Adjunctive therapy with lipid-lowering agents in COVID-19: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Many commonly used drugs were evaluated as repurposed treatment options since the emergence of the COVID-19 pandemic. The benefit of lipid-lowering agents has been controversial in this regard. In this systematic review, we assessed the effect of these medications as adjunctive therapy in COVID-19 by the inclusion of randomized controlled trials (RCTs). METHODS: We searched four international databases including PubMed, the Web of Science, Scopus, and Embase for RCTs in April 2023. The primary outcome was mortality, while other efficacy indices were considered secondary outcomes. In order to estimate the pooled effect size of the outcomes, considering the odds ratio (OR) or standardized mean difference (SMD) and 95% confidence interval (CI), random-effect meta-analyses was conducted. RESULTS: Ten studies involving 2,167 COVID-19 patients using statins, omega-3 fatty acids, fenofibrate, PCSK9 inhibitors, and nicotinamide as intervention compared to control or placebo, were included. No significant difference was found in terms of mortality (OR 0.96, 95% CI 0.58 to 1.59, p-value = 0.86, I2 = 20.4%) or length of hospital stay (SMD -0.10, 95% CI -0.78 to 0.59, p-value = 0.78, I2 = 92.4%) by adding a statin to the standard of care. The trend was similar for fenofibrate and nicotinamide. PCSK9 inhibition, however, led to decreased mortality and an overall better prognosis. Omega-3 supplementation showed contradicting results in two trials, suggesting the need for further evaluation. CONCLUSION: Although some observational studies found improved outcomes in patients using lipid-lowering agents, our study found no benefit in adding statins, fenofibrate, or nicotinamide to COVID-19 treatment. On the other hand, PCSK9 inhibitors can be a good candidate for further assessment. Finally, there are major limitations in the use of omega-3 supplements in treating COVID-19 and more trials are warranted to evaluate this efficacy.

Triglyceride Lowering with Pemafibrate to Reduce Cardiovascular Risk.

BACKGROUND: High triglyceride levels are associated with increased cardiovascular risk, but whether reductions in these levels would lower the incidence of cardiovascular events is uncertain. Pemafibrate, a selective peroxisome proliferator-activated receptor α modulator, reduces triglyceride levels and improves other lipid levels. METHODS: In a multinational, double-blind, randomized, controlled trial, we assigned patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia (triglyceride level, 200 to 499 mg per deciliter), and high-density lipoprotein (HDL) cholesterol levels of 40 mg per deciliter or lower to receive pemafibrate (0.2-mg tablets twice daily) or matching placebo. Eligible patients were receiving guideline-directed lipid-lowering therapy or could not receive statin therapy without adverse effects and had low-density lipoprotein (LDL) cholesterol levels of 100 mg per deciliter or lower. The primary efficacy end point was a composite of nonfatal myocardial infarction, ischemic stroke, coronary revascularization, or death from cardiovascular causes. RESULTS: Among 10,497 patients (66.9% with previous cardiovascular disease), the median baseline fasting triglyceride level was 271 mg per deciliter, HDL cholesterol level 33 mg per deciliter, and LDL cholesterol level 78 mg per deciliter. The median follow-up was 3.4 years. As compared with placebo, the effects of pemafibrate on lipid levels at 4 months were -26.2% for triglycerides, -25.8% for very-low-density lipoprotein (VLDL) cholesterol, -25.6% for remnant cholesterol (cholesterol transported in triglyceride-rich lipoproteins after lipolysis and lipoprotein remodeling), -27.6% for apolipoprotein C-III, and 4.8% for apolipoprotein B. A primary end-point event occurred in 572 patients in the pemafibrate group and in 560 of those in the placebo group (hazard ratio, 1.03; 95% confidence interval, 0.91 to 1.15), with no apparent effect modification in any prespecified subgroup. The overall incidence of serious adverse events did not differ significantly between the groups, but pemafibrate was associated with a higher incidence of adverse renal events and venous thromboembolism and a lower incidence of nonalcoholic fatty liver disease. CONCLUSIONS: Among patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia, and low HDL and LDL cholesterol levels, the incidence of cardiovascular events was not lower among those who received pemafibrate than among those who received placebo, although pemafibrate lowered triglyceride, VLDL cholesterol, remnant cholesterol, and apolipoprotein C-III levels. (Funded by the Kowa Research Institute; PROMINENT ClinicalTrials.gov number, NCT03071692.).

