Lower Low-density Lipoprotein Cholesterol Research Articles

Comparison of the efficacy and safety of Shanhuang Jiangzhi tablets and atorvastatin in the treatment of patients with hyperlipidaemia

ObjectivesTo compare the efficacy and safety of Shanhuang Jiangzhi tablets and atorvastatin in reducing blood lipid levels.MethodsPatients with hyperlipidaemia admitted to the cardiac centre between January 2019 and December 2020 were included in the study. A total of 1063 patients with hyperlipidaemia took either Shanhuang Jiangzhi tablets (n = 372) or atorvastatin (n = 691) and met the inclusion and exclusion criteria. Clinical data, including total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol, were retrospectively evaluated after propensity score matching (PSM) analysis. The adverse events were also recorded during the therapy process.ResultsFollowing PSM analysis, both groups were well matched across all parameters. Compared with the baseline, Shanhuang Jiangzhi tablets had greater effects on TC, TG and LDL-C, and the difference was statistically significant (p < 0.001). Furthermore, the results showed that Shanhuang Jiangzhi tablets are similar to atorvastatin in reducing TC and LDL-C, and all p-values were > 0.05. However, the decrease of TG was greater in the Shanhuang Jiangzhi group (p < 0.001). Clinical adverse reactions of Shanhuang Jiangzhi tablets are rare and have no statistical significance compared with atorvastatin (p = 0.682).ConclusionsShanhuang Jiangzhi tablets have a higher hypotriglyceridaemic performance than atorvastatin and an equivalent ability to lower TC and LDL-C. In addition, Shanhuang Jiangzhi tablets are a low-risk option for lowering blood lipids.

Genetic insights into the association of statin and newer nonstatin drug target genes with human longevity: a Mendelian randomization analysis

BackgroundIt remains controversial whether the long-term use of statins or newer nonstatin drugs has a positive effect on human longevity. Therefore, this study aimed to investigate the genetic associations between different lipid-lowering therapeutic gene targets and human longevity.MethodsTwo-sample Mendelian randomization analyses were conducted. The exposures comprised genetic variants that proxy nine drug target genes mimicking lipid-lowering effects (LDLR, HMGCR, PCKS9, NPC1L1, APOB, CETP, LPL, APOC3, and ANGPTL3). Two large-scale genome-wide association study (GWAS) summary datasets of human lifespan, including up to 500,193 European individuals, were used as outcomes. The inverse-variance weighting method was applied as the main approach. Sensitivity tests were conducted to evaluate the robustness, heterogeneity, and pleiotropy of the results. Causal effects were further validated using expression quantitative trait locus (eQTL) data.ResultsGenetically proxied LDLR variants, which mimic the effects of lowering low-density lipoprotein cholesterol (LDL-C), were associated with extended lifespan. This association was replicated in the validation set and was further confirmed in the eQTL summary data of blood and liver tissues. Mediation analysis revealed that the genetic mimicry of LDLR enhancement extended lifespan by reducing the risk of major coronary heart disease, accounting for 22.8% of the mediation effect. The genetically proxied CETP and APOC3 inhibitions also showed causal effects on increased life expectancy in both outcome datasets. The lipid-lowering variants of HMGCR, PCKS9, LPL, and APOB were associated with longer lifespans but did not causally increase extreme longevity. No statistical evidence was detected to support an association between NPC1L1 and lifespan.ConclusionThis study suggests that LDLR is a promising genetic target for human longevity. Lipid-related gene targets, such as PCSK9, CETP, and APOC3, might potentially regulate human lifespan, thus offering promising prospects for developing newer nonstatin therapies.

Sex X Time Interactions in Lp(a) and LDL-C Response to Evolocumab.

The aim of this study was to evaluate whether there were significant sex x time interactions in lipoprotein(a) (Lp(a)) and low-density lipoprotein cholesterol (LDL-C) response to treatment with the Proprotein Convertase Subtilisin/Kexin type 9 inhibitor (PCSK9i) Evolocumab, in a real-life clinical setting. For this purpose, we pooled data from 176 outpatients (Men: 93; Women: 83) clinically evaluated at baseline and every six months after starting Evolocumab. Individuals who had been on PCSK9i for less than 30 months and nonadherent patients were excluded from the analysis. Over time, absolute values of Lp(a) plasma concentrations significantly decreased in the entire cohort (p-value < 0.001) and by sex (p-value < 0.001 in men and p-value = 0.002 in and women). However, there were no sex-related significant differences. Absolute plasma concentrations of LDL-C significantly decreased over time in the entire cohort and by sex (p-value < 0.001 always), with greater improvements in men compared to women. The sex x time interaction was statistically significant in LDL-C (all p-values < 0.05), while absolute changes in Lp(a) were not influenced by either sex or time (all p-value > 0.05). Our data partially reinforce the presence of differences in response to treatment to PCSK9i between men and women and are essential to gain a better understanding of the relationship between LDL-C and Lp(a) lowering in response to PCSK9i. Further research will clarify whether these sex-related significant differences translate into a meaningful difference in the long-term risk of ASCVD.

Assessing the impact of physical activity on bone density, cardiopulmonary function, and metabolic health in stroke survivors.

