Reduction In Low-density Lipoprotein Cholesterol Levels Research Articles

Evaluating the role of PCSK9 inhibitors in reducing cardiovascular events among statin-intolerant patients: a systematic review and meta-analysis

Objective: To assess the efficacy and safety of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors in reducing major adverse cardiovascular events (MACE) in statin-intolerant patients, focusing on low-density lipoprotein cholesterol (LDL-C) reduction and cardiovascular outcomes. Methods: A systematic review and meta-analysis were conducted according to the PRISMA guidelines. Randomised control trails (RCTs) and observational studies from PubMed, Cochrane Library, and Web of Science databases were included. Independent reviewers extracted the data, and the analyses were performed using fixed- and random-effects models. Heterogeneity was evaluated using the I2 statistic and publication bias was assessed using Egger’s test. Results: Fifteen studies involving 69–18 924 participants were included. PCSK9 inhibitors reduced LDL-C levels by 50–70% and lowered the risk of MACE by 12% (OR 0.88). Minimal heterogeneity (I2 = 0%) indicated consistency across studies. Subgroup analysis showed greater efficacy in high-risk populations (e.g., acute coronary syndrome and familial hypercholesterolemia). Adverse events were mild, with minimal muscle-related side effects. Conclusion: PCSK9 inhibitors are effective and safe alternatives for LDL-C reduction and cardiovascular risk mitigation in patients with statin intolerance. Their efficacy, favorable safety profile, and consistency across studies highlight their potential for managing dyslipidemia, particularly in high-risk groups. Further research on long-term outcomes is required.

The Safety Profile of Inclisiran in Patients with Dyslipidemia: A Systematic Review and Meta-Analysis.

Inclisiran is a novel drug that employs ribonucleic acid (RNA) interference to lower the levels of the proprotein convertase subtilisin/kexin type 9 (PCSK9) protein. It has demonstrated a significant reduction in LDL cholesterol levels compared to a placebo. We aim to comprehensively evaluate the safety of using Inclisiran in patients with dyslipidemia and ASCVD or an ASCVD risk equivalent. Four electronic databases, namely, Pubmed/MEDLINE, Web of Science, Embase, and ClinicalTrials.gov, were searched from inception to June 2024 to identify relevant randomized controlled trials (RCTs) comparing safety profiles of Inclisiran and the control group. The outcomes investigated were all-cause mortality, major adverse cardiovascular events (MACEs), injection-site adverse events, new-onset or worsening type 2 diabetes mellitus (T2DM), and nasopharyngitis. The effect estimates of outcomes were assessed using the risk ratio (RR) with a 95% confidence interval (CI). Random-effects meta-analysis was conducted using the restricted maximum likelihood method. Subgroup analysis was performed based on different dosing regimens. The study included 7 RCTs, enrolling 4790 patients (age 63.8 ± 9.7 years, 33.2% females) who received Inclisiran. Compared to the control group, Inclisiran use did not yield a significant effect on all-cause mortality (RR, 0.92; 95% CI, 0.54 to 1.54; I2 = 0%), MACEs (RR, 0.98; 95% CI, 0.82 to 1.17; I2 = 0%), nasopharyngitis (RR, 1.10; 95% CI, 0.83 to 1.45; I2 = 0%), and T2DM (RR, 1.02; 95% CI, 0.85 to 1.21; I2 = 0%). However, Inclisiran use demonstrated a significant increase in injection-site adverse events (RR, 6.50; 95% CI, 3.20 to 13.20; I2 = 29%). Inclisiran use significantly increased injection-site reactions, with no increase in mortality, T2DM, or nasopharyngitis. It demonstrates a generally favorable safety profile, making it a promising option for lipid management in individuals at high cardiovascular risk, such as those with ASCVD or equivalent conditions. While it effectively improves dyslipidemia, decision-makers should be aware of an increased incidence of injection-site reactions, which, though typically mild, warrant consideration in clinical practice. Further trials are required to assess the safety of Inclisiran, particularly the association of the severity of injection-site adverse events over longer treatment durations.

