Reduction In LDL-C Levels Research Articles

Relaxant Effect of Rosuvastatin in Isolated Rat Aorta with Perivascular Adipose Tissue

Objective: Rosuvastatin displays favorable pleiotropic effects on vascular system to reduce the risk of cardiovascular events besides providing an intensive reduction in LDL-C levels. The role of perivascular adipose tissue (PVAT) in modulating the vasorelaxant effect of rosuvastatin is not evaluated so far. The present study aimed to investigate the vascular relaxant effect of rosuvastatin in rat aortic rings with intact PVAT, as well as to evaluate the possible mechanisms underlying this effect in relation to nitric oxide (NO) and prostaglandin pathways. Methods: Thoracic aorta rings with intact PVAT, isolated from male Wistar rats (n=5), were mounted on an isolated organ bath system. Endothelium-dependent responses to acetylcholine (Ach,10-6-10-4M) were obtained in aortic rings precontracted submaximally with phenylephrine (Phe,10-6-3x105M). The concentration-dependent relaxant effect of rosuvastatin (10-7-10-4M) was examined in the absence and presence of NO inhibitor, L-NOARG (10-4M, 30min.) and cyclooxygenase inhibitor, indomethacin (10-5M, 30min.). Vascular relaxation capacity of aortic rings was checked by the nitrovasodilator, sodium nitroprusside (SNP,10-6 M) at the end of the experiments. Results: Rosuvastatin (10-7-10-4M) produced concentration-dependent relaxations in Phe-precontracted rat aortic rings with intact PVAT. Pretreatment with L-NOARG significantly attenuated the relaxant responses to rosuvastatin in isolated rat aortic rings with intact PVAT. However, pretreatment with indomethacin did not modify the relaxations to rosuvastatin. In the aortic rings, maximal relaxation responses to Ach and SNP were determined to be 75.87±2.68% and 102.54±2.92%, respectively. Conclusions: This study will provide a basis for investigating the interaction between PVAT and statins in vascular homeostasis.

Evolocumab for early reduction of LDL-C levels in patients with acute ischemic stroke: a randomized controlled trial

BackgroundLow-density lipoprotein cholesterol (LDL-C) has been determined as an established risk factor for acute ischemic stroke (AIS). Despite the recommendation for in-hospital initiation of high-intensity statin therapy in AIS patients, achieving the desired target LDL-C levels remains challenging. Evolocumab, a highly effective and quickly acting agent for reducing LDL-C levels, has yet to undergo extensively exploration in the acute phase of AIS. The aim was to assess the LDL-C reduction efficacy and safety of early application of evolocumab during the in-hospital phase of AIS patients.MethodsAn unblinded, single-center, prospective randomized controlled trial involving hospitalized AIS patients was conducted in the Second Affiliated Hospital of Guangxi Medical University in China. Patients were randomly assigned 1:1 to receive evolocumab 420 mg every 4 weeks or not, on top of standard of care (SOC) treatment (atorvastatin 40 mg/day and ezetimibe 10 mg/day), administered in-hospital until after 8 weeks. The primary outcome was the absolute change of LDL-C levels and the rate of achieving targeted lipid control at 8 weeks.ResultsTotally, 120 patients were recruited from January 2023 to December 2023. Mean LDL-C levels decreased from 3.15 mmol/L to 0.85 mmol/L in the evolocumab group, and from 3.17 mmol/L to 2.22 mmol/L in the control group, with the difference in mean change from baseline was −1.37 [95% confidence interval (CI) = −1.70 to −1.04, p < 0.001] at week 8. The rate of patients achieving targeted LDL-C <1.4 mmol/L was 81.67% in evolocumab group as compared with 13.33% in control group. Adverse events were similar in both groups.ConclusionOur study indicated that evolocumab added to high-intensity statin and ezetimibe therapy resulted in substantial reduction in LDL-C levels in early AIS patients and was well tolerated.Clinical trial registrationClinicalTrials.gov, identifier NCT05697185.

