potent therapeutic approach in the management of hypercholesterolaemia, addressing several substantial, unmet clinical needs. PCSK9 monoclonal antibodies, evolocumab and alirocumab, as well as inclisiran, which is a small interfering RNA that halts the transcription of PCSK9 mRNA, are being increasingly used in current clinical practice, as they induce intensive LDL-C reductions without any significant safety and tolerability concerns. Based on the success of these agents, the concept of PCSK9 targeting with novel agents with enhanced biological properties, or via different administration routes, has received considerable attention. In this regard, numerous antisense oligonucleotides, peptides, and proteins are currently under evaluation in randomised controlled trials, yielding propitious results up to date; they may enter clinical use in the coming years. Meanwhile, a PCSK9 vaccine, as well as genome editing via clustered regularly interspaced palindromic repeats/Cas9, hold great promise to eradicate LDL-C altogether as a cardiovascular risk factor. This review aims to present and discuss the current clinical and scientific evidence pertaining to the field of medications that exert their biological effect by targeting PCSK9, which are either in use in clinical practice, or are currently being evaluated in pre-clinical or clinical studies, and may prove beneficial in the near future.

Establishing a multi-specialty consensus in the clinical need for hypercholesterolemia management and its implication for patients access to innovative therapies.

Increased level of blood LDL-C has a causal and cumulative effect on advancing atherosclerotic cardiovascular diseases (ASCVD). European guidelines for treating high LDL-C levels have been recently updated. However, in France, several challenges (e.g., physician and patient awareness, healthcare management) limit the application of management guidelines. The aim of this study was to understand the current opinions and perceived unmet clinical needs in recognising and managing hypercholesterolemia as an ASCVD risk factor, and to explore consensus around factors that support the effective management of elevated LDL-C. An expert group of cardiologists, endocrinologists, biology/genetics researchers, and a health technology assessments expert, from France was convened. The current management of hypercholesterolemia and barriers to achieving LDL-C goals in France were discussed and 44 statements were developed. Wider consensus was assessed by sending the statements as a 4-point Likert Scale questionnaire to cardiologists and endocrinologists across France. The consensus threshold was defined as ≥75%. A total of 101 responses were received. Consensus was very high (>90%) in 25 (57%) statements, high (≥75%) in 18 (41%) statements and was not achieved (<75%) only in 1 (2%) of statements. Overall, 43 statements achieved consensus. Based on consensus levels, key recommendations for improving current guidelines and approaches to care have been developed. Implementation of these recommendations will lead to better concordance with international treatment guidelines and increase levels of education for healthcare practitioners and patients. In turn, this will improve the available treatment pathways for cardiovascular diseases, potentially creating improved patient outcomes in the future.

Impact of conducting a genetic study on the management of familial hypercholesterolemia

Clinically diagnosed FH may require a genetic test (GT) to confirm diagnosis. GT availability/accessibility is resource-dependent and usually restricted to specialized clinics. While GT has a diagnostic value, it has not yet defined its impact on long-term management and prognosis of FH. The aim was to identify the clinical characteristics associated with the request for a GT in suspected heFH. Retrospective study including adult patients with clinically suspected to be FH. Positive GT (GT+) was defined as having a pathogenic/likely pathogenic variant. Patients were stratified in those conducted/not conducted a genetic study and within the former, those who had/did not have a GT+. From 4854 patients included, 3090 were performed a GT (GT+: 2113). Median follow-up: 6.2 years. A younger age, FH-related physical signs, premature coronary disease, higher LDLc and lower BMI and triglycerides, associated higher odds of being conducted a genetic study. These patients had higher baseline LDLc (252mg/dL vs. 211mg/dL among clinically diagnosed patients) and experienced larger reductions over the follow-up (157.7mg/dL, vs. 113.5mg/dL, respectively). A similar pattern was observed among patients with GT+ (vs. negative GT). LDLc target attainment was low but increased to 66-95% when a triple combination with statin/ezetimibe/PCSK9-inhibitor was used. Cardiovascular events occurred in 3.2% and 3.1% of patients who conducted/not conducted a genetic study. Patients conducted a genetic analysis and those with GT+ tended to present the events earlier. genetic study, vs. having a clinical-only diagnosis, impacts the management of FH. Cardiovascular prognosis was similar in both groups, perhaps as a result of the more intensive management of patients with a genetic study.

