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Purpose of Review The Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) demonstrated the clinical benefit of the combination of ezetimibe-simvastatin compared to placebo-simvastatin following acute coronary syndrome (ACS). This review highlights key findings from this study with particular attention to the practice-changing impact on guidelines for low-density lipoprotein cholesterol (LDL-C) reduction after ACS, especially among high-risk populations. Recent Findings Consistent reductions in LDL-C have been reported with newer lipid-lowering therapies (proprotein convertase subtilisin/kexin type 9 inhibitors, cholesterol ester transfer proteins, bempedoic acid) in combination with statin in high-risk subgroups. Since high-risk subgroups remain a focus of guidelines, exploration of high-risk subgroups can help define the optimal use of new therapies. Summary Ezetimibe reduced the LDL-C by 16.7 mg/dL compared to placebo at 1 year, resulting in a significant reduction in the primary composite endpoint (absolute risk difference 2.0%; relative risk difference 6.4%, hazard ratio, 0.936; 95% confidence interval, 0.89 to 0.99; P  = 0.016). The benefits achieved with ezetimibe in both LDL-C reduction and the primary clinical composite across 10 pre-specified high-risk subgroups, including the elderly; women; patients with diabetes, prior coronary artery bypass graft, history of stroke, polyvascular disease, low baseline LDL-C, renal dysfunction, prior heart failure, and an elevated TIMI risk score for secondary prevention, were similar or greater than in the corresponding non-high-risk subgroups. Safety events were similar between ezetimibe and placebo across the high-risk subgroups. These data support the addition of ezetimibe to statin therapy in high-risk patients who require additional therapy to lower the LDL-C post-ACS.

Risk prediction following acute coronary syndrome (ACS) remains challenging. Data-driven machine-learning algorithms can potentially identify patients at high risk of clinical events. The Improved Reduction of Outcomes: Vytorin Efficacy International Trial randomized 18,144 post-ACS patients to ezetimibe + simvastatin or placebo + simvastatin. We performed hierarchical cluster analysis to identify patients at high risk of adverse events. Associations between clusters and outcomes were assessed using Cox proportional hazards models. The primary outcome was cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, unstable angina hospitalization, or coronary revascularization ≥30 days after randomization. We evaluated ezetimibe's impact on outcomes across clusters and the ability of the cluster analysis to discriminate for outcomes compared with the Global Registry of Acute Coronary Events (GRACE) score. Five clusters were identified. In cluster 1 (n = 13,252), most patients experienced a non-STEMI (54.8%). Cluster 2 patients (n = 2,719) had the highest incidence of unstable angina (n = 83.3%). Cluster 3 patients (n = 782) all identified as Spanish descent, whereas cluster 4 patients (n = 803) were primarily from South America (56.2%). In cluster 5 (n = 587), all patients had ST elevation. Cluster analysis identified patients at high risk of adverse outcomes (log-rank p <0.0001); Cluster 2 (vs 1) patients had the highest risk of outcomes (hazards ratio 1.33, 95% confidence interval 1.24 to 1.43). Compared with GRACE risk, cluster analysis did not provide superior outcome discrimination. A consistent ezetimibe treatment effect was identified across clusters (interaction p = 0.882). In conclusion, cluster analysis identified significant difference in risk of outcomes across cluster groups. Data-driven strategies to identify patients who may differentially benefit from therapies and for risk stratification require further evaluation.

Lipoprotein(a) is similar to LDL cholesterol but contains apolipoprotein(a). A trial tested the effects of an oligonucleotide drug targeting apo(a) mRNA on lipoprotein(a) concentrations in patients with CVD.

In this trial, patients with stroke or TIA and atherosclerosis who received a statin with or without ezetimibe were randomly assigned to an LDL cholesterol target of less than 70 mg per deciliter or to a target range of 90 to 110 mg per deciliter. At a median follow-up of 3.5 years, the incidence of a composite cardiovascular end point was 12% lower in the lower-target group than in the higher-target group. The incidence of cerebral hemorrhage did not differ significantly between the two groups.

Reducing LDL cholesterol prevents atherosclerotic cardiovascular disease (ASCVD) events. The aim of this study was to evaluate the LDL cholesterol-lowering efficacy of a fixed-dose combination (FDC) of obicetrapib, a CETP inhibitor, and ezetimibe. This randomised, double-blind trial across 48 US sites including hospitals, private and group practices, and independent research centres included participants at least 18 years old with pre-existing or high risk for ASVCD or heterozygous familial hypercholesterolaemia with LDL cholesterol concentrations of 1·8 mmol/L (70 mg/dL) or greater despite maximally tolerated lipid-lowering therapy excluding ezetimibe, or having statin intolerance. Participants were randomly assigned (1:1:1:1) to obicetrapib 10 mg plus ezetimibe 10 mg FDC, obicetrapib 10 mg monotherapy, ezetimibe 10 mg monotherapy, or placebo administered daily for 84 days. The co-primary endpoints in the intention-to-treat population were the percent LDL cholesterol changes in the FDC group compared with placebo, ezetimibe monotherapy, and obicetrapib monotherapy, and the placebo-adjusted change in the obicetrapib monotherapy group. The trial was prospectively registered (NCT06005597) and is completed. Between March 4 and July 3, 2024, 407 participants were randomly assigned. The median age was 68·0 years (IQR 62·0–73·0) and 177 (43%) were female. Mean baseline LDL cholesterol was 2·4 mmol/L, 2·5 mmol/L, 2·6 mmol/L, and 2·5 mmol/L in the placebo (n=102), ezetimibe monotherapy (n=101), obicetrapib monotherapy (n=102), and FDC groups (n=102), respectively. At day 84, percent differences in LDL cholesterol reduction with the FDC were –48·6% (95% CI –58·3 to –38·9) versus placebo, –27·9% (–37·5 to –18·4) versus ezetimibe, and –16·8% (–26·4 to –7·1) versus obicetrapib. Obicetrapib monotherapy decreased LDL cholesterol by 31·9% (22·1 to 41·6) versus placebo. Adverse event rates were similar in the FDC (52 [51%] of 102), obicetrapib (55 [54%] of 102), and ezetimibe (54 [53%] of 101) groups and lowest with placebo (38 [37%] of 102). Serious adverse event rates were generally similar across FDC (three [3%] of 102), obicetrapib (six [6%] of 102), ezetimibe (seven [7%] of 101), and placebo (four [4%] of 102) groups. Deaths occurred in one [1%] of 102 participants with FDC, one [1%] of 102 with obicetrapib, one [1%] of 101 with ezetimibe, and none with placebo. Combination therapy of obicetrapib and ezetimibe significantly reduced LDL cholesterol. This oral, single-pill therapy could improve LDL cholesterol management in patients with pre-existing or high risk for ASCVD. NewAmsterdam Pharma.