Altered Basal Lipid Metabolism Underlies the Functional Impairment of Naive CD8+ T Cells in Elderly Humans.

Aging is associated with functional deficits in the naive T cell compartment, which compromise the generation of de novo immune responses against previously unencountered Ags. The mechanisms that underlie this phenomenon have nonetheless remained unclear. We found that naive CD8+ T cells in elderly humans were prone to apoptosis and proliferated suboptimally in response to stimulation via the TCR. These abnormalities were associated with dysregulated lipid metabolism under homeostatic conditions and enhanced levels of basal activation. Importantly, reversal of the bioenergetic anomalies with lipid-altering drugs, such as rosiglitazone, almost completely restored the Ag responsiveness of naive CD8+ T cells. Interventions that favor lipid catabolism may therefore find utility as adjunctive therapies in the elderly to promote vaccine-induced immunity against targetable cancers and emerging pathogens, such as seasonal influenza viruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Seaweeds and Their Natural Products for Preventing Cardiovascular Associated Dysfunction.

Cardiovascular disease (CVD), which involves the onset and exacerbation of various conditions including dyslipidemia, activation of the renin-angiotensin system, vascular endothelial cell damage, and oxidative stress, is a leading cause of high mortality rates and accounts for one-third of deaths worldwide. Accordingly, as dietary changes in daily life are thought to greatly reduce the prevalence of CVD, numerous studies have been conducted to examine the potential use of foods and their bioactive components for preventing and treating CVD. In particular, seaweeds contain unique bioactive metabolites that are not found in terrestrial plants because of the harsh environment in which they survive, leading to in vitro and in vivo studies of their prevention and treatment effects. This review summarizes studies that focused on the beneficial effects of seaweeds and their natural products targeting markers involved in a cascade of mechanisms related to CVD pathogenesis. The purpose of this review is to describe the potential of seaweeds and their natural products for preventing and treating CVD based on in vivo and in vitro studies. This review provides a basis for future research in the field of marine drugs.

The impact of atherosclerotic cardiovascular disease, dyslipidaemia and lipid lowering therapy on Coronavirus disease 2019 outcomes: an examination of the available evidence.

PURPOSE OF REVIEW: Coronavirus Disease 2019 (COVID19) has caused significant global morbidity and mortality, especially in persons with underlying cardiovascular disease. There have been concerns that lipid-lowering therapy (LLT) increases angiotensin-converting enzyme 2 levels. Conversely, pleiotropic effects of statins can theoretically protect against severe COVID19 infection, supporting evidence from other respiratory illnesses in which statin use probably confers benefit. RECENT FINDINGS: There is an abundance of studies that show that statins are safe and potentially protect against severe COVID19 infection (critical illness and death), even when adjustment for potential confounders is undertaken. However, the evidence is limited to retrospective cohorts. The benefit for patients with diabetes is less clear. There is a paucity of evidence for other LLT agents. Available clinical guidelines recommend the ongoing use of LLT in patients with COVID19 (unless specifically contra-indicated) and the data from available studies support these. SUMMARY: In patients with COVID19 infection, LLT should be continued. However, the current findings need substantiating in larger prospective clinical studies with specific examination of the possible mechanisms by which LLT confers benefit from COVID19.

Lipid-lowering therapy in high cardiovascular risk patients during COVID-19 pandemic: keep focused on the target.

To the Editor COVID-19 (COrona VIrus Disease) patients with cardiovascular (CV) disease, multiple CV risk factors or comorbidities (i.e., arterial hypertension and diabetes) were shown to be more prone to a worse prognosis. SARS-CoV-2 is a still unknown enemy and the role of concomitant cardiovascular therapies has been controversial in the early stages, particularly with regard to Angiotensin-Converting Enzyme inhibitors...

