Benefits of intensive lipid-lowering therapies in patients with acute coronary syndrome: a systematic review and meta-analysis.

BACKGROUND: Previous meta-analyses have investigated the efficacy of lipid-lowering therapies for atherosclerotic cardiovascular disease; however, few have focused on patients with acute coronary syndrome (ACS). This meta-analysis aimed to compare the benefits of intensive lipid-lowering therapy with those of background statin therapy in patients with ACS. METHODS: Searches were performed on PubMed, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases for articles published until April 13, 2023. Randomized controlled trials that compared intensive lipid-lowering therapies and background statin therapies in patients with prior ACS and recorded the outcome of three-point major cardiovascular events (MACE) were included. The risk ratio (RR) with 95% confidence interval (CI) was used as a measure of primary and secondary outcomes. RESULTS: Nine trials involving 38,640 patients with ACS were identified. Pooled results suggested that intensive lipid-lowering therapies are associated with a reduction in the risk of three-point MACE (RR, 0.88; 95% CI, 0.83-0.94; p < 0.001), recurrent ACS (RR, 0.82; 95% CI, 0.71-0.96; p = 0.013), nonfatal myocardial infarction (MI) (RR, 0.87; 95% CI, 0.81-0.93; p < 0.001), stroke (RR, 0.83; 95% CI, 0.73-0.94; p = 0.003), and unstable angina-related hospitalization (RR, 0.57; 95% CI, 0.33-0.99; p = 0.046), but not all-cause mortality (RR, 0.94; 95% CI, 0.82-1.07; p = 0.329), cardiovascular disease-related mortality (RR, 0.96; 95% CI, 0.88-1.06; p = 0.457) or coronary revascularization (RR, 0.89; 95% CI, 0.79-1.00; p = 0.057). CONCLUSIONS: Intensive lipid-lowering therapies may reduce the risk of three-point MACE, recurrent ACS, nonfatal MI, stroke, and hospitalization for unstable angina in patients with ACS undergoing background statin therapy. These results may assist in clinical decision-making for the secondary prevention of cardiovascular events to initiate intensive lipid-lowering therapies immediately after ACS.

Ezetimibe protects against Gentamycin-induced ototoxicity in rats by antioxidants, anti-inflammatory mechanisms, and BDNF upregulation.

OBJECTIVE: The threat of hearing loss has become a universal reality. Gentamycin (GM) can lead to ototoxicity and may result in permanent hearing loss. This study aimed to elucidate whether the hypolipidemic drug Ezetimibe (EZE) has a possible underlying mechanism for protecting rats from GM-induced ototoxicity. METHODS AND RESULTS: 30 male Wister albino rats were separated into three groups, ten in each group: control, GM, and GM + EZE. At the end of the experiment, rats underwent hearing threshold evaluation via auditory brainstem response (ABR), carotid artery blood flow velocity (CBV), and resistance (CVR) measurement, in addition to a biochemical assessment of serum malondialdehyde (MDA), nitric oxide (NO), catalase (CAT), hemeOxygenase-1 (HO-1), and tumor necrosis factor-α (TNF-α). Also, real-time PCR was employed to quantify the levels of brain-derived neurotrophic factor (BDNF). Cochlea was also studied via histological and immunohistochemical methods. GM revealed a significant increase in CVR, MDA, NO, and TNF-α and a significant decrease in ABR, CBV, CAT, HO-1, and cochlear BDNF expression. EZE supplementation revealed a significant rise in ARB in addition to CBV and a decline in CVR and protected cochlear tissues via antioxidant, anti-inflammatory, and antiapoptotic mechanisms via downregulating Caspase-3 immunoreaction, upregulating proliferating cellular nuclear antigen (PCNA) immunoreaction, and upregulating of the cochlear BDNF expression. Correlations were significantly negative between BDNF and MDA, NO, TNF-α, COX 2, and caspase-3 immunoreaction and significantly positive with CAT, HO-1, and PCNA immunoreaction. DISCUSSION: EZE can safeguard inner ear tissues from GM via antioxidant, anti-inflammatory, and antiapoptotic mechanisms, as well as upregulation of BDNF mechanisms.

