Statins reduce the risk of cardiovascular morbidity and mortality in patients with or at risk for cardiovascular disease and their use is expanding, especially in elderly. Statins are prescribed on a ...long-term basis and may undergo drug-drug interactions (DDIs) with other drugs. Statins have different safety and tolerability, and this might affect the possibility of DDIs with other cardiovascular drugs, increasing the risk of statin-associated myopathy and hepatotoxicity. Polypharmacy and pharmacogenetic variability are potential causes of statin DDIs. Thus, the safety and adverse effects of statins, particularly in patients receiving multiple medications at risk of DDIs, are a matter of special concern.
The purpose of this manuscript is to give an update on the potential statin DDIs and related adverse drug reactions (myopathy and hepatotoxicity), with special considerations on polypharmacy in elderly population, HIV patients, cardiovascular drugs and liver toxicities. The potential DDIs among statins and monoclonal antibodies including the recently approved PCSK9 inhibitors are also extensively discussed in the present review.
A better understanding of the incidence and clinical significance of statin DDIs will help physicians in fine-tuning the lipid-lowering therapeutic interventions thus providing their patients with an evidence-based, safe and cost-effective clinical support.
Many studies have pinpointed the significant contribution of liver-mediated drug metabolism and transport to the complexity of drug-induced liver injury (DILI). Phase I cytochrome P450 (CYP450) ...enzymes can lead to altered drug metabolism and formation of toxic metabolites, whilst Phase II enzymes are also associated with DILI. The emerging role of hepatic transporters in regulating the movement of endogenous and exogenous chemicals (e.g., bile acids and drugs) across cellular and tissue membranes is critical in determining the pathophysiology of liver disease as well as drug toxicity and efficacy. Genetic and environmental factors can have a significant impact on drug metabolism and transporter proteins, consequently increasing the risk of DILI in susceptible individuals. The assessment of these factors therefore represents an important approach for predicting and preventing DILI, by better understanding the pharmacological profile of a specific drug. This review focuses on the mechanisms of DILI associated with drug metabolism and hepatic transport, and how they can be influenced by underlying factors.
Treatment with statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, has proven beneficial preventive effects on cardiovascular events. However, discontinuation due to intolerance ...and non-adherence remain two of the major gaps in both primary and secondary prevention. This leads many patients with high-risk of atherosclerotic cardiovascular disease (ASCVD) to be inadequately treated or not to achieve target lipid level goals, and as consequence they undergo an increased risk of cardiovascular events. The aim of this review is thus to give an overview of the reasons for discontinuation and on the possible mechanisms behind them. Although statins, as a class, are generally safe, they are associated with an increased risk of diabetes mellitus and hepatic transaminase elevations. Incidence of cataracts or cognitive dysfunction and others presented in the literature (e.g. proteinuria and haematuria) have been never confirmed to have a causal link. Conversely, debated remains the effect on myalgia. Muscle side effects are the most commonly reported, although myalgia is still believed by some to be the result of a nocebo/drucebo effect. Concerning mechanisms behind muscular side effects, no clear conclusions have been reached. Thus, if on one side it is important to identify individuals either at higher risk to develop a side effect, or with confirmed risk factors and conditions of statin intolerance, on the other side alternative strategies should be identified to avoid an increased ASCVD risk.
Abstract Contrary to the long-standing and widely accepted belief that polymorphonuclear neutrophils (PMN) are of marginal relevance in atherosclerosis, evidence revealing a previously unappreciated ...role of PMN in the process of atherosclerosis is being accumulating. Systemic inflammation involving activated PMN is clearly associated with unstable conditions of coronary artery disease and an increased number of circulating neutrophils is a well-known risk indicator of future cardiovascular outcomes. Furthermore, PMN are activated in a number of clinical conditions associated with high risk of developing atherosclerosis and are detectable into culprit lesions of patients with coronary artery disease. At present, pharmacological interventions aimed at blocking neutrophil emigration from the blood into the arterial wall and/or inhibiting neutrophil-mediated inflammatory functions are not an option for treating atherosclerosis. Nevertheless, several lines of evidence suggest that part of the atheroprotective effects of statins as well as HDL and HDL apolipoproteins may be related to their ability to modulate neutrophilic inflammation in the arterial wall. These hypotheses are not definitely established and warrant for further study. This Review describes the evidence suggesting that PMN may have a causative role in atherogenesis and atheroprogression and discusses the potential importance of modulating neutrophilic inflammation as part of a novel, improved strategy for preventing and treating atherosclerosis.