SAFETY AND EFFICACY OF PITAVASTATIN IN DYSLIPDEMIC/HYPERLIPIDEMIC PATIENTS

Background: Dyslipidemia and hyperlipidemia are prevalent conditions worldwide, characterized by abnormal lipid levels such as elevated LDL cholesterol, total cholesterol, or triglycerides, which increase the risk of cardiovascular diseases. Statins are widely used for lipid management, with pitavastatin emerging as a promising option due to its potent lipid-lowering effects and favorable safety profile. This study evaluates the safety and efficacy of pitavastatin in dyslipidemic and hyperlipidemic patients. Objective: To assess the safety and efficacy of pitavastatin in reducing LDL cholesterol, total cholesterol, and triglycerides in dyslipidemic and hyperlipidemic patients. Methods: A randomized controlled trial (RCT) was conducted, enrolling 200 participants aged ≥18 years with dyslipidemia or hyperlipidemia. Participants were randomized in a 1:1 ratio to receive either pitavastatin 4 mg or placebo once daily for 12 weeks. Randomization was performed using a computer-generated sequence, with blinding maintained for participants, investigators, and staff. The primary endpoint was the percent change in LDL cholesterol levels from baseline to week 12. Secondary endpoints included changes in total cholesterol, triglycerides, HDL cholesterol, and adverse events. Laboratory evaluations were performed at baseline and at weeks 4, 8, and 12. Results: Of the 200 participants, 52% were male, with a mean age of 55 years. The pitavastatin group achieved a significant 29.6% reduction in LDL cholesterol levels compared to 1.2% in the placebo group (p<0.001). Total cholesterol levels decreased by 22.4% in the pitavastatin group versus 1.6% in the placebo group (p<0.001). Triglycerides were reduced by 12.9% in the pitavastatin group compared to 0.9% in the placebo group (p=0.01). HDL cholesterol levels showed no significant difference between groups (-1.5% vs. -0.8%, p=0.36). Adverse events were reported by 16% of participants in the pitavastatin group and 12% in the placebo group, with no statistically significant difference (p=0.36). Conclusion; Pitavastatin demonstrated significant efficacy in reducing LDL cholesterol, total cholesterol, and triglycerides in dyslipidemic and hyperlipidemic patients, with a safety profile comparable to placebo. These findings support its role as an effective therapeutic option for managing dyslipidemia and hyperlipidemia.

Management of Hypercholesterolemia in Patients with Coronary Artery Disease: A Glimpse into the Future.

Cardio-cerebral vascular diseases due to atherosclerosis are still the leading cause of death worldwide. Low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B have been identified as the primary factors responsible for the atherosclerotic process, with a causal effect. Many drugs aimed at reducing LDL-C levels are already on the market, acting in different ways in terms of mechanism of action, efficacy, and safety. Moreover, new lipid-lowering agents and new technologies in the fields of gene editing and immunotherapy are currently under investigation. A more recent biomarker associated with an increased risk of plaque generation, progression, and subsequent ASCVD is the lipoprotein (a) and, in the next few years, it will be the new target of pharmacological therapy. The aim of this review is to present the landscape of therapies already approved to reduce LDL-C levels, evaluating their efficacy, tolerability, and indications. Moreover, we take a glimpse into the future to evaluate experimental novel therapies to lower LDL-C levels that will be approved in the next few years or are under clinical evaluation.

Efficacy of Low-Density Lipoprotein Cholesterol Apheresis in the Treatment of Familial Hypercholesterolemia: Single Center Experience.

Familial hypercholesterolemia (FH) is a genetic disorder associated with extremely high levels of low-density lipoprotein cholesterol (LDL-C) and increased incidence of cardiovascular disease. We aimed to evaluate the efficacy and long-term outcomes of lipoprotein apheresis (LA) in the treatment of FH. Cardiovascular events that occurred before and after LA treatment were evaluated by reviewing previous medical records of patients with FH. Thirteen patients (female/male: 8/5) were included in this study. The mean Dutch score was 20±4. All patients were treated with a combination of statin and ezetimibe. Before the onset of LA, 8 patients had a history of coronary artery disease, and the median age at onset of cardiovascular disease (CVD) in these patients was 24 years. At the initiation of LA, the median age was 22 years and the mean LDL-C level was 410±130 mg/dL. The mean duration of LA treatment was 13.9±6.9 years. The mean LDL-C levels before and after the latest three LA treatments were 267±63.4 and 71.5±23.4 mg/dL, respectively. The mean reduction in LDL-C levels after LA was 73±8.2%. De novo cardiovascular events occurred in 10 patients during LA treatment; six of these patients had a known history of CVD before LA. Eight of these patients underwent invasive procedures for therapeutic purposes and the total number of procedures was 12. LA is an effective method of reducing LDL-C levels and an additional treatment option that may slow disease progression in patients with FH who are at high risk of cardiovascular events.

Sex-related differences in response to lomitapide in HoFH: A subanalysis of the Pan-European Lomitapide retrospective observational study.

