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Sitosterolemia is an autosomal recessive and very rare disease. Its main characteristic is that there is a greater absorption and a decrease in the excretion of sterols, which leads to them being deposited in tissues. It is given by mutations in the ABCG5 or ABCG8 genes found on chromosome 2p21. In this clinical note, we describe the first two patients with familial sitosterolemia described in Colombia, brothers, one of them with xanthomas in extremities as the only symptom, and the other, completely asymptomatic. Genetic studies were performed as a diagnostic test in both patients, where a pathogenic homozygous variant could be identified in the ABCG8 gene in the first case (symptomatic), and a heterozygous variant in the ABCG8 gene in the second case (asymptomatic); the first patient has responded to treatment with ezetimibe. In conclusion, xanthomas should be studied in depth in pediatric age as they may be the only visible sign of such complex and hereditary diseases as familial sitosterolemia, which can be controlled and prevent cardiovascular complications of the disease., (Copyright © 2024 Sociedad Española de Arteriosclerosis. Publicado por Elsevier España, S.L.U. All rights reserved.)

Objective: We questioned whether the baseline status of low-density lipoprotein cholesterol (LDL-C), cholesterol synthesis and absorption, and the changes in these parameters determine the change in serum LDL-C under statin or ezetimibe treatment or under combination treatment., Materials and Methods: 37 mildly hypercholesterolemic healthy male subjects were studied under placebo, simvastatin (20 mg/d), ezetimibe (10 mg/d), and combination treatment. We correlated the change of LDL-C (ΔLDL-C) under treatment with the placebo end values of LDL-C (baseline), whole-body cholesterol synthesis, and hepatic cholesterol synthesis (serum lathosterol to cholesterol ratio) as well as fractional absorption rate (FAR) of cholesterol and serum campesterol to cholesterol ratio. The change in serum LDL-C was also correlated with the changes in synthesis and absorption parameters., Results: ΔLDL-C was highly negatively related to baseline LDL-C under ezetimibe (p < 0.0001), simvastatin (p < 0.0001), and combination treatment (p < 0.0001). Under combination treatment, LDL-C lowering appears possible from baseline values of 10 mg/dL upwards, while ΔLDL-C was independent of the baseline value (-50 to -60%). ΔLDL-C was positively associated with placebo FAR under ezetimibe (p = 0.0106) and combination treatment (p = 0.0457). No associations were found between ΔLDL-C and baseline values for synthesis nor between ΔLDL-C and changes in synthesis and absorption surrogate markers., Conclusion: Under ezetimibe, simvastatin, and combination treatment, ΔLDL-C is predominantly dependent on the baseline LDL-C concentration. We hypothesize that the concentration gradient between serum LDL-C and hepatic cellular cholesterol determines the efficiency of serum LDL-C lowering. Combination treatment is the preferred treatment.

Over the last decade, several innovative therapeutic options have been developed and marketed for the management of hypercholesterolemia. However, the impossibility of a contextual update of international guidelines and the limits imposed by national regulatory authorities do not allow the use of these treatments in many patients, in particular in those at higher cardiovascular risk. Real-world studies show that the use of lipid-lowering therapies is inadequate even among patients at higher cardiovascular risk, with only 20% achieving recommended low-density lipoprotein cholesterol (LDL-C) levels and the use of combination therapies implemented in only 24% of patients. This review aims to highlight the benefits of an approach based on combination therapy and to propose a therapeutic algorithm that includes oral combination therapy, where necessary also in triple association (statin, ezetimibe and bempedoic acid), as an initial approach based on the most favorable cost-effectiveness ratio for patients at higher cardiovascular risk and the use of injectable anti-proprotein convertase subtilisin/kexin 9 therapies if the recommended LDL-C goal is not achieved.

Ezetimibe is a cholesterol absorption inhibitor that blocks the intestinal absorption of both biliary and dietary cholesterol, thereby lowering primarily low density lipoprotein-cholesterol (LDL-chol) in human studies. This study aimed to investigate the effects of ezetimibe on dyslipidemia control in nine dogs with hypercholesterolemia. Changes in total cholesterol (T-chol) and each lipoprotein fractions were evaluated at 0, 2, and 4 months following initiation of ezetimibe treatment. A significant decrease in T-chol was observed, and a mean T-chol concentration below 400 mg/dL was achieved at 2 and 4 months. Furthermore, a significant decrease in LDL-chol was observed (-53.3% and -64.3% at 2 and 4 months, respectively). Taken together, treatment of ezetimibe could lower LDL-chol levels in dogs with hypercholesterolemia.

Background: Heterozygous 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., Objective: Here, we describe treatment patterns and LDL-C goal attainment in pediatric HeFH using longitudinal real-world data., Methods: This 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., Results: We 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., Conclusion: Pediatric 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., Competing Interests: Declaration of competing interest • NP has received honoraria from ADEN-ALLP, Alexion AMGEN, Amryt, Biocodex, Elsevier, Kowa, Lactalis, Nestlé NHS, NHC, Nutricia-Danone, Orphan Europ, Sanofi, Shire, Ultragenyx • PT has participated in one scientific committee at Ultragenyx laboratories • YP has received honoraria from Servier, Viatris, AMGEN, Sanofi, Bouchara-Recordati • JPR has received remuneration from Sanofi, Ultragenyx • EB has received honoraria from AstraZeneca, AMGEN, MSD, Sanofi and Regeneron, Aegerion/Amryt, Lilly, Ionis-pharmaceuticals, Akcea, Alexion pharma, Servier, Novartis, Mylan/Viatris, Organon and Genfit • AG reports grants and personal fees from AMGEN, Sanofi, Regeneron, Mylan Viatris, MSD, Akcea Therapeutics, Amryt and Ultragenyx. • SB has received honoraria for board, conferences, clinical trial or congress from Aegerion, Akcea, Elivie, Novartis, Sanofi or AMGEN • PP, LR, AV, RR have no conflict of interest related to this article., (Copyright © 2024 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.)

Objectives: Chronic low-grade inflammation is widely recognized as a pathophysiological defect contributing to β-cell failure in type 2 diabetes mellitus (T2DM). Statin therapy is known to ameliorate CD8+ T cell senescence, a mediator of chronic inflammation. However, the additional immunomodulatory roles of ezetimibe are not fully understood. Therefore, we investigated the effect of statin or statin/ezetimibe combination treatment on T cell senescence markers., Methods: In this two-group parallel and randomized controlled trial, we enrolled 149 patients with T2DM whose low-density lipoprotein cholesterol (LDL-C) was 100 mg/dL or higher. Patients were randomly assigned to either the rosuvastatin group (N=74) or the rosuvastatin/ezetimibe group (N=75). The immunophenotype of peripheral blood mononuclear cells and metabolic profiles were analyzed using samples from baseline and post-12 weeks of medication., Results: The fractions of CD8+CD57+ (senescent CD8+ T cells) and CD4+FoxP3+ (T reg ) significantly decreased after intervention in the rosuvastatin/ezetimibe group (-4.5 ± 14.1% and -1.2 ± 2.3%, respectively), while these fractions showed minimal change in the rosuvastatin group (2.8 ± 9.4% and 1.4 ± 1.5%, respectively). The degree of LDL-C reduction was correlated with an improvement in HbA1c (R=0.193, p =0.021). Changes in the CD8+CD57+ fraction positively correlated with patient age (R=0.538, p =0.026). Notably, the fraction change in senescent CD8+ T cells showed no significant relationship with changes in either HbA1c ( p =0.314) or LDL-C ( p =0.592). Finally, the ratio of naïve to memory CD8+ T cells increased in the rosuvastatin/ezetimibe group ( p =0.011), but not in the rosuvastatin group ( p =0.339)., Conclusions: We observed a reduction in senescent CD8+ T cells and an increase in the ratio of naive to memory CD8+ T cells with rosuvastatin/ezetimibe treatment. Our results demonstrate the immunomodulatory roles of ezetimibe in combination with statins, independent of improvements in lipid or HbA1c levels., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ju, Lim, Song, Kim, Kang, Yi, Joung, Lee, Kim and Ku.)

