Combination Of Ezetimibe Research Articles

Abstract 10315: Cost-Effectiveness of Bempedoic Acid in Patients with Established Atherosclerotic Cardiovascular Disease

Introduction: Non-statin therapies may improve long-term outcomes in patients with atherosclerotic cardiovascular disease (ASCVD) who experience statin-associated side effects (SASE). Objective: To examine the cost-effectiveness of a newly approved combination of bempedoic acid and ezetimibe (BAEze) in patients with ASCVD from a U.S. healthcare sector perspective. Methods: State-transition Markov model of US adults with ASCVD and low-density lipoprotein cholesterol (LDL-C) ≥70mg/dL on maximally tolerated statin and ezetimibe. The study cohort was stratified by concurrent statin use: high-intensity (group1), moderate-/low-intensity (group 2), or no statin due to severe SASE (group 3). The intervention group received BAEze (annual cost $2,447) instead of ezetimibe. We estimated baseline LDL-C from NHANES; relative LDL-C lowering and rate of adverse events from randomized trials; and the relationship between LDL-C lowering and cardiovascular events from meta-analyses of statin trials. The main outcome was lifetime incremental cost-effectiveness ratio (ICER), with a threshold of $100,000 per quality-adjusted-life-year (QALY) gained. Results: BAEze had an ICER of $188,000/QALY in group 1 (95% UI: 141,500-284,600; cost-effective in 0% of 10,000 probabilistic simulations) and $175,600/QALY (132,700-264,700; cost-effective in 0% simulations) in group 2. In group 3, BAEze produced 0.28 incremental QALYs at a lifetime cost of $25,600, yielding an ICER of $92,600/QALY (66,000-152,100; cost-effective in 59% simulations). Conclusions: Among US adults with ASCVD, cost-effectiveness of BAEze varies substantially by concurrent statin use, and only meets conventional cost-effectiveness thresholds among patients unable to take a statin due to severe SASE. Our findings argue for the selective use of BAEze among patients with ASCVD and severe SASE but should be updated when more data on long-term effectiveness and safety become available.

LDLc reduction with fixed-dose combination rosuvastatin-ezetimibe in patients with coronary heart disease that are not candidates for PCSK9 inhibitors treatment

Abstract Background Statin plus ezetimibe combination has a recommendation class IIa, level of evidence B, for low-density lipoprotein cholesterol (LDLc) reduction. Since LDLc treatment target for patients with coronary heart disease (CHD) has been recently reduced to <55 mg/dl most patients might need lipid-lowering drugs combinations and fixed-dose combinations are known to increase adherence. Current indications for PCSK9 inhibitors accepted for reimbursement in Spain in patients with CHD are LDL >100 mg/dl despite maximal dose tolerated of statins or any of previous patients with statin intolerance and LDL >100 mg/dl. Methods Investigator-initiated retrospective analysis of patients with coronary heart disease that received fixed-dose combination with rosuvastatin-ezetimibe between 2019 and 2020 in a specialized unit for patients with CHD. Inclusion criteria were: CHD and LDLc <100 mg/dl despite statin treatment or >100 mg/dl without previous lipid-lowering treatments. We also analysed patients in whom treatment was initiated at discharge from and acute coronary syndrome (ACS) or with chronic coronary syndrome (CCS) Results We analyzed 137 patients, 79.4% males, mean age 62. (12.3) and 24.1% with ACS. Statin treatment before initiation fixed-dose combination was higher in patients with CCS (71.2% vs. 8.2%; p<0.01). Mean LDLc before treatment was 103.0 (30.5) mg/dl and it was higher in patients with ACS (121.3 (40.2) vs. 97.4 (24.4); p<0.001). Median time to second blood test was 203 days (IQR 122–300); mean post-treatment LDLc was 60.8 (21.2) mg/dl and no difference (p=0.18) was found in patients with ACS vs CCS: 56.0 (26.1) vs. 62.4 (19.2) mg/dl. Mean LDLc reduction was 38.5% and it was higher in was higher in ACS patients (49.9% vs. 34.7%) (figure). LDLc <55 mg/dl was achieved in 42.1% of the patients, more frequently in patients with ACS: 59.3% vs. 36.3% (p=0.036). No increase in transaminases was detected and a reduction in triglycerides was found (149.1 (100.4) to 124.7 (82.3) mg/dl; p=0.041). Conclusions Treatment with a fixed-dose combination with rosuvastatin-ezetimibe in patients with CHD not candidate for PCSK9 inhibitors is effective and safe for LDLc reduction especially in patients discharged after an ACS. Funding Acknowledgement Type of funding sources: None.

