Low-density Lipoprotein Cholesterol Reduction Research Articles

Simvastatin reduces chronic kidney disease and renal failure risk in type 2 diabetes patients: post hoc ACCORD trial analysis.

Type 2 diabetes mellitus (T2DM) poses a substantial global health concern. Statins are widely used among T2DM patients for managing dyslipidemia, preventing cardiovascular disease (CVD), and offering renal protection. However, the extent to which their renal protective effects contribute to reducing the incidence of severe renal complications, including chronic kidney disease (CKD) and renal failure, is not well-defined. This investigation scrutinizes the impact of simvastatin versus placebo on renal outcomes among T2DM patients utilizing data from the ACCORD trial. It encompasses incidence rate comparisons, Kaplan-Meier estimates, Cox proportional hazards models, and mediation analyses. The study consisted of 3,619 individuals diagnosed with T2DM, among which 2,753 were treated routinely with simvastatin, while 866 did not receive any statin therapy. After adjusting for baseline characteristics and time-dependent covariates, simvastatin treatment was associated with a 71% reduction in the risk of CKD (HR 0.29, 95% CI 0.27-0.31, p < 0.01) and a 47% reduction in the risk of renal failure (HR 0.53, 95% CI 0.44-0.65, p < 0.01) compared to the statin-free group. Further subgroup analysis, accounting for the initial lipid and kidney profiles, indicated variable impacts of simvastatin on CKD and renal failure outcomes. Nevertheless, a consistent reduction in CKD risk was observed across all subgroups within the statin-treated population. Additional mediation analysis revealed that the reduction in low-density lipoprotein cholesterol (LDL-C) may be a potential mediator in the association between simvastatin and CKD, with a mediation effect of 14.9%, (95% CI 0.11-0.19, p < 0.01). Administering statins, specifically simvastatin, to T2DM patients at elevated risk for CVD, is likely to offer augmented renal advantages, notably in lowering the occurrence of CKD and renal failure. This protective effect against CKD manifests regardless of initial lipid profiles, albuminuria, and estimated glomerular filtration rate (eGFR) levels. The association between simvastatin and CKD may be partially mediated by LDL-C reduction.

Abstract 4131775: Effectiveness of Lipid-lowering therapy with Bempedoic Acid plus Ezetimibe in a Real-world Cohort

Introduction: Bempedoic acid and the combination with ezetimibe (BA+EZE) have demonstrated low-density lipoprotein cholesterol (LDL-C) lowering in clinical trials of adults with primary hyperlipidemia at high risk for or with cardiovascular disease. The impact of BA+EZE on LDL-C outcomes in a real-world cohort has not been studied. Aim: To evaluate the effectiveness of BA+EZE on LDL-C reduction and goal achievement using real-world data. Methods: This was a retrospective cohort study using deidentified electronic health records and linked claims data. Adult patients were included if they had a pharmacy claim for BA+EZE from March 1, 2020 to March 15, 2024 (date of first pharmacy claim = index date ), had ≥1 baseline LDL-C lab result on or within 6 months prior to the index date, and ≥2 LDL-C lab results post-index, including 1 lab result 12 months post-index (±60 days). Patients with documented use of ezetimibe on or within 6 weeks prior to index were excluded. For all patients with available valid lab results, LDL-C was determined at baseline (the value closest to but not after the index date), 3 months (±30 days), 6 months (±60 days) and 12 months (±60 days). Results: A total of 615 BA+EZE patients were identified (mean age 62±11 years, 52% women). At baseline, 64% had evidence of statin use in the prior 12 months and the mean LDL-C was 131±52 mg/dl. Figure 1 shows the change in the proportion of patients achieving LDL-C control at index, 3-, 6-, and 12-months post-index. The proportion of patients achieving LDL-C &lt;100 mg/dL more than doubled from index (30%) to 3 months (67%), and was sustained through 12 months (55%). At 12 months, there were fewer patients with LDL-C ≥130 mg/dL (24% vs 47% at index). The mean LDL-C reduction was 28% at 3 months (to 94±47 mg/dL), 27% at 6 months (96±44 mg/dL), and 22% at 12 months (102±47 mg/dL) (p&lt;0.0001 for all vs index). Conclusion: Patients who initiated BA+EZE showed early and sustained improvements in LDL-C. Future research should consider the impact of time on therapy and adherence on LDL-C control.

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.

Systematic review and meta-analysis assessing the status of carotid intima–media thickness and lipid profiles in type 2 diabetes mellitus

ObjectivesCarotid intima–media thickness (CIMT) is a measurement for subclinical atherosclerosis and has been associated with overall cardiovascular diseases, especially in type 2 diabetes mellitus (T2DM). We aimed to assess the...