Homozygous familial hypercholesterolemia (HoFH) is a hereditary lipid metabolism disorder characterized by severe elevation of low-density lipoprotein cholesterol (LDL-C) and heightened risk of premature atherosclerotic cardiovascular disease (ASCVD). Lomitapide, an inhibitor of microsomal triglyceride transfer protein, has shown promise in reducing LDL-C levels, albeit with variable response in real-world settings. Sex-based differences in treatment efficacy and safety remain unclear. This post-hoc analysis of the Pan-European Lomitapide Study investigated sex-specific disparities in the efficacy and safety of lomitapide in HoFH patients (N=38 women and N=37 men). Data were collected from HoFH patients receiving lomitapide across Europe. Clinical characteristics, lipid profile, and adverse events were compared between women and men. Results indicate comparable baseline characteristics and cardiovascular risk factors between sexes. While LDL-C reduction was comparable at each time point between the two groups, women exhibited a trend towards greater reduction compared to men, particularly evident at 6 months (-53.0% vs -32.9% p=0.051). Annual LDL-C reduction did not differ between sexes (-4.83%±7.02 vs -4.03%±9.74 p=0.526). No differences in the median lomitapide dose or the intensity of concomitant lipid lowering therapies were observed between sexes. Notably, gastrointestinal disturbances were more prevalent in women (78 events in women vs 32 in men, p=0.0002), although most adverse events were manageable. Event-free survival curves for ASCVD did not significantly differ between sexes (p=0.363). Lomitapide demonstrates comparable efficacy in reducing LDL-C levels in men and women with HoFH, with potential sex-specific variations in tolerability.

Obicetrapib Alone and in Combination with Ezetimibe Reduces Atherosclerotic Lesion Prevalence, Size and Severity in ApoE*3-Leiden.CETP Mice

Background and Aims: Obicetrapib is a selective, potent, cholesteryl ester transfer protein (CETP) inhibitor in clinical development for the treatment of hypercholesterolemia and reduction of cardiovascular risk. It strongly reduces apolipoprotein B (ApoB) and low-density lipoprotein cholesterol (LDL-C) and increases plasma high-density lipoprotein cholesterol (HDL-C). Ezetimibe is a potent, selective inhibitor of biliary and dietary cholesterol absorption from the small intestine, also reducing LDL-C levels. The current study evaluated the effect of obicetrapib monotherapy and in combination with ezetimibe on atherosclerosis development in a mouse model for hyperlipidemia and atherosclerosis.Methods: Female ApoE*3-Leiden.CETP transgenic mice were fed a Western diet with 0.05% w/w cholesterol (equivalent to daily human intake) or this diet containing obicetrapib alone (2 mg/kg/day), ezetimibe alone (on average 0.6 mg/kg/day), or the combination of obicetrapib and ezetimibe. After 28 weeks of treatment, atherosclerosis development was measured in the aortic roots.Results: Obicetrapib, ezetimibe, and the combination reduced total plasma cholesterol levels (-31%, -19% and -53%), mainly attributed to a decrease in non-HDL-C levels (-53%, -19% and -75%). Obicetrapib and combination treatment nearly completely blocked CETP activity (-98% and -98%). Obicetrapib, ezetimibe, and the combination reduced atherosclerotic lesion size (-90%, -50% and -98%) and reduced severe lesions (-82%, -31% and -98%). The percentage of unaffected segments was increased by obicetrapib and the combination treatment (+347%, +442%).Conclusions: Obicetrapib alone and the combination with ezetimibe robustly lowers non-HDL-C levels and impedes atherosclerosis development through a large decrease in atherosclerotic lesion size and severity.

Assessing the impact of evolocumab on thin-cap fibroatheroma and endothelial function in patients with very high-risk atherosclerotic cardiovascular disease: a study protocol for a randomized controlled trial.

The prevalence of very high-risk atherosclerotic cardiovascular disease (ASCVD) is significant in China, with suboptimal rates of low-density lipoprotein cholesterol (LDL-C) compliance exacerbating plaque instability and causing a higher incidence of major adverse cardiac events (MACEs). Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) are effective in reducing LDL-C levels, increase the stability of vulnerable plaque, and influence the progression of atherosclerosis through multiple mechanisms as demonstrated in animal studies. However, there is currently a lack of in vivo evidence regarding the efficacy and safety of high-intensity statin therapy combined with PCSK9i in the secondary prevention of ASCVD in the Chinese population. This study aims to demonstrate the efficacy of high-intensity statins combined with PCSK9i on vulnerable plaques in very high-risk ASCVD patients through intravascular imaging and non-invasive endothelial function test. This randomized, open-label, prospective clinical study involves 240 patients with very high-risk ASCVD who meet the criteria outlined in the 2023 Chinese lipid management guidelines. Patients recruitment will be processed in Beijing Anzhen Hospital from January 2021 to December 2024. Patients with thin-cap fibroatheroma (TCFA) detected by optical coherence tomography (OCT) are randomly assigned in a 1:1 ratio to the evolocumab group (evolocumab 140 mg every 2 weeks plus atorvastatin 40 mg nightly) or the standard treatment group (atorvastatin 40 mg nightly). The primary endpoint is the absolute change of the minimum fibrous cap thickness (FCT) at a median follow-up of 1 year. The secondary endpoints are other OCT metrics, assessment of MACE rates, alterations in serum lipid profiles and markers of inflammation, endothelial function, and adverse drug reactions. Logistic regression, analysis of covariance (ANCOVA), Kaplan-Meier curve survival analysis, and Cox regression will be used to investigate the relationship between variables and endpoints. The purpose of this study is to evaluate the efficacy of high-intensity statin therapy combined to PCSK9i for the secondary prevention of coronary artery disease in Chinese patients with very high-risk ASCVD. The results will provide evidence to optimize the management of this high-risk population. This study was registered on chictr.org.cn (ChiCTR2000032570).

