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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).)

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).)

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to improve cardiovascular outcomes when added to conventional statin therapy. This study aims to investigate the efficacy and safety of in-hospital initiation of PCSK9 inhibitors among patients with acute myocardial infarction (AMI) based on real-world experience., Methods and Results: Data were collected from the Biobank of the First Affiliated Hospital of Xi'an Jiaotong University between January 2016 and December 2020. A total of 7556 AMI patients were screened for eligibility. Propensity Score Match (PSM) was employed, and covariates were age, sex, admission blood pressure and lipid profiles. Eligible participants were (1) propensity-matched 1:2:2 of statin plus evolocumab (dual therapy) vs. statin vs. statin plus ezetimibe. Ninety-five statin plus evolocumab users achieved significantly decreased low density lipoprotein (LDL) levels (0.92 ± 0.62 mmol/L in the 1st month and 1.17 ± 0.73 in the 3rd month) and a promising attainment rate of LDL (79.5% in the 1st month and 80.0% in the 3rd month) compared to the other two groups. (2) Propensity-matched 1:2:2 of statin plus ezetimibe evolocumab (triple therapy) vs. statin vs. statin plus ezetimibe. Similarly, 75 triple medication users achieved significantly decreased LDL levels and a promising attainment rate of LDL compared to the other two groups. In-hospital mortality and readmission rates within 3 months were then analyzed, and a decreased readmission rate was observed with PCSK9i therapy., Conclusions: Based on the present single-center real-world PSM-adjusted study, PCSK9i has been effective in short-term lipid control among AMI patients. The long-term effectiveness for reducing major cardiovascular events among AMI patients based on real-world experience remains to be explored., Trial Registration: The study was registered at ClinicalTrials.gov, ClinicalTrials.gov ID: NCT05184530., (© 2022. The Author(s).)

Background: The effect of ezetimibe, Niemann-Pick C1-like 1 inhibitor, on liver fat is not clearly elucidated. Our primary objective was to evaluate the efficacy of ezetimibe plus rosuvastatin versus rosuvastatin monotherapy to reduce liver fat using magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) in patients with non-alcoholic fatty liver disease (NAFLD)., Methods: A randomized controlled, open-label trial of 70 participants with NAFLD confirmed by ultrasound who were assigned to receive either ezetimibe 10 mg plus rosuvastatin 5 mg daily or rosuvastatin 5 mg for up to 24 weeks. The liver fat change was measured as average values in each of nine liver segments by MRI-PDFF. Magnetic resonance elastography (MRE) was used to measure liver fibrosis change., Results: Combination therapy significantly reduced liver fat compared with monotherapy by MRI-PDFF (mean difference: 3.2%; p = 0.020). There were significant reductions from baseline to study completion by MRI-PDFF for both the combination and monotherapy groups, respectively (18.1 to 12.3%; p < 0.001 and 15.0 to 12.4%; p = 0.003). Individuals with higher body mass index, type 2 diabetes, insulin resistance, and severe liver fibrosis were likely to be good responders to treatment with ezetimibe. MRE-derived change in liver fibrosis was not significantly different (both groups, p > 0.05). Controlled attenuation parameter (CAP) by transient elastography was significantly reduced in the combination group (321 to 287 dB/m; p = 0.018), but not in the monotherapy group (323 to 311 dB/m; p = 0.104)., Conclusions: Ezetimibe and rosuvastatin were found to be safe to treat participants with NAFLD. Furthermore, ezetimibe combined with rosuvastatin significantly reduced liver fat in this population., Trial Registration: The trial was registered at ClinicalTrials.gov (registration number: NCT03434613 )., (© 2022. The Author(s).)

Background: Colorectal cancer (CRC) is a malignancy of the large intestine, whose development and prognosis have been demonstrated to be associated with altered lipid metabolism. High cholesterol intake is associated with an increased risk of CRC, and elevated serum cholesterol levels are known to be correlated with risk of developing CRC. Niemann-Pick C1-Like 1 (NPC1L1), a target of ezetimibe, plays an essential role in the absorption of intestinal cholesterol. However, whether the altered expression of NPC1L1 affects CRC development and prognosis is currently unknown., Methods: Data corresponding to patients with CRC were obtained from The Cancer Genome Atlas (TCAG). Datasets from the Genome Data Analysis Center (GDAC) platform were analyzed to compare the expression of NPC1L1 in normal and CRC tissues using the Mann-Whitney U test and chi-square test. Further, the datasets from the Gene Expression Omnibus (GEO) database were analyzed. The log-rank test and multivariate Cox proportional hazard regression analysis were performed to determine whether NPC1L1 significantly affects the prognosis of CRC., Results: The expression of NPC1L1 was found to be upregulated in CRC and was significantly associated with the N and pathological stages but not with the histological type, age, and sex. Increased NPC1L1 expression in CRC was related to poor patient survival, as evidenced by the Kaplan-Meier and multivariate regression analyses., Conclusions: As high expression of NPC1L1 was associated with CRC development, pathological stage, and prognosis, NPC1L1 can serve as an independent prognostic marker for CRC., (© 2021. The Author(s).)

