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1.
Baseline Low-Density Lipoprotein Cholesterol and Clinical Outcomes of Combining Ezetimibe With Statin Therapy in IMPROVE-IT.
Oyama, K, Giugliano, RP, Blazing, MA, Park, JG, Tershakovec, AM, Sabatine, MS, Cannon, CP, Braunwald, E
Journal of the American College of Cardiology. 2021;(15):1499-1507
Abstract
BACKGROUND The 2018 U.S. cholesterol management guideline recommends additional lipid-lowering therapy with ezetimibe for secondary prevention in very high-risk patients with low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dL despite maximally tolerated statin. OBJECTIVES The purpose of this study was to evaluate the relationship between baseline LDL-C above and below 70 mg/dL and the benefit of adding ezetimibe to statin in patients post-acute coronary syndrome (ACS). METHODS IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) was a double-blind, placebo-controlled, randomized trial of ezetimibe/simvastatin vs placebo/simvastatin in post-ACS patients followed for 6 years (median). A total of 17,999 patients were stratified by LDL-C at qualifying event into 3 groups (50-<70, 70-<100, and 100-125 mg/dL). The primary endpoint was a composite of cardiovascular death, major coronary events, or stroke. RESULTS Absolute differences in median LDL-C achieved at 4 months between treatment arms were similar (17-20 mg/dL). The effect of ezetimibe/simvastatin vs placebo/simvastatin on primary endpoint was consistent regardless of baseline LDL-C of 50-<70 mg/dL (HR: 0.92 [95% CI: 0.80-1.05]), 70-<100 mg/dL (HR: 0.93 [95% CI: 0.87-1.01]), or 100-125 mg/dL (HR: 0.94 [95% CI: 0.86-1.03]; P interaction = 0.95). Normalized relative risk reductions per 1-mmol/L difference in achieved LDL-C at 4 months between treatment arms were 21% in patients with baseline LDL-C of 50-<70 mg/dL, 16% in those with 70-<100 mg/dL, and 13% in those with 100-125 mg/dL (P interaction = 0.91). No significant treatment interactions by baseline LDL-C were present for safety endpoints. CONCLUSIONS Adding ezetimibe to statin consistently reduced the risk for cardiovascular events in post-ACS patients irrespective of baseline LDL-C values, supporting the use of intensive lipid-lowering therapy with ezetimibe even in patients with baseline LDL-C <70 mg/dL. (IMPROVE-IT: Examining Outcomes in Subjects With Acute Coronary Syndrome: Vytorin [Ezetimibe/Simvastatin] vs Simvastatin [P04103]; NCT00202878).
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2.
Treating Coronary Artery Disease: Beyond Statins, Ezetimibe, and PCSK9 Inhibition.
Musunuru, K
Annual review of medicine. 2021;:447-458
Abstract
Statins, ezetimibe, and PCSK9 inhibitors are currently the standard of care for the prevention and treatment of coronary artery disease. Despite their widespread use, coronary artery disease remains the leading cause of death worldwide, a fact that pleads for the development of new protective therapies. In no small part due to advances in the field of human genetics, many new therapies targeting various lipid traits or inflammation have recently received approval from regulatory agencies such as the US Food and Drug Administration or fared favorably in clinical trials. This wave of new therapies promises to transform the care of patients at risk for life-threatening coronary events.
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3.
Circulating Mature PCSK9 Level Predicts Diminished Response to Statin Therapy.