Stroke survivors often face motor impairments leading to decreased physical activity, which can, in turn, result in secondary health-related issues like cardiovascular and pulmonary impairment and osteoporosis. This research finds out the impact of physical activity on bone mineral density, cardiopulmonary health, and metabolic status in stroke survivors. The goal is to generate knowledge to inform rehabilitation strategies, emphasizing the significant role of regular exercise in enhancing the health of individuals recovering from stroke. This study was conducted using a cross-sectional study design, and involved 100 stroke survivors selected through stratified random sampling. Physical activity was measured using the validated Stroke-Specific Physical Activity Questionnaire. Health outcomes were assessed through various means: bone mineral density via the OSTEOKJ3000 ultrasonic bone densitometer; resting heart rate and blood pressure via an automated monitor; lipid profiles through the CardioChek PA analyzer; Hb1Ac levels via the A1CNow + System; and respiratory parameters through a spirometer. Statistical analysis revealed bone mineral density is positively correlated with physical activity (R = 0.53, P < .001). Additionally, an association was found between physical activity and improved cardiopulmonary function (resting heart rate r = -0.45, P < .001; forced expiratory volume in one second R = 0.30, P = .0023; forced vital capacity R = 0.28, P = .0041). Moreover, higher physical activity levels correlated with lower low-density lipoprotein cholesterol levels (r = -0.35, P = .0007), higher high-density lipoprotein cholesterol levels (R = 0.33, P = .0012), and better glycaemic control (HbA1c r = -0.40, P = .0002). This study highlights the significant benefits of physical activity for stroke survivors, showing positive impacts on bone density, cardiopulmonary function, and metabolic health. It underscores the need to include regular exercise in rehabilitation strategies to mitigate secondary health complications and enhance the overall health of stroke survivors. Future research should continue investigating the potential benefits of physical activity in this population.

Proprotein convertase subtilisn/kexin type 9 inhibitors and small interfering RNA therapy for cardiovascular risk reduction: A systematic review and meta-analysis.

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of mortality worldwide. Atherosclerosis occurs due to accumulation of low-density lipoprotein cholesterol (LDL-c) in the arterial system. Thus, lipid lowering therapy is essential for both primary and secondary prevention. Proprotein convertase subtilisn/kexin type 9 (PCSK9) inhibitors (Evolocumab, Alirocumab) and small interfering RNA (siRNA) therapy (Inclisiran) have been demonstrated to lower LDL-c and ASCVD events in conjunction with maximally tolerated statin therapy. However, the degree of LDL-c reduction and the impact on reducing major adverse cardiac events, including their impact on mortality, remains unclear. The purpose of this study is to examine the effects of PCSK9 inhibitors and small interfering RNA (siRNA) therapy on LDL-c reduction and major adverse cardiac events (MACE) and mortality by conducting a meta-analysis of randomized controlled trials. Using Pubmed, Embase, Cochrane Library and clinicaltrials.gov until April 2023, we extracted randomized controlled trials (RCTs) of PCSK9 inhibitors (Evolocumab, Alirocumab) and siRNA therapy (Inclisiran) for lipid lowering and risk of MACE. Using random-effects models, we pooled the relative risks and 95% CIs and weighted least-squares mean difference in LDL-c levels. We estimated odds ratios with 95% CIs among MACE subtypes and all-cause mortality. Fixed-effect model was used, and heterogeneity was assessed using the I2 statistic. In all, 54 studies with 87,669 participants (142,262 person-years) met criteria for inclusion. LDL-c percent change was reported in 47 studies (n = 62,634) evaluating two PCSK9 inhibitors and siRNA therapy. Of those, 21 studies (n = 41,361) included treatment with Evolocumab (140mg), 22 (n = 11,751) included Alirocumab (75mg), and 4 studies (n = 9,522) included Inclisiran (284mg and 300mg). Compared with placebo, after a median of 24 weeks (IQR 12-52), Evolocumab reduced LDL-c by -61.09% (95% CI: -64.81, -57.38, p<0.01) and Alirocumab reduced LDL-c by -46.35% (95% CI: -51.75, -41.13, p<0.01). Inclisiran 284mg reduced LDL-c by -54.83% (95% CI: -59.04, -50.62, p = 0.05) and Inclisiran 300mg reduced LDL-c by -43.11% (95% CI: -52.42, -33.80, p = 0.01). After a median of 8 months (IQR 6-15), Evolocumab reduced the risk of myocardial infarction (MI), OR 0.72 (95% CI: 0.64, 0.81, p<0.01), coronary revascularization, 0.77 (95% CI: 0.70, 0.84, p<0.01), stroke, 0.79 (95% CI: 0.66, 0.94, p = 0.01) and overall MACE 0.85 (95% CI: 0.80, 0.89, p<0.01). Alirocumab reduced MI, 0.57 (0.38, 0.86, p = 0.01), cardiovascular mortality 0.35 (95% CI: 0.16, 0.77, p = 0.01), all-cause mortality 0.60 (95% CI: 0.43, 0.84, p<0.01), and overall MACE 0.35 (0.16, 0.77, p = 0.01). PCSK9 inhibitors (Evolocumab, Alirocumab) and siRNA therapy (Inclisiran) significantly reduced LDL-c by >40% in high-risk individuals. Additionally, both Alirocumab and Evolocumab reduced the risk of MACE, and Alirocumab reduced cardiovascular and all-cause mortality.

Phytosterols: Potential Therapeutic Effects and Challenges in Food Industry.

