Search

Background: This study investigated whether intensive lipid-lowering therapy with pitavastatin and ezetimibe lowers the incidence of heart failure (HF) events in patients with acute coronary syndrome (ACS)., Methods and Results: In the HIJ-PROPER study, 1,734 patients with ACS were randomly assigned to either pitavastatin plus ezetimibe therapy (n=864) or pitavastatin monotherapy (n=857). We examined the incidence of HF between these 2 groups over a 3.9-year period after ACS. The primary endpoint of the study was hospitalization for HF. The mean low-density lipoprotein cholesterol levels during the follow-up period were 65.1 mg/dL in the pitavastatin plus ezetimibe group and 84.6 mg/dL in the pitavastatin monotherapy group. The incidence of HF hospitalization was significantly lower in the pitavastatin plus ezetimibe group than in the pitavastatin monotherapy group (19 [2.2%] vs. 40 [4.7%] patients; hazard ratio 0.47, 95% confidence interval 0.27-0.81; P<0.005). This trend was consistent after multivariable analysis using multiple models., Conclusions: Intensive lipid-lowering therapy with pitavastatin and ezetimibe is associated with a lower incidence of hospitalization for HF in patients with ACS.

Background: The trans intestinal cholesterol excretion (TICE) pathway is a potential therapeutic target to reduce plasma low-density lipoprotein (LDL) cholesterol levels. TICE encompasses the direct excretion of cholesterol by enterocytes into feces. In mice, TICE has been shown to be stimulated by a hydrophilic bile acid pool, resulting in increased fecal neutral sterol loss and reduced plasma cholesterol levels. We investigated whether treatment with a hydrophilic bile acid, ursodeoxycholic acid (UDCA), would increase fecal neutral sterols in humans as a proxy for TICE., Methods and Results: We performed a randomized, double-blind, placebo-controlled, cross-over trial in 20 male participants aged >18 years, with plasma LDL cholesterol levels ≥2.6 mmol/L. After a run-in period of ezetimibe 20 mg once daily for 3 weeks, patients were randomized to UDCA 600 mg or placebo orally once daily for 2 weeks. After a 3 week washout, patients underwent the alternate treatment. At baseline, mean (SD) age, body mass index, and plasma LDL cholesterol were 59±11.3 years, 26.4±3.1 kg/m 2 , and 3.9±0.8 mmol/L, respectively. After UDCA treatment, the plasma bile acid hydrophobicity index was reduced compared with placebo (-118.7% versus +2.3%, P <0.001). The fecal neutral sterols did not change (-5.8% versus +18.8%, P =0.51) and treatment with UDCA increased LDL cholesterol with 0.39 mmol/L (+8.1% versus -3.64%, P =0.002) when compared with placebo., Conclusions: UDCA in combination with ezetimibe increased plasma bile acid hydrophilicity in healthy subjects with LDL cholesterol levels >2.6 mmol/L but did not result in increased fecal neutral sterols or decreased LDL cholesterol. This suggests that TICE is not stimulated by an increase in the hydrophilicity of the bile acid pool in humans.

Background: Non-alcoholic fatty liver disease (NAFLD) is now the most common cause of chronic liver disease. Studies have found that ezetimibe may be utilized as a supplemental treatment for NAFLD. Additionally, many clinical trials reported the potential impacts of ezetimibe on patients with NAFLD, although some conclusions remain controversial. Therefore, this study aimed to evaluate the effects of ezetimibe on patients with NAFLD., Method: Online search was conducted across databases including PubMed, Embase, Scopus, Web of Science, Cochrane Library, Wanfang, VIP, and CNKI to retrieve all relevant controlled studies on the treatment of NAFLD with ezetimibe from the inception of the databases until April 2024. This meta-analysis comprised 10 randomized controlled trials (RCTs). Statistical analysis was conducted using the Meta package in R v4.3.2., Results: A total of ten RCTs were included in this study, encompassing 578 patients (290 in the ezetimibe group and 288 in the control group) diagnosed with NAFLD/non-alcoholic steatohepatitis (NASH). The results indicated that ezetimibe significantly reduced levels of aspartate aminotransferase ( P < 0.01), glutamyl transferase (γ-GT) ( P < 0.01), total cholesterol ( P < 0.01), low-density lipoprotein cholesterol ( P < 0.01), high-sensitivity C-reactive protein ( P < 0.01), and interleukin-6 ( P < 0.01), and markedly increased levels of glycated hemoglobin ( P = 0.02)., Conclusions: Ezetimibe may partially improve transaminase levels and positively impact liver function in patients with NAFLD/NASH., Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023461467., 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 Jiao, Wang, Liu, Zhao and Zhang.)

Background: Dyslipidemia is an important risk factor for acute myocardial infarction. However, real-world data on its prevalence and lipid management trends for Korean patients with acute myocardial infarction are limited. This study aimed to determine the 10-year temporal trends in dyslipidemia prevalence and lipid management in this patient population., Methods and Findings: The study used a merged database of two nationwide observational cohorts (2011-2020) that included 26,751 participants. The primary endpoints were the achievement rates of the (1) absolute low-density lipoprotein cholesterol (LDL-C) target of <70 mg/dL (<1.8 mmol/L), (2) relative LDL-C target reduction of >50% from the baseline, (3) absolute or relative LDL-C target (American target), and (4) both absolute and relative LDL-C targets (European target). The dyslipidemia prevalence increased from 11.1% to 17.1%, whereas the statin prescription rate increased from 92.9% to 97.0% from 2011 to 2020. The rate of high-intensity statin use increased from 12.80% in 2012 to 69.30% in 2020. The rate of ezetimibe use increased from 4.50% in 2016 to 22.50% in 2020. The high-intensity statin and ezetimibe prescription rates (0.20% to 9.30% from 2016 to 2020) increased gradually. The absolute and relative LDL-C target achievement rates increased from 41.4% and 20.8% in 2012 to 62.5% and 39.5% in 2019, respectively. The American (45.7% in 2012 to 68.6% in 2019) and European (16.5% in 2012 to 33.8% in 2019) target achievement rates also increased., Conclusions: The adoption of lipid management guidelines in clinical practice has improved. However, continued efforts are needed to reduce the risk of recurrent ischemic events., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Oh et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Coronary heart disease (CHD) patients are considered high cardiovascular risks. Guidelines recommend low-density lipoprotein cholesterol (LDL-C) target levels below 55 mg/dl with > 50% reduction from baselines. These levels can be reached by a combination of statins, ezetimibe, and anti-protein convertase subtilisin/kexin type 9 (anti-PCSK9) agents. Our clinical impression was that CHD patients do not reach LDL-C target levels, despite the wide availability., Objectives: To evaluate whether hospitalization would result in changes in lipid lowering regimens and short-term compliance., Methods: We conducted a retrospective cohort study using data of CHD patients who were admitted to internal medicine wards at Clalit Health Services medical centers because of anginal syndrome during 2020-2022. The data were evaluated for demographic and clinical characteristics; LDL-C level at admission, 6 months previously, and 3 months and 6-9 months after discharge; rates of reaching LDL-C target levels; and lipid lowering treatment at admission, discharge, and 6-9 months after., Results: The cohort included 10,540 patients. One-third and three-quarters did not have lipids level measurements up to 6 months before and during hospitalization, respectively. Only one-fifth of the patients reached LDL-C values before and during admission (median LDL-C 72 mg/dl; range 53-101). Approximately half were treated with high-dose potent statins. Only 10% were treated with ezetimibe. Hospitalization did not have a clinically significant effect on short-term lipid lowering treatment or LDL-C levels., Conclusions: Gaps were noted between guidelines and clinical practice for reaching LDL-C target levels. Further education and strict policy are needed.

Backgruound: Atherogenic dyslipidemia, which is frequently associated with type 2 diabetes (T2D) and insulin resistance, contributes to the development of vascular complications. Statin therapy is the primary approach to dyslipidemia management in T2D, however, the role of non-statin therapy remains unclear. Ezetimibe reduces cholesterol burden by inhibiting intestinal cholesterol absorption. Fibrates lower triglyceride levels and increase high-density lipoprotein cholesterol (HDL-C) levels via peroxisome proliferator- activated receptor alpha agonism. Therefore, when combined, these drugs effectively lower non-HDL-C levels. Despite this, few clinical trials have specifically targeted non-HDL-C, and the efficacy of triple combination therapies, including statins, ezetimibe, and fibrates, has yet to be determined., Methods: This is a multicenter, prospective, randomized, open-label, active-comparator controlled trial involving 3,958 eligible participants with T2D, cardiovascular risk factors, and elevated non-HDL-C (≥100 mg/dL). Participants, already on moderate-intensity statins, will be randomly assigned to either Ezefeno (ezetimibe/fenofibrate) addition or statin dose-escalation. The primary end point is the development of a composite of major adverse cardiovascular and diabetic microvascular events over 48 months., Conclusion: This trial aims to assess whether combining statins, ezetimibe, and fenofibrate is as effective as, or possibly superior to, statin monotherapy intensification in lowering cardiovascular and microvascular disease risk for patients with T2D. This could propose a novel therapeutic approach for managing dyslipidemia in T2D.