Background: This cross-sectional study aimed to identify actionable factors to improve LDL-cholesterol target achievement and overcome underuse of lipid-lowering treatments in high- or very-high-cardiovascular risk patients., Methods: We evaluated healthcare records of 934,332 subjects from North-Italy, including subjects with available lipid profile and being on statin treatments up to December 2018. A 6-month-period defined adherence with proportion-of-days-covered ≥ 80%. Treatment was classified as high-intensity-statin (HIS) + ezetimibe, HIS-alone, non-HIS (NHIS) + ezetimibe or NHIS alone., Results: We included 27,374 subjects without and 10,459 with diabetes. Among these, 30% and 36% were on secondary prevention, respectively. Adherence was high (78-100%) and increased with treatment intensity and in secondary prevention. Treatment intensity increased in secondary prevention, but only 42% were on HIS. 2019-guidelines LDL-cholesterol targets were achieved in few patients and more often among those with diabetes (7.4% vs. 10.7%, p < 0.001). Patients in secondary prevention had mean LDL-cholesterol levels aligned slightly above 70 mg/dl (range between 68 and 73 mg/dl and between 73 and 85 mg/dl in patients with and without diabetes, respectively). Moreover, the differences in mean LDL-cholesterol levels observed across patients using treatments with well-stablished different LDL-lowering effect were null or much smaller than expected (HIS vs. NHIS from - 3 to - 11%, p < 0.001, HIS + ezetimibe vs. HIS-from - 4 to + 5% n.s.). These findings, given the observational design of the study, might suggest that a "treat to absolute LDL-cholesterol levels" approach (e.g., targeting LDLc of 70 mg/dl) was mainly used by physicians rather than an approach to also achieve the recommended 50% reduction in LDL-cholesterol levels. Our analyses suggested that female sex, younger age, higher HDL-c, and elevated triglycerides are those factors delaying prescription of statin treatments, both in patients with and without diabetes and in those on secondary prevention., Conclusions: Among patients on statin treatment and high adherence, only a small proportion of patients achieved LDL-cholesterol targets. Late initiation of high-intensity treatments, particularly among those with misperceived low-risk (e.g., female subjects or those with high HDL-cholesterol), appears as pivotal factors needing to be modified to improve CVD prevention., (© 2021. The Author(s).)

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).

In the last 50 years, several clinical and epidemiological studies during have shown that increased levels of low-density lipoprotein cholesterol (LDLc) are associated with the development and progression of atherosclerotic lesions. The discovery of β-Hydroxy β-methylglutaryl-CoA reductase inhibitors (statins), that possess LDLc-lowering effects, lead to a true revolution in the prevention and treatment of cardiovascular diseases. Statins remain the cornerstone of LDLc-lowering therapy. Lipid-lowering drugs, such as ezetimibe and bile acid sequestrants, are prescribed either in combination with statins or in monotherapy (in the setting of statin intolerance or contraindications to statins). Microsomal triglyceride transfer protein inhibitors and protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are other drug classes which have been investigated for their potential to decrease LDLc. PCSK9 have been approved for the treatment of hypercholesterolemia and for the secondary prevention of cardiovascular events. The present narrative review discusses the latest (2019) guidelines of the European Atherosclerosis Society/European Society of Cardiology for the management of dyslipidemia, focusing on LDLc-lowering drugs that are either already available on the market or under development. We also consider "whom, when and how" do we treat in terms of LDLc reduction in the daily clinical practice.

Background: The aim of this study was to compare and summarize the lipid-altering effects of combination therapy with ezetimibe and statins (E/S) and a double dose of statin (D/S) monotherapy on patients with hypercholesterolemia., Methods: We conducted search on 2 medical databases, PubMed and EMBASE to identify all relevant studies. A meta-analysis was performed to clarify the efficacy in the two groups. Only double-blind Randomized controlled study (RCTs) of efficacy evaluation in the two groups with ezetimibe and statins and a double dose of statin in participants with hypercholesterolemia that examined low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC) and high-density lipoprotein (HDL) were included. Two reviewers extracted data from all primary studies independently. The primary data were the level of LDL-C, TC and HDL-C concentrations at the end point and are expressed as mean and standard deviation (SD)., Results: A total of 11 double-blind, active or placebo-controlled studies with 1926 hypercholesterolemia adults randomized to ezetimibe 10 mg added to ongoing statins (N = 994) or statin titration (doubling) (N = 932) were pooled for the global meta-analysis. The effect size between treatment groups within individual studies was assessed by weighted mean difference (MD) using a random- or fixed-effect model. The result showed that the participants in E/S group get obvious lower LDL-C [MD = -13.14 mg/dL, 95%CI (-16.83, -9.44), p = 0.00001] and TC concentration [MD = -23.79 mg/dL, 95%CI (-38.65, -8.93), p = 0.002] from baseline to follow-up, comparing to the D/S group. Besides, no significant between-group differences were observed for concentrations of HDL-C [MD = 0.46 mg/dL, 95%CI (- 1.14, 2.06), p = 0.57]. According to subgroup analysis, the combination of ezetimibe and atorvastatin (10 mg) [MD = -16.98 mg/dL, p < 0 .0001] or simvastatin (20 mg) [MD = -17.35 mg/dL, p < 0 .0001] showed stronger ability of reducing LDL-C than combination of ezetimibe and rosuvastatin (10 mg) [MD = -9.29 mg/dL, p = 0.05]. The efficacy of short-term (endpoint time between 6 to 16 week) and long-term (52 week) treatment in the LDL-C between two groups did not show significant differences. Besides, only participants from Asia treated with combination therapy were associated with a significant lower LDL-C concentration [MD = -14.7 mg/dL, p < 0 .0001]., Conclusions: The addition of ezetimibe to statin appears to be more effective on reducing LDL-C and TC concentrations than doubling the statin dose. Moreover, the ability to reduce cholesterol levels of combinations therapy with ezetimibe and different statins or to participants from different geographic location may vary, based on this meta-analysis, while more samples are needed to verify.

