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Drug combinations rather than increasing doses of one drug can achieve greater efficacy and lower risks. Thus, as an alternative to high-intensity statin monotherapy, moderate-intensity statin with ezetimibe combination therapy can lower LDL cholesterol concentrations effectively while reducing adverse effects. However, evidence from randomised trials to compare long-term clinical outcomes is needed. In this randomised, open-label, non-inferiority trial, patients with atherosclerotic cardiovascular disease (ASCVD) at 26 clinical centres in South Korea were randomly assigned (1:1) to receive either moderate-intensity statin with ezetimibe combination therapy (rosuvastatin 10 mg with ezetimibe 10 mg) or high-intensity statin monotherapy (rosuvastatin 20 mg). The primary endpoint was the 3-year composite of cardiovascular death, major cardiovascular events, or non-fatal stroke, in the intention-to-treat population with a non-inferiority margin of 2·0%. This trial is registered with ClinicalTrials.gov, NCT03044665 and is complete. Between Feb 14, 2017, and Dec 18, 2018, 3780 patients were enrolled: 1894 patients to the combination therapy group and 1886 to the high-intensity statin monotherapy group. The primary endpoint occurred in 172 patients (9·1%) in the combination therapy group and 186 patients (9·9%) in the high-intensity statin monotherapy group (absolute difference −0·78%; 90% CI −2·39 to 0·83). LDL cholesterol concentrations of less than 70 mg/dL at 1, 2, and 3 years were observed in 73%, 75%, and 72% of patients in the combination therapy group, and 55%, 60%, and 58% of patients in the high-intensity statin monotherapy group (all p<0·0001). Discontinuation or dose reduction of the study drug by intolerance was observed in 88 patients (4·8%) and 150 patients (8·2%), respectively (p<0·0001). Among patients with ASCVD, moderate-intensity statin with ezetimibe combination therapy was non-inferior to high-intensity statin monotherapy for the 3-year composite outcomes with a higher proportion of patients with LDL cholesterol concentrations of less than 70 mg/dL and lower intolerance-related drug discontinuation or dose reduction. Hanmi Pharmaceutical.

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.

•A fixed-dose triple combination of Fimasartan, atorvastatin, and ezetimibe (FAE) effectively controls both blood pressure and LDL-cholesterol simultaneously.•The safety profile of the FAE triple therapy is comparable to that of its individual components, confirming its tolerability.•The single-pill FAE combination may simplify treatment regimens for patients, potentially improving medication adherence.•This is the first phase III clinical trial to validate the efficacy and safety of the fixed-dose FAE combination therapy. Essential hypertension and primary hypercholesterolemia are common and independent cardiovascular risk factors that frequently coexist and warrant integrated management. This study aimed to evaluate the efficacy and safety of triple combination therapy (FMS + ATO/EZE) with Fimasartan (FMS), atorvastatin (ATV), and ezetimibe (EZE) compared with atorvastatin/ezetimibe (ATO/EZE) dual therapy or Fimasartan (FMS) monotherapy in patients with hypertension and hypercholesterolemia. This multicenter, randomized clinical trial was conducted across 25 clinical trial institutions in the Republic of Korea. A total of 315 participants were screened, of whom 148 eligible participants were randomized to receive FMS + ATO/EZE (n = 49), ATO/EZE (n = 49), or FMS (n = 50). The primary efficacy endpoints were the change in mean sitting systolic blood pressure (msSBP) from baseline to week 8 in the FMS + ATO/EZE group compared with that in the ATO/EZE group and the percentage change in low-density lipoprotein cholesterol (LDL-C) from baseline to week 8 in the FMS + ATO/EZE group compared with that in the FMS group. Safety was assessed based on treatment-emergent adverse events (TEAEs). In the full analysis set, the FMS + ATO/EZE group demonstrated superior reduction in msSBP compared to the ATO/EZE group (least squares [LS] mean difference: –7.26 ± 2.84 mm Hg; 95% confidence interval [CI]: –12.91, –1.61; P = 0.0124). Similarly, the percentage reduction in LDL-C was significantly greater in the FMS + ATO/EZE group than in the FMS group (LS mean difference: –58.02% ± 4.03%; 95% CI: –66.03, –50.02; P < 0.0001). The incidence of TEAEs was comparable across treatment groups: FMS + ATO/EZE (20.83%), ATO/EZE (22.45%), and FMS (16.00%) (P = 0.7030). Serious adverse events occurred in 1.36% of the total safety population, without significant difference between the groups (P = 0.5480). Triple combination therapy with FMS + ATO/EZE was superior to dual therapy or monotherapy in reducing both BP and LDL-C levels in patients with essential hypertension accompanied by primary hypercholesterolemia. The safety profile was comparable with that of the individual components, confirming the tolerability and safety of FMS + ATO/EZE therapy. However, the 8-week follow-up period and enrollment of an exclusively Korean cohort may limit the assessment of long-term effects and generalizability to other ethnic populations.