Background: Real-world utilization data for evolocumab, the first proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor to be introduced in Japan in 2016, to date are limited. This study aimed to clarify the current real-world patient user profiles of evolocumab based on large-scale health claims data., Methods and Results: This retrospective database study examined patients from a health administrative database (MDV database) who initiated evolocumab between April 2016 (baseline) and November 2021. Characteristics and clinical profiles of this patient population are described. In all, 4,022 patients were included in the final analysis. Most evolocumab prescriptions occurred in the outpatient setting (3,170; 78.82%), and 940 patients (23.37%) had a recent diagnosis of familial hypercholesterolemia. Common recent atherosclerotic cardiovascular disease events at baseline included myocardial infarction (1,633; 40.60%), unstable angina (561; 13.95%), and ischemic stroke (408; 10.14%). Comorbidity diseases included hypertension (2,504; 62.26%), heart failure (1,750; 43.51%), diabetes (1,199; 29.81%), and chronic kidney disease (297; 7.38%). Among the lipid-lowering regimens concomitant with evolocumab, ezetimibe+statin was used most frequently (1,281; 31.85%), followed by no concomitant lipid-lowering regimen (1,190; 29.59%), statin (950; 23.62%), and ezetimibe (601; 14.94%). The median evolocumab treatment duration for all patients was 260 days (interquartile range 57-575 days)., Conclusions: This study provides real-world insights into evolocumab utilization in Japan for optimizing patient care and adherence to guideline-based therapies to better address hypercholesterolemia in Japan.

Visceral cestodiases, like cysticercoses and echinococcoses, are caused by cystic larvae from parasites of the Cestoda class and are endemic or hyperendemic in many areas of the world. Current therapeutic approaches for these diseases are complex and present limitations and risks. Therefore, new safer and more effective treatments are urgently needed. The Niemann-Pick C1 (NPC1) protein is a cholesterol transporter that, based on genomic data, would be the solely responsible for cholesterol uptake in cestodes. Considering that human NPC1L1 is a known target of ezetimibe, used in the treatment of hypercholesterolemia, it has the potential for repurposing for the treatment of visceral cestodiases. Here, phylogenetic, selective pressure and structural in silico analyses were carried out to assess NPC1 evolutive and structural conservation, especially between cestode and human orthologs. Two NPC1 orthologs were identified in cestode species (NPC1A and NPC1B), which likely underwent functional divergence, leading to the loss of cholesterol transport capacity in NPC1A. Comparative interaction analyses performed by molecular docking of ezetimibe with human NPC1L1 and cestode NPC1B pointed out to similarities that consolidate the idea of cestode NPC1B as a target for the repurposing of ezetimibe as a drug for the treatment of visceral cestodiases., (© 2024. The Author(s).)

Background and Objectives: Patients with previous acute myocardial infarction are at significantly higher risk of recurrent events. Early and intensive lipid-lowering therapy targeting low-density lipoprotein cholesterol is a key strategy for reducing cardiovascular risk in post-acute myocardial infarction patients worldwide. This study aimed to assess patients' real-life lipid-lowering treatment gaps after acute myocardial infarction using a global network, TriNetX, of anonymous, real-time patient data. The uniqueness of the study was the use of the novel, evolving, and constantly improving TriNetX platform and the evaluation of its feasibility for clinical research. Materials and Methods: A retrospective study was conducted on global repository patients in 2020, diagnosed with acute myocardial infarction, with a three-year follow-up. Results : After acute myocardial infarction, the prescribing rate of lipid-lowering medication (statins, ezetimibe and PCSK9I) was insufficient to reach target LDL-C values. The mean LDL-C level decreased from 2.7 mmol/L (103 mg/dL) as measured on the day of AMI to 1.97 mmol/L (76 mg/dL) between 31D and 3M. During the second and third years, the mean LDL-C value was stable (around 2.0 mmol/L (78 mg/dL)). LDL-C goals were not sufficiently reached, as only 7-12% of patients were reported to have LDL-C values < 55 mg/dL (1.4 mmol/L) and 13-20% of patients were reported to have LDL-C values < 70 mg/dL (1.8 mmol/L) during the follow-up periods. This means that a substantial number of patients remain at a very high risk for CV complications and mortality. Most cardiovascular complications happen within three months after acute myocardial infarction. Conclusions: Gaps remain between the recommendations for managing LDL-C in guidelines and what occurs in real life. The TriNetX platform is an innovative platform with significant potential and should be further developed for clinical research, as it enables the use of valuable interinstitutional data.

Background: It remains controversial whether adding ezetimibe to low/moderate-intensity statins has a more beneficial impact on the treatment efficacy and safety of patients with existing atherosclerotic cardiovascular disease (ASCVD) compared to high-intensity statin regimens., Hypothesis: A combination of low/moderate-intensity statins plus ezetimibe might be more effective and safer than high-intensity statin monotherapy., Methods: We searched databases for randomized controlled trials comparing lipid profile alterations, drug-related adverse events, and MACE components between high-intensity statin monotherapy and low/moderate-intensity statin plus ezetimibe combination therapy. Pooled risk ratios (RR), mean differences (MD), and 95% confidence intervals (95% CI) were estimated using a random-effects model., Results: Our comprehensive search resulted in 32 studies comprising 6162 patients treated with monotherapy against 5880 patients on combination therapy. Combination therapy was more effective in reducing low-density lipoprotein cholesterol (LDL-C) levels compared to monotherapy (MD = -6.6, 95% CI: -10.6 to -2.5); however, no significant differences were observed in other lipid parameters. Furthermore, the combination therapy group experienced a lower risk of myalgia (RR = 0.27, 95% CI: 0.13-0.57) and discontinuation due to adverse events (RR = 0.61, 95% CI: 0.51-0.74). The occurrence of MACE was similar between the two treatment groups., Conclusions: Adding ezetimibe to low/moderate-intensity statins resulted in a greater reduction in LDL-C levels, a lower rate of myalgia, and less drug discontinuation compared to high-intensity statin monotherapy in patients with existing cardiovascular disease. However, according to our meta-analysis, the observed reduction in LDL-C levels in the combination group did not correlate with a reduction in MACE compared to the high-intensity statin group., (© 2024 The Author(s). Clinical Cardiology published by Wiley Periodicals, LLC.)

Atherosclerosis (AS), as the main pathophysiological basis of coronary heart disease, can develop into carotid atherosclerotic plaque (CAP) through intimal inflammation, necrosis, fibrosis and calcification. However, there are few reports on the clinical drug selection of CAP. The aim of this study was to explore the effects of atorvastatin and ezetimibe on CD147, HIF-1, MMP-2 and VEGF in CAP under the guidance of IVUS, so as to provide basis for CAP of the best drug. 32 male New Zealand rabbits were divided into the control group, the model group, the atorvastatin group and the ezetimibe group randomly. The levels of serum LDL-C and MMP-2 have a significant decrease in atorvastatin group and ezetimibe group (P <0.05). The level of serum CD147 has a significant decrease in ezetimibe group (P <0.05). The average OD value of HIF-1 in atorvastatin group decreased significantly (P <0.05). The relative expression of CD147 and VEGF decreased significantly in atorvastatin group (P <0.05). There were different degrees of fibrous plaque and lipid plaque in model group, atorvastatin group and ezetimibe group. There exists a significant decline of CD147, HIF-1, MMP-2 and VEGF by atorvastatin in plaque, but the effect of ezetimibe is not obvious.

