Bile Acid Sequestrants Research Articles

Representativeness of women and racial/ethnic minorities in randomized clinical trials on bempedoic acid

Background and Aims : Women and racial minorities have continued for a long time to be underrepresented in randomized clinical trials testing lipid-lowering therapies (i.e. statins, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, ezetimibe, bile acid sequestrants, fibrates, niacin, and omega-3 polyunsaturated fatty acids).

Disease burden of primary biliary cholangitis and associated pruritus based on a cross-sectional US claims analysis

ObjectiveIn order to identify areas of unmet need in patients with primary biliary cholangitis (PBC), this study sought to use real-world observational healthcare data to characterise the burden in patients...

Cholesterol-Lowering Effects of Asperidine B, a Pyrrolidine Derivative from the Soil-Derived Fungus Aspergillus sclerotiorum PSU-RSPG178: A Potential Cholesterol Absorption Inhibitor.

Isolated secondary metabolites asperidine B (preussin) and asperidine C, produced by the soil-derived fungus Aspergillus sclerotiorum PSU-RSPG178, were found to exhibit inhibitory effects against 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase and oxidative stress in an in vitro assay. Whether or not the known pyrrolidine asperidine B and the recently isolated piperidine asperidine C have lipid-lowering effects remains unknown. Thus, this study aimed to investigate the hypocholesterolemic effects of asperidines B and C and identify the mechanisms involved in using in vitro, ex vivo, and in vivo models. The results show that both compounds interfered with cholesterol micelle formation by increasing bile acid binding capacity, similar to the action of the bile acid sequestrant drug cholestyramine. However, only asperidine B, but not asperidine C, was found to inhibit cholesterol uptake in Caco-2 cells by up-regulating LXRα without changing cholesterol transporter NPC1L1 protein expression. Likewise, reduced cholesterol absorption via asperidine-B-mediated activation of LXRα was also observed in isolated rat jejunal loops. Asperidine B consistently decreases plasma cholesterol absorption, similar to the effect of ezetimibe in rats. Therefore, asperidine B, the pyrrolidine derivative, has therapeutic potential to be developed into a type of cholesterol absorption inhibitor for the treatment of hypercholesterolemia.

COVID-19, dyslipidemia and familial hypercholesterolemia: an up-date

COVID-19 (coronavirus disease 2019) is an infection caused by the SARS-CoV-2 coronavirus, which can evolve into a severe respiratory condition, affecting the world population in a pandemic manner. In this study, we aimed to update the findings of the mechanisms that associate dyslipidemia with COVID-19 infection, the evolution of severe form and the influence of lipid-lowering treatment on outcomes. The search was performed in the PubMed and Embase databases and the selection was based on dyslipidemia and COVID-19 studies, which resulted in 31 articles. In results, the evidence in changes in cholesterol metabolism was found in SARS-CoV-2 virus infection with variations in high-density lipoprotein (HDL) levels. In addition, it provided an increase in triglycerides (TG) and very-low-density lipoprotein cholesterol (VLDLc). Patients with familial hypercholesterolemia (FH) with COVID-19 representing a group of individuals who develop early atherosclerotic disease with a higher risk of cardiovascular event, which should intensify the lipid-lowering treatment due to the potential risk of coronary endothelial dysfunction caused by viral infection. Cholesterol modifying drugs have a potential to change the life cycle of the virus, resulting in a range of pleiotropic effect on infectivity, immunity and inflammation, such as statins, fibrates, ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors (iPCSK9), omega-3 fatty acids, bile acids sequestrants and nicotinic acid. As dyslipidemia is one of the main risk factors for the severe form of COVID-19, causing endothelial dysfunction previously installed in dyslipidemic patients, the use of lipid-lowering drugs can reduce the risk factors for the unfavorable outcome in these patients.