Lipid-Lowering Medications for Managing Dyslipidemia: A Narrative Review.

Dyslipidemia refers to the change in the normal levels of one or more lipid components in the bloodstream, which include triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C). Dyslipidemia represents a substantial source of danger for cardiovascular disease (CVD). Effectively managing dyslipidemia involves a thorough strategy that includes changing one's lifestyle and using medications that are specifically designed to target the complex processes involved in lipid metabolism. Lipid-lowering treatments play a crucial role in this approach, providing a wide range of medications that are developed to specifically target different components of dyslipidemia. Statins are the main drug among these medications. Other drugs that are used with statin or as monotherapy include fibrates, omega-3 fatty acids (OM3FAs), ezetimibe, bile acid sequestrants, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and bempedoic acid. Using the PubMed database, we reviewed the literature about dyslipidemia, drugs used for treating dyslipidemia, their efficacy parameters, and common adverse events. We also reviewed the international guidelines for treating dyslipidemia and discussed the future of lipid-lowering medications. More trials and experiments are still required to verify the effectiveness of many lipid-lowering drugs and to know their common adverse events to be able to manage them properly.

Safety and Effectiveness of High-Intensity Statins Versus Low/Moderate-Intensity Statins Plus Ezetimibe in Patients With Atherosclerotic Cardiovascular Disease for Reaching LDL-C Goals: A Systematic Review and Meta-Analysis.

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

Study Design and Protocol for a Randomized Controlled Trial to Assess Long-Term Efficacy and Safety of a Triple Combination of Ezetimibe, Fenofibrate, and Moderate- Intensity Statin in Patients with Type 2 Diabetes and Modifiable Cardiovascular Risk Factors (ENSEMBLE).

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

The impact of statin-ezetimibe combination therapy versus statin monotherapy on coronary plaque regression in patients with acute coronary syndrome: a meta-analysis.

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

Unmasking a Case of Sitosterolaemia: An Approach for Diagnosis and Management.

This report presents a 57-year-old female with a history of dyslipidaemia, intolerant to statins and currently managed on evolocumab. Despite a healthy lifestyle, lipid panel abnormalities persisted, leading to an investigation that revealed heterozygous mutations in the ABCG8 gene, confirming a diagnosis of sitosterolaemia. The patient's unique response to lipid-lowering medications typified this rare disorder, necessitating specialised genetic testing for diagnosis. Management involved dietary modifications and the introduction of ezetimibe, evolocumab and atorvastatin, demonstrating the personalised nature of treatment. The case underscores the importance of considering sitosterolaemia in unexplained lipid abnormalities and highlights the challenges in diagnosis and management. Ongoing research is crucial for refining diagnostic and therapeutic strategies for this clinically significant disorder, emphasising the need for a multidisciplinary approach to patient care. LEARNING POINTS: Recognise the significance of considering sitosterolaemia in differential diagnosis for unexplained lipid abnormalities.Understand the challenges in diagnosing and managing sitosterolaemia, especially in patients with atypical responses to conventional lipid-lowering therapies.

Repurposing ezetimibe as a neuroprotective agent in a rotenone-induced Parkinson's disease model in rats: Role of AMPK/SIRT-1/PGC-1α signaling and autophagy.