Background: Achievement of low-density lipoprotein cholesterol (LDL-C) goal is the most important for the patients with atherosclerotic cardiovascular diseases (ASCVD) who received lipid-lowering therapy. It is unclear that whether combination of ezetimibe with statin is superior to double-dose of statin regarding both of the lipid-lowering efficacy and improvement of inflammation in Chinese patients with ASCVD. Therefore, this study was performed to compare the effects of these two regimes on lipid profiles and inflammation markers., Methods: In this randomized control study, ninety eight patients with ASCVD, who were naïve to statins or other lipid-lowering agents, were enrolled into the study, and randomly assigned into two groups, A40 group (atorvastatin 40 mg/d, n = 50), A20E10 group (atorvastatin 20 mg/d combined with ezetimibe 10 mg/d, n = 48).The patients were followed up at week 4 and week 12 after treatment. The lipid profiles and oxidative low-density lipoprotein cholesterol (ox-LDL) were measured at the end of study., Results: There were no differences in clinical characteristics including lipid, ox-LDL and hypersensitive C reactive protein (Hs-CRP) among groups at baseline. However, the average level of LDL-C was lower in group A20E10 than that in group A40 significantly (1.59 ± 0.44 mmol/L vs 1.99 ± 0.56 mmol/L, p = 0.001) during follow-up at week 12 after treatment. Importantly, the higher rate of achievement of LDL-C goal was attained at group of combination statin with ezetimibe (79.2% in group A20E10 vs 50.0% in group A40, p = 0.016). The difference of the level of ox-LDL between both the groups after 12 weeks treatment had not statistical significance (3.63 ± 1.13 U/L in group A20E10 vs 4.14 ± 1.32 U/L in group A40, p = 0.077).Similarly, the level of Hs-CRP between both the groups after treatment was not significantly different (p > 0.05)., Conclusions: In this randomized study, the data showed that a combination of moderate statin and ezetimibe achieved more reduction of LDL-C compared to the double-dose statin but similar impact on inflammation markers.

Background: Although there were many studies reporting the combination therapy of Ezetimibe and Atorvastatin's efficacy and Atorvastatin monotherapy's, the conclusions were controversial. Therefore, a systematic review and meta analysis of combination therapy and monotherapy were conducted., Methods: PubMed, Cochrane Library and Embase were searched for studies of the combination therapy of Ezetimibe and Atorvastatin and Atorvastatin monotherapy published up to October 20, 2017. Two investigators assessed the articles for eligibility and evaluated quality.The changed values and the efficacy of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), Total Cholesterol (TC) and Triglyceride (TG) indicators were the outcomes. Four doses of the comparisons were included: the combination therapy of Ezetimibe (10 mg) and Atorvastatin (10 mg) (E10 + A10) versus Atorvastatin (20 mg) monotherapy (A20); E10 + A10 vs. A10; E10 + A20 vs. A40; E10 + A40 vs. A80. Review manager software 5.1 was used for quality assessment and Stata version 12.0 software was used for statistical analysis., Results: eventeen studies (11 publications) were included in the meta analysis. Compared with Atorvastatin monotherapy, the overall efficacy of combination therapy of Ezetimibe and Atorvastatin on lowering LDL-C (MD = - 15.38, 95% CI: -16.17 to - 14.60; I 2  = 26.2%, n = 17), TC (MD = - 9.51, 95% CI: -10.28 to - 8.74; I 2  = 33.7%, n = 17) and TG (MD = - 6.42, 95% CI: -7.78 to - 5.06; I 2  = 0%, n = 15) and raising HDL-C (MD = 0.95, 95% CI: 0.34 to 1.57; I 2  = 0%, n = 17) was significant. The efficacy of the comparison on HDL-C was largely significant for the different doses., Conclusions: The overall efficacy and subgroup's efficacy of combination therapy of Ezetimibe and Atorvastatin on lowering LDL-C, TC and TG was significantly better than Atorvastatin monotherapy's. The overall and the E10 + A10/A20 group's effectiveness of combination therapy on rasing HDL-C were significantly.

