Lower Low-density Lipoprotein Research Articles

PCSK9 inhibition attenuates alcohol-associated neuronal oxidative stress and cellular injury

Alcohol Use Disorder (AUD) is a persistent condition linked to neuroinflammation, neuronal oxidative stress, and neurodegenerative processes. While the inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) has demonstrated effectiveness in reducing liver inflammation associated with alcohol, its impact on the brain remains largely unexplored. This study aimed to assess the effects of alirocumab, a monoclonal antibody targeting PCSK9 to lower systemic low-density lipoprotein cholesterol (LDL-C), on central nervous system (CNS) pathology in a rat model of chronic alcohol exposure. Alirocumab (50 mg/kg) or vehicle was administered weekly for six weeks in 32 male rats subjected to a 35 % ethanol liquid diet or a control liquid diet (n = 8 per group). The study evaluated PCSK9 expression, LDL receptor (LDLR) expression, oxidative stress, and neuroinflammatory markers in brain tissues. Chronic ethanol exposure increased PCSK9 expression in the brain, while alirocumab treatment significantly upregulated neuronal LDLR and reduced oxidative stress in neurons and brain vasculature (3-NT, p22phox). Alirocumab also mitigated ethanol-induced microglia recruitment in the cortex and hippocampus (Iba1). Additionally, alirocumab decreased the expression of pro-inflammatory cytokines and chemokines (TNF, CCL2, CXCL3) in whole brain tissue and attenuated the upregulation of adhesion molecules in brain vasculature (ICAM1, VCAM1, eSelectin). This study presents novel evidence that alirocumab diminishes oxidative stress and modifies neuroimmune interactions in the brain elicited by chronic ethanol exposure. Further investigation is needed to elucidate the mechanisms by which PCSK9 signaling influences the brain in the context of chronic ethanol exposure.

EFFECT OF SEX AND AGE ON MORPHOMETRIC, PHYSIOLOGICAL AND BLOOD PROFILE OF MIXED BRED RABBIT

This study was conducted to assess the morphometric, physiological and blood parameters of mixbred rabbits at different ages. One hundred and sixty rabbits comprising New Zealand White and Chinchilla Crossbreds were used. Body weight and body linear parameters were measured and recorded on weekly basis. Generalised Linear Model Procedure of SAS software was used to analyse the data set to examine the effects of sex and age on these parameters. The results indicated that sex significantly (P<0.05) affected morphometric and physiological parameters at 4, 8, 12, 32 and 48 weeks. Does (female rabbits) performed better than bucks (male rabbits) in almost all the traits studied. Buck at 8 weeks had higher rectal temperature while, higher values for pulse rate were recorded among the does and bucks at 32 weeks. Higher respiratory rate was observed in bucks at 48 weeks and for does at 32-48 weeks. Sex however had no significant effect on all haematological parameters. Sex had significant effect (P<0.05) on aspartate amino transferase (AST), alanine amino transferase (ALT), alkaline phosphate (ALP), cholesterol (CHOL), triglyceride (TRG), low density lipoprotein (LDL), urea, creatinine and globulin (GLOB) of the crossbred rabbits at different ages. The higher aspartate amino transfererase (AST), alanine amino transferase (ALT), alkaline phosphate (ALP), cholesterol (CHOL), triglyceride (TRG), low density lipoprotein (LDL), globulin (GLOB) and urea were recorded in bucks at 48 weeks while the lowest low-density lipoprotein (LDL) was recorded for bucks at 32 weeks but creatinine was higher at 48 weeks of age among the does. Age had significant (P<0.05) effect on morphometric, physiological and blood parameters. The highest rectal temperature was recorded at 8 weeks of age while highest respiratory rate was recorded for rabbits at 48 weeks. The higher creatinine, basophils and urea values were recorded for rabbits at 48 weeks old. Body weight influenced the morphometric, physiology and blood parameter of crossbred rabbits. It can be suggested to rabbit farmers that sex and age must be taken into account for optimal production.

A Study to Evaluate the Effect of Sodium-Glucose Co-transporter 2 (SGLT2) Inhibitors on Oxidative Stress Parameters in Type 2 Diabetes Mellitus Patients.

