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CNS Neuroscience & Therapeutics Apr 2024The relationship between Protein Convertase Subtilisin Kexin Type 9 inhibitor (PCSK9i) and psychiatric adverse events (AEs) remains unclear due to the limitations of...
BACKGROUND
The relationship between Protein Convertase Subtilisin Kexin Type 9 inhibitor (PCSK9i) and psychiatric adverse events (AEs) remains unclear due to the limitations of clinical trials. In this study, PCSK9i-related psychiatric AEs were realistically observed and systematically summarized in the real world by data mining the FDA AE Reporting System (FAERS).
METHOD
Total AEs between the third quarter of 2015 and the first quarter of 2023 were obtained from FAERS. Psychiatric AEs were identified using disproportionality analysis and clinical prioritization of signals using a rating scale, followed by univariate logistic regression to explore factors influencing psychiatric AEs.
RESULTS
Psychiatric AEs accounted for 6.7% of the total number of PCSK9i reports. Eighteen psychiatric AEs were defined as PCSK9i-related psychiatric adverse events (ppAEs) (lower 95% CI of both ROR >1 and IC > 0). The median age of ppAE reports was 68 years, and female patients accounted for 22.67% of reports, including 41.40% of reports with a serious outcome. Eleven (61.11%) and seven (38.89%) ppAEs were classified as weak and moderate clinical priority, respectively. The median time to onset of ppAEs was 149 and 196 days after treatment with evolocumab and alirocumab, respectively. Patients weighing ≥80 kg were 1.59 times more likely to experience ppAEs.
CONCLUSION
The results of this study facilitate the prioritization of psychiatric AE signals by healthcare professionals with the goal of mitigating the risk of PCSK9i-related psychiatric AEs. However, as an exploratory study, our findings need to be confirmed in large-scale prospective studies.
Topics: Aged; Female; Humans; Databases, Factual; Mental Disorders; PCSK9 Inhibitors; Pharmacovigilance; Proprotein Convertase 9; Prospective Studies
PubMed: 37950531
DOI: 10.1111/cns.14522 -
Atherosclerosis Nov 2023Sex-specific differences in the response to lipid-lowering therapies have been reported. Here, we assessed the effect of bempedoic acid in women and men using pooled,...
BACKGROUND AND AIMS
Sex-specific differences in the response to lipid-lowering therapies have been reported. Here, we assessed the effect of bempedoic acid in women and men using pooled, patient-level data from four phase 3 clinical trials of bempedoic acid.
METHODS
Patients were grouped into two pools: 1) atherosclerotic cardiovascular disease (ASCVD) and/or heterozygous familial hypercholesterolemia (HeFH) "on statins" and 2) "low-dose or no statin". Percent changes from baseline to at least week 12 in low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), apolipoprotein B (Apo B), and high-sensitivity C-reactive protein (hsCRP), as well as safety, were analyzed by statin pool and sex.
RESULTS
Overall, 3623 patients were included (bempedoic acid, 2425; placebo, 1198). Significant reductions in lipid parameters and hsCRP were observed with bempedoic acid vs. placebo in both sexes in the ASCVD and/or HeFH on statins (n = 3009) and the low-dose or no statin (n = 614) pools (p ≤ 0.002). Compared with men, women had significantly greater placebo-corrected reductions in LDL-C (-21.2% vs. -17.4%; p = 0.044), non-HDL-C (-17.3% vs. -12.1%; p = 0.003), TC (-13.8% vs. -10.5%; p = 0.012), and Apo B (-16.0% vs. -11.3%; p = 0.004) in the ASCVD and/or HeFH on statins pool. Women had similar reductions to men in lipid parameters in the low-dose or no statin pool and hsCRP in both pools. The safety of bempedoic acid was comparable between sexes.
CONCLUSIONS
In this pooled analysis, women experienced significant improvements in levels of LDL-C and other lipid parameters with bempedoic acid.