Background: Lysosomal acid lipase deficiency is an autosomal recessive metabolic disease with a wide range of severity from Wolman Disease to Cholesterol Ester Storage Disease. Recently enzyme replacement therapy with sebelipase alpha has been approved by drug agencies for treatment of this lysosomal disease. Ezetimibe is an azetidine derivative which blocks Niemann Pick C1-Like 1 Protein; as its consequence, plasmatic concentration of low density lipoproteins and other apoB-containing lipoproteins, that are the substrate of lysosomal acid lipase, are decreased. Furthermore, ezetimibe acts by blocking inflammasome activation which is the cause of liver fibrosis in steatohepatitis and in lysosomal storage diseases., Results: Two patients with Cholesterol Ester Storage Disease were treated with ezetimibe for 9 years and a third patients for 10 years. Treatment was supplemented with low dose of atorvastatin in the first two patients during the last 6 years. All patients showed a significant reduction of alanine aminotransferase, cholesterol and triglyceride. Furthermore, no progression of liver fibrosis was demonstrated., Conclusion: In this observational case series, ezetimibe is effective, safe, and sustainable treatment for lysosomal acid lipase deficiency. Further studies are warranted to demonstrate that ezetimibe is an alternative therapy to enzyme replacement therapy.

Background: The utility of ezetimibe in preventing cardiovascular outcomes remains controversial. To guide future assessments of the effectiveness of ezetimibe in routine care, we evaluated how this medication has been prescribed to high-risk older adults in Ontario, Canada., Methods: Using linked healthcare databases, we carried out a population-based cohort study of older adults who were discharged from hospital following an acute myocardial infarction from 2005 until 2014. We ascertained the rate of ezetimibe initiation within 6 months of their discharge. We also examined the characteristics of new ezetimibe prescriptions, as well as the predictors for receiving the therapy., Results: Seventy one thousand one hundred twenty five older adults were hospitalized for an acute myocardial infarction between 2005 and 2014 (mean age 78.36 ± 7.71 years, 45.8% women). Only 1230 (1.7%) patients were newly prescribed ezetimibe within 6 months of their hospital discharge. The median duration of continuous use of ezetimibe was 1.2 years (IQR 0.3-3.5 years). Ezetimibe was prescribed more often to patients living in rural areas, with a history of coronary artery disease, on high-potency statins, and, with evidence of healthcare follow-up after hospital discharge. Prescriptions were less common in men, older patients, those living in long-term care facilities, those with a history of congestive heart failure, and those who were hospitalized for a myocardial infarction in more recent years., Conclusions: Real-world drug effectiveness studies can help to complement the findings of randomized controlled trials. In our region however, only a small proportion of high-risk older adults received a prescription for ezetimibe following a myocardial infarction. Clinical and research implications are discussed.

Background: Current international guidelines on dyslipidemia are not concordant on various aspects of management. Also, there are no uniformly accepted Indian guidelines. We, therefore, performed a physician survey to understand lipid management practices in India., Methods: An anonymous survey questionnaire was administered to gauge physicians' self-reported behavior regarding lipid management aspects. Results were expressed in terms of percentages based on the number of responses obtained., Results: A total of 404 physicians participated in the survey. Eighty-eight percent respondents ordered a lipid profile before starting statin therapy, and 80% preferred to set lipid targets, though the tools used for calculating cardiovascular risk varied. Atorvastatin was preferred over rosuvastatin in primary prevention (72.9 vs. 32.4%), secondary prevention (54.6 vs. 46.7%), diabetic patients (56.3 vs. 40.3%) and post-ACS (78.3 vs. 34%). High-intensity statins were preferred by 73.7% of respondents in post-ACS cases. Fifty percent doctors chose not to use a statin in diabetic patients, irrespective of their LDL-C levels. The most preferred drug option for managing atherogenic dyslipidemia and moderate hypertriglyceridemia was statin-fibrate combination (55.1%) and fibrates (35.4%), respectively. Sixty-three percent doctors preferred to prescribe statins in patients with moderately high LDL-C and normal triglycerides, without CHD or CHD risk equivalents. Around 28% of doctors preferred not to use pharmacotherapy for managing isolated low HDL. Of the participants, 73% used fibrates in ≤20% of their dyslipidemic patients, with fenofibrate being the most preferred (90.5%). Ezetimibe was mainly used in patients with uncontrolled LDL-C despite statin therapy (52.4% respondents). Most preferred approaches to manage statin intolerance included reducing statin dose (39%) and stopping and restarting statins at a lower dose (34.5%). Fifty-two percent of doctors chose not to alter pre-existing therapy in patients who had LDL-C levels at goal but elevated non-HDL-C levels., Conclusion: This is the first survey in India that provides useful insights into Indian physicians' self-reported perspectives on managing dyslipidemia in routine clinical practice. Despite concordance with the currently available guidelines in certain aspects, there is incongruence in managing specific dyslipidemia problems. Further continuing medical education and the development of evidence-based, India-specific lipid guidelines can help reduce some of these differences.