Increases in serum total and low-density lipoprotein (LDL) cholesterol are known as hypercholesterolemia, and it is a significant risk factor for the emergence of cardiovascular illnesses. Any action strategy for lowering serum cholesterol is supported by lifestyle changes. Phytosterols are organic substances from the triterpene family. Phytosterols can lower serum LDL cholesterol levels because of their structural resemblance to cholesterol. Phytosterols are used to enrich or fortify a broad spectrum of food products. Phytosterols are quickly oxidized, just like cholesterol and unsaturated fatty acids. The utilization of free phytosterols for the manufacture of functional meals is highlighted in this chapter, which also focuses on the therapeutic effects of phytosterols and their technological concerns in the industrial field.

Safety and Tolerability of Inclisiran forTreatment of Hypercholesterolemia in7 Clinical Trials.

Inclisiran is a small interfering RNA agent to lower low-density lipoprotein cholesterol. The purpose of this study was to provide reliable evidence to date on the long-term safety profile of inclisiran. This post hoc analysis comprised patients treated with 300mg inclisiran sodium or placebo in the completed (ORION-1, -3, -5, -9, -10, and -11) and ongoing (ORION-8) trials. Exposure-adjusted incidence rates and Kaplan-Meier estimates of cumulative incidence of reported treatment-emergent adverse events (TEAE), abnormal laboratory measurements, and incidence of antidrug antibodies were analyzed. This analysis included 3,576 patients treated with inclisiran for up to 6 years and 1,968 patients treatedwith placebo for up to 1.5 years, with 9,982.1 and 2,647.7 patient-years of exposure, respectively. Baseline characteristics were balanced between groups. Kaplan-Meier analyses showed that TEAEs that were serious or led to discontinuation; hepatic, muscle, and kidney events; incident diabetes; and elevations of creatine kinase or creatinine accrued at a comparable rate between groups for up to 1.5 years, with similar trends continuing for inclisiran beyondthis period. Numerically fewer major cardiovascular events reported as TEAEs occurred with inclisiran during this period. Treatment-induced antidrug antibodies were uncommon with inclisiran (4.6%), with few of these persistent (1.4%) and not associated with greater incidence of TEAEs leading to study drug discontinuation or serious TEAEs. Long-term treatment with inclisiran was well tolerated in a diverse population, without new safety signals, supporting the safety of inclisiran in patients with dyslipidemia.

Evolution of More Aggressive LDL-Cholesterol Targets and Therapies for Cardiovascular Disease Prevention

Over the last half-century, discussions on the exact targets for low-density lipoprotein cholesterol (LDL-C) reduction have evolved towards a more aggressive approach with lower LDL-C targets, particularly for high-risk patients with pre-existing atherosclerotic cardiovascular disease (ASCVD). A wealth of cardiovascular outcome trials have shown the efficacy of statin therapy in general, as well as the incremental impact of high-intensity statin therapy in particular. More recent trials have further demonstrated the impact of non-statin therapies, including ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors, and, most recently, bempedoic acid, on reducing ASCVD outcomes. The availability of these and other newer therapies has prompted clinicians to strive for lower LDL-C targets to address residual ASCVD risk after statin therapy. This paper will provide an overview of the historical trends in lipid management and therapeutics and review the current state of evidence for lower LDL-C targets in clinical guidelines and recommendations.

Clinical Significance of Serum High-Density Lipoprotein Cholesterol and Its Dynamic Change in Patients with Lymphoma-Associated Hemophagocytic Lymphohistiocytosis

Background: The lipid profile in serum is frequently dysregulated in lymphoma-associated hemophagocytic lymphohistiocytosis (HLH). We aimed to explore the clinical significance of serum lipoprotein cholesterol in lymphoma-associated HLH. Methods: Patients with lymphoma-associated HLH were included. Serum levels of baseline low-density lipoprotein cholesterol (LDL-c) and high-density lipoprotein cholesterol (HDL-c) were collected. Serum levels of LDL-c and HDL-c after treatment (first test after treatment, time interval ≥ 14 days) were also collected. Results: A total of 169 lymphoma-associated HLH were included. T/NK-cell lymphomas (n=88, 52.1%) account for over half of cases. Low HDL-c (&amp;lt; 1.03 mmol/L) was observed in 161 (95.3%) patients and low LDL-c (&amp;lt; 2.6 mmol/L) was presented in 145 (85.8%) patients. The best cutoff of 0.50 mmol/L for HDL-c was determined to predict the 60-day survival. Patients with HDL-c ≥ 0.50 mmol/L showed a significantly higher 60-day survival rate than patients with HDL-c &amp;lt;0.50 mmol/L (70.9% vs 42.2%, p &amp;lt; 0.001.). Patients with HDL-c ≥ 0.50 mmol/L also showed longer overall survival (OS) (median OS: 346 days vs 34 days, p &amp;lt; 0.001). LDL-c showed no significant impacts on 60-day survival and OS. Dynamic data of HDL-c were available in 69.2% (117) of the patients. The median interval between the two tests was 18 (IQR: 15-25) days. The level of HDL-c after treatment increased in 80.3% (94/117) of the patients. The ratio of post-treatment HDL-c/baseline HDL-c was calculated and the median number was 1.67 (IQR: 1.05-2.48). The ratio was significantly lower in the patients with T/NK-cell malignancies than those with B-cell lymphomas (median 1.40 versus 1.97, p &amp;lt; 0.001). A ratio of 0.78 was determined as the best cutoff to predict the 60-day survival. Patients with a ratio&amp;lt;0.78 had significantly reduced 60-day survival (42.4% vs 76.6%, P=0.0035, Figure 1A) and OS (median 36 days vs 407 days, P=0.0001, Figure 1B). Then we divided these patients with available data into two groups based on baseline HDL-c and the ratio of post-treatment HDL-c/baseline HDL-c: Group 1 included patients with baseline HDL-c ≥ 0.5 mmol/L and Ratio ≥ 0.78, while others were classified as Group 2. Patients in Group 2 had significantly reduced 60-day survival (57.5% vs 87.6%, P=0.0003, Figure 1C) and OS (median 107 days vs not reached, P=0.0001, Figure 1D) than Group 1. Conclusion: Our study demonstrated serum HDL-c and its dynamic Change were robust and clinically feasible markers for predicting the outcomes of patients with lymphoma-associated HLH.