High-intensity statin (HIS) is recommended for high-risk patients in current guidelines. However, the risk of hemorrhagic stroke (HS) with HIS is a concern for Asians. Pitavastatin carries pharmacological differences compared with other statins. We compared the risk of HS in patients treated with pitavastatin-ezetimibe vs. HIS. We conducted a population-based, propensity score-matched cohort study using data from the Taiwan National Health Insurance Research Database. From January 2013 to December 2018, adults (≥ 18 years) who received pitavastatin 2-4 mg/day plus ezetimibe 10 mg/day (combination group, N = 3,767) and those who received atorvastatin 40 mg/day or rosuvastatin 20 mg/day (HIS group, N = 37,670) were enrolled. The primary endpoint was HS. We also assessed the difference of a composite safety endpoint of hepatitis or myopathy requiring hospitalization and new-onset diabetes mellitus. Multivariable Cox proportional hazards model was used to evaluate the relationship between study endpoints and different treatment. After a mean follow-up of 3.05 ± 1.66 years, less HS occurred in combination group (0.74%) than in HIS group (1.35%) [adjusted hazard ratio (aHR) 0.65, 95% confidence interval (CI) 0.44-0.95]. In subgroup analysis, the lower risk of HS in combination group was consistent among all pre-specified subgroups. There was no significant difference of the composite safety endpoint between the 2 groups (aHR 0.91, 95% CI 0.81-1.02). In conclusion, pitavastatin-ezetimibe combination treatment had less HS compared with high-intensity atorvastatin and rosuvastatin. Pitavastatin-ezetimibe may be a favorable choice for Asians who need strict lipid control but with concern of HS.

Objective: To investigate the effects of statin monotherapy and statin-ezetimibe combination therapy on coronary plaque regression in acute coronary syndrome patients., Methods: The systematic review was conducted from July to September 2022 and comprised search on PubMed, ScienceDirect and Cochrane databases to identify studies from January 2010 to July 2022 assessing the effects of statin-ezetimibe combination therapy versus statin monotherapy on coronary plaque regression in patients with acute coronary syndrome. The outcomes of interest were total atheroma volume, plaque volume, and percent atheroma volume assessed by intravascular ultrasound. Meta-analyses were performed on the studies, and mean differences with 95% confidence interval were estimated using Review Manager v5.4., Results: Of the 730 studies identified, 12(1.64%) were shortlisted, and, of them, 5(41.7%) were analysed in detail. There were a total of 557 patients with a mean follow-up of 9 ± 2.43 months. The difference between baseline and follow-up showed significant lowering in total atheroma volume, plaque volume, and percent atheroma volume (p<0.05) in the patients who were receiving statin-ezetimibe combination therapy., Conclusions: Adding ezetimibe to statin medication was found to be significantly more successful in reducing coronary plaque than statin monotherapy.

Background: Statins are lipid-lowering drugs with favorable anti-inflammatory effects. This study aimed to explore different statin-based lipid-lowering strategies to reduce high-sensitivity C-reactive protein (hs-CRP)., Hypothesis: The hypothesis is that different statin-based lipid-lowering strategies might reduce hs-CRP., Methods: This retrospective study included 3653 patients who underwent percutaneous coronary intervention (PCI). Three statin-based lipid-lowering strategies were investigated, including different types of statins (atorvastatin vs. rosuvastatin), statin combined with ezetimibe therapy (vs. without), and intensive statin therapy (vs. regular). The hs-CRP levels and blood lipid indicators were measured at baseline and after 1-month lipid-lowering therapy. Multivariable linear regression analysis and structural equation mode analysis were conducted to verify the association between different lipid-lowering strategies, Δhs-CRP (%) and ΔLDL-C (%)., Results: Totally, 3653 patients were enrolled with an average age of 63.81 years. Multivariable linear regression demonstrated that statin combined with ezetimibe therapy was significantly associated with decreased Δhs-CRP (%) (β = -0.253, 95% CI: [-0.501 to -0.005], p = 0.045). The increased ΔLDL-C (%) was an independent predictor of elevated levels of Δhs-CRP (%) (β = 0.487, 95% CI: [0.15-0.824], p = 0.005). Furthermore, structural equation model analysis proved that statin combined with ezetimibe therapy (β = -0.300, p < 0.001) and intensive statin therapy (β = -0.032, p = 0.043) had an indirect negative effect on Δhs-CRP via ΔLDL-C., Conclusions: Compared with routine statin use, statin combined with ezetimibe therapy and intensive statin therapy could further reduce hs-CRP levels., (© 2024 The Author(s). Clinical Cardiology published by Wiley Periodicals LLC.)

Background: Melanoma proliferation is partly attributed to dysregulated lipid metabolism. The effectiveness of lipid-lowering drugs in combating cutaneous melanoma (CM) is a subject of ongoing debate in both in vitro and clinical studies., Method: This study aims to evaluate the causal relationship between various lipid-lowering drug targets, namely 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR, targeted by statins), Proprotein convertase subtilisin/kexin type 9 (PCSK9, targeted by alirocumab and evolocumab), and Niemann-Pick C1-like 1 (NPC1L1, targeted by ezetimibe), and the outcomes of cutaneous melanoma. To mimic the effects of lipid-lowering drugs, we utilized two genetic tools: analysis of polymorphisms affecting the expression levels of drug target genes, and genetic variations linked to low-density lipoprotein cholesterol levels and drug target genes. These variations were sourced from genome-wide association studies (GWAS). We applied Summary-data-based Mendelian Randomization (SMR) and Inverse Variance Weighted Mendelian Randomization (IVW-MR) to gauge the effectiveness of these drugs., Results: Our findings, with SMR results showing an odds ratio (OR) of 1.44 (95% CI: 1.08-1.92; P = 0.011) and IVW-MR results indicating an OR of 1.56 (95% CI: 1.10-2.23; P = 0.013), demonstrate a positive correlation between PCSK9 expression and increased risk of CM. However, no such correlations were observed in other analyses., Conclusion: The study concludes that PCSK9 plays a significant role in the development of CM, and its inhibition is linked to a reduced risk of the disease., (© 2024. The Author(s).)

Background: In liver cirrhosis, chronic inflammation is associated with an increase in oxidative stress, and subsequently an increase in the concentration of oxidized low-density lipoprotein (ox-LDL). Ezetimibe is a lipid-lowering agent with anti-inflammation and anti-oxidative stress activities. This study aimed to investigate the effect of ezetimibe treatment on ox-LDL in cirrhotic rats., Methods: Biliary cirrhosis was induced in Sprague-Dawley rats with common bile duct ligation (BDL). Sham-operated rats served as surgical controls. Ezetimibe (10 mg/kg/d) or vehicle was administered in the sham-operated or BDL rats for 4 weeks, after which hemodynamic parameters, biochemistry data, and oxidative stress were evaluated. Plasma and intrahepatic ox-LDL levels were also examined, and hepatic proteins were analyzed to explore the mechanism of ezetimibe treatment., Results: The BDL rats had typical features of cirrhosis including jaundice, impaired liver function, hyperlipidemia, and elevated ox-LDL levels compared to the sham-operated rats. Ezetimibe treatment did not affect hemodynamics, liver biochemistry, or plasma lipid levels. However, it significantly reduced oxidative stress, plasma levels of ox-LDL, and tumor necrosis factor α. In addition, ezetimibe upregulated the hepatic protein expression of an ox-LDL scavenger (lectin-like ox-LDL rececptor-1), which resulted in reductions in intrahepatic ox-LDL and fat accumulation in the BDL rats. Nevertheless, ezetimibe treatment did not ameliorate hepatic inflammation or liver fibrosis., Conclusion: Ezetimibe reduced plasma and intrahepatic ox-LDL levels in the cirrhotic rats. Furthermore, it ameliorated intrahepatic fat accumulation and oxidative stress. However, ezetimibe did not alleviate hepatic fibrosis or inflammation in the biliary cirrhotic rats., Competing Interests: Conflicts of interest: Dr. Ching-Chih Chang, Dr. Hui-Chun Huang, Dr. Ming-Chih Hou, and Dr. Fa-Yauh Lee, editorial board members at Journal of the Chinese Medical Association , have no roles in the peer review process of or decision to publish this article. The other authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2024, the Chinese Medical Association.)