Background: Lowering cholesterol levels decreases the risk of atherosclerotic diseases. Effective ways to stably reduce LDL-C level are warranted in type 2 diabetic patients, a high-risk population for CVD, with various anti-diabetic therapeutic background. The RESEARCH study focuses on LDL-C reduction in this population along with modifications of the lipid profiles. We evaluated long-term ezetimibe add-on therapy in T2DM patients with hypercholesterolemia., Methods: In a randomized, multicenter, open-label, prospective study, a total of 109 T2DM patients not attaining LDL-C target value despite first-line dose statin (10 mg of atorvastatin or 1 mg of pitavastatin) therapy in Japan were recruited. We investigated the difference in cholesterol lowering effect between ezetimibe (10 mg) add-on statin (EAT) group and double-dose statin (DST) group. Changes of parameters related to atherosclerotic event risks were assessed., Results: The reduction of LDL-C was larger in the EAT group (28.3%) than in the DST group (9.2%) at 52 weeks as well as the primary endpoint of 12 weeks. EAT achieved significant lower levels of TC and apo B, respectively. Both treatments attained significant reduction in sd-LDL-C or hsCRP on this long-term basis. Notably, sd-LDL-C in EAT reduced as low as 36.1 ± 14.9 mg/dl to reach near the threshold (35.0 mg/dl) for atherosclerosis with significantly higher achievement rate (55.6%) than DST treatment. Simultaneously, hsCRP reduction by EAT attained as low value as 0.52 ± 0.43 mg/l., Conclusions: In the present 52-week long-term period, ezetimibe add-on therapy showed a robust advantage in lowering LDL-C and in attaining target LDL-C values compared with the doubling of statin dose. Moreover, it's meaningful that sd-LDL, powerfully atherogenic lipoprotein, exhibited prominent decrease consistently prominently by ezetimibe add-on therapy. DM patients with hypercholesterolemia are at high risk for CAD, and adding ezetimibe onto usual-dose statin treatment in Japan has been suggested as the first-line therapy for those DM patients who failed to attain the target LDL-C value (UMIN000002593).

Background: The influence of lipid-lowering therapy on high-density lipoprotein (HDL) is incompletely understood. We compared the effect of two lipid-lowering strategies on HDL functions and identified some HDL-related proteins., Methods: Thirty two patients were initially screened and HDLs of 21 patients were finally analyzed. Patients were randomized to receive atorvastatin 20 mg (n = 11) or atorvastatin 5 mg/ezetimibe 10 mg combination (n = 10) for 8 weeks. The cholesterol efflux capacity and other anti-inflammatory functions were assessed based on HDLs of the participants before and after treatment. Pre-specified HDL proteins of the same HDL samples were measured., Results: The post-treatment increase in cholesterol efflux capacities was similar between the groups (35.6% and 34.6% for mono-therapy and combination, respectively, p = 0.60). Changes in nitric oxide (NO) production, vascular cell adhesion molecule-1 (VCAM-1) expression, and reactive oxygen species (ROS) production were similar between the groups. The baseline cholesterol efflux capacity correlated positively with apolipoprotein (apo)A1 and C3, whereas apoA1 and apoC1 showed inverse associations with VCAM-1 expression. The changes in the cholesterol efflux capacity were positively correlated with multiple HDL proteins, especially apoA2., Conclusions: Two regimens increased the cholesterol efflux capacity of HDL comparably. Multiple HDL proteins, not limited to apoA1, showed a correlation with HDL functions. These results indicate that conventional lipid therapy may have additional effects on HDL functions with changes in HDL proteins., Trial Registration: ClinicalTrials.gov, number NCT02942602 .

Background: Rhabdomyolysis is a widely recognized yet rare complication in statin use. Rhabdomyolysis might be triggered by the prescription of high doses of statins or by statin accumulation due to interactions with concomitant medication. Muscle cell destruction as evidenced by myoglobin elevation can induce potentially life-threatening acute renal failure., Case Presentation: We report a case of a 70-year-old obese white man with sudden onset of severe rhabdomyolysis with consecutive renal failure. His medication included low-dose simvastatin, which he had taken for 6 years up until the event. The statin was withdrawn immediately. After 3 days of veno-venous hemofiltration his renal function was completely restored., Conclusions: Clinicians in both primary and special care might be unaware that side effects of statins do occur even after a long uneventful statin medication; they should be advised not to exclude that possibility upfront, even if a patient has tolerated the medication for years.

