Treatment Of Hypercholesterolemia Research Articles

Eliminate LDL cholesterol after heart attack … but only for a while.

There is a clear demonstration of the inverse linear correlation between LDL cholesterol levels and clinical benefit. However, the timing of the action of lipid-lowering drugs is not clear. According to animal studies with recombinant lipoprotein A-1, the composition of atherosclerosis changes within 40 h (with variations in lipid and inflammatory contents). Progression-regression studies of atherosclerosis in humans confirm the data, highlighting a rapid change in the plaque over 5 weeks. The data are also in line with what emerges from the survival curves of the old study comparing atorvastatin 80 mg vs. placebo (Myocardial Ischaemia Reduction with Aggressive Cholesterol Lowering). The spacing of the curves occurs after only 4 weeks, indicating the precociousness of the favourable effects of powerful statins. Finally, a recent Odyssey post hoc analysis compared the risk of cardiac death and coronary revascularization between a group in which alirocumab lowered LDL cholesterol to below 15 mg (Group 1 and in which the drug was therefore stopped) against the subjects in the placebo group (Group 2), applying a propensity score matching. The primary endpoint occurred in a lower percentage of patients in Group 1 (6.4 vs. 8.4%). Furthermore, patients in Group 1 had a significantly lower hazard ratio (HR) for major adverse cardiovascular events [0.72; 95% confidence interval (CI) 0.51-0.997; P = 0.047] compared with the entire alirocumab group vs. placebo (HR 0.85; 95% CI 0.78-0.93; P < 0.001). According to these preliminary observations, aggressive and early treatment of hypercholesterolaemia in subjects with acute coronary syndrome translates into improved clinical results compared with a strategy that provides for more gradual control. These data will need to be confirmed through further prospective clinical studies and ideally with early conducted atherosclerosis regression studies.

Treatment of pediatric heterozygous familial hypercholesterolemia 7 years after the EAS recommendations: Real-world results from a large French cohort

BackgroundHeterozygous familial hypercholesterolemia (HeFH) predisposes to premature cardiovascular diseases. Since 2015, the European Atherosclerosis Society has advocated initiation of statins at 8–10 years of age and a low-density lipoprotein cholesterol (LDL-C) target of <135 mg/dL. Longitudinal data from large databases on pharmacological management of pediatric HeFH are lacking. ObjectiveHere, we describe treatment patterns and LDL-C goal attainment in pediatric HeFH using longitudinal real-world data. MethodsThis was a retrospective and prospective multicenter cohort study (2015–2021) of children with HeFH, diagnosed genetically or clinically, aged <18 years, and followed up in the National French Registry of FH (REFERCHOL). Data on the study population as well as treatment patterns and outcomes are summarized as mean±SD. ResultsWe analyzed the data of 674 HeFH children (age at last visit: 13.1 ± 3.6 years; 82.0 % ≥10 years; 52.5 % females) who were followed up for a mean of 2.8 ± 3.5 years. Initiation of lipid-lowering therapy was on average at 11.8 ± 3.0 years of age for a duration of 2.5 ± 2.8 years. At the last visit, among patients eligible for treatment (573), 36 % were not treated, 57.1 % received statins alone, 6.4 % statins with ezetimibe, and 0.2 % ezetimibe alone. LDL-C was 266±51 mg/dL before treatment and 147±54 mg/dL at the last visit (−44.7 %) in treated patients. Regarding statins, 3.3 %, 65.1 %, and 31.6 % of patients received high-, moderate-, and low-intensity statins, respectively. Overall, 59 % of children on statin therapy alone and 35.1 % on bitherapy did not achieve the LDL-C goal; fewer patients in the older age group did not reach the treatment goal. ConclusionPediatric patients with FH followed up in specialist lipid clinics in France receive late treatment, undertreatment, or suboptimal treatment and half of them do not reach the therapeutic LDL-C goal. Finding a more efficient framework for linking scientific evidence to clinical practice is needed.

