Low-density Lipoprotein Cholesterol Research Articles

Impact of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors onLipoprotein(a): A Meta-Analysis and Meta-Regression of Randomized Controlled Trials.

Lipoprotein(a) [Lp(a)] has been independently associated with increased cardiovascular risk. The authors examined the effect of monoclonal antibody proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9is) on plasma Lp(a) levels across multiple trials. Studies were retrieved comparing the effect of PCSK9i vs placebo on Lp(a) levels. The primary outcome was percent change in Lp(a) levels. Factors associated with the treatment effect were determined by meta-regression analysis. Subgroup analyses were done to explore potential treatment effect differences. PCSK9i reduced Lp(a) levels on average of-27% (95%CI:-29.8% to-24.1%, P<0.001). Factors associated with the treatment effect included mean percent change in low-density lipoprotein cholesterol (P=0.003, beta coefficient 0.34, 95%CI: 0.11-0.57, tau2=94.8, R2=11.82) and apolipoprotein B (P<0.002, beta coefficient 0.4, 95%CI: 0.14-0.64, tau2=93.68, R2=11.86). Subgroup analyses revealed consistent treatment effect amongst comparators vs placebo:-27.69% (95%CI:-30.85% to-24.54%, P<0.001), vs ezetimibe:-24.0% (95%CI:-29.95% to-18.01%, P<0.001), type of PCSK9i, evolocumab:-29.35% (95%CI:-33.56% to-25.14%, P<0.001) vs alirocumab:-24.50% (95%CI:-27.96% to-21.04%, P<0.001), and presence of familial hypercholesterolemia:-25.63% (95%CI:-31.96% to-19.30%, P<0.001 vs no familial hypercholesterolemia:-27.22%; 95%CI:-30.34% to-24.09%, P<0.001). Varying treatment effects were noted in the duration of treatment (12weeks or shorter:-32.43% [95%CI:-36.63% to-28.23% vs >12weeks:-22.31%] [95%CI:-25.13% to-19.49%, P<0.001]), P interaction< 0.01. PCSK9is reduce Lp(a) levels by an average of 27%. Mean percent change in low-density lipoprotein cholesterol and apolipoprotein B were associated with treatment effect.

Genetically mimicked effects of evinacumab on psoriasis: a drug target Mendelian randomization study.

Dyslipidemia has been reported to contribute to the psoriasis pathogenesis. Thus, evinacumab, a novel lipid-lowering drug targeting angiopoietin-like 3, may have therapeutic potential to treat and/or manage psoriasis. Summary statistics were obtained from genome-wide association studies addressing psoriasis (FinnGen Consortium; n=216,752) and serum lipid concentrations (United Kingdom Biobank; n=403,943-440,546). Two-sample Mendelian randomization analyses were conducted to evaluate the associations of serum lipid concentrations and genetically mimicked effects of evinacumab, respectively, with the risks of psoriasis and its subtypes. Genetically determined per standard deviation increase in triglyceride concentrations was associated with increased risk of psoriasis (OR: 1.17, 95% CI: 1.03-1.32, p=0.018), whereas that in low-density lipoprotein-cholesterol (LDL-C) was associated with both psoriasis (OR: 1.22, 95% CI: 1.05-1.43, p=0.011) and its subtypes, including arthropathic psoriasis (OR: 1.30, 95% CI: 1.02-1.65, p=0.032), psoriasis vulgaris (OR: 1.87, 95% CI: 1.16-2.99, p=0.0095), and guttate psoriasis (OR: 2.19, 95% CI: 1.17-4.07, p=0.014). Moreover, genetically mimicked effects of evinacumab, via angiopoietin-like 3 inhibition, significantly reduced the risk of psoriasis (OR: 0.752 per standard deviation reduction in triglycerides, 95% CI: 0.577-0.982, p=0.036) and arthropathic psoriasis (OR: 0.266 per standard deviation reduction in LDL-C, 95% CI: 0.0886-0.799, p=0.018). The genetically mimicked effect of evinacumab has the potential to reduce the risk of psoriasis and arthropathic psoriasis by lowering circulating triglyceride and LDL-C concentrations, respectively. These findings suggest that evinacumab may help prevent psoriasis and psoriatic arthritis progression in clinical practice.

Epiberberine Improves Hyperglycemia and Ameliorates Insulin Sensitivity in Type 2 Diabetic Mice.

Type 2 diabetes mellitus (T2DM) is a metabolic syndrome characterised by absolute or relative insufficiency of insulin secretion. The alkaloids from Rhizoma coptidis have potential hypoglycemic effects. Epiberberine (EPI), a protoberberine alkaloid extracted from Rhizome coptidis, has been found to regulate lipid metabolism. Our study aimed to investigate the antidiabetic effects of EPI on mice with T2DM, as well as its underlying mechanism. The T2DM model in mice was established using a combination of high-fat diet and streptozotocin. Animals were divided into the control, T2DM, EPI-low dose (50 mg/kg EPI), EPI-medium dose (100 mg/kg EPI), EPI-high dose (200 mg/kg EPI) and metformin (MTF) (200 mg/kg MTF) groups. Body weight, water/food intake, serum lipids, blood glucose tolerance, insulin sensitivity, histopathological alterations, insulin signalling pathway and inflammation-related pathways in each group were detected. EPI significantly reduced blood glucose levels and water/food intake in T2DM mice. EPI reduced the levels of total cholesterol, total triglyceride, low-density lipoprotein cholesterol, aspartate aminotransferase and alanine aminotransferase, and elevated the levels of high-density lipoprotein cholesterol in serum. EPI effectively improved oral glucose tolerance, alleviated hepatic insulin resistance, decreased glycosylated haemoglobin levels and increased liver glycogen content. EPI ameliorated the histopathological alterations of skeletal muscle and liver in T2DM mice. EPI stimulated the insulin signalling pathway by increasing glucose transporter type 4 levels and activating insulin receptor substrate-1, phosphatidylinositol 3-kinase and protein kinase B in skeletal muscle and liver. EPI reduced the levels of proinflammatory cytokine in serum and inhibited the activation of mitogen-activated protein kinase signalling in skeletal muscle and liver of diabetic mice. Overall, these data demonstrate that EPI alleviates the symptoms of T2DM, providing new insights into EPI as a therapeutic compound for the alleviation of T2DM.