Obicetrapib Alone and in Combination with Ezetimibe Reduces Non-HDL-Cholesterol by Enhanced LDL-Receptor-Mediated VLDL Clearance and Increased Net Fecal Sterol Excretion in ApoE*3-Leiden.CETP Mice

Background and Aims: Obicetrapib is a selective cholesteryl ester transfer protein (CETP) inhibitor in clinical development for the treatment of hypercholesterolemia and cardiovascular risk. It reduces apolipoprotein B (ApoB) and low-density lipoprotein cholesterol (LDL-C) and increases high-density lipoprotein cholesterol (HDL-C). Ezetimibe reduces absorption of biliary and dietary cholesterol from the small intestine, also reducing LDL-C levels. The current study elucidates the mechanism for decreases in non-HDL-C by obicetrapib alone and with ezetimibe in a mouse model for hyperlipidemia and atherosclerosis.Methods: Female ApoE*3-Leiden.CETP transgenic mice were fed a Western diet with 0.05% w/w cholesterol (equivalent to daily human intake) or this diet containing obicetrapib (2 mg/kg/day), ezetimibe (1 mg/kg/day), or obicetrapib with ezetimibe.Results: Obicetrapib, ezetimibe, and the combination reduced total plasma cholesterol levels (-42%, -23% and -62%).Obicetrapib alone and in combination with ezetimibe nearly completely blocked CETP activity (-99% and -100%) resulting in increased HDL-C (+260% and +245%) and ApoA1 (98% and 81%). Obicetrapib, ezetimibe, and the combination enhanced clearance of VLDL-like particles (half-life: -44%, -23% and -57%) and enhanced hepatic LDL receptor expression (+63% and +74%). Increased bile acid excretion in obicetrapib-treated mice (+41%) and increased neutral sterol excretion in ezetimibe-treated mice was observed, and was more pronounced in combination with obicetrapib (+68% and +100%), resulting in a net fecal sterol loss.Conclusions: Obicetrapib alone and with ezetimibe reduced non-HDL-C levels by increased VLDL lipolysis, increased VLDL clearance and elevated LDL receptor levels, and enhanced fecal bile acid and neutral sterol excretion.

A Meta-analysis of the Regulation of Low-Density Lipoprotein Cholesterol and Proprotein Convertase Subtilisin-Kexin Type 9 with Inclisiran.

This study aimed to systematically evaluate the regulation of low-density lipoprotein cholesterol (LDL-C) and proprotein convertase subtilisin-kexin type 9 (PCSK9) with inclisiran using a meta-analysis. A comprehensive search of PubMed, Embase, the Cochrane Library, and Web of Science was conducted for randomized controlled trials of inclisiran published up to April 2024. Stata software was used for statistical analysis of outcome indicators from the included studies. Egger's test was employed to assess the risk of publication bias. A total of 10 studies involving 5208 participants were included in this meta-analysis. The results indicated that inclisiran significantly reduced LDL-C levels (weighted mean difference [WMD] - 48.17%; 95% confidence interval [CI] - 51.78 to - 44.56%; P < 0.01) and PCSK9 levels (WMD - 77.91%; 95% CI - 82.99 to - 72.84; P < 0.01) compared with the control group. The incidence of adverse reactions in the inclisiran group did not differ significantly from that in the placebo group (relative risk [RR] 1.03; 95% CI 0.99-1.09; P = 0.15). Similarly, there was no significant difference in the incidence of cardiovascular adverse events between the inclisiran and placebo groups (RR 0.92; 95% CI 0.74-1.16; P = 0.49). Sensitivity analysis showed that the exclusion of any single study did not significantly affect the final results. Current evidence suggests that inclisiran significantly lowers LDL-C and PCSK9 levels. The incidence of adverse events and cardiovascular adverse events was not significantly different from that with other drugs.

Pleiotropic Effects of PCSK9 Inhibitors on Cardio-Cerebrovascular Diseases.