Bergamot (Citrus bergamia) peel extract as new hypocholesterolemic agent modulating PCSK9 expression

Citrus bergamia extracts have been studied for the management of hypercholesterolemia disorders. Up to now limited information is available concerning the activity of its main phytoconstituents towards the main targets of the cholesterol homeostasis. In the present study, the effects of bergamot peel extract and isolated constituents, namely glycosidic and non-glycosidic flavonoids, one coumarin and one limonoid on the low-density lipoprotein receptor (LDLR) and proprotein convertase subtilisin/kexin type 9 (PCSK9) were evaluated by using cultured HuH7 cell line. Furthermore, for the first time the effects of bergamot peel extract were studied to describe a potential hypolipidemic action. Significant differences were observed due to glycosylation and different substitution on flavanone moiety (O-methylation). Considering the thirteen isolated compounds, both naringenin-7-O-rutinoside (NA-rut) and apigenin-6,8-C-glicoside induced the expression of the LDLR while no effect was observed on PCSK9. However, hesperetin (HE) and its derivatives, hesperetin-7-O-glucoside and hesperetin-7-O-neohesperidoside (HE-glu, HE-neo) and eriodictyol (ER) showed a statin-like effect since a significant increase of both LDLR and PCSK9 expression were detected. Furthermore, bergamot peel extract (BE) firstly demonstrated a significant reduction of PCSK9 expression, indicating a potential adjuvant action to statins. BE, HE-neo, and NA-rut reduced intracellular sterols and the expression of PCSK9 transcription factor HNF1-α. BE also significantly improved the LDL uptake u Huh7 cells. Based on the present data, bergamot peel constituents can play a role in the management of hypercholesterolemia, on one hand they may produce an adjuvant action in combination with statins, while on the other hand they may have a statin-like effect. Additionally, BE may be a good candidate as an adjuvant to statins action.

Evaluation of the impact of the management of hypercholesterolemia using a pre-established regimen in patients with very high cardiovascular risk

Evaluation of the impact of the management of hypercholesterolemia using a pre-established regimen in patients with very high cardiovascular risk

ANMCO Position paper: Inclisiran: an innovative therapeutic approach for the clinical management of hypercholesterolemia

Research focused on lipid-lowering treatments has led to the development of new therapeutic options aimed at cardiovascular risk reduction. Gene silencing represents one of the most innovative approaches to reduce low-density lipoprotein cholesterol (LDL-C). Inclisiran is a small interfering RNA that inhibits proprotein convertase subtilisin/kexin type 9 synthesis and promotes LDL-C clearance by enhancing LDL-C receptor expression on hepatocyte cell surface. Several clinical studies have demonstrated inclisiran efficacy in terms of LDL-C reduction (~50%) with a dosage regimen of 300 mg administered twice a year after the first two doses administered at time 0 and after 90 days. Inclisiran use has recently been approved by the European and American drug regulatory agencies as a therapeutic option in addition to the maximum tolerated statin therapy in adults with primary hypercholesterolemia or mixed dyslipidemia who need further LDL-C reduction.

Bile Acid Sequestrants Based on Natural and Synthetic Gels.

Bile acid sequestrants (BASs) are non-systemic therapeutic agents used for the management of hypercholesterolemia. They are generally safe and not associated with serious systemic adverse effects. Usually, BASs are cationic polymeric gels that have the ability to bind bile salts in the small intestine and eliminate them by excretion of the non-absorbable polymer-bile salt complex. This review gives a general presentation of bile acids and the characteristics and mechanisms of action of BASs. The chemical structures and methods of synthesis are shown for commercial BASs of first- (cholestyramine, colextran, and colestipol) and second-generation (colesevelam and colestilan) and potential BASs. The latter are based on either synthetic polymers such as poly((meth)acrylates/acrylamides), poly(alkylamines), poly(allylamines) and vinyl benzyl amino polymers or biopolymers, such as cellulose, dextran, pullulan, methylan, and poly(cyclodextrins). A separate section is dedicated to molecular imprinting polymers (MIPs) because of their great selectivity and affinity for the template molecules used in the imprinting technique. Focus is given to the understanding of the relationships between the chemical structure of these cross-linked polymers and their potential to bind bile salts. The synthetic pathways used in obtaining BASs and their in vitro and in vivo hypolipidemic activities are also introduced.