Objective: To enhance the detection, management and monitoring of Chinese children afflicted with sitosterolemia by examining the physical characteristics and genetic makeup of pediatric patients., Methods: In this group, 26 children were diagnosed with sitosterolemia, 24 of whom underwent genetic analysis. Patient family medical history, physical symptoms, tests for liver function, lipid levels, standard blood tests, phytosterol levels, cardiac/carotid artery ultrasounds, fundus examinations, and treatment were collected., Results: The majority (19, 73.1%) of the 26 patients exhibited xanthomas as the most prevalent manifestation. The second most common symptoms were joint pain (7, 26.9%) and stunted growth (4, 15.4%). Among the 24 (92.3%) patients whose genetics were analyzed, 16 (66.7%) harbored ABCG5 variants (type 2 sitosterolemia), and nearly one-third (8, 33.3%) harbored ABCG8 variants (type 1 sitosterolemia). Additionally, the most common pathogenic ABCG5 variant was c.1166G > A (p.Arg389His), which was found in 10 patients (66.7%). Further analysis did not indicate any significant differences in pathological traits among those carrying ABCG5 and ABCG8 variations (P > 0.05). Interestingly, there was a greater abundance of nonsense variations in ABCG5 than in ABCG8 (P = 0.09), and a greater frequency of splicing variations in ABCG8 than ABCG5 (P = 0.01). Following a change in diet or a combination of ezetimibe, the levels of cholesterol and low-density lipoprotein were markedly decreased compared to the levels reported before treatment., Conclusion: Sitosterolemia should be considered for individuals presenting with xanthomas and increased cholesterol levels. Phytosterol testing and genetic analysis are important for early detection. Managing one's diet and taking ezetimibe can well control blood lipids., (© 2024. The Author(s).)

Aim: Ezetimibe administration with ongoing statin therapy is an effective option for further lowering low-density lipoprotein cholesterol (LDL-C) levels. Thus, we investigated the long-term efficacy and safety of fixed-dose combination of pitavastatin/ezetimibe (K-924 LD: 2 mg/10 mg; K-924 HD: 4 mg/10 mg)., Methods: We conducted a phase III, multicenter, open-label trial involving patients with hypercholesterolemia receiving pitavastatin (2 or 4 mg) who had not achieved their LDL-C management target. Patients were enrolled into the K-924 LD and HD groups based on whether they had received pitavastatin 2 and 4 mg, respectively, and treated for 52 weeks. K-924 was administered orally once daily. The primary objective was to examine the percent change in LDL-C from baseline at week 52 with last observation carried forward imputation (LOCF) in all patients., Results: Of the 109 patients evaluated, 62 and 47 were assigned to the K-924 LD and HD groups, respectively. In all patients, LDL-C decreased by -30.3±14.3% (p＜0.001) from baseline (134.4±37.9 mg/dL). Consequently, 91.8% and 37.5% of the patients for primary and secondary prevention reached their LDL-C management target, respectively. These results were consistent in both the K-924 LD and HD groups. In the safety analysis, a single adverse drug reaction occurred in a patient in the K-924 HD group., Conclusion: After replacing pitavastatin monotherapy, K-924 was found to be effective and well-tolerated over 52 weeks. Thus, K-924 can contribute to intensifying LDL-C-lowering therapy without increasing the number of medications.

Background: Higher cholesterol absorption has been reported to be related to a higher incidence of cardiovascular events (CVEs). The KEEP (Kyushu Elderly Ezetimibe Phytosterol) study, a substudy of the EWTOPIA 75 (Ezetimibe Lipid-Lowering Trial on Prevention of Atherosclerotic Cardiovascular Disease in 75 or Older) study, investigated the relationships of cholesterol absorption and synthesis markers with CVEs in older old individuals with hypercholesterolemia, particularly in relation to ezetimibe treatment., Methods and Results: Eligible patients were those aged ≥75 years who had low-density lipoprotein cholesterol ≥140 mg/dL, no history of coronary artery disease, and no recent use of lipid-lowering drugs. Participants were randomly assigned into a diet-only or diet-plus-ezetimibe group. Baseline and 24-week follow-up blood samples were analyzed for cholesterol absorption (eg, campesterol) and synthesis markers (eg, lathosterol). Of 1287 patients, 1061 patients with baseline measurement were analyzed. Over a median follow-up of 4.0 years, 64 CVEs occurred. Higher campesterol levels at baseline were significantly associated with a lower risk of CVEs. After adjustment for sex, age, and treatment, the hazard ratios for the lowest to highest quartile categories of baseline campesterol were 1.00 (reference), 0.59 (95% CI, 0.30-1.17), 0.44 (95% CI, 0.21-0.94), and 0.44 (95% CI, 0.21-0.93), respectively (trend P =0.01). This association persisted after further adjustment for hypertension, diabetes, and other cardiovascular risk factors. Neither interactions with ezetimibe treatment nor mediating effects of the changes in cholesterol absorption markers were observed., Conclusions: The KEEP study indicated that higher campesterol levels without lipid-lowering drugs were associated with a lower incidence of CVEs in older old individuals with hypercholesterolemia who were subsequently treated with diet or ezetimibe., Registration: URL: https://www.umin.ac.jp; unique identifier: UMIN000017769.

"The lower, the better" is the recommended approach in the management of high LDL cholesterol. Unfortunately, this does not always achieve as in the case of a 69-year-old woman referred to our Institute for her lipid profile (LDL cholesterol 412mg/dl), bilateral xanthelasma and cutaneous xanthomas. With a maximized and personalized lipid-lowering therapies (rosuvastatin, ezetimibe, PCSK9i and lipoprotein apheresis), after only six months, the patient showed an impressive regression in her cutaneous xanthomas., (Copyright © 2023 Sociedad Española de Arteriosclerosis. Publicado por Elsevier España, S.L.U. All rights reserved.)

Introduction: Many patients with primary hypercholesterolemia do not achieve their plasma low-density lipoprotein cholesterol (LDL-C) goals with statin alone under a recommended dose of statin (e.g., 10 mg rosuvastatin) in China. The objective of this phase III study was to evaluate the efficacy and safety of a new single-pill combination (SPC) of rosuvastatin 10 mg/ezetimibe 10 mg (R10/E10) in this population., Methods: This was a randomized, double-blind, double-dummy, active-controlled study in patients with primary hypercholesterolemia inadequately controlled with statin alone. The participants were randomized 1:1 to receive SPC R10/E10 or R10. The primary objective was to demonstrate the superiority of SPC R10/E10 vs. R10 in reducing the LDL-C levels after 8 weeks., Results: This trial randomized 305 participants to SPC R10/E10 (n = 153) and R10 (n = 152). The superiority of SPC R10/E10 over R10 was demonstrated with the least square (LS) mean difference of percent change in LDL-C from baseline to week 8: - 13.85% (95% confidence interval [CI] - 20.15% to - 7.56%, P < 0.0001). The proportion of participants who achieved the LDL-C target (< 2.6 mmol/l) at week 8 was larger with SPC R10/E10 (n = 80, 54.1%) than with R10 (n = 42, 29.2%) (Odds ratio = 2.80, 95% CI 1.70 to 4.61, P < 0.0001). No unexpected safety findings were reported., Conclusion: The results suggest that SPC R10/E10 improve LDL-C reduction and goal achievement in Chinese patients with primary hypercholesterolemia not adequately controlled on statin therapy, without new safety findings., Trial Registration: ClinicalTrials.gov (NCT04669041)., (© 2023. The Author(s).)

Background: We compared the efficacy and safety of low-intensity atorvastatin and ezetimibe combination therapy with moderate-intensity atorvastatin monotherapy in patients requiring cholesterol-lowering therapy., Methods: At 19 centers in Korea, 290 patients were randomized to 4 groups: atorvastatin 5 mg and ezetimibe 10 mg (A5E), ezetimibe 10 mg (E), atorvastatin 5 mg (A5), and atorvastatin 10 mg (A10). Clinical and laboratory examinations were performed at baseline, and at 4-week and 8-week follow-ups. The primary endpoint was percentage change from baseline in low-density lipoprotein (LDL) cholesterol levels at the 8-week follow-up. Secondary endpoints included percentage changes from baseline in additional lipid parameters., Results: Baseline characteristics were similar among the study groups. At the 8-week follow-up, percentage changes in LDL cholesterol levels were significantly greater in the A5E group (49.2%) than in the E (18.7%), A5 (27.9%), and A10 (36.4%) groups. Similar findings were observed regarding the percentage changes in total cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B levels. Triglyceride levels were also significantly decreased in the A5E group than in the E group, whereas high-density lipoprotein levels substantially increased in the A5E group than in the E group. In patients with low- and intermediate-cardiovascular risk, 93.3% achieved the target LDL cholesterol levels in the A5E group, 40.0% in the E group, 66.7% in the A5 group, and 92.9% in the A10 group. In addition, 31.4% of patients in the A5E group, 8.1% in E, 9.7% in A5, and 7.3% in the A10 group reached the target levels of both LDL cholesterol < 70 mg/dL and reduction of LDL ≥ 50% from baseline., Conclusions: The addition of ezetimibe to low-intensity atorvastatin had a greater effect on lowering LDL cholesterol than moderate-intensity atorvastatin alone, offering an effective treatment option for cholesterol management, especially in patients with low and intermediate risks., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background and Objectives : Lipid-lowering agents such as ezetimibe are recommended in uncontrolled hyperlipidemia for primary and secondary prevention of cardiovascular disease. Carotid intima-media thickness (CIMT) is a surrogate marker of atherosclerosis and a predictor of cardiovascular and cerebral events. The effects of ezetimibe on CIMT have been inconsistently reported. The aim of this meta-analysis is to compare the effects of ezetimibe/statin and statin alone therapies on CIMT reduction. Materials and Methods : The PubMed, Embase, and Cochrane library databases were searched for randomized controlled trials (RCTs) published prior to 26 January 2023 with the MeSH keywords 'Ezetimibe' and 'Carotid Intima-Media Thickness'. The results were presented as standard mean difference (SMD) with 95% confidence intervals using the random-effect model method, and heterogeneity was assessed. Subgroup, meta-regression, and sensitivity analyses were conducted. Results : Five RCTs with 642 participants were included. CIMT reduction was not significantly different between the ezetimibe/statin and statin alone groups. However, in subgroup analyses, CIMT in the ezetimibe/statin group was significantly reduced in patients with non-familial hypercholesterolemia (SMD: -0.34 mm and p = 0.002) and in patients with secondary prevention (SMD: -0.38 mm and p = 0.002). The low-density lipoprotein cholesterol level was significantly reduced in the ezetimibe/statin group (SMD: -0.58 mg/dL and p < 0.001). Conclusions : The effect of ezetimibe on CIMT reduction was shown in non-familial hypercholesterolemia and secondary prevention. These results suggest that the efficacy of ezetimibe may vary with potential CIMT reduction benefits in certain subpopulations.