Mediterranean Diet and Olive Oil Redox Interactions on Lactate Dehydrogenase Mediated by Gut Oscillibacter in Patients with Long-COVID-19 Syndrome

Chronic viral inflammation is associated with oxidative stress and changes in gut microbiota. The Mediterranean diet (MD), with recognized anti-inflammatory and antioxidant properties, modulates gut microorganisms, specifically on the interaction between extra virgin olive oil, a key component of the MD with well-documented antioxidant effects. This study investigated the influence of adherence to MD and antioxidant-rich foods (extra virgin olive oil) on biochemical, inflammatory, and microbiota profiles in patients with chronic inflammation defined as a prolonged inflammatory response due to immune dysregulation following the acute phase of the viral infection. Participants were classified into low (n = 54) and high (n = 134) MD adherence groups (cut-off of 7 points based on previous studies utilizing the same threshold in the assessment of MD adherence). Gut microbiota was sequenced using the 16S technique, and the adherence to MD was assessed using a validated questionnaire for a Spanish population. High adherence to the MD was linked to significant improvements in inflammatory and oxidative stress markers, including reductions in LDL-cholesterol, glucose, and lactate dehydrogenase (LDH) levels, an indicative of redox balance, as well as a significant higher consumption of antioxidant foods. Moreover, gut microbiota analysis revealed distinct compositional shifts and a lower abundance of the Oscillibacter genus in the high adherence group. Notably, a significant interaction was observed between MD adherence and extra virgin olive oil consumption, with Oscillibacter abundance influencing LDH levels, suggesting that the MD antioxidant properties may modulate inflammation through gut microbiota-mediated mechanisms. These findings provide new evidence that adherence to the Mediterranean diet can reduce inflammatory markers in patients with long-COVID-19, a population that has not been extensively studied, while also highlighting the potential role of the bacterial genus Oscillibacter in modulating this effect.

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.

Recaticimab as Add-On Therapy to Statins for Nonfamilial Hypercholesterolemia: The Randomized, Phase 3 REMAIN-2 Trial

BackgroundCurrently available antiproprotein convertase subtilisin/kexin type 9 monoclonal antibodies can effectively decrease low-density lipoprotein cholesterol (LDL-C) levels, but require frequent dosing. Recaticimab is a novel humanized monoclonal antibody against proprotein convertase subtilisin/kexin type 9. In a phase 1b/2 trial, recaticimab as add-on to stable statins showed robust LDL-C reduction with a dosing interval up to every 12 weeks (Q12W) in patients with hypercholesterolemia. ObjectivesREMAIN-2 (REcaticiMab Add-on therapy In patients with Nonfamilial hypercholesterolemia) aimed to assess the efficacy and safety of 48-week treatment with recaticimab as add-on therapy to statins in nonfamilial hypercholesterolemia. MethodsREMAIN-2 was a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial. During the run-in period, patients received stable moderate or high-intensity statin, with or without cholesterol absorption inhibitors (ezetimibe) or fenofibrate, for ≥4 weeks. Patients with an LDL-C of ≥1.8 mmol/L (if with atherosclerotic cardiovascular disease [ASCVD]) or ≥2.6 mmol/L (if without ASCVD) were then randomized (2:2:2:1:1:1) to receive recaticimab 150 mg every 4 weeks (Q4W), 300 mg every 8 weeks (Q8W), or 450 mg Q12W, or matching placebo injections (Q4W, Q8W, or Q12W) for 48 weeks. The primary efficacy endpoint was percentage change from baseline to week 24 in LDL-C level. ResultsA total of 689 randomly assigned patients received treatment (mean age, 55.8 years; male, 64.4%; ASCVD history, 69.5%; concomitant ezetimibe, 11.2%; mean baseline LDL-C, 2.8 mmol/L). Percentage change in LDL-C from baseline to week 24 was significantly more pronounced with recaticimab vs placebo (P < 0.0001), with least-squares mean differences of −62.2% (95% CI: −67.0% to −57.4%), −59.7% (95% CI: −65.0% to −54.4%), and −53.4% (95% CI: −58.7% to −48.2%) for the 150 mg Q4W, 300 mg Q8W, and 450 mg Q12W regimens, respectively. The decreases in LDL-C with recaticimab were maintained through week 48. Secondary lipid variables, including non–high-density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a) also favored the recaticimab groups. During the treatment period, the incidence of treatment-related adverse events (28.5% vs 26.6%) and serious treatment-related adverse events (0.4% vs 0.4%) was similarly low in both the recaticimab and placebo groups. ConclusionsRecaticimab as add-on to stable statin therapy significantly decreased LDL-C levels at week 24 and sustained the decreases through week 48, providing a novel therapeutic alternative with a dosing interval of up to every 12 weeks in patients with nonfamilial hypercholesterolemia.