Abstract P400: Trajectories of Psychological Well-Being Are Associated With High Cardiovascular Health Late in Life: Findings From the Women’s Health Initiative

Introduction: Psychological well-being (PWB) may influence cardiovascular health (CVH) through what the American Heart Association has called the “mind-heart-body connection”. However, few studies have examined longitudinal relationships between positive PWB and CVH. We estimated associations between trajectories of PWB and Life’s Essential 8 (LE8) achievement. Hypothesis: We hypothesized that women who maintained high levels of PWB over time would have higher LE8 scores later in life. Methods: We conducted group-based trajectory modelling in the Women’s Health Initiative (WHI) to identify latent trajectories of PWB among those with ≥3 measurements of purpose in life (PIL, N=29,717) and personal growth (PG, N=12,148). PIL and PG scores were calculated according to participants’ responses to the FACIT-Sp Meaning Subscale and Ryff’s Scales of PWB, collected between 2000-2021. The selection of trajectory models was informed by statistical criteria and prior literature. Late life CVH (2018-2021) was summarized by LE8, with scoring adapted based on available data: self-reported treatment for hypertension, diabetes, and hypercholesterolemia, and historical food frequency questionnaires were used. Logistic regression was performed to estimate associations between PIL and PG trajectory group membership and high CVH (LE8≥80), summarized by odds ratios (OR) and 95% confidence intervals (CI). Logistic models adjusted for baseline age, WHI study arm, race, marital status, income, and education in those with complete data (PIL N=28,033; PG N=11,495). Results: On average, PIL trajectories spanned 17 years (age 66-83) and three latent groups were identified: high/decreasing (n=12,073; 47.4%), moderate/decreasing (n=12,096; 44.1%), and low/stable (n=2,548; 8.6%). Compared to those in the low/stable group, women in the moderate/decreasing and high/decreasing PIL groups had significantly higher odds of having high CVH (OR 1.47 [1.35, 1.61] and OR 2.09 [1.92, 2.28], respectively). These associations were robust to adjustment for demographics and social determinants of health: moderate/decreasing (aOR 1.40 [1.27, 1.53]), high/decreasing (aOR 1.88 [1.71, 2.07]). PG trajectories spanned 9 years (age 74-83) and high/stable (n=3,832, 31.5%), moderate/stable (n=5,692, 46.9%), and low/stable (n=2,624, 21.6%) latent groups were identified. Membership in moderate/stable (OR 1.53 [1.40, 1.69] and high/stable (OR 1.95 [1.75, 2.16]) PG trajectory groups was also significantly associated with odds of having high CVH. These associations remained significant after adjustment (moderate/stable aOR 1.40 [1.27, 1.55]; high/stable aOR 1.64 [1.46, 1.84]). Conclusions: Maintaining high levels of PIL and PG may contribute to better CVH late in life. Further research is needed to investigate how strategies to improve PWB may be integrated within cardiovascular care among older adults.

Effect of Gracilaria changii extract and its fraction in reverse cholesterol transport by targeting SR-BI gene

This present study aimed to investigate the effects of Gracilaria changii (Red seaweed) extract and its fraction on scavenger receptor class B type I (SR-BI) gene expressions. In vitro studies of the activity of G. changii extract and its fraction against the therapeutic target for hypocholesterolemia were conducted using high-density lipoprotein (HDL) receptor SR-BI via luciferase assay in HepG2 cells. In the current study, methanol crude extract (MCE) and Fraction-2 of G. changii showed the highest expression levels of the SR-BI gene via luciferase assay and increased SR-BI mRNA expression compared to the negative control. Metabolite profiling of the MCE of G. changii by GC-MS revealed nine major compounds, comprising various fatty acids, particularly hexadecenoic acid. Therefore, the MCE and Fraction-2 of G. changii have the potential to be explored in the treatment of hypercholesterolaemia to prevent or reduce the severity of atherosclerosis development.

Familial hypercholesterolaemia: a genetic condition with associated cardiovascular risk

Familial hypercholesterolaemia is a common genetic condition that affects the liver's ability to clear low-density lipoprotein cholesterol from the bloodstream. It affects around one in 250 individuals and is characterised by elevated lipid levels from birth. The causal relationship between raised lipids and cardiovascular disease is well established and the impact of this is evident in familial hypercholesterolaemia. These individuals find themselves at increased risk of premature cardiovascular events as a result of the cumulative lifetime burden of excess cholesterol in the bloodstream. Most individuals with familial hypercholesterolaemia remain undiagnosed and therefore untreated. Early detection and treatment of familial hypercholesterolaemia provides an opportunity to initiate cardiovascular risk prevention, which can reduce the individual's level of risk to that of the general population. Increasing nurses' genetic knowledge and raising awareness of conditions such as familial hypercholesterolaemia can help to improve current rates of detection and provide nurses with the necessary skills to recognise and support patients and their families.