Investigating linear and nonlinear associations of LDL cholesterol with incident chronic kidney disease, atherosclerotic cardiovascular disease and all-cause mortality: A prospective and Mendelian randomization study

Background and aimsObservational studies suggest potential nonlinear associations of low-density lipoprotein cholesterol (LDL-C) with cardio-renal diseases and mortality, but the causal nature of these associations is unclear. We aimed to determine the shape of causal relationships of LDL-C with incident chronic kidney disease (CKD), atherosclerotic cardiovascular disease (ASCVD) and all-cause mortality, and to evaluate the absolute risk of adverse outcomes contributed by LDL-C itself. MethodsObservational analysis and one-sample Mendelian randomization (MR) with linear and nonlinear assumptions were performed using the UK Biobank of >0.3 million participants with no reported prescription of lipid-lowering drugs. Two-sample MR on summary-level data from the Global Lipid Genetics Consortium (N = 296,680) and the CKDGen (N = 625,219) was employed to replicate the relationship for kidney traits. The 10-year probabilities of the outcomes was estimated by integrating the MR and Cox models. ResultsObservationally, participants with low LDL-C were significantly associated with a decreased risk of ASCVD, but an increased risk of CKD and all-cause mortality. Univariable MR showed an inverse total effect of LDL-C on incident CKD (HR [95% CI]:0.84 [0.73–0.96]; p = 0.011), a positive effect on ASCVD (1.41 [1.29–1.53]; p<0.001), and no significant causal effect on all-cause mortality. Multivariable MR, controlling for high-density lipoprotein cholesterol (HDL-C) and triglycerides, identified a positive direct effect on ASCVD (1.32 [1.18–1.47]; p<0.001), but not on CKD and all-cause mortality. These results indicated that genetically predicted low LDL-C had an inverse indirect effect on CKD mediated by HDL-C and triglycerides, which was validated by a two-sample MR analysis using summary-level data from the Global Lipid Genetics Consortium (N = 296,680) and the CKDGen consortium (N = 625,219). Suggestive evidence of a nonlinear causal association between LDL-C and CKD was found. The 10-year probability curve showed that LDL-C concentrations below 3.5 mmol/L were associated with an increased risk of CKD. ConclusionsIn the general population, lower LDL-C was causally associated with lower risk of ASCVD, but appeared to have a trade-off for an increased risk of CKD, with not much effect on all-cause mortality. LDL-C concentration below 3.5 mmol/L may increase the risk of CKD.

High diet quality indices associated with lower risk of lipid profile abnormalities in Taiwanese kidney transplant recipients

Cardiovascular disease (CVD) and its risk factors seem to be linked with deteriorated graft function and persists as the major cause of mortality in kidney transplant recipients (KTRs). Diet quality is associated with CVD prevention in the healthy population, however, less study focuses on KTRs. The study aimed to determine the association between diet quality indices and lipid profile abnormalities as risk factors for CVD in KTRs. This prospective study enrolled 106 KTRs who had functioning allografts from September 2016. Lipid profiles included low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglyceride (TG) and were based on the National Cholesterol Education Program Adult Treatment Panel III recommendations. Three-day dietary data were collected by a well-trained registered dietitian. The Alternative Healthy Eating Index-Taiwan (AHEI-Taiwan), Alternative Healthy Eating Index-2010 (AHEI-2010), and Healthy Eating Index-2015 (HEI-2015) scores were calculated and divided into quartiles and compared accordingly. KTRs’ mean LDL-C, HDL-C, TC, and TG levels were 119.8 ± 36.6 mg/dL, 52.0 ± 17.9 mg/dL, 205.8 ± 43.9 mg/dL, and 160.2 ± 121.6 mg/dL, respectively. Compared with the lowest quartile, only the highest quartile of AHEI-Taiwan had lower TC and LDL-C levels. After adjustment for age, gender, energy, Charlson comorbidity index, transplant duration, and dialysis duration, logistic regression analysis revealed that the highest quartile of AHEI-Taiwan had 82% (odds ratio [OR], 0.18; 95% confidence interval [CI] 0.04–0.72, p < 0.05) lower odds of high TC and 88% (OR 0.12; 95% CI 0.03–0.58, p < 0.05) lower odds of high LDL-C, and the highest quartile of HEI-2015 had 77% (OR 0.23; 95% CI 0.05–0.95, p < 0.05) lower odds of high LDL-C. Higher adherence to a healthy diet as per AHEI-Taiwan and HEI-2015 guidelines associated with lower risk of lipid profile abnormalities in KTRs.