As a severe neurological disorder, Parkinson's disease (PD) is distinguished by dopaminergic neuronal degeneration in the substantia nigra (SN), culminating in motor impairments. Several studies have shown that activation of the AMPK/SIRT1/PGC1α pathway contributes to an increase in mitochondrial biogenesis and is a promising candidate for the management of PD. Furthermore, turning on the AMPK/SIRT1/PGC1α pathway causes autophagy activation, which is fundamental for maintaining neuronal homeostasis. Interestingly, ezetimibe is an antihyperlipidemic agent that was recently reported to possess pleiotropic properties in neurology by triggering the phosphorylation and activation of AMPK. Thus, our study aimed to investigate the neuroprotective potential of ezetimibe in rats with rotenone-induced PD by activating AMPK. Adult male Wistar rats received rotenone (1.5 mg/kg, s.c.) every other day for 21 days to induce experimental PD. Rats were treated with ezetimibe (5 mg/kg/day, i.p.) 1 h before rotenone. Ezetimibe ameliorated the motor impairments in open field, rotarod and grip strength tests, restored striatal dopamine and tyrosine hydroxylase in the SN, up-regulated p-AMPK, SIRT1, and PGC1α striatal expression, upsurged the expression of ULK1, beclin1, and LC3II/I, reduced Bax/Bcl2 ratio, and alleviated rotenone-induced histopathological changes in striatum and SN. Our findings also verified the contribution of AMPK activation to the neuroprotective effect of ezetimibe by using the AMPK inhibitor dorsomorphin. Together, this work revealed that ezetimibe exerts a neuroprotective impact in rotenone-induced PD by activating AMPK/SIRT-1/PGC-1α signaling, enhancing autophagy, and attenuating apoptosis. Thus, ezetimibe's activation of AMPK could hold significant therapeutic promise for PD management.

Ezetimibe use and mortality after myocardial infarction: A nationwide cohort study.

Background: The inhibition of intestinal cholesterol absorption by ezetimibe improves outcomes after myocardial infarction (MI), yet real-world data on ezetimibe is scarce. We studied the usage of ezetimibe and association with outcome after MI. Methods: Consecutive MI patients in Finland (2010-2018) were retrospectively studied (N = 57,505; 65 % men; mean age 69 years). The study data were collected from national registries. The median follow-up was 4.5 (IQR 2.8-7.1) years. Between-group differences were adjusted for using multivariable regression. Ezetimibe use was studied with competing risk analyses. Results: The cumulative incidence of ezetimibe use was 3.7 % at 90 days, 13.4 % at 5 years, and 19.8 % at 10 years. Younger age was one of the strongest predictors of ezetimibe use (adj.sHR 6.67; CI 5.88-7.69 for patients aged <60 vs ≥80 years). Women were more likely to use ezetimibe during follow-up than men. The average proportion of patients using ezetimibe during follow-up was 6.8 %. (11.7 % at 10 years). Ezetimibe was discontinued by 43.6 % of patients during follow-up. Patients with early ezetimibe therapy after MI had lower all-cause mortality during follow-up (33.6% vs 45.1 %; adj.HR 0.77; CI 0.69-0.86; P < 0.0001). Early ezetimibe use was associated with lower mortality irrespective of sex, age, atrial fibrillation, diabetes, heart failure, malignancy, revascularization, or statin use. Ongoing ezetimibe therapy during follow-up was associated with lower mortality in a time-dependent analysis (adj.HR 0.53; CI 0.48-0.59; P < 0.0001). Conclusions: Ezetimibe is associated with a lower risk of death after MI, yet its therapeutic use is limited, and discontinuation is frequent.

Sitosterolemia With Two Heterozygous Variants Including a Novel Mutation c.1800T>A in the ABCG5 Gene: A Case Report of a Rare Condition in a Young Saudi Girl.

Sitosterolemia is a rare autosomal recessively inherited lipid disorder characterized by an accumulation and deposition of phytosterols in various tissues with decreased biliary excretion leading to various complications. We report a case of a three-year-old Saudi girl who exhibited xanthomas and elevated cholesterol levels. Initially, she was misdiagnosed with familial hypercholesterolemia, but subsequent testing of the low-density lipoprotein receptor gene by next-generation sequencing ruled out this condition. Two heterozygous variants were identified in the ABCG5 gene through a whole exome sequencing study. These variants, namely c.1336C>T and c.1800T>A, have been characterized as pathogenic and likely pathogenic, respectively, with the latter being a novel mutation associated with sitosterolemia. The patient responded positively to treatment with ezetimibe, resulting in controlled cholesterol levels and decreased xanthoma size.