Lipid homeostasis and mevalonate pathway in COVID-19: Basic concepts and potential therapeutic targets.

Despite encouraging progresses achieved in the management of viral diseases, efficient strategies to counteract infections are still required. The current global challenge highlighted the need to develop a rapid and cost-effective strategy to counteract the SARS-CoV-2 pandemic. Lipid metabolism plays a crucial role in viral infections. Viruses can use the host lipid machinery to support their life cycle and to impair the host immune response. The altered expression of mevalonate pathway-related genes, induced by several viruses, assures survival and spread in host tissue. In some infections, statins, HMG-CoA-reductase inhibitors, reduce cholesterol in the plasma membrane of permissive cells resulting in lower viral titers and failure to internalize the virus. Statins can also counteract viral infections through their immunomodulatory, anti-inflammatory and anti-thrombotic effects. Beyond statins, interfering with the mevalonate pathway could have an adjuvant effect in therapies aimed at mitigating endothelial dysfunction and deregulated inflammation in viral infection. In this review we depicted the historical and current evidence highlighting how lipid homeostasis and mevalonate pathway targeting represents a valid approach to rapidly neutralize viruses, focusing our attention to their potential use as effective targets to hinder SARS-CoV-2 morbidity and mortality. Pros and cons of statins and Mevalonate-pathway inhibitors have been also dissected.

Dyslipidemia in breast cancer patients increases the risk of SAR-CoV-2 infection.

Breast cancer (BC) is the most diagnosed and second leading cause of death among women worldwide. Elevated levels of lipids have been reported in BC patients. On the other hand, lipids play an important role in coronavirus infections including the newly emerged disease caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and designated COVID-19 by WHO. Cancer patients including BC have been reported to be at higher risk of SARS-CoV-2 infection, which is mostly attributed to the chronic immunosuppressive status of cancer patients along with the use of cytotoxic drugs. Here in this review, we highlighted the role of dyslipidemia associated with BC patients in the incidence and severity of SARS-CoV-2 infection. Elevated levels of lipids namely phospholipids, cholesterol, sphingolipids, and eicosanoids in the serum of BC patients and their re-localization to the alveolar spaces can increase susceptibility and/or severity due to SARA-CoV-2 infection. Therefore, manipulation of dyslipidemia in BC patients should be recommended as prophylactic and therapy against SARS-CoV-2 infection.

Managing hyperlipidaemia in patients with COVID-19 and during its pandemic: An expert panel position statement from HEART UK.

The emergence of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which causes Coronavirus Disease 2019 (COVID-19) has resulted in a pandemic. SARS-CoV-2 is highly contagious and its severity highly variable. The fatality rate is unpredictable but is amplified by several factors including advancing age, atherosclerotic cardiovascular disease, diabetes mellitus, hypertension and obesity. A large proportion of patients with these conditions are treated with lipid lowering medication and questions regarding the safety of continuing lipid-lowering medication in patients infected with COVID-19 have arisen. Some have suggested they may exacerbate their condition. It is important to consider known interactions with lipid-lowering agents and with specific therapies for COVID-19. This statement aims to collate current evidence surrounding the safety of lipid-lowering medications in patients who have COVID-19. We offer a consensus view based on current knowledge and we rated the strength and level of evidence for these recommendations. Pubmed, Google scholar and Web of Science were searched extensively for articles using search terms: SARS-CoV-2, COVID-19, coronavirus, Lipids, Statin, Fibrates, Ezetimibe, PCSK9 monoclonal antibodies, nicotinic acid, bile acid sequestrants, nutraceuticals, red yeast rice, Omega-3-Fatty acids, Lomitapide, hypercholesterolaemia, dyslipidaemia and Volanesorsen. There is no evidence currently that lipid lowering therapy is unsafe in patients with COVID-19 infection. Lipid-lowering therapy should not be interrupted because of the pandemic or in patients at increased risk of COVID-19 infection. In patients with confirmed COVID-19, care should be taken to avoid drug interactions, between lipid-lowering medications and drugs that may be used to treat COVID-19, especially in patients with abnormalities in liver function tests.