Chronic heat stress is capable of reducing the growth performance, causing damage to the liver structure, and altering the liver glucose metabolism and lipid metabolism in largemouth bass (Micropterus salmoides L.).

High temperatures cause abnormal energy metabolism and inhibit the growth of fish in aquaculture. However, the mechanism of energy metabolism under chronic heat stress is still unknown. In this study, largemouth bass (Micropterus salmoides, LMB) was treated with 25℃, 29℃, and 33℃ for 8weeks. Then, the growth performance, liver tissue damage, serum lipid indicator, hepatic glycogen, and triglyceride levels were analyzed. The growth data showed that the 33℃ group had a lower weight gain rate (WGR), specific growth rate (SGR), feeding rate (FR), and higher feed conversion rate (FCR) in comparison with those in the 25℃ and 29℃ groups. However, there were no significant differences between the 25℃ and 29℃ groups. The most severe damage to liver tissue was observed in the 33℃ group, characterized by cellular vacuolation and marginalization of cell nuclei. The levels of triglyceride, total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol in the serum were decreased with the rising temperatures. However, the hepatic triglyceride levels were increased, with a decrease in hepatic glycogen levels. Compared with the 25℃ group, the expressions of gluconeogenesis pathway-related genes (phosphoenolpyruvate carboxykinase (Pepck) and glucose-6-phosphatase (G6pase)) and glucose transport pathway-related gene (glucose transporter 2 (Gltu2)) were down-regulated in the 33℃ group. In contrast, the expression of the glycolysis pathway-related gene (pyruvate kinase (Pk)) was up-regulated. In addition, the expressions of fatty acid β oxidation pathway-related genes (peroxisome proliferator-activated receptor-Alpha (Pparα) and carnitine palmityl transferase 1 (Cpt1)), adipogenesis pathway-related genes (peroxisome proliferator-activated receptor-Gamma (Pparγ), fatty acid synthase (Fas), acetyl-CoA carboxylase (Acc)), and lipolysis pathway-related genes (adipose triglyceride lipase (Agtl) and hormone-sensitive lipase (Hsl)) were down-regulated under chronic heat stress. In conclusion, our results indicated that enhancement of the glycolysis pathway and inhibition of the gluconeogenesis pathway and lipid metabolism contribute to coping with chronic heat stress for LMB. Our study provides useful information for alleviating the heat stress response of LMB through nutritional regulation in the future.

Management of a young HoFH patient during pregnancy using Lipoprotein Apheresis (whole blood): A novel experience.

The pregnancy of a patient with homozygous familial hypercholesterolemia (HoFH) represents a challenge in the clinical setting due to the high cardiovascular risk of the mother and maternal-fetal morbidity. The lipid lowering drugs are generally contraindicated and lipoprotein apheresis (LA) is the only accepted treatment in HoFH pregnant woman. Liposorber D, an LA technique on whole blood, has good efficacy, safety, and short operative time. We present a 31-year-old Caucasian pregnant woman with HoFH clinical phenotype on lipid-lowering treatment with Lomitapide and Evolocumab, discontinued during pregnancy. In multidisciplinary team it was decided to submit the patient to LA throughout the pregnancy. Liposorber D sessions (a whole blood technique) were performed on a strict weekly frequency. The treatment resulted in massive decrease of total cholesterol (TC) and LDL cholesterol (LDL-c), with no significant side effects. The pregnancy presented a normal course and a cesarean section was performed on clinical indications unrelated to the use of LA. She gave birth to a healthy male child at 37 weeks of gestation. LA is considered the only effective, safe and accepted therapy during HoFH pregnancy. This is the first reported case of successful pregnancy treated with Liposorber D, a whole blood LA technique. LA with dextran sulfate has been an effective and safe choice for the mother and fetus. Furthermore it was reasonably well tolerated from the beginning of pregnancy management to its conclusion.

Improvement of measured and perceived disability in overweight patients with Multiple Sclerosis trough different patterns of Mediterranean hypocaloric diet.

overweight and other cardiovascular risk factors are known contributors to disability accrual in Multiple Sclerosis (MS). We aimed to explore the impact of three hypocaloric dietetic patterns, based on the Mediterranean diet, on cardiovascular risk and clinical status in overweight persons with MS (pwMS). overweight pwMS (body mass index-BMI ≥25 kg/m2) were prospectively enrolled, randomly allocated to three hypocaloric dietetic plans differing in macronutrients composition (carbohydrates/proteins/lipids: diet A 65 %/15 %/20 %; diet B 35 %/25 %/40 %; diet C 50 %/20 %/30 %) and followed-up for 1 year (6 months of dietetic intervention + 6 months of observation). The Multiple Sclerosis Performance Test, a self-administered, iPad®-based system for quantifying cognition, upper and lower extremity motor function, and vision was performed at baseline, 6 and 12 months. Questionnaires for the evaluation of sleep quality, fatigue, anxiety, depression, stigma, social participation and satisfaction were administered. Information about cardiovascular risk parameters (BMI, waist circumference-WC, umbilical circumference-UC, hip circumference-HP, blood pressure, HDL and LDL cholesterol, triglycerides, glycemia) were collected. Adherence to the dietetic plan was quantified as days of complete to insufficient adherence across the treatment period. Between-group comparisons were performed with Chi-square and ANOVA; longitudinal analyses with one-way ANOVA for repeated measures and mixed-design ANOVA. fifty-three patients completed the study (diet A n = 19, diet B n = 18, diet C n = 16). The three groups were well matched for sex, age, disease duration and EDSS. Along the 6 months of dietetic intervention, no difference in adherence was detected across the three dietetic plans (p = 0.84). Overall, patients showed a significant weight loss over time (p < 0.001) with no difference across diets (p = 0.34). BMI, WC, UC, HC and cholesterol improved over time (p ranging from 0.06 to 0.001), with no differences across diets (p ranging from 0.16 to 0.58). Among all tested clinical variables, fatigue, anxiety, information processing speed and manual dexterity improved significantly (p = 0.005, p = 0.012, p = 0.013, p = 0.005), with no differences across diets (p = 0.84, p = 0.89, p = 0.53, p = 0.72). dietetic interventions in overweight pwMS, irrespective of their specific macronutrients composition, are able to improve the cardiovascular profile, the perception of subjective symptoms as well as objective disability scores.