Introduction Diabetes mellitus (DM) is a global health issue with 50 million diabetics currently residing in India. Hyperglycemia causes tissue damage due to mitochondrial overproduction of reactive oxygen species. Sodium-glucose cotransporter-2 (SGLT2) inhibitors (SGLT2i) have shown a decrease in oxidative stress by either amelioration of free-radical generation or potentiation of cellular antioxidative capacity in preclinical studies. However, there is a paucity of published clinical studies. Hence, this study was undertaken to evaluate the effect of co-administration of SGLT2i with other drugs on oxidative stress in type 2 DM (T2DM) patients. Methods A prospective, parallel, open-label study in T2DM patients attending endocrinology OPDwas conducted for a period of 12 months. At the clinician's discretion, patients were grouped as SGLT2i as an add-on to standard drugs vs standard drugs alone. Blood samples were collected at baseline and at the end of 12 weeks to estimate malondialdehyde (MDA), nitric oxide (NO), and glutathione (GSH) levels. Secondary parameters - glycemic indices and lipid profile - were estimated every four weeks. Results A total of 32 patients were enrolled in the study (16 per group). There was a significant decrease in MDA (p < 0.05) and NO (p < 0.01) and a highly significant increase in GSH (p < 0.001) at 12 weeks from baseline in the SGLT2i group. A reduction in fasting blood sugar (FBS) and post-prandial blood sugar (PPBS) and a 0.56% difference in HbA1c were also noted in the SGLT2i group.Significant lowering of low-density lipoprotein (LDL, p < 0.05) and elevation in HDL levels (p < 0.05) from baseline was seen in the SGLT2i group. Conclusion Co-administration of SGLT2i with antidiabetic drugs demonstrated a significant effect in improving oxidative stress biomarkers and glycemic and lipid profiles among T2DM patients.

Prevalence of iron deficiency in type 2 diabetes mellitus patients and its association with altered lipid profile

Abstract Background: The escalation of diabetes mellitus poses a significant public health challenge in India. This condition impacts iron metabolism, potentially causing variations in the iron profile. This study aimed to ascertain the prevalence of iron deficiency in individuals with type 2 diabetes mellitus and explore its associated factors. Materials and Methods: A cross-sectional study was conducted on adult patients with type 2 diabetes mellitus at a tertiary care center in Eastern India. Biochemical assessments encompassed fasting plasma glucose, post-prandial glucose, glycosylated hemoglobin (HbA1c), lipid profile, renal function tests, complete hemogram, and iron profile. Anthropometric measurements were conducted using standardized procedures. Results: This study revealed that among the 203 participants, the prevalence of iron deficiency was 63.5% (95% confidence interval: 56.5–70.2). Anemia was observed in 34% of patients (men &lt;13 g/dL, women &lt;12 g/dL). The mean levels of serum iron, ferritin, total iron binding capacity, and transferrin saturation were 62.9 ± 26.1 μg/dL, 100.6 ± 103.2 ng/mL, 392.3 ± 72 μg/dL, and 16.6 ± 7.5%, respectively. The mean fasting blood sugar, post-prandial blood sugar, and HbA1c values were 154.2 ± 63 mg/dL, 229.3 ± 92.1 mg/dL, and 7.7 ± 1.5%, respectively. There were no significant differences in iron levels between genders or between poorly controlled and well-controlled diabetics. However, significant associations were observed between iron deficiency and lower total cholesterol levels, low-density lipoprotein, and triglycerides. Conclusion: This study concludes that iron deficiency is highly prevalent among diabetic patients in India and is associated with lipid profile alterations.