PCSK9 inhibitors in the research progress of atherosclerotic cardiovascular diseases

Abstract. Atherosclerosis is a major global health issue, with cardiovascular diseases leading to over 4 million deaths in China in 2019. Effective management of atherosclerosis is crucial for reducing its incidence and mortality, with LDL-C reduction being a key strategy. This study examines the role of PCSK9 in atherosclerosis and the therapeutic potential of PCSK9 inhibitors, focusing on their ability to lower LDL-C levels and prevent cardiovascular events A literature review was conducted, analyzing the mechanisms of PCSK9 in lipid metabolism and the efficacy of various PCSK9 inhibitors, including monoclonal antibodies, antisense oligonucleotides, and small interfering RNA. PCSK9 inhibitors, such as Alirocumab, evolocumab, and Inlisiran, have demonstrated effectiveness in reducing LDL-C levels. Inlisiran, in particular, offers a long-lasting effect and has shown significant potential in clinical trials. Nucleic acid-based treatments are emerging as promising options with advantages such as sustained efficacy and a broad application scope, despite the need for further research to address delivery and off-target effects.

Homozygous familial hypercholesterolemia in Spain. Data from Registry of the Spanish Atherosclerosis Society.

Subjects with HoFH, confirmed by the presence of two pathogenic variants in the genes mentioned above, included in the registry from 2013 to June 2023 with an updated review were analyzed. 71 HoFH subjects were included. 40.8% were women, aged 52 [24-62] years, 57 adults and 13 children. The median follow-up was 7 [4-13] years. Age of diagnosis was 14 [2-26] years, with 10% of ASCVD at diagnosis and 27% of current ASCVD at 40.6 (13.4) years of age. 38% were on PCSK9i, 9 patients on lomitapide, 9 on LDL apheresis and 1 patient on evinacumab. Subjects with more than 4 therapies achieved >80% reduction in LDLc. In the last visit, the median LDLc was 139.3 [89.4-204.2] mg/dL. ASCVD was strongly associated with male sex and family history of ASCVD, relative risk 5.26 (1.53-18.10) and 2.53 (1.03-6.26), p<0.05, respectively. Only 18% and 10% meet the recommended LDLc goal in primary and secondary prevention respectively. The current situation of HoFH in Spain is better than expected, with marked reductions in LDLc levels with new treatments. In this population, recommended LDLc goals are difficult to achieve despite maximum lipid-lowering therapy. ASCVD has been reduced and delayed by two decades.

Clinical impact of ≥ 50% reduction of low density lipoprotein cholesterol following lipid lowering therapy on cardiovascular outcomes in patients with acute coronary syndrome

BackgroundCurrent guidelines advocate achieving a fixed LDL-C target and ≥ 50% reduction in LDL-C levels. However, sufficient LDL-C reduction is often not achieved even in patients achieving a fixed LDL-C target. ObjectivesThis study investigated the clinical impact of insufficient LDL-C reduction following lipid lowering therapy on cardiovascular outcomes acute coronary syndrome (ACS) patients. MethodsA total of 561 consecutive ACS patients who had undergone PCI and LDL-C level measurement at index PCI and 12 months afterwards were evaluated retrospectively. we investigated a relationship between ≥ 50% LDL-C reduction and cardiovascular events including the composite of cardiac death, myocardial infarction, target vessel revascularization and stent thrombosis. ResultsOf the patients, 145 (25.8%) achieved ≥50% LDL-C reduction within 12 months. There were no significant differences in cardiovascular events between patients achieving the LDL-C target of 55 mg/dL and those not achieving it (23.6% vs. 19.3%, p=0.77), whereas the incidence of cardiovascular events was higher in the <50% LDL-C reduction group than the ≥50% LDL-C reduction group (26.0% vs. 12.4%, p=0.009). Even in patients with LDL-C <55 mg/d/L, cardiovascular events were more frequently in the < 50% LDL-C reduction group than the ≥ 50% LDL-C reduction group (28.8% vs. 13.2%, p=0.04). Cox proportional hazard models revealed that <50% LDL-C reduction was an independent predictor of cardiovascular outcomes (HR: 2.03, 95%CI: 1.23-3.36). ConclusionThe current study underscores the significance of achieving ≥50% LDL-C reduction in addition to a target of 55 mg/dL in preventing additional cardiovascular events in ACS patients.