Competing Interests: Conflicts of interest The authors declare no conflicts of interest.

Introduction and Objective: The cardiovascular prevention strategy by autonomous communities can be variable since the competences in health are transferred. The objective of the study was to determine the degree of dyslipidaemia control and the lipid-lowering pharmacological therapy used in patients at high/very high cardiovascular risk (CVR) by autonomous communities., Methods: Observational, cross-sectional, descriptive study based on a consensus methodology. Information on the clinical practice of 145 health areas belonging to 17 Spanish autonomous communities was collected through face-to-face meetings and questionnaires administered to the 435 participating physicians. Furthermore, aggregate non-identifiable data were compiled from 10 consecutive dyslipidaemic patients that each participant had recently visited., Results: Of the 4010 patients collected, 649 (16%) had high and 2458 (61%) very high CVR. The distribution of the 3107 high/very high CVR patients was balanced across regions, but there were inter-regional differences (P<.0001) in the achievement of target LDL-C <70 and <55mg/dL, respectively. High-intensity statins in monotherapy or in combination with ezetimibe and/or PCSK9 inhibitors were used in 44, 21 and 4% of high CVR patients, while in those at very high CVR it rose to 38, 45 and 6%, respectively. The use of these lipid-lowering therapies at national level was significantly different between regions (P=.0079)., Conclusions: Even though the distribution of patients at high/very high CVR was similar between autonomous communities, inter-territorial differences were identified in the degree of achievement of LDL cholesterol therapeutic goal and use of lipid-lowering therapy., (Copyright © 2023 Sociedad Española de Arteriosclerosis. Publicado por Elsevier España, S.L.U. All rights reserved.)

Pharmacological reduction of LDL-cholesterol (LDL-C) is a major treatment strategy in limiting atherosclerotic cardiovascular (ASCVD) risk. Statins remain the primary therapeutic cornerstone in ASCVD prevention. Furthermore, ezetimibe, bempedoic acid, and PCSK9 inhibition have recently also shown to reduce cardiovascular risk. Unfortunately, a treatment gap remains between guideline-recommended LDL-C goals and what is achieved in real-world practice. An important reason for this is the limited use of novel and effective non-statin lipid-lowering therapies. In order to achieve LDL-C treatment goals and, ultimately, reduction of cardiovascular events, a combination lipid-lowering therapy needs to be considered as the standard of care for patients at very high cardiovascular risk., Competing Interests: D. Sinning hat Vortrags- bzw. Beratungshonorare von Amgen, Sanofi-Aventis, Daiichi-Sankyo, Novartis und Berlin-Chemie Menarini erhalten. U. Landmesser hat Vortrags- bzw. Beratungshonorare von Amgen, Sanofi-Aventis, Daiichi-Sankyo, Novartis, Medicines Company, Bayer, NovoNordisc und Berlin-Chemie Menarini erhalten., (Thieme. All rights reserved.)

Background and Aims: We aimed to understand the impact of physicians' perception about LDL-cholesterol (LDLc) control on the management of patients with dyslipidemia in Spain., Methods: We performed a cross-sectional and multicenter study, in which 435 healthcare professionals participated in face-to-face meetings, collecting qualitative and quantitative information related to hypercholesterolemia management. Additionally, aggregated anonymized data of the last 10 patients with hypercholesterolemia attended by each physician were collected., Results: A total of 4,010 patients (8%, 13%, 16% and 61% with low, moderate, high, and very high cardiovascular [CV] risk) were included. Physicians' perception was that 62% of their patients attained LDLc goals (66%, 63%, 61% and 56%, for low, moderate, high and very high CV risk, respectively). However, when looking into the data only 31% (vs 62% p<0.01) of patients attained the LDLc goals (47%, 36%, 22% and 25%, respectively). Overall, 33% of patients were taking high intensity statins, 32% statin/ezetimibe, 21% low/moderate intensity statins and 4% PCSK9 inhibitors. These numbers were 38%, 45%, 8% and 6% for very high risk patients and 44%, 21%, 21% and 4% for high CV risk patients. In 32% of patients, a change in lipid lowering therapy was performed after the visit, mainly combining statins/ezetimibe (55%)., Conclusions: In Spain, most patients with dyslipidemia do not achieve the recommended LDLc goals because of an insufficient intensification of lipid lowering therapy. On the one hand, this is in part due to physicians misperception on preventive LDLc control and the need for repeated advice to patient, and, on the other, to the lack of patient adherence., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Juan Cosin-Sales: has received conference fees from Almirall, Amgen, Daiichi-Sankyo, Ferrer, MSD, Novartis, Organon, Rovi and Sanofi; has participated in advisory services for Almirall, Amgen, MSD and Sanofi; and has received research grants from Amgen, Ferrer, MSD and Sanofi. Raquel Campuzano: has received conference fees from Amgen, Daiichi-Sankyo, Ferrer, Mylan, MSD, Organon, Sanofi, Servier and Novartis; has participated in advisory services for Novartis, Amgen, Sanofi and Servier; and has received collaborations to scientific or research projects from Amgen, Daiichi-Sankyo, Ferrer, Organon, Servier and Novartis. José Luis Díaz: has received fees for presentations, advisory services or scientific collaborations from Amgen, Bayer, Boëringher, BMS, Lilly, MSD, Mylan, Novartis, Novo-Nordisk, Pfizer, Rovi, Rubió, Sanofi, Daiichi-Sankyo and Servier. Carlos Escobar: has received fees for conferences/advisory services from: Almirall, Amgen, Daiichi-Sankyo, Esteve, Ferrer, MSD, Novartis, Organon, Rovi, Sanofi, Servier and Viatris. María Rosa Fernández: has received fees for conferences from Amgen, Sanofi, Ferrer, Daiichi-Sankyo, Organon and Rovi; has participated in advisory services for Novartis, Amgen, Sanofi and Amarin. Juan José Gómez-Doblas: has received fees for conferences from Amgen, Sanofi, Daiichi-Sankyo, Organon and MSD; has participated in advisory services for Amgen, Sanofi and Amarin; and has received collaborations to scientific or research projects from Amgen, Sanofi, Ferrer and Daiichi-Sankyo. José María Mostaza: has participated in advisory services and/or conferences, or has carried out projects for Pfizer, Amarin, Ferrer, Sanofi, Amgen, Alter, Servier, Novartis and Daiichi-Sankyo. Juan Pedro-Botet: has received fees for conferences from Amarin, Amgen, Daiichi-Sankyo, Esteve, MSD, Sanofi and Viatris; and has participated in advisory services for Amarin, Amgen, Daiichi-Sankyo, Esteve, Ferrer, Sanofi and Viatris. Núria Plana: has received fees for conferences from Amgen, Sanofi, Daiichi-Sankyo Mylan and Alexion. Pedro Valdivielso: has received fees for conferences from Amgen, Sanofi, Ferrer, Amarin, Akcea, Sobi, MSD, Novartis and Daiichi-Sankyo; has participated in advisory services for Daiichi-Sankyo, Amgen, Sanofi, Akcea and Amarin; and has received research grants from Ferrer and Akcea., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: A decade ago, systemic inflammation became widely recognized as an etiology of type 2 diabetes mellitus (T2DM) and complications thereof. Senescent CD8 + T cells of T2DM patients exhibit increased secretion of pro-inflammatory cytokines and enhanced expression of cytotoxic molecules, contributing to systemic inflammation. Recently, many anti-inflammatory roles played by statins and ezetimibe (cholesterol-lowering drugs) have been reported. We will explore the effects of statin/ezetimibe therapy on CD8 + T cell senescence in patients with T2DM and hypercholesterolemia., Methods: This 2-group, parallel, randomized, controlled clinical trial will recruit 108 subjects with T2DM and low-density lipoprotein-cholesterol (LDL-C) levels ≥100 mg/dL and randomly assign them to rosuvastatin/ezetimibe and rosuvastatin groups at a 1:1 ratio. Blood samples will be drawn at baseline and after 12 weeks of medication. The primary outcomes will be the LDL-C-lowering effects after 12 weeks. The secondary outcomes will be changes in the senescent (CD28 - CD57+) CD8 + T cell proportions; the levels of circulating pro-inflammatory cytokines, cytotoxic molecules, interleukin-1, transforming growth factor-β, fasting glucose, and HbA1c; and biochemical indices of kidney, liver, and muscle function. Symptoms and signs of predictable adverse events (myopathy and hepatitis) will be routinely monitored., Discussion: We will evaluate the effects of statin/ezetimibe on CD8 + T cell senescence. Statin/ezetimibe may exert a beneficial immunomodulatory effect., Competing Interests: The authors have no conflicts of interest to disclose, (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Lipoprotein(a) is a presumed risk factor for atherosclerotic cardiovascular disease. Olpasiran is a small interfering RNA that reduces lipoprotein(a) synthesis in the liver., Methods: We conducted a randomized, double-blind, placebo-controlled, dose-finding trial involving patients with established atherosclerotic cardiovascular disease and a lipoprotein(a) concentration of more than 150 nmol per liter. Patients were randomly assigned to receive one of four doses of olpasiran (10 mg every 12 weeks, 75 mg every 12 weeks, 225 mg every 12 weeks, or 225 mg every 24 weeks) or matching placebo, administered subcutaneously. The primary end point was the percent change in the lipoprotein(a) concentration from baseline to week 36 (reported as the placebo-adjusted mean percent change). Safety was also assessed., Results: Among the 281 enrolled patients, the median concentration of lipoprotein(a) at baseline was 260.3 nmol per liter, and the median concentration of low-density lipoprotein cholesterol was 67.5 mg per deciliter. At baseline, 88% of the patients were taking statin therapy, 52% were taking ezetimibe, and 23% were taking a proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor. At 36 weeks, the lipoprotein(a) concentration had increased by a mean of 3.6% in the placebo group, whereas olpasiran therapy had significantly and substantially reduced the lipoprotein(a) concentration in a dose-dependent manner, resulting in placebo-adjusted mean percent changes of -70.5% with the 10-mg dose, -97.4% with the 75-mg dose, -101.1% with the 225-mg dose administered every 12 weeks, and -100.5% with the 225-mg dose administered every 24 weeks (P&lt;0.001 for all comparisons with baseline). The overall incidence of adverse events was similar across the trial groups. The most common olpasiran-related adverse events were injection-site reactions, primarily pain., Conclusions: Olpasiran therapy significantly reduced lipoprotein(a) concentrations in patients with established atherosclerotic cardiovascular disease. Longer and larger trials will be necessary to determine the effect of olpasiran therapy on cardiovascular disease. (Funded by Amgen; OCEAN[a]-DOSE ClinicalTrials.gov number, NCT04270760.)., (Copyright © 2022 Massachusetts Medical Society.)