HDL proteome and apolipoproteins concentrations in severe ICU COVID-19 patients

BackgroundSARS-CoV-2 infection affects both lipid metabolism and lung function. The severity of the disease has been associated with reduced levels of both high-density lipoprotein (HDL) and low-density lipoprotein cholesterol. Despite the crucial role that these nanoparticles play in SARS-CoV-2 infection, few studies have examined their structure during COVID-19 beyond HDL quantity.The study aimed to assess apolipoprotein levels in COVID-19 patients who either survived or died following ICU admission. In addition, ICU survivors and non-survivors were compared for HDL particle size and proteome.MethodsBetween February and April 2020, our study enrolled 37 COVID-19 patients upon their intensive care unit admission. Among them, 18 survived the disease, while 19 succumbed to it. We used mass spectrometry to assess plasma levels of 14 apolipoproteins and LCAT. Additionally, we analyzed HDL subpopulation distribution by utilizing native polyacrylamide gel electrophoresis. HDL particles were isolated from both surviving and non-surviving patients using ultracentrifugation, followed by characterization of their proteomes with NanoLC-MS/MS.ResultsPlasma apolipoproteins, including Apo A-II, Apo Cs (I, II, III), Apo H, Apo J, Apo M, and LCAT, were decreased in patients who did not survive COVID-19. However, no alterations were noted in the distribution of HDL subpopulations in relation to mortality. HDL composition was further altered based on mortality, displaying a decline in Apo H and paraoxonase 3.ConclusionIn conclusion, we have shown an alteration in plasma apolipoproteins and HDL composition between surviving COVID-19 patients and non-survivors. Some markers, such as Apo H, are more predictive than baseline lipid concentrations such as HDL-C. These markers appear to provide a more accurate indication of mortality during COVID-19 compared with baseline lipid concentrations such as HDL-C.

Young Healthy Individuals With a First-Degree Relative With Type 1 Diabetes Displayed Adverse Lipid Changes.

Timeline of atherosclerosis in children with type 1 diabetes is unknown. We aimed to investigate if familial risk of type 1 diabetes is associated with pro-atherosclerotic changes. Young first-degree relatives to patients with paediatric type 1 diabetes and sex and age matching controls were enrolled at Skåne University Hospital, Sweden between 2006 and 2015. Conventional lipids, human leukocyte antigen DQ2/8, inflammatory biomarkers, and history of respiratory infections were determined. A total of 117 first-degree relatives and 43 controls were recruited (50% boys) at median of 13.4 years of age (IQR 8.0). Relatives had lower BMI Z-score (p = 0.03) and frequency of respiratory infections (p = 0.03) compared to controls, but higher low-density lipoprotein (LDL, p = 0.04) and total cholesterol (p = 0.01). In multivariable regression models adjusted for confounders LDL was 0.35 mmol/L higher (95% CI 0.10-0.61) and total cholesterol was 0.46 mmol/L higher (95% CI 0.15-0.77) in relatives. Relatives with ≥ 4 respiratory infections/year had higher LDL than controls with < 4 infections/year (p = 0.035). Human leukocyte antigen DQ2/8 frequency and inflammatory biomarkers did not differ between groups. Healthy young relatives to patients with type 1 diabetes display adverse lipid changes, probably related to their genetic susceptibility to this disease and recent respiratory infections.

The effect of bedtime snacks on morning fasting blood glucose in gestational diabetes mellitus: a randomized controlled trial.