Apolipoprotein B and the regression of lipidic plaque in statin-treated type 2 DM patients with coronary artery disease: the pre-specified sub-analysis from the OPTIMAL randomized controlled trial

Abstract Introduction Type 2 diabetic mellitus (T2DM) patients more likely present vulnerable form of diseases. Despite lowering LDL-C level with a statin, their on-going cardiovascular risks still exist, which indicates the need to identify additional therapeutic targets in T2DM patients. Apolipoprotein B (ApoB) is a proatherogenic lipoprotein. Atherosclerosis is promoted via the influx of ApoB into vessel wall. The current ESC guideline recommends ApoB levels as a secondary therapeutic target under control of LDL-C levels with a statin. However, it remains to be fully determined about the association of ApoB levels with plaque vulnerability in statin-treated T2DM patients. Purpose To elucidate whether serial change in ApoB levels affects the degree of atheroma progression and lipidic plaque materials on NIRS/IVUS imaging. Methods The OPTIMAL randomized controlled trial compared the efficacy of continuous glucose monitoring guided versus HbA1c-guided glycemic control on coronary atherosclerosis in 94 statin-treated T2DM patients with CAD. Serial NIRS/IVUS imaging was conducted at baseline and week 48 to monitor non-culprit lesions. The current study included 71 patients with serial ApoB levels at both baseline and week 48. Clinical demographics and NIRS/IVUS-derived measures were compared in those with and without any reduction of ApoB levels. Results All of study subjects received a statin, and over 60% of them were treated with high-intensity statin. Under these lipid-lowering therapies, 60.6% of study subjects exhibited any reduction of ApoB levels, accompanied by a greater reduction of LDL-C levels. Patients with any reduction of ApoB levels were more likely to be older (67.4±10.0 vs. 71.7±7.3 years, p=0.03), whereas there were no significant differences in the proportion of established risk factors between the two groups. Baseline NIRS/IVUS-derived PAV (47.1±12.9 vs. 44.8±15.4%, p=0.54) and maxLCBI4mm [290.5 (205.5, 338.7) vs. 270.0 (97.0, 416.0), p=0.76] were comparable in patients with and without any reduction of ApoB. On serial NIRS/IVUS imaging analysis, the progression rate of atheroma volume did not differ between the two groups (-0.4±0.2 vs. -0.3±0.2mm3, p=0.77). However, patients with any reduction of ApoB more frequently presented a regression of maxLCBI4mm (27.6±0.1 vs. 61.5±0.1%, p=0.01). Multivariate analysis adjusting age, female and high-intensity statin use demonstrated change in ApoB as an independent factor associated with regression of maxLCBI4mm (OR=0.94, 95%CI=0.91-0.98, p=0.002). Conclusion In statin-treated T2DM patients with CAD, any reduction of ApoB levels was associated with a greater regression of NIRS-derived maxLCBI4mm. The current findings indicate a potential anti-atherosclerotic effect of lowering ApoB levels, which induces delipidation of diabetic coronary atheroma. ApoB may be an important therapeutic target to modulate lipidic plaque materials in T2DM patients receiving a statin.

Genetic association of lipids and lipid lowering drug target genes with sarcoidosis

To determine the potential causal association between serum lipid levels and sarcoidosis, and to investigate the potential impact of lipid lowering agents on sarcoidosis. Two-sample Mendelian randomization (TSMR) was used to investigate the association between lipid levels (including LDL-c, HDL-c, TG, and TC) and sarcoidosis risk. In addition, we used Mendelian drug target randomization (DMR) to analyze the relationship between drug targets for lowering LDL-c levels (HMGCR, PCSK9, and NPC1L1) and drug targets for lowering TG levels (LPL and APOC3) and the risk of sarcoidosis. According to the TSMR analysis, a positive correlation was observed between the serum LDL-c concentration and sarcoidosis incidence (n = 153 SNPs, OR = 1.232, 95% CI = 1.018–1.491; p = 0.031). Similarly, serum TG concentration was found to be positively associated with sarcoidosis (n = 52 SNPs, OR = 1.287, 95% CI = 1.024–1.617; p = 0.03). The DMR results demonstrated a positive correlation between PCSK9-mediated serum LDL-c levels and sarcoidosis (n = 35 SNPs, OR = 1.681, 95% CI = 1.220–2.315; p = 0.001). Similarly, serum TG levels mediated by LPL were positively associated with sarcoidosis (n = 28 SNPs, OR = 1.569, 95% CI = 1.223–2.012; p = 0.0003). This study suggested that elevated serum TG and LDL-c levels may increase the risk of sarcoidosis. PCSK9-mediated reduction of LDL-C levels (simulating the effects of PCSK9 inhibitors) and LPL-mediated reduction of TG levels (simulating the effects of LPL-related lipid lowering drugs) can decrease the risk of developing sarcoidosis.