This study aimed to compare the pharmacokinetic (PK) profiles of a fixed-dose combination (FDC) tablet of telmisartan/rosuvastatin/ezetimibe/amlodipine 80/20/10/5 mg and a loose-dose combination (LDC) of two FDC tablets, ezetimibe/rosuvastatin 10/20 mg and telmisartan/amlodipine 80/5 mg, in healthy Korean male subjects. This study was conducted as a randomized, open-label, two-sequence, four-period crossover study. The subjects received the FDC or the LDC of telmisartan, rosuvastatin, ezetimibe, and amlodipine twice, with a 21-day washout in each period. Each sequence was composed of either FDC/LDC/FDC/LDC or LDC/FDC/LDC/FDC in that order. Serial blood samples for PK analysis were collected up to 48 h after rosuvastatin dosing and 72 h after telmisartan, ezetimibe, and amlodipine dosing. The PK parameters were calculated by a noncompartmental method, and safety profiles were evaluated throughout the study. Fifty-four healthy Korean male subjects were enrolled, and 42 subjects completed the study. The concentration‒time profiles of telmisartan, rosuvastatin, ezetimibe, and amlodipine were similar between the FDC and LDC groups. For each compound, the geometric mean ratios (90% confidence intervals) of the peak concentration and area under the plasma concentration‒time curve of FDC to LDC were within the conventional bioequivalence criteria of 0.8–1.25. Both the FDC and LDC treatments were well tolerated and determined to be safe. The FDC and LDC treatments with telmisartan, rosuvastatin, ezetimibe, and amlodipine showed pharmacokinetic bioequivalence, indicating that the FDC of telmisartan/rosuvastatin/ezetimibe/amlodipine 80/20/10/5 mg can be used as an alternative to the LDC treatment.

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.

Objective Rosuvastatin plus ezetimibe improves the lipid-lowering effect through different mechanisms of action. This study intended to compare the efficacy and safety of the fixed-dose combination (FDC) of rosuvastatin/ezetimibe vs. rosuvastatin alone in hypercholesterolemia patients. Methods ROSE-CH (ROSuvastatin and Ezetimibe in Chinese Hypercholesterolemia patients) was a multicenter, randomized, double-blind, positive drug-controlled, superiority-tested phase III clinical trial; 743 patients were randomized into rosuvastatin/ezetimibe 10/10 mg, 5/10 mg, and 2.5/10 mg groups, as well as rosuvastatin 10 mg and 5 mg groups at a 1:1:1:1:1 ratio. A total of 143, 127, 263, and 137 patients had low, intermediate, high, and very-high baseline atherosclerotic cardiovascular disease (ASCVD) risks. The study period spanned from December 24, 2021, to December 6, 2022. Results Efficacy and safety assessments were conducted in 670 and 696 patients. Percentage change in low-density lipoprotein cholesterol (LDL-C) from baseline to week (W)12 was greater in the rosuvastatin/ezetimibe 10/10 mg group vs. rosuvastatin 10 mg group [least-squares means (LSmean): -51.48% vs. -42.47%], rosuvastatin/ezetimibe 5/10 group vs. rosuvastatin 5 mg group (LSmean: -50.08% vs. -40.17%), and rosuvastatin/ezetimibe 2.5/10 mg group vs. the rosuvastatin 5 mg group (LSmean: -48.47% vs. -40.17%) (all P  < 0.001). The same trend was observed for the percentage change in LDL-C from baseline to W4 and W8 (all P  < 0.001). In patients with baseline very high ASCVD risk, the achievement of LDL-C target at W12 was higher in rosuvastatin/ezetimibe 10/10 mg vs. rosuvastatin 10 mg groups and rosuvastatin/ezetimibe 2.5/10 mg vs. rosuvastatin 5 mg groups (both P  < 0.05). The incidence of adverse events was 36.0%, 38.7%, 25.2%, 31.4%, and 38.6% in each group. Regarding serious adverse events, the incidence was 2.2%, 2.9%, 0.7%, 3.6%, and 0.7% in each group. The incidence of drug-related adverse events was relatively high, which was 26.6%, 31.4%, 18.5%, 23.6%, and 29.0% in each group, respectively, irrespective of the absence of serious drug-related adverse events. Conclusion The FDC of rosuvastatin/ezetimibe has superior LDL-C-lowering effects over rosuvastatin alone, with good safety profiles in hypercholesterolemia patients.