Soluble epidermal growth factor receptor (sEGFR) levels are elevated in patients with type 2 diabetes mellitus (T2DM) and positively correlate with blood glucose and cholesterol levels. However, how cholesterol-lowering treatment in patients with T2DM affects the sEGFR level is unknown. Therefore, we investigated the change of serum sEGFR after cholesterol-lowering treatment in type 2 diabetic patients with hypercholesterolemia. This study is a non-randomized, prospective observational study. A total of 115 patients were treated in either the rosuvastatin monotherapy group (R group, 5 mg/day, n = 59) or the rosuvastatin/ezetimibe combination therapy group (RE group, 5 mg/10 mg/day, n = 56) for 12 weeks. We measured serum levels of lipids and sEGFR using an ELISA kit before and after 12 weeks of treatment in each group. The low-density lipoprotein cholesterol (LDL-C) level was significantly reduced (from 130.27 ± 27.09 to 76.24 ± 26.82 mg/dL; P < .001) after 12 weeks of treatment and more so in the RE group than in the R group (from 131.68 ± 28.72 to 87.13 ± 27.04 mg/dL, P < .001 in the R group; from 128.78 ± 25.58 to 64.75 ± 21.52 mg/dL, P < .001 in the RE group; R vs RE group, P < .001). The sEGFR level was significantly decreased after 12 weeks of treatment (from 50.34 ± 13.31 to 45.75 ± 11.54 ng/mL; P = .007). The RE group only showed a significant reduction in the sEGFR level after treatment (from 50.94 ± 12.10 to 44.80 ± 11.36 ng/mL; P = .007). Moreover, the sEGFR level was significantly reduced only when the LDL-C level was significantly reduced (from 50.46 ± 10.66 to 46.24 ± 11.86 ng/mL; P = .043). The serum sEGFR level was significantly reduced by cholesterol-lowering treatment with rosuvastatin alone or rosuvastatin/ezetimibe. We suggested that sEGFR may play a significant role in insulin resistance (IR) and inflammation, which are central pathophysiological mechanisms. We confirmed the possibility of using sEGFR as a biomarker to predict a good response to lipid-lowering treatment in type 2 diabetes patients with hypercholesterolemia., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

The last 50 years have experienced a rapid evolution in the development of lipid-lowering agents to reduce low-density lipoprotein cholesterol levels. This significant advance in medicine has not occurred without debate. Whether lowering blood cholesterol levels was beneficial has remained one of the most controversial issues during the past 50 years. The discovery of statins was the revolution that made it possible to delay and stop the progression of the atherosclerotic process resulting in improved health and longevity for millions of people. To date, statins remain the drugs of choice for the treatment of hypercholesterolemia. Despite their use, the risk of cardiovascular events persists. Therefore, the use of non-statin drugs, such as ezetimibe or PCSK9 inhibitors, in combination with statins has been shown to further reduce the risk of cardiovascular events. This review aims to summarize the advances in the field of lipid-lowering therapies over the past 50 years, focusing on advances in the development of drug therapies up to and including gene silencing or gene editing treatments that are expected in the near future.

Objective: Network meta-analysis was used to derive estimates of the relative efficacy of inclisiran, evolocumab, alirocumab, bempedoic acid, and ezetimibe in patients with hypercholesterolemia and/or at increased cardiovascular risk due to elevated low-density lipoprotein cholesterol taking maximum tolerated dose statins., Methods: Clinical trials published through February 2021 comparing percent change from baseline in low-density lipoprotein cholesterol were identified via a systematic review. Bayesian network meta-analyses were performed for patients with atherosclerotic cardiovascular disease and/or high cardiovascular risk on maximally tolerated statins in the base case, which included 23 trials., Results: Results from the base-case analyses demonstrated that inclisiran, evolocumab, and alirocumab provide superior efficacy over placebo, bempedoic acid, and ezetimibe in terms of reduction in low-density lipoprotein cholesterol. Inclisiran was also comparable to alirocumab (mean difference: 0.78% [95% CrI: -8.35, 9.88]) and evolocumab (8.16%, [95% CrI: -1.82, 18.49]). Findings of a scenario which also included trials conducted in patients with heterozygous familial hypercholesterolemia were consistent with the base case. There was evidence of statistical heterogeneity across the included trials, roughly equivalent to variation of 5-10% change in low-density lipoprotein cholesterol, suggesting that any differences between treatments that were greater than 5-10% are generalizable., Conclusions: This study provides insight regarding the comparative efficacy of drugs for which no head-to-head trials exist and suggests that inclisiran, alirocumab, and evolocumab are expected to provide similar clinically meaningful improvements in low-density lipoprotein cholesterol in patients with hypercholesterolemia on maximally tolerated statins who are at increased cardiovascular risk.