Evaluating changes in body composition, bone mass, and metabolic profile in an animal model undergoing transfeminine hormone therapy and physical exercise

Background & AimsGender-affirming hormone therapy (GAHT) is essential for transgender individuals seeking body modifications. For transfeminine people assigned male at birth, GAHT typically involves a combination of antiandrogens and estrogens. Despite its importance, the scientific literature presents inconsistencies regarding the effects of these hormones on nutritional status, body composition, and biochemical markers. This study aims to evaluate the impact of estradiol enanthate and dihydroxyprogesterone acetophenide (E2EN/DHPA) hormonal treatment, in conjunction with resistive physical exercise, on body composition and metabolic profiles. MethodsTwenty-eight male rats were divided into three groups: MO (control group, n=8), receiving sesame oil vehicle; MH (n=11), receiving E2EN/DHPA; and MEH (n=9), receiving E2EN/DHPA along with physical exercise. The hormonal treatment was administered every ten days for two months, while the exercise regimen involved stair climbing with progressively increasing weights, performed five times weekly for seven weeks. Evaluated parameters included body mass index (BMI), body composition (fat and lean mass), bone mineral density (BMD), and lipid profile (triglycerides, HDL-C, LDL-C). ResultsThe rats that received E2EN/DHPA showed significant changes in body composition and BMI, regardless of exercise. The MH group had increased body fat, while both the MH and MEH groups had decreased bone area and mineral content. However, BMD remained the same across all groups. Elevated triglyceride levels were observed, and the MEH group also had reduced LDL-C levels. HDL-C levels did not show significant variation. ConclusionThe study's findings show similarities to changes seen in transfeminine individuals undergoing GAHT with estrogen and antiandrogens. These changes include decreased muscle mass, increased body fat, preserved bone mineral density, and elevated triglycerides. The study also found that resistance exercise positively impacted lipid profiles, particularly in reducing LDL-C. These results highlight the need for further research and comparative trials on hormone therapy regimens.

PCSK9 Monoclonal Antibodies Have Come a Long Way.

This review examines the pivotal role of monoclonal antibodies against PCSK9 in lipid-lowering therapy, emphasizing their biological and clinical impact. Randomized controlled trials have validated that PCSK9 monoclonal antibodies (Mabs) effectively reduce LDL-c levels by approximately 50%, even when added to maximal statin therapy. They moreover produce a notable 15-20% relative decrease in major cardiovascular events, with a greater reduction among high-risk patients and no evidence for serious adverse effects, assuaging previous concerns. This review highlights the benefits of PCSK9 Mabs in high cardiovascular risk patients. Despite their efficacy and safety, these therapies are hindered by limited access, and require broader integration into clinical practice to optimize therapeutic outcomes.

In ASCVD, an inclisiran-first strategy reduced LDL-C levels and statin discontinuation at 330 d.

Koren MJ, Rodriguez F, East C, et al. An "inclisiran first" strategy vs usual care in patients with atherosclerotic cardiovascular disease. J Am Coll Cardiol. 2024;83:1939-1952. 38593947.

Physician preferences for treatment of low-density lipoprotein cholesterol among patients with atherosclerotic cardiovascular disease (ASCVD)–A discrete choice experiment

ObjectiveApproximately 80 % of patients with atherosclerotic cardiovascular disease (ASCVD) do not achieve the guideline-based target for low-density lipoprotein (LDL-C) levels in current clinical practice, particularly the 95 % of ASCVD patients receiving oral statin monotherapy. The objective was to determine physician prescribing preferences for LDL-C lowering therapies beyond statins for patients with ASCVD. MethodsA discrete choice experiment (DCE) survey was administered to cardiologists and primary care physicians in the United States, presenting a series of treatment choices systematically varied across 8 treatment attributes: % LDL-C reduction, myalgias, other side effects, route and frequency of administration, time to prior authorization, patient monthly out-of-pocket cost (mOOP), and adherence. Data were analyzed using logistic regression to estimate preference weights for each attribute. ResultsA total of 200 cardiologists and 50 primary care physicians (PCPs) completed the survey. Both exhibited similar prescribing preferences, highly valuing efficacy in reducing LDL-C levels and minimization of patients OOP cost. Each additional 10 % reduction in LDL-C was associated with a 69 % relative increase in physician preference. By contrast, a 10 % relative decrease in preference was observed for each $10 additional monthly mOOP. Compared to PCPs, cardiologists tended to place more emphasis on LDL-C reduction, being more willing to accept higher mOOP or side effects. Although oral therapies were preferred, injectable therapies, like the PCSK9 siRNA-like drug, administered less frequently that allowed for greater LDL-C reduction were seen as having considerable utility, especially among patients with a history of medication nonadherence. ConclusionThese results document considerable preference similarities among cardiologist and PCP prescribers of LDL-C lowering therapies for ASCVD. Broad availability of several therapies with varying administration frequencies and product profiles are likely of great value to prescribing physicians aiming to achieve target LDL-C concentrations. Considering all aspects of treatment, most participants preferred a PCSK9 siRNA-like drug.