Disentangling the impact of gluteofemoral versus visceral fat accumulation on cardiometabolic health using sex-stratified Mendelian randomization

Background and aimsIndividuals with a higher abdominal adipose tissue accumulation are at higher risk of developing cardiometabolic diseases. For a given body mass index (BMI), women typically present lower abdominal adipose tissue accumulation compared to men. Whether abdominal adiposity is a causal driver of cardiometabolic risk, or a mere marker of ectopic fat deposition is debated. MethodsWe investigated the sex-specific and sex-combined impact of height and BMI-adjusted gluteofemoral adipose tissue (GFATadj) adjusted abdominal subcutaneous adipose tissue (ASATadj) and adjusted visceral adipose tissue (VATadj) on cardiometabolic traits and diseases using Mendelian randomization. ResultsLeveraging genome-wide summary statistics on GFATadj, ASATadj and VATadj from 39,076 UK Biobank participants with full-body magnetic resonance imaging available, we found that GFATadj is associated with a more favourable cardiometabolic risk profile including lower low density lipoprotein (LDL) cholesterol, triglycerides, fasting glucose, fasting insulin, liver enzyme levels and blood pressure as well as higher high density lipoprotein (HDL) cholesterol levels. GFATadj also is negatively associated with ischemic stroke, coronary artery disease, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD). ASATadj is not associated with cardiometabolic traits and diseases, whereas VATadj is associated with liver fat accumulation but not with NAFLD or other cardiometabolic traits or diseases. Although the absolute effect sizes of GFATadj on LDL cholesterol were more pronounced in women compared to men, most associations did not differ by sex. ConclusionsThe inability of subcutaneous fat depots to efficiently store energy substrates could be the causal factor underlying the association of visceral lipid deposition with cardiometabolic health.

Moderate-intensity statin plus ezetimibe vs high-intensity statin according to baseline LDL-C in the treatment of atherosclerotic cardiovascular disease: A post-hoc analysis of the RACING randomized trial

Background and aimsWhether the effect of a combination strategy rather than increasing doses of one drug to lower low-density lipoprotein cholesterol (LDL-C) levels is consistent across baseline LDL-C levels remains uncertain. MethodsIn the RACING trial, which showed a non-inferiority of moderate-intensity statin with ezetimibe (rosuvastatin 10 mg with ezetimibe 10 mg) to high-intensity statin (rosuvastatin 20 mg) for the primary outcome (3-year composite of cardiovascular death, major cardiovascular event, or stroke), the heterogeneity in treatment effect according to baseline LDL-C levels was assessed for the primary and secondary outcomes (clinical efficacy and safety). ResultsOf 3780 participants, 2817 participants (74.5%) had LDL-C <100 mg/dL, and 963 participants (25.5%) had LDL-C ≥100 mg/dL. The treatment effect of combination therapy versus high-intensity statin monotherapy was similar among the lower LDL-C subset (8.8% vs. 10.2%; hazard ratio [HR] 0.85, 95% confidence interval [CI] 0.67 to 1.08, p = 0.19) and the higher LDL-C subset (10.8% vs. 9.6 %; HR 1.14, 95% CI 0.76 to 1.7, p = 0.53) without a significant interaction (interaction p = 0.22). Of the secondary outcomes, the 1-, 2-, and 3-year achievement of LDL-C <70 mg/dL was greater in the combination therapy group regardless of baseline LDL-C levels. ConclusionsAmong ASCVD patients, there was no heterogeneity in the effect of moderate-intensity statin plus ezetimibe combination therapy in the higher and lower baseline LDL-C levels for the 3-year composite of cardiovascular outcomes.

Association of LDL cholesterol levels and all cause mortality in a real world analysis using data from an international network

Abstract Background Current cholesterol guidelines have recommended low low-density lipoprotein cholesterol (LDL-C) treatment targets for secondary prevention of cardiovascular disease. However, recent studies have suggested that very low or very high levels of LDL-C may be associated with increased mortality and other adverse outcomes. The association between LDL-C levels and mortality remains to be determined. Methods and Results This cohort study included data from a large multinational electronic health record network (TriNetX) of patients aged 18 years or older with coronary artery disease. LDL-C levels were divided into 4 categories: &amp;lt;30 (cohort 1), 30-50 (cohort 2), 50-70 (cohort 3), and 70-100 (cohort 4). Deaths were ascertained by linkage to death records in the last 10 years before the analysis. Five-year Kaplan-Meier curves and hazard ratios were calculated. We identified 1,136,600 patients, of whom 36,060 had LDL-C &amp;lt;30 mg/dL, 282,500 had LDL-C &amp;lt;50 mg/dL, 255,964 had LDL-C 50-70 mg/dL and 596,136 had LDL-C 70-100 mg/dL. Comparative analyzes were performed on the cohorts (cohort 1 vs. cohort 2, cohort 2 vs. cohort 3, and cohort 3 vs. cohort 4) after propensity score matching. After adjustment, individuals of cohort 2 (n = 36,004), compared with those of cohort 1 (n = 36,004), had higher all-cause mortality (HR 1.086; CI 95% 1.064-1.109, p &amp;lt;0.0001), individuals of cohort 3 (n = 244,908), compared to those of cohort 2 (n = 270,359), had higher risk of all-cause mortality (HR 1.063; 95% CI 1.055-1.1071, p &amp;lt;0.0001), and induviduals of cohort 4 (n = 254,465), compared with those of cohort 3 (n = 254,465), had lower risk of all-cause mortality (HR 0.937; CI 95% 0.929-0.944, p &amp;lt;0.0001). Conclusions Lower LDL-C levels are associated with a reduced risk of all-cause mortality in patients with coronary artery disease.