Studies comparing efficacy and safety of moderate-intensity statin plus ezetimibe versus high-intensity statin in patients with atherosclerotic cardiovascular disease (ASCVD) and type 2 diabetes (T2DM) are scarce. In this multicenter non-inferiority randomized trial, 223 ASCVD patients with T2DM were randomly assigned to receive either rosuvastatin 20 mg once daily or single-pill combination of rosuvastatin 10 mg plus ezetimibe 10 mg once daily for 24 weeks. Laboratory parameters and clinical events were evaluated at 12 and 24 weeks. Primary efficacy endpoint was the least square mean percent (LSM %) change of low-density lipoprotein cholesterol (LDL-C) level at 24 weeks from baseline. At 24 weeks, the LDL-C LSM % change from baseline was − 13.5 in the high-intensity rosuvastatin group and − 20.5 in the combination group, with the between-group difference remaining within the predefined non-inferiority margin ( p  = 0.06). Decrease in apolipoprotein B level at 24 weeks from baseline was significantly greater in the combination group than in the high-intensity rosuvastatin group (−15.6% vs. −9.9%, p -value = 0.008). Rates of achieving LDL-C < 55 mg/dL were higher in the combination group than in the high-intensity rosuvastatin group, with a significant difference at 12 weeks ( p  = 0.01), though the difference at 24 weeks was not statistically significant ( p  = 0.09). Incidence of total adverse events was lower in the combination groups than in the high-intensity rosuvastatin group ( p  = 0.048). Single-pill combination of moderate-intensity rosuvastatin plus ezetimibe was non-inferior to high-intensity rosuvastatin in LDL-C lowering efficacy with good safety profile in ASCVD patients with T2DM.

This study aimed to assess the efficacy of ezetimibe in combination with metformin versus metformin alone in patients with metabolic dysfunction-associated fatty liver disease (MAFLD) and type 2 diabetes mellitus. Patients were randomly divided into two groups: one receiving ezetimibe and metformin (Met + EZY) and the other receiving metformin alone (Met group) for six months. Parameters were measured at baseline (T1), after three months (T2), and after six months (T3). The findings indicated that insulin levels and HOMA-IR exhibited a significant decrease from T1 to T2 in the Met + EZY group ( p  < 0.05). Malondialdehyde (MDA) and triglycerides levels also demonstrated significant decreases from T1 to T2 in the Met + EZY group ( p  < 0.05). The expression of peroxisome proliferator-activated receptor gamma ( PPAR-γ ) and adiponectin ( ADIPO ) showed a significant increase from T1 to T2 in the Met + EZY group ( p  < 0.01). Additionally, ADIPO expression showed a significant increase from T1 to T3 ( p  < 0.001) in both groups. When comparing the two treatment groups, PPAR-γ and ADIPO expression were significantly higher in the Met + EZY group during T2 and T3 compared to the Met group ( p  < 0.001). Combination therapy appears to be more effective than metformin treatment alone and should be used cautiously.

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 ).

Obicetrapib is a potent, selective cholesteryl ester transfer protein (CETP) inhibitor that significantly lowers low-density lipoprotein cholesterol (LDL-C). Additive reductions in LDL-C occur when obicetrapib is combined with ezetimibe. The impact of obicetrapib and ezetimibe fixed-dose combination (FDC) on coronary plaque burden is unknown. Favorable changes in noncalcified coronary atherosclerotic plaque volume (NCPV) may indicate a potential beneficial effect on atherosclerotic cardiovascular disease (ASCVD) events. REMBRANDT is a placebo-controlled, double-blind, randomized trial designed to assess the efficacy of obicetrapib and ezetimibe FDC on coronary plaque burden. Individuals aged 45 years or older with ASCVD (imaging evidence of vascular disease or clinically manifested ASCVD) and an LDL-C of ≥70 mg/dL despite maximally tolerated lipid-modifying therapy are eligible to participate. Eligible participants (N = 300) will be randomized in a 1:1 ratio to obicetrapib 10 mg and ezetimibe 10 mg FDC once daily or placebo tablet once daily. The primary efficacy outcome of REMBRANDT is percent change in total NCPV from baseline to 18 months as assessed by coronary computed tomographic angiography (CCTA). Secondary endpoints include absolute change in total NCPV, percent and absolute change in NCPV in the most diseased coronary segment, percent change in LDL-C, and change in perivascular fat attenuation index from baseline to 18 months. The REMBRANDT trial will determine whether the favorable effects of obicetrapib and ezetimibe FDC on LDL-C translate to a reduction in coronary plaque burden as a potential mechanism for ASCVD risk reduction. NCT06305559.