Background: This study was performed to compare the effects of three different lipid-lowering therapies (statins, ezetimibe, and colestimide) on lipoprotein lipase and endothelial lipase masses in pre-heparin plasma (pre-heparin LPL and EL mass, respectively) from patients with familial hypercholesterolemia (FH). FH is usually treated by coadministration of these three drugs., Methods: The pre-heparin LPL and EL masses were measured in fresh frozen plasma drawn and stored at various time points during coadministration of the three drugs from patients with heterozygous FH harboring a single mutation in the LDL receptor (n = 16, mean age 63 years). The patients were randomly divided into two groups based on the timing when ezetimibe was added., Results: Plasma LPL mass concentration was significantly reduced by rosuvastatin at 20 mg/day (median = 87.4 [IQR: 71.4-124.7] to 67.5 [IQR: 62.1-114.3] ng/ml, P < 0.05). In contrast, ezetimibe at 10 mg/day as well as colestimide at 3.62 g/day did not alter its level substantially (median = 67.5 [IQR: 62.1-114.3] to 70.2 [IQR: 58.3-106.2], and to 74.9 [IQR: 55.6-101.3] ng/ml, respectively) in the group starting with rosuvastatin followed by the addition of ezetimibe and colestimide. On the other hand, the magnitude in LPL mass reduction was lower in the group starting with ezetimibe at 10 mg/day before reaching the maximum dose of 20 mg/day of rosuvastatin. Plasma EL mass concentration was significantly increased by rosuvastatin at 20 mg/day (median = 278.8 [IQR: 186.7-288.7] to 297.0 [IQR: 266.2-300.2] ng/ml, P < 0.05), whereas other drugs did not significantly alter its level., Conclusion: The effects on changes of LPL and EL mass differed depending on the lipid-lowering therapy, which may impact the prevention of atherosclerosis differently.

Background: Metabolic syndrome (MetS) and insulin resistance (IR) are increasing in prevalence, are associated with higher risk for coronary heart disease (CHD), and may potentially influence the responses to lipid-altering drug therapy. This study evaluated the effects of MetS factors (abdominal obesity, depleted high-density lipoprotein cholesterol [HDL-C], and elevated triglycerides, blood pressure, and fasting glucose) and IR on ezetimibe/simvastatin and atorvastatin treatment efficacy in patients with MetS., Methods: This post-hoc analysis of a multicenter, 6-week, double-blind, randomized, parallel group study of 1128 subjects with hypercholesterolemia, MetS, and moderately high/high CHD risk evaluated the effects of baseline MetS factors/IR on percent change from baseline in lipids, apolipoproteins, and high-sensitivity C-reactive protein (hs-CRP), after treatment with the usual starting doses of ezetimibe/simvastatin (10/20 mg) versus atorvastatin (10 mg, 20 mg) and next higher doses (10/40 mg versus 40 mg)., Results: Ezetimibe/simvastatin and atorvastatin efficacy was generally consistent across MetS factor/IR subgroups. Ezetimibe/simvastatin produced greater incremental percent reductions in LDL-C, non-HDL-C, apolipoprotein B, total cholesterol, and lipoprotein ratios for all subgroups, and larger percent increases in HDL-C and apolipoprotein AI for all but non-obese and HDL-C ≥ 40 mg/dL subgroups than atorvastatin at the doses compared. Triglycerides, very-LDL-C, and hs-CRP results were more variable but similar between treatment groups., Conclusion: The magnitude of lipid-altering effects produced by each treatment regimen was generally similar across all MetS and IR subgroups. Ezetimibe/simvastatin produced greater percent reductions in most lipid fractions than atorvastatin at the dose comparisons studied, and all treatments were generally well tolerated. (Registered at clinicaltrials.gov: NCT00409773).

Background: HIV-infected patients on antiretroviral therapy frequently develop dyslipidemias and, despite therapy with potent lipid-lowering agents, a high percentage does not achieve guideline recommended lipid targets. In this study, we examined the efficacy of combination treatment with a statin and the cholesterol transport blocker, ezetimibe, vs. monotherapy with a statin in HIV-infected patients not achieving lipid goals., Methods: This was a 12-week, prospective, randomized, open-label clinical trial. Patients were eligible if they had an apolipoprotein B (apoB) >0.80 g/L despite therapy with rosuvastatin 10 mg daily for a minimum of 12 weeks. Patients were randomized to take ezetimibe 10 mg/rosuvastatin 10 mg or rosuvastatin 20 mg for 12 weeks. Percentage and absolute change in apoB (primary outcome), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), non-HDL-C, apoliporpotein A1 (apoA1), apoB/apoA1, TC/HDL-C, atherogenic index of plasma (API), and high-sensitivity C-reactive protein (hsCRP) were compared. Changes in safety parameters (such as AST, ALT, CK) and clinical symptoms were also assessed., Results: Forty-three patients (23 on ezetimibe 10 mg/rosuvastatin 10 mg and 20 on rosuvastatin 20 mg) completed the trial. Baseline characteristics did not differ between the groups. Significant improvements in apoB were seen with both ezetimibe plus rosuvastatin (mean of -0.17 g/L, p < 0.001) and rosuvastatin 20 mg (mean of -0.13 g/L, p = 0.03) treatment groups, but did not differ between groups (p = 0.53). Significant between-group differences were observed for mean TC (-1.01 mmol/L vs. -0.50 mmol/L, p = 0.03), TG (-0.62 mmol/L vs -0.17 mmol/L, p = 0.03), and non-HDL-C (-0.97 mmol/L vs. -0.53 mmol/L, p = 0.03) all in favour of the ezetimibe plus rosuvastatin group. Two patients, both in the rosuvastatin 20 mg group, experienced mild myalgias; neither discontinued the study., Conclusions: The addition of ezetimibe to rosuvastatin appears to be safe in patients with HIV. Furthermore, the combination of ezetimibe and rosuvastatin improved TG, AIP and non-HDL cholesterol levels more than a dose increase in rosuvastatin in patients with HIV-associated dyslipidemia.