Stability Indicating Method Development and Validation for the Estimation of Bempedoic Acid and Ezetimibe by Reverse Phase– Ultra Performance Liquid Chromatography

A simple, accurate, precise method was developed to simultaneously estimate the bempedoic acid (BEM) and ezetimibe (EZT) in bulk and pharmaceutical dosage form using RP-UPLC. Combination of bempedoic acid and ezetimibe is used to treat adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease. Chromatographic separation was carried out using X-Bridge phenyl 150 x 4.6 mm, 3.5 μ column at a 1.0 mL/min flow rate. The mobile phase consisted of 0.1% formic acid buffer and acetonitrile (70:30%v/v). The retention times of BEM and EZT were found to be 1.157 and 3.208 minutes, respectively. The temperature was maintained at ambient. The optimized wavelength for BEM and EZT was 230 nm. The method developed has been statistically validated according to ICH guidelines. %RSD of BEM and EZT were and found to be 0.6 and 1.4, respectively. %Recovery was obtained as 100.0% and 101.40% for BEM and EZT, respectively. LoD, LoQ values were obtained from regression equations of Bempedoic acid and Eetimibe were 0.27 μg/mL, 0.015 μg/mL and 2.7 μg/mL, 0.15 μg/mL respectively. The method obeys Beer’s law in the concentration range of 27–337.5 μg/mL (R2 = 0.9991) for BEM, and 1.5–18.75 μg/mL (R2 = 0.9993) for EZT. The method showed good reproducibility and recovery with %RSD less than 2. Forced degradation studies established the stability-indicating capability of the method under stress conditions like acid, base, peroxide, UV, thermal, humidity. Retention times were decreased and that run time was decreased. Hence, the chromatographic method developed was simple and economical and can be adopted in regular quality control test in Industries. It is said to be rapid, specific, sensitive, robust, and reliable and can be effectively applied for routine analysis in research institutions, quality control departments in industries.

The Effects of Statin Dose, Lipophilicity, and Combination of Statins plus Ezetimibe on Circulating Oxidized Low-Density Lipoprotein Levels: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Background Elevated plasma low-density lipoprotein cholesterol (LDL-C) is the main risk factor for atherosclerotic cardiovascular disease (ASCVD). Statins are the drugs of choice for decreasing LDL-C and are used for the prevention and management of ASCVD. Guidelines recommend that subjects with high and very high ASCVD risk should be treated with high-intensity statins or a combination of high-intensity statins and ezetimibe. The lipophilicity or hydrophilicity (solubility) of statins is considered to be important for at least some of their LDL-C lowering independent pleiotropic effects. Oxidative modification of LDL (ox-LDL) is considered to be the most important atherogenic modification of LDL and is supposed to play a crucial role in atherogenesis and ASCVD outcomes. Objective The aim of this systematic review and meta-analysis was to find out what are the effects of statin intensity, lipophilicity, and combination of statins plus ezetimibe on ox-LDL. Methods PubMed, Scopus, Embase, and Web of Science were searched from inception to February 5, 2021, for randomized controlled trials (RCTs). Two independent and blinded authors evaluated eligibility by screening the titles and abstracts of the studies. Risk of bias in the studies included in this meta-analysis was evaluated according to the Cochrane instructions. Meta-analysis was performed using Comprehensive Meta-Analysis (CMA) V2 software. Evaluation of funnel plot, Begg's rank correlation, and Egger's weighted regression tests were used to assess the presence of publication bias. Results Among the 1427 published studies identified by a systematic databases search, 20 RCTs were finally included in the systematic review and meta-analysis. A total of 1874 patients are included in this meta-analysis. This meta-analysis suggests that high-intensity statin treatment is associated with a significant decrease in circulating concentrations of ox-LDL when compared with low-to-moderate treatment (SMD: -0.675, 95% CI: -0.994, -0.357, p < 0.001; I2: 55.93%). There was no difference concerning ox-LDL concentration between treatments with hydrophilic and lipophilic statins (SMD: -0.129, 95% CI: -0.330, -0.071, p = 0.206; I2: 45.3%), but there was a significant reduction in circulating concentrations of ox-LDL associated with statin plus ezetimibe combination therapy when compared with statin monotherapy (SMD: -0.220, 95% CI: -0.369, -0.071, p = 0.004; I2: 0%). Conclusion High-dose statin or combination of statins with ezetmibe reduces plasma ox-LDL in comparison low-to-moderate intensity statin therapy alone. Statin lipophilicity is not associated with reduction in ox-LDL plasma concentrations.