Cardiovascular Safety of Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate in Virologically Suppressed PLWHIV: A Comparative Analysis of CVD Scores.

The Aim of this study is to assess the cardiovascular safety of doravirine/lamivudine/tenofovir disoproxil fumarate (DOR/3TC/TDF). We analyzed data from 37 virologically suppressed people living with HIV starting DOR/3TC/TDF, collecting viro-immunological and metabolic parameters as well as the 10-year risk of cardiovascular disease (10Y-CD) using both the Framingham risk score and D:A:D score.After 48 weeks, we observed a significant reduction in 10Y-CD both via the Framingham score (-0.7, p = .021) and the D:A:D score (-0.41, p = .012). After 96 weeks, we registered a significant reduction in 10Y-CD calculated via the D:A:D score (-0.98, p = .009). Regarding serum lipid markers, after 48 weeks we observed a significant reduction in total cholesterol (-17 mg/dL, p < .001), triglycerides (-21 mg/dL, p = .015), and LDL cholesterol (-8 mg/dL, p = .022). After 96 weeks, we registered a significant reduction in total cholesterol (-19 mg/dL, p < .001). DOR/3TC/TDF has shown a favorable metabolic profile, with a significant reduction in 10Y-CD, independently from the use of lipid-lowering drugs.

Safety and Effectiveness of Low-Density Lipoprotein Cholesterol-Lowering Therapy With Evolocumab for Familial Hypercholesterolemia/Hypercholesterolemia in Japan: A Real-World, Postmarketing, Single-Arm Study.

Evolocumab is the first monoclonal antibody against proprotein convertase subtilisin/kexin type 9 approved in Japan for familial hypercholesterolemia (FH) and hypercholesterolemia; however, data on its safety and effectiveness in the real-world setting in Japan are limited. This real-world, postmarketing, single-arm study assessed the safety and effectiveness of low-density lipoprotein cholesterol lowering with evolocumab in patients with homozygous/heterozygous familial hypercholesterolemia and hypercholesterolemia with high risk in Japan (668 sites). The primary safety end point was the incidence (percentage) and number of patients with adverse drug reactions and serious adverse events during the 104-week follow-up. Primary effectiveness end points included the percentage change in low-density lipoprotein cholesterol levels from baseline to week 12, assessed using 2-sided paired t tests. The safety and effectiveness sets comprised 3724 (homozygous FH, n=108; heterozygous FH, n=2009; hypercholesterolemia with high risk, n=1607) and 2797 (homozygous FH, n=91; heterozygous FH, n=1615; hypercholesterolemia with high risk, n=1091) patients, respectively. Overall, mean age and disease duration were 63.2 and 12.3 years, respectively. Serious adverse drug reactions and serious adverse events were experienced by 0.5% and 10.3% of patients; the incidence rates of myocardial infarction and stroke were 0.7% and 0.3%, respectively. A significant mean±SD percentage change in low-density lipoprotein cholesterol levels was observed at week 12 among patients with homozygous FH (-45.7%±28.2; P<0.001), heterozygous FH (-55.9%±28.8; P<0.001), and hypercholesterolemia with high risk (-63.3%±23.7; P<0.001). Evolocumab was well tolerated, and real-world patients with familial hypercholesterolemia and hypercholesterolemia with high risk in Japan had sustained low-density lipoprotein cholesterol reduction. URL: https://www.clinicaltrials.gov; Unique Identifier: NCT02808403.

PHARMACOLOGICAL STRATEGIES TO PREVENT CARDIOVASCULAR EVENTS IN HIGH-RISK PATIENTS

INTRODUCTION: Cardiovascular diseases (CVDs) remain the leading cause of global mortality, and high-risk patients, such as those with a history of myocardial infarction, diabetes, uncontrolled hypertension, or severe dyslipidemia, are especially vulnerable to adverse cardiovascular events. Pharmacological strategies aimed at preventing these events in high-risk patients are essential to reduce morbidity and mortality associated with CVDs. These strategies include the use of antiplatelet agents, statins, angiotensin-converting enzyme inhibitors (ACEIs), and beta-blockers, which have shown efficacy in the secondary prevention of events such as myocardial infarction and stroke. OBJECTIVES: Given the importance of this topic, this study aims to explore the most effective pharmacological strategies to prevent cardiovascular events in patients considered at high risk. The study aims to elucidate the main drugs used, their mechanisms of action, as well as the relevance of their clinical application for the reduction of fatal and non-fatal cardiovascular events in these patients. METHODOLOGY: The study was developed based on an integrative literature review, based on searches in the Virtual Health Library (VHL), PubMed and SciELO databases. The search terms used included: “Cardiovascular prevention”, “High-risk patients”, and “Pharmacological strategies”. Articles published in the last five years were selected to ensure the relevance and timeliness of the information. RESULTS: Pharmacological strategies to prevent cardiovascular events in high-risk patients include the use of antiplatelet agents such as aspirin, which reduces platelet aggregation and prevents arterial thrombosis. Statins, which reduce LDL cholesterol levels, have been shown to significantly reduce the risk of myocardial infarction and stroke. In addition, ACE inhibitors and beta-blockers have shown benefits in patients with heart failure and hypertension, reducing cardiovascular mortality. Individualizing treatment, considering the comorbidities and characteristics of each patient, is essential to optimize clinical results. CONCLUSION: Pharmacological strategies play a crucial role in the prevention of cardiovascular events in high-risk patients. The combination of medications such as antiplatelet agents, statins, ACE inhibitors and beta-blockers, when applied individually and according to clinical guidelines, can significantly reduce the incidence of serious cardiovascular events. Awareness of the importance of the correct use of these therapies and adherence to treatment are essential to improve the quality of life and increase the longevity of patients.