While guidelines recommend bedtime snacks for women with gestational diabetes mellitus (GDM), there is insufficient evidence championed those recommendation. To evaluate if bedtime snacking is effective in preventing high fasting blood glucose incidence among women with GDM. An open-label, parallel-group, randomized controlled trial was conducted from December 2023 to July 2024 at Ma'anshan Maternal and Child Health Care Center, Anhui, China. A total of 62 GDM cases at the nutrition clinics were enrolled, and were randomly and equally allocated to groups of bedtime snacks (25g nuts, intervention group) and no bedtime snacks (control group). The intervention was lasted for 8 weeks, during which fasting blood glucose was measured 3 times per week, 1-hour postprandial glucose and 2-hour postprandial glucose 2 times per week with a home glucometer. In the late pregnancy (approximately at 34 weeks), the glycated haemoglobin, high-density lipoprotein, low-density lipoprotein, triglycerides, total cholesterol were measured in the laboratory and birth outcomes information (birth weight, gestational weeks at delivery, delivery mode) were collected. The primary outcomes were the level of fasting blood glucose and the hyper-fasting blood glucose incidence during 8-week duration. The secondary outcomes were the level of the glycated haemoglobin, high-density lipoprotein, low-density lipoprotein, triglycerides and total cholesterol in the late pregnancy. Generalized estimating equations and analysis of covariates were conducted for the analysis of the primary outcomes. The multivariate linear regression was conducted for the analysis of the secondary outcomes. Post-hoc analysis was also conducted for the indicators of 1-hour postprandial glucose, 2-hour postprandial glucose and perinatal outcomes applying generalized estimating equations, analysis of covariates, the multivariate linear regression and logistics regression. After adjusting for maternal age, pre-pregnancy body mass index, mid-pregnancy glucose, mid-pregnancy blood lipids and diet in late pregnancy, neither the average fasting blood glucose (control group: 4.90 mmol l-1, intervention group: 4.96 mmol l-1) (β = 0.05, [95%CI-0.22 to 0.31], P = 0.720) nor hyper-fasting blood glucose incidence (control group: 0.19, intervention group:0.26) (β = 0.07, [95%CI-0.07 to 0.20], P = 0.335) were significant different between the two groups. And we found low-density lipoprotein level were higher in the intervention group (3.21 mmol l-1) compared to the control group (2.52 mmol l-1) (β = 0.70, [95%CI0.07 to 1.34], P = 0.031). Additionally, post-hoc analysis showed that the incidence of elevated 1-hour postprandial glucose was significantly higher in the intervention group (0.42) than in the control group (0.28) (β = 0.14, [95%CI0.01 to 0.27], P = 0.036). No difference was found regarding any perinatal outcomes between the two groups. Bedtime snack did not reduce the risk of morning hyperglycaemia and adverse perinatal outcomes in women with gestational diabetes mellitus, but exacerbated lipid markers and the 1-hour postprandial glucose profile. Our study did not support clinicians and relevant guidelines to recommend bedtime snacking as a form of glycaemic control in women with GDM. Clinical trial identification number: ChiCTR2300078399. URL of the registration site: https://www.chictr.org.cn/bin/project/edit?pid=210400 .

Evolocumab safety and efficacy in hypercholesteremia patients with or without diabetes: a retrospective real-world analysis

BackgroundProprotein convertase subtilisin/kexin type 9 inhibitors effectively reduce LDL cholesterol and adverse cardiovascular events with a safety profile comparable to a placebo. Limited real-world data exists on their effectiveness in different patient groups. This study evaluated evolocumab’s efficacy and safety in hypercholesteremia patients with and without diabetes.MethodIn a large tertiary hospital in Saudi Arabia, patients aged 18 and above who initiated evolocumab therapy were screened for eligibility between January 2017 and July 2023. All patients who had been on maximally tolerated statin and ezetimibe therapy for at least 4 months before starting evolocumab were included. The included participants were then divided into diabetic and non-diabetic groups and assessed for evolocumab’s efficacy and safety. Efficacy was measured by LDL-C reduction and target achievement, while safety was assessed by examining glycemic control changes, new-onset diabetes (NOD) and hepatic enzyme levels. Data analysis included descriptive and comparative methods, with significance set at p < 0.05.ResultsA total of 151 patients were included, with an average age of 51.77 years. The majority of patients were male (67.6%) and obese (81.5%). Around 55% had diabetes, and 63% had established atherosclerotic cardiovascular disease at baseline. During a mean follow-up period of 13.17 months, the average reduction in LDL-C from baseline was − 34.21, − 28.66, and − 39.61% for the overall cohort, non-diabetic patients, and diabetic patients, respectively. In the overall cohort, 34.4 and 24.5% reached the target LDL-C levels of less than 1.4 mmol/L (55 mg/dL) and less than 1.8 mmol/L (70 mg/dL), respectively. Worsening of glycemic control (HbA1C increase > 0.5) was observed in 25.83% of the overall cohort, 16.18% of non-diabetics, and 33.74% of diabetics. An HbA1C increase > 1 was observed in 13.25% of the overall cohort, 2.94% in non-diabetics and 21.69% in diabetics. Five patients (3.3%) developed NOD.ConclusionThe study demonstrated that the addition of evolocumab to maximally tolerated statin and ezetimibe therapy reduced LDL-C levels but with a smaller average reduction and a lower proportion of patients achieving recommended LDL-C targets than in landmark clinical trials. Additionally, there was a potential negative effect on glycemic control, warranting further investigation.

Analysis of 26 Studies of the Impact of Coconut Oil on Lipid Parameters: Beyond Total and LDL Cholesterol

Coconut oil (CNO) is often characterized as an “artery-clogging fat” because it is a predominantly saturated fat that ostensibly raises total cholesterol (TChol) and LDL cholesterol (LDL-C). Whereas previous analyses assessed CNO based on the relative effects on lipid parameters against other fats and oils, this analysis focuses on the effects of CNO itself. Here, we review the literature on CNO and analyze 984 lipid profile data sets from 26 CNO studies conducted over the past 40 years. This analysis shows considerable heterogeneity among CNO studies regarding participant selection, the amount consumed, and the study duration. The analysis reveals that, overall, CNO consumption gives variable TChol and LDL-C values, but that the HDL-cholesterol (HDL-C) values increase and triglycerides (TG) decrease. This holistic lipid assessment, together with the consideration of lipid ratios, shows that CNO does not pose a health risk for heart disease. Because the predominantly medium-chain fatty acid profile of CNO is significantly different from that of lard and palm oil, studies using these as reference materials do not apply to CNO. This paper concludes that the recommendation to avoid consuming coconut oil due to the risk of heart disease is not justified.