Comparing the outcomes of statins and PCSK9 inhibitors in LDL management in patients with heterozygous familial hypercholesterolemia (HeFH) and diabetes

Background: Aggressive lipid-lowering methods are required for cardiovascular risk management when heterozygous familial hypercholesterolemia (HeFH) is combined with diabetes mellitus. Though statins have been the mainstay of treatment, a viable substitute is the development of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors. Comparative information about their safety and effectiveness in this population is still lacking, though. Aim: This study aims to systematically compare the outcomes of statins and PCSK9 inhibitors in LDL management for patients with HeFH and diabetes. Methodology: A retrospective cohort study was conducted at Hayabad Medical Complex, encompassing 62 individuals with HeFH and diabetes mellitus. Data on demographic characteristics, treatment regimens, LDL-C reduction efficacy, cardiovascular outcomes, safety profile, and patient adherence were analyzed. Results: PCSK9 inhibitors demonstrated superior efficacy in reducing LDL-C levels compared to statins, achieving a mean reduction of 70.9% versus 55.8%, respectively. Moreover, individuals receiving PCSK9 inhibitors experienced a significantly lower incidence of cardiovascular events (2 events vs. 6 events) and reported higher levels of patient satisfaction. Both therapies exhibited a favorable safety profile. Conclusion: Our findings underscore the potential of PCSK9 inhibitors as a preferred therapeutic option over statins in patients with HeFH and diabetes, offering superior LDL-C reduction efficacy, cardiovascular risk reduction, and patient satisfaction. These results highlight the importance of personalized treatment approaches in optimizing cardiovascular risk management. Keywords: heterozygous Familial Hypercholesterolemia, diabetes mellitus, statins, PCSK9 inhibitors, LDL-C reduction, cardiovascular outcomes, patient satisfaction

Efficacy of AI-Guided (GenAISTM) Dietary Supplement Prescriptions versus Traditional Methods for Lowering LDL Cholesterol: A Randomized Parallel-Group Pilot Study.

Emerging evidence suggests that personalized dietary supplement regimens can significantly influence lipid metabolism and cardiovascular risk. The efficacy of AI-guided dietary supplement prescriptions, compared with standard physician-guided prescriptions, remains underexplored. In a randomized, parallel-group pilot study, 70 patients aged 40-75 years with LDL-C levels between 70 and 190 mg/dL were enrolled. Participants were randomized to receive either AI-guided dietary supplement prescriptions or standard physician-guided prescriptions for 90 days. The primary endpoint was the percent change in LDL-C levels. Secondary endpoints included changes in total cholesterol, HDL-C, triglycerides, and hsCRP. Supplement adherence and side effects were monitored. Sixty-seven participants completed the study. The AI-guided group experienced a 25.3% reduction in LDL-C levels (95% CI: -28.7% to -21.9%), significantly greater than the 15.2% reduction in the physician-guided group (95% CI: -18.5% to -11.9%; p < 0.01). Total cholesterol decreased by 15.4% (95% CI: -19.1% to -11.7%) in the AI-guided group compared with 8.1% (95% CI: -11.5% to -4.7%) in the physician-guided group (p < 0.05). Triglycerides were reduced by 22.1% (95% CI: -27.2% to -17.0%) in the AI-guided group versus 12.3% (95% CI: -16.7% to -7.9%) in the physician-guided group (p < 0.01). HDL-C and hsCRP changes were not significantly different between groups. The AI-guided group received a broader variety of supplements, including plant sterols, omega-3 fatty acids, red yeast rice, coenzyme Q10, niacin, and fiber supplements. Side effects were minimal and comparable between groups. AI-guided dietary supplement prescriptions significantly reduce LDL-C and triglycerides more effectively than standard physician-guided prescriptions, highlighting the potential for AI-driven personalization in managing hypercholesterolemia.