Kuyama, N, Kataoka, Y, Takegami, M, Nishimura, K, Harada-Shiba, M, Hori, M, Ogura, M, Otsuka, F, Asaumi, Y, Noguchi, T, et al
Journal of the American Heart Association. 2021;(11):e019525
Abstract
Background Statin-mediated efficacy of lowering low-density lipoprotein (LDL) cholesterol varies in each individual, and its diminished response is associated with worse outcomes. However, there is no established approach to predict hyporesponse to statins. PCSK9 (proprotein convertase subxilisin/kexin type 9) is a serine-protease associated with LDL metabolism, which circulates as mature and furin-cleaved PCSK9. Since mature PCSK9 more potently degrades the LDL receptor, its evaluation may enable the identification of statin hyporesponders. Methods and Results We analyzed 101 statin-naive patients with coronary artery disease who commenced a statin. PCSK9 subtypes at baseline and 1 month after statin use were measured by ELISA. Hyporesponse to statins was defined as a percent reduction in LDL cholesterol <15%. The relationship between each PCSK9 subtype level and hyporesponse to statins was investigated. Statins significantly lowered LDL cholesterol level (percent reduction, 40%±21%), whereas 11% of study participants exhibited a hyporeseponse to statins. Multivariable logistic regression analysis demonstrated that baseline mature PCSK9 level was an independent predictor for hyporesponse to statins even after adjusting clinical characteristics (mature PCSK9 per 10-ng/mL increase: odds ratio [OR], 1.12; 95% CI, 1.01-1.24 [P=0.03]), whereas furin-cleaved level was not (per 10-ng/mL increase: OR, 1.37; 95% CI, 0.73-2.58 [P=0.33]). Receiver operating characteristic curve analysis identified mature PCSK9 level of 228 ng/mL as an optimal cutoff to predict hyporesponse to statins (area under the curve, 0.73 [sensitivity, 0.91; specificity, 0.56]). Conclusions Baseline mature PCSK9 level >228 ng/mL is associated with hyporesponse to statins. This finding suggests that mature PCSK9 might be a potential determinant of hyporesponse to statins.
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4.
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.
Jamialahmadi, T, Baratzadeh, F, Reiner, Ž, Simental-Mendía, LE, Xu, S, Susekov, AV, Santos, RD, Sahebkar, A
Mediators of inflammation. 2021;:9661752
Abstract
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; I 2: 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; I 2: 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; I 2: 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.
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5.
Effect of Atorvastatin (10 mg) and Ezetimibe (10 mg) Combination Compared to Atorvastatin (40 mg) Alone on Coronary Atherosclerosis.
Oh, PC, Jang, AY, Ha, K, Kim, M, Moon, J, Suh, SY, Lee, K, Han, SH, Kang, WC
The American journal of cardiology. 2021;:22-28
Abstract
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.
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6.
Baseline low-density lipoprotein cholesterol predicts the benefit of adding ezetimibe on statin in statin-naïve acute coronary syndrome.
Im, J, Kawada-Watanabe, E, Yamaguchi, J, Arashi, H, Otsuki, H, Matsui, Y, Sekiguchi, H, Fujii, S, Mori, F, Ogawa, H, et al
Scientific reports. 2021;(1):7480
Abstract
We aimed to evaluate the effect of baseline low-density lipoprotein cholesterol (LDL-C) on the outcomes of patients with the acute coronary syndrome (ACS) receiving pitavastatin monotherapy or the combination of pitavastatin + ezetimibe. In the HIJ-PROPER study, 1734 ACS patients with dyslipidemia were randomly assigned to receive pitavastatin or pitavastatin + ezetimibe therapy. Statin-naïve participants (n = 1429) were divided into two groups based on the median LDL-C level (131 mg/dL) at enrollment. The primary endpoint was a composite of all-cause death, non-fatal myocardial infarction, non-fatal stroke, unstable angina, and ischemia-driven coronary revascularization. The median follow-up was 3.2 years. In the < 131 mg/dL group (n = 686), LDL-C changes were - 34.0% and - 49.8% in the pitavastatin monotherapy and pitavastatin + ezetimibe-treated groups (P < 0.0001), respectively; in the ≥ 131 mg/dL group (n = 743), LDL-C changes were - 42.9% and - 56.4% (P < 0.0001, respectively. Kaplan-Meier analyses revealed that the primary endpoint was not significantly different between the treatment groups for the < 131 mg/dL group, however, it was significantly lower in patients treated with pitavastatin + ezetimibe in the ≥ 131 mg/dL group (Hazard ratio = 0.72, 95% confidence interval = 0.56-0.91, P = 0.007, P value for interaction = 0.012). Statin-naïve ACS patients with baseline LDL-C < 131 mg/dL did not clinically benefit from pitavastatin + ezetimibe, while patients with baseline LDL-C ≥ 131 mg/dL treated with pitavastatin + ezetimibe showed better clinical results than those treated with pitavastatin monotherapy.Clinical Trial Registration: Original HIJ PROPER study; URL: http://www.umin.ac.jp/ctr . Unique Identifier; UMIN000002742, registered as an International Standard Randomized Controlled Trial.