Background: Pediatric patients with homozygous familial hypercholesterolemia (HoFH) have an increased risk of atherosclerotic cardiovascular disease and difficulty meeting low-density lipoprotein cholesterol (LDL-C) goals. In this post hoc analysis, we evaluated pooled safety and efficacy data from 3 studies in pediatric patients with HoFH treated with the PCSK9 (proprotein convertase subtilisin/kexin type 9) monoclonal antibody inhibitor evolocumab., Methods: Patients with HoFH aged 10 to 17 years received treatment with open-label evolocumab 420 mg subcutaneously monthly or biweekly in the TAUSSIG, RAMAN, or HAUSER-OLE clinical studies. All patients received background statins with or without ezetimibe. Study duration ranged from 12 to 260 weeks. The primary end point was treatment-emergent adverse events per 100 patient-years. Efficacy end points were changes from baseline to week 12 in lipids and PCSK9., Results: Of the 39 patients in the pooled analysis, 69.2% were males, median age was 13.0 years, and 79.5% (31/39) had genotyped HoFH with LDLR pathogenic variants. Overall, median exposure to evolocumab was 18.2 (Q1, Q3: 3.0, 18.5) months. Treatment-emergent adverse events with an exposure-adjusted patient incidence rate of ≥5% were upper respiratory tract infection (6.6%), influenza (5.2%), and acne (5.0%) per 100 patient-years. Exposure-adjusted patient incidence of serious treatment-emergent adverse events was 13.3% per 100 patient-years. Excluding 4 patients receiving lipoprotein apheresis, week 12 median percentage change from baseline in LDL-C was -2.9% (Q1, Q3: -21.7, 1.5); however, 42.9% (15/35) of patients achieved ≥15% reduction in LDL-C from baseline. Residual LDLR (LDL receptor) activity was not associated with a reduction in LDL-C., Conclusions: In this pooled data analysis from 3 studies in pediatric patients with HoFH, evolocumab was well tolerated, with no new safety signals reported. These safety findings are consistent with findings from previous studies of evolocumab. Patients showed marked variability in LDL-C reduction. Results from this pooled analysis support guidelines suggesting a trial of PCSK9 inhibitor therapy regardless of estimated residual LDLR function., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01624142, NCT03403374, and NCT02624869., Competing Interests: Disclosures F.J. Raal has received research grants, honoraria, or consulting fees for professional input and lectures from Sanofi, Regeneron, Amgen, and Novartis; and travel support to attend the 2023 European Atherosclerosis Society (EAS) Congress from EAS. R.A. Hegele reports receiving consulting fees from Acasti, Aegerion, Akcea/Ionis, Amgen, Boston Heart, HLS Therapeutics, Novartis, Pfizer, Regeneron, Sanofi, and Ultragenyx; and lecture fees from Amgen, HLS Therapeutics, and Novartis. A. Ruzza is a former employee and a stockholder of Amgen. He is a current employee and a stockholder of GlaxoSmithKline. He holds a pending patent application PCT/US2021/034489 on PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors and methods of use thereof to treat cholesterol-related disorders. J.A.G. López, A.K. Bhatia, H. Wang, and J. Wu are employees and stockholders of Amgen. D. Gaudet reports receiving research grants, honoraria, or consulting fees for professional input and lectures from Alnylam, Amgen, Applied Therapeutics, Arrowhead, Boehringer Ingelhein, Chiesi (Amryt), CRISPR Therapeutics, Eli Lilly, Esperion, Ionis, Kowa, New Amsterdam Pharma, Novartis, Novo Nordisk, Pfizer, Regeneron, Sanofi, Ultragenyx, Uniqure, and Verve Therapeutics. A. Wiegman reports research support for pharmaceutical trials of lipid-lowering agents from Amgen, Sanofi-Regeneron Pharmaceuticals, Novartis, Silence Therapeutics, Esperion, and Ultragenyx; and is member of a safety board for Amryt. R.D. Santos reports receiving consulting fees and lecture fees from Abbott, Amgen, Amryt, AstraZeneca, Aché, Biolab, Getz Pharma, Eli Lilly, Libbs, Merck, PTC Therapeutics, Novo Nordisk, Novartis, and Sanofi-Regeneron Pharmaceuticals; and grant support from Amgen, Kowa, Esperion, Novartis, and Sanofi-Regeneron Pharmaceuticals. The other author reports no conflicts.

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.

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.)

This study aimed to investigate the impact of the latest guidelines on the real-world clinical practice of initial lipid-lowering therapy, especially on the use of ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in China. All adult patients diagnosed with acute myocardial infarction in our hospital between August 31, 2018, and August 31, 2020, were divided into the following 2 groups: those patients treated before the latest guideline release, and those patients treated after the release. A propensity score-matched method was used, and logistic regression was used to assess the association with intensive statin, ezetimibe and PCSK9 inhibitor usage together with treatment results between the 2 groups. A total of 325 patients were enrolled in this study, including 141 patients who were admitted before the release of the latest guideline and 184 patients who were admitted after the release. After a median follow-up time of 8.20 months, the mean low-density lipoprotein cholesterol was 1.87 ± 0.59 mmol/L (1.87 ± 0.55 in the before group vs 1.88 ± 0.62 in the after group, P = .829). After propensity score matching, the initial usage of intensive statin therapy was decreased after guideline release without statistical significance (17.00% vs 28.00%, P = .090), whereas the usage of ezetimibe and PCSK9 inhibitors was increased (19.00% vs 8.00%, P = .039; and 10.00% vs 3.00%, P = .085, respectively). In logistic regression models, the release of the guideline was associated with a statistically significantly increased use of ezetimibe (odds ratio [OR]: 1.91; 95% confidence interval [CI]: 1.21, 3.02; P = .005), a marginally decreased use of intensive statins (OR: 0.68; 95% CI: 0.45, 1.03; P = .069) and a marginally increased use of PCSK9 inhibitors (OR: 1.31; 95% CI: 0.98, 1.76; P = .068). In this single-center, real-world data analysis, after the release of the 2019 European Society of Cardiology/European Atherosclerosis Society guidelines, an increasing number of patients with a recent acute myocardial infarction were initially receiving ezetimibe and PCSK9 inhibitors., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

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).)

This study aimed to compare and evaluate the efficacy of the blood pressure (BP) control and cholesterol-lowering effects and safety of combination therapy with telmisartan, rosuvastatin, and ezetimibe versus rosuvastatin and ezetimibe double therapy or telmisartan single therapy in dyslipidemia patients with hypertension. After a wash-out/therapeutic lifestyle change period of ≥4 weeks, a total of 100 eligible patients were randomized and received one of three treatments for 8 weeks: (1) telmisartan 80 mg/rosuvastatin 20 mg/ezetimibe 10 mg (TRE), (2) rosuvastatin 20 mg/ezetimibe 10 mg (RE), or (3) telmisartan 80 mg (T). The primary endpoint was the efficacy evaluation of TRE by comparing changes in mean sitting systolic blood pressure (msSBP) and mean percentage change in low-density lipoprotein-C (LDL-C) from baseline after 8 weeks of treatment. The least square (LS) mean (SE) changes in msSBP at 8 weeks compared with baseline were -23.02 (3.04) versus -7.18 (3.09) mmHg in the TRE and RE groups, respectively (p < .0001), and -25.80 (2.74) versus -14.92 (2.65) mmHg in the TRE and T groups, respectively (p = .0005). The percentage changes in the mean (SD) LDL-C at 8 weeks compared with baseline were -54.97% (3.49%) versus -0.17% (3.23%) in the TRE and T groups, respectively (p < .0001). No serious adverse events occurred, and no statistically significant differences in the incidence of overall AEs and adverse drug reactions occurred among the three groups. TRE therapy significantly decreased msSBP and LDL-C compared to RE or T therapy with comparable safety and tolerability profiles., (© 2024 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

Patients with CKD are at increased risk for cardiovascular events. Clinical studies suggest statins reduce all-cause mortality and cardiovascular events in patients with CKD. Lipid lowering therapy with statin with or without ezetemibe is recommended for most of the patients in patients with eGFR <60 mL/min and also in those who have an increased urinary albumin-to-creatinine ratio (≥3 mg/mmol) for at least 3 months. Evidence suggests that it should not be started for hemodialysis patients without evidence of ASCVD. Patients who were already taking statins or statin/ezetimibe combination at the time of dialysis should consider continuing these medications, especially if they have ASCVD. Fibrates should not be used in conjunction with statins in patients with CKD, and ezetimibe monotherapy is also not recommended. The role of PCSK9 inhibitors is evolving suggests that it is effective in lowering LDL cholesterol without affecting the renal outcomes., 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 © 2024 Cardiological Society of India. Published by Elsevier, a division of RELX India, Pvt. Ltd. All rights reserved.)