The Influence of Balneotherapy Using Salty Sulfide-Hydrogen Sulfide Water on Selected Markers of the Cardiovascular System: A Prospective Study.

Background: The sulfide-hydrogen sulfide brine balneotherapy (HSBB), including a combination of dissolved hydrogen sulfide (H2S) gas, inorganic sulfur ions (S2-), and hydrosulfide ions (HS-), is one of the most important and most effective forms of spa treatment in patients with osteoarticular disorders (OADs). Some cardiovascular diseases (CVDs) are often considered to be contraindications to HSBB since the presence of thiol groups may lead to an increased quantity of reactive oxygen species (ROS), which damage the vascular endothelium, and endothelial dysfunction is considered to be the main cause of atherosclerosis. However, there are a number of literature reports suggesting this theory to be false. H2S is a member of the endogenous gaseous transmitter family and, since it is a relatively recent addition, it has the least well-known biological properties. H2S-NO interactions play an important role in oxidative stress in CVDs. The general objective of this study was to assess the cardiovascular safety of HSBB and analyze the effect of HSBB on selected cardiovascular risk markers. Methods: A total of 100 patients at the age of 76.3 (±7.5) years from the Włókniarz Sanatorium in Busko-Zdrój were initially included in the study. The following parameters were assessed: age, sex, height, body weight, body surface area (BSA), body mass index (BMI), systolic (SBP) and diastolic blood pressure (DBP), heart rate, the diagnosis of OAD that was the indication for balneotherapy, creatinine (CREAT), glomerular filtration rate (GFR), lipid panel, C-reactive protein (CRP), uric acid (UA), and fibrinogen (FIBR) and cardiovascular markers: (cardiac troponin T (cTnT), N-terminal pro-B-type natriuretic peptide (NT-proBNP). Results: A significant decrease in DBP and a trend towards SBP reduction were observed over the course of the study. A significant decrease was observed in CRP levels decreasing from 2.7 (±3.6) mg/L to 2.06 (±1.91) mg/L, whereas FIBR rose significantly from 2.95 (±0.59) g/L to 3.23 (±1.23) g/L. LDL-C levels decreased slightly, statistically significant, from 129.36 (±40.67) mg/dL to 123.74 (±36.14) mg/dL. HSBB did not affect the levels of evaluated cardiovascular biomarkers, namely NT-proBNP (137.41 (±176.52) pg/mL vs. 142.89 (±182.82) pg/mL; p = 0.477) and cTnT (9.64 (±4.13) vs. 9.65 (±3.91) ng/L; p = 0.948). A multiple regression analysis of pre-balneotherapy and post-balneotherapy values showed cTnT levels to be independently correlated only with CREAT levels and GFR values. None of the assessed parameters independently correlated with the NT-proBNP level. Conclusions: HSBB resulted in a statistically significant improvement in a subclinical pro-inflammatory state. HSBB has a beneficial effect in modifying key cardiovascular risk factors by reducing LDL-C levels and DBP values. HSBB has a neutral effect on cardiovascular ischemia/injury. Despite slightly elevated baseline levels of the biochemical marker of HF (NT-proBNP), HSBB causes no further increase in this marker. The use of HSBB in patients with OAD has either a neutral effect or a potentially beneficial effect on the cardiovascular system, which may constitute grounds for further studies to verify the current cardiovascular contraindications for this form of therapy.

Effect of anti-PCSK9 drugs on the association of PCSK9 to LDL

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein that is known to interact with the LDL receptor, thereby promoting its degradation and blunting the uptake of LDL from the circulation. In this context, anti-PCSK9 monoclonal antibodies (mAbs) and siRNAs have been approved for the treatment of hypercholesterolaemia. Previous studies have shown that a significant proportion of circulating PCSK9 is associated with LDL. The aim of our research is to investigate the effect of mAbs and siRNA on the association of PCSK9 protein with LDL. In this study, 10 statin-intolerant patients received treatment with anti-PCSK9 mAbs or siRNA, in addition to therapy with a low-dose statin and ezetimibe. Their plasma samples were analysed before and after 1, 3, and 6/9 months of treatment. The results showed that both the monoclonal antibodies and inclisiran reduced LDL-C levels by 50% to 60%. LDL-C levels decreased from 92±28 mg/dL to 44±26 mg/dL after siRNA treatment and reached 97±9, 27±10, 32±14, and 23±10 mg/dL after mAbs therapy. The circulating PCSK9 level decreased by 70% after the first siRNA injection, while it increased 10-fold after mAbs therapy. Regardless of treatment, the percentage of PCSK9 bound to LDL did not vary from baseline and remained constant during the treatment period. Whether this is of physiological relevance remains to be addressed.