Topics: Male; Humans; Female; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Cholesterol, LDL; C-Reactive Protein; Hypercholesterolemia; Fatty Acids; Dicarboxylic Acids; Cholesterol; Atherosclerosis; Apolipoproteins B; Anticholesteremic Agents; Treatment Outcome
PubMed: 37648637
DOI: 10.1016/j.atherosclerosis.2023.117192 -
Translational Psychiatry Jul 2023Statins are commonly prescribed medications widely investigated for their potential actions on the brain and mental health. Pre-clinical and clinical evidence suggests... (Review)
Review
Statins are commonly prescribed medications widely investigated for their potential actions on the brain and mental health. Pre-clinical and clinical evidence suggests that statins may play a role in the treatment of depressive disorders, but only the latter has been systematically assessed. Thus, the physiopathological mechanisms underlying statins' putative antidepressant or depressogenic effects have not been established. This review aims to gather available evidence from mechanistic studies to strengthen the pharmacological basis for repurposing statins in depression. We used a broad, well-validated search strategy over three major databases (Pubmed/MEDLINE, Embase, PsychINFO) to retrieve any mechanistic study investigating statins' effects on depression. The systematic search yielded 8068 records, which were narrowed down to 77 relevant papers. The selected studies (some dealing with more than one bodily system) described several neuropsychopharmacological (44 studies), endocrine-metabolic (17 studies), cardiovascular (6 studies) and immunological (15 studies) mechanisms potentially contributing to the effects of statins on mood. Numerous articles highlighted the beneficial effect of statins on depression, particularly through positive actions on serotonergic neurotransmission, neurogenesis and neuroplasticity, hypothalamic-pituitary axis regulation and modulation of inflammation. The role of other mechanisms, especially the association between statins, lipid metabolism and worsening of depressive symptoms, appears more controversial. Overall, most mechanistic evidence supports an antidepressant activity for statins, likely mediated by a variety of intertwined processes involving several bodily systems. Further research in this area can benefit from measuring relevant biomarkers to inform the selection of patients most likely to respond to statins' antidepressant effects while also improving our understanding of the physiopathological basis of depression.
Topics: Humans; Depression; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Affect; Brain; Databases, Factual
PubMed: 37438361
DOI: 10.1038/s41398-023-02533-z -
Frontiers in Public Health 2023This review delves into the intersection of two prevalent conditions, hyperlipidemia and rotator cuff injuries, both of which bear substantial healthcare burdens. Our... (Review)
Review
This review delves into the intersection of two prevalent conditions, hyperlipidemia and rotator cuff injuries, both of which bear substantial healthcare burdens. Our investigation begins with an exploration of rotator cuff injuries, common musculoskeletal disorders that severely impair shoulder functionality and quality of life. These injuries are notably pervasive among sports enthusiasts and the older adult, with an incidence rate estimated at 5-10% in the general population. Despite their widespread occurrence and the diverse, multifactorial etiological factors, effective treatment strategies remain elusive. We then examine hyperlipidemia, a metabolic disorder affecting approximately 40% of the global adult population. Characterized by elevated levels of cholesterol and triglycerides, hyperlipidemia can precipitate severe cardiovascular complications and presents a significant socioeconomic burden. Although current management strategies encompass lifestyle modifications and pharmacological interventions, the condition remains a formidable health challenge. Central to this review is the exploration of a potential association between hyperlipidemia and rotator cuff injuries. We aim to synthesize the current understanding of hyperlipidemia's role in the pathophysiology of rotator cuff injuries, thereby offering fresh insights into their common etiological underpinnings, potential therapeutic targets, and drugs, such as Statins. The influence of other lipid-lowering therapeutics on tendon health is also considered, and further research into the molecular pathways and potential therapeutic benefits of these drugs is required. This pursuit aligns with broader efforts to enhance patient outcomes, minimize healthcare burdens, and contribute to the global understanding of these prevalent conditions.
Topics: Humans; Aged; Rotator Cuff Injuries; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Rotator Cuff; Quality of Life
PubMed: 37965515
DOI: 10.3389/fpubh.2023.1279118 -
Cell Death & Disease Jul 2023Cell-to-cell propagation of protein aggregates has been implicated in the progression of neurodegenerative diseases. However, the underlying mechanism and modulators of...
Cell-to-cell propagation of protein aggregates has been implicated in the progression of neurodegenerative diseases. However, the underlying mechanism and modulators of this process are not fully understood. Here, we screened a small-molecule library in a search for agents that suppress the propagation of α-synuclein and mutant huntingtin (mHtt). These screens yielded several molecules, some of which were effective against both α-synuclein and mHtt. Among these molecules, we focused on simvastatin and pravastatin. Simvastatin administration in a transgenic model of synucleinopathy effectively ameliorated behavioral deficits and α-synuclein accumulation, whereas pravastatin had no effect. Because only simvastatin enters the brain effectively, these results suggest that inhibition of brain cholesterol synthesis is important in simvastatin effects. In cultured cells, accumulation of intracellular cholesterol, induced by genetic ablation of the NPC1 gene or by pharmacological treatment with U18666A, increased α-synuclein aggregation and secretion. In contrast, lowering cholesterol using methyl-β-cyclodextrin or statins reversed α-synuclein aggregation and secretion in NPC1-knockout cells. Consistent with these observations, feeding a high-fat diet aggravated α-synuclein pathology and behavioral deficits in the preformed fibril-injected mouse model, an effect that was also reversed by simvastatin administration. These results suggest that statins suppress propagation of protein aggregates by lowering cholesterol in the brain.