The Pleiotropic Effects of Lipid-Modifying Interventions: Exploring Traditional and Emerging Hypolipidemic Therapies.

Atherosclerotic cardiovascular disease poses a significant global health issue, with dyslipidemia standing out as a major risk factor. In recent decades, lipid-lowering therapies have evolved significantly, with statins emerging as the cornerstone treatment. These interventions play a crucial role in both primary and secondary prevention by effectively reducing cardiovascular risk through lipid profile enhancements. Beyond their primary lipid-lowering effects, extensive research indicates that these therapies exhibit pleiotropic actions, offering additional health benefits. These include anti-inflammatory properties, improvements in vascular health and glucose metabolism, and potential implications in cancer management. While statins and ezetimibe have been extensively studied, newer lipid-lowering agents also demonstrate similar pleiotropic effects, even in the absence of direct cardiovascular benefits. This narrative review explores the diverse pleiotropic properties of lipid-modifying therapies, emphasizing their non-lipid effects that contribute to reducing cardiovascular burden and exploring emerging benefits for non-cardiovascular conditions. Mechanistic insights into these actions are discussed alongside their potential therapeutic implications.

Ezetimibe ketone protects against renal ischemia-reperfusion injury and attenuates oxidative stress via activation of the Nrf2/HO-1 signaling pathway.

Recently, ezetimibe (EZM) has been suggested to be a potent Nrf2 activator that is important for preventing oxidative stress. Interestingly, we found that its metabolite ezetimibe ketone (EZM-K) also has antioxidant effects. Thus, we investigated the role of EZM-K in preventing renal ischemia‒reperfusion injury (RIRI). Cultured NRK-52E cells were subjected to simulated IR with or without EZM-K. Rats were used to simulate in vivo experiments. EZM-K alleviated H2O2-induced apoptosis and reactive oxygen species (ROS) and upregulated Nrf2 and HO-1 levels in NRK-52E cells. A HO-1 and a Nrf2 inhibitor reversed the protective effects of EZM-K. In the rat RIRI model, pretreatment with EZM-K activated the Nrf2/HO-1 signaling pathway, suppressed tubular injury and inflammation, and improved renal function. EZM-K significantly prevented renal injury caused by ischemia‒reperfusion via the Nrf2/HO-1 signaling axis both in vivo and in vitro. The other metabolite of EZM, ezetimibe glucuronide (EZM-G) had no protective effects against ROS in RIRI. EZM-G also had no antioxidant effects and could not activate Nrf2/HO-1 signal pathway. Our findings also indicated the therapeutic potential of EZM-K in preventing RIRI.

Therapy for Hyperlipidemia.

Significant advances in atherosclerotic cardiovascular (ASCVD) risk stratification and treatment have occurred over the past 10 years. While the lipid panel continues to be the basis of risk estimation, imaging for coronary artery calcium is now widely used in estimating risk at the individual level. Statins remain first-line agents for ASCVD risk reduction but in high-risk patients, ezetimibe, proprotein convertase subtilisin kexin-9 inhibitors, and bempedoic acid can be added to further reduce individual cardiovascular risk based on results of cardiovascular outcomes trials. Results of randomized control trials do not support use of medications targeted at triglyceride lowering for ASCVD risk reduction, but icosapent ethyl can be considered.

Ezetimibe, Niemann-Pick C1 like 1 inhibitor, modulates hepatic phospholipid metabolism to alleviate fat accumulation.