The impact of treatment with bile acid sequestrants on quality of life in patients with bile acid diarrhoea

BackgroundBile acid diarrhoea (BAD) can be severely debilitating and negatively affect patients’ quality of life (QoL). We carried out a multi-centre prospective study exploring QoL outcomes in patients with BAD after treatment with colesevelam.MethodsPatients with or without a positive 23-seleno-25-homotaurocholic acid (SeHCAT) scan were recruited and categorised into four groups: SeHCAT negative control group (CG), idiopathic BAD, post-cholecystectomy (PC) and post-terminal ileal resection for Crohn’s disease (CD). Patients with a positive SeHCAT were treated with colesevelam and dosing was titrated to symptomatic response. Patients were reviewed at 4- and 8-weekly intervals and QoL was evaluated by EQ-5D-3L, SF-36, IBDQ-32 at each visit (where relevant). Patients with a negative SeHCAT (CG cohort) completed one set of questionnaires before being discharged from the study.Results47 patients (BAD = 24, PC = 12, CD = 11) completed paired QoL questionnaires before and after treatment and 30 CG patients completed a baseline questionnaire. There was a significant improvement in IBDQ-32 mean scores before and after treatment in CD patients [134.6 (95%CI 112.5–156.6) and 158.4 (136.1–180.6), respectively (p = 0.007). Following treatment, BAD patients had significantly improved mean SF-36 scores in the “Role limitation due to physical health” dimension (p = 0.02) and in the overall mental component summary (p = 0.03). Prior to starting treatment, BAD patients had the lowest scores in the ‘activity’ dimension of the EQ-5D-3L (p = 0.04), which improved significantly after treatment (p = 0.002). Overall, the BAD and CD cohort showed improved mean scores with treatment in all components of the SF-36 and EQ-5D-3L, while the PC cohort showed a general decline in mean scores after treatment. 55% of patients clinically responded to treatment of which 41.7%, 58.3% and 81.8% responded from the BAD, PC and CD groups respectively. Correlations between those deemed as responders with improvements on the SF-36 and EQ-5D dimensions were not statistically significant.ConclusionOur results demonstrate improved QoL in the BAD and CD cohort with treatment. Further larger studies are recommended specifically investigating the PC cohort and whether patients may improve with newer treatments such as FXR agonists.Trial registration Ethical approval REC Ref: 16/LO/1325.

*An Unsolved Case: FH or Sitosterolemia?

<h3>Lead Author's Financial Disclosures</h3> Nothing to disclose. <h3>Study Funding</h3> None. <h3>Background/Synopsis</h3> A 51-year-old woman with diabetes mellitus (A1c 6.7%), obesity (BMI 34), hyperlipidemia, and recurrent choledocholithiasis pending cholecystectomy, presents to UVA Prevention Clinic. Hyperlipidemia was diagnosed at age 22. Cholesterols have ranged from 290 to 520ng/dL on rosuvastatin 40mg daily. Family history was negative for premature coronary artery disease, but notable for high cholesterol in her mother and teenage child. Exam demonstrated left eyelid xanthelasma and red-yellow scaly patch on her left elbow. Labs revealed cholesterol 400ng/dL, LDL 307ng/dL, HDL 43ng/dL, triglycerides 223ng/dL, and HgA1c 6.7%. Colestipol 1mg BID and ezetimibe 10mg daily were initiated. Follow-up labs demonstrated cholesterol 284ng/dL, HDL 43ng/dL, LDL 199ng/dL and triglycerides 199ng/dL. Genetic testing for familial hypercholesteremia (FH) revealed an Increased Risk Allele on ABCG8 (c.55G>C, p.Asp19His) and a Variant of Uncertain Significance on ABCG8 f(c.275G>A, p.Ser92Asn). Subsequent sitosterol level testing, on medications, was 4.3mg/L (normal < 6.0). <h3>Objective/Purpose</h3> This abstract serves as an educational unsolved clinical vignette. <h3>Methods</h3> Sitosterolemia is an autosomal recessive disorder of lipid metabolism characterized by net increased intestinal absorption via decreased biliary excretion of plant sterols. Sitosterolemia has considerable overlap with FH but is significantly rarer1. Both cause xanthomas and premature coronary atherosclerosis sitosterolemia presentation also causes choledocholithiasis, hemolysis, splenomegaly, and arthralgia/arthritis. LDL levels in FH are consistently high whereas in sitosterolemia levels vary considerably with diet. <h3>Results</h3> Diagnostic criteria for sitosterolemia is comprised of four categories: clinical manifestations, serum sitosterol levels, exclusion of FH and cerebroteinous xanthomatosis, and pathogenic mutations. For definitive diagnosis, pathogenic mutations in ABCG5 or ABCG8 must be identified. Accurate diagnosis is changing management. Lower intake of plant sterol rich foods are recommended in sitosterolemia, foods usually considered beneficial in FH3. Ezetimibe and bile-acid sequestrants are shown to reduce sitosterol and cholesterol levels through decreased intestinal sterol absorption. <h3>Conclusions</h3> The patient described above has findings possibly consistent with sitosterolemia. Her Dutch FH score of 9, used for clinical diagnosis of FH, is consistent with definitive FH. The diagnostic dilemma has multiple potential approaches: A) Stopping colestipol and ezetimibe, liberalizing diet, and retesting sitosterol levels. B) Continuing current medications, reinforcing a traditional heart-healthy diet, and adding a PCSK-9i for presumed FH. C) Continuing current medications, adding a PCSK-9i for presumed FH, but encouraging a sitosterolemia diet low in plant sterols. D) Continuing current medications, reinforcing a sitosterolemia diet low in plant sterols, and rechecking lipids in 3-4 months.

