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Purpose: The objective of this investigation is to examine the benefits and potential risks of these drugs in individuals by varying baseline low-density lipoprotein cholesterol (LDL-C) values, utilizing the concept of the number needed to treat (NNT)., Methods: We extensively searched electronic databases, such as PubMed, EMBASE, Cochrane, and Web of Science, up to 6 August 2023. Baseline LDL-C values were stratified into four categories: < 100, 100-129, 130-159, and ≥ 160 mg/dL. Risk ratios (RRs) and NNT values were computed., Results: This analysis incorporated data from 46 randomized controlled trials (RCTs), encompassing a total of 237,870 participants. The meta-regression analysis demonstrated an incremental diminishing risk of major adverse cardiovascular events (MACE) with increasing baseline LDL-C values. Statins exhibited a significant reduction in MACE [number needed to treat to benefit (NNTB) 31, 95% confidence interval (CI) 25-37], but this effect was observed only in individuals with baseline LDL-C values of 100 mg/dL or higher. Ezetimibe and PCSK9 inhibitors also were effective in reducing MACE (NNTB 18, 95% CI 11-41, and NNTB 18, 95% CI 16-24). Notably, the safety outcomes of statins and ezetimibe did not reach statistical significance, while the incidence of injection-site reactions with PCSK9 inhibitors was statistically significant [number needed to treat to harm (NNTH) 41, 95% CI 80-26]., Conclusion: Statins, ezetimibe, and PCSK9 inhibitors demonstrated a substantial capacity to reduce MACE, particularly among individuals whose baseline LDL-C values were relatively higher. The NNT visually demonstrates the gradient between baseline LDL-C and cardiovascular disease (CVD) risk., Systematic Review Registration: Registration: PROSPERO identifier number: CRD42023458630., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Aim: Statin therapy is considered the gold standard for treating hypercholesterolemia. This updated meta-analysis aims to compare the efficacy and safety of a low/moderate-intensity statin in combination with ezetimibe compared with high-intensity statin monotherapy in patients with atherosclerotic cardiovascular disease (ASCVD)., Methods: A systematic search of two databases (PubMed and Cochrane CENTRAL) was conducted from inception to January 2023 and a total of 21 randomized clinical trials (RCTs) were identified and included in the analysis. Data were pooled using Hedges's g and a Mantel-Haenszel random-effects model to derive standard mean differences (SMDs) and 95% confidence intervals (Cis). The primary outcome studied was the effect of these treatments on lipid parameters and safety events., Results: The results revealed that combination therapy was more effective in reducing low-density lipoprotein cholesterol (LDL-C) levels (SMD= - 0.41; CI - 0.63 to - 0.19; P = 0.0002). There was no significant change in the levels of high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), triglyceride (TG), high-sensitivity C-reactive protein (hs-CRP), Apo A1, or Apo B. The safety of these treatments was assessed by the following markers alanine aminotransferase (ALT), aspartate aminotransferase (AST), and creatine phosphokinase (CK), and a significant difference was only observed in CK (SMD: - 0.81; CI - 1.52 to - 0.10; P = 0.02)., Conclusion: This meta-analysis demonstrated that the use of low/moderate-intensity statin combination therapy significantly reduced LDL-C levels compared with high-intensity statin monotherapy, making it preferable for patients with related risks. However, further trials are encouraged to evaluate potential adverse effects associated with combined therapy., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Few data are available regarding the efficacy and safety of a single-pill combination (SPC) consisting of four medications in patients with concomitant hypertension and dyslipidemia., Objective: We aimed to determine the efficacy and tolerability of a fixed-dose SPC consisting of 5 mg amlodipine, 100 mg losartan, 20 mg rosuvastatin, and 10 mg ezetimibe (A/L/R/E) in patients with concomitant hypertension and dyslipidemia., Methods: This was a 14-week, randomized, multicenter, double-blind, placebo-controlled, phase III clinical trial. In total, 145 patients were randomized to receive A/L/R/E, A/L, or L/R/E. The primary endpoints were the average change in the low-density lipoprotein cholesterol (LDL-C) level in the A/L/R/E and A/L groups and the sitting systolic blood pressure (sitSBP) in the A/L/R/E and L/R/E groups. The numbers of patients with adverse drug reactions (ADRs) were compared as safety variables., Results: The average percentage change in the LDL-C level as the least squares mean (LSM) from the baseline LDL-C level at the end of the 8-week treatment was - 59.0% in the A/L/R/E group and 0.2% in the A/L group (LSM difference - 59.2, 95% confidence interval [CI] - 68.1 to - 50.4; p < 0.0001). The average change in the sitSBP as the LSM was - 15.8 mmHg in the A/L/R/E group and -4.7 mmHg in the L/R/E group (LSM difference - 11.1, 95% CI - 16.8 to - 5.4; p = 0.0002). No ADRs occurred in the A/L/R/E group., Conclusions: A/L/R/E as an SPC could be an effective treatment for patients with hypertension and dyslipidemia without significant safety issues., Clinical Trials Registration: NCT04074551 (registered 30 August 2019)., (© 2023. The Author(s).)