Adherence to Lipid-Lowering Treatment by Single-Pill Combination of Statin and Ezetimibe.

IntroductionAlthough several studies have shown that a simplified cardiovascular drug treatment leads to better treatment adherence, limited and conflicting findings have been reported on the separate or single-pill combination of the now recommended association between a statin and ezetimibe. We addressed this issue in a large cohort of patients newly treated with statins to whom ezetimibe was additionally administered, either separately or as a single-pill combination.MethodsA total of 256,012 patients (age 40–80 years) from the Lombardy Region (Italy) newly treated with statins during 2011–2013 were followed until 2018 to identify those to whom ezetimibe was added. The 2881 and 5351 patients who started a two-pill or a single-pill combination, respectively, of statin and ezetimibe were identified and matched for propensity score. Adherence to drug therapy at 1 year was measured as the ratio between the number of days in which the drug was available and the days of follow-up (the proportion of days covered; PDC). Patients who had a PDC > 75% or < 25% were, respectively, defined as highly and poorly adherent to drug therapy. Analysis was extended to the association between adherence and the risk of fatal/non-fatal cardiovascular events.ResultsCompared to those prescribed a two-pill combination, those prescribed a single-pill combination had an 87% (75–99%) greater odds of being highly adherent and a 79% (72–84%) lower odds of being poorly adherent to treatment. These advantages were manifest in all strata of age, sex, and clinical profile. The risk of cardiovascular outcomes decreased by 55% in patients with high adherence compared to those with low adherence.ConclusionPatients who were prescribed a single-pill combination of statin/ezetimibe more frequently exhibit a good adherence and less frequently bad adherence to treatment than those prescribed a two-pill combination of these drugs.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-021-01892-7.

Effects of Fixed-dose Combination of Low-intensity Rosuvastatin and Ezetimibe Versus Moderate-intensity Rosuvastatin Monotherapy on Lipid Profiles in Patients With Hypercholesterolemia: A Randomized, Double-blind, Multicenter, Phase III Study

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

Effect of Atorvastatin (10 mg) and Ezetimibe (10 mg) Combination Compared to Atorvastatin (40 mg) Alone on Coronary Atherosclerosis

It remains inconclusive whether the additional low-density lipoprotein cholesterol (LDL-C) lowering effects of ezetimibe added to statin on coronary atherosclerosis and clinical outcomes are similar to those of statin monotherapy in the setting of comparable LDL-C reduction. We aimed to determine whether there were distinguishable differences in their effects on coronary atherosclerosis with intermediate stenosis between the combination of moderate-intensity statin plus ezetimibe and high-intensity statin monotherapy. Forty-one patients with stable angina undergoing percutaneous coronary intervention were randomized to receive either atorvastatin 10 mg plus ezetimibe 10 mg (ATO10/EZE10) or atorvastatin 40 mg alone (ATO40). The intermediate lesions were evaluated using a near-infrared spectroscopy-intravascular ultrasonography at baseline and after 12 months in 37 patients. The primary endpoint was percent atheroma volume (PAV). Mean LDL-C levels were significantly reduced by 40% and 38% from baseline in the ATO10/EZE10 group (n=18, from 107 mg/dL to 61 mg/dL) and ATO40 group (n=19, from 101 mg/dL to 58 mg/dL), respectively, without between-group difference. The absolute change of PAV was -2.9% in the ATO10/EZE10 group and -3.2% in the ATO40 group. The mean difference (95% confidence interval) for the absolute change in PAV between the 2 groups was 0.5% (-2.4% to 2.8%), which did not exceed the pre-defined non-inferiority margin of 5%. There was no significant reduction in lipid core burden index in both groups. In conclusion, the combination of atorvastatin 10 mg and ezetimibe 10 mg showed comparable LDL-C lowering and regression of coronary atherosclerosis in the intermediate lesions, compared with atorvastatin 40 mg alone.