Exocrine pancreatic insufficiency after bariatric surgery: a bariatric surgery center of excellence experience.

Gastrointestinal symptoms such as diarrhea, bloating, abdominal pain, and nausea are common after bariatric surgery (BS) and can lead to significant morbidity. While many diagnoses can explain these symptoms, post-bariatric exocrine pancreatic insufficiency (EPI) is becoming increasingly recognized as contributor to gastrointestinal symptoms. The frequency and outcomes of EPI after BS are not well understood. We investigated the prevalence and outcomes of EPI over 18years at a tertiary bariatric referral center. A retrospective review of patients who underwent primary or revisional BS from 2002 to 2020 was performed. Patients were included if they were suspected of having EPI or underwent fecal elastase testing (FE-1). EPI diagnosis was defined as positive FE-1 testing or improvement with empiric pancreatic enzyme replacement therapy (PERT). EPI was suspected in 261 patients, and 190 were tested via FE-1 (89.5%) or empirically treated (10.5%). EPI was diagnosed in 79 (41.6%) patients and was associated with older age and lower BMI. Therapeutic PERT was given to 65 patients diagnosed with EPI, and 56 (86.2%) patients reported improved symptoms. Patients who underwent RYGB and BPD-DS were more likely to have EPI than those after SG (47.9% and 70.0% vs 17.4%, p < 0.01). EPI diagnosis was associated with a history chronic pancreatitis. While diarrhea and abdominal pain were the most common symptoms prompting FE-1 testing, no symptoms were significantly associated with EPI. EPI was also associated with abnormal fecal fat results and treatment with bile acid sequestrants, but not small intestinal bacterial overgrowth. This study highlights that exocrine pancreatic insufficiency can account to for previously unexplained GI complaints after bariatric surgery. Therefore, bariatric surgery programs should consider this diagnosis in symptomatic patients, especially following RYGB and BPD-DS. Further work to define patient factors that should prompt evaluation, optimal treatment, and prevention is necessary.

Mechanism, clinical consequences, and management of dyslipidemia in children with nephrotic syndrome

Dyslipidemia in nephrotic syndrome (NS) is often characterized by marked increases in the levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol, and other lipoproteins, such as very low-density lipoprotein, intermediate-density lipoprotein, and lipoprotein(a). It has been suggested that impaired catabolism of lipoproteins and cholesterol is mainly due to decreased lipoprotein lipase and hepatic lipase activity, and increased biosynthesis of lipoproteins in the liver. The management strategies for dyslipidemia in patients with NS consist of lifestyle modification, lipid-lowering agents represented by statins, second-line agents such as fibrates and bile acid sequestrants, and lipid apheresis. Compared with dyslipidemia in adult NS patients, whose risks of atherosclerotic disease and progressive renal injury are considered high, clinical data on dyslipidemia in pediatric NS patients are limited. Therefore, it is necessary to pay more attention to the evaluation and management of dyslipidemia in pediatric patients with NS in clinical practice.