Despite numerous improvements in the management of acute coronary syndrome(ACS), it is a major cause of mortality in India. Lipids play a critical role in pathogenesis of ACS and reduction of lipid parameters plays a pivotal role in secondary prevention. High total cholesterol and high low-density lipoprotein(LDL) are the major lipid abnormalities globally as well as in Indians. Among all the lipid parameters, LDL is the primary target of lipid-lowering therapies across the globe. High-dose statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors, and bempedoic acid are recommended therapies for LDL reduction in ACS patients. Statins have pleiotropic effects on the modulation of thrombogenesis, endothelial dysfunction, and myocardial protection. Multiple randomised controlled trials and meta-analyses have shown that the use of high-dose statin has significant benefits in ACS. LDL reduction goal is < 55 mg/dl or at least 50 % reduction from the baseline regardless of age or gender. Non-fasting LDL should be measured soon after the ACS as it varies minimally with food intake. The first line of therapy after ACS is to advise lifestyle modifications, combination therapy including high-dose statin with ezetimibe, and evaluation after 4-6 weeks of the index event. If the goal is not achieved then PCSK 9 inhibitors or Bempedoic acid should be used in combination with statins and ezetimibe to reduce recurrent ischaemic events. Despite the proven effect of these lipid-lowering therapies, undertreatment is still a big hurdle across the globe. Prohibitive costs, adverse effects, medication non-adherence, variation in health practice in different countries, and clinical inertia to prescribe this medication by physicians are the main reasons for the undertreatment., 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 © 2024 Cardiological Society of India. Published by Elsevier, a division of RELX India, Pvt. Ltd. All rights reserved.)

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 long-term outcome of first-line moderate-intensity statin with ezetimibe combination therapy for secondary prevention after percutaneous coronary intervention in patients with acute coronary syndrome (ACS) compared to high-intensity statin monotherapy remains elusive. The objective of this study was to compare the effectiveness of moderate-intensity statin and ezetimibe combination therapy with high-intensity statin monotherapy. We conducted a nationwide, population-based, retrospective, cohort study of patients with ACS from 2013 to 2019. The patients using combination therapy were matched (1:1) to those using monotherapy. The primary outcome was a composite of myocardial infarction, stroke and all-cause mortality. We estimated the hazard ratios (HR) and 95% confidence intervals (CIs) using the Cox proportional hazards regression. After propensity score matching, 10,723 pairs were selected. Men accounted for 70% of the patients and 37% aged > 70 years. The primary endpoint occurred in 1297 patients (12.1%) in the combination group and in 1426 patients (13.3%) in the monotherapy group, and decreased risk (HR 0.85, 95% CI 0.78-0.92, P < 0.001) in the combination group. Among the patients with ACS, moderate-intensity statin with ezetimibe combination therapy was associated with decreased risk of adverse cardiovascular outcomes compared with high-intensity statin monotherapy in a nationwide population-based study representing routine clinical practice., (© 2024. The Author(s).)

The inability to tolerate sufficient doses of statins, statin intolerance (SI), contributes to the non-achievement of guideline-recommended low-density lipoprotein cholesterol (LDL-C) treatment targets. Patients with SI require alternative lipid-lowering therapies (LLT). We conducted a simulation study on LDL-C target achievement with oral LLT (ezetimibe, bempedoic acid) in patients with SI, using representative data of 2.06 million German outpatients. SI was defined using literature-informed definitions based on electronic medical records (EMR). Among n = 130,778 patients with hypercholesterolaemia, available LDL-C measurement, and high or very-high cardiovascular risk, 8.6% met the definition of SI. Among patients with SI, 7.7% achieved the LDL-C target at baseline. After simulation of the stepwise addition of treatment with ezetimibe and bempedoic acid, 22.6 and 52.0% achieved the LDL-C target, respectively. The median achieved LDL-C was 80 and 62 mg/dL, the corresponding reductions from baseline were 20.0 and 38.0%, respectively. A higher proportion of patients classified as high risk achieved the target compared to those at very-high risk (58.1 vs. 49.9%). In conclusion, in patients with increased cardiovascular risk meeting the definition of SI based on EMR, combination LLT with ezetimibe and bempedoic acid has the potential to substantially increase the proportion of patients achieving clinically relevant LDL-C reductions., (© 2024. The Author(s).)

Aims: The HEYMANS study observed patients receiving evolocumab as part of routine clinical hyperlipidemia management. It was designed to capture data on clinical parameters relevant to health authorities and physicians., Methods: This was a European multi-country observational cohort serial chart review study; data on the Swiss cohort are reported here. Patients were prescribed evolocumab as per the Swiss reimbursement criteria in force at the time and were invited chronologically. The study consisted of a 6-month period prior to initiation of evolocumab, a 12-month core observation period (entered by 75 patients, completed by 74 patients), and an 18-month extended observation period (entered by 40 patients, completed by 34 patients). The primary objective was to describe the clinical characteristics of patients receiving evolocumab. Secondary objectives included to describe lipid levels, evolocumab use, and patterns of use of other lipid-lowering therapies (LLT, that is, statins and/or ezetimibe) over time. The study was conducted in the Swiss cohort between May 2017 and June 2021., Results: Patients who received evolocumab in Swiss routine practice mostly were in secondary prevention (93%) and had a history of statin intolerance (85%) with 53% receiving no background LLT. One-third had familial hypercholesterolemia. Patients initiated evolocumab at a median low-density lipoprotein cholesterol (LDL-C) of 3.6 mmol/L, which decreased by 54% within 3 months to 1.6 mmol/L and was stable thereafter. Overall, 61% achieved the LDL-C goal of <1.4 mmol/L with more patients attaining this goal when they received evolocumab with a statin and/or ezetimibe (84%) compared to 41% when receiving evolocumab alone. An LDL-C reduction of ⩾50% was achieved by 85% of patients. Persistence with evolocumab at 12 months was 85%., Conclusion: In Swiss clinical practice, evolocumab was mainly prescribed to patients with very high cardiovascular risk, who had very high LDL-C levels. Most patients continued to use evolocumab throughout the study period. In these patients, LDL-C was reduced by >50% within 3 months and LDL-C reductions were maintained over time. Guideline-recommended LDL-C goals for this very high-risk cohort were more frequently attained in patients receiving a combination of statin and/or ezetimibe and evolocumab., Trial Registration: ClinicalTrials.gov Identifier: NCT02770131.

Backgruound: Type 2 diabetes mellitus (T2DM) induces endothelial dysfunction and inflammation, which are the main factors for atherosclerosis and cardiovascular disease. The present study aimed to compare the effects of rosuvastatin monotherapy and rosuvastatin/ezetimibe combination therapy on lipid profile, insulin sensitivity, and vascular inflammatory response in patients with T2DM., Methods: A total of 101 patients with T2DM and dyslipidemia were randomized to either rosuvastatin monotherapy (5 mg/day, n=47) or rosuvastatin/ezetimibe combination therapy (5 mg/10 mg/day, n=45) and treated for 12 weeks. Serum lipids, glucose, insulin, soluble intercellular adhesion molecule-1 (sICAM-1), and peroxiredoxin 4 (PRDX4) levels were determined before and after 12 weeks of treatment., Results: The reduction in low density lipoprotein cholesterol (LDL-C) by more than 50% from baseline after treatment was more in the combination therapy group. The serum sICAM-1 levels increased significantly in both groups, but there was no difference between the two groups. The significant changes in homeostasis model assessment of insulin resistance (HOMA-IR) and PRDX4 were confirmed only in the subgroup in which LDL-C was reduced by 50% or more in the combination therapy group. However, after adjusting for diabetes mellitus duration and hypertension, the changes in HOMA-IR and PRDX4 were not significant between the two groups., Conclusion: Although rosuvastatin/ezetimibe combination therapy had a greater LDL-C reduction effect than rosuvastatin monotherapy, it had no additional effects on insulin sensitivity and vascular inflammatory response. Further studies are needed on the effect of long-term treatment with ezetimibe on insulin sensitivity and vascular inflammatory response.