Combination therapy with GalNAc-siRNA drugs targeting both PCSK9 and APOC3 resulted in enhanced lipid lowering in mice

Abstract Introduction Aggressive lowering of both atherogenic low-density lipoprotein cholesterol (LDL-C) and triglyceride-rich lipoproteins (TRLs) could reduce residual atherosclerotic cardiovascular disease (ASCVD) risk. Drugs targeting PCSK9 or APOC3 have shown good lipid-lowering effects in clinic. Here, we have developed GalNAc-conjugated siRNAs, RBD7022 targeting PCSK9 and RBD5044 targeting APOC3, as novel therapeutic agents to lower LDL-C and triglyceride (TG) plasma levels respectively. Each drug shows potent and durable effect in silencing its own target. However, it is unknown whether the combined therapy with siRNA drugs targeting both PCSK9 and APOC3 will generate enhanced effects in lipid lowering. Purpose To investigate the effects of fixed-dose combination of RBD7022 and RBD5044 on LDL-C, TG and total cholesterol (TC). Methods RBD7022 and RBD5044 completely match the human PCSK9 and APOC3 transcripts respectively. RBD7022 has 2 nucleotide mismatches with mouse pcsk9, but still shows silencing activity in mice, while RBD5044 has no activity due to 5 mismatches with mouse apoc3. Therefore, humanized APOC3 transgenic mice were used in this study, which had serious hypertriglyceridemia with relatively high cholesterol and TG levels. They were randomized into 8 groups with treatment of RBD7022 (1 mg/kg or 3 mg/kg), RBD5044 (3 mg/kg or 6 mg/kg), or 3 different dose combinations of RBD7022 and RBD5044, as well as PBS control. All animals were administrated once on Day 1. Plasma was collected to quantify lipid biomarkers. Results RBD7022 showed a robust effect on LDL-C reduction, with inhibition rates of 45% in 3 mg/kg and 43% in 6 mg/kg, indicating 3 mg/kg was a saturated dose for RBD7022 in LDL-C lowering. RBD5044 showed a dose-dependent effect on LDL-C reduction, with inhibition rate of 52% at 1 mg/kg and 59% at 3 mg/kg. Interestingly, significantly enhanced LDL-C reduction was observed in the combination groups, with 67% reduction in LDL-C at RBD5044 1 mg/kg plus RBD7022 3 mg/kg, 73% reduction in LDL-C at RBD5044 3 mg/kg plus RBD7022 3 mg/kg and 78% reduction in LDL-C at RBD5044 3 mg/kg plus RBD7022 6 mg/kg, showing dose-dependent effects (Figure 1A). Enhanced TC reduction was also found in combination at RBD5044 3 mg/kg plus RBD7022 6 mg/kg compared with RBD5044 or RBD7022 alone. RBD5044 showed a dose dependent effect on TG reduction with inhibition rates of 56% at 1 mg/kg and 83% at 3 mg/kg. RBD7022 treatment alone did not show significant effect on TG reduction. No added effects of RBD7022 on TG levels was found in the combination with RBD5044, indicating the TG lowering was induced by RBD5044. Conclusions The combination of RBD7022 targeting PCSK9 and RBD5044 targeting APOC3 simultaneously reduce LDL-C and TC levels. The combination of RBD7022 and RBD5044 could be a better therapeutic option to further reduce LDL-C, particularly for mixed hyperlipidemia patients and other high-risk individuals with both high LDL-C and high TG levels.Figure 1

Remnant cholesterol lowering in cardiovascular disease risk reduction in statin trials: meta-regression analyses