Background and Objective: To describe the clinical characteristics, the reasons for initiating therapy and the effects of treatment in the initial phase of evolocumab availability in the Nephrology Units of Spain., Material and Methods: Retrospective, observational and multicentric study that included patients initiating treatment with evolocumab (from February 2016 to August 2018), in 15 Nephrology Units in Spain. The demographic and clinical characteristics of the patients, the lipid lowering treatment and the evolution of the lipid profiles between 24 weeks pre-initiation and 12±4 weeks post-initiation of evolocumab were reviewed., Results: 60 patients were enrolled: 53.3% women; mean (SD) age, 56.9 (12.8) years, 45.0% with familial hypercholesterolemia (FH) (5.0% homozygous and 40.0% heterozygous) and 65.0% with atherosclerotic cardiovascular disease. The mean (SD) eGFR was 62.6 (30.0) ml/min/1.73m 2 (51.7% of patients had eGFR <60ml/min/1.73m 2 [CKD stage>2]), 50.0% had proteinuria (>300mg/g) and 10.0% had nephrotic syndrome. Other CV risk factors were hypertension (75.0%), diabetes (25.0%), and smoking (21.7%). A 40.0% of patients were statin intolerant. At evolocumab initiation, 41.7% of patients were on a high intensity statin, 18.3% on moderate intensity statin and 50.0% were receiving ezetimibe. Mean (SD) LDL-c at evolocumab initiation was 179.7 (62.9) mg/dL (53.4% of patients with LDL-c ≥160mg/dL and 29.3% ≥190mg/dL). After 12 weeks, evolocumab resulted in LDL-c reductions of 60.1%. At week 12, 90.0% of patients reached LDL-c levels <100mg/dL, 70.0% <70mg/dL, and 55.0% <55mg/dL, while mean eGFR levels and statin use remained stable., Conclusion: In Nephrology Units of Spain, evolocumab was predominantly prescribed in patients with FH, chronic renal disease (CRD>2) and secondary prevention, with LDL-c levels above those recommended by the guidelines. Evolocumab used in clinical practice significantly reduced the LDL-c levels in all patients included in the study., (Copyright © 2022. Published by Elsevier España, S.L.U.)

Background: The risk of cardiovascular disease in type 1 diabetes remains extremely high, despite marked advances in blood glucose control and even the widespread use of cholesterol synthesis inhibitors. Thus, a deeper understanding of insulin regulation of cholesterol metabolism, and its disruption in type 1 diabetes, could reveal better treatment strategies., Methods: To define the mechanisms by which insulin controls plasma cholesterol levels, we knocked down the insulin receptor, FoxO1, and the key bile acid synthesis enzyme, CYP8B1. We measured bile acid composition, cholesterol absorption, and plasma cholesterol. In parallel, we measured markers of cholesterol absorption and synthesis in humans with type 1 diabetes treated with ezetimibe and simvastatin in a double-blind crossover study., Results: Mice with hepatic deletion of the insulin receptor showed marked increases in 12α-hydroxylated bile acids, cholesterol absorption, and plasma cholesterol. This phenotype was entirely reversed by hepatic deletion of FoxO1 . FoxO1 is inhibited by insulin and required for the production of 12α-hydroxylated bile acids, which promote intestinal cholesterol absorption and suppress hepatic cholesterol synthesis. Knockdown of Cyp8b1 normalized 12α-hydroxylated bile acid levels and completely prevented hypercholesterolemia in mice with hepatic deletion of the insulin receptor (n=5-30), as well as mouse models of type 1 diabetes (n=5-22). In parallel, the cholesterol absorption inhibitor, ezetimibe, normalized cholesterol absorption and low-density lipoprotein cholesterol in patients with type 1 diabetes as well as, or better than, the cholesterol synthesis inhibitor, simvastatin (n=20)., Conclusions: Insulin, by inhibiting FoxO1 in the liver, reduces 12α-hydroxylated bile acids, cholesterol absorption, and plasma cholesterol levels. Thus, type 1 diabetes leads to a unique set of derangements in cholesterol metabolism, with increased absorption rather than synthesis. These derangements are reversed by ezetimibe, but not statins, which are currently the first line of lipid-lowering treatment in type 1 diabetes. Taken together, these data suggest that a personalized approach to lipid lowering in type 1 diabetes may be more effective and highlight the need for further studies specifically in this group of patients.

Objective: The protein encoded by mitogen-inducible gene 6 (MIG6) plays an essential role in the regulation of cholesterol homeostasis and bile acid synthesis in mice. However, the physiological functions of MIG6 remain poorly understood in humans. Therefore, we aimed to evaluate the relationship between the serum MIG6 concentration and low-density lipoprotein (LDL)-cholesterol in patients undergoing cholesterol-lowering treatment., Methods: We performed a non-randomized, prospective controlled trial. In total, 63 patients with type 2 diabetes and hypercholesterolemia were treated using either rosuvastatin monotherapy or rosuvastatin/ezetimibe combination therapy for 12 weeks. We then compared their serum lipid and MIG6 concentrations before and after treatment., Results: The serum LDL-cholesterol concentration of the participants significantly decreased and the concentration of MIG6 significantly increased during treatment. In addition, higher pre-treatment serum concentrations of MIG6 were associated with larger reductions in LDL-cholesterol, regardless of the therapeutic agent used., Conclusions: Serum MIG6 concentration significantly increases alongside the reduction in LDL-cholesterol achieved using cholesterol-lowering therapies in patients with diabetes and hypercholesterolemia. This is the first study to provide evidence that MIG6 may be involved in human cholesterol metabolism. CRIS registration number : KCT0003477. https://cris.nih.go.kr.

Cholesterol is an important component of cell membrane. However, elevated level of serum cholesterol is a key risk factor for heart disease. Niemann-Pick C1-Like 1 (NPC1L1) is the crucial target involving in cholesterol cellar uptake. Ezetimibe is the first, and only, NPC1L1 inhibitor approved for the treatment of hypercholesterolemia through decreasing cholesterol absorption for nearly two decades. That means that the development of NPC1L1 inhibitors encounters much challenge, as well as offers exciting therapeutic opportunities. Substantial efforts have been undertaken to develop NPC1L1 inhibitors. The present review describes the mechanism of cholesterol transport by NPC1L1, highlights the development of NPC1L1 inhibitors, and discusses the current challenges., Competing Interests: Declaration of competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Objective: In primary hypercholesterolemia many people treated with statins do not reach their plasma LDL-C goals and are at increased risk of cardiovascular disease (CVD). This study aimed to evaluate efficacy and safety of a new fixed-dose combination (FDC) formulation of rosuvastatin/ezetimibe (R/E) in this population., Methods: This was a multicenter, multinational, randomized, double-blind, double-dummy, active-controlled, parallel-arm study of FDC R/E in people with primary hypercholesterolemia at very high risk (VHR) or high risk (HR) of CVD, inadequately controlled with 20 mg or 10 mg stable daily dose of rosuvastatin or equipotent dose of another statin. The primary objective was to demonstrate superiority of FDC R/E versus rosuvastatin monotherapy uptitrated to 40 mg (R40) or 20 mg (R20) in reduction of LDL-C after 6 weeks., Results: Randomized VHR participants (n = 244) were treated with R40, R40/E10, or R20/E10; randomized HR participants (n = 208) received R10/E10 or R20. In VHR participants, superiority of R40/E10 and R20/E10 versus R40 was demonstrated on LDL-C percent change from baseline to Week 6 with least squares mean differences (LSMD) of -19.66% (95% CI: -29.48% to -9.84%; P < .001) and -12.28% (95% CI: -22.12% to -2.44%; P = .015), respectively. In HR participants, superiority of R10/E10 over R20 was not demonstrated (LSMD -5.20%; 95% CI: -15.18% to 4.78%; P = .306), despite clinically relevant LDL-C reduction with R10/E10. No unexpected safety findings were reported., Conclusions: The results from this study suggest that R/E FDCs improve LDL-C reduction and goal achievement in people with primary hypercholesterolemia inadequately controlled with statins and at VHR/HR of CVD.