Background: Patients with atherosclerotic cardiovascular disease who require additional low-density lipoprotein cholesterol (LDL-C) lowering despite maximally tolerated statins have a significant unmet medical need and are at increased risk of future cardiovascular events and a reduced quality of life., Objective: We aimed to estimate the percentage of cardiovascular events avoided following treatment with a fixed-dose combination of bempedoic acid plus ezetimibe (BA+EZE FDC) versus ezetimibe (EZE) in patients with atherosclerotic cardiovascular disease receiving maximally tolerated statins across a range of baseline LDL-C levels., Methods: A Markov cohort simulation model estimated major adverse cardiovascular events avoided over a lifetime horizon among patients with atherosclerotic cardiovascular disease and baseline LDL-C levels from 80 to >200 mg/dL. BA+EZE FDC was compared with EZE based on mean percent LDL-C reductions versus placebo reported in a phase III trial. Health outcomes for the average patient were extrapolated to a US population of 100,000 persons using evidence on contemporary LDL-C levels from the National Health and Nutrition Examination Survey., Results: Among patients with atherosclerotic cardiovascular disease not at the LDL-C goal with maximally tolerated statins, the addition of BA+EZE FDC compared with the addition of EZE was predicted to provide incremental absolute reductions in major adverse cardiovascular events dependent on baseline LDL-C levels at the population level. For those with baseline LDL-C of 101-110 mg/dL (n = 15,237), there were 4.9% (744) fewer events predicted, while for patients with baseline LDL-C of > 200 mg/dL (n = 1689), 10.9% (184) fewer events were predicted through the addition of BA+EZE FDC versus EZE., Conclusions: Further LDL-C reductions through the addition of BA+EZE FDC to maximally tolerated statins are predicted to reduce major adverse cardiovascular events compared with the addition of EZE. Benefits are potentially greater among those with higher starting LDL-C., (© 2022. The Author(s).)

Despite the availability of lipid-lowering therapies (LLTs) that are safe and effective, the overall rate of low-density lipoprotein cholesterol (LDL-C) control at a population level in real-life studies is low. Higher-intensity treatment, earlier intervention, and longer-term treatment have all been shown to improve outcomes. However, in clinical practice, actual exposure to LLT is a product of the duration and intensity of, and adherence to, the treatment. To increase exposure to LLTs, the European Society of Cardiology guidelines recommended a stepwise optimization of LLTs by increasing statin intensity to the maximally tolerated dose, with subsequent addition of ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. Evidence from randomized controlled trials performed in a range of patients suggested that adding ezetimibe to statins rather than doubling the statin dose resulted in significantly more patients at LDL-C goal and significantly fewer patients discontinuing treatment because of adverse events. In addition, data showed that combination treatments effectively increased exposure to LLT. Despite these data and recommendations, optimization of LLT is often limited to increasing statin dose. Therapeutic inertia and poor treatment adherence are significant and prevalent barriers to increasing treatment exposure. They are known to be influenced by pill burden and complexity of treatment. Single-pill combinations provide a strategic approach that supports the intensification of treatment without increasing pill burden or treatment complexity. Single-pill combinations, compared with free associations, have been shown to increase the adherence to LLT and the percentage of patients at LDL-C goal., (© 2021. The Author(s).)