Background Major cardiovascular events (MACE) after percutaneous coronary intervention (PCI) are among the most common causes of death in patients. Lipid-lowering strategies seem to affect these events. Reaching the best regimen for controlling lipid abnormalities is important. This study aimed to compare the effect of ezetimibe and atorvastatin versus atorvastatin alone in short-term major cardiovascular events in patients after PCI in Bandar Abbas in 2018. Methods This double-blinded randomized controlled trial was done in Bandar Abbas in 2018 on 224 patients. Patients were randomly divided into two groups either to receive ezetimibe and atorvastatin (group A) or atorvastatin alone (group B). Patients were followed for 1 month for major cardiovascular events and drug side effects. Data was analyzed using SPSS software. Results Patients in the two groups had similar baseline characteristics. The mean low-density lipoproteins (LDL) level was 69.83 ± 28.8 in group A and 82.45 ± 29.9 in group B ( P  = 0.014). At the end of the study, high-sensitivity C-reactive protein (hs-CRP) values were notably lower in group A ( P value = 0.005). Three (2.7%) patients in group A and 1 patient (0.9%) in group B had a myocardial infarction ( P value = 0.313). Also, 11 patients (9.8%) in group A and 13 patients (11.6%) in group B had unstable angina ( P value = 0.666). No patients had death, cerebrovascular event, or stent thrombosis in the two groups. Conclusion Although adding ezetimibe to atorvastatin can decrease LDL and hs-CRP levels in short-term follow-up; it is not effective in lowering short-term major cardiovascular events in patients after PCI. Studies with longer-term follow-up are recommended. Trial registration IRCT, IRCT20171028037047N1. Registered on 22 June 2018, https://irct.behdasht.gov.ir/trial/28808 .

Objective This study aimed to compare the lipid‐lowering effect and safety of low‐intensity atorvastatin (5 mg) plus ezetimibe (10 mg) combination therapy (A5E10) with monotherapy regimens–atorvastatin 5 mg [A5], ezetimibe 10 mg [E10], and atorvastatin 10 mg [A10])–in dyslipidemia patients. Methods A randomized, double‐blind, placebo‐controlled trial involving 252 dyslipidemia patients was conducted at 25 centers in South Korea (NCT05970679). Participants aged ≥ 19 years were randomized into four groups: A5E10, A5, E10, and A10. The primary endpoint was the percentage change in low‐density lipoprotein cholesterol (LDL‐C) levels from baseline to 8 weeks. Secondary endpoints included changes in other lipid parameters, lipid ratios, LDL‐C goal achievement rates and safety assessments. Results The mean age of the patients was 63 years, and 51.2% were male. The A5E10 group showed significantly greater LDL‐C reduction (47.6%) compared with A5 (33.4%), E10 (19.4%), and A10 (40.1%) at 8 weeks (p < 0.0001). A5E10 also significantly reduced triglyceride, non‐high‐density lipoprotein cholesterol, and apolipoprotein B levels. In addition, a significant reduction in LDL‐C levels was observed over the 4 weeks, with a 46.7% reduction in LDL‐C levels after 4 weeks of A5E10 administration. No severe adverse events were observed in the A5E10 group. Conclusion The combination of low‐intensity atorvastatin and ezetimibe was more effective than moderate‐intensity atorvastatin monotherapy in lowering LDL‐C levels and improving other lipid parameters. It was well‐tolerated and demonstrated rapid benefits within a month, offering a promising alternative for patients with low to moderate cardiovascular risk who do not achieve adequate control with statin monotherapy. The combination of low‐dose atorvastatin (5 mg) and ezetimibe (10 mg) significantly reduced LDL‐C levels by 47.6%, outperforming monotherapies in patients with dyslipidemia. This combination therapy showed rapid efficacy, achieving a 46.7% reduction in LDL‐C within just 4 weeks of treatment. In addition to lowering LDL‐C, the therapy improved other lipid parameters, including non‐HDL‐C and Apo B, offering a comprehensive lipid‐lowering effect with a favorable safety profile.