Cardiovascular disease (CVD) and ischemic stroke (IS) are the primary causes of mortality worldwide. Hypercholesterolemia has been recognized as an independent risk factor for CVD and IS. Numerous clinical trials have unequivocally demonstrated that reducing levels of low-density lipoprotein cholesterol (LDL-C) significantly mitigates the risk of both cardiac and cerebral vascular events, thereby enhancing patient prognosis. Consequently, LDL-C reduction remains a pivotal therapeutic strategy for CVD and IS. However, despite intensive statin therapy, a significant proportion of high-risk hypercholesterolemic patients fail to achieve sufficient reductions in LDL-C levels. In response to this challenge, an inhibitor targeting proprotein convertase subtilisin-kexin type 9 (PCSK9) has been developed as a therapeutic intervention for hyperlipidemia. Numerous randomized controlled trials (RCTs) have conclusively demonstrated that the combination of PCSK9 inhibitors and statins significantly enhances prognosis not only in patients with CVD, but also in those afflicted with symptomatic intracranial artery stenosis (sICAS). PCSK9 inhibitors significantly reduce LDL-C levels by binding to the PCSK9 molecule and preventing its interaction with LDLRs. This prevents degradation of the receptor and increases uptake of LDL-C, thereby decreasing its concentration in blood. Besides significantly reducing LDL-C levels, PCSK9 inhibitors also demonstrate anti-inflammatory and anti-atherosclerotic properties while promoting plaque stabilization and inhibiting platelet aggregation and thrombosis. This article aims to provide a comprehensive review based on the relevant literature regarding the evolving understanding of pleiotropic effects associated with PCSK9 inhibitors, particularly focusing on their impact on the cardiovascular system and central nervous system.

Lowering low-density lipoprotein cholesterol targets to below 1.0 mmol/L in acute coronary syndrome patients: a potential new standard

Despite significant advancements in the diagnosis and treatment of ischemic heart disease primarily, atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of death worldwide. Low-density lipoprotein cholesterol (LDL-C) plays a causal role in the development and progression of atherosclerosis. Randomized controlled trials have demonstrated that achieving lower LDL-C levels in patients with acute coronary syndrome (ACS) can stabilize or even reverse coronary plaque. This article examines existing evidence to explore whether further reducing LDL-C levels in all ACS patients (not just those with recurrent events) to below 1.0 mmol/L, lower than current guideline recommendations, could effectively reduce the incidence of adverse cardiovascular events.

Hyperchylomicronemia causes endothelial cell inflammation and increases atherosclerosis.

The effect of increased triglycerides (TGs) as an independent factor in atherosclerosis development has been contentious, in part, because severe hypertriglyceridemia associates with low levels of low-density lipoprotein cholesterol (LDL-C). To test whether hyperchylomicronemia, in the absence of markedly reduced LDL-C levels, contributes to atherosclerosis, we created mice with induced whole-body lipoprotein lipase (LpL) deficiency combined with LDL receptor (LDLR) deficiency. On an atherogenic Western-type diet (WD), male and female mice with induced global LpL deficiency (iLpl -/-) and LDLR knockdown (Ldlr kd ) developed hypertriglyceridemia and elevated cholesterol levels; all the increased cholesterol was in chylomicrons or large VLDL. After 12 weeks on a WD, atherosclerotic lesions both in the brachiocephalic artery and the aortic root were more severe in iLpl -/- /Ldlr kd mice compared to the control Ldlr kd mice. One likely mechanism for this is that exposure of the aorta to hyperchylomicronemia led to endothelial cell inflammation. Thus, our data show that intact chylomicrons contribute to atherosclerosis, explain the association of postprandial lipemia and vascular disease, and prove that hyperchylomicronemia is not benign.

PCSK9 Inhibitors: Focus on Evolocumab and Its Impact on Atherosclerosis Progression.

This paper investigates the therapeutic use of PCSK9 inhibitors, particularly Evolocumab, as monoclonal antibodies for the treatment of atherosclerosis based on recent literature reviews. PCSK9 is an outstanding example of a breakthrough in medical science, with advancements in understanding its biological function driving substantial progress in atherosclerosis treatment. Atherosclerotic cardiovascular disease (ASCVD) is a leading global cause of mortality, imposing substantial financial burdens on healthcare systems. Elevated low-density lipoprotein cholesterol (LDL-C), a modifiable risk factor, plays a pivotal role in the development of ASCVD. Emerging treatments such as PCSK9 inhibitors are now being introduced to combat this issue, with the goal of reducing ASCVD risk by directly targeting LDL-C levels. This discovery highlighted the potential of monoclonal antibodies to inhibit PCSK9, thereby enhancing LDL-C receptor activity. This breakthrough led to the development of Alirocumab and Evolocumab inhibitors, which typically reduce LDL-C levels by approximately 50%. This research underscores the importance of PCSK9 inhibitors in treating ASCVD, drawing on evidence from various randomized controlled trials such as FOURIER, ODYSSEY OUTCOMES, and VESALIUS-CV. These trials have also shown that PCSK9 inhibitors are effective and safe for the treatment of several cardiovascular disorders. PCSK9 inhibitors are therefore useful in patients who do not reach their target LDL-C levels when on the highest doses of statins or patients with very high cardiovascular risk who cannot tolerate statins at all.