A REVIEW ON CLINICAL OUTCOMES OF BEMPEDOIC ACID AS ADD-ON THERAPY WITH EZETIMIBE FOR THE TREATMENT OF HYPERLIPIDEMIA

Background: Cardiovascular complications are one of the leading causes of global mortality. Statins are intended to produce beneficial effects in reducing the risk of morbidity and mortality in cardiovascular patients. However, it becomes negligible in statin intolerant patients mainly due to muscle related symptoms. Objective: The objective of the study is to summarize the results of the studies available on safety and efficacy of bempedoic acid/ezetimibe combination treatment in statin intolerant patients. Methods: After comprehensive literature survey, in Cochrane Library, PubMed, Embase and Medline, randomized controlled studies involving statin intolerant hyperlipidemia, patients with low- density lipoprotein ≥200 mg/dl and at high risk of cardiovascular disease treated with Bempedoic acid and ezetimibe combination were selected. Results: For final quality analysis two clinical trials were selected to assess the safety and efficacy of the combination of Bempedoic acid and Ezetimibe. Data shows Bempedoic acid and Ezetimibe combination significantly lowered the low-density lipoprotein compared to the control groups (placebo vs Bempedoic acid vs ezetimibe). In addition, the data shows significant reduction in highly sensitive C- reactive protein, non-high density lipoprotein cholesterol, total cholesterol and apolipoprotein B. Conclusion: Overall, we conclude that the combination of Bempedoic acid and Ezetimibe can be considered as a treatment of choice for the treatment of hyperlipidemia for patients with statin-intolerance or maximally tolerated even to low-dose statins.

Patient"s awareness of recommended LDL-C goals in primary prevention and observed achievement

Abstract Funding Acknowledgements Type of funding sources: None. Introduction The novel 2019 ESC/EAS Guidelines on lipids recommend more intensive reduction on LDL-C across CV risk categories in comparison with the 2016 edition. Purpose This cross-sectional observation study aims to assess whether patients on lipid lowering therapy, as a primary prevention measure, are aware of the new set goals and if they achieved them. Methods Patients, taking currently any statin as a primary prevention measure, visiting the Emergency Department of a tertiary hospital in northern Greece were invited to participate by answering a short questionnaire followed by a phone call to provide the exact lab results or other details. Results In total 412 eligible patients (54.1% female) were enrolled from January to October 2020 (mean age 61 ± 13 years old). Mean duration of statin prescription was about 8 years (7.8 ± 5 years). The majority (381, 92.5%) of patients reported lab tests yearly while most of them (394, 95.6%) were being followed up in outpatient clinics or private offices. Patients were allocated into CV categories: low (48, 11.7%), medium (239, 58.0%), high (108, 26.2%) and very high (17, 4.1%). The estimated 10-year risk of CV death was calculated using SCORE. Almost two thirds of the patients (282, 68.4%) were taking moderate intensity statins (as monotherapy) while one out of ten (45, 10.9%) was taking a statin plus ezetimibe combination. No patient was prescribed a PCSK9 inhibitor. Only two out of five (171, 41.5%) patients reached the LDL-C goal, though differences were noted between risk categories with almost half of the low and medium CV risk patients achieving the desired LDL-L level: low (23, 47.9%), medium (124, 51.9%), high (21, 19.4%) and very high (3, 17.6%). No significant difference was observed in terms of potency of statin. As expected, patients taking a statin and ezetimibe combination achieved lower LDL-C levels, with almost two thirds (31 out of 45 patients, 68.9%) reaching the goal. No information could be collected regarding why patients not reaching the goal were not offered a statin of higher potency and/or dosing, a combination with ezetimibe or a PCSK9 inhibitor. Disturbingly enough, none of the patient was aware that the LDL-C goals recommended by scientific societies had been lowered in 2019, while only 29 patients (7.0%) could recall discussing LDL-C goals with their physician. Moreover, merely three patients could remember the calculation of any CV risk score. The majority of the patients (379, 92.0%) reported that they would like to know their personal CV risk score and their LDL-C goal. Conclusions Greek primary prevention patients taking statins are overall unaware of the novel set LDL-C goals and it seems that they have not been offered a total CV risk score assessment. Hardly acceptable attainment of LDL-C goals was observed. Further research is warranted to assess the barriers that obstruct a satisfactory goal achievement. Abstract Figure.