Background: Patients with previous strokes are at a higher risk of stroke recurrence. Current guidelines recommend a range of low-density lipoprotein cholesterol (LDL-C)-lowering treatments to reduce the risk of recurrent stroke. However, the optimal agent for decreasing LDL-C to lower the risk of recurrent stroke remains unclear. This study aimed to assess the relative effects of various LDL-C -lowering agents for secondary stroke prevention., Methods: Several databases were searched from inception up to 2022. Only randomized controlled trials that compared different LDL-C-lowering agents in adult patients with previous strokes were included. The primary endpoint was a recurrent stroke. The surface under the cumulative ranking curve (SUCRA) was also applied to estimate the overall ranking probability of the treatment agents for each outcome., Results: Overall, nine trials comprising 17,226 patients were included. Ezetimibe plus statins (RR: 0.56, 95% CrI: 0.35-0.87) and statins alone (RR: 0.90, 95% CrI: 0.81-1.00) reduced the risk of stroke recurrence. Ezetimibe plus statins was superior to statins alone in decreasing the incidence of recurrent stroke (RR: 0.62, 95% CrI: 0.39-0.95). However, treatment with statins was related to an increased risk of hemorrhagic stroke compared to placebo (RR: 1.57, 95% CrI: 1.13-2.21). All agents were related to a decreased incidence of major adverse cardiovascular events., Conclusion: Treatment with ezetimibe plus statins was suggested as the most efficacious in decreasing the incidence of recurrent stroke. The analysis also revealed that statin monotherapy was related to an increased risk of hemorrhagic stroke., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Currently, hepatocellular carcinoma (HCC) is characterized by its unfavorable prognosis and resistance to conventional chemotherapy and radiotherapy. Drug repositioning, an approach aimed at identifying novel therapeutic applications for existing drugs, presents a cost-effective strategy for developing new anticancer agents. We explored the anticancer properties of Ezetimibe, a widely used oral lipid-lowering drug, in the context of HCC. Our findings demonstrate that Ezetimibe effectively suppresses HCC cell proliferation through paraptosis, an apoptotic-independent cell death pathway. The examination of HCC cells lines treated with Ezetimibe using light microscopy and transmission electron microscopy (TEM) showed cytoplasmic vacuolation in the perinuclear region. Notably, the nuclear membrane remained intact in both Ezetimibe-treated and untreated HCC cell lines. Probe staining assays confirmed that the cytoplasmic vacuoles originated from dilated endoplasmic reticulum (ER) compartments rather than mitochondria. Furthermore, a dose-dependent accumulation of reactive oxygen species (ROS) was observed in Ezetimibe-treated HCC cell lines. Co-treatment with the general antioxidant NAC attenuated vacuolation and improved cell viability in Ezetimibe-treated HCC cells. Moreover, Ezetimibe induced paraptosis through proteasome activity inhibition and initiation of the unfolded protein response (UPR) in HCC cell lines. In our in vivo experiment, Ezetimibe significantly impeded the growth of HCC tumors. Furthermore, when combined with Sorafenib, Ezetimibe exhibited a synergistic antitumor effect on HCC cell lines. Mechanistically, Ezetimibe induced paraptosis by targeting NPC1L1 to inhibit the PI3K/AKT/mTOR signaling pathway. In conclusion, our study highlights the potential of Ezetimibe as an anticancer agent by triggering paraptosis in HCC cells.

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.)

We aimed to evaluate sex differences in the effects of moderate-intensity statin with ezetimibe combination therapy (rosuvastatin 10 mg plus ezetimibe) versus high-intensity statin (rosuvastatin 20 mg) monotherapy in patients with atherosclerotic cardiovascular disease (ASCVD). This was a sex-specific subgroup analysis of the RACING trial that evaluated the interaction between sex and treatment strategies for the primary outcome (composite of cardiovascular death, major cardiovascular events, or nonfatal stroke at 3 years). Of 3780 patients in the RACING trial, 954 (25.2%) were women. Regardless of sex, the effect of moderate-intensity statin with ezetimibe combination therapy on primary outcome compared with high-intensity statin monotherapy was similar (hazard ratio [HR] 0.98 [0.63-1.52] in women; HR 0.90 [0.71-1.14] in men). The rate of discontinuation or dose reduction of study drugs due to intolerance was lower in the ezetimibe combination group than in the high-intensity statin monotherapy group in both women (4.5% vs. 8.6%, P = 0.014) and men (4.8% vs. 8.0%, P < 0.001). LDL cholesterol levels of < 70 mg/dL at 1, 2, and 3 years were more frequently achieved in the ezetimibe combination group than in the high-intensity statin monotherapy group (all P < 0.001) in both sexes. There were no significant interactions between sex and treatment groups regarding the primary outcome, discontinuation, or dose reduction of study drugs, or the proportion of achievement of LDL cholesterol levels < 70 mg/dL. The effect of ezetimibe combination therapy for the 3-year composite outcomes was not different in both men and women. The benefits of ezetimibe combination therapy on LDL cholesterol lowering and drug tolerance were similarly observed regardless of sex.Trial registration: https://clinicaltrials.gov ; Unique identifier: NCT03044665., (© 2023. The Author(s).)

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.

Aims: The study aimed to investigate low-density lipoprotein cholesterol (LDL-C) goal achievement rates in patients receiving LDL-C-lowering therapy using recent real-world data, following the 2017 revision of the Japan Atherosclerosis Society Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases (JAS GL2017)., Methods: Patients with documented LDL-C test results were extracted from the Medical Data Vision claims database between July 2018 and June 2021 and divided into three groups according to JAS GL2017: primary prevention high risk (Group I, LDL-C goal ＜120 mg/dL), secondary prevention (Group II, LDL-C goal ＜100 mg/dL), and secondary prevention high risk (Group III, LDL-C goal ＜70 mg/dL)., Results: The mean LDL-C value was 108.7 mg/dL (n=125,235), 94.4 mg/dL (n=57,910), and 90.6 mg/dL (n=33,850) in Groups I, II, and III, respectively. Intensive statin monotherapy (pitavastatin, rosuvastatin, or atorvastatin) was the most frequently prescribed lipid-lowering treatment (21.6%, 30.8%, and 42.7% in Groups I, II, and III, respectively), followed by ezetimibe (2.5%, 7.1%, and 8.5% in Groups I, II, and III, respectively). LDL-C goals were achieved by 65.5%, 60.6%, and 25.4% of patients overall in Groups I, II, and III, respectively. Achievement rates were 83.9%, 75.3%, and 29.5% in patients prescribed intensive statin monotherapy and 82.3%, 86.4%, and 46.4% in those prescribed statin and ezetimibe combinations in Groups I, II, and III, respectively. In Group III, the proportion of patients with familial hypercholesterolemia prescribed statin and ezetimibe combinations achieving LDL-C goals was low (32.5%)., Conclusions: The proportion of patients achieving LDL-C goals for secondary prevention in the high-risk group remains low even with statin and ezetimibe combination therapy.

Aims: Patients with familial hypercholesterolemia (FH) are known to have higher exposure to coronary risk than those without FH with similar low-density lipoprotein cholesterol (LDL-C) level. Lipid-lowering medications (LLMs) are the mainstay treatments to lower the risk of premature coronary artery disease in patients with hypercholesterolemia. However, the LLM prescription pattern and its effectiveness among Malaysian patients with FH are not yet reported. The aim of this study was to report the LLM prescribing pattern and its effectiveness in lowering LDL-C level among Malaysian patients with FH treated in specialist hospitals., Methods: Subjects were recruited from lipid and cardiac specialist hospitals. FH was clinically diagnosed using the Dutch Lipid Clinic Network Criteria. Patients' medical history was recorded using a standardized questionnaire. LLM prescription history and baseline LDL-C were acquired from the hospitals' database. Blood samples were acquired for the latest lipid profile assay., Results: A total of 206 patients with FH were recruited. Almost all of them were on LLMs (97.6%). Only 2.9% and 7.8% of the patients achieved the target LDL-C of ＜1.4 and ＜1.8 mmol/L, respectively. The majority of patients who achieved the target LDL-C were prescribed with statin-ezetimibe combination medications and high-intensity or moderate-intensity statins. All patients who were prescribed with ezetimibe monotherapy did not achieve the target LDL-C., Conclusion: The majority of Malaysian patients with FH received LLMs, but only a small fraction achieved the therapeutic target LDL-C level. Further investigation has to be conducted to identify the cause of the suboptimal treatment target attainment, be it the factors of patients or the prescription practice.