Sitosterolemia is a rare form of dyslipidemia that has diverse clinical manifestations, and insufficient knowledge of the disease frequently leads to a delay in diagnosis. We report a case of sitosterolemia in a 26-year-old Chinese woman, characterized by anemia, thrombocytopenia, persistent hypercholesterolemia, premature atherosclerosis, extensive xanthoma, and arthralgia-tenosynovitis. Successive misdiagnoses of Evans syndrome and familial hypercholesterolemia had been made, and the patient had responded minimally to steroid therapy, splenectomy, and statin treatment; therefore, she was referred to our hospital. On admission, a peripheral blood smear revealed the presence of abnormally shaped erythrocytes and giant platelets. Multiple atherosclerotic lesions, sites of tenosynovitis, and carotid sheath xanthomas were identified on ultrasonography. Compound heterozygous mutations of the ABCG5 gene, including a hot variant (c.1,336, exon10 C>T, p.(R446*)) and a novel variant (c.1,325-3(IVS9)&#95;c.1325-2(IVS9)delCA) were separately identified in her parents by pedigree analysis. Plant sterols analysis by high performance liquid chromatography method revealed remarkably elevated plasma plant sterol concentrations after drug withdrawal but reduced rapidly after restarting ezetimibe during follow-up period. After 21 months of treatment with ezetimibe and a low-plant sterol diet, her hematologic abnormalities, tenosynovitis, and hypercholesterolemia had significantly improved; and ultrasonography showed that her skin and carotid sheath xanthomas had resolved or shrunk. This case demonstrates that morphological changes in blood cells on a peripheral blood smear, ultrasonographic findings and ABCG5/ABCG8 gene screening are valuable, and plant sterol analysis in serum is crucial to confirm diagnosis and assess treatment adequacy for sitosterolemia., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Purpose: We investigated whether the combination therapy of low-intensity rosuvastatin and ezetimibe is an useful alternative to moderate-intensity rosuvastatin monotherapy in patients requiring cholesterol-lowering therapy., Methods: This was a multicenter randomized, double-blind study to investigate the safety and efficacy of a fixed-dose combination of rosuvastatin 2.5 mg and ezetimibe 10 mg (R2.5+E10) compared to those of ezetimibe 10 mg monotherapy (E10), rosuvastatin 2.5 mg (R2.5), and rosuvastatin 5 mg monotherapy (R5) in patients with hypercholesterolemia. A total of 348 patients at 15 centers in Korea were screened, and 279 patients were randomized to different groups in the study. Clinical and laboratory examinations were performed at baseline and 4 and 8 weeks after intervention. The primary endpoint was the percentage change of low-density lipoprotein (LDL) cholesterol levels at the 8-week follow-up., Findings: Baseline characteristics were similar among the four groups. There were significant changes in lipid profiles at the 8-week follow-up. A greater decrease in the LDL cholesterol levels (primary endpoint) were found in the R2.5+E10 group (-45.7±18.6%) than in the E10 group (-16.7±14.7%, p<0.0001), R2.5 group (-32.6±15.1%, p<0.0001), and R5 group (-38.9±13.9%, p=0.0003). Similar outcomes were observed regarding the decrease in total cholesterol, non-high-density lipoprotein (HDL) cholesterol, and apolipoprotein B protein. In addition, changes in the triglyceride and HDL levels in the R2.5+E10 group were significantly different compared with those in the E10 group; however, the changes were similar to those in the other treatment groups. In patients with low and moderate risk, all patients achieved the target LDL cholesterol levels in the R2.5+E10 group (100%) compared to 13.0% in the E10 group, 47.6% in the R2.5 group, and 65.2% in the R5 group. Adverse effects were rare and similar in the four groups., Implications: Fixed-dose combination of low-intensity rosuvastatin and ezetimibe was more effective in lowering LDL cholesterol and achieving LDL cholesterol goals than moderate-intensity rosuvastatin monotherapy. These findings suggest that the combination therapy of low-intensity rosuvastatin and ezetimibe is an useful alternative to moderate-intensity rosuvastatin monotherapy for cholesterol management, particularly in patients with low and moderate risk. ClinicalTrials.gov identifier: NCT04652349., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction : Statins are powerful lipid-lowering agents which reduce cardiovascular (CV)-related morbidity and mortality. However, a large proportion of patients cannot attain the target low-density lipoprotein cholesterol (LDL-C) levels, despite receiving maximally tolerated doses of high-intensity statins. Also, adherence to treatment may be reduced due to statin-induced myopathy or other side effects. For these reasons, guidelines recommend adding the cholesterol absorption inhibitor ezetimibe. Areas covered : Authors discuss the main pharmacological characteristics of rosuvastatin and ezetimibe, their lipid-lowering and pleiotropic effects, as well as the clinical effects of the fixed dose combination of these drugs when used to treat dyslipidemia. Expert opinion : The rosuvastatin/ezetimibe combination is safe and effective in patients with hypercholesterolemia or dyslipidemia with or without diabetes and with or without cardiovascular disease. This drug combination enabled higher proportions of patients to achieve recommended LDL-C goals than rosuvastatin monotherapy or the simvastatin/ezetimibe combination, without additional adverse events. Despite the lack of additional CV outcomes data and comparisons with atorvastatin/ezetimibe, rosuvastatin/ezetimibe appears as a potent and generally well-tolerated drug combination eligible for the management of hypercholesterolemia and dyslipidemia in adults. Recently, the 40 mg rosuvastatin/10 mg ezetimibe fixed combination was approved and is also evaluated.

Autosomal recessive hypercholesterolemia (ARH) is a rare form of genetic hypercholesterolemia caused by mutations in low density lipoprotein receptor adaptor protein 1 (LDLRAP1). The proband first presented with linear eruptive xanthomas over her ankles, knees and elbows, with low density lipoprotein cholesterol (LDL-C) of 16.0 mmol/L (618.7 mg/dL), at 2.5 years old. Next generation sequencing revealed a novel homozygous mutation in LDLRAP1 exon 5 (c.466delG). In the first year, drug regimens of either cholestyramine or simvastatin, reduced her LDL-C to 10.5 mmol/L (406 mg/dL) and 11.7 mmol/L (452.4 mg/dL), respectively. Combination simvastatin and ezetimibe was the mainstay of therapy from age 5 - 10 years. Her lowest achieved LDL-C was 6.3 mmol/L (243.6 mg/dL). Switching to atorvastatin did not lead to further reduction. Carotid intima-media thickness was 0.47 mm (> 97 th percentile) and 0.32 mm (75 - 95 th percentile) at ages 8 years and 11 years, respectively. Addition of monthly injections of evolocumab for 3 months, led to an increase in LDL-C, from 7.0 mmol/L (270.7 mg/dL) to a range of [(8.4 - 9.1) mmol/L or (324.8 - 351.9) mg/dL]. In this report, a decade-long lipid management is described in a patient with ARH. Residual activity of LDLRAP1 is a likely determinant of her response. Clinical management remains sub-optimal and options for the paediatric population are limited. Novel classes of cholesterol-lowering medications are needed for this ultra-rare and severe hypercholesterolemia., (Copyright © 2021. Published by Elsevier Inc.)

What Is Known and Objectives: This study investigated the additional low-density lipoprotein cholesterol (LDL-C) reductions and target (LDL-C < 100 mg/dL) achievement rates in patients after switching from statin monotherapy to statin/ezetimibe combination therapy, in clinical practice., Methods: This retrospective study used data recovered from the electronic medical record systems of two tertiary care medical centres for patients treated between 2015 and 2017. Patients prescribed statin/ezetimibe combination therapy after switching from statin monotherapy were enrolled. The observed LDL-C reductions and the percentage of patients achieving LDL-C levels of <100 mg/dL, after 3 months of treatment, were assessed relative to baseline values., Results and Discussion: A total of 4252 patients with prescriptions for statin/ezetimibe combination therapy were enrolled. Changing from statin monotherapy to the combination therapy resulted in additional LDL-C level reductions of 31.0-41.0% (all intensity groups, P < .01). Similarly, 88.3-91.1% of the enrolled patients successfully achieved LDL-C levels of <100 mg/dL (all intensity groups, P < .01). A subgroup analysis of patients with baseline LDL-C levels ≥ 100 mg/dL showed that switching from moderate- or high-intensity statin monotherapy to a rosuvastatin/ezetimibe combination showed greater LDL-C reductions than did switching to an atorvastatin/ezetimibe combination, within the same statin intensity groups., What Is New and Conclusion: The present study provides real-world evidence of the LDL-C reduction benefits associated with statin/ezetimibe combinations in the clinical practice setting. The results also demonstrate that if statin monotherapy does not effectively help patients reach their target LDL-C goals, changing to a statin/ezetimibe combination prescription may show enhanced LDL-C-lowering effects and improve the likelihood of achieving LDL-C targets, in real practice., (© 2020 John Wiley & Sons Ltd.)

Background: In an attempt to improve low density lipoprotein-cholesterol (LDL-C) level control in patients ineffectively treated with statins, we evaluated the effectiveness of a fixed-dose combination (FDC) of 10 mg rosuvastatin and ezetimibe and its relation to the timing of drug administration., Methods: A randomized, open label, single center, crossover study involving 83 patients with coronary artery disease and hypercholesterolemia with baseline LDL-C ≥ 70 mg/dL. In arm I the FDC drug was administered in the morning for 6 weeks, then in the evening for the following 6 weeks and vice versa in arm II. The primary endpoint was the change in LDL-C after 6 and 12 weeks., Results: The median LDL-C concentration at baseline, after 6 and 12 weeks respectively was: 98.10 mg/dL (Q1;Q3: 85.10;116.80), 63.14 mg/dL (50.70;77.10) and 59.40 mg/dL (49.00;73.30); p < 0.001. LDL-C levels were similar regardless of the timing of drug administration (morning 62.50 mg/dL [50.70;76.00] vs. evening 59.70 mg/dL [48.20;73.80]; p = 0.259], in both time points: 6 week: 63.15 mg/dL (50.75;80.65) vs. 63.40 mg/dL (50.60;74.00), p = 0.775; and 12 week: 62.00 mg/dL (50.20;74.40) vs. 59.05 mg/dL (47.65;66.05), p = 0.362. The absolute change in LDL-C concentration for the morning vs. evening drug administration was - 6 week: -34.6 mg/dL (-56.55; -19.85) (-34.87%) vs. -31.10 mg/dL (-44.20; -16.00) (-35.87%) (p not significant); 12. week: -34.20 mg/dL (-47.8; -19.0) (-37.12%) vs. -37.20 mg/dL (-65.55; -23.85) (-40.06%) (p not significant). The therapy was safe and well tolerated., Conclusions: Fixed-dose combination of rosuvastatin and ezetimibe significantly and permanently decreases LDL-C regardless of the timing of drug administration.