Bempedoic Acid's Chemistry, Pharmacological Characteristics and Bioanalytical Techniques: An Updated Review

Background: Elevated blood cholesterol has been established as a major risk factor for atherosclerotic cardiovascular disease (ASCVD). Adults with hyperlipidemia have a significantly increased risk of developing cardiovascular diseases (CVD). First-line treatments for hyperlipidemia include statins, which help raise HDL-C levels in cases of severe and familial hypercholesterolemia and decrease LDL-C and TG levels. Numerous adverse effects on muscles have been associated with statins, such as asymptomatic elevations in blood creatine kinase activity and potentially fatal rhabdomyolysis. Non-statin drugs are advised for people whose very high cardiovascular risk or heterozygous familial hypercholesterolemia make statin therapy insufficient. A novel lipid-lowering medication with a distinct mode of action is bempedoic acid. Elevated blood cholesterol is a significant risk factor for atherosclerotic cardiovascular disease (ASCVD). Individuals with hyperlipidemia are at a higher risk for developing cardiovascular diseases. Statins are the primary treatment for hyperlipidemia, raising HDL-C levels and lowering LDL-C and TG levels. However, statins can adversely affect muscles, including muscle-related complications like increased blood creatine kinase activity and rhabdomyolysis. Therefore, nonstatin drugs may be recommended for individuals. Bempedoic acid is a brand-new, first-in-class, oral small molecule that inhibits cholesterol manufacturing like statins, consequently reducing lowdensity lipoprotein cholesterol (LDL-C) through activating LDL receptors. Methods: This study offers helpful information on how to utilize bempedoic acid to decrease LDLC, as well as recommendations for which individuals could benefit and safety monitoring tips during therapy. A novel family of drugs called bempedoic acid is identified as a prodrug that becomes bempedoyl- CoA in the liver via an enzyme called very longchain consisting of acyl-CoA synthetase 1. Bempedoic acid can control cholesterol metabolism. Low-density lipoprotein cholesterol levels appeared to be dramatically reduced by bempedoic acid, according to clinical investigations. The toleration of bempedoic acid was good. Results: A cardiovascular outcomes trial is now evaluating bempedoic acid to determine its impact on major cardiovascular events in patients with or at high risk for cardiovascular disease and statin intolerance. Conclusion: This review describes the chemistry, mechanism of action, pharmacokinetics, analytical potential, and safety of bempedoic acid. Bempedoic acid is an effective and often well-tolerated drug used to further reduce LDL-C levels in patients taking the maximum dosage of tolerated statins or to control LDL-C levels in persons who can not take statins. The results of the clear Outcomes research, which is looking into whether bempedoic acid might reduce the frequency of serious cardiovascular events, are expected in 2025.

Alternative LDL Cholesterol–Lowering Strategy vs High-Intensity Statins in Atherosclerotic Cardiovascular Disease

In patients with atherosclerotic cardiovascular disease (ASCVD), intensive lowering of low-density lipoprotein (LDL) cholesterol levels with high-intensity statins is generally recommended. However, alternative approaches considering statin-related adverse effects and intolerance are needed. To compare the long-term efficacy and safety of an alternative LDL cholesterol-lowering strategy vs high-intensity statin strategy in patients with ASCVD in randomized clinical trials. PubMed, Embase, and other websites (ClinicalTrials.gov, European Society of Cardiology, tctMD) were systematically searched from inception to April 19, 2024. Randomized clinical trials comparing an alternative LDL cholesterol-lowering strategy vs a high-intensity statin strategy in patients with ASCVD, with presence of cardiovascular events as end points. Individual patient data were obtained from randomized clinical trials that met the prespecified eligibility criteria: RACING (Randomized Comparison of Efficacy and Safety of Lipid-Lowering With Statin Monotherapy vs Statin/Ezetimibe Combination for High-Risk Cardiovascular Disease) and LODESTAR (Low-Density Lipoprotein Cholesterol-Targeting Statin Therapy vs Intensity-Based Statin Therapy in Patients With Coronary Artery Disease). The moderate-intensity statin with ezetimibe combination therapy in the RACING trial and the treat-to-target strategy in the LODESTAR trial were classified as alternative LDL cholesterol-lowering strategies. The primary analysis was based on a 1-stage approach. The primary end point was a 3-year composite of all-cause death, myocardial infarction, stroke, or coronary revascularization. The secondary end points comprised clinical efficacy and safety end points. Individual patient data from 2 trials including 8180 patients with ASCVD (mean [SD] age, 64.5 [9.8] years; 2182 [26.7%] female; 5998 male [73.3%]) were analyzed. The rate of the primary end point did not differ between the alternative strategy and high-intensity statin strategy groups (7.5% [304 of 4094] vs 7.7% [310 of 4086]; hazard ratio, 0.98; 95% CI, 0.84-1.15; P = .82). The mean (SD) LDL cholesterol level during treatment was 64.8 (19.0) mg/dL in the alternative strategy group and 68.5 (20.7) mg/dL in the high-intensity statin strategy group (P < .001). The alternative strategy group had a lower rate of new-onset diabetes (10.2% [271 of 2658] vs 11.9% [316 of 2656]; P = .047), initiation of antidiabetic medication for new-onset diabetes (6.5% [173 of 2658] vs 8.2% [217 of 2656]; P = .02), and intolerance-related discontinuation or dose reduction of assigned therapy (4.0% [163 of 4094] vs 6.7% [273 of 4086]; P < .001). Results of this systematic review and individual patient data meta-analysis suggest that compared with a high-intensity statin strategy, the alternative LDL cholesterol-lowering strategy demonstrated comparable efficacy regarding 3-year death or cardiovascular events in patients with ASCVD, with an associated reduction in LDL cholesterol levels and risk for new-onset diabetes and intolerance. PROSPERO CRD42024532550.