Research Progress in the Clinical Treatment of Familial Hypercholesterolemia.

Familial hypercholesterolemia (FH) is an autosomal dominant inheritable disease with severe disorders of lipid metabolism. It is mainly marked by increasing levels of plasma total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C), xanthoma, corneal arch, and early-onset coronary heart disease (CHD). The prevalence of FH is high, and it is dangerous and clinically underdiagnosed. The clinical treatment for FH includes both pharmacological and non-pharmacological treatment, of which non-pharmacological treatment mainly includes therapeutic lifestyle change and dietary therapy, LDL apheresis, liver transplantation and gene therapy. In recent years, many novel drugs have been developed to treat FH more effectively. In addition, the continuous maturity of non-pharmacological treatment techniques has also brought more hope for the treatment of FH. This paper analyzes the pathogenic mechanism and the progress in clinical treatment of FH. Furthermore, it also summarizes the mechanism and structure-activity relationship of FH therapeutic drugs that have been marketed. In a word, this article provides a reference value for the research and development of FH therapeutic drugs.

Impact of statins in the liver: A bane or a boon?

Treatment of hypercholesterolemia with statins is considered one of the cornerstones in the management of atherosclerotic cardiovascular diseases. Statins exert their hypolipidemic effects by inhibiting HMG-CoA reductase, the key enzyme in cholesterol biosynthesis. Beyond cholesterol reduction, statins exhibit pleiotropic effects, including anti-inflammatory, antioxidant, and antiproliferative actions, making them valuable in mitigating atherosclerotic and non-atherosclerotic diseases. Though concerns of hepatotoxicity have been associated with the use of statins, extensive evidence suggests that the risk of statin-induced liver injury (SILI) is rare, with an incidence of &lt;1%. Hepatic adverse effects include reversible asymptomatic transaminase elevation (most frequent), hepatitis, cholestasis, and rarely acute liver failure. While hepatotoxicity concerns should not be dismissed, the evidence overwhelmingly supports the safety of statins. Contrary to the myth of statin hepatotoxicity, real-world data and extensive research emphasize the safety and benefits of statins. They are therapeutic in various liver-related conditions, mainly non-alcoholic fatty liver disease. This scientific review aims to provide a comprehensive overview of statins, shedding light on their mechanism of action, hepatotoxicity concerns, and therapeutic potential in various liver-related conditions.

PCSK9 vaccines: a promising new strategy for the treatment of hypercholesterolemia?

PCSK9 vaccines: a promising new strategy for the treatment of hypercholesterolemia?

Simultaneous determination of BGT-002 and its acyl glucuronide metabolite ZM326E-M2 in human plasma by liquid chromatography-tandem mass spectrometry and its application to a pharmacokinetic study

BGT-002, a new type of ATP-citrate lyase inhibitor, is a promising therapeutic for treatment of hypercholesterolemia. After an oral administration of BGT-002 to subjects, it underwent extensive metabolism and an acyl monoglucuronide (ZM326E-M2) on 1- carboxylic acid group was the major circulating metabolite. In this study, an LC-MS/MS method was developed and validated for the simultaneous determination of BGT-002 and ZM326E-M2 in plasma and the evaluation of their pharmacokinetic characteristics in humans. After extraction from the plasma by acetonitrile-induced protein precipitation, the analytes were separated on a Waters ACQUITY UPLC® BEH C18 column using acetonitrile and 2 mM ammonium acetate containing 0.1% formic acid as the mobile phase for gradient elution. Negative electrospray ionization was performed using multiple reaction monitoring (MRM) of m/z 501.3→325.4 for ZM326E-M2 and m/z 507.3→331.2 for D6-ZM326E-M2, and pseudo-MRM of m/z 325.3→325.3 for BGT-002 and m/z 331.3→331.3 for D6-ZM326E, respectively. The method was validated with respect to accuracy, precision, linearity, stability, selectivity, matrix effect, and recovery. The analytical range in human plasma was linear over a concentration range of 0.0500–50.0 μg/mL for BGT-002 and 0.0100–10.0 μg/mL for ZM326E-M2. The pharmacokinetic results showed that after a single oral administration of 100 mg BGT-002, the parent drug was rapidly absorbed with a mean time to peak concentration (tmax) of 1.13 h, compared with BGT-002, the tmax (4.00 h) of ZM326E-M2 was significantly delayed. The peak concentration and plasma exposure of ZM326E-M2 were about 14.1% and 19.5% of the parent drug, suggesting that attention should be paid to the safety and efficacy of ZM326E-M2 in clinical research.