Previous individual trials of alirocumab (a PCSK9 monoclonal antibody) showed significant low-density lipoprotein cholesterol reductions with overall treatment-emergent adverse event (TEAE) rates comparable with controls. This analysis evaluated safety data from 14 trials (4 phase 2 and 10 phase 3, 8 to 104 weeks; n = 5,234), in 2 pools according to control (placebo/ezetimibe). Overall, 3,340 patients received alirocumab (4,029 patient-years' exposure), 1,276 received placebo, and 618 received ezetimibe. Incidence of deaths, serious TEAEs, discontinuations because of TEAEs, and overall TEAEs were similar between alirocumab and control groups. Alirocumab was associated with a higher incidence of local injection site reactions (7.4% vs 5.3% with placebo; 3.1% vs 2.3% with ezetimibe), pruritus (1.3% vs 0.4% placebo; 0.9% vs 0.5% ezetimibe), and upper respiratory tract infection signs and symptoms (2.1% vs 1.1% placebo; 1.3% vs 0.8% ezetimibe). Incidence of musculoskeletal, neurologic, neurocognitive, ophthalmologic, hepatic events, and TEAEs related to diabetes/diabetes complications was similar between alirocumab and control groups. In a prespecified analysis of phase 3 studies, adjudicated major adverse cardiovascular events (coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, and unstable angina requiring hospitalization) occurred in 1.8% alirocumab versus 2.6% placebo patients (hazard ratio 0.69, 95% confidence interval 0.43 to 1.11) and 2.8% alirocumab versus 1.5% ezetimibe patients (hazard ratio 1.4, 95% confidence interval 0.65 to 3.02). In conclusion, pooled safety data from 14 trials demonstrate that alirocumab is generally well tolerated with a favorable safety profile.

Current guidelines recommend that patients with established atherosclerotic cardiovascular disease (ASCVD) use high-intensity statin therapy to lower low-density lipoprotein (LDL)-cholesterol levels by at least 50%, irrespective of age. However, in real-world practice, there is reluctance to maintain statin use in response to side-effects, particularly statin-associated muscle symptoms (SAMS). Moreover, no randomized trial has been conducted on the safety of statin therapy in elderly patients. This investigator-initiated, multicenter, randomized clinical trial aimed to investigate the incidence of SAMS and its effect on LDL-cholesterol levels in elderly patients with established ASCVD. Eligible patients were aged 70 years or older with established ASCVD. Consecutive patients who met the inclusion criteria were randomized in a 1:1 fashion to receive either intensive statin monotherapy (rosuvastatin 20 mg) or combination therapy (rosuvastatin/ezetimibe, 5/10 mg). The primary endpoint of the study is SAMS at 6 months with regard to treatment strategy. Positive SAMS results are defined as patients with a proposed statin myalgia index score of 7 or higher. The key secondary end-points are target LDL-cholesterol achievement (LDL < 70 mg/dL), incidence of myopathy, rhabdomyolysis, frequency of drug discontinuation, and creatinine kinase, aspartate transaminase, alanine transaminase, total cholesterol, LDL-cholesterol, high-density lipoprotein-cholesterol, triglyceride, and highly sensitive C-reactive protein levels at 6 months. The SaveSAMS study is a multicenter, randomized trial that will compare the incidence of SAMS in patients with established ASCVD who are 70 years or older on intensive statin monotherapy to that combination therapy.