Despite the widespread use of statins and ezetimibe to decrease low-density lipoprotein cholesterol (LDL-C) levels and associated atherosclerotic cardiovascular disease (ASCVD), many patients do not achieve adequate LDL-C lowering as per the recommended American College of Cardiology (ACC)/American Heart Association (AHA) and European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines and demonstrate residual cardiovascular risk. The introduction of proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors in 2015 was a promising addition to hypercholesterolemia therapies, but their cost and subcutaneous administration has limited their use, and therefore, new affordable and patient friendly treatment strategies are crucial to help reduce ASCVD risk. Bempedoic acid, a drug currently under investigation, is a small molecule that has been shown to upregulate LDL receptors, decrease LDL-C, and reduce atherosclerotic plaque formation in hypercholesterolemic patients. Furthermore, bempedoic acid is a prodrug that becomes activated by an enzyme expressed primarily in the liver, allowing it to avoid the potential myotoxicity associated with statin therapy. The purpose of this review is to summarize the major clinical studies evaluating bempedoic acid and describe its potential addition to currently approved lipid-lowering therapies.

Introduction: Statins are the first-line treatment to reduce cardiovascular (CV) events, mainly by reducing low-density-lipoprotein cholesterol (LDL-C), but many patients need additional treatments to reach the current lipid goals., Areas Covered: Herein, the authors review the published literature on the efficacy and safety of the therapies that are most often added to statins to achieve lipid targets., Expert Opinion: Ezetimibe is usually the first additional treatment to achieve LDL-C targets. It reduces LDL-C by about a further 20% and has an excellent safety and tolerability profile. The monoclonal antibody proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, evolocumab, and alirocumab, can reduce LDL-C by ≥50% when added to statins and they also have a well-established safety and tolerability record. The recently approved bempedoic acid is well tolerated and appears to be free of skeletal muscle-related problems, but the CV outcome study with this drug has not been completed. Inclisiran, a small-interfering RNA targeting PCSK9 is at an advanced stage of development and the available data indicate a satisfactory safety profile and LDL-C lowering efficacy similar to the PCSK9 monoclonal antibodies with the advantage of less frequent administration.

We herein report a rare case presenting with severe hypercholesterolemia, massive Achilles tendon xanthomas, and multi-vessel coronary artery disease. Initially, the patient was misdiagnosed with familial hypercholesterolemia. However, a genetic analysis using our custom sequencing panel covering genes associated with Mendelian lipid disorders revealed him to have a genetic basis of sitosterolemia with compound heterozygous mutations in the adenosine triphosphate binding cassette subfamily G5 (ABCG5) gene. A comprehensive genetic analysis can be particularly useful for diagnosing cases with severe phenotypes, leading to appropriate and medical therapies. Our patient was refractory to statins, whereas ezetimibe and PCSK9 inhibitor with a low-plant-sterol diet successfully reduced his serum levels of low-density lipoprotein cholesterol.

Sitosterolemia is caused by homozygous or compound heterozygous gene mutations in either ATP-binding cassette subfamily G member 5 (ABCG5) or 8 (ABCG8). Since ABCG5 and ABCG8 play pivotal roles in the excretion of neutral sterols into feces and bile, patients with sitosterolemia present elevated levels of serum plant sterols and in some cases also hypercholesterolemia. A 48-year-old woman was referred to our hospital for hypercholesterolemia. She had been misdiagnosed with familial hypercholesterolemia at the age of 20 and her serum low-density lipoprotein cholesterol (LDL-C) levels had remained about 200-300 mg/dL at the former clinic. Although the treatment of hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors was ineffective, her serum LDL-C levels were normalized by ezetimibe, a cholesterol transporter inhibitor. We noticed that her serum sitosterol and campesterol levels were relatively high. Targeted analysis sequencing identified a novel heterozygous ABCG5 variant (c.203A>T; p.Ile68Asn) in the patient, whereas no mutations were found in low-density lipoprotein receptor (LDLR), proprotein convertase subtilisin/kexin type 9 (PCSK9), or Niemann-Pick C1-like intracellular cholesterol transporter 1 (NPC1L1). While sitosterolemia is a rare disease, a recent study has reported that the incidence of loss-of-function mutation in the ABCG5 or ABCG8 gene is higher than we thought at 1 in 220 individuals. The present case suggests that serum plant sterol levels should be examined and ezetimibe treatment should be considered in patients with hypercholesterolemia who are resistant to HMG-CoA reductase inhibitors.

Statin therapy is the gold standard for hypercholesterolemia. However, a significant number of patients cannot achieve their target low-density lipoprotein (LDL) levels despite a maximal dose of statin therapy, and some cannot tolerate statins at all. Approval of proprotein convertase subtilisin/kexin type 9 inhibitors has been revolutionary for those patients. However, the need for frequent injections limits patient compliance with their use. Recently, a twice-yearly injection of inclisiran, a small interfering RNA, has been shown to inhibit hepatic synthesis of proprotein convertase subtilisin/kexin type 9. However, patient randomized clinical trial has been underpowered for clinical end points, necessitating a meta-analysis of those trials. The weighted mean difference was used to describe continuous variables, and pooled risk ratios, calculated using a random effects model, were used to describe discrete variables. Data from 3 randomized clinical trials comprising 3,660 patients showed that inclisiran decreased LDL cholesterol levels by 51% (95% Confidence Interval, 48 to 53%; p < 0.001) compared with placebo. It was associated with a 24% lower major adverse cardiovascular events rate (risk ratios = 0.76; 95% Confidence Interval, 0.61 to 0.92). It also significantly decreased total cholesterol by 37%, apolipoprotein B by 41%, and non high-density lipoprotein (HDL) cholesterol by 45% (all p < 0.001). No differences were found in adverse events, abnormalities in liver function tests, or creatine kinase levels between the treatment strategies. However, a mild injection site reaction occurred more frequently in the inclisiran group. In conclusions, in patients with hypercholesterolemia, inclisiran decreased LDL level by 51% without significant adverse effects. Additionally, it was associated with a lower major adverse cardiovascular event rate., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To present the first registry used to analyse the clinical profile of patients treated with evolocumab in Spain, including the effectiveness on the lipid profile and safety in the «real world» setting., Methods: Multicentre, retrospective, and observational study of patients starting treatment with evolocumab from February 2016 to May 2017 in clinical practice in Spanish cardiology units., Results: A total of 186 patients (mean age 60.3 ± 9.8 years were included, 35.5% with familial hypercholesterolaemia, and 94.1% with a previous cardiovascular event) from 31 cardiology units. Baseline lipid profile: Total cholesterol 219.4 ± 52.2 mg/dL, LDL-cholesterol 144.0 ± 49.0mg/dL, HDL-cholesterol 47.7 ± 13.0mg/dL, and triglycerides 151.0 ± 76.2mg/dL. At the time of initiating evolocumab, 53.8% of patients were taking statins (50% had partial or total intolerance to statins), and 51.1% ezetimibe. In all cases, the dose of evolocumab used was 140 mg, mainly every 2 weeks (97.3%). Evolocumab compliance was high (92.3%). Treatment with evolocumab was interrupted in 6 patients (3.2%), with only 1 (0.5%) due to a probable side effect. Evolocumab significantly reduced total cholesterol (30.9% at week 2, and 39.3% at week 12; P<.001), LDL cholesterol (44.4% and 57.6%, respectively; P<.001), and triglycerides (14.8% and 5.2%, respectively; P<001), with no significant changes in HDL-cholesterol (6.7% and 2.0%; P=.14)., Conclusions: In clinical practice, evolocumab is associated with reductions in LDL cholesterol, with nearly 60% after 12 weeks of treatment, and with low rates of interruptions due to side effects and high medication compliance. These results are consistent with those reported in randomised clinical trials., (Copyright © 2020. Publicado por Elsevier España, S.L.U.)