Sex Differences in Diagnosis, Treatment, and Cardiovascular Outcomes in Homozygous Familial Hypercholesterolemia

Homozygous familial hypercholesterolemia (HoFH) is a rare genetic condition characterized by extremely increased low-density lipoprotein (LDL) cholesterol levels and premature atherosclerotic cardiovascular disease (ASCVD). Heterozygous familial hypercholesterolemia (HeFH) is more common than HoFH, and women with HeFH are diagnosed later and undertreated compared to men; it is unknown whether these sex differences also apply to HoFH. To investigate sex differences in age at diagnosis, risk factors, lipid-lowering treatment, and ASCVD morbidity and mortality in patients with HoFH. Sex-specific analyses for this retrospective cohort study were performed using data from the HoFH International Clinical Collaborators (HICC) registry, the largest global dataset of patients with HoFH, spanning 88 institutions across 38 countries. Patients with HoFH who were alive during or after 2010 were eligible for inclusion. Data entry occurred between February 2016 and December 2020. Data were analyzed from June 2022 to June 2023. Comparison between women and men with HoFH regarding age at diagnosis, presence of risk factors, lipid-lowering treatment, prevalence, and onset and incidence of ASCVD morbidity (myocardial infarction [MI], aortic stenosis, and combined ASCVD outcomes) and mortality. Data from 389 women and 362 men with HoFH from 38 countries were included. Women and men had similar age at diagnosis (median [IQR], 13 [6-26] years vs 11 [5-27] years, respectively), untreated LDL cholesterol levels (mean [SD], 579 [203] vs 596 [186] mg/dL, respectively), and cardiovascular risk factor prevalence, except smoking (38 of 266 women [14.3%] vs 59 of 217 men [27.2%], respectively). Prevalence of MI was lower in women (31 of 389 [8.0%]) than men (59 of 362 [16.3%]), but age at first MI was similar (mean [SD], 39 [13] years in women vs 38 [13] years in men). Treated LDL cholesterol levels and lipid-lowering therapy were similar in both sexes, in particular statins (248 of 276 women [89.9%] vs 235 of 258 men [91.1%]) and lipoprotein apheresis (115 of 317 women [36.3%] vs 118 of 304 men [38.8%]). Sixteen years after HoFH diagnosis, women had statistically significant lower cumulative incidence of MI (5.0% in women vs 13.7% in men; subdistribution hazard ratio [SHR], 0.37; 95% CI, 0.21-0.66) and nonsignificantly lower all-cause mortality (3.0% in women vs 4.1% in men; HR, 0.76; 95% CI, 0.40-1.45) and cardiovascular mortality (2.6% in women vs 4.1% in men; SHR, 0.87; 95% CI, 0.44-1.75). In this cohort study of individuals with known HoFH, MI was higher in men compared with women yet age at diagnosis and at first ASCVD event were similar. These findings suggest that early diagnosis and treatment are important in attenuating the excessive cardiovascular risk in both sexes.

Monitoring and treatment of hypercholesterolemia after an atherosclerotic cardiovascular disease event in Denmark from 2015 to 2020

Background and Aims.Lowering the blood concentration of low-density lipoprotein cholesterol (LDL-C), is a cornerstone in preventing atherosclerotic cardiovascular disease (ASCVD). Current European guidelines recommends LDL-C < 1.4 mmol/L for secondary prevention in high-risk patients. The aim of this study is to investigate monitoring and treatment of hypercholesterolemia one year after a ASCVD event. MethodsDanish patients with hypercholesterolemia and an incident ASCVD event from 2015 to 2020 were included in this nationwide cohort study. Patients' LDL-C measurements and lipid-lowering treatment were followed for one year after ASCVD event, or until death or migration. Imputation was used to estimate absolute LDL-values when patients were unmeasured. ResultsA total of 139,043 patients were included in the study with a mean follow-up time of 10.4 months. During the one-year period, 120,020 (86%) patients had their LDL-C measured at least once, 83,723 (60%) patients were measured at least twice. During the period one to six months after ASCVD event 25,999 (19%) achieved an LDL-C < 1.4 mmol/L, 93,349 (67%) failed to achieve an LDL-C < 1.4 mmol/L, and 196,950 (14%) had died or migrated. Missing LDL-C values were estimated via imputation. At the end of month twelve, 60,583 (44%) patients were in statin monotherapy, 2926 (2%) were treated with other lipid-lowering treatment, 42,869 (31%) were in no treatment, and 32,665 (23%) had died or migrated. ConclusionsMany Danish patients are not appropriately followed-up with LDL-C measurements, and a substantial number of patients are not in lipid-lowering treatment one year after an ASCVD event.