Abstract Background Remnant cholesterol is a causal risk factor for cardiovascular disease. Purpose We tested the hypothesis that remnant cholesterol reduction explains part of the cardiovascular disease risk reduction in statin trials. Methods We included statin trials with &amp;gt;1,000 participants and available data on lipid levels. Baseline and follow-up low-density lipoprotein (LDL) and remnant cholesterol levels were extracted. LDL and remnant cholesterol reductions were differences between intervention and reference groups at year one. Risk ratios for any statin use and per 1 mmol/L (39 mg/dL) LDL and remnant cholesterol reductions were estimated using meta-regressions. Results We included 29 statin trials with 191,202 participants and 26,639 major cardiovascular events. On an absolute scale when LDL cholesterol was reduced 1 mmol/L (39 mg/dL), remnant cholesterol was reduced 0.17 mmol/L (7 mg/dL) (Figure 1). On a relative scale when LDL cholesterol was reduced 20%, remnant cholesterol was reduced 12%. The risk ratio for statin use versus reference was 0.82 (95% confidence interval: 0.81-0.84) for major cardiovascular events (Figure 2). Risk ratios per 1 mmol/L (39 mg/dL) reductions were 0.82 (0.80-0.83) for LDL cholesterol and 0.37 (0.33-0.41) for remnant cholesterol for major cardiovascular events. Corresponding risk ratios for 1 mmol/L (39 mg/dL) LDL and remnant cholesterol reductions were 0.78 (0.75-0.80) and 0.30 (0.25-0.35) for coronary events, 0.86 (0.82 -0.90) and 0.48 (0.38-0.61) for stroke, and 0.93 (0.91-0.95) and 0.71 (0.62-0.80) for any death, respectively. Conclusions Remnant cholesterol lowering likely explain part of the cardiovascular disease risk reduction in statin trials. Figure 1. Remnant cholesterol reduction as a function of LDL cholesterol reduction. Regressions were calculated using inverse-variance weighted unadjusted linear regressions. LDL = low-density lipoprotein. LDL-C = LDL cholesterol. R-C = Remnant cholesterol. ∆ = change from baseline to 1 year follow-up. Figure 2. RR for MACE for statin use and cholesterol reductions. Risk ratios were calculated using fixed and random effects inverse-variance weighted meta-regressions. CI = confidence interval. LDL = low-density lipoprotein. LDL-C = LDL cholesterol. MACE = major cardiovascular events. R-C = remnant cholesterol. RR = risk ratio.Figure 1Figure 2

SHR-1918, a monoclonal antibody against angiopoietin-like 3, in healthy subjects: a randomized, double-blind, placebo-controlled, phase 1 study

Abstract Background Low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) are important risk factors for atherosclerotic cardiovascular disease. Angiopoietin-like 3 (ANGPTL3) is involved in the regulation of lipid metabolism and can increase serum TG and LDL-C levels by reducing their clearance. SHR-1918 is an ANGPTL3 monoclonal antibody developed to inhibit ANGPTL3 activity, thereby reducing the level of TG and LDL-C. Purpose This phase 1 single ascending dose study aimed to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity of SHR-1918 in healthy subjects. Methods Six dose cohorts were planned, including 100, 300, 450, 750, 900 (optional), and 1200 (optional) mg. For each cohort, 12 healthy subjects were enrolled and randomized (9:3) to receive single subcutaneous SHR-1918 or placebo. Subjects were observed for seven days post-dose and followed up to Day 148 for the 100 mg cohort and Day 190 for the other dose cohorts. The primary endpoints were safety and tolerability. Results A total of 72 subjects were enrolled in the six dose cohorts from 100 to 1200 mg (SHR-1918, n = 54; placebo, n = 18). SHR-1918 was well-tolerated at tested doses. Treatment-emergent adverse events (TEAEs) were reported in 49 (90.7%) subjects in the SHR-1918 group and 17 (94.4%) subjects in the placebo group. The most common TEAEs were upper respiratory tract infection (25.9% with SHR-1918 vs. 27.8% with placebo), protein urine present (22.2% vs. 22.2%), and blood uric acid increased (16.7% vs. 16.7%). All TEAEs were mild or moderate in severity. There were no serious adverse events or TEAEs leading to death. Serum concentration of SHR-1918 generally increased with increasing doses. Maximum serum concentration was reached 8.0 to 10.0 days after injection, and mean t½ was 29.4 to 53.3 days across the dose range. SHR-1918 exposure exhibited in a slightly greater-than-dose-proportional manner from 100 to 1200 mg. Serum LDL-C and TG levels markedly and rapidly decreased in all SHR-1918 dose cohorts and remained under the baseline value up to the end of follow-up period for the higher doses, whereas those in the placebo group were above baseline at most follow-up visits (Figure 1 and 2). In the 750 to 1200 mg cohorts, the largest decline in LDL-C from baseline ranged from -46.5% to -49.1%, and the maximum decrease in TG ranged from -67.4% to -82.8%. On Day 85, there remained to be 36.9% to 39.0% reduction in LDL-C and 59.9% to 79.1% reduction in TG for the higher doses. Anti-drug antibody was not detected in SHR-1918-treated subjects. Conclusions SHR-1918 was well-tolerated and showed promising efficacy in healthy subjects. A phase 2 study has initiated to evaluate SHR-1918 in hyperlipidemic patients (NCT06109831).Serum LDL-C after SHR-1918 injectionSerum TG after SHR-1918 injection