Influence of cholesterol levels on NSAID-associated risks after myocardial infarction: a nationwide population-based cohort study

Abstract Introduction Non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat pain, fever, and inflammation, but they can increase the risk of recurrent myocardial infarction (MI), ischemic stroke, atrial fibrillation, and death in patients with MI. Consequently, the European Society of Cardiology warns against using NSAIDs in patients with manifest cardiovascular disease and in high-risk individuals, such as those with dyslipidemia. However, no study has investigated whether NSAID-associated cardiovascular risks differ according to patients’ low-density lipoprotein cholesterol (LDL-C) levels. Purpose To examine whether LDL-C levels influence the cardiovascular risk associated with NSAID use after first-time MI. Methods Using Danish health registries, we conducted a population-based cohort study of all adult patients with a first-time MI hospitalization during 2010–2020 with an LDL-C value before discharge. Based on the latest LDL-C value, we categorized patients into a low and high LDL-C group (&amp;lt;3 vs. ≥3 mmol/L). We used multivariate Cox regression to compute adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for the association between NSAID use (modelled in time-varying manner) and a major adverse cardiovascular event (MACE), defined as a composite of recurrent MI, ischemic stroke, and all-cause death. We repeated the analysis by changing the cut-off value for LDL-C to 1.8 and 1.4 mmol/L. Results We followed 50,573 patient with a first-time MI for a mean of 3.5 years (66% males, median age of 68 years. During NSAID use, 521 patients experienced a MACE: 312 in the low LDL-C group and 209 in the high LDL-C group. The HRs for MACE comparing NSAID use with non-use were 1.21 (1.11–1.32) overall, 1.19 (1.06–1.33) in the low LDL-C group, and 1.23 (1.07–1.41) in the high LDL-group. The HRs in the low and high LDL-C groups were 1.09 (0.88–1.34) vs. 0.94 (0.74–1.19) for recurrent MI, 0.97 (0.66–1.41) vs. 1.27 (0.86–1.87) for ischemic stroke, and 1.22 (1.07–1.39) vs. 1.54 (1.30–1.83) for all-cause death. Changing the cut-off value for LDL-C to 1.8 and 1.4 mmol/L showed consistent results. Conclusion In patients with a first-time MI, NSAID use was associated with an increased risk of MACE. The LDL-C level did not influence the association between NSAID use and MACE, but it might influence the association between NSAID use and all-cause death. Thus, healthcare providers should be mindful of the increased cardiovascular risk associated with NSAID use in patients with previous MI, regardless of LDL-C values.

Course of the effects of LDL-cholesterol reduction on cardiovascular risk over time: a meta-analysis of 59 trials

Abstract Background Therapies lowering low-density lipoprotein cholesterol (LDL-c) are widely used to reduce cardiovascular disease (CVD) risk in patients with or at high risk of CVD. Therapy is usually continued lifelong, but whether the effects of LDL-c reduction remain stable over time is uncertain. This study aimed to establish the course of the relative treatment effects of LDL-c reduction on cardiovascular risk over time, i.e. treatment duration and age. Methods Randomized controlled trials (RCTs) of LDL-c lowering therapies were identified through a search in MEDLINE and EMBASE (1966-January 2023). RCTs of guideline-recommended therapies (i.e. statins, ezetimibe, and proprotein convertase subtilisin–kexin type 9 inhibitors [PCSK9i]) were selected for the primary analyses, with RCTs of other therapies included in sensitivity analyses. Random-effects meta-analyses were performed to establish the average relative risk (RR) for major vascular events (cardiovascular death, myocardial infarction or other acute coronary syndrome, coronary revascularization, or stroke) per 1 mmol/L LDL-c reduction. Course of the effects over time was assessed using random-effects meta-regression analyses for the association between follow-up duration, age, and the RR for major vascular events per 1 mmol/L LDL-c reduction. Analyses were also stratified for primary and secondary prevention. Results A total of 59 trials (26 statin trials, 2 ezetimibe trials, 3 statin/ezetimibe combination trials, 7 PCSK9i trials, and 21 other trials) were selected, including 394,989 participants and 49,642 major vascular events. Mean follow-up was 3.9 years (range 0.9-9.7), and age was 63.8 years (range 48.0-77.0). The average RR for major vascular events per 1 mmol/L LDL-c reduction was 0.78 (95% confidence interval [CI] 0.75-0.81), with slightly larger risk reductions in primary (RR 0.74; 95% CI 0.68-0.81) as compared to secondary prevention (RR 0.80; 95% CI 0.77-0.83). Follow-up duration was not associated with the RR for major vascular events (p = 0.615), with the meta-regression line showing a stable RR over follow-up time (RR for change per year 0.994; 95% CI 0.971-1.017). The RR for major vascular events increased (i.e. risk reduction decreased) with age in primary prevention (RR for change per 5 years 1.094; 95% CI 1.028-1.165; p = 0.018), but remained largely unchanged in secondary prevention (RR for change per 5 years 0.986; 95% CI 0.943-1.031; p = 0.533). Consistent results were found for statin trials only, and all trials combined. Conclusions The relative treatment effects of LDL-c reduction are stable over time in secondary prevention, but may decrease with age in primary prevention.Meta-analysisMeta-regression analyses