Lopinavir-Ritonavir in SARS-CoV-2 Infection and Drug-Drug Interactions with Cardioactive Medications.

Lopinavir-ritonavir combination is being used for the treatment of SARS-CoV-2 infection. A low dose of ritonavir is added to other protease inhibitors to take advantage of potent inhibition of cytochrome (CYP) P450 3A4, thereby significantly increasing the plasma concentration of coadministered lopinavir. Ritonavir also inhibits CYP2D6 and induces CYP2B6, CYP2C19, CYP2C9, and CYP1A2. This potent, time-dependent interference of major hepatic drug-metabolizing enzymes by ritonavir leads to several clinically important drug-drug interactions. A number of patients presenting with acute coronary syndrome and acute heart failure may have SARS-CoV-2 infection simultaneously. Lopinavir-ritonavir is added to their prescription of multiple cardiac medications leading to potential drug-drug interactions. Many cardiology, pulmonology, and intensivist physicians have never been exposed to clinical scenarios requiring co-prescription of cardiac and antiviral therapies. Therefore, it is essential to enumerate these drug-drug interactions, to avoid any serious drug toxicity, to consider alternate and safer drugs, and to ensure better patient care.

[Lipid treatment in the period COVID-19]. / Tratamiento hipolipemiante en la era COVID-19.

BACKGROUND AND OBJECTIVES: The COVID-19 pandemic has shown that cardiovascular diseases carry a higher risk of mortality. Doubts have been raised regarding lipid therapy in these patients. The objectives are to analyze the efficacy and safety of lipid lowering therapy in patients with COVID-19. MATERIAL AND METHODS: A review of the scientific literature was conducted in PubMed, CDC Reports, NIH, and NCBI SARS-CoV-2 using the keywords: COVID-2, statins, ezetimibe, PCSK9 inhibitors, hypercholesterolemia, and hypolipidemic drugs. RESULTS: The statins should continue to use patients with COVID-19 based on their efficacy, safety, immunosuppressive effects, anti-inflammatory availability and accessibility. Depending on the cardiovascular risk levels of these patients, the use of high potency statins and/or ezetimibe and/or iPCSK9 may be necessary in patients with high and very high cardiovascular risk. Patients treated with iPCSK9 should continue treatment for its beneficial effects in preventing cardiovascular disease. Patients with familial hypercholesterolemia and COVID-19 are especially vulnerable to cardiovascular disease and should continue to receive severe lipid lowering therapy. CONCLUSIONS: In patients with COVID-19, the majority of baseline CVDs are of atherosclerotic origin, with the worst prediction for patients with high risk and very high risk of CVD. In these patients, intensive treatment with statins and/or fixed combination with ezetimibe and/or iPCSK9 plays a fundamental role.

Fenofibrate increases the amount of sulfatide which seems beneficial against Covid-19.

Fenofibrate, which is a PPAR-alfpha agonist, increases the level of sulfatide. In this letter we hypothesize on the background of various findings that this is beneficial against COVID-19. Fenofibrate has been used for decades against hypercholesterolemia and has no serious side effects. Therefore, a trial giving fenofibrate to patients with corona virus infection is recommended.

Clinical approach to the inflammatory etiology of cardiovascular diseases.

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.

Brief recommendations on the management of adult patients with familial hypercholesterolemia during the COVID-19 pandemic.

Individuals with Familial Hypercholesterolaemia (FH) are at very high risk of cardiovascular disease, which is associated with poor outcomes from coronavirus infections. COVID-19 puts strain on healthcare systems and may impair access to routine FH services. On behalf of the International Lipid Expert Panel (ILEP) and the European FH Patient Network (FH Europe), we present brief recommendations on the management of adult patients with FH during the COVID-19 pandemic. We discuss the implications of COVID-19 infections for FH patients, the importance of continuing lipid-lowering therapy where possible, issues relating to safety monitoring and service delivery. We summarise the evidence for additional benefits of statins and other lipid-lowering drugs during viral infections. The recommendations do not override in any way the individual responsibility of physicians to make appropriate and accurate decisions taking into account the condition of a given patient and the doses, rules, and regulations applicable to drugs and devices at the time of their prescription/use.