Circulating Amyloid beta 1-40 is independently associated with statin treatment and LDL cholesterol reduction: a prospective cohort study

Abstract Background Accumulating evidence suggests that circulating amyloid beta 1-40 (Aβ40), a pro-inflammatory and pro-atherogenic peptide, is associated with atherosclerotic cardiovascular disease (ASCVD), providing incremental prognostic value and risk stratification refinement in primary and secondary prevention settings. Existing evidence supports conflicting off-target effects of statins on plasma Aβ40. We aim to explore the impact of cardiovascular risk reduction through statin therapy on Aβ40 plasma levels in subjects with dyslipidemia and with/without ASCVD. Methods In this prospective study, patients with dyslipidemia who visited for the first time our lipid clinic for risk stratification and treatment plan assessment (n=146) were consecutively recruited. Αβ40 was measured in plasma samples by enzyme-linked immunosorbent assay at baseline and after a mean follow-up of 5.2 and 15 months. Patients in whom statin treatment was initiated or intensified in terms of dose or regimen (n= 68) were compared against patients not treated with statins or with unchanged statin intensity (n = 78). Statin intensity treatment was defined based on the European Society of Cardiology (ESC) guidelines. Results Increased Aβ40 plasma levels at baseline were associated with ASCVD presence, decreased glomerular filtration rate (GFR), and history of heart failure (p&amp;lt;0.05 for all). An increase in Aβ40 circulating levels between baseline and follow-up 1 was observed in patients in whom statin treatment was initiated or intensified (p=0.041). However, in patients not treated with statins or treated with unchanged statin intensity, an increase in Aβ40 circulating levels was observed between follow-up 1 and follow-up 2 (p=0.05, Figure 1A). These changes in Aβ40 were significantly different between the two groups during the short follow-up period (β=0.226, p for interaction =0.025) independently from age and changes in GFR, systolic blood pressure, and LDL-C. Additionally, patients who achieved a reduction in low-density lipoprotein cholesterol (LDL-C) ≥ 50% in follow-up 2 have unchanged Aβ40 levels during the long follow-up period, while an increase in Aβ40 was observed in the rest population (p=0.012, Figure 1B). These changes were significantly different between the two LDL-C groups independently of statin treatment and changes in high sensitive C-reactive protein (hs-CRP) (β= -0.231, p for interaction=0.035). Conclusion In a dyslipidemic population, statin initiation or intensification and LDL-C decrease showed a short-term increase and a long-term return to initial levels, respectively, in circulating Aβ40 levels. From a mechanistic point of view, our findings suggest that statins have an impact on Aβ40, possibly through an LDL-C-dependent and a non-LDL-C-dependent pathway. Further studies are needed to evaluate the utility of circulating Aβ40 as a novel biomarker in ASCVD risk reduction assessment.

Efficacy of combination lipid lowering therapy in achieving low density lipoprotein cholesterol targets after one month of event in patients with acute coronary syndrome

Abstract Introduction Rapid reduction in low-density lipoprotein cholesterol (LDL-C) levels reduces the risk of recurrent events in patients with acute coronary syndrome (ACS) with benefits proportional to LDL-C reduction. Early use of combination lipid-lowering therapy (LLT) is therefore recommended. Proprotein convertase subtilisin/kexin type-9 inhibitors (PCSK9i) combined with high-intensity statins (HIS) improve LDL-C goal attainment but are unaffordable for many patients in India and worldwide. Purpose We share our experience with the use of dual RE (rosuvastatin plus ezetimibe) and triple REB (rosuvastatin plus ezetimibe and bempedoic acid) combination LLT in patients admitted with ACS. Methods All ACS patients admitted to our institute over one year (January 2023 to December 2023) were considered in this retrospective analysis. Those with unavailable lipid profile reports, either at the time of ACS or at 1-month follow-up, were excluded. Clinical and laboratory details were obtained from hospital records. The primary objective was to assess the percentage change in LDL-C levels from index event to 4 weeks follow-up. Results A total of 299 patients were included, out of which 60 were on HIS alone, 71 were on RE, and 168 were on REB (Figure). The majority (99%) of patients in the REB group were statin naïve, compared to the other two groups. The baseline mean LDL-C levels at the time of the index event were 95.3+30.5, 103.2+39.6, and 115.6+32.9 mg/dl, respectively (p&amp;lt;0.001) (Table). The mean LDL-C levels at four weeks post-ACS reduced to 52.9+21.2, 45.9+20.5, and 43.7+15.4 mg/dl, respectively (p&amp;lt;0.01). The percentage reduction in LDL-C level was 44.4%, 55.5%, and 62.2%, respectively (p&amp;lt;0.001). REB enabled 70.8% and 95.2% of patients to achieve the Lipid Association of India, and American College of Cardiology recommended LDL-C targets of &amp;lt;50 mg/dl and &amp;lt;70 mg/dl within 4 weeks. These target levels were achieved in 67.6% and 88.7% of patients on the dual RE therapy and 50% and 81.6% of patients, respectively, on HIS alone. Conclusion Our study demonstrates the capacity to rapidly achieve LDL-C goals after ACS with triple REB therapy, an affordable regimen compared to costly PCSK9i therapy.Figure.Lipid lowering strategies usedComparison of study groups