#4732 GLUCOCORTICOID-RELATED ADVERSE EFFECTS IN THE TREATMENT OF ANCA-ASSOCIATED VASCULITIS

Abstract Background and Aims Upcoming glucocorticoid (GC)-sparing treatment strategies like avacopan could potentially diminish or replace the need of GC therapy for ANCA-associated-vasculitis (AAV) in the future. Therefore, a proper assessment of GC-related morbidity in AAV is required to provide further justification of such therapies. The aim of this study was therefore to assess the incidence of common toxicities and to further investigate the effect of GC-treatment on the incidence and management of diabetes mellitus, arterial hypertension and hypercholesterolemia. Method In this single-centre-cohort-study we screened medical records for patients with a diagnosis of AAV admitted to the Robert-Bosch-hospital (RBK) in Stuttgart, Germany on a regular basis. We assessed the dosage and duration of immunosuppressive therapy used to treat AAV, as well as the incidence and therapies of arterial hypertension, diabetes mellitus and hypercholesterolemia. For this study, we observed the vasculitis time course during the acute phase (180 days) after either the initial diagnosis or relapse for each patient. Results We included 74 patients admitted to the RBK since 2004 up to the current date. Most common subtype of AAV was GPA (n = 48 patients), followed by MPA (n = 22) and EGPA (n = 4). Including relapses, a total of 127 events were observed. We followed patients for a mean time of 8 years (SD 3.9, 0.9 - 18.0 years). Mean duration of glucocorticoid therapy in total was 4.2 years (SD 3.6, 0.3-14.7 years). All of the patients received prednisolone, whereas 73% of the patients furthermore were administered methylprednisolone for induction therapy. Overall, 34% of the patients were diagnosed with diabetes before or after the diagnosis of AAV (14% pre-existing diabetes, 20% new-onset diabetes). Daily and accumulated GC-dose did not differ between patients with or without diabetes. However, there was a significant higher accumulated GC dose in patients requiring insulin-therapy for diabetes management in comparison to those with oral antidiabetics (p-value = 0.0214). 89% of the patients were treated with antihypertensive therapy (38% pre-exisiting hypertension, 51% new-onset hypertension). We found that the accumulated dose of prednisolone within the first 180 days after a vasculitis event was not significantly higher for patients with documented hypertension. However, we detected that the mean accumulated GC dose after a vasculitis event was significantly higher for the subgroup of patients in whom an escalation of antihypertensive therapy was initiated in comparison to the patients whose therapy was stable or even deescalated (p-value = 0.0001). With regard to hypercholesterolaemia, there was no statistical difference in the accumulated GC-dose during the acute course between patients requiring statin-therapy and those who did not. Conclusion GC related toxicities are common in patients with AAV. This study provides additional evidence about the incidence of treatment related harms in AAV to further promote importance of alternative reduced dose or even GC free treatment approaches. This may be relevant in detecting risk groups for whom upcoming GC-sparing treatment strategies such as avacopan are essential to reduce treatment-related harm.

Comprehensive computational study in the identification of novel potential cholesterol lowering agents targeting proprotein convertase subtilisin/kexin type 9

The enzymatic target proprotein convertase subtilisin/kexin type 9 (PCSK9) is critically involved in the regulation of the lipoprotein metabolism leading to the degradation of low-density lipoprotein receptors (LDLRs) upon binding. Drugs that lower LDL cholesterol (LDL-C) through the inhibition of PCSK9 are useful in the management of hypercholesterolemia which greatly reduces the associated risk of atherosclerotic cardiovascular disease (CVD). In 2015, anti-PCSK9 monoclonal antibodies (mAbs), alirocumab and evolocumab were approved but owing to their high costs their prior authorization practices were impeded, reducing their long-term adherence. This has drawn considerable attention for the development of small-molecule PCSK9 inhibitors. In this research work, novel and diverse molecules with affinity towards PCSK9 thereby having ability to lower cholesterol. A hierarchical multistep docking was implemented to identify small molecules from chemical libraries with a score cutoff −8.00 kcal/mol, thereby weeding all the non-potential molecules. A set of seven representative molecules Z1139749023, Z1142698190, Z2242867634, Z2242893449, Z2242894417, Z2242909019, and Z2242914794 have been identified from a comprehensive computational study which included assessment of pharmacokinetics and toxicity profiles and binding interactions along with in-depth analysis of structural dynamics and integrity using prolong molecular dynamics (MD) simulation (in-duplicate). Furthermore the binding affinity of these PCSK9 inhibitory candidates molecules was ascertained over 1000 trajectory frames using MM-GBSA calculations. The molecules reported herein are propitious candidates for further development through necessary experimental considerations. Communicated by Ramaswamy H. Sarma