Aim: To compare the efficacy and safety of colesevelam and ezetimibe as second-line low density lipoprotein-cholesterol (LDL-c)-lowering options in type 2 diabetes (T2D)., Materials and Methods: GOAL-RCT is a 24-week, open-label, randomized, pragmatic clinical trial. Subjects with T2D with uncontrolled HbA1c (7.1%-10%) and LDL-c (>2.0 mmol/L) were randomized 1:1 to colesevelam 3.75 g or ezetimibe 10 mg daily. The primary composite outcome was the proportion of participants achieving an LDL-c target of ≤2.0 mmol/L and HbA1c target of ≤7.0%. Intention to treat analysis was performed., Results: Two hundred subjects were enrolled: mean age 59 ± 10 years; mean HbA1c 8.0%; mean LDL-c 2.5 mmol/L; 97% on statin therapy. The primary composite outcome was achieved by similar proportions of participants with colesevelam (14.6%) and ezetimibe (10.5%) (P non-inferiority  < .001, P superiority = .41). LDL-c reduction from baseline was less with colesevelam compared with ezetimibe (14.0% vs. 23.2%, P < .01), as was the proportion of subjects achieving an LDL-c target of ≤2.0 mmol/L (47.6% and 67.0%, respectively; P = .007). Mean HbA1c was reduced with colesevelam (-0.26 ± 0.10%), while no change was observed with ezetimibe (difference P = .06). Adverse events and discontinuation rates were higher for colesevelam (20.2% and 31.1%) compared with ezetimibe (7.2% and 6.2%), respectively., Conclusions: Among subjects with T2D, the initiation of colesevelam or ezetimibe led to similar achievement of primary composite outcome (LDL-c and HbA1c within target), with ezetimibe recording a greater LDL-c reduction and better tolerability than colesevelam., (© 2020 John Wiley & Sons Ltd.)

Rosuvastatin/ezetimibe combines two lipid-lowering agents: rosuvastatin, an HMG-CoA reductase inhibitor (i.e. statin) with particularly strong inhibitory effects on hepatic cholesterol synthesis, and ezetimibe, which inhibits the intestinal absorption of cholesterol. A fixed-dose combination (FDC) of rosuvastatin/ezetimibe is indicated as an adjunctive therapy to diet for the management of primary hypercholesterolemia in adults in numerous countries worldwide. In well-designed clinical trials evaluating the therapeutic efficacy of rosuvastatin/ezetimibe administered as either separate agents or as an FDC, rosuvastatin/ezetimibe was significantly more effective than rosuvastatin monotherapy (including at double the dose of rosuvastatin) or simvastatin/ezetimibe in reducing low-density lipoprotein cholesterol (LDL-C) and total cholesterol in adults with hypercholesterolemia. Furthermore, rosuvastatin/ezetimibe enabled significantly higher proportions of patients to achieve recommended LDL-C levels than rosuvastatin monotherapy or simvastatin/ezetimibe. Rosuvastatin/ezetimibe did not significantly differ from rosuvastatin monotherapy with respect to incidences of treatment-related or serious adverse events in these short-term trials and displayed a similar safety profile to simvastatin/ezetimibe. While additional cardiovascular outcomes data and head-to-head comparisons with atorvastatin/ezetimibe would be of interest, rosuvastatin/ezetimibe is a potent and generally well-tolerated drug combination that extends the range of options available for the pharmacological management of primary hypercholesterolemia in adults.

Objective: To compare the efficacy and safety profile of alirocumab (PCSK9 inhibitor) versus ezetimibe on top of maximally tolerated statin dose in high cardiovascular risk Chinese patients with hyperlipidemia. Methods: The ODYSSEY EAST study was a randomized, double-blinded, double dummy, active-control, parallel group, multi-centers clinical trial, the Chinese sub-population included 456 patients with hyperlipidemia and high cardiovascular risk on maximally tolerated statin dose. Patients were randomized (2∶1) to receive the subcutaneous injection of alirocumab (75 mg Q2W; with dose up titration to 150 mg Q2W at week 12 if low-density lipoprotein cholesterol (LDL-C) was ≥1.81 mmol/L at week 8) or the oral administration of ezetimibe (10 mg daily) for 24 weeks. The primary endpoint was percentage change in calculated LDL-C from baseline to week 24. Key secondary efficacy endpoints included percentage change from baseline to week 12 or 24 in LDL-C (week 12) and other lipid parameters, including apolipoprotein (Apo) B, non-high-density lipoprotein cholesterol (non-HDL-C), TC, lipoprotein(a) (Lp(a)), HDL-C, fasting triglycerides (TG), and Apo A1, and the proportion of patients reaching LDL-C<1.81 mmol/L at week 24. Safety profile of therapeutic drugs was also assessed during the treatment period. Results: The mean age of 456 Chinese patients was (59.5±10.9) years, 341(74.8%) patients were male, 303 patients (66.4%) in alirocumab group and 153 patients (33.5%) in ezetimibe group. Demographic characteristics, disease characteristics, and lipid parameters at baseline were similar between the two groups. LDL-C was reduced more from baseline to week 12 and 24 in alirocumab group versus ezetimibe group, the difference of their least-squares mean (standard error) percent change were(-35.2±2.2)% and (-36.9±2.5)% (both P <0.001). At 12 weeks, alirocumab had significant reduction on Lp(a), Apo B, total cholesterol and non HDL-C, the difference of their least-squares mean (standard error) percent change were (-40.3±2.8)%, (-27.7±1.8)%, (-19.6±1.5)% and (-27.7±1.9)%, respectively (all P <0.001). At 24 weeks, the percent of patients who reached LDL-C<1.81 mmol/L and LDL-C<1.42 mmol/L was significantly higher in alirocumab group (85.3% and 70.5%) than in ezetimibe group (42.2% and 17.0%, both P <0.001), and alirocumab use was also associated with significant reduction on Lp(a), Apo B, total cholesterol and non HDL-C, the difference of their least-squares mean (standard error) percent change were (-37.2±2.8)%, (-29.1±2.0)%, (-21.6±1.6)% and (-29.6±2.2)%, respectively (all P <0.001). The incidence of treatment related adverse events was similar between the two treatment groups (223/302 patients (73.8%) in alirocumab group and 109/153 patients (71.2%) in ezetimibe group). Respiratory infection, urinary infection, dizziness and local injection-site reactions were the most frequently reported adverse events. Conclusions: In high cardiovascular risk patients with hyperlipidemia from China on maximally tolerated statin dose, the reduction of LDL-C induced by alirocumab is more significant than that induced by ezetimibe. Both treatments were generally safe during the observation period of study.

Purpose of Review: Statins represent the cornerstone for the treatment of hypercholesterolemia, although muscle-related side effects and dysregulation of glucose metabolism have strongly limited their adherence and compliance especially in primary prevention therapy. The purpose of the present review is to provide the most recent evidence of the efficacy and safety of statins in monotherapy or combination with new lipid-lowering drugs., Recent Findings: Recent "life-long" analysis conducted on young familial hypercholesterolemia patients, elderly hypocholesterolemic subjects, and from a 20-year follow-up of randomized controlled trial (RCT) have been published confirming that the cardiovascular benefits of statin therapy, in patients for whom it is recommended by current guidelines, greatly outweigh the risks of side effects. In addition, recent therapies to be used in combination with statins have shown to increase the percentage of patients at goal for low-density lipoprotein - cholesterol (LDL-C) with a good safety profile. The cardiovascular (CV) benefits of monoclonal antibodies anti-proprotein convertase subtilisin/kexin type 9 (PCSK9) and ezetimibe, in patients under statin therapy, have been proven by specific RCT, while we are still waiting for the results of bempedoic acid and the small-interfering RNA (si-RNA) anti-PCSK9 inclisiran. Taken together, the approval of new pharmacological agents to be used in combination with statins represents the future for a tailored therapy of cardiovascular disease patients.

Background: Several studies have investigated the association between non-statin lipid-lowering therapy and regression of atherosclerosis. However, these studies were mostly small and their results were not always robust. The objectives were: (1) to define if a dual lipid-lowering therapy (statin + non-statin drugs) is associated with coronary atherosclerosis regression, estimated by intravascular ultrasound (IVUS); (2) to assess the association between dual lipid-lowering-induced changes in low density lipoprotein cholesterol (LDL-C) and non-high-density-lipoprotein cholesterol (non-HDL-C) levels and atherosclerosis regression., Methods: A meta-analysis including trials of non-statin lipid-lowering therapy, reporting LDL-C, non-HDL-C and total atheroma volume (TAV) with a minimum of 6 months of follow-up was performed. The primary endpoint was defined as the change in TAV measured from baseline to follow-up, comparing groups of subjects on statins alone versus combination of statin and non-statin drugs. The random-effects model and meta-regression were performed., Results: Eight eligible trials of non-statin lipid-lowering drugs (1759 patients) were included. Overall, the dual lipid-lowering therapy was associated with a significant reduction in TAV [- 4.0 mm 3 (CI 95% -5.4 to - 2.6)]; I 2  = 0%]. The findings were similar in the stratified analysis according to the lipid-lowering drug class (ezetimibe or PCSK9 inhibitors). In the meta-regression, a 10% decrease in LDL-C or non-HDL-C levels, was associated, respectively, with 1.0 mm 3 and 1.1 mm 3 regressions in TAV., Conclusion: These data suggests the addition of ezetimibe or PCSK9 inhibitors to statin therapy results in a significant regression of TAV. Reduction of coronary atherosclerosis observed with non-statin lipid-lowering therapy is associated to the degree of LDL-C and non-HDL-C lowering. Therefore, it seems reasonable to achieve lipid goals according to cardiovascular risk and regardless of the lipid-lowering strategy used (statin monotherapy or dual treatment).