Post-translational regulation of the low-density lipoprotein receptor provides new targets for cholesterol regulation.

The amount of the low-density lipoprotein receptor (LDLR) on the surface of hepatocytes is the primary determinant of plasma low-density lipoprotein (LDL)-cholesterol level. Although the synthesis and cellular trafficking of the LDLR have been well-documented, there is growing evidence of additional post-translational mechanisms that regulate or fine tune the surface availability of the LDLR, thus modulating its ability to bind and internalise LDL-cholesterol. Proprotein convertase subtilisin/kexin type 9 and the asialoglycoprotein receptor 1 both independently interact with the LDLR and direct it towards the lysosome for degradation. While ubiquitination by the E3 ligase inducible degrader of the LDLR also targets the receptor for lysosomal degradation, ubiquitination of the LDLR by a different E3 ligase, RNF130, redistributes the receptor away from the plasma membrane. The activity of the LDLR is also regulated by proteolysis. Proteolytic cleavage of the transmembrane region of the LDLR by γ-secretase destabilises the receptor, directing it to the lysosome for degradation. Shedding of the extracellular domain of the receptor by membrane-type 1 matrix metalloprotease and cleavage of the receptor in its LDL-binding domain by bone morphogenetic protein-1 reduces the ability of the LDLR to bind and internalise LDL-cholesterol at the cell surface. A better understanding of how the activity of the LDLR is regulated will not only unravel the complex biological mechanisms controlling LDL-cholesterol metabolism but also could help inform the development of alternative pharmacological intervention strategies for the treatment of hypercholesterolaemia.

Low-Density Lipoprotein Cholesterol-Lowering Drugs: A Narrative Review.

The modern history of cholesterol-lowering drugs started in 1972 when Dr. Akira Endo identified an active compound (compactin) that inhibited cholesterol biosynthesis from the culture broth of blue-green mold (Penicillium citrinum Pen-51). Since 1987, statins have represented the milestone for the treatment of atherosclerotic cardiovascular disease. A new therapy for the treatment of hypercholesterolemia since the discovery of statins is ezetimibe, the first and only agent inhibiting intestinal cholesterol absorption. Ezetimibe was approved by the FDA in October 2002. A year later, the association between gain-of-function PCSK9 genetic mutations and hypercholesterolemia was reported, and this discovery opened a new era in lipid-lowering therapies. Monoclonal antibodies and small-interfering RNA approaches to reduce PCSK9 were developed and approved for clinical use in 2015 and 2022, respectively. Finally, the newly approved bempedoic acid, an oral adenosine triphosphate citrate lyase inhibitor that lowers LDL-C, is able to reduce major adverse cardiovascular events in both primary and secondary prevention. In the present narrative review, we summarize the pharmacological properties and the clinical efficacy of all these agents currently used for a tailored therapy of hypercholesterolemia in patients with atherosclerotic cardiovascular disease.

New Oral PCSK9 Inhibitor: "MK-0616".

MK-0616, a novel oral macrocyclic peptide inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9), represents a significant advancement in the treatment of hypercholesterolemia. Unlike current PCSK9 inhibitors, which are injectable monoclonal antibodies and siRNA molecules, MK-0616 offers a patient-friendly alternative. The development of MK-0616 involved innovative synthetic chemistry and in vitro mRNA display technology. This cutting-edge approach led to the creation of an orally administered peptide with the ability to cover a larger portion of PCSK9 compared to smaller, linear peptides. Phase 1 and 2b clinical trials have demonstrated MK-0616's safety, efficacy, and pharmacokinetics. These trials indicate the drug's dose-dependent systemic absorption and long half-life. Notably, MK-0616 has exhibited comparable low-density lipoprotein cholesterol-lowering effects to currently available PCSK9 inhibitors, all while maintaining good tolerability in diverse patient populations, including those concurrently on statin therapy. As MK-0616 advances to Phase 3 trials, its lipid-lowering potential for heterozygous familial hypercholesterolemia and its impact on reducing the time to adverse cardiac events will be evaluated in a broad and diverse population, including underrepresented groups. The results achieved so far are promising for individuals with hypercholesterolemia, as they offer a potential solution for effectively lowering low-density lipoprotein cholesterol in patients on statin therapy and mitigating the risk of cardiovascular events. Ongoing research and monitoring will be critical to establish its long-term safety and efficacy, but MK-0616 may emerge as a valuable addition to the array of lipid-lowering therapies available to patients.