Cardiovascular events in patients treated with bempedoic acid vs. placebo: systematic review and meta-analysis

Abstract Aims Reduction of low-density lipoprotein cholesterol (LDL-C) decreases cardiovascular mortality and morbidity. Bempedoic acid represents a promising novel lipid modifying agent for patients who cannot reach guideline recommended LDL-C goals or statin-intolerant patients, but data on safety and cardiovascular outcomes are limited. We therefore aimed to systematically review randomized controlled trials investigating bempedoic acid versus placebo in patients with hyperlipidemia. Methods A systematic search on the databases PubMed, Web of Science, and Embase until 20 March 2023 was performed. All randomized trials comparing bempedoic acid (180 mg daily) with placebo in patients with an indication for lipid-lowering therapy were included. As primary endpoint we analysed three-point major adverse cardiovascular events (MACE) consisting of cardiovascular death, non-fatal myocardial infarction (MI) or non-fatal stroke. The analysis was carried out using the odds ratio as the outcome measure. Due to the expected heterogeneity across studies a random-effects model was fitted to the data. Results Out of 258 manuscripts, 10 manuscripts fulfilled the inclusion criteria. In total, these trials included 18,200 patients (9,765 on bempedoic acid, 8,435 on placebo). Bempedoic acid significantly reduced MACE compared to placebo (OR 0.84 [95% CI 0.76-0.96]; p&amp;lt;0.001; I2=0%). The endpoint reduction was driven by a lower rate of non-fatal MI, whereas bempedoic acid had no significant effect on stroke (OR 0.86 [95% CI 0.69-1.08]; p=0.20, I2=0%) and all-cause mortality (OR 1.19 [95% CI 0.73-1.93]; p=0.49; I2=18%). Conclusion Bempedoic acid reduced non-fatal MI in patients with hyperlipidemia, whereas it had no significant effect on stroke and all-cause mortality.Figure.Forest plot for three-point MACE

Temporal trends in lipid management among Korean patients following acute myocardial infarction from 2011 to 2020

Abstract Background/Purpose Real-world data trends on dyslipidaemia prevalence and lipid management for patients following acute myocardial infarction (AMI) are lacking in South Korea, one of the Asia-Pacific nations. Our study aimed to evaluate the 10-year temporal trends of dyslipidaemia prevalence and lipid management in this patient population. Methods The study utilized datasets from two Korean AMI observational cohort (2011–2020) including a total of 26,751 participants (Figure 1A). The primary endpoints were as follows: (1) absolute low-density lipoprotein cholesterol (LDL-C) target of &amp;lt;70 mg/dL; (2) relative LDL-C target of &amp;gt;50% LDL-C reduction from the baseline; (3) absolute or relative LDL-C target (American target); and (4) both absolute and relative LDL-C targets (European target). Results The prevalence of dyslipidaemia increased from 11.1% to 17.1% (Table 1, Figure 1B), while the statin prescription rates increased from 92.9% to 97.0% from 2011 to 2020. High-intensity statin use increased from 12.80% in 2012 to 69.30% in 2020 (Table 1) Interestingly, the yearlong substantial increases in the prescription rates of high-intensity statins were prominent between 2013 (21.9%) and 2014 (37.7%) and between 2018 (52.4%) and 2019 (66.1%), which may have been influenced by major revisions to the international lipid management guidelines and their adoption (Figure 1C). Ezetimibe use increased from 4.50% in 2016 to 22.50% in 2020. The achievement rate of the absolute and relative LDL-C targets increased from 41.4% and 20.8% in 2012 to 62.5% and 39.5% in 2019, respectively (Table 1). The achievement rates of the American (45.7% in 2012 to 68.6% in 2019) and European (16.5% in 2012 to 33.8% in 2019) targets showed similar increasing trends (Table 1, Figure 1D). Conclusions Despite the adoption of lipid management guidelines in clinical practice has improved, some patients some patients are unable to reduce their LDL-C concentrations to their target levels. Our real-world analyses emphasise the need for multidirectional and continued efforts to optimise lipid management and improve the clinical outcomes in these patients.Figure 1