Objective: To assess the benefits and harms of lipid-lowering therapies used to prevent or manage cardiovascular disease including bile acid sequestrants (BAS), ezetimibe, fibrates, niacin, omega-3 supplements, proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, and statins., Data Sources: MEDLINE, the Cochrane Database of Systematic Reviews, and a grey literature search., Study Selection: Systematic reviews of randomized controlled trials published between January 2017 and March 2022 looking at statins, ezetimibe, PCSK9 inhibitors, fibrates, BAS, niacin, and omega-3 supplements for preventing cardiovascular outcomes were selected. Outcomes of interest included major adverse cardiovascular events (MACE), cardiovascular mortality, all-cause mortality, and adverse events., Synthesis: A total of 76 systematic reviews were included. Four randomized controlled trials were also included for BAS because no efficacy systematic review was identified. Statins significantly reduced MACE (6 systematic reviews; median risk ratio [RR]=0.74; interquartile range [IQR]=0.71 to 0.76), cardiovascular mortality (7 systematic reviews; median RR=0.85, IQR=0.83 to 0.86), and all-cause mortality (8 systematic reviews; median RR=0.91, IQR=0.88 to 0.92). Major adverse cardiovascular events were also significantly reduced by ezetimibe (3 systematic reviews; median RR=0.93, IQR=0.93 to 0.94), PCSK9 inhibitors (14 systematic reviews; median RR=0.84, IQR=0.83 to 0.87), and fibrates (2 systematic reviews; mean RR=0.86), but these interventions had no effect on cardiovascular or all-cause mortality. Fibrates had no effect on any cardiovascular outcomes when added to a statin. Omega-3 combination supplements had no effect on MACE or all-cause mortality but significantly reduced cardiovascular mortality (5 systematic reviews; median RR=0.93, IQR=0.93 to 0.94). Eicosapentaenoic acid ethyl ester alone significantly reduced MACE (1 systematic review, RR=0.78) and cardiovascular mortality (2 systematic reviews; RRs of 0.82 and 0.82). In primary cardiovascular prevention, only statins showed consistent benefits on MACE (6 systematic reviews; median RR=0.75, IQR=0.73 to 0.78), cardiovascularall-cause mortality (7 systematic reviews, median RR=0.83, IQR=0.81 to 0.90), and all-cause mortality (8 systematic reviews; median RR=0.91, IQR=0.87 to 0.91)., Conclusion: Statins have the most consistent evidence for the prevention of cardiovascular complications with a relative risk reduction of about 25% for MACE and 10% to 15% for mortality. The addition of ezetimibe, a PCSK9 inhibitor, or eicosapentaenoic acid ethyl ester to a statin provides additional MACE risk reduction but has no effect on all-cause mortality., (Copyright © 2023 the College of Family Physicians of Canada.)

Dyslipidemia has been widely recognized as a significant risk factor for coronary atherosclerosis disease (CAD). In fact, lipid variability has emerged as a more reliable predictor of cardiovascular events. In this study, we aimed to examine the variability in plasma lipids under two different lipid-lowering regimens (intensive statin therapy versus the combination of conventional-dose statins with ezetimibe). In total, we have retrospectively examined 1275 patients with CAD from January 2009 to April 2019 and divided them into two groups: intensive statin group and conventional-dose statins combined with ezetimibe group. All patients were followed up for at least 1 year. Lipid variability was verified by standard deviation (SD), coefficient of variation (CV), and variability independent of mean (VIM) triple methods. Multiple linear regression and subgroup analyses were performed. In the overall participants, the mean age was 62.3 ± 10.4 years old, and 72.8% were male. Multivariate linear regression analysis indicated that the intensive statin group had lower variability in terms of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and non-high-density lipoprotein cholesterol (non-HDL-C) in all SD, CV, and VIM triple methods than statins combined with ezetimibe group (P for all <0.05). Similar results were established in the subgroup analyses based on atorvastatin or rosuvastatin, diabetes mellitus or not, and hypertension or not (P for all < 0.05). Thus, we can conclude that intensive statin therapy could contribute in lowering lipid variability than conventional-dose statins combined with ezetimibe therapy among patients with CAD.

Background We aimed to compare statin monotherapy and upfront combination therapy of statin and ezetimibe in patients with acute coronary syndromes (ACSs). Methods and Results The study included consecutive patients with ACS included in the PL-ACS (Polish Registry of Acute Coronary Syndromes), which is a national, multicenter, ongoing, prospective observational registry that is mandatory for patients with ACS hospitalized in Poland. Data were matched using the Mahalanobis distance within propensity score matching calipers. Multivariable stepwise logistic regression analysis, including all variables, was next used in propensity score matching analysis. Finally, 38 023 consecutive patients with ACS who were discharged alive were included in the analysis. After propensity score matching, 2 groups were analyzed: statin monotherapy (atorvastatin or rosuvastatin; n=768) and upfront combination therapy of statin and ezetimibe (n=768 patients). The difference in mortality between groups was significant during the follow-up and was present at 1 (5.9% versus 3.5%; P =0.041), 2 (7.8% versus 4.3%; P =0.019), and 3 (10.2% versus 5.5%; P =0.024) years of follow-up in favor of the upfront combination therapy, as well as for the overall period. For the treatment, rosuvastatin significantly improved prognosis compared with atorvastatin (odds ratio [OR], 0.790 [95% CI, 0.732-0.853]). Upfront combination therapy was associated with a significant reduction of all-cause mortality in comparison with statin monotherapy (OR, 0.526 [95% CI, 0.378-0.733]), with absolute risk reduction of 4.7% after 3 years (number needed to treat=21). Conclusions The upfront combination lipid-lowering therapy is superior to statin monotherapy for all-cause mortality in patients with ACS. These results suggest that in high-risk patients, such an approach, rather than a stepwise therapy approach, should be recommended.

Background: Many patients with atherosclerotic cardiovascular disease (ASCVD) are not on guideline-recommended statin therapy. We evaluated utilization of statins and other lipid-lowering therapy (LLT), and changes in low-density lipoprotein cholesterol (LDL-C), among patients with ASCVD over a 1-year period., Methods: LLT and LDL-C levels at the first outpatient visit (January 1, 2017-December 31, 2018) and 1-year follow-up were evaluated using data from Cerner Real-World Data, an electronic health record-derived data set from 92 US health systems. Logistic regression was used to evaluate factors associated with high-intensity statin use., Results: We identified 322 153 patients with ASCVD (median age 69 years, 58.8% men, 81.8% White). Overall, 76.1% of patients were on statins, with only 39.4% on high-intensity statins. Men were more likely to receive high-intensity statins than women (multivariable-adjusted odds ratio, 1.34 [95% CI, 1.30-1.38]). Increasing age was associated with lower odds of statin use (odds ratio, 0.79 per 5-year increase at 60 years [95% CI, 0.78-0.81]). Patients with peripheral artery disease (odds ratio, 0.40 [95% CI, 0.37-0.42]) and cerebrovascular disease (odds ratio, 0.75 [95% CI, 0.70-0.80]) had lower odds of using high-intensity statins than those with coronary artery disease. At baseline, most patients (61.3%) had elevated LDL-C (≥70 mg/dL), including 59.8% of those on low/moderate-intensity statins and 76.1% on no statin; only 45.3% achieved an LDL-C <70 mg/dL at 1 year. Nonstatin LLT use was low (ezetimibe, 4.4%; proprotein convertase subtilisin/kexin type 9 inhibitors, 0.7%). Among patients on no statin or low/moderate-intensity statin at baseline, 14.8% and 13.4%, respectively, were on high-intensity statins at 1 year., Conclusions: Among patients with ASCVD in routine care, high-intensity statins are underutilized, and uptitration and use of nonstatin therapy are uncommon. Women, older adults, and individuals with noncardiac ASCVD are particularly undertreated. Concerted efforts are needed to address therapeutic inertia for lipid management in patients with ASCVD., Competing Interests: Disclosures Drs Navar and Peterson received research support to their institution from Esperion Therapeutics, Inc for the conduct of this study. Dr Navar has received funding for research to her institution from Bristol Myers Squibb, Amgen, Esperion Therapeutics, Inc, and Janssen Pharmaceuticals, and honoraria and consulting fees from AstraZeneca, Boehringer Ingelheim, Bayer, Esperion Therapeutics, Inc, Janssen Pharmaceuticals, Eli Lilly, Novo Nordisk, Novartis, New Amsterdam, Cerner Corporation, and Pfizer, outside the scope of this study. Dr Peterson has received research funding to his institution from Amgen, Bristol Myers Squibb, and Janssen, and consulting fees from Pfizer, Janssen Pharmaceuticals, Novo Nordisk, Novartis, and Bayer, outside of the current work. Dr Gillard is employed by Esperion Therapeutics, Inc. Dr Israel is a former employee of Esperion Therapeutics Inc. The other authors report no conflicts.