Background: Ezetimibe, which lowers cholesterol by blocking the intestinal cholesterol transporter Niemann-Pick C1 like 1, is reported to reduce hepatic steatosis in humans and animals. Here, we demonstrate the changes in hepatic metabolites and lipids and explain the underlying mechanism of ezetimibe in hepatic steatosis. Methods: We fed Otsuka Long-Evans Tokushima Fatty (OLETF) rats a high-fat diet (60 kcal % fat) with or vehicle (control) or ezetimibe (10 mg kg-1) via stomach gavage for 12 weeks and performed comprehensive metabolomic and lipidomic profiling of liver tissue. We used rat liver tissues, HepG2 hepatoma cell lines, and siRNA to explore the underlying mechanism. Results: In OLETF rats on a high-fat diet, ezetimibe showed improvements in metabolic parameters and reduction in hepatic fat accumulation. The comprehensive metabolomic and lipidomic profiling revealed significant changes in phospholipids, particularly phosphatidylcholines (PC), and alterations in the fatty acyl-chain composition in hepatic PCs. Further analyses involving gene expression and triglyceride assessments in rat liver tissues, HepG2 hepatoma cell lines, and siRNA experiments unveiled that ezetimibe's mechanism involves the upregulation of key phospholipid biosynthesis genes, CTP:phosphocholine cytidylyltransferase alpha and phosphatidylethanolamine N-methyl-transferase, and the phospholipid remodeling gene lysophosphatidylcholine acyltransferase 3. Conclusion: This study demonstrate that ezetimibe improves metabolic parameters and reduces hepatic fat accumulation by influencing the composition and levels of phospholipids, specifically phosphatidylcholines, and by upregulating genes related to phospholipid biosynthesis and remodeling. These findings provide valuable insights into the molecular pathways through which ezetimibe mitigates hepatic fat accumulation, emphasizing the role of phospholipid metabolism.

Comparison of Statin With Ezetimibe Combination Therapy Versus Statin Monotherapy for Primary Prevention in Middle-Aged Adults.

BACKGROUND AND OBJECTIVES: Lipid lowering therapy is essential to reduce the risk of major cardiovascular events; however, limited evidence exists regarding the use of statin with ezetimibe as primary prevention strategy for middle-aged adults. We aimed to investigate the impact of single pill combination therapy on clinical outcomes in relatively healthy middle-aged patients when compared with statin monotherapy. METHODS: Using the Korean National Health Insurance Service database, a propensity score match analysis was performed for baseline characteristics of 92,156 patients categorized into combination therapy (n=46,078) and statin monotherapy (n=46,078) groups. Primary outcome was composite outcomes, including death, coronary artery disease, and ischemic stroke. And secondary outcome was all-cause death. The mean follow-up duration was 2.9±0.3 years. RESULTS: The 3-year composite outcomes of all-cause death, coronary artery disease, and ischemic stroke demonstrated no significant difference between the 2 groups (10.3% vs. 10.1%; hazard ratio (HR), 1.022; 95% confidence interval [CI], 0.980-1.064; p=0.309). Meanwhile, the 3-year all-cause death rate was lower in the combination therapy group than in the statin monotherapy group (0.2% vs. 0.4%; p<0.001), with a significant HR of 0.595 (95% CI, 0.460-0.769; p<0.001). Single pill combination therapy exhibited consistently lower mortality rates across various subgroups. CONCLUSIONS: Compared to the statin monotherapy, the combination therapy for primary prevention showed no difference in composite outcomes but may reduce mortality risk in relatively healthy middle-aged patients. However, since the study was observational, further randomized clinical trials are needed to confirm these findings.

Efficacy and Safety of Bempedoic Acid in Patients With Hyperlipidemia and Non-alcoholic Fatty Liver Disease.