Preoperative cardiovascular assessment as an opportunity to (re)affirm the 2019 ESC/EAS guidelines recommended LDL-C goal

Abstract Funding Acknowledgements Type of funding sources: None. Introduction The novel 2019 ESC/EAS Guidelines on lipids recommend a more intensive reduction on LDL-C across CV risk categories in comparison with the 2016 edition. Purpose This cross-sectional observation study aimed to assess whether patients on lipid lowering therapy were aware of the new set LDL-C goals and if they achieved them. Methods Patients, taking at the time any statin, attending the preoperative CV assessment outpatient clinic at a city hospital in northern Greece were invited to participate. Results In total 625 eligible patients (45.1% female) were enrolled during 2020 (mean age 67 ± 9 years old). Mean duration of statin prescription was about 10 years (9.7 ± 7 years). About two thirds of the patients (402, 64.3%) had established atherosclerotic cardiovascular disease (ASCVD) and the rest were allocated into CV risk categories: low (24, 10.8%), medium (135, 60.5%), high (59, 26.5%) and very high (5, 2.2%). The estimated 10-year risk of CV death was calculated using SCORE. The majority (552, 88.3%) of the patients reported lab tests at least biannually. The majority of the participants (556, 89.0%) were taking a statin as monotherapy of either low (17, 2.7%), medium (237, 37.9%) or high (302, 48.3%) potency. One tenth (65, 10.4%) were prescribed a combination of ezetimibe with a medium or high potency statin. Lastly, only four patients (0.6%) were prescribed a PCSK9 inhibitor. Less than a quarter of the participants (143, 22.9%) had achieved the recommended LDL-C levels. Approximately, one out of six patients with established ASCVD had a LDL-C lower than 55mg/dL (68, 16.9%), while only one out of three primary prevention patients (75, 33.6%) had reached the LDL-C levels recommended for their allocated risk category. As expected, the higher the potency of the statin, the higher the percentage of patients reaching the goal. Moreover, twelve out of the sixty five the patients (18.5%) on ezetimibe combination therapy achieved the LDL-C goal. Lastly, three of the four patients (75.0%) on a PCSK9 inhibitor had attained the desired LDL-C level. No information could be collected regarding why patients not reaching the goal were not offered a statin of higher potency and/or dosing, a combination with ezetimibe or a PCSK9 inhibitor, accordingly. Disturbingly enough, none of the patient was aware that the LDL-C goals recommended by scientific societies had been lowered in 2019, although 94 patients (15.0%) could recall discussing LDL-C goals with their physician. The majority of the patients (427, 93.0%) reported that they would like to know the recommended (personal) LDL-C goals. Conclusions Greek patients taking statins were overall unaware of the novel set LDL-C goals. Hardly acceptable attainment of the LDL-C goal was observed. The preoperative assessment visit can be used to monitor the guidelines implementation. Further research is warranted to assess the barriers that obstruct a satisfactory goal achievement. Abstract Figure. Patients achieving LDL-C goal

Attainment of the 2019 ESC/EAS recommended LDL-C goal in Greek patients with established atherosclerotic cardiovascular disease

Abstract Funding Acknowledgements Type of funding sources: None. Introduction The novel 2019 ESC/EAS Guidelines on lipids recommend a more intensive reduction on LDL-C for patients with established atherosclerotic cardiovascular disease (ASCVD) in comparison with the 2016 edition. Purpose This cross-sectional observation study aims to assess whether patients on lipid lowering therapy, as a secondary prevention measure, are aware of the new set goals and if they achieved them. Methods Patients with known ASCVD, taking currently any statin, visiting the Emergency Department of a tertiary hospital in northern Greece were invited to participate by answering a short questionnaire followed by a phone call to provide the exact lab results or other details. Data were analyzed with the SPSS software version 20.0 for Windows (SPSS Inc., Chicago, Illinois, USA) Results In total 459 eligible patients (37.9% female) were enrolled from January to October 2020 (mean age 68 ± 12 years old). Mean duration of statin prescription was about 11 years (11.2 ± 6 years). The majority (431, 93.9%) of the patients reported lab tests yearly. The majority of the participants (406, 88.5%) were taking a statin as monotherapy of either low (11, 2.4%), medium (174, 37.9%) or high (221, 48.1%) potency. One tenth (50, 10.9%) were prescribed a combination of ezetimibe with a medium or high potency statin. Lastly, only three patients (0.7%) were prescribed a PCSK9 inhibitor. Approximately, one out of six patients had a LDL-C lower than 55mg/dL (78, 17.0%). As expected, the higher the potency of the statin, the higher the percentage of patients reaching the goal: low (1 of 11 patients, 9.1%), medium (21 of 174 patients, 12.1%) and high potency (45 of 221 patients, 20.4%). Moreover, nine out of the fifty the patients (18.0%) on ezetimibe combination therapy achieved the LDL-C goal. Lastly, two of the three patients (66.7%) on a PCSK9 inhibitor had attained the desired LDL-C level. No information could be collected regarding why patients not reaching the goal were not offered a statin of higher potency and/or dosing, a combination with ezetimibe or a PCSK9 inhibitor, accordingly. Disturbingly enough, none of the patient was aware that the LDL-C goals recommended by scientific societies had been lowered in 2019, although 71 patients (15.5%) could recall discussing LDL-C goals with their physician, even though none of the patients recalled the limit of 55mg/dL. The majority of the patients (427, 93.0%) reported that they would like to know their personal LDL-C goal. Conclusions Greek patients with established ASCVD taking statins are overall unaware of the novel set LDL-C goals. Hardly acceptable attainment of the LDL-C goal was observed. Further research is warranted to assess the barriers that obstruct a satisfactory goal achievement. Abstract Figure. Patients achieving LDL-C goal