Supplementation of yam bean (Pachyrhizus erosus L.) fiber ameliorates dyslipidemia, liver pathology and hypersecretion of metabolic hormones in mice fed a highfat diet

Introduction: Yam bean (Pachyrhizus erosus L.) offers numerous health benefits. However, the effects of its dietary fiber (yam bean fiber, YBF) on dyslipidemia, liver disease, and the overproduction of metabolic hormones, specifically glucagon-like peptide-1 (GLP1) and fibroblast growth factor 21 (FGF21), resulting from a high-fat diet (HFD) remain underexplored. Thus, our present investigation sought to address this gap. Methods: Adult male mice (n = 24) were randomly assigned into four different groups such as normal diet (ND) as a control group, HFD, and HFD supplemented with either 2.5% or 10% YBF. After a 12-week dietary regimen, plasma lipid profiles, liver histology and biochemistry, and the levels of FGF21 and GLP-1 were assessed. Results: YBF supplementation, especially at 10% dose, effectively lowered total serum cholesterol, triglyceride (TG), and low-density lipoprotein (LDL) compared with those fed HFD (P &lt; 0.05). YBF also reduced liver weight and mitigated the elevation of malondialdehyde (MDA) and the depletion of catalase (CAT) activity induced by HFD in liver tissues (P &lt; 0.05). Furthermore, 10% YBF supplementation effectively countered liver pathology, including central vein enlargement, hepatic steatosis, inflammation, abnormal sinusoids, and hepatocyte degeneration caused by HFD (P &lt; 0.05). YBF at 10% also attenuated the HFDinduced hypersecretion of FGF21 and GLP-1 hormones. Conclusion: Our findings indicate that YBF supplementation could counteract the adverse effects of HFD, particularly in terms of dyslipidemia, liver disease, and metabolic hormone imbalances. Incorporating YBF into diets may thus offer protective benefits against HFDinduced metabolic diseases and associated health issues.

Fixed-dose combination therapy for the prevention of atherosclerotic cardiovascular disease.

Fixed-dose combination (FDC) therapy, also known as polypill therapy, targets risk factors for atherosclerotic cardiovascular disease (ASCVD) and has been proposed as a strategy to reduce global ASCVD burden. Here we conducted a systematic search for relevant studies from 2016-2022 to assess the effects of FDC therapy for prevention of ASCVD. The studies selected include randomized trials evaluating FDC therapy with at least one blood pressure-lowering drug and one lipid-lowering drug. The study data were independently extracted, the quality of evidence was appraised by multiple reviewers and effect estimates were pooled using a fixed-effect meta-analysis when statistical heterogeneity was low to moderate. The main outcomes of the analysis were all-cause mortality, fatal and nonfatal ASCVD events, adverse events, systolic blood pressure, low-density lipoprotein cholesterol and adherence. Among 26 trials (n = 27,317 participants, 43.2% female and mean age range 52.9-76.0), FDC therapy was associated with lower low-density lipoprotein cholesterol and systolic blood pressure, with higher rates of adherence and adverse events in both primary and mixed secondary prevention populations. For studies with a mostly primary prevention population, FDC therapy was associated with lower risk of all-cause mortality by 11% (5.6% versus 6.3%; relative risk (risk ratio) of 0.89; 95% confidence interval 0.78 to 1.00; I2 = 0%; four trials and 16,278 participants) and risk of fatal and nonfatal ASCVD events by 29% (6.1% versus 8.4%; relative risk (risk ratio) of 0.71; 95% confidence interval 0.63 to 0.79; I2 = 0%; five trials and 15,503 participants). One adequately powered trial in an exclusively secondary prevention population showed that FDC therapy reduced the risk of major adverse cardiovascular events by 24%. These findings support adoption and implementation of polypills to lower risk for all-cause mortality and ASCVD.

Impact of changes in Achilles tendon thickening on cardiovascular events in patients with familial hypercholesterolemia