An investigational in vivo base editing medicine targeting ANGPTL3, VERVE-201, achieves potent and LDLR-independent liver editing in mouse models

Abstract Background VERVE-201 is an investigational medicine composed of a messenger RNA for an adenine base editor and a guide RNA that targets the ANGPTL3 gene packaged in a GalNAc lipid nanoparticle (LNP). Delivered via a one-time intravenous infusion, VERVE-201 is designed to inactivate ANGPTL3 in the liver and thereby lower low-density lipoprotein cholesterol (LDL-C) concentrations to treat atherosclerotic cardiovascular disease (ASCVD). VERVE-201 is initially being developed for the treatment of homozygous familial hypercholesterolemia—a rare genetic disorder in which severe or complete low-density lipoprotein receptor (LDLR)-deficiency leads to marked elevations in LDL-C and premature ASCVD. Purpose We first evaluated the potential of VERVE-201 to achieve on-target ANGPTL3 editing in human liver cells in vitro and humanized ANGPTL3 mice in vivo. Second, while standard LNPs are taken up into hepatocytes primarily by the LDLR, the GalNAc targeting ligand included in the VERVE-201 LNP is expected to enable LDLR-independent delivery via an alternate receptor (ASGPR). We test the hypothesis that VERVE-201mu (mouse surrogate of VERVE-201) can achieve comparable degree of Angptl3 editing in wild-type mice and those with partial (Ldlr+/-) or complete (Ldlr-/-) LDLR-deficiency. Methods VERVE-201 was first assessed in primary human hepatocytes at a range of doses in vitro. To assess whether VERVE-201 edits the human ANGPTL3 gene in vivo, a human ANGPTL3 mouse model was generated and VERVE-201 was evaluated at 7 dose levels ranging from 0.1 to 3.0 mg/kg (n=4 in each group). Next, one of four doses of VERVE-201mu ranging from 0.25 to 2.0 mg/kg or a vehicle control was administered to wild type, Ldlr+/−, and Ldlr−/− mice (n=5 in each genotype treatment group). In mouse experiments, tissue and blood samples were collected 7 days following dosing for evaluation. Results In primary human hepatocytes, VERVE-201 achieved potent and dose-responsive ANGPTL3 editing in cells from each of three donors. In human ANGPTL3 mice, VERVE-201 treatment resulted in dose-responsive liver ANGPTL3 editing. In mice treated with the highest dose of 3 mg/kg, mean liver editing of 64% and reduction in blood ANGPTL3 protein of 98% were observed. In wild type, Ldlr+/−, and Ldlr−/− mice, VERVE-201mu was similarly well-tolerated and achieved highly consistent potency across the doses studied (Figure). In mice treated with the highest dose of 2.0 mg/kg, mean liver Angptl3 editing of 60% and reductions in blood ANGPTL3 protein of 99% were observed, with no detectable differences across wild-type, Ldlr+/−, and Ldlr−/− mice. Conclusions These nonclinical data support the potential of VERVE-201 to enable precise and potent ‘once-and-done’ ANGPTL3 inactivation in the context of the severe or complete LDLR deficiency that occurs in homozygous familial hypercholesterolemia, a patient population that struggles to achieve adequate LDL-C reduction even on multiple lipid-lowering therapies.

The effect of proprotein convertase subtilisin/kexin type 9 inhibition on the plasma proteome: a SPIRE sub-study

Abstract Background The plasma proteome is an intermediate phenotype for disease and is a tool to inform on pharmacological mechanisms of effect. For selective low-density lipoprotein cholesterol (LDL-C) lowering by proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition, multiple studies have demonstrated that its potent LDL-C lowering effect coincides with marked reductions in both cellular and arterial plaque inflammation, despite unaltered high-sensitivity C-reactive protein (hs-CRP) levels. Purpose In the present study, we set out to investigate potential anti-inflammatory effects of PCSK9 inhibition using plasma proteomics. Methods In 190 patients participating in the SPIRE-1/2 trials, 184 targeted proteins were measured at baseline and after 12 months of bococizumab treatment using the Cardiovascular II and III panels (Sweden). Of the included patients, 96 patients received placebo and 94 received 150mg of bococizumab, once every two weeks. Considering the development of auto-antibodies in some patients, patients with LDL-C reduction below 15% were excluded. The primary outcome was the fold change in protein levels after 12 months compared to baseline. The Benjamini-Hochberg method was used to adjust for multiple comparisons with a false discovery rate (FDR) of 5%. The findings were compared to the LoDoCo2 sub-study which used the same proteomic panels. Results In the placebo group, there was no significant change in any of the proteins. In the bococizumab group (n=77, mean age 62.2±9.7 years and 70 [91%] male), LDL-C levels were reduced from 114±41 mg/dL to 47±34 mg/dL (mean reduction 66±29 mg/dL) on top of statin therapy while there was a neutral effect on hs-CRP (median change 0.0 mg/L IQR [-0.8,1.1]). PCSK9 was the only protein with change upon treatment with bococizumab (24.4±11.0 vs. 15.0±10.7; PFDR=0.033; Figure 1A). In comparison, treatment of colchicine in the LoDoCo2 sub-study was associated with a significant change in 60 proteins (Figure 1B). Conclusion Here, we show that PCSK9 inhibition with bococizumab resulted in a highly selective reduction of PCSK9 plasma levels without robustly affecting other circulating proteins in the measured panels, implying PCSK9 inhibition lowers ASCVD risk via pure lipid lowering pathways. Our study reinforces the neutral systemic inflammatory effect of PCSK9 inhibition on top of statin therapy. The local effects on cellular and vascular inflammation by PCSK9 inhibition observed in earlier studies most likely reflect a direct consequence of a reduced cholesterol content in inflammatory cells and plaques, subsequently leading to a local anti-inflammatory effect. These findings support the combination of targeted anti-inflammatory therapies on top of potent LDL-C lowering in order to further reduce the residual inflammatory risk.