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Inflammation is an obligatory marker of arterial disease, both stemming from the inflammatory activity of cholesterol itself and from well-established molecular mechanisms. Raised ...progenitor cell recruitment after major events and clonal hematopoiesis related mechanisms have provided an improved understanding of factors regulating inflammatory phenomena. Trials with inflammation antagonists have led to an extensive evaluation of biomarkers such as the high sensitivity C reactive protein (hsCRP), not exerting a causative role, but frequently indicative of the individual cardiovascular (CV) risk. Aim of this review is to provide indication on the anti-inflammatory profile of agents of general use in CV prevention, i.e. affecting lipids, blood pressure, diabetes as well nutraceuticals such as n-3 fatty acids. A crucial issue in the evaluation of the benefit of the anti-inflammatory activity is the frequent discordance between a beneficial activity on a major risk factor and associated changes of hsCRP, as in the case of statins vs PCSK9 antagonists. In hypertension, angiotensin converting enzyme inhibitors exert an optimal anti-inflammatory activity, vs the case of sartans. The remarkable preventive activity of SLGT-2 inhibitors in heart failure is not associated with a clear anti-inflammatory mechanism. Finally, icosapent ethyl has been shown to reduce the CV risk in hypertriglyceridemia, with a 27 % reduction of hsCRP. The inflammation-based approach to arterial disease has considerably gained from an improved understanding of the clinical diagnostic strategy and from a better knowledge on the mode of action of numerous agents, including nutraceuticals.
Background
A consensus of experts has proposed to replace the term nonalcoholic fatty liver disease (NAFLD), whose global prevalence is 25%, with metabolic dysfunction‐associated fatty liver disease ...(MAFLD), to describe more appropriately the liver disease related to metabolic derangements. MAFLD is closely intertwined with type 2 diabetes, obesity, dyslipidaemia, all linked to a rise in the risk of cardiovascular disease (CVDs). Since controversy still stands on whether or not NAFLD/MAFLD raises the odds of CVD, the present review aims to evaluate the impact of NAFLD/MAFLD aetiologies on CV health and the potential correction by dietary and drug approaches.
Results
Epidemiological studies indicate that NAFLD raises risk of fatal or non‐fatal CVD events. NAFLD patients have a higher prevalence of arterial plaques and stiffness, coronary calcification, and endothelial dysfunction. Although genetic and environmental factors strongly contribute to NAFLD pathogenesis, a Mendelian randomization analysis indicated that the PNPLA3 genetic variant leading to NAFLD may not be causally associated with CVD risk. Among other genetic variants related to NAFLD, TM6SF2 appears to be protective, whereas MBOAT7 may favour venous thromboembolism.
Conclusions
NAFLD is correlated to a higher CVD risk which may be ameliorated by dietary interventions. This is not surprising, since new criteria defining MAFLD include other metabolic risk abnormalities fuelling development of serious adverse extrahepatic outcomes, for example CVD. The present lack of a targeted pharmacological approach makes the identification of patients with liver disease at higher CVD risk (eg diabetes, hypertension, obesity or high levels of C‐reactive protein) of major clinical interest.
Purpose of Review
Current guidelines for the management of arterial hypertension endorse β-adrenergic receptor blocking agents (beta-blockers, BBs) as being particularly useful for hypertension in ...specific situations such as symptomatic angina, tachycardia, post-myocardial infarction, heart failure with reduced ejection fraction (HFrEF), and as an alternative to angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) in hypertensive women planning pregnancy or at least of child-bearing potential. One of the most common uses of BBs is in patients with a recent myocardial infarction, with or without hypertension. Although this one use is specifically in a setting of atherosclerotic cardiovascular disease (ASCVD), it is not primarily for atheroprevention, but rather for cases with impaired systolic function, and it is intended primarily to lessen adverse cardiac remodeling and worsening of congestive heart failure (CHF). The BB class consists of numerous agents which differ widely in pharmacologic properties and physiologic effects. These differences include selectivity for β-adrenergic receptors and their subtypes, hydro- or lipophilicity, effects on blood pressure and heart rate, influence on lipoprotein and glucose metabolism, and direct impact on the artery wall, including platelet reactivity, endothelial function, infiltration of inflammatory cells and on inflammation per se, and on smooth muscle cell proliferation. Importantly, BBs are not commonly used for prevention of atherosclerosis or ASCVD per se. Many studies of early-generation BBs showed adverse effects on lipoprotein levels and metabolism of glucose and insulin and thus discouraged their use in atheroprevention. Nevertheless, newer BBs often have neutral or favorable metabolic effects on these important factors in ASCVD pathophysiology, and recent scientific studies now document direct beneficial effects of BBs on the artery wall. This document reviews both types of newer data, not only to encourage consideration of BB treatment to reduce ASCVD in the present, but also to call for future research to better explore the clinical settings in which BBs may be proven to have additional benefit in preventing ASCVD when added to the better-established treatments for dyslipidemia and diabetes.
Recent Findings
Relatively recent publications have clarified the diversity among BBs regarding adverse, neutral, or favorable effects on lipoproteins (especially triglycerides (TG) and low-density lipoprotein (LDL)) and on glucose/insulin metabolism. Specifically, the newer BBs (metoprolol ER, carvedilol ER, bisoprolol, and nebivolol) are now documented to be metabolically beneficial. These new data are complex but instructive regarding potential mechanisms of the diverse effects of various BBs on metabolism. Further and more importantly, these new data refute the traditional, but now outmoded, concept that BBs are universally harmful metabolically and therefore must be used sparingly, if at all, for atheroprevention. Recent studies have also reported exciting new data regarding how certain BBs can reduce platelet adhesion and improve the function of the major cell types in the artery wall, including the endothelium, macrophages, and smooth muscle cells. Specifically, BBs can improve endothelial function by enhancing arterial vasodilation and by reducing monocyte adhesion and transmigration. Further, BBs can decrease numbers and activity of inflammatory cells, including decreasing proliferation of smooth muscle cells and their transformation into inflammatory cells. These data help with the crucial step of distinguishing among available BBs regarding their likely overall arterial effects, whether to accelerate or prevent the development of atherosclerosis. In this regard, there is even some limited published information beyond these intermediary steps, going directly to the clinically more important endpoints of atherosclerosis and ASCVD events.