BackgroundAchilles tendon thickening (ATT) can be ameliorated by lowering low-density lipoprotein (LDL) levels in patients with familial hypercholesterolemia (FH). The Japan Atherosclerosis Society (JAS) defines ATT as ≥8.0 mm in males and ≥7.5 mm in females. We aimed to determine the clinical impact of changes in ATT on the development of major adverse cardiovascular events (MACE). MethodsPatients with clinically diagnosed heterozygous FH (HeFH) (N = 1273; 614 males, 659 females) with ATT data from X-ray were assessed. Patients were divided into four groups: patients without ATT from baseline until follow-up (group 1), patients without ATT at baseline but developed ATT at follow-up (group 2), patients with ATT at baseline but regressed at follow-up (group 3), and patients with ATT from baseline until follow-up (group 4). Cox proportional hazard models were used to assess the factors associated with MACE, including cardiovascular death and any coronary events. ResultsOn follow-up (median: 10.9 years), 142 MACEs were observed, and the median ATT regressed from 7.8 to 7.6 mm. Changes in ATT were significantly associated with the occurrence of MACE in all groups, when compared to group 1 (hazard ratio [HR]: 2.73; 95 % confidence interval [CI]: 1.33–4.13 [p < 0.001], HR: 2.18, 95 % CI: 1.08–3.28, [p < 0.001], HR: 6.34, 95 % CI: 3.10–9.58, [p < 0.001], in groups 2, 3, and 4, respectively). ConclusionsAssessing ATT has diagnostic value and allows for risk stratification among patients with HeFH.

Modulatory Effects of Lactarius hatsudake on Obesity and Gut Microbiota in High-Fat Diet-Fed C57BL/6 Mice.

Lactarius hatsudake (LH), a great wild endemic fungus, contains rich nutritional components with medicinal properties. The effects of LH on body weight, liver weight, liver injury, blood lipids, and gut microbiota in C57BL/6 mice fed a high-fat diet (HFD) for 8 weeks was examined in this research. Though there was no clear impact on weight loss, the findings indicate that LH treatment effectively decreased liver damage caused by HFD, as well as lowered serum total cholesterol, triacylglycerol, and low-density lipoprotein cholesterol levels. Additionally, it positively influenced gut microbiota to resemble that of mice on a normal diet. In HFD-fed mice, LH markedly boosted the levels of Parabacteroides, unclassified Muribaculaceae, Oscillibacter, and unclassified Oscillospiraceae, while reducing the abundance of Lachnospiraceae NK4A136 group and Erysipelatoclostridium, as well as the ratio of Firmicutes to Bacteroidetes. Further analysis of correlation indicate a possible connection between obesity and gut microbiota. Obesity-related indices show a positive association with unclassified Eubacterium coprostanoligenes group, Blautia, and Erysipelatoclostridium, while displaying a negative correlation with unclassified Muribaculaceae, unclassified Clostridia vadinBB60 group, Helicobacter, Oscillibacter, unclassified Ruminococcaceae, Parabacteroides, and unclassified Oscillospiraceae. The results suggest that LH can help combat obesity and may have the potential to be utilized as a functional food.

Effect of clinical decision support for severe hypercholesterolemia on low-density lipoprotein cholesterol levels

Severe hypercholesterolemia/possible familial hypercholesterolemia (FH) is relatively common but underdiagnosed and undertreated. We investigated whether implementing clinical decision support (CDS) was associated with lower low-density lipoprotein cholesterol (LDL-C) in patients with severe hypercholesterolemia/possible FH (LDL-C ≥ 190 mg/dL). As part of a pre-post implementation study, a CDS alert was deployed in the electronic health record (EHR) in a large health system comprising 3 main sites, 16 hospitals and 53 clinics. Data were collected for 3 months before (‘silent mode’) and after (‘active mode’) its implementation. Clinicians were only able to view the alert in the EHR during active mode. We matched individuals 1:1 in both modes, based on age, sex, and baseline lipid lowering therapy (LLT). The primary outcome was difference in LDL-C between the two groups and the secondary outcome was initiation/intensification of LLT after alert trigger. We identified 800 matched patients in each mode (mean ± SD age 56.1 ± 11.8 y vs. 55.9 ± 11.8 y; 36.0% male in both groups; mean ± SD initial LDL-C 211.3 ± 27.4 mg/dL vs. 209.8 ± 23.9 mg/dL; 11.2% on LLT at baseline in each group). LDL-C levels were 6.6 mg/dL lower (95% CI, −10.7 to −2.5; P = 0.002) in active vs. silent mode. The odds of high-intensity statin use (OR, 1.78; 95% CI, 1.41–2.23; P < 0.001) and LLT initiation/intensification (OR, 1.30, 95% CI, 1.06–1.58, P = 0.01) were higher in active vs. silent mode. Implementation of a CDS was associated with lowering of LDL-C levels in patients with severe hypercholesterolemia/possible FH, likely due to higher rates of clinician led LLT initiation/intensification.