Umbrella Review on Non-Statin Lipid-Lowering Therapy.

The main aim of this review was to summarize current evidence on approved and emerging non-statin lipid-lowering therapies. Recent literature on U.S. FDA approved non-statin lipid-lowering therapies and evolving lipid-lowering drugs currently under development was reviewed. In the past 20 years, the emergence of non-statin cholesterol-lowering drugs has changed the landscape of dyslipidemia management. Food and Drug Administration approval of non-statin lipid-lowering therapies such as ezetimibe, proprotein convertase subtilisin/Kexin type 9 (PCSK9) inhibitors (evolocumab, alirocumab), bempedoic acid and combination of bempedoic acid and ezetimibe, evinacumab and other triglyceride-lowering agents (eg, icosapent ethyl) has emerged. The European Commission has also recently approved inclisiran for treatment of hypercholesterolemia and mixed hypercholesterolemia even though FDA has put the approval of this drug on hold. Recent guidelines have incorporated PCSK9 inhibitors to treat patients with primary hyperlipidemia and patients with very high-risk ASCVD, who could not achieve adequate lipid-lowering with combination therapy of maximally tolerated statin and ezetimibe. Icosapent ethyl use as an adjunct therapy to statins is also recommended to reduce the risk of ASCVD in patients with hypertriglyceridemia. Despite cost limitations, the uptake of PCSK9 inhibitors is increasing. Approval of bempedoic acid alone or in combination with ezetimibe has provided additional oral lipid-lowering drug alternatives to ezetimibe. Various lipid-lowering drug targets are under investigation.

New therapeutic agents marketed in 2020: Part 2

New therapeutic agents marketed in 2020: Part 2

A Study to Compare Hypolipidemic Effects of Allium Sativum (Garlic) Alone and in Combination with Atorvastatin or Ezetimibe in Experimental Model

Abstract Background: Dyslipidemia is a major cause of atherosclerosis and atherosclerosis induced conditions. Atorvastatin is an effective drug for dyslipidemia and reduce the risk of cardiovascular morbidity and mortality. Ezetimibe is used as an adjunct to statins hypercholesterolemia. Garlic is known for the hypolipidemic effect in traditional medicine. There are very limited studies comparing the additive effects of Allium sativum on atorvastatin and ezetimibe. Aims: To compare the additive hypolipidemic effects of Allium sativum with atorvastatin and ezetimibe. Setting and Design: The experimental study was done in Department of Pharmacology and Biochemistry, Burdwan Medical College, Burdwan from February 2014 - October 2015. Material and Methods: Dyslipidemia rat by (induced by atherogenic diet) were randomized into five groups of six rats in each and each cage was labelled for identification of different groups and treated with drugs (atorvastatin, ezetimibe, garlic homogenate, atorvastatin + garlic homogenate, ezetimibe + garlic homogenate) for twelve weeks and assessment of lipid profiles were done. Change of parameters checked for any significant difference by appropriate statistical tests. Results: Significant TC (Total Cholesterol) &amp; TG (Triglyceride) concentrations reduction were maximum among ezetimibe group (51% and 47%) respectively. LDL (Low Density Lipoprotein) &amp; VLDL (Very Low-Density Lipoprotein) concentrations reduction were maximum (62% and 26%) among combination of atorvastatin and garlic group when compared to other treatment groups. HDL (High Density Lipoprotein) concentration was maximally increased (31%) among combination ezetimibe and garlic group which was also statistically significant. Conclusion: Garlic have significant hypolipidemic effect when used in combination with atorvastatin and ezetimibe.

Low dose of ROSuvastatin in combination with EZEtimibe effectively and permanently reduce low density lipoprotein cholesterol concentration independently of timing of administration (ROSEZE): A randomized, crossover study - preliminary results.