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7.
Bempedoic Acid: A New Tool in the Battle Against Hyperlipidemia.
Powell, J, Piszczatoski, C
Clinical therapeutics. 2021;(2):410-420
Abstract
PURPOSE This article discusses the pharmacology of bempedoic acid, the trials that led to United States Food and Drug Administration (FDA) approval of its use, and the overall safety and efficacy of this therapy in heterozygous familial hypercholesterolemia, established atherosclerotic cardiovascular disease (ASCVD), and hyperlipidemia. METHODS A database search of PubMed and ClinicalTrials.gov was conducted for articles published between January 2012 to September 2020 and containing the key words bempedoic acid, ezetimibe, Nexletol and Nexlizet. Trials from the CLEAR series were selected, as they played a pivotal role in the establishment of FDA approval, along with additional trials published after FDA approval, which provided novel evidence on the use of bempedoic acid in the treatment of hypercholesterolemia. Publications that were not randomized, controlled trials were not included in this review. Only randomized controlled trials in which ezetimibe was used in conjunction with bempedoic acid were included in this review as they were relevant to the new FDA approval of bempedoic acid. FINDINGS The findings of the present review show that bempedoic acid is both an effective and well-tolerated option for the treatment of hypercholesterolemia when used without ezetimibe in addition to standard therapy. It also appears that the combination with ezetimibe increases the cholesterol-lowering effect more than either agent alone when added to standard therapy. IMPLICATIONS Hypercholesteremia continues to be a major contributing factor leading to ASCVD. Bempedoic acid is an additional treatment option, along with both statins and diet and exercise, for reducing cholesterol levels and ASCVD events. With the new FDA approval, bempedoic acid may offer an effective therapy for reducing low-density lipoprotein cholesterol in patients at high risk for cardiovascular events due to established ASCVD or heterozygous familial hypercholesterolemia.
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8.
Effectiveness and Safety of Novel Nutraceutical Formulation Added to Ezetimibe in Statin-Intolerant Hypercholesterolemic Subjects with Moderate-to-High Cardiovascular Risk.
Mazza, A, Nicoletti, M, Lenti, S, Torin, G, Rigatelli, G, Pellizzato, M, Fratter, A
Journal of medicinal food. 2021;(1):59-66
Abstract
The effectiveness of statins in the primary and secondary prevention of cardiovascular (CV) diseases has been widely proven. However, the onset of adverse events associated with their use prevents to achieve the therapeutic targets recommended by the guidelines (GL) for the management of dyslipidemia. In the event of statin intolerance, the GL recommend to use bile acid sequestrants, fibrates, and ezetimibe in monotherapy, but their benefits in improving lipid pattern are quite modest. This study aims at evaluating the effectiveness and safety of a nutraceutical compound (NC) associated with ezetimibe (EZE) on the lipid profile in statin-intolerant patients with moderate-to-high CV risk. Ninety-six statin-intolerant hypertensive and hypercholesterolemic subjects treated pharmacologically with EZE 10 mg daily were randomized in open label (n = 48) to take for 3 months a NC containing Monacolin-K (MK), Berberine Hydrochloride (BC), t-Resveratrol (RES), Quercetin (QUER), and Chromium (CH) in the form of a gastro-resistant tablet that improves enteric bioaccessibility and bioavailability of these substances. The control group (n = 48) took only EZE in monotherapy at the same dosage; both groups followed a standardized lipid-lowering diet. The total serum cholesterol (TC), low density lipoprotein cholesterol (LDLC), high density lipoprotein cholesterol (HDLC), triglycerides (TG), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and creatinine phosphokinase (CPK) levels were compared at the follow-up in both groups using Student's t-test. TC and LDL levels reduced in both groups, but were lower in the group treated with EZE + NC (-25.9% vs. -15%, P < .05 and -38.7% vs. -21.0%, P < .05, respectively). No changes were observed in either group regarding a decrease in TG (-9.4% vs. -11.7%, NS) and an increase in HDLC (+4.2% vs. +1.1%, NS). The AST, ALT, and CPK levels increased in the group treated with the EZE + NC compared to the control group, but were still within the acceptable range. There was no difference concerning the lipid-lowering treatment between gender, and no patient withdrew from the study. In the short term, the EZE + NC combination therapy is well tolerated and effective in improving TC and LDLC levels in statin-intolerant patients with moderate-to-high CV risk.