Quantitative or qualitative biomolecular changes in blood serum composition induced by childhood obesity: A Fourier transform infrared examination

Childhood obesity (CO) negatively affects one in three children and stands as the fourth most common risk factor of health and well-being. Clarifying the molecular and structural modifications that transpire during the development of obesity is crucial for understanding its progression and devising effective therapies. The study was indeed conducted as part of an ongoing CO treatment trial, where data were collected from children diagnosed with CO before the initiation of non-drug treatment interventions. Our primary aim was to analyze the biochemical changes associated with childhood obesity, specifically focusing on concentrations of lipids, lipoproteins, insulin, and glucose. By comparing these parameters between the CO group (n = 60) and a control group of healthy children (n = 43), we sought to elucidate the metabolic differences present in individuals with CO. Our biochemical analyses unveiled lower LDL (low-density lipoproteins) levels and higher HDL (high-density lipoproteins), cholesterol, triglycerides, insulin, and glucose levels in CO individuals compared to controls. To scrutinize these changes in more detail, we employed Fourier transform infrared (FTIR) spectroscopy on the serum samples. Our results indicated elevated levels of lipids and proteins in the serum of CO, compared to controls. Additionally, we noted structural changes in the vibrations of glucose, β-sheet, and lipids in CO group. The FTIR technique, coupled with principal component analysis (PCA), demonstrated a marked differentiation between CO and controls, particularly in the FTIR region corresponding to amide and lipids. The Pearson test revealed a stronger correlation between biochemical data and FTIR spectra than between 2nd derivative FTIR spectra. Overall, our study provides valuable insights into the molecular and structural changes occurring in CO.

Reason for Discontinuing the Drug in Patients Using Statins

Objective: In recent years, there has been a lot of news about the negative effects of statin use on patients. Our study aimed to investigate the reasons for drug discontinuation in patients with indications for statin use.&#x0D; Materials and Methods: 180 patients who were indicated to start statin treatment for any reason were included in the study. Demographic and clinical characteristics of the patients, cardiovascular disease risk factors, and lipid levels at admission were determined.&#x0D; Results: It was determined that 81.1% of the patients were started on statin treatment. It was observed that patients using regular medication had lower LDL (low-density lipoprotein) and total cholesterol levels than those who did not use medication regularly (p

Study on the related factors of TCM constitution and hemodynamics in patients with coronary heart disease.

The concepts of "individualization" and "preventive treatment" should be incorporated into the precise diagnosis and treatment of coronary heart disease (CHD). Both hemodynamics and Chinese medicine constitution studies align with these two concepts. This study utilized data from 81 patients with CHD, including 12 patients with balanced constitution (BC), 20 patients with blood stasis constitution (BSC), 17 patients with phlegm-dampness constitution (PDC), 15 patients with qi-deficiency constitution (QDC), and 17 patients with other constitutions. Clinical data provided information on the patients' blood property, heart function, degree of coronary stenosis, coronary hemodynamics, and so on. These parameters were compared between patients with balanced constitution vs. biased constitutions as well as between those with blood stasis constitution, phlegm-dampness constitution, and qi-deficiency constitution. Compared to biased constitution (BC), patients with balanced constitution exhibited lower total cholesterol (TC) levels and low-density lipoprotein (LDL) levels. Additionally, they had lighter stenosis degrees in the Left anterior descending branch (LAD) and Left circumflex branch (LCX) branches. The hemodynamic condition of the LAD and LCX was better for those with balanced constitution; however there was no difference in heart function. Among the groups categorized by blood stasis, phlegm dampness or qi deficiency constituions, patients classified under phlegm dampness had higher levels of LDL compared to those classified under blood stasis or qi deficiency, while patients classified under qi deficiency had higher levels of blood glucose compared to those classified under blood stasis or phlegm dampness. Hemodynamic environments also differed among the LAD and LCX for each group but there were no significant differences observed in heart function or degree of coronary stenosis among these three groups. The balanced constitution demonstrates superior blood property, degree of coronary artery stenosis, and coronary hemodynamics compared to the biased constitution. Furthermore, among the three constitutions with CHD, variations in blood property and certain hemodynamic parameters are observed. These findings emphasize the significant clinical value of incorporating physical factors into the diagnosis and treatment of patients with CHD.