Functional bowel disorders with diarrhoea: Clinical guidelines of the United European Gastroenterology and European Society for Neurogastroenterology and Motility.

Irritable bowel syndrome with diarrhoea (IBS‐D) and functional diarrhoea (FDr) are the two major functional bowel disorders characterized by diarrhoea. In spite of their high prevalence, IBS‐D and FDr are associated with major uncertainties, especially regarding their optimal diagnostic work‐up and management. A Delphi consensus was performed with experts from 10 European countries who conducted a literature summary and voting process on 31 statements. Quality of evidence was evaluated using the grading of recommendations, assessment, development, and evaluation criteria. Consensus (defined as >80% agreement) was reached for all the statements. The panel agreed with the potential overlapping of IBS‐D and FDr. In terms of diagnosis, the consensus supports a symptom‐based approach also with the exclusion of alarm symptoms, recommending the evaluation of full blood count, C‐reactive protein, serology for coeliac disease, and faecal calprotectin, and consideration of diagnosing bile acid diarrhoea. Colonoscopy with random biopsies in both the right and left colon is recommended in patients older than 50 years and in presence of alarm features. Regarding treatment, a strong consensus was achieved for the use of a diet low fermentable oligo‐, di‐, monosaccharides and polyols, gut‐directed psychological therapies, rifaximin, loperamide, and eluxadoline. A weak or conditional recommendation was achieved for antispasmodics, probiotics, tryciclic antidepressants, bile acid sequestrants, 5‐hydroxytryptamine‐3 antagonists (i.e. alosetron, ondansetron, or ramosetron). A multinational group of European experts summarized the current state of consensus on the definition, diagnosis, and management of IBS‐D and FDr.

Pathophysiology and Clinical Management of Bile Acid Diarrhea.

Bile acid malabsorption (BAM) represents a common cause of chronic diarrhea whose prevalence is under-investigated. We reviewed the evidence available regarding the pathophysiology and clinical management of bile acid diarrhea (BAD). BAD results from dysregulation of the enterohepatic recirculation of bile acids. It has been estimated that 25–33% of patients with functional diarrhea and irritable bowel syndrome with diarrhea have BAM. Currently, the selenium homotaurocholic acid test is the gold standard for BAD diagnosis and severity assessment. However, it is an expensive method and not widely available. The validation of the utility in the clinical practice of several other serum markers, such as 7α-hydroxy-4-cholesten-3-one (C4) and the fibroblast growth factor 19 (FGF19) is ongoing. The first-line treatment of patients with BAD is bile acid sequestrants. Patients that are refractory to first-line therapy should undergo further diagnostics to confirm the diagnosis and to treat the underlying cause of BAD. An early and correct diagnosis of BAD would improve patient’s quality of life, avoiding additional diagnostic tests that burden health care systems. Considering the limited availability and tolerability of specific medications for BAD treatment, future research is awaited to identify other therapeutic approaches, such as gut microbiota modulating therapies.

Effects of Bile Acid Modulation by Dietary Fat, Cholecystectomy, and Bile Acid Sequestrant on Energy, Glucose, and Lipid Metabolism and Gut Microbiota in Mice.