Abstract 4136741: Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors and Lipid Reduction: A Network Meta-Analysis

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors offer additional lipid reduction beyond that achieved with statins. However, the optimal PCSK9 therapy for lowering lipid levels in patients with hypercholesterolemia and/or hyperlipidemia on background statin therapy remains unclear. Methods: PubMed and EMBASE databases were searched for RCTs assessing tafolecimab, evolocumab or alirocumab vs. placebo (administrated Q2W or Q4W, 12-week treatment) in patients with hypercholesterolemia and/or hyperlipidemia on medium-intensity statin up to March 28, 2024. The outcomes of interest were the percentage change in low-density lipoprotein cholesterol (LDL-C) or lipoprotein(a) from baseline to the 12th week. A frequentist random-effect network meta-analysis was applied to calculate MD and 95% CI using Stata 16.0 software. Results: A total of 4960 patients [PCSK9 inhibitors (n=3230), placebo (n=1730)] across 13 RCTs were included. At week 12, tafolecimab, evolocumab and alirocumab (either Q2W or Q4W) all induced significant reductions in LDL-C levels compared to placebo ( Figure ). The efficacy of evolocumab Q2W was significantly higher compared with alirocumab Q2W (MD=-18.67%, 95% Cl [-29.59%, -7.74%]), while similar LDL-C reduction was observed in tafolecimab Q2W vs. alirocumab Q2W and evolocumab Q2W vs. tafolecimab Q2W. Furthermore, tafolecimab Q4W and evolocumab Q4W were more effective in lowering LDL-C levels compared to alirocumab Q4W (tafolecimab vs. alirocumab: MD=-23.66%, 95% Cl [-32.58%, -14.74%]; evolocumab vs. alirocumab: MD=-25.84%, 95% Cl [-34.21%, -17.46%]), while there was no difference between evolocumab Q4W and tafolecimab Q4W. Lastly, the ranking of the effects for reducing lipoprotein(a) levels was as follows: tafolecimab &gt; evolocumab&gt; alirocumab (either Q2W or Q4W). Conclusions: In patients with hypercholesterolemia and/or hyperlipidemia treated with medium-intensity statins, tafolecimab and evolocumab (either Q2W or Q4W) might be preferred choices for lowering LDL-C. Additionally, tafolecimab (either Q2W or Q4W) appears to be the most effective agent for reducing lipoprotein(a) levels.

Abstract 4131951: The Safety Profile Of Inclisiran In Patients With Dyslipidemia And Intermediate To High Atherosclerotic Cardiovascular Disease Risk: A Systematic Review And Meta-Analysis