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

Combination of Statin and Ezetimibe versus Statin Monotherapy on Cardiovascular Disease and Type 2 Diabetes Incidence among Adults with Impaired Fasting Glucose: a Propensity-Matched Nationwide Cohort Study.

ObjectiveWe investigated the effects of statin-ezetimibe combination therapy compared with statin-only treatment on the hazard of incident type 2 diabetes (T2D), myocardial infarction (MI), and stroke among adults with impaired fasting glucose (IFG) in a real-world setting.MethodsThe Korean National Health Insurance Service datasets from 2002 to 2017 were used for this propensity-matched nationwide cohort study. Among 56,633 IFG patients without baseline cardiovascular disease (CVD) and/or T2D who initiated statin therapy with or without ezetimibe, 1,155 with statin-ezetimibe combination therapy were matched based on a propensity score at a 1:5 ratio with 5,775 patients who received statin monotherapy. The hazards of T2D, MI, and stroke were compared between these treatment groups.ResultsThe incidence rate per 1,000 person-years was 19.62 (statin monotherapy group) and 21.02 (combined treatment group) for T2D, 1.53 (statin monotherapy group) and 1.70 (combined treatment group) for MI, and 1.99 (statin monotherapy group) and 2.06 (combined treatment group) for stroke. The hazards of T2D, MI, and stroke were not significantly different between the statin monotherapy group and the statin-ezetimibe combination therapy group.ConclusionThe combination of ezetimibe in addition to statin treatment was not associated with a significantly different risk of T2D and CVDs compared with statin monotherapy in Korean adults with IFG.

Comparison of the Effects of High-intensity Statin Therapy with Moderate-Intensity Statin and Ezetimibe Combination Therapy on Major Adverse Cardiovascular Events in Patients with Acute Myocardial Infarction: a Nationwide Cohort Study.

ObjectiveWe compared the effects of high-intensity statin monotherapy versus moderate-intensity statin and ezetimibe combination therapy on major adverse cardiovascular events (MACE) in patients with acute myocardial infarction (AMI).MethodsUsing the Korean National Health Insurance Service database, we screened 82,941 patients with AMI who underwent percutaneous coronary intervention (PCI) between 2013 and 2016. Among them, we identified 9,908 patients treated with atorvastatin 40 mg (A40, n=4,041), atorvastatin 20 mg + ezetimibe 10 mg (A20+E10, n=233), rosuvastatin 20 mg (R20, n=5,251), or rosuvastatin 10 mg + ezetimibe 10 mg (R10+E10, n=383). The primary outcome was MACE, a composite of all-cause death, non-fatal myocardial infarction undergoing PCI, repeat revascularization, and ischemic stroke. Multivariable analyses were performed using the inverse probability of treatment weighting method.ResultsThe incidence rate of MACE in the overall population was 42.97 cases per 1,000 person-years. There was no significant difference in the risk of composite outcomes of MACE between the groups. However, the R10+E10 group showed a higher risk of all-cause death (hazard ratio, 2.07; 95% confidence interval, 1.08–3.94) than the A40 group (reference group) in the weighted multivariable model.ConclusionsIn this study, there was no significant difference in the composite outcome of MACE between high-intensity statin monotherapy and moderate-intensity statin and ezetimibe combination therapy.

Combination of bempedoic acid, ezetimibe, and atorvastatin in patients with hypercholesterolemia: A randomized clinical trial

Background and aimsMany patients with hypercholesterolemia fail to achieve sufficient low-density lipoprotein cholesterol (LDL-C) lowering despite use of guideline-recommended lipid-lowering therapies. This study evaluated LDL-C lowering with the combination of bempedoic acid, ezetimibe, and atorvastatin. MethodsThis was a phase 2, randomized, double-blind, placebo-controlled study (NCT03051100). After washout of lipid-lowering drugs, patients were randomized 2:1 to triple therapy (bempedoic acid 180 mg, ezetimibe 10 mg, and atorvastatin 20 mg; n = 43) or placebo (n = 20) once daily for 6 weeks. The primary endpoint was percent change from baseline in LDL-C at week 6. ResultsMean age for the 63 randomized patients was 61.2 years; baseline LDL-C was 154.8 mg/dL. At week 6, mean LDL-C lowering with triple therapy (−63.6%) was significantly greater than with placebo [–3.1%; difference, −60.5% [(95% CI, −68.0% to −53.0%); p < 0.001]. Significant reductions with triple therapy vs. placebo were also observed for non–high-density lipoprotein cholesterol, total cholesterol, apolipoprotein B, and high-sensitivity C-reactive protein (p < 0.001 for all). With triple-therapy, 90% of patients achieved LDL-C <70 mg/dL and 95% of patients had ≥50% lower LDL-C from baseline to week 6; no patients in the placebo group met either goal. The majority of treatment-emergent adverse events were mild to moderate in severity. No patients experienced clinically relevant elevations in aminotransferase or creatine kinase levels. ConclusionsAmong patients with hypercholesterolemia, the combination of bempedoic acid, ezetimibe, and atorvastatin significantly lowered LDL-C, allowing more than 90% of patients in this study to reach guideline-recommended LDL-C goals.