Background: Goal attainment of guideline-recommended low-density lipoprotein cholesterol (LDL-C) is suboptimal. Little is known about how patient factors influence physicians' treatment decision-making in hypercholesterolemia. We examined physicians' treatment recommendations in high-risk patients whose LDL-C remained uncontrolled despite statin monotherapy., Methods: Physicians completed a questionnaire prior to randomization into period I of a two-period randomized controlled trial evaluating LDL-C goal attainment in patients whose LDL-C remained ≥100 mg/dL after 5 weeks' treatment with atorvastatin 10 mg/day (NCT01154036). Physicians' treatment recommendations were surveyed for two hypothetical and one real scenario: (1) LDL-C presumed near goal (between 100-105 mg/dL), (2) LDL-C presumed far from goal (~120 mg/dL), and (3) observed baseline LDL-C of enrolled patients. Prognostic factors considered during decision-making were identified by regression analysis. Observed lipid outcomes at the end of period I (following 6 weeks' treatment with ezetimibe 10 mg plus atorvastatin 10 mg, atorvastatin 20 mg, or rosuvastatin 10 mg) were compared with estimated LDL-C outcomes for physicians' treatment recommendations after 6 weeks (based on individual patients' pre-randomization LDL-C and expected incremental change)., Results: Questionnaires were completed for 1,534 patients. No change in therapy, or double atorvastatin dose, were frequently recommended, even when LDL-C was far from goal (6.5% and 52.2% of patients, respectively). Double atorvastatin dose was commonly recommended in all scenarios (43-52% of patients). More intensive LDL-C-lowering regimens were recommended infrequently e.g. double atorvastatin dose and add ezetimibe only <12% in all scenarios. Overall, cardiovascular risk factors and desire to achieve a more aggressive LDL-C goal were prominent factors in decision-making for treatment. Comparison of observed and estimated LDL-C levels showed that physicians tended to overestimate the effectiveness of their recommendations., Conclusions: This study provides insight into physicians' perspectives on clinical management of hypercholesterolemia and highlights a gap in knowledge translation from guidelines to clinical practice. The need for lower LDL-C and cardiovascular risk were key drivers in clinical decision-making, but physicians' treatment choices were more conservative than guideline recommendations, potentially resulting in poorer LDL-C reduction. When compared with actual outcomes, projected LDL-C control was better if physicians used more comprehensive strategies rather than simply doubling the statin dose., Trial Registration: Clinicaltrials.gov: NCT01154036.

Background: Recent evidence points to an increased incidence of new-onset diabetes and a negative impact on glucose parameters with statin use. This study examined the safety of ezetimibe vs placebo for change from baseline to week 24 in HbA1c (primary endpoint), glycoalbumin, and fasting plasma glucose (secondary endpoints) in Japanese subjects with type 2 diabetes and hypercholesterolemia., Methods: This was a randomized, double-blind, placebo-controlled, parallel-group, multi-site trial. Adults with type 2 diabetes and hypercholesterolemia whose LDL-C measured <140 mg/dl (subjects receiving lipid-lowering drugs) or <160 mg/dl (subjects not receiving lipid-lowering drugs) at the start of the screening phase, were randomized after a 5-week wash-out period to ezetimibe 10 mg or placebo (1:1) for 24 weeks. Changes in HbA1c, glycoalbumin and fasting plasma glucose from baseline to week 24 were evaluated. The non-inferiority margin was set at 0.5% for HbA1c., Results: Overall, 152 subjects were randomized (75 to ezetimibe and 77 to placebo). From baseline to 24 weeks, HbA1c significantly increased in both the ezetimibe and placebo groups (between-treatment difference 0.08 [95% CI: -0.07 to 0.23]). Ezetimibe was statistically non-inferior to placebo. At 24 weeks, the mean change from baseline in glycoalbumin levels (between-treatment differences 0.00 [95% CI: -0.47, 0.47]) and fasting plasma glucose (between-treatment differences -4.8 [95% CI: -12.1, 2.1]) were similar in both treatment groups., Conclusions: These results suggest that ezetimibe 10 mg does not result in dysregulation of glucose metabolism in Japanese patients with type 2 diabetes and hypercholesterolemia over 24 weeks of treatment., Trial Registration: ClinicalTrials.gov identifier NCT01611883 .