Classical and Novel Lipid-Lowering Therapies for Diabetic Patients with Established Coronary Artery Disease or High Risk of Coronary Artery Disease-A Narrative Clinical Review.

Diabetic atherosclerosis is a complex process that is characterized by diffuse and unstable lesions increasing 2-4-fold the risk of adverse cardiovascular (CV) events. Diabetic dyslipidemia has a predominant role in coronary artery disease (CAD) and has been the target of classical and emerging pharmaceutical agents with established or promising CV benefits. The aim of the present narrative review was to summarize the effects of classical and novel lipid-lowering pharmaceutical agents on lipid profile and CV outcomes in diabetic patients with established CAD or high risk of CAD. Statins remain the first-line treatment for all diabetic patients since they considerably ameliorate lipid parameters and non-lipid CV risk factors, leading to reduced CV morbidity and mortality. Complementary to statins, ezetimibe exerts lipid-lowering properties with modest but significant reductions in major adverse cardiovascular events (MACEs) and CV mortality. PCSK9 inhibitors considerably reduce LDL-C levels and lower MACEs in diabetic patients. On the other hand, fibrates may confer a very modest decline in MACE incidence, while the CV impact of omega-3 fatty acids is promising but remains questionable. Bempedoic acid and inclisiran have a potential therapeutic role in the management of diabetic dyslipidemia, but this is still not adequately documented. Given the heightened CV risk among individuals with diabetes, more decisive results would be of great importance in the utility of all these drugs.

RNA Interference-based Therapies for the Reduction of Cardiovascular Risk.

Globally, there remains an unwavering increase in the incidence of cvd - from 271 million in 1990 to 523 million in 2019. Among the several modifiable and non-modifiable risk factors of heart disease, dyslipidemia is an important and prevalent risk factor mediated by both genetics and lifestyle factors. Hence, lowering lipid levels, specifically, ldl-c levels (low-density lipoprotein cholesterol), is a key strategy in decreasing the risk of cardiovascular disease. A reduction of 20 mg/dl in ldl-c levels has been found to prevent 2-3 cases of coronary artery disease (cad) for every 1000 individuals. Studies have also found reductions in ldl-c levels to be associated with a mortality benefit. However, ldl-c levels reduction may not eliminate the risk of significant cardiovascular events.

Effects of roxadustat on thyroid hormone levels and blood lipid metabolism in patients undergoing hemodialysis: a retrospective study.

Background: Roxadustat is commonly used to treat renal anemia. However, the potential effects of roxadustat on metabolism and organs other than the kidneys have recently attracted increased attention. Objective: This study aimed to examine the regulatory effects of roxadustat on thyroid hormones and blood lipid metabolism in patients with end-stage kidney disease (ESKD) undergoing hemodialysis. Methods: Eighty ESKD patients on hemodialysis and taking roxadustat were enrolled. Hemoglobin, thyroid hormones (TSH, FT3, FT4), and blood lipid profiles (TC, LDL-C, TG, HDL-C) were assessed before and after treatment. Changes in these parameters were compared, and relevant causative factors were analyzed. Results: Roxadustat significantly increased Hb, lowered TSH, FT4, TC, and LDL-C levels (all P<0.001). Patients were categorized into three groups based on post-treatment TSH inhibition percentage: Q1(≥70%), Q2(30%-70%), Q3(≤30%). Pre-treatment TSH decreased with reduced TSH inhibition (P<0.05). Post-treatment, TC, LDL-C, TSH, FT3, and FT4 increased with reduced TSH inhibition (all P<0.05).TC and LDL-C significantly decreased post-treatment in Q1 and Q2 (P<0.05). Correlation analysis showed a positive correlation between ΔTSH and pre-treatment TSH levels (r=0.732, P<0.001). The proportion of patients with ≥70% TSH inhibition increased with higher pre-treatment TSH levels (P for trend <0.05). ΔLDL-C and ΔTSH were positively correlated (r=0.278, P<0.05), with ΔTSH identified as an influencing factor in multiple linear regression (β=0.133, 95% CI [0.042, 0.223], P<0.05). Conclusion: Roxadustat effectively improves anemia in ESKD patients while inhibiting TSH and FT4 secretion and reducing TC and LDL-C levels. Decreases in TSH levels correlate with baseline TSH levels, and lowered blood lipid levels are associated with decreased TSH levels.