The Role of Paraoxonase-1 Activity, Apolipoprotein B Levels, and Apolipoprotein B/Apolipoprotein A-I Ratio as Risk Markers for Aortic Stenosis in Patients with a Bicuspid Aortic Valve

The bicuspid aortic valve (BAV) is commonly associated with the early degeneration of the aortic valve. Up to 45% of BAV patients over the age of 50 develop aortic stenosis (AS). Although published data indicate a robust interplay between lipids and calcific AS in tricuspid aortic valve patients, the studies on the BAV population are lacking. We aimed to evaluate the association between selected lipid markers and the occurrence of AS in BAV patients. Methods: The study included 76 adults (21 female) with a BAV diagnosed by echocardiography, divided by age and AS diagnosis. Biochemical parameters concentrations in serum were measured: high density lipoprotein cholesterol (HDL-C) levels by standard enzymatic colorimetric tests, low density lipoprotein cholesterol (LDL-C) levels by the Friedewald formula, apolipoprotein A-I (Apo AI) and apolipoprotein B (Apo B) serum concentration by the nephelometric method, and paraoxonase-1 activity (PON-1 ASE) and arylesterase activity (PON-1 ARE) based on paraoxon and phenyl acetate hydrolysis. Results: A total of 54 patients (15 female) were more than 45 years old and 22 (6 female) were 45 or less years old. BAV patients with AS aged ≤45 had higher levels of Apo B, compared to those without AS [110.5 (102–132) vs. 95.6 (77–101) mg/d; p 0.044]. Similarly, Apo B/Apo AI ratio was higher in BAV patients with AS aged ≤45, compared to those without AS [(0.8 (0.7–1) vs. 0.6 (0.5–0.7); p 0.029]. In the group aged ≤45, Apo B showed a positive correlation with the aortic valve peak transvalvular velocity (AV Vmax) measurement (R Spearman 0.6, p 0.004). We found also that, among young BAV patients, those with AS had a lower level of PON-1 ARE compared to the cohort without AS [63.4 (52–80) vs. 85.3 (70–102); p 0.012]. We did not find any differences in lipid parameters in patients aged &gt;45. Conclusions The metabolic link between Apo B level and Apo B/AI ratio with AS presence in BAV patients under 45 years of age suggests a significant impact of these parameters on the earlier development of AS in the BAV population. Molecules associated with high density lipoprotein and its antioxidant function, such as PON1, are valuable markers for AS development, compared to HDL-C and LDL-C levels.

Mechanisms of GLP-1 receptor agonist-induced weight loss: A review of central and peripheral pathways in appetite and energy regulation.

Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) have become central in managing obesity and type 2 diabetes, primarily through appetite suppression and metabolic regulation. This review explores the mechanisms underlying GLP-1 RA-induced weight loss, focusing on central and peripheral pathways. Centrally, GLP-1 RAs modulate brain regions controlling appetite, influencing neurotransmitter and peptide release to regulate hunger and energy expenditure. Peripherally, GLP-1 RAs improve glycemic control by enhancing insulin secretion, reducing glucagon release, delaying gastric emptying, and regulating gut hormones. They also reduce triglycerides and low-density lipoprotein cholesterol, mitigate adipose tissue inflammation, and minimize ectopic fat deposition, promoting overall metabolic health. Emerging dual and triple co-agonists, targeting GLP-1 alongside glucose-dependent insulinotropic polypeptide, and glucagon pathways, may enhance weight loss and metabolic flexibility. Understanding these mechanisms is crucial as the therapeutic landscape evolves, offering clinicians and researchers insights to optimize the efficacy of current and future obesity treatments.

Mendelian randomization analysis does not support a causal influence between lipoprotein(A) and immune-mediated inflammatory diseases

Observational studies have reported an association between lipoprotein(a) (Lp(a)) and immune-mediated inflammatory diseases (IMIDs). This study used Mendelian Randomization (MR) and multivariable MR (MVMR) to explore the causal relationship between lipoprotein(a) [Lp(a)] and immune-mediated inflammatory diseases (IMIDs). We performed a bidirectional two-sample mendelian randomization analyses based on genome-wide association study (GWAS) summary statistics of Lp(a) and nine IMIDs, specifically celiac disease (CeD), Crohn’s disease (CD), ulcerative colitis (UC), inflammatory bowel disease (IBD), multiple sclerosis (MS), psoriasis (Pso), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes (T1D), and summary-level data for lipid traits. Furthermore, we performed MVMR to examine the independence of relationship between Lp(a) and IMIDs after controlling other lipid traits, namely high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG). We didn’t observe a causal association between Lp(a) and the risk of IMIDs in univariable and multivariable MR analysis, challenging previous observational studies. However, genetically predicted lipid traits HDL-C was associated with increased risk of Type 1 diabetes (T1D). The identification of potential mechanisms underlying the observed associations in observational studies necessitates further investigation.

Lowering LDL cholesterol by PCSK9 inhibition: a new era of gene silencing, RNA, and alternative therapies.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) discovery has added a new paradigm to our understanding of cholesterol homeostasis and lipid metabolism. Since its discovery, PCSK9 inhibitors have become a widely investigated therapeutic class for lipid management in cardiovascular diseases and hypercholesterolemia. Scientists have explored different approaches for PCSK9 inhibition, such as monoclonal antibodies (mAbs), gene silencing and gene editing techniques, vaccines, mimetic peptides, and small molecules. European Medicines Agency (EMA) and United States Food and Drug Administration (US FDA) have approved only three PCSK9 inhibitors, including two monoclonal antibodies and one small interfering ribonucleic acid (siRNA). Despite the efficacy of approved large molecules, high costs and the need for regular injection have limited their adherence to the patient. This review aims to provide an understanding of PCSK9's function in Low-Density Lipoprotein Cholesterol (LDL-C) management, its current treatment, recent advancements, and potential future development of small molecules in the class of PCSK9 inhibitors.