Topics: Animals; Mice; alpha-Synuclein; Cholesterol; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pravastatin; Protein Aggregates; Simvastatin
PubMed: 37500624
DOI: 10.1038/s41419-023-05977-9 -
Diabetologia Jun 2024Dyslipidaemias are major cardiovascular risk factors, especially in people with diabetes. In this area, next-generation therapies targeting circulating lipoparticle... (Review)
Review
Dyslipidaemias are major cardiovascular risk factors, especially in people with diabetes. In this area, next-generation therapies targeting circulating lipoparticle metabolism (LDL, VLDL, chylomicrons, HDL) have recently been approved by the European and US medical agencies, including anti- proprotein convertase subtilisin/kexin 9 (PCSK9) antibodies; an siRNA targeting PCSK9; bempedoic acid, which targets ATP citrate lyase; an antisense oligonucleotide targeting apolipoprotein C-III; an anti-angiopoietin-like 3 antibody; and a purified omega-3 fatty acid, icosapent ethyl. Other therapies are in different phases of development. There are several important considerations concerning the link between these new lipid-lowering therapies and diabetes. First, since concerns were first raised in 2008 about an increased risk of new-onset diabetes mellitus (NODM) with intensive statin treatment, each new lipid-lowering therapy is being evaluated for its associated risk of NODM, particularly in individuals with prediabetes (impaired fasting glucose and/or impaired glucose tolerance). Second, people with diabetes represent a large proportion of those at high or very high cardiovascular risk in whom these lipid-lowering drugs are currently, or will be, prescribed. Thus, the efficacy of these drugs in subgroups with diabetes should also be closely considered, as well as any potential effects on glycaemic control. In this review, we describe the efficacy of next-generation therapies targeting lipoprotein metabolism in subgroups of people with diabetes and their effects on glycaemic control in individuals with diabetes and prediabetes and in normoglycaemic individuals.
Topics: Humans; Hyperlipidemias; Hypolipidemic Agents; Diabetes Mellitus, Type 2; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Diabetes Mellitus
PubMed: 38376536
DOI: 10.1007/s00125-024-06100-z -
Cell Death & Disease Aug 2023Statins are the most prescribed lipid-lowering agents worldwide. Their use is generally safe, although muscular toxicity occurs in about 1 in 10.000 patients. In this...
Statins are the most prescribed lipid-lowering agents worldwide. Their use is generally safe, although muscular toxicity occurs in about 1 in 10.000 patients. In this study, we explored the role of the endocannabinoid system (ECS) during muscle toxicity induced by simvastatin. In murine C2C12 myoblasts exposed to simvastatin, levels of the endocannabinoids AEA and 2-AG as well the expression of specific miRNAs (in particular miR-152) targeting the endocannabinoid CB1 gene were increased in a time-dependent manner. Rimonabant, a selective CB1 antagonist, exacerbated simvastatin-induced toxicity in myoblasts, while only a weak opposite effect was observed with ACEA and GAT211, selective orthosteric and allosteric agonists of CB1 receptor, respectively. In antagomiR152-transfected myoblasts, simvastatin toxicity was in part prevented together with the functional rescue of CB1. Further analyses revealed that simvastatin in C2C12 cells also suppresses PKC and ERK signaling pathways, which are instead activated downstream of CB1 receptor stimulation, thus adding more insight into the mechanism causing CB1 functional inactivation. Importantly, simvastatin induced similar alterations in skeletal muscles of C57BL/6 J mice and primary human myoblasts. In sum, we identified the dysregulated expression of the endocannabinoid CB1 receptor as well as the impairment of its downstream signaling pathways as a novel pathological mechanism involved in statin-induced myopathy.