Background: Elevated cholesterol in type 2 diabetes mellitus (DM) can cause endothelial dysfunction. An effective clinical therapy to improve endothelial dysfunction remains to be established. Different cardiovascular actions between treatments for the inhibition of cholesterol absorption and the suppression of cholesterol synthesis for achieving improvement in endothelial function are unknown in DM., Methods: Stable patients with type 2 DM and mildly elevated low-density lipoprotein cholesterol were enrolled. We evaluated peripheral microvascular endothelial function using reactive hyperemia peripheral arterial tonometry (RH-PAT) examination and calculated a natural logarithmic transformed value for the RH-PAT index (LnRHI). We randomly assigned 33 patients to each monotherapy: cholesterol synthesis suppression using atorvastatin (5 mg/day, n=16) or cholesterol absorption inhibition using ezetimibe (10 mg/day, n=17). Patients were prospectively followed for 6 months. Serum lipids and LnRHI were repeatedly examined before and after each therapy., Results: LDL significantly decreased in both groups, but the percent changes of LDL showed a greater decrease in the atorvastatin group compared with the ezetimibe group (-34.5±7.8% vs. -21.9±9.6%, p<0.01). Serum levels of non-esterified free fatty acids (NEFA) significantly decreased in the ezetimibe group but not in the atorvastatin group (ezetimibe group: 561.1±236.8 to 429.7±195.9, p<0.01; atorvastatin group: 538.8±319.5 to 520.2±227.3, p=0.75). The percent decrease in NEFA was significantly greater in the ezetimibe group compared with the atorvastatin group (-19.9±27.4% vs. 11.3±44.1%, p<0.05). LnRHI showed a significant increase in the ezetimibe group but not in the atorvastatin group (ezetimibe group: 0.471±0.157 to 0.678±0.187, p<0.01; atorvastatin group: 0.552±0.084 to 0.558±0.202, p=0.64). The percent changes in LnRHI were significantly greater in the ezetimibe group compared with the atorvastatin group (63.3±89.2% vs. 7.4±41.2%, p<0.05)., Conclusions: In patients with type 2 DM, ezetimibe monotherapy significantly reduced LDL and NEFA, and improved peripheral microvascular endothelial dysfunction. Ezetimibe could potentially exhibit beneficial effects on lipid disorders and microvascular endothelial dysfunction in DM.

Background: Dyslipidemia management situation in Chinese patients with high risk and very high risk has been demonstrated very low, despite the wide use of statins. The effects and safety of the combined treatment of ezetimibe (EZ) and statins in Chinese patients with acute coronary syndrome (ACS) and type 2 diabetes mellitus (T2DM) remain unknown., Methods: Chinese Patients with ACS and T2DM were divided into the statins group (n=40) and the combination group of EZ and statins (n=44). In order to evaluate the clinical effects on lipids-lowering, systemic inflammation response and clinical safety, the follow-up of all patients was carried out at day 7th and 30th after treatment., Results: The level of low-density lipoprotein cholesterol (LDL-C) in combination group and statins group was 1.87±0.42 and 2.18±0.58 mmol/L at day 7th, 1.51±0.29 and 1.94±0.49 mmol/L at day 30th, respectively. The control rates of LDL-C level in the combination group and the statins group were 77% and 45% at day 30(th), respectively. There was no significant improvement on high-density lipoprotein cholesterol (HDL-C) level during follow-up. The triglyceride (TG) levels were significantly reduced in both groups, while no obvious difference was observed between two groups. No significant difference on serum high-sensitivity C-reactive protein (hs-CRP) level between two groups was observed. Moreover, we did not observe any significant correlation between serum lipids levels and serum hs-CRP level during follow-up. The liver dysfunction and muscle related side effects (MRSE), creatine kinase (CK) and myopathy were not observed in both groups., Conclusion: Our study demonstrated that it is feasible to initiate combination therapy during acute phase for Chinese patients with ACS and T2DM, which can bring more significant effect on LDL-C-lowering and improve the control rate of LDL-C level with good safety.

Background: Ezetimibe ameliorates serum low-density lipoprotein cholesterol (LDL-c) and it has been approved for the treatment of hypercholesterolemia. However, the effects of ezetimibe on specific biomarkers have not been fully clarified in obese Japanese patients., Methods: A total of 101 patients (47 males and 54 females) were registered in this study during 2011 and 2012. All patients were over 20 years old, were obese [body mass index (BMI) ≥ 25 kg/m(2)] and had hypercholesterolemia (LDL-c ≥ 120 mg/dl). After excluding 10 subjects (7 who dropped out and 3 with missing data), 91 patients (39 males and 52 females) were analyzed. They were treated with 10 mg ezetimibe once a day for 24 weeks and were evaluated at 12 and 24 weeks., Results: Following 12 weeks of ezetimibe therapy, BMI (p < 0.001), waist circumference (p < 0.001), total cholesterol (p < 0.001), LDL-c (p < 0.001), non high-density lipoprotein cholesterol [HDL-c] (p < 0.001), triglycerides (p < 0.05) and remnant-like particle cholesterol (RLP-c; p < 0.001) were significantly decreased. Following 24 weeks of ezetimibe therapy, BMI (p < 0.05), waist circumference (p < 0.001), total cholesterol (p < 0.001), LDL-c (p < 0.001), non HDL-c (p < 0.001), triglycerides (p < 0.05), RLP-c (p < 0.001), insulin (p < 0.05) and hepatocyte growth factor (HGF; p < 0.05) were significantly decreased. In contrast, HDL-c (p < 0.001) was significantly increased., Conclusions: Ezetimibe ameliorated not only atherogenic lipid profiles but also anthropometric factors, insulin resistance and biomarkers such as HGF. Ezetimibe may have pleiotropic effects on obese patients with hypercholesterolemia.