The Application of Peptide Nucleic Acids (PNA) in the Inhibition of Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) Gene Expression in a Cell-Free Transcription/Translation System.

Proprotein convertase subtilisin/kexin 9 (PCSK9) is a protein that plays a key role in the metabolism of low-density lipoprotein (LDL) cholesterol. The gain-of-function mutations of the PCSK9 gene lead to a reduced number of surface LDL receptors by binding to them, eventually leading to endosomal degradation. This, in turn, is the culprit of hypercholesterolemia, resulting in accelerated atherogenesis. The modern treatment for hypercholesterolemia encompasses the use of biological drugs against PCSK9, like monoclonal antibodies and gene expression modulators such as inclisiran-a short, interfering RNA (siRNA). Peptide nucleic acid (PNA) is a synthetic analog of nucleic acid that possesses a synthetic peptide skeleton instead of a phosphate-sugar one. This different structure determines the unique properties of PNA (e.g., neutral charge, enzymatic resistance, and an enormously high affinity with complementary DNA and RNA). Therefore, it might be possible to use PNA against PCSK9 in the treatment of hypercholesterolemia. We sought to explore the impact of three selected PNA oligomers on PCSK9 gene expression. Using a cell-free transcription/translation system, we showed that one of the tested PNA strands was able to reduce the PCSK9 gene expression down to 74%, 64%, and 68%, as measured by RT-real-time PCR, Western blot, and HPLC, respectively. This preliminary study shows the high applicability of a cell-free enzymatic environment as an efficient tool in the initial evaluation of biologically active PNA molecules in the field of hypercholesterolemia research. This cell-free approach allows for the omission of the hurdles associated with transmembrane PNA transportation at the early stage of PNA selection.

Plant Sterols and Stanols for Pediatric Patients with Increased Cardiovascular Risk.

The atherosclerotic process begins in childhood and progresses throughout adult age. Hypercholesterolemia, especially familial hypercholesterolemia (FH) and metabolic dysfunctions linked to weight excess and obesity, are the main atherosclerosis risk factors in pediatric patients and can be detected and treated starting from childhood. Nutritional intervention and a healthy-heart lifestyle are cornerstones and first-line treatments, with which, if necessary, drug therapy should be associated. For several years, functional foods enriched with plant sterols and stanols have been studied in the treatment of hypercholesterolemia, mainly as nutritional complements that can reduce LDL cholesterol; however, there is a lack of randomized controlled trials defining their long-term efficacy and safety, especially in pediatric age. This review aims to evaluate what the main published studies on sterols and stanols in pediatric subjects with dyslipidemia have taught us, providing an updated picture of the possible use of these dietary supplements in children and adolescents with dyslipidemia and increased cardiovascular risk. Nowadays, we can state that plant sterols and stanols should be considered as a valuable therapy in pediatric patients with hypercholesterolemia, bearing in mind that nutritional and lifestyle counseling and, when necessary, pharmacologic therapy, are the cornerstones of the treatment in developmental age.