Bile acid metabolism, involved with the digestion and absorption of nutrients in the gut, is linked to the gut microbiota community, greatly impacting the host’s metabolism. We examined the hypothesis that the modulation of bile acid metabolism by dietary fat contents, gallbladder removal (GBX; cholecystectomy), and bile acid sequestrant (BAS; cholestyramine) treatment could alter energy, glucose, and lipid metabolism through the changes in the gut microbiota. Mice were randomly assigned to the following six groups: (1) Sham GBX surgery (Sham) + low fat/high carbohydrate diet (LFD), (2) Sham + high fat diet (HFD), (3) Sham + HFD + BAS, (4) GBX + LFD, (5) GBX + HFD, and (6) GBX + HFD + BAS. BAS groups received 2% cholestyramine. After an 8-week intervention, energy, glucose, and lipid metabolism, and the gut microbiota community were measured. HFD groups exhibited higher body weight gain than LFD, and GBX increased the weight gain comped to Sham groups regardless of BAS in HFD (p < 0.05). Homeostatic model assessment for insulin resistance (HOMA-IR) was higher in HFD than LFD, and GBX increased it regardless of BAS. Serum lipid profiles were worsened in GBX + HFD compared to Sham + LFD, whereas BAS alleviated them, except for serum HDL cholesterol. Hepatic tumor-necrosis-factor-α (TNF-α) mRNA expression and lipid peroxide contents increased with GBX and BAS treatment compared to Sham and no BAS treatment (p < 0.05). Hepatic mRNA expression of sterol regulatory element-binding transcription factor 1c (SREBP1c) and peroxisome proliferator-activated receptor gamma (PPAR-γ) exhibited the same trend as that of tumor necrosis factor-α (TNF-α). The α-diversity of gut bacteria decreased in GBX + HFD and increased in GBX + HFD + BAS. Akkermentia, Dehalobacterium, SMB53, and Megamonas were high in the Sham + LFD, and Veillonella and Streptococcus were rich in the Sham + HFD, while Oscillospira and Olsenella were high in Sham + HFD + BAS (p < 0.05). GBX + LFD increased Lactobacillus and Sutterella while GBX + HFD + BAS elevated Clostridium, Alistipes, Blautia, Eubacterium, and Coprobacillus (p < 0.05). In conclusion, the modulation of bile acid metabolism influences energy, glucose, and lipid metabolisms, and it might be linked to changes in the gut microbiota by bile acid metabolism modulation.

Iron deficiency linked to altered bile acid metabolism promotes Helicobacter pylori-induced inflammation-driven gastric carcinogenesis.

Gastric carcinogenesis is mediated by complex interactions among Helicobacter pylori, host, and environmental factors. Here, we demonstrate that H. pylori augmented gastric injury in INS-GAS mice under iron-deficient conditions. Mechanistically, these phenotypes were not driven by alterations in the gastric microbiota; however, discovery-based and targeted metabolomics revealed that bile acids were significantly altered in H. pylori–infected mice with iron deficiency, with significant upregulation of deoxycholic acid (DCA), a carcinogenic bile acid. The severity of gastric injury was further augmented when H. pylori–infected mice were treated with DCA, and, in vitro, DCA increased translocation of the H. pylori oncoprotein CagA into host cells. Conversely, bile acid sequestration attenuated H. pylori–induced injury under conditions of iron deficiency. To translate these findings to human populations, we evaluated the association between bile acid sequestrant use and gastric cancer risk in a large human cohort. Among 416,885 individuals, a significant dose-dependent reduction in risk was associated with cumulative bile acid sequestrant use. Further, expression of the bile acid receptor transmembrane G protein–coupled bile acid receptor 5 (TGR5) paralleled the severity of carcinogenic lesions in humans. These data demonstrate that increased H. pylori–induced injury within the context of iron deficiency is tightly linked to altered bile acid metabolism, which may promote gastric carcinogenesis.

Gastrointestinal neoplasia: carcinogenic interaction between bile acids and Helicobacter pylori in the stomach.

Bile acids modulate cell functions in health and disease, however, the mechanisms underlying their actions on neoplastic cells in the gastrointestinal (GI) tract remain largely unknown. In this issue of the JCI, Noto et al. comprehensively analyzed how interactions between Helicobacter pylori infection, iron deficiency, and bile acids modulate gastric inflammation and carcinogenesis. The investigators used sophisticated models, including INS-GAS mice with elevated serum gastrin and gastric acid secretion, in which H. pylori infection mimics human disease progression, to show that selected bile acids potentiated the carcinogenic effects of H. pylori infection and iron depletion. This elegant work has broad translational implications for microbe-associated GI neoplasia. Importantly, bile acid sequestration robustly attenuated the combined effects of H. pylori infection and iron depletion on gastric inflammation and cancer.