Hyperlipidemia and its association with cardiovascular diseases have been significant public health concerns for many decades. Statins have long been the primary therapeutic option for lowering cholesterol levels and reducing cardiovascular mortality. However, a substantial number of patients either do not achieve optimal lipid goals with maximally tolerated statin doses or experience statin intolerance. In recent years, there have been remarkable developments in the field of hyperlipidemia management, leading to the approval of novel hypolipidemic drugs in North America and Europe. This article reviews the clinical development of bempedoic acid, a promising new drug, alone and in combination with ezetimibe, as an alternative approach to managing hyperlipidemia. The Phase I trials established the safety and tolerability of bempedoic acid, paving the way for further investigation in Phase II and Phase III trials. Multiple phase II studies evaluated the lipid-lowering efficacy of bempedoic acid as monotherapy or in combination with other hypolipidemic agents, showing significant improvements in lipid levels and inflammatory markers. The recently approved fixed drug combination of bempedoic acid and ezetimibe presents a viable option for patients who need additional LDL-C lowering alongside dietary modifications and maximally tolerated statin therapy.

A Comparison of Rosuvastatin Monotherapy and Rosuvastatin Plus Ezetimibe Combination Therapy in Patients With Type 2 Diabetes: A Meta-Analysis of Randomized Controlled Trials.

Type 2 diabetes mellitus is a metabolic condition where vascular inflammation and oxidative stress contribute to disease progression and associated complications. Although statins are recommended for managing dyslipidemia in diabetes, additional therapies are often required to achieve target lipid levels. This meta-analysis aimed to evaluate the efficacy of rosuvastatin monotherapy versus combination therapy with ezetimibe in patients with type 2 diabetes. A systematic literature search was conducted across multiple databases until April 2024, identifying six randomized controlled trials meeting the inclusion criteria. The meta-analysis revealed that the rosuvastatin plus ezetimibe combination resulted in significantly greater reductions in total cholesterol (mean difference, or MD: 19.49; 95% CI: 13.99 to 24.99), triglycerides (MD: 13.44; 95% CI: 2.04 to 24.85), and low-density lipoprotein cholesterol (MD: -17.68; 95% CI: 12.85 to 22.51) compared to rosuvastatin monotherapy. Conversely, rosuvastatin monotherapy achieved a greater reduction in HbA1c levels (MD: -0.11; 95% CI: -0.17 to -0.04). Subgroup analysis demonstrated that using the same dose of rosuvastatin in both groups led to more significant improvements in lipid parameters with lower heterogeneity. The findings suggest that the rosuvastatin-ezetimibe combination may be a more effective lipid-lowering strategy for patients with type 2 diabetes, though larger studies are needed to assess long-term safety and optimal dosing. Additionally, while rosuvastatin monotherapy provided modest HbA1c reductions, the clinical relevance remains uncertain, and potential risks with high-dose statins should be considered.

Pharmacokinetic Interactions Between the Fixed-Dose Combination of Ezetimibe/Rosuvastatin 10/20 Mg and the Fixed-Dose Combination of Telmisartan/Amlodipine 80/5 Mg in Healthy Subjects.