Harnessing RNA Interference for Cholesterol Lowering: The Bench-to-Bedside Story ofInclisiran.

Lowering low-density lipoprotein cholesterol (LDL-C) is a cornerstone of reducing risk for atherosclerotic cardiovascular disease. Despite the approval of nonstatin therapies for LDL-C lowering over the past 2 decades, these medications are underused, and most patients are still not at guideline-recommended LDL-C goals. Barriers include poor adherence, clinical inertia, concern for side effects, cost, and complex prior authorization processes. With atherosclerotic cardiovascular disease-related mortality increasing globally, there remains a need for additional therapeutic options for lowering LDL-C as part of an atherosclerotic cardiovascular disease prevention strategy. Following the identification of PCSK9 (proprotein convertase subtilisin/kexin type 9) as a promising therapeutic target, inclisiran was developed using the natural process of RNA interference for robust, sustained prevention of hepatic PCSK9 synthesis. Twice-yearly maintenance subcutaneous inclisiran (following initial loading doses at Day 1 and Day 90) reduces circulating LDL-C levels by ≈50% versus placebo when added to maximally tolerated statins. Long-term safety and tolerability of inclisiran have been assessed, with studies underway to evaluate the effects of inclisiran on cardiovascular outcomes and to provide additional safety and effectiveness data. In 2021, <20 years after the discovery of PCSK9, inclisiran became the first RNA interference therapeutic approved in the United States for LDL-C lowering in patients with established atherosclerotic cardiovascular disease or familial hypercholesterolemia and has since been approved for use in patients with primary hyperlipidemia. This article reviews the journey of inclisiran from bench to bedside, including early development, the clinical trial program, key characteristics of inclisiran, and practical points for its use in the clinic.

Childhood maltreatment is longitudinally associated with cardiometabolic biomarkers through marital quality: Do health locus of control and eating habits matter?

Childhood maltreatment is longitudinally associated with cardiometabolic biomarkers through marital quality: Do health locus of control and eating habits matter?

Updates on Non-Statin LDL-Lowering Therapy.

There is ample evidence of the benefits and safety of low-density lipoprotein (LDL)-lowering therapies in the prevention of atherosclerotic cardiovascular disease. While statins remain the first-line agent for LDL reduction, several new therapies are now available. This narrative review provides an overview of currently available non-statin LDL-lowering agents, specifically mechanisms of action and data on efficacy and safety. It also discusses recommendations on their use in clinical practice. Ezetimibe, PCSK9 inhibitors, and bempedoic acid have proven safe and efficacious in reducing cardiovascular events in large randomized controlled trials. Inclisiran is a promising agent that suppresses PCSK9 mRNA translation and is currently under investigation in a large clinical outcomes randomized controlled trial assessing its effect on clinical outcomes. Expert consensus advocates for lower LDL targets in higher risk patients and escalation to or a combination of non-statin therapies as needed to achieve these goals.

Cost-effectiveness of dietary supplement ingredients versus generic statins for LDL reduction