Introduction: Inclisiran is a novel drug that employs ribonucleic acid (RNA) interference to lower levels of the proprotein convertase subtilisin/kexin type 9 (PCSK9) protein, thereby improving the clearance of low-density lipoprotein (LDL) cholesterol from the bloodstream. It is given through subcutaneous injections at specified intervals and significantly reduces LDL cholesterol levels in patients with dyslipidemia and with intermediate to high risk of atherosclerotic cardiovascular disease (ASCVD). Goal: We aim to evaluate the safety of the use of inclisiran in patients with dyslipidemia and intermediate to high ASCVD risk. Methods: Three electronic databases of MEDLINE, Web of Science, and Embase were searched from inception to May 5th 2024 to identify relevant randomized controlled trials (RCTs) comparing safety profiles of inclisiran versus the control group . The primary outcome was all-cause mortality. Secondary outcomes were major adverse cardiovascular events (MACE), injection-site reaction and all treatment-emergent adverse events (TEAE). The effect estimates of outcomes were assessed using risk ratio (RR) with a 95% confidence interval (CI). Random-effects meta-analysis was conducted using the restricted maximum likelihood method given the inter-study variance was inevitable. The subgroup analysis was performed based on different dosing regimens. Results: We included 7 RCTs enrolling 4790 patients (63.8 ± 9.7 years, 66.8 % males) who received inclisiran. Compared to the control group, the use of inclisiran did not yield a significant effect on all-cause mortality (RR, 0.92; 95% CI, 0.54 to 1.54; I 2 = 0%), MACE (RR, 0.98; 95% CI, 0.82 to 1.17; I 2 = 0%), and TEAE (RR, 1.76; 95% CI, 0.74 to 4.15; I 2 = 74%). However, inclisiran use significantly increased injection-site reaction (RR, 7.08; 95% CI, 3.42 to 14.64; I 2 = 27%). Results are illustrated in the accompanying figure. Conclusions: Inclisiran use significantly increased injection-site reaction, with no increase in mortality and TEAE. Further trials are required to comprehensively assess the safety of inclisiran in the management of dyslipidemia in patients with ASCVD risk.

Efficacy and diabetes risk of moderate-intensity statin plus ezetimibe versus high-intensity statin after percutaneous coronary intervention

BackgroundsHigh-intensity statin is recommended for patients undergoing percutaneous coronary intervention (PCI), and ezetimibe is recommended to be added in patients not achieving low-density lipoprotein cholesterol (LDL-C) targets. Moderate-intensity statin plus ezetimibe can reduce LDL-C levels similar to high-intensity statin. The aim of this study is to examine the long-term efficacy and safety of moderate-intensity statin plus ezetimibe as the first-line strategy compared to high-intensity statin in patients undergoing PCI.MethodData was obtained from the Health Insurance Review and Assessment Service database of South Korea. Patients who underwent PCI from 2012 to 2017 were included. The primary efficacy endpoint was major adverse cardiac cerebrovascular events (MACCEs), a composite of all-cause death, revascularization, or ischemic stroke. The safety endpoint was new-onset diabetes mellitus (DM).ResultsA total of 45,501 patients received high-intensity statin (n = 38,340) or moderate-intensity statin plus ezetimibe (n = 7,161). Among propensity-score-matched 7,161 pairs, MACCEs occurred in 1,460 patients with high-intensity statin and 1,406 patients with moderate-intensity statin plus ezetimibe (33.8% vs. 31.9%, hazard ratio 0.96, 95% confidence interval 0.89–1.03, P = 0.27) at a median follow-up of 2.7 years. DM was newly diagnosed in 398 patients with high-intensity statin and 342 patients with moderate-intensity statin plus ezetimibe (12.5% vs. 10.7%; hazard ratio 0.84, 95% confidence interval 0.73–0.97, P = 0.02).ConclusionIn patients undergoing PCI, moderate-intensity statin plus ezetimibe demonstrated a similar risk of MACCEs but a lower risk of new-onset DM than high-intensity statin. Early combination treatment of moderate-intensity statin and ezetimibe may be a useful and safe lipid-lowering strategy after PCI.Graphical abstractCumulative incidence according to the first-line lipid-lowering strategy in patients undergoing percutaneous coronary intervention. Abbreviation: MACCE, major adverse cardiac cerebrovascular events; PCI, percutaneous coronary intervention.

Gene-Based Targeting for Treatment of Hypercholesterolemia and Prevention of Atherosclerotic Cardiovascular Disease

Familial hypercholesterolemia, characterized by high levels of LDL cholesterol is a monogenic metabolic disorder linked to atherosclerotic cardiovascular disease. Several genetic mutations in genes such as LDLR and PSK9 are thought to cause familial hypercholesterolemia. This ultimately causes dysfunction of the LDLR pathway, increasing circulating LDL levels. Current treatment revolves around decreasing LDL cholesterol levels in the blood. Statins are the current gold standard while sterol absorption inhibitors (ezetimibe) and PCSK9 inhibitors (evolocumab) are either used as primary treatment in individuals with statin intolerance, or supplementary treatment otherwise. However, CRISPR-Cas9 offers an upstream therapeutic intervention, inducing mutations in pathogenic genes (such as LDLR) to upregulate or downregulate gene expression and subsequently reduce LDL cholesterol levels. This technology thus has great potential as a two-fold treatment option, offering an effective solution for familial hypercholesterolemia, while simultaneously diminishing the risk of atherosclerotic cardiovascular disease. A limitation to current research exists in the sole analysis of monogenic factors in genetic screening, thus polygenic, multifactorial analyses are required to assess more holistic treatment plans. Furthermore, there exist current limitations to CRISPR-Cas9 including ethical limitations and social considerations revolving around the perpetuation of social inequities through technology necessitating future research on global health policies.