Early lowering of LDL-C is a more cost-effective strategy than lowering LDL-C later in life: a cost-effectiveness analysis using Mendelian Randomisation

Abstract Background Early control of low-density lipoprotein-cholesterol (LDL-C) is an effective way to reduce the risk of coronary heart disease (CHD). However, a comprehensive assessment of cost-effectiveness of different lipid-lowering strategies (LLS) for primary prevention of CHD across different ages is lacking. Objective To assess the cost-effectiveness of four different LLS initiated at ages 30, 40, 50, and 60 years on the primary prevention of CHD from the UK National Health Service perspective. Design, setting and participants: We developed a microsimulation model, based on the causal effect of LDL-C on myocardial infarction (MI) or coronary death derived from Mendelian randomisation, comparing initiation of an LLS to current standard of care (control). Data were primarily drawn from 458,727 participants of the UK Biobank study with available data on date of birth, LDL-C, and who were free of MI at first assessment (between 2006 and 2010), with follow-up until 2021. Interventions: The four LLS were: 1) low/moderate intensity statins; 2) high intensity statins; 3) low/moderate intensity statins and ezetimibe; and 4) inclisiran. Main outcomes measures: The incremental cost-effectiveness ratio (ICER), defined as the incremental healthcare costs divided by the incremental quality-adjusted life years (QALYs) for each LLS compared to control, with 3.5% annual discounting. Results The most effective intervention, low/moderate intensity statins and ezetimibe, was projected to lead to a gain in QALYs of 0.068 per person at age 30 and 0.026 at age 60 compared to control (Figure). The age of intervention with the lowest ICER was age 40, with ICERs of £2,524 (95% uncertainty interval: 1,383, 3,796), £4,466 (3,163, 6,134) £11,118 (8,632, 14,177), and £1,405,123 (1,117,1113, 1,789,012) per QALY gained for strategies 1-4 from age 40 years, respectively (Table). Conclusions LDL-C lowering from early ages is a more cost-effective strategy than late intervention. The approach to primary prevention of CHD may improve with a shift to early and sustained lowering of LDL-C. Figure – Results of 1,000 probabilistic sensitivity analyses presented in a common cost-effectiveness plane, by age of intervention. Inclisiran excluded due to very high costs. Solid line: £20,000 per quality-adjusted life year (QALY) willingness-to-pay threshold; dashed line: £30,000 per QALY willingness-to-pay threshold. Any dot to the right of these lines is considered cost-effective. Table – Summary of LLS interventions by age of intervention. Abbreviations: MI – Myocardial infarction; YLL – Years of life lived; QALYs – Quality-adjusted life-years; ICER – Incremental cost-effectiveness ratio.FigureTable

Moderate-intensity statin plus ezetimibe combination therapy versus high-intensity statin monotherapy according to baseline LDL-C levels: a prespecified subgroup analysis of RACING Trial

Abstract Aims To compare the effects of moderate-intensity statin plus ezetimibe combination therapy to high-intensity statin monotherapy based on baseline low-density lipoprotein cholesterol (LDL-C) levels. Methods and results In the RACING trial, 3780 atherosclerotic cardiovascular disease (ASCVD) patients were randomly assigned to moderate-intensity statin plus ezetimibe combination therapy or high-intensity statin monotherapy based on baseline LDL-C levels of &amp;lt;100 mg/dL (n=2817) or ≥100 mg/dL (n=963). In the prespecified analysis, the primary outcome (a composite of cardiovascular death, major cardiovascular event, or stroke at 3 years) and key secondary outcome (achievement of LDL-C &amp;lt;70 mg/dL) were reported according to baseline LDL-C levels. The occurrence of the primary outcome did not differ between the combination therapy and the monotherapy groups among those with lower and higher baseline LDL-C levels (8.6% versus 10.1%, hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.37 to 1.09; and 10.5% versus 9.3%, HR 1.13, 95% CI 0.76 to 1.70, respectively) without an interaction (P=0.232). The 1-, 2-, and 3-year achievement of LDL-C &amp;lt;70 mg/dL was greater in the combination therapy group, regardless of baseline LDL-C levels. For secondary safety outcomes, no significant interactions between the treatment strategies and baseline LDL-C levels were found. Conclusion Among ASCVD patients, the effect of moderate-intensity statin plus ezetimibe combination therapy was consistent across the baseline LDL-C levels for the 3-year composite of cardiovascular death, major cardiovascular event, or stroke, and even associated with greater achievement of LDL-C &amp;lt;70 mg/dL compared to high-intensity statin monotherapy.