Background: The RACING (randomized comparison of efficacy and safety of lipid-lowering with statin monotherapy versus statin/ezetimibe combination for high-risk cardiovascular diseases) trial examined the effects of combination therapy with moderate-intensity statin and ezetimibe in patients with atherosclerotic cardiovascular disease compared with high-intensity statin monotherapy., Objectives: This observational study was conducted to evaluate the impact of 2 treatment strategies used in the RACING trial in clinical practice., Methods: After stabilized inverse probability of treatment weighting, a total of 72,050 patients who were prescribed rosuvastatin after drug-eluting stent implantation were identified from a nationwide cohort database: 10,794 patients with rosuvastatin 10 mg plus ezetimibe 10 mg (combination lipid-lowering therapy) and 61,256 patients with rosuvastatin 20 mg monotherapy. The primary endpoint was the 3-year composite event of cardiovascular death, myocardial infarction, coronary artery revascularization, hospitalization for heart failure treatment, or nonfatal stroke in accordance with the RACING trial., Results: Combination lipid-lowering therapy was associated with a lower occurrence of the primary endpoint (11.6% vs 15.2% for those with high-intensity statin monotherapy; HR: 0.75; 95% CI: 0.70-0.79; P < 0.001). Compared with high-intensity statin monotherapy, combination lipid-lowering therapy was associated with fewer discontinuations of statin (6.5% vs 7.6%; HR: 0.85; 95% CI: 0.78-0.94: P < 0.001) and a lower occurrence of new-onset diabetes requiring medication (7.7% vs 9.6%; HR: 0.80; 95% CI: 0.72-0.88; P < 0.001)., Conclusions: In clinical practice, combination lipid-lowering therapy with ezetimibe and moderate-intensity statin was associated with favorable clinical outcomes and drug compliance in patients treated with drug-eluting stent implantation. (CONNECT DES Registry; NCT04715594)., Competing Interests: Funding Support and Author Disclosures This work was supported by the Cardiovascular Research Center, Seoul, Korea. The funder had no role in the design and conduct of the study; data collection, management, statistical analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. All authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Importance: Many patients with coronary artery disease (CAD) do not achieve the guideline-directed goals for low-density lipoprotein cholesterol (LDL-C) levels., Objective: To estimate reductions in the rates of adverse events associated with CAD in a large US military veteran population that may be achieved through use of optimized statin therapy alone or with ezetimibe compared with the prevailing lipid-lowering therapy (LLT)., Design, Setting, and Participants: In this observational cohort study, US military veterans with CAD were identified by coronary angiography between June 2015 and September 2020 across 82 US Department of Veterans Affairs health care facilities., Exposures: The exposures were observed LLT, LLT with an optimized statin regimen, and LLT with optimized statin and ezetimibe., Main Outcomes and Measures: Observed rates of death, myocardial infarction, stroke, and coronary revascularization, and potential reductions in those outcomes with optimized LLT based on expected further reductions in LDL-C levels and application of formulas from The Cholesterol Treatment Trialists' Collaboration., Results: The analysis cohort comprised 111 954 veterans (mean [SD] age, 68.4 [8.8] years; 109 390 men [97.7%]; 91 589 White patients [81.8%]; 17 592 Black patients [15.7%]). The median (IQR) observation period for this study was 3.4 (2.1-4.0) years. At the time of index angiography, 66 877 patients (59.7%) were treated with statin therapy, and 623 patients (0.6%) were treated with ezetimibe. At 6 months, the number of patients with statin prescriptions increased to 74 400 (68.7%), but the number of patients with high-intensity statin prescriptions was only 57 297 (52.9%). At 6 months, ezetimibe use remained low (n = 1168 [1.1%]), and LDL-C levels were 70 mg/dL or more in 56 405 patients (52.1%). At 4 years, observed incidences of death, myocardial infarction, stroke, and coronary revascularization were 21.6% (95% CI, 21.3%-21.8%), 5.0% (95% CI, 4.9%-5.2%), 2.2% (95% CI, 2.1%-2.3%), and 15.4% (95% CI, 15.2%-15.7%), respectively. With optimized statin treatment, projected absolute reductions in these incidences were 1.3% (95% CI, 0.9%-1.7%), 0.8% (95% CI, 0.7%-1.0%), 0.2% (95% CI, 0.1%-0.3%), and 2.3% (95% CI, 2.0%-2.7%), respectively. With optimized statin and ezetimibe treatment, projected absolute reductions were 1.8% (95% CI, 1.2%-2.4%), 1.1% (95% CI, 0.9%-1.3%), 0.3% (95% CI, 0.2%-0.4%), and 3.1% (95% CI, 2.6%-3.6%), respectively., Conclusions and Relevance: In this cohort study of veterans with CAD, suboptimal LLT was prevalent in the clinical setting. Optimization of statin therapy was projected to produce clinically relevant reductions in the risks of death and cardiovascular events. Despite a lesser lipid-lowering efficacy of ezetimibe, its widespread use on a population level in conjunction with optimized statin therapy may be associated with further meaningful reductions in cardiovascular risk.

Aim: Several clinical trials using intravascular ultrasound (IVUS) evaluation have demonstrated that intensive lipid-lowering therapy by statin or a combination therapy with statin and ezetimibe results in significant regression of coronary plaque volume. However, it remains unclear whether adding ezetimibe to statin therapy affects coronary plaque composition and the molecular mechanisms of plaque regression. We conducted this prospective IVUS analysis in a subgroup from the CuVIC trial., Methods: The CuVIC trial was a prospective randomized, open, blinded-endpoint trial conducted among 11 cardiovascular centers, where 260 patients with coronary artery disease who received coronary stenting were randomly allocated into either the statin group (S) or the combined statin and ezetimibe group (S＋E). We enrolled 79 patients (S group, 39 patients; S＋E group, 40 patients) in this substudy, for whom serial IVUS images of nonculprit lesion were available at both baseline and after 6-8 months of follow-up., Results: After the treatment period, the S＋E group had significantly lower level of low-density lipoprotein cholesterol (LDL-C; 80.9±3.7 vs. 67.7±3.8 mg/dL, p=0.0143). Campesterol, a marker of cholesterol absorption, and oxysterols (β-epoxycholesterol, 4β-hydroxycholesterol, and 27-hydroxycholesterol) were also lower in the S＋E group. IVUS analyses revealed greater plaque regression in the S＋E group than in the S group (-6.14% vs. -1.18% for each group, p=0.042). It was noteworthy that the lowering of campesterol and 27-hydroxycholesterol, but not LDL-C, had a significant positive correlation with plaque regression., Conclusions: Compared with statin monotherapy, ezetimibe in combination with statin achieved significantly lower LDL-C, campesterol, and 27-hydroxycholesterol, which resulted in greater coronary plaque regression.

This review aims to examine the complex interaction between dyslipidemia, platelet function, and related drug treatments. In particular, the manuscript provides an overview of the effects of major hypolipidemic drugs on platelet function. Indeed, growing evidence supports the view that statins, ezetimibe, PCSK9 inhibitors, inclisiran, and icosapent ethyl also act as antithrombotics. It is known that platelets play a key role not only in the acute phase of coronary syndromes but also in the early phase of atherosclerotic plaque formation. The goal of cholesterol-lowering therapy is to reduce cardiovascular events. The direct effects of cholesterol-lowering drugs are widely described in the literature. Lowering LDL-c (low-density lipoprotein cholesterol) by 1 mmol/L results in a 22-23% reduction in cardiovascular risk. Numerous studies have examined the direct antithrombotic effects of these drugs on platelets, endothelium, monocytes, and smooth muscle cells, and thus, potentially independent of blood LDL-cholesterol reduction. We reviewed in vitro and in vivo studies evaluating the complex interaction between hypercholesterolemia, hypertriglyceridemia, platelet function, and related drug treatments. First, we discussed the role of statins in modulating platelet activation. Discontinuation of statin therapy was associated with increased cardiovascular events with increased ox-LDL, P-selectin, and platelet aggregation. The effect of PCSK9-I (inhibitors of proprotein convertase subtilisin/kexin type 9, PCSK9 involved in the degradation of LDL receptors in the liver) was associated with a statistically significant reduction in platelet reactivity, calculated in P2Y12 reaction units (PRU), in the first 14 days and no difference at 30 days compared to placebo. Finally, in patients with hypertriglyceridemia, the REDUCE-IT study showed that icosapent ethyl (an ethyl ester of eicosapentaenoic acid that reduces triglyceride synthesis and improves triglyceride clearance) resulted in a 25% reduction in ischemic events and cardiovascular death. However, to date, there is not yet clear clinical evidence that the direct antithrombotic effects of the drugs may have a beneficial impact on outcomes independently from the reduction in LDL-C or triglycerides.