Improving cardiometabolic risk factors in Aboriginal and Torres Strait Islander people in northeast Arnhem Land: single arm trial of a co-designed dietary and lifestyle program.

To evaluate the impact of a 4-month dietary and lifestyle program co-designed and led by Aboriginal and Torres Strait Islander people on weight and metabolic markers, diet, and physical activity in overweight and obese adults in a remote Indigenous community. Single arm, pre-post intervention study. Adult residents (18-65 years) of a remote Northern Territory community with body mass index (BMI) values of at least 25 kg/m2 or waist circumferences exceeding 94 cm (men) or 80 cm (women). Hope for Health, a culturally sensitive 4-month program supporting self-managed health improvement based on dietary and lifestyle change, 1 August to 30 November 2022. Weight loss of at least 5%; changes in BMI, waist circumference, other metabolic markers (blood pressure, biomarkers of metabolic health and inflammation), diet, and physical activity; participant perceptions of the program. We assessed outcomes for 55 participants who completedweight assessments at both baseline and program end(mean age, 42.5 years [standard deviation, 10.1 years]; 36 women [65%]). Forty participants lost and 15 gained weight; overall mean weight loss was 1.5 kg (95% confidence interval [CI], 0.5-2.4 kg), and ten participants (18%; 95% CI, 9-31%) achieved at least 5% weight reduction. The mean change in BMI (53 participants) was -0.60 kg/m2 (95% CI, -0.93 to -0.27 kg/m2), in waist circumference (53 participants) -3.2 cm (95% CI, -4.7 to -1.7 cm), and in low-density lipoprotein cholesterol level (37 participants) -0.28 mmol/L (95% CI, -0.47 to -0.08 mmol/L); the relative decline in the HbA1c level geometric mean (50 participants) was 11% (95% CI, 6-15%). The intake of breads and cereals (median change, -1.5 [95% CI, -2.0 to -1.0] serves/day) and sugar-sweetened beverages (-0.6 [95% CI, -1.4 to -0.1] serves/day) declined; the amount of moderate and vigorous physical activity increased by a median of 103 min/day (95% CI, 74-136 min/day; 19 participants). The program focus on integrating healthy bodies and networks of kin, healthy governance, vibrant language and ceremony, and a healthy environment were seen as central to its value and benefit. Community appreciation of the program and the improvements in cardiometabolic risk factors are encouraging, providing an example of a culturally sensitive, co-designed initiative led by Indigenous people for reducing the prevalence of chronic disease in remote areas. Australian New Zealand Clinical Trials Registry (ACTRN12622000174785; prospective: 2 February 2022).

Targeting PCSK9, through an innovative cVLP-based vaccine, enhanced the therapeutic activity of a cVLP-HER2 vaccine in a preclinical model of HER2-positive mammary carcinoma.

HER2-targeted therapies have revolutionized the treatment of HER2-positive breast cancer patients, leading to significant improvements in tumor response rates and survival. However, resistance and incomplete response remain considerable challenges. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition is a novel therapeutic strategy for the management of dyslipidemia by enhancing the clearance of low-density lipoprotein cholesterol receptors, however recent evidence also shows links between PCSK9 and cancer cells. We present an innovative immunization approach combining capsid virus-like particle (cVLP)-based vaccines against HER2 and PCSK9. The therapeutic activity of the combined vaccine was evaluated in female mice challenged with HER2-positive mammary carcinoma cells. Controls included untreated mice and mice treated with cVLP-PCSK9 and cVLP-HER2 as standalone therapies. Antibodies elicited by vaccinations were detected through ELISA immunoassay. The functional activity of the antibodies was tested in 3D-soft agar assay on human HER2 + + + trastuzumab sensitive and resistant cells. Mice vaccinated with cVLP-HER2 + cVLP-PCSK9 displayed tumor regression from the 40th day after cell challenge in 100% of mice remaining tumor-free even 4months later. In contrast, 83% of mice treated with cVLP-HER2 vaccine alone experienced an initial tumor regression, followed by tumor relapse in 60% of subjects. Untreated mice and mice treated with the cVLP-PCSK9 vaccine alone developed progressive tumors within 1-2months after cell injection. The combined vaccine approach elicited strong anti-human HER2 antibody responses (reaching 1-2mg/ml range) comprising multiple immunoglobulins isotypes. cVLP-PCSK9 vaccine elicited anti-PCSK9 antibody responses, resulting in a marked reduction in PCSK9 serum levels. Although the anti-PCSK9 response was reduced when co-administered with cVLP-HER2, it remained significant. Moreover, both cVLP-HER2 + cVLP-PCSK9 and cVLP-HER2 alone induced anti-HER2 antibodies able to inhibit the 3D growth of human HER2 + + + BT-474 and trastuzumab-resistant BT-474 C5 cells. Strikingly, antibodies elicited by the combined vaccination were more effective than those elicited by the cVLP-HER2 vaccine alone in the inhibition of trastuzumab-resistant C5 cells. The results indicate that cVLP-PCSK9 vaccination shows adjuvant activity when combined with cVLP-HER2 vaccine, enhancing its therapeutic efficacy against HER2-positive breast cancer and holding promise in overcoming the challenges posed by resistance and incomplete responses to HER2-targeted therapy.