First clinical experiences with inclisiran in real world setting

Abstract Background Inclisiran is the first-in-class small interfering RNA (siRNA) PCSK9 inhibitor. In clinical trials, inclisiran showed effective and sustained LDL-C reduction of approximately 50%. However, data about the efficacy and safety in clinical setting are scarce. We aim to investigate the efficacy and safety in clinical practice. Methods Registry of all consecutive patients who started with inclisiran at a lipid clinic of a university hospital. Patients were eligible if they fulfilled reimbursement criteria in the Netherlands; very high risk patients with FH and/or ASCVD and not on target LDL-C levels despite maximally tolerated oral lipid lowering medication. Patients were included if they started with inclisiran as first line (group 1) or switched from PCSK9 monoclonal antibody (mAbs) to inclisiran (group 2). LDL-C levels were measured 3 months after administration of inclisiran initiation. Median change of LDL-C levels was calculated on an individual and group level. Results We analysed 50 patients (26 women, 33 patients with FH), median [25th percentile; 75th percentile] age of 64 [52; 68] years. Patients who newly started Inclisiran (group 1) showed a LDL-C decrease of 39 [-50; -33]%. Patients who used statins as co-medication had a higher median LDL-C decrease compared to those without statin use (45% vs. 38%). However, patients who switched from mAbs to Inclisiran (group 2) had an increase in LDL-C of +41 [+3; +97]% (figure 1). Almost half of the patients (42%) experienced a mild burning sensation. During follow-up 6 patients (12%) reported side effects as abdominal complains, dizziness, fatigue and flu-like symptoms in the first week after administration. One patient stopped treatment because of perceived side effects like fatigue and myalgia. Conclusions Our initial experience of inclisiran in a clinical setting showed slightly less reduction in LDL-C levels compared to clinical trials but a similar safety profile. Moreover, patients who switched from PCSK9 mAbs to inclisiran showed an increase in LDL-C levels implying that inclisiran is less potent in LDL-C reduction compared to PCSk9 mAbs.Figure 1Waterfallplot LDL-C change

Abstract 18261: Efficacy and Safety of Bempedoic Acid for Prevention of Cardiovascular Events and Diabetes Mellitus: A Systematic Review and Meta-Analysis of Randomized Control Trials

Background: Bempedoic acid (BA) is considered an alternative therapy for hyperlipidemia (HLD) in statin-intolerant patients. Given the positive results from the CLEAR-OUTCOMES trial, we performed a meta-analysis pooling recently conducted randomized control trials (RCTs) to provide a comprehensive clinical evaluation of the safety and efficacy of BA. Hypothesis: Bempedoic acid therapy in HLD patients with statin intolerance may be associated with a significant reduction in LDL-C levels, and CV events. Methods: All RCTs reporting CV outcomes and/or % change in LDL-C from baseline till completion of follow-up duration in HLD patients with statin-intolerance were included in MEDLINE, Google Scholar, and Scopus databases (Inception to April 2023). The outcome measures were summary random effects risk ratio (RR) and mean differences (MD) with 95% confidence intervals. Results: Twelve RCTs were included with 18 510 patients (10,033 BA vs. 8,477 placebo). BA therapy resulted in greater significant % reduction in LDL-C levels post-treatment (mean difference from baseline: 21.73% [-26.94, -16.51], p&lt;0.00001) with no significant impact of the male sex, age, and follow-up duration on LDL-C upon meta-regression analysis. The risk of MACE (RR, 0.86 [0.79, 0.93], p &lt; 0.0004), coronary artery revascularization (RR, 0.81 [0.72, 0.91], p = 0.0005), and myocardial infarction (RR, 0.71 [0.51, 0.99], p= 0.04) were significantly reduced with BA ( Figure 1) . However, no significant reduction in cardiac death (RR, 1.05 [0.89, 1.24], p = 0.56) was observed. A total of 1,019 new-onset DM events (521/6027 with BA; 498/4946 with placebo) were reported, and demonstrated a non-significant lower risk of new-onset or worsening DM (RR 0.83; 95% CI [0.62, 1.13]; P = 0.24) with BA vs. placebo. Conclusion: BA was observed to be safe, efficacious, associated with improved cardiovascular outcomes, and with no effect on new-onset or worsening DM among HLD patients with statin intolerance.