BackgroundWhile statin therapy is the preferred treatment for hyperlipidemia, literature supports the low-density lipoprotein (LDL) lowering effects associated with red yeast rice, berberine, and Silybum marianum. Dietary supplements may be perceived as a more affordable alternative to prescription medication. ObjectiveWe determined cost-effectiveness of generic pravastatin versus single-ingredient dietary supplements in relation to LDL lowering effect. MethodsData from meta-analyses and systematic reviews was extracted to calculate pooled weighted mean LDL differences amongst generic pravastatin and single ingredient dietary supplements. The effect was then divided by average 30-day costs and compared amongst agents. ResultsThe greatest difference was seen in pravastatin 40 mg [MD -57.88 mg/dL (95%CI: - 64.80 to −50.96)], followed by pravastatin 10 mg [MD -41.30 mg/dL (95%CI: 63.30 to - 19.40)], red yeast rice [MD -25.39 (95%CI: −32.98 to −17.81)], berberine [MD -15.13 (95%CI: −21.78 to −8.48)], and Silybum marianum [MD -9.51 mg/dL (95%CI: −22.13 to - 0.10)]. were divided by mean difference to calculate cost per mg/dL reduction in LDL. Cost-effectiveness was greatest for pravastatin 10 mg [$0.66/mg/dL LDL reduction (range: $0.39 to $1.13)], followed by pravastatin 40 mg [$0.74/mg/dL LDL reduction (range: $0.66 to $0.84)], berberine [$0.81/mg/dL LDL reduction (range: $0.56 to $1.44)], red yeast rice [$0.84/mg/dL reduction (range: $0.67 to $1.13)], and Silybum marianum [$0.88/mg/dL LDL reduction (range: $0.38 to $82.02)]. ConclusionPravastatin is most cost-effective in each scenario whether or not prescription insurance is utilized.

Treatment intensification with bempedoic acid to achieve LDL-C goal in patients with ASCVD: A simulation model using a real-world patient cohort in the US

Background and aimsGuidelines recommend that high-risk patients with atherosclerotic cardiovascular disease (ASCVD) be treated with maximally tolerated statins to lower low-density lipoprotein cholesterol (LDL-C) levels and reduce the risk of major adverse cardiovascular events. In patients whose LDL-C remains elevated, non-statin adjunct therapies, including ezetimibe (EZE), bempedoic acid (BA), and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are recommended. MethodsThe impact of BA and EZE in a fixed-dose combination (FDC) on LDL-C goal attainment was evaluated using a simulation model developed for a United States cohort of high-risk adults with ASCVD. Treatment was simulated for 73,056 patients not at goal (LDL-C >70 mg/dL), comparing BA + EZE (FDC), EZE only, and no oral adjunct therapy (NOAT). The addition of PCSK9 inibitors was assumed after 1 year in patients not at LDL-C goal. Treatment efficacy was estimated from clinical trials. Patient-level outcomes were predicted over a 10-year horizon accounting for treatment discontinuation and general mortality. ResultsBaseline mean age of the cohort was 67 years, most were White (79%) and male (56%). A majority had established coronary artery disease (75%), 48% had diabetes, and mean LDL-C was 103.0 mg/dL. After 1 year, 79% of patients achieved LDL-C goal (mean, 61.1 mg/dL) with BA + EZE (FDC) compared to 58% and 42% with EZE (71.7 mg/dL) and NOAT (78.4 mg/dL), respectively. ConclusionsThis simulation shows that adding BA + EZE (FDC) to maximally tolerated statins would result in more patients achieving LDL-C goal than adding EZE alone or NOAT.

Effect of Statin Therapy on Cardiovascular Outcome in Stroke Patients with Low Baseline Low-Density Lipoprotein Cholesterol.

To investigate whether post-stroke statin therapy reduces subsequent major vascular events in statin-naïve patients with pretreatment low-density lipoprotein cholesterol (LDL-C) below the recommended target (≤70 mg/dL for atherosclerotic stroke and ≤100 mg/dL for non-atherosclerotic stroke) at stroke onset. Patients from an ongoing stroke registry who had an ischemic stroke between 2011 and 2020 were screened. Statin naïve patients with baseline LDL-C below the target were assessed. The effect of post-stroke statin therapy on major vascular events (composite of recurrent stroke, myocardial infarction, and death) was investigated using weighted Cox regression analyses using stabilized inverse probability treatment weighting. The baseline LDL-C level of the 1,858 patients (mean age 67.9 ± 15.3 years, 61.4% men, 13.2% atherosclerotic stroke) included in the study was 75.7 ± 17.0 mg/dL. Statins were prescribed to 1,256 (67.7%) patients (low-to-moderate intensity, 23.5%; high intensity, 44.1%). Post-stroke statin therapy was associated with a lower risk of major vascular events during 1-year follow-up (weighted hazard ratio 0.55, 95% confidence interval 0.42-0.71). In a subgroup of patients who were at very high risk of atherosclerotic cardiovascular disease with LDL-C <55 mg/dL or patients who were not at very high risk of atherosclerotic cardiovascular disease with LDL-C <70 mg/dL, post-stroke statin therapy was also associated with a reduction in major vascular events (weighted hazard ratio 0.45, 95% confidence interval 0.29-0.70). The intensity of the most beneficial statin varied by subtype of stroke. Statin therapy may improve vascular outcomes after ischemic stroke, even in cases of LDL-C below the target without pre-stroke lipid-lowering therapy. ANN NEUROL 2024;95:876-885.