Bempedoic Acid and Ezetimibe for the Treatment of Hypercholesterolemia: A Systematic Review and Meta-Analysis of Randomized Phase II/III trials.

A systematic literature search was conducted to identify randomized controlled trials (RCTs) comparing bempedoic acid and ezetimibe, versus placebo or ezetimibe alone, to 30 August 2020. A meta-analysis was conducted to investigate the efficacy of bempedoic acid and ezetimibe on lipid parameters and highly sensitive C-reactive protein (hsCRP) levels in patients with hypercholesterolemia or established atherosclerotic cardiovascular disease (ASCVD). Mean differences (MDs) or relative risk (RR) with their corresponding 95% confidence intervals (CIs), using random-effects models, were used to provide pooled estimates. A total of three phase II and III RCTs, comprising 388 patients, of whom 49.2% were treated with bempedoic acid and ezetimibe, and 197 controls, were identified. The duration of treatment was 12 weeks. Bempedoic acid and ezetimibe significantly reduced low-density lipoprotein cholesterol (MD - 29.14%, 95% CI - 39.52 to - 18.76; p<.001), total cholesterol (MD - 15.78%, 95% CI - 20.84 to - 10.72; p=0.01), non-high-density lipoprotein cholesterol (MD - 18.36%, 95% CI - 24.60 to - 12.12; p=0.01), and hsCRP levels (MD - 30.48%, 95% CI - 44.69 to - 16.28; p=0.04). No significant effects on triglycerides (MD - 8.35%, 95% CI - 16.08 to - 0.63; p=0.72) and improvement in high-density lipoprotein cholesterol (MD 1.63%, 95% CI - 4.03 to 7.28; p=0.92) were observed with the fixed-dose combination therapy. Regarding safety, bempedoic acid and ezetimibe combination was associated with a non-significant increased risk of drug-related adverse events (RR 1.61, 95% CI 0.86-2.35) and overall adverse events (RR 1.16. 95% CI 0.97-1.35); however, the incidence of discontinuation of therapy (RR 0.75, 95% CI 0.35-1.49) was lower. This review found bempedoic acid and ezetimibe significantly lowered lipid parameters, attenuated hsCRP levels, and had an acceptable safety profile for the treatment of hypercholesterolemia and ASCVD.

A Randomised Controlled Study of High Dose Statin Versus Statin Plus Ezetimibe Therapy in Patients with Acute Coronary Syndrome

AIM: To assess the efficacy of statin and ezetimibe combination compared to statin given as monotherapy in maintaining optimum cholesterol level. METHODOLOGY: A Prospective Randomized Interventional study was conducted including 68 patients with ACS with the duration of six months carried out in the Cardiology Department of tertiary care Hospital, Kerala. SPSS 20 version was used to perform the statistical analysis of the collected data. Independent t-test was used to compare quantitative variables between control and case group and paired t-test for comparison of demographic variables. The level of significance was 0.05. RESULTS AND DISCUSSION: Mean LDL-C of control group at baseline was found to be 129.64mg/dL and that of case group was found to be 125.73mg/dL. Mean difference was found to be 3.90. On using Independent t-test, there was no significant difference in LDL-C between the groups with p= 0.664 (t value= 0.437). Mean LDL-C of control group on review was found to be 125.42mg/dL and that of case group was found to be 109.33mg/ dl. Mean difference was found to be 16.09. On using Independent t-test, there was significant difference in LDL-C between the groups with p&lt;0.05 (t value=2.036). CONCLUSION: The LDL-C levels plummets the most in patients who are at highest risk of recurrent coronary event. Therapy using a combination of statin and ezetimibe resulted in remarkable reduction in elevated lipid cholesterol with a similar safety profile compared with doubling of statin dose. Its superior lipid altering efficacy by dual inhibition of cholesterol synthesis and intestinal absorption makes it a drug of choice for ACS.