Lipid-lowering therapy with Inclisiran in the real-world setting: initial data from a national health care service

Abstract Introduction Inclisiran, a first-in-class siRNA enabling long-term inhibition of PCSK9 synthesis, demonstrates good safety and efficacy profile in randomized clinical trials. Challenges for real-life use of inclisiran include limited access to therapy, injections by medical staff, lack of cardiovascular outcome data, and concern from adverse effects considering the novel mechanism and long-term activity. Real-life data on the potential to attain lipid-goals and reduce treatment gaps is lacking. We investigated the implementation of inclisiran in real-world clinical setting in Israel. Methods Data from a nationwide healthcare organization on patients initiating inclisiran therapy during the period of 3/2022-11/2023. Patients’ characteristics, efficacy, use of combination lipid-lowering therapies, and attainment of low-density lipoprotein cholesterol (LDL-C) goals, were evaluated. Results Inclisiran was initiated by 503 patients (57% women; mean age 66±11 years). Atherosclerotic cardiovascular disease was present in 54%, and peak historical LDL-C levels &amp;gt;190 mg/dL documented in 64%. Prior exposure to PCSK9 monoclonal antibodies was evident in 28%. Follow-up lipid profile &amp;gt;2 months after filling first prescription, was available in 397 patients (347 with ≥2 injections). In patients treated by inclisiran only (n=254), median LDL-C reduction from peak historical levels was 57% (IQR, 48%-67%), and from pre-injection levels 40% (19%-54%). In those with concomitant oral lipid-lowering therapies (n=143), median LDL-C reduction from peak levels was 66% (IQR, 55%-73%), and from pre-injection levels 46% (23%-59%) (Figure). LDL-C &amp;lt;70 mg/dL was attained by 39% and LDL-C &amp;lt;55 mg/dL by 21.9%. Of those treated with concomitant statin therapy, 38% attained LDL-C &amp;lt;55 mg/dL. Overall, 6.5% did not persist with inclisiran therapy after initial injection. Conclusions In real-life practice, inclisiran showed good efficacy with positive short-term adherence. However, attainment rates of lipid-goals were suboptimal due to limited use of combination lipid-lowering therapy and high-rates of severe hypercholesterolemia in our patient population cohort.Waterfall Plot of LDL-C (%) Reduction

Efficacy of diet with low glycemic index on coronary artery disease

Abstract Background Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide, with dietary factors playing a significant role in its pathogenesis. The glycemic index (GI) of foods has been implicated in cardiovascular health, with low GI diets hypothesized to reduce the risk of CAD and improve outcomes [1]. However, the efficacy of low glycemic index diets in patients with established CAD remains uncertain. Objective This study aimed to assess the efficacy of a low glycemic index diet on coronary artery disease by evaluating changes in cardiovascular biomarkers and major adverse cardiovascular events (MACE) using Kaplan-Meier analysis and Cox regression models. Material and Methods A randomized controlled trial was conducted involving 156 patients with established coronary artery disease (Aged 43-75 years, mean age 62.4±12.7 years, male=57%). Participants were randomized to either a low glycemic index diet group or a control group receiving standard dietary advice. Changes in cardiovascular biomarkers, including lipid profiles, inflammatory markers, and glycemic control parameters, were assessed at baseline and follow-up visits. Major adverse cardiovascular events, including myocardial infarction, stroke, and cardiovascular death, were recorded over a median follow-up period of 6.2±2.4 years. Kaplan-Meier analysis and Cox regression models were used to evaluate the association between adherence to a low glycemic index diet and MACE. Results Preliminary analysis demonstrated significant improvements in cardiovascular biomarkers, including reductions in LDL cholesterol, triglycerides, and inflammatory markers, in the low glycemic index diet group compared to the control group (p &amp;lt; 0.05). Kaplan-Meier analysis revealed a lower incidence of MACE in patients adherent to the low glycemic index diet compared to non-adherent patients (log-rank p &amp;lt; 0.05). Cox regression analysis confirmed the independent association between adherence to a low glycemic index diet and reduced risk of MACE after adjusting for confounding factors (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.60-0.95; p &amp;lt; 0.001). Conclusion Our findings suggest that a low glycemic index diet may be efficacious in reducing cardiovascular risk and improving outcomes in patients with coronary artery disease. Adherence to a low glycemic index diet was associated with favorable changes in cardiovascular biomarkers and a reduced risk of major adverse cardiovascular events. Further research is warranted to confirm these findings and elucidate the mechanisms underlying the cardioprotective effects of low glycemic index diets.