Background: Management of hypertension and hyperlipidemia, which are common comorbid risk factors for cardiovascular diseases, require multiple medications. The development of a fixed-dose combination (FDC) containing ezetimibe, rosuvastatin, telmisartan, and amlodipine aims to enhance patient adherence and persistence, but the potential interactions among the four medications have not been studied. This study aimed to evaluate the pharmacokinetic (PK) interactions between the FDC of ezetimibe/rosuvastatin 10/20 mg (ER) and the FDC of telmisartan/amlodipine 80/5 mg (TA). Methods: An open-label, single-sequence, three-period, three-treatment crossover study was conducted in healthy male subjects. All subjects received ER for 7 days, TA for 9 days and ER combined with TA for 7 days during each treatment period. For PK analysis of total/free ezetimibe, rosuvastatin, telmisartan, and amlodipine, serial blood samples were collected for 24 hours at steady state. Safety profiles were assessed throughout the study. Results: Thirty-eight subjects were enrolled, and 34 subjects completed the study. The systemic exposure to each active ingredient after coadministration of the two FDCs was similar to that after each FDC alone. The geometric mean ratios and 90% confidence intervals for the maximum plasma concentration (µg/L) and the area under the plasma concentration-time curve (h·µg/L) of the combination therapy to monotherapy, assessed at steady state, were as follows: total ezetimibe, 1.0264 (0.8765-1.2017) and 0.9359 (0.7847-1.1163); free ezetimibe, 1.5713 (1.2821-1.9257) and 0.9941 (0.8384-1.1788); rosuvastatin, 2.1673 (1.7807-2.6379) and 1.1714 (0.9992-1.3733); telmisartan, 1.0745 (0.8139-1.4186) and 1.1057 (0.8379-1.4591); and amlodipine, 0.9421 (0.8764-1.0126) and 0.9603 (0.8862-1.0405). Both combination therapy and monotherapy were well tolerated by the subjects. Conclusion: The coadministration of ezetimibe/rosuvastatin 10/20 mg and ezetimibe/rosuvastatin 10/20 mg was well tolerated in healthy subjects, and the PK interaction between those two FDCs was not clinically significant.

Differential Adherence to Free and Single-Pill Combination of Rosuvastatin/Ezetimibe: Findings from a Real-World Analysis in Italy.

INTRODUCTION: Adherence to cardiovascular drug treatment can significantly benefit from a reduced pill burden, but data on this matter derived from real-life settings are currently scanty. This analysis assessed the possible changes in adherence in patients treated with rosuvastatin and ezetimibe (ROS/EZE) as free multi-pill combination who switched to ROS/EZE as single-pill combination in the setting of real clinical practice in Italy. METHODS: A retrospective analysis was conducted on the administrative databases for a catchment area of about seven million health-assisted residents. Adults receiving ROS/EZE as a single-pill combination from January 2010 to June 2020 (followed up to 2021) were identified. The date of the first prescription of single-pill combination of ROS/EZE was considered as the index date. The analysis included the users of ROS/EZE as a free combination during the year before the index date. Baseline demographic and clinical characteristics were collected during the period of data availability prior to the index date. Adherence to therapy was evaluated as proportion of days covered (PDC), namely the percentage of days during which a patient had access to medication, in the 12-month interval preceding or following the index date (PDC < 25% non-adherence; PDC = 25-75% partial adherence; PDC > 75% adherence). RESULTS: A total of 1219 patients (61.1% male, aged 66.2 ± 10.4 years) were included. Cardiovascular comorbidities were found in 83.3% of them, diabetes in 26.4%, and a combination of both in 16.2%. Single-pill combination of ROS/EZE was associated with a higher proportion of adherent patients compared to free-pill combination (75.2% vs 51.8%, p < 0.001). CONCLUSIONS: This real-world analysis suggested that switching from a regimen based on separate pills to one based on a single-pill combination resulted in improved adherence to ROS/EZE therapy.

Lipid-lowering therapy to control low-density lipoprotein (LDL) cholesterol levels is essential for cardiovascular risk prevention. Successful therapy depends on the type of lipid-lowering therapy, i.e., low or high statin intensity and combination of statins with ezetimibe or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and adherence to therapy, i.e., whether the patient actually takes their pills as prescribed. If there are fewer pills to be taken, this can help patients to follow their treatment. Single-pill combinations of two drugs could facilitate adherence and thus the chances of reaching the recommended lipid targets. Here, we analyzed a sample of Italian patients with dyslipidemia to examine whether the switch from a free combination of two separate pills of rosuvastatin and ezetimibe to a single-pill combination of the same drugs could improve adherence to therapy. We found that the proportion of adherent patients increased from about just over half (51.8%) to about three-fourths (75.1%) when switching from two-pill to single-pill combination of rosuvastatin and ezetimibe. These findings suggest that simplifying therapy can help improve patient adherence, which is essential for reaching lipid targets and ultimately for alleviating atherosclerotic cardiovascular disease.