First Report of Inclisiran Utilization for Hypercholesterolemia Treatment in Real-world Clinical Settings in a Middle East Population

Inclisiran is the first small interfering RNA-based treatment approved for reducing pro-atherogenic lipoproteins in patients with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease, who require additional lowering of low-density lipoprotein cholesterol (LDL-C). We report the first evaluation of the effects of inclisiran in a Middle East population. We conducted a retrospective review of patients initiating inclisiran treatment at an outpatient diabetology, endocrinology, and cardiology center between May 2021 and December 2022. All patients followed up for 90 days or more, or with at least 1 lipid determination post initiation were included. Participants were categorized into primary prevention (n = 57) and secondary prevention (n = 89) groups according to previous atherosclerotic cardiovascular disease. Inclisiran was initiated in 146 patients; mean (SD) age was 54.8 (12.12) years, 82 patients (56.2%) were male, 28 patients (19.2%) had received a diagnosis of familial hypercholesterolemia, 89 patients (61%) had received a diagnosis of diabetes mellitus, and 35 patients (23.9%) had a statin intolerance. Median (interquartile range) follow-up was 137 (90 to 193) days. At 90 days, median (interquartile range) reductions in serum LDL-C and triglycerides were -37.9% (-9.5% to -51.2%) and -12.0% (-9.8% to -40.5%), respectively, in primary prevention and -54.1% (-17.1% to -71.4%) and -15.3% (-14% to -38.8%), respectively, in secondary prevention (all, P < 0.001). LDL-C goals were attained in 110 patients (75.3%). Nonattainment of LDL-C goal was attributed to system effect in 26 patients (72.2%), biological effect in 5 patients (13.9%), and discontinuation of treatment in 5 patients (13.9%). Therapy was well tolerated. This study is the first from the Middle East and North Africa region that reported the real-world efficacy and safety profile of inclisiran in a mixed-risk population of patients with heterozygous familial hypercholesterolemia and other non-familial hypercholesterolemia indications. Clinically meaningful and sustained reductions in pro-atherogenic lipids with good tolerability were observed after inclisiran initiation. Fewer AEs were reported in this predominantly Arabic population, consistent with previous safety reports for inclisiran. It is important to note that no patient stopped inclisiran treatment due to AEs. Strengths of our study included an optimal cohort, patient heterogeneity, and high retention. In addition, we were able to report mean robust effects of inclisiran and good medication tolerability, quite like randomized studies and open-label extension periods. Despite this, our study had some limitations, including selection bias due to the retrospective design and the absence of a comparative group.

Molecular mechanism study and potential active ingredients prediction of Danhe granules in the treatment of hypercholesterolemia via TICE

AbstractThis study aims to explore the molecular mechanism and potential active ingredients of Danhe granules in improving the blood lipid level of hypercholesterolemia by intestinal TICE (transintestinal cholesterol excretion) through in vivo experimental research, network pharmacology methods, and molecular docking. The diet‐induced hypercholesterolemia rat model evaluated the effects of Danhe granules on fecal cholesterol levels and intestinal TICE‐related protein expression in rats. Based on the experimental results, the network pharmacology method was used to predict the potential active ingredients, and the binding strength between the potential active ingredients and key targets was further confirmed by molecular docking. Danhe granules increased LDLR, ABCG5, ABCB1, and LXRα which can promote the uptake of cholesterol by intestinal cells and the excretion of cholesterol into the intestine, and then reduce the levels of serum LDL‐C and TC and increase the level of fecal TC, so as to achieve the effect of treating hypercholesterolemia. The results of network pharmacology and molecular docking showed that 19 active ingredients had good binding activity with the targets. These may be the active ingredients of Danhe granules for the treatment of hypercholesterolemia. This study revealed the molecular mechanism of Danhe granules in the treatment of hypercholesterolemia via TICE, and preliminarily clarified the potential effective ingredients. It provides new ideas for the treatment of hypercholesterolemia and the development of new drugs.

A Case Report of Giant Tuberous Xanthoma with Type IIa Familial Hypercholesterolemia

Abstract Tuberous xanthomas are nontender, yellow to red papules to nodules that occur on the extensor surface, and trauma-prone areas such as the elbows, knees, Achilles tendon, and buttocks. A 10-year-old female child born out of second-degree consanguineous marriage presented with multiple skin-colored nodular lesions on axillary folds, both elbows, cubital fossa, medial side of the wrist, interphalangeal joints, buttocks, knees, popliteal fossa, and Achilles tendons. After complete evaluation, diagnosis of familial hypercholesterolemia type IIa with tuberous xanthoma was made. Tuberous xanthoma usually presents in combined type III dyslipidemias, but in our case, it is presented in type IIa familial hypercholesterolemia. Early diagnosis and treatment of familial hypercholesterolemia are important for preventing complications.

What are the benefits and harms of statin treatment for familial hypercholesterolemia in children/adolescents?

What are the benefits and harms of statin treatment for familial hypercholesterolemia in children/adolescents?