Topics: Humans; Animals; Mice; Mice, Inbred C57BL; Simvastatin; Endocannabinoids; Receptor, Cannabinoid, CB1; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Muscle, Skeletal; MicroRNAs
PubMed: 37612317
DOI: 10.1038/s41419-023-06080-9 -
Indian Heart Journal Mar 2024Despite numerous improvements in the management of acute coronary syndrome(ACS), it is a major cause of mortality in India. Lipids play a critical role in pathogenesis... (Review)
Review
Despite numerous improvements in the management of acute coronary syndrome(ACS), it is a major cause of mortality in India. Lipids play a critical role in pathogenesis of ACS and reduction of lipid parameters plays a pivotal role in secondary prevention. High total cholesterol and high low-density lipoprotein(LDL) are the major lipid abnormalities globally as well as in Indians. Among all the lipid parameters, LDL is the primary target of lipid-lowering therapies across the globe. High-dose statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors, and bempedoic acid are recommended therapies for LDL reduction in ACS patients. Statins have pleiotropic effects on the modulation of thrombogenesis, endothelial dysfunction, and myocardial protection. Multiple randomised controlled trials and meta-analyses have shown that the use of high-dose statin has significant benefits in ACS. LDL reduction goal is < 55 mg/dl or at least 50 % reduction from the baseline regardless of age or gender. Non-fasting LDL should be measured soon after the ACS as it varies minimally with food intake. The first line of therapy after ACS is to advise lifestyle modifications, combination therapy including high-dose statin with ezetimibe, and evaluation after 4-6 weeks of the index event. If the goal is not achieved then PCSK 9 inhibitors or Bempedoic acid should be used in combination with statins and ezetimibe to reduce recurrent ischaemic events. Despite the proven effect of these lipid-lowering therapies, undertreatment is still a big hurdle across the globe. Prohibitive costs, adverse effects, medication non-adherence, variation in health practice in different countries, and clinical inertia to prescribe this medication by physicians are the main reasons for the undertreatment.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Acute Coronary Syndrome; Cholesterol, LDL; Ezetimibe; Dyslipidemias; Anticholesteremic Agents; Proprotein Convertase 9; Dicarboxylic Acids; Fatty Acids
PubMed: 38307382
DOI: 10.1016/j.ihj.2024.01.011 -
Acta Pharmaceutica (Zagreb, Croatia) Sep 2023The advancements in proteomics have provided a better understanding of the functionality of apolipoproteins and lipoprotein-associated proteins, with the HDL lipoprotein...
The advancements in proteomics have provided a better understanding of the functionality of apolipoproteins and lipoprotein-associated proteins, with the HDL lipoprotein fraction being the most studied. The focus of this study was to evaluate the HDL proteome in dyslipidemic subjects without an established cardiovascular disease, as well as to test whether rosuvastatin treatment alters the HDL proteome. Patients with primary hypercholesterolemia or mixed dyslipidemia were assigned to 20 mg/day rosuvastatin and blood samples were drawn at study entry and after 12 weeks of treatment. A label-free LC-MS/MS protein profiling was conducted, coupled with bioinformatics analysis. Sixty-nine HDL proteins were identified, belonging to four main biological function clusters: lipid transport and metabolism; platelet activation, degranulation, and aggregation, wound response and wound healing; immune response; inflammatory and acute phase response. Five HDL proteins showed statistically significant differences in the abundance (Anova ≤ 0.05), before and after rosuvastatin treatment. Platelet factor 4 variant (PF4V1), Pregnancy-specific beta-1-glycoprotein 2 (PSG2), Profilin-1 (PFN1) and Keratin type II cytoskeletal 2 epidermal (KRT2) showed decreased expressions, while Integrin alpha-IIb (ITGA2B) showed an increased expression after treatment with rosuvastatin. The ELISA validation of PFN1 segregated the subjects into responders and non-responders, as PFN1 levels after rosuvastatin were shown to mostly depend on the subjects' inflammatory phenotype. Findings from this study introduce novel insights into the HDL proteome and statin pleiotropism.
Topics: Female; Pregnancy; Humans; Proteome; Rosuvastatin Calcium; Chromatography, Liquid; Tandem Mass Spectrometry; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Profilins
PubMed: 37708957
DOI: 10.2478/acph-2023-0034 -
Biochemical Pharmacology Sep 2023Nucleoside-based drugs, recognized as purine or pyrimidine analogs, have been potent therapeutic agents since their introduction in 1950, deployed widely in the... (Review)
Review
Nucleoside-based drugs, recognized as purine or pyrimidine analogs, have been potent therapeutic agents since their introduction in 1950, deployed widely in the treatment of diverse diseases such as cancers, myelodysplastic syndromes, multiple sclerosis, and viral infections. These antimetabolites establish complex interactions with cellular molecular constituents, primarily via activation of phosphorylation cascades leading to consequential interactions with nucleic acids. However, the therapeutic efficacy of these agents is frequently compromised by the development of drug resistance, a continually emerging challenge in their clinical application. This comprehensive review explores the mechanisms of resistance to nucleoside-based drugs, encompassing a wide spectrum of phenomena from alterations in membrane transporters and activating kinases to changes in drug elimination strategies and DNA damage repair mechanisms. The critical analysis in this review underlines complex interactions of drug and cell and also guides towards novel therapeutic strategies to counteract resistance. The development of targeted therapies, novel nucleoside analogs, and synergistic drug combinations are promising approaches to restore tumor sensitivity and improve patient outcomes.
Topics: Humans; Nucleosides; Antineoplastic Agents; Neoplasms; Drug Resistance; Membrane Transport Proteins; Antimetabolites
PubMed: 37567317
DOI: 10.1016/j.bcp.2023.115741