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9.
The effect of twelve weeks of treatment with ezetimibe on HDV RNA level in patients with chronic hepatitis D.
Abbas, Z, Saad, M, Asim, M, Abbas, M, Samejo, SA
The Turkish journal of gastroenterology : the official journal of Turkish Society of Gastroenterology. 2020;(2):136-141
Abstract
BACKGROUND/AIMS: Sodium taurocholate co-transporting polypeptide (NTCP) is the receptor for the hepatitis B virus (HBV) and hepatitis D virus (HDV) entry into hepatocytes. Ezetimibe is a cholesterol-lowering drug that possesses the pharmacophore features to inhibit NTCP. This study evaluates the efficacy of ezetimibe in patients with chronic HDV infection in a nonrandomized trial. MATERIALS AND METHODS This proof of concept phase 2 trial evaluated the efficacy and safety of ezetimibe 10 mg daily in (interferon treatment-experienced or interferon ineligible) patients with chronic hepatitis D (CHD). Forty-four patients with CHD were recruited, 38 male and 6 female patients, mean age 35.2±8.7 (range 19-64). Fifteen (34%) patients were on concomitant nucleoside therapy, and cirrhosis was present in 14 subjects. The primary therapeutic endpoint was a decline in HDV RNA at one log or more from the baseline at week 12. RESULTS The mean HDV RNA level was 5.4±1.3 log10 IU/mL. HBeAg was non-reactive in 43 (98%). HBV DNA was undetectable in 28 (64%). One patient stopped treatment at week 4, and one patient did not follow-up. One log or more reduction in the HDV RNA levels was observed in 18/44 (41%) patients. No log reduction occurred in 16 patients, and 8 experienced a log increase. No adverse effects from the concomitant nucleoside analogue use or clinical cirrhosis were observed. The drug exhibited a positive safety profile. CONCLUSION Treatment of CHD patients with ezetimibe resulted in a one log reduction of viral load in 43% (18/42) of the patients who completed the 12 weeks of therapy.
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10.
An innovative lipid-lowering approach to enhance attainment of low-density lipoprotein cholesterol goals.
Buonvino, C, Chopard, R, Guillon, B, Puymirat, E, Farnier, M, Ferrières, J, Krempf, M, Bruckert, E, Meneveau, N, Schiele, F
European heart journal. Acute cardiovascular care. 2020;(8):879-887
Abstract
AIMS: To improve attainment of LDL-cholesterol (LDL-c) targets, an expert group proposed an algorithm for lipid-lowering therapy during hospitalization for acute coronary syndrome and during follow-up. We aimed to assess adherence to this algorithm, and evaluate its impact on LDL-c levels and on attainment of therapeutic LDL-c targets in a population of post-acute coronary syndrome patients. METHODS AND RESULTS Prospective, observational study including patients admitted for acute coronary syndrome between February 2017 and September 2018. Patients admitted without statins or ezetimibe were considered 'naïve'. Baseline LDL-c was admission LDL-c in naïve patients, and for those taking lipid-lowering therapy at admission, baseline LDL-c was back-calculated. In line with the most recent guidelines, the target was a >50% reduction in naïve LDL-c and <55 mg/dL. In total, 270 patients were analysed, mean age 67 ± 12 years, 78% men, 26% diabetic. At admission, 175 (65%) were naïve, 95 (35%) had previous lipid-lowering therapy, of which 13 (5%) statin+ezetimibe. Average LDL-c at admission was 120 ± 47 mg/dL (136 ± 44 mg/dL in naïve, 91 ± 39 mg/dL in pretreated patients). Discharge prescription was in compliance with the algorithm in 204 (76%) patients. Average LDL-c at two months was 57 ± 28 mg/dL; it was <55 mg/dL in 135 (50%), and 178 (66%) achieved a >50% reduction. Overall, 125/270 (46%) achieved the LDL-c goal. The reduction in LDL-c observed at two months persisted at five months. CONCLUSION Prescription of high-intensity statins, associated with ezetimibe where applicable, achieves LDL-c levels <55 mg/dL in 50% of patients at two months, and attains therapeutic goals defined by the European Society of Cardiology in 46% of cases.