BACKGROUND AND OBJECTIVE: A limited number of trials have evaluated the efficacy of a fixed-dose combination of bempedoic acid and ezetimibe for the treatment of hypercholesterolemia. The aim of this meta-analysis of existing studies was to evaluate the efficacy and safety of fixed-dose bempedoic acid and ezetimibe combination therapy for the treatment of hypercholesterolemia., Methods: 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., Results: 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., Conclusion: 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.

Despite the widespread use of statins and ezetimibe to decrease low-density lipoprotein cholesterol (LDL-C) levels and associated atherosclerotic cardiovascular disease (ASCVD), many patients do not achieve adequate LDL-C lowering as per the recommended American College of Cardiology (ACC)/American Heart Association (AHA) and European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines and demonstrate residual cardiovascular risk. The introduction of proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors in 2015 was a promising addition to hypercholesterolemia therapies, but their cost and subcutaneous administration has limited their use, and therefore, new affordable and patient friendly treatment strategies are crucial to help reduce ASCVD risk. Bempedoic acid, a drug currently under investigation, is a small molecule that has been shown to upregulate LDL receptors, decrease LDL-C, and reduce atherosclerotic plaque formation in hypercholesterolemic patients. Furthermore, bempedoic acid is a prodrug that becomes activated by an enzyme expressed primarily in the liver, allowing it to avoid the potential myotoxicity associated with statin therapy. The purpose of this review is to summarize the major clinical studies evaluating bempedoic acid and describe its potential addition to currently approved lipid-lowering therapies.

Elevated serum low-density lipoprotein cholesterol (LDL-C) is a major risk factor for coronary heart disease (CHD). Many guidelines recommend LDL-C as a primary treatment target, and statins represent the cornerstone of treatment for lipid management. Recently revised guidelines recommend even more intense management of LDL-C, especially in patients at moderate and high risk. However, LDL-C levels in the Chinese population differ from those in Western populations, and the benefits and safety of the maximum allowable dose of statins have yet to be determined. Furthermore, in practice, many patients do not achieve the increasingly stringent LDL-C goals. Consequently, alternative approaches to lipid management are required. Combination therapy with ezetimibe and a statin, which have complementary mechanisms of action, is more effective than statin monotherapies, even at high doses. Several clinical studies have consistently shown that combination therapy with ezetimibe and simvastatin lowers LDL-C more potently than statin monotherapies. Moreover, the safety and tolerability profile of the combination therapy appears to be similar to that of low-dose statin monotherapies. This review discusses the role of simvastatin in combination with ezetimibe in controlling dyslipidemia in Chinese patients, particularly the efficacy and safety of combination therapy in light of recently published clinical data.

The use of low-density lipoprotein cholesterol (LDL-C)-lowering medications has led to a significant reduction of cardiovascular risk in both primary and secondary prevention. Statin therapy, one of the cornerstones for the prevention and treatment of cardiovascular disease (CVD), has been demonstrated to be effective in lowering LDL-C levels and in reducing the risk for CVD and is generally well-tolerated. However, compliance with statins remains suboptimal. One of the main reasons is limitations by adverse events, notably myopathies, which can lead to non-compliance with the prescribed statin regimen. Reducing the burden of elevated LDL-C levels is critical in patients with CVD as well as in patients with very high baseline levels of LDL-C (e.g. patients with familial hypercholesterolaemia), as statin therapy is insufficient for optimally reducing LDL-C below target values. In this review, we discuss alternative treatment options after maximally tolerated doses of statin therapy, including ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and cholesteryl ester transfer protein (CETP) inhibitors. Difficult-to-treat patients may benefit from combination therapy with ezetimibe or a PCSK9 inhibitor (evolocumab or alirocumab, which are now available). Updates of treatment guidelines are needed to guide the management of patients who will best benefit from these new treatments.