P-587. Durable Virological Suppression, Reduced Body Weight, and Improved Serum Cholesterol after Switch to Tenofovir DF-Containing, Ainuovirine-Based Antiretroviral Regimen in People with HIV-1: the 96-Week Results of the SPRINT Trial, a Randomized, Active-Controlled Phase 3 Extensional Study

Abstract Background The SPRINT trial was a multi-center, randomized, double-blind, active-controlled study in virologically suppressed people with HIV-1 (PWHs) switching from efavirenz-based antiretroviral (ARV) regimen. This study compared the efficacy and safety profiles of switch to tenofovir DF (TDF) containing, ainuovirine (ANV) based regimen (ACC008), and that to tenofovir alafenamide (TAF) containing, boosted elvitegravir (EVG/c) based regimen. ACC008 was shown to be non-inferior in virological efficacy but with reduced weight gain and improved lipid profile compared to the comparator at 48 weeks. We herein reported the week 48 to 96 results of the extensional study period as prespecified.Figure 1.Durable virological suppression after switch to ACC008 from efavrienz- and boosted elvitegravir-based antiretroviral regimens. Snapshot analysis of the proportion of participant with HIV-1 RNA&amp;lt;50 copies/mL. *Switching to ACC008 after 48 weeks of E/C/F/TAF treatment (mITT-E). ACC008, ainuovirine/ lamivudine/ tenofovir disoproxil; E/C/F/TAF, elvitegravir/ cobicistat/ emtricitabine/ tenofovir alafenamide. mITTE, modified intention-to-treat-exposed. Methods Out of 762 adult PWHs randomized in the SPRINT trial, 755 PWHs continued the extensional study, and all received open-label ACC008 for additional 48 weeks (ACC008→ACC008 arm, n=378; comparator→ACC008 arm, n=377). The primary efficacy endpoint was the proportion of PWHs with plasma HIV-1 RNA below 50 copies/mL at week 96 as per the snapshot algorithm. Primary safety outcomes of interest included changes in body weight, and serum low-density lipoprotein cholesterol (LDL-C) at week 96 from week 48.Figure 2.Significant weight loss after switch to ACC008 from E/C/F/TAF at weeks 48-96.*Switching to ACC008 after 48 weeks of E/C/F/TAF treatment. ACC008, ainuovirine/ lamivudine/ tenofovir disoproxil; E/C/F/TAF, elvitegravir/ cobicistat/ emtricitabine/ tenofovir alafenamide. Results At 96 weeks, 96.6% (368/381) of PWHs maintained virological suppression in ACC008→ACC008 arm as per the intention-to-treat-exposed analysis (ITT-E, n=381); 96.6% (364/377) of PWHs remained virologically suppressed in comparator→ACC008 arm as per the modified ITT-E analysis (mITT-E, n=377). Changes in body weight (least square mean) from week 48 were -0.67 kg for comparator→ACC008 arm, and -0.02 kg for ACC008→ACC008 arm (estimated treatment difference [95%CI], -0.65 kg [-1.18, -0.13], p=0.015) at week 96, respectively. Changes in serum LDL-C from week 48 were -0.24 mmol/L, and -0.05 mmol/L (-0.19 mmol/L [-0.34, -0.03], p=0.019) at week 96, respectively.Figure 3.Significant LDL-C decline after switch to ACC008 from E/C/F/TAF at weeks 48-96.*Switching to ACC008 after 48 weeks of E/C/F/TAF treatment. ACC008, ainuovirine/ lamivudine/ tenofovir disoproxil; E/C/F/TAF, elvitegravir/ cobicistat/emtricitabine/ tenofovir alafenamide; LDL-C, low-density lipoprotein cholesterol. Conclusion Switch to tenofovir DF-containing, ANV-based regimen maintained virological suppression, and that from TAF-containing, EVG/c-based regimen also resulted in high suppression at week 98. Additional benefits included weight loss and serum LDL-C decline after switch to tenofovir DF-containing, ANV-based from TAF-containing, EVG/c-based regimen. Disclosures Hong Qin, MD, PhD, Jiangsu Aidea Pharmaceutical Co., Ltd: Honoraria

P-588. Improved Lipid Profile in Virologically Suppressed People with HIV-1 Switching to Tenofovir DF-Containing, Ainuovirine-Based Compared to Tenofovir Alafenamide-Containing, Boosted Elvitegravir-Based Antiretroviral Regimen: the Secondary Analyses of 48-Week Results of the SPRINT Trial, a Randomized, Active-Controlled Phase 3 Study