Summary
The negative metabolic effects observed with the use of traditional/earlier generations of BBs have discouraged use of any BBs to prevent ASCVD. These adverse effects are not seen, however, with newer BBs. Thus, BBs continue to be a useful component of combination regimens not only in the treatment of arterial hypertension, heart failure, and arrhythmia, but also potentially in the prevention of atherosclerosis and ASCVD. Despite this exciting potential, further research is greatly needed to better establish the possible benefits of the most promising BBs as they might work in combination with other better-established atheropreventive agents. Specifically, there is a need for randomized, prospective, cardiovascular outcome trials (CVOTs) in high-risk patients, adding a BB to background LDL-lowering (statins, etc.), TG-lowering (specifically icosapent ethyl, which reduces ASCVD in patients with high TG, although apparently not via TG-lowering), and/or anti-diabetic (sodium glucose transport-2 inhibitors, SGLT2i, and glucagon-like protein-1 receptor agonists, GLP1-RA) treatments, as indicated in a given subject population.
Intraplaque release of inflammatory cytokines from macrophages is implicated in atherogenesis by inducing the proliferation and migration of media smooth muscle cells (SMCs). PCSK9 is present and ...released by SMCs within the atherosclerotic plaque but its function is still unknown. In the present study, we tested the hypothesis that PCSK9 could elicit a pro-inflammatory effect on macrophages. THP-1-derived macrophages and human primary macrophages were exposed to different concentrations (0.250 ÷ 2.5 µg/ml) of human recombinant PCSK9 (hPCSK9). After 24 h incubation with 2.5 µg/ml PCSK9, a significant induction of IL-1β, IL-6, TNF-α, CXCL2, and MCP1 mRNA, were observed in both cell types. Co-culture of THP-1 macrophages with HepG2 overexpressing hPCSK9 also showed the induction of TNF-α (2.4 ± 0.5 fold) and IL-1β (8.6 ± 1.8 fold) mRNA in macrophages. The effect of hPCSK9 on TNF-α mRNA in murine LDLR
bone marrow macrophages (BMM) was significantly impaired as compared to wild-type BMM (4.3 ± 1.6 fold vs 31.1 ± 6.1 fold for LDLR
and LDLR
, respectively). Finally, a positive correlation between PCSK9 and TNF-α plasma levels of healthy adult subjects (males 533, females 537) was observed (B = 8.73, 95%CI 7.54 ÷ 9.93, p < 0.001). Taken together, the present study provides evidence of a pro-inflammatory action of PCSK9 on macrophages, mainly dependent by the LDLR.
The direct oral anticoagulants (DOACs), dabigatran, rivaroxaban, apixaban, and edoxaban, are becoming the most commonly prescribed drugs for preventing ischemic stroke in patients with non-valvular ...atrial fibrillation (NVAF) and for the treatment and prevention of venous thromboembolism (VTE). Rivaroxaban was also recently approved for the treatment of patients with a recent acute coronary syndrome (ACS). Their use demonstrated to have a favorable risk-benefit profile, with significant reductions in stroke, intracranial hemorrhage, and mortality compared to warfarin, but with increased gastrointestinal bleeding. Nevertheless, their safety profile is compromised in multimorbidity patients requiring contemporary administration of several drugs. Comorbidity and polypharmacy have a high prevalence in elderly patients, who are also more susceptible to bleeding events. The combination of multiple treatments can cause relevant drug–drug interactions (DDIs) by affecting the exposure or the pharmacological activities of DOACs. Although important differences of the pharmacokinetic (PK) properties can be observed between DOACs, all of them are substrate of P-glycoprotein (P-gp) and thus may interact with strong inducers or inhibitors of this drug transporter. On the contrary, rivaroxaban and, to a lower extent, apixaban, are also susceptible to drugs altering the cytochrome P450 isoenzyme (CYP) activities. In the present review, we summarize the potential DDI of DOACs with several classes of drugs that have been reported or have characteristics that may predict clinically significant DDIs when administered together with DOACs. Possible strategies, including dosage reduction, avoiding concomitant administration, or different time of treatment, will be also discussed to reduce the incidence of DDI with DOACs. Considering the available data from specific clinical trials or registries analysis, the use of DOACs is associated with fewer clinically relevant DDIs than warfarin, and their use represents an acceptable clinical choice. Nevertheless, DDIs can be significant in certain patient conditions so a careful evaluation should be made before prescribing a specific DOAC.
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