The impact of statins treatments for plaque characteristics in stable angina pectoris patients with very low and high low-density lipoprotein cholesterol levels: an intracoronary optical coherence tomography study.

Low-density lipoprotein cholesterol (LDL-C) levels are recommended according to the patient's risk factors based on guidelines. In patients achieving low LDL-C levels, the need for statins is uncertain, and the plaque characteristics of patients not treated with statins are unclear. In addition, the difference in plaque characteristics with and without statins is unclear in similarly high LDL levels. We evaluate the impact of statins on plaque characteristics on optical coherence tomography (OCT) in patients with very low LDL-C levels and high LDL-C levels. A total of 173 stable angina pectoris patients with 173 lesions undergoing OCT before percutaneous coronary intervention were evaluated. We divided the LDL-C levels into three groups: < 70mg/dL (n = 48), 70mg/dL ≤ LDL-C < 100mg/dL (n = 71), and ≥ 100mg/dL (n = 54). Among patients with LDL-C < 70mg/dL, patients not treated with statins showed a significantly higher C-reactive protein level (0.27 ± 0.22mg/dL vs. 0.15 ± 0.19mg/dL, p = 0.049), and higher incidence of thin-cap fibroatheromas (TCFAs; 44% [7/16] vs. 13% [4/32], p = 0.021) than those treated with statins. Among patients with LDL-C level ≥ 100mg/dL, patients treated with statins showed a significantly higher prevalence of familial hypercholesterolemia (FH) (38% [6/16] vs. 5% [2/38], p = 0.004), lower incidence of TCFAs (6% [1/16] vs. 39% [15/38], p = 0.013), healed plaques (13% [2/16] vs. 47% [18/38], p = 0.015), and higher incidence of fibrous plaques (75% [12/16] vs. 42% [16/38], p = 0.027) than patients not treated with statins. While patients achieved a low LDL-C, patients not treated with statins had high plaque vulnerability and high systemic inflammation. While patients had a high LDL-C level with a high prevalence of FH, patients treated with statins had stable plaque characteristics.

ANGPTL3 and ApoC-III inhibitors for treating hypertriglyceridemia in context: horses for courses?

Hypertriglyceridemia (HTG) is an independent and casual risk factor for atherosclerotic cardiovascular disease (ASCVD). There is an unmet need for more effective treatments for patients with HTG. Angiopoietin-like protein 3 (ANGPTL3) and apolipoprotein C-III (apoC-III) are key regulators of triglyceride-rich lipoprotein (TRL) metabolism. We review recent clinical trials targeting ANGPTL3 and apoC-III with monoclonal antibody and nucleic acid therapies, including antisense oligonucleotides and small interfering RNA. ANGPTL3 and apoC-III inhibitors are effective in lowering plasma triglycerides and TRLs, with possibly greater efficacy with the inhibition of apoC-III. By contrast to ANGPTL3 inhibition that has the advantage of greater lowering of plasma low-density lipoprotein (LDL)-cholesterol and apoB levels, apoC-III inhibition only has a modest or no effect in lowering plasma LDL-cholesterol and apoB concentrations. Therapeutic inhibition of ANGPTL3 and apoC-III can correct HTG possibly by reducing production and increasing catabolism of TRL particles, but this remains to be formally investigated in patients with HTG. Novel agents targeting ANGPTL3 and apoC-III can correct HTG and potentially lower risk of ASCVD in patients with HTG. The long-term safety and cost-effectiveness of these agents await confirmation in ongoing and future studies.