Abstract Background ACC008 is a tenofovir DF (TDF) containing, ainuovirine (ANV), a new-generation NNRTI, based fixed-dose combination (FDC). This FDC has shown noninferior virological efficacy but improved lipid profile compared to tenofovir alafenamide (TAF) containing, boosted elvitegravir (EVG/c) regimen among virologically suppressed people with HIV-1 (PWHs) switching from NNRTI-based regimen. We herein reported the secondary analyses of 48-week lipids profile as prespecified.Figure 1.Lipid metabolism adverse events at week 48.ACC008, ainuovirine/ lamivudine/ tenofovir disoproxil; E/C/F/TAF, elvitegravir/ cobicistat/ emtricitabine/ tenofovir alafenamide; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; TC, total cholesterol; TG, triglyceride. Methods Virologically suppressed PWHs were randomized to ACC008 (n=381) or comparator arm (n=381) for 48 weeks. Changes from baseline (CFBs) in serum lipids were primary safety outcome of interest, including LDL-C, non-HDL-C, total cholesterol (TC), triglycerides (TG), and HDL-C. Other secondary safety outcomes of interest included lipid metabolism adverse events (AEs), and atherosclerotic cardiovascular disease (ASCVD) risk stratification as per the primary prevention target for Chinese low-risk adults.Figure 2.The proportions of PWHs with optimal/acceptable serum lipids and with decreased HDL-C at week 48.ACC008, ainuovirine/ lamivudine/ tenofovir disoproxil; E/C/F/TAF, elvitegravir/ cobicistat/ emtricitabine/ tenofovir alafenamide; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; PWHs, peoples with HIV; TC, total cholesterol; TG, triglyceride. For indicators of serum lipids, optimal/acceptable level is defined as LDL-C＜2.6 mmol/L, non-HDL-C ＜3.4 mmol/L, TC ＜5.2 mmol/L, or TG＜1.7 mmol/L, and decreased HDL-C as ＜1.0 mmol/L. Results Primary safety outcomes of interest were reported elsewhere. PWHs on ACC008 experienced significantly less frequent lipid metabolism AEs compared to those on comparator (elevated LDL-C, 6.0% vs. 21.3%, estimated treatment difference [95%CI], 0.152 [0.105, 0.200], p&amp;lt; 0.001; elevated cholesterol, 5.0% vs. 31.8%, 0.268 [0.216, 0.319], p&amp;lt; 0.001; elevated TG, 11.8% vs. 34.1%, 0.223 [0.165, 0.280], p&amp;lt; 0.001), but a marginally more frequent decreased HDL-C AE (9.4% vs. 5.5%, 0.039 [0.002, 0.078], p=0.040). The two arms showed a comparable ASCVD risk stratification at the baseline. However, ACC008 arm had a significantly greater proportion of PWHs with optimal/acceptable LDL-C (&amp;lt; 2.6 mmol/L, 49.2% vs. 27.4%, 0.213 [0.144, 0.278], p&amp;lt; 0.01), non-HDL-C (&amp;lt; 3.4 mmol/L, 70.5%, 35.4%, 0.344 [0.275, 0.408], p&amp;lt; 0.001), TC (&amp;lt; 5.2 mmol/L, 90.6% vs. 59.8%, 0.307 [0.249, 0.363], p&amp;lt; 0.001), and TG (&amp;lt; 1.7 mmol/L, 84.0% vs. 53.0%, 0.310 [0.246, 0.370], p&amp;lt; 0.001), but also those with decreased HDL-C (&amp;lt; 1.0 mmol/L, 28.6% vs. 17.3%, 0.113 [0.053, 0.172], p&amp;lt; 0.001) compared to comparator arm at week 48. Conclusion TDF-containing, ANV-based ARV regimen improved lipid metabolism in virologically suppressed adult PWHs with noncompromised virologically efficacy compared to TAF-containing, EVG/c-based regimen. Disclosures Hong Qin, MD, PhD, Jiangsu Aidea Pharmaceutical Co., Ltd: Honoraria

P-589. Cholesterol Control in Virologically Suppressed People with HIV-1 Switching to Tenofovir DF-containing, Ainuovirine-Based Compared to Tenofovir Alafenamide-Containing, Boosted Elvitegravir-Based Antiretroviral Regimen: Hypercholesterolemic Subgroup Analyses of the SPRINT Trial, a Randomized, Active-Controlled Phase 3 Study

Abstract Background In the SPRINT trial, virologically suppressed people with HIV-1 (PWHs) switched to tenofovir DF (TDF) containing, ainuovirine (ANV, ACC008) based or tenofovir alafenamide (TAF) containing, boosted elvitegravir (EVG/c, comparator) based antiretroviral (ARV) regimen from efavirenz-based regimen.Figure 1.CFB in LDL-C at week 48 by baseline level.ACC008, ainuovirine/ lamivudine/ tenofovir disoproxil; CFB, change from baseline; E/C/F/TAF, elvitegravir/ cobicistat/ emtricitabine/ tenofovir alafenamide; LDL-C, low density lipoprotein cholesterol. Methods Baseline hypercholesterolemia was defined as serum LDL-C at 3.0 mmol/L or above; acceptable lipidemic control was defined as post-treatment serum LDL-C below 3.0 mmol/L, and good lipidemic control as post-treatment serum LDL-C below 2.6 mmol/L as recommended by the European AIDS Clinical Society. Changes from baseline (CFBs) in LDL-C (least square mean) at week 48 were compared using the mixed effects models for repeated measures with treatment as fixed factor and baseline LDL-C measurement as a covariate, all nested within visits. The proportions of PWHs with good/acceptable lipidemic control were analyzed using the logistic regression method with baseline serum LDL-C adjusted at week 48.Figure 2.Proportions of participants with acceptable and good LDL-C control at week 48ACC008, ainuovirine/ lamivudine/ tenofovir disoproxil; E/C/F/TAF, elvitegravir/ cobicistat/ emtricitabine/ tenofovir alafenamide; LDL-C, low density lipoprotein cholesterol. Acceptable lipidemic control, LDL-C＜3.0 mmol/L; Good lipidemic control, LDL-C＜2.6 moml/L. Results The proportions of PWHs with hypercholesterolemia were comparable between the two arms (35.2% [134/381] vs. 35.7% [136/381]) with a similar mean value of 3.49 ± 0.42 vs. 3.52 ± 0.40 mmol/L at baseline. CFB in LDL-C showed a significantly greater decline in ACC008 arm compared to that in comparator arm at week 48 (-0.40 vs. 0.06 mmol/L, estimated treatment difference [95%CI], -0.46 mmol/L [-0.59, -0.33], p&amp;lt; 0.001). The proportions of PWHs with acceptable/good lipidemic control were significantly greater in ACC008 arm than those in comparator arm (acceptable, 45.5% [61/134] vs. 19.1% [26/136], 0.264 [0.154, 0.366], p&amp;lt; 0.001; good, 18.7% [25/134] vs. 8.1% [11/136], 0.106 [0.024, 0.188], p&amp;lt; 0.001) at week 48. Conclusion Hypercholesterolemia was prevalent in virologically suppressed PWHs on efavirenz-based ARV regimen. Switch to TDF-containing, ANV-based regimen resulted in greater LDL-C decline and better lipidemic control compared to that to TAF-containing, EVG/c-based regimen. Disclosures Hong Qin, MD, PhD, Jiangsu Aidea Pharmaceutical Co., Ltd: Honoraria