Representativeness of women and racial/ethnic minorities in randomized clinical trials on bempedoic acid

Abstract Funding Acknowledgements Type of funding sources: None. Background Women and racial minorities have continued for a long time to be underrepresented in randomized clinical trials testing lipid-lowering therapies (i.e. statins, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, ezetimibe, bile acid sequestrants, fibrates, niacin, and omega-3 polyunsaturated fatty acids). Purpose We sought to investigate presence of disparities in trials testing the new emergent lipid-lowering drug bempedoic acid (BA). Methods Several databases were searched with the use of a purposedly developed search strategy. To minimize the chances of missing data, the identified clinical trials were subsequently searched on http://www.clinicaltrials.gov. Original studies were included in the analysis if they met the following inclusion criteria: (i) being a clinical trial with either multicentre or single-centre design and (ii) having an appropriate controlled design for BA. Results Considering together, the overall participation rate and the mean participation rate across the clinical studies, men, whites and non-Hispanic/Latinos were sufficiently represented compared with their proportion in the disease population. Non-whites and Asians were underrepresented. Women, blacks and Hispanic/Latinos were from adequately to over-represented across clinical trials, though in the pooled population their portion was lower than their share of the disease population. Conclusions Further efforts are needed to enhance the representativeness of clinical trials according to race and sex and ensure complete information about efficacy and safety of treatment with BA.

Dyslipidemia Management in Pregnancy: Why Is It not Covered in the Guidelines?

Despite the elevation of lipid values during pregnancy is mostly physiological, evidence suggest that it may be associated with adverse events. This article reviews the characteristics of lipid disorders and the possible management with dyslipidemia in pregnant women. Among many available groups of lipid-lowering drugs, only bile acid sequestrants are approved for the treatment of dyslipidemia during pregnancy. Ezetimibe and fenofibrate might be considered if benefits outweigh the potential risk. Statins are still contraindicated due to the results mainly from animal studies and series of human cases. However, recent systematic reviews and meta-analyses showed that their use may not be detrimental, and in some selected cases may be beneficial. Especially, in some groups of pregnant patients with very high cardiovascular risk-those already after an event, or with established cardiovascular disease, with homozygous familial hypercholesterolemia; in such cases the final decision should weight the potential risk of discontinuation of therapy. Finally, we need to wait for the data with new drugs, including PCSK9 inhibitors and especially inclisiran, which (still hypothetically) might be a very interesting option as it may be used just before the pregnancy and immediately after with the duration of about 9months between injections. The decisions on lipid-lowering therapy in pregnant patients should be individualized. Despite design and ethical difficulties with such studies, further investigations on dyslipidemia treatment during pregnancy are highly awaited.

Undertreatment or Overtreatment With Statins: Where Are We?

Statins, in addition to healthy lifestyle interventions, are the cornerstone of lipid-lowering therapy. Other low-density lipoprotein (LDL)-lowering drugs include ezetimibe, bile acid sequestrants, and PCSK9 inhibitors. As new evidence emerges from new clinical trials, therapeutic goals change, leading to renewed clinical guidelines. Nowadays, LDL goals are getting lower, leading to the “lower is better” paradigm in LDL-cholesterol (LDL-C) management. Several observational studies have shown that LDL-C control in real life is suboptimal in both primary and secondary preventions. It is critical to enhance the adherence to guideline recommendations through shared decision-making between clinicians and patients, with patient engagement in selecting interventions based on individual values, preferences, and associated conditions and comorbidities. This narrative review summarizes the evidence regarding the benefits of lipid-lowering drugs in reducing cardiovascular events, the pleiotropic effect of statins, real-world data on overtreatment and undertreatment of lipid-lowering therapies, and the changing LDL-C in targets in the clinical guidelines of dyslipidemias over the years.

Advancements in the Treatment of Homozygous Familial Hypercholesterolemia.

Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder with extreme elevations of low-density lipoprotein cholesterol (LDL-C) leading to premature atherosclerotic cardiovascular disease (ASCVD) as early as in childhood. Management of HoFH centers around aggressive and adequate reduction of LDL-C levels to slow the trajectory of ASCVD development. Historically, lowering LDL-C levels in HoFH has been challenging because of both the markedly elevated LDL-C levels (often ＞400 mg/dL) and reduced response to treatment options, such as statins, for which the mechanism of action requires a functional LDL receptor. However, the treatment landscape for HoFH has rapidly progressed over the last decade. While statins and ezetimibe remain first-line treatment, patients often require addition of multiple therapies to achieve goal LDL-C levels. The PCSK9 inhibitors are an important recent addition to the available treatment options, along with lomitapide, bile acid sequestrants, and, possibly, bempedoic acid. Additionally, ANGPTL3 has emerged as an important therapeutic target, with evinacumab being the first available ANGPTL3 inhibitor on the market for the treatment of patients with HoFH. For patients who cannot achieve adequate LDL-C reduction, lipoprotein apheresis may be necessary, with the added benefit of reducing lipoprotein(a) levels that carries an added risk if also elevated in patients with HoFH. Finally, gene therapy and genome editing using CRISPR/Cas-9 are moving through clinical development and may dramatically alter the future landscape of treatment for HoFH.

Inclisiran: A Novel Small Interfering RNA Drug for Low-Density Lipoprotein Reduction.

Inclisiran increases the number of low-density lipoprotein surface receptors expressed on hepatocytes using small interfering RNA directed against proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA. This novel mechanism can reduce low-density lipoprotein by ≈50%, like reductions achieved with high-intensity statins or PCSK9-inhibiting monoclonal antibodies. Inclisiran is indicated in the treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease, unable to achieve target LDL concentrations with diet and maximally tolerated statin therapy. It is more expensive than PCSK9-inhibiting monoclonal antibodies and still lacks clinical evidence for the expected reduction in atherosclerotic cardiovascular disease events when added to statin therapy. Although some patients experience injection-site reactions of mild or moderate severity, current evidence suggests a strong safety profile with total and serious adverse events approximating that of placebo. The dosing protocol of inclisiran offers its biggest clinical advantage over PCSK9-inhibiting monoclonal antibodies, being administered only every 6 months after initial baseline and 3-month doses rather than every second or fourth week. Unlike PCSK9-inhibiting monoclonal antibodies, inclisiran has not as yet been noted to induce neutralizing antidrug antibodies that can impact drug efficacy. Thus, inclisirin is a novel small interfering RNA molecule that provides further options in the management of hypercholesterolemia refractory to statins alone. However, cost and evidence considerations suggest it should not supplant adjunctive therapy with the PCSK9-inhibiting monoclonal antibodies, despite having an efficacy, safety, tolerability, and drug interaction profile superior to other antihypercholesterolemic options such as lomitapide, niacin, bile acid sequestrants, and bempedoic acid.

Familial hypercholesterolemia in China requires greater efforts

Familial hypercholesterolemia in China requires greater efforts

The Role of Non-statin Lipid-Lowering Medications in Youth with Hypercholesterolemia.

Lifestyle modification is additive to lipid-lowering medications in the treatment of heterozygous familial hypercholesterolemia (HeFH), which does not respond sufficiently to statin therapy. While both are also important in homozygous familial hypercholesterolemia (HoFH), additional measures such as apheresis may be needed. The purpose of this review is to identify non-statin medications to lower cholesterol that are available for children and adolescents as adjunctive therapy. Ezetimibe is commonly used as second-line pharmacotherapy for treatment of HeFH and HoFH. Colesevelam, a bile acid sequestrant, may be considered for adjunct therapy. Since 2015, the PCSK9 inhibitor evolocumab has been available for adolescents, and its FDA approval has now expanded to age 10years. The ANGPTL3 inhibitor evinacumab has been approved for children age 12years and older. A clinical trial for lomitapide is in progress. Approvals for PCSK9 and ANGPTL3 inhibitors have expanded opportunities for children and adolescents with HeFH and HoFH to achieve lower LDL-C levels.