Statins in hospitalized COVID-19 patients: A systematic review and meta-analysis of randomized controlled trials.

This systematic review and meta-analysis aimed to determine the efficacy of statins in hospitalized patients with coronavirus disease-2019 (COVID-19). A systematic search was made of PubMed, Embase, Cochrane Library, and clinicaltrials.gov, without language restrictions. Randomized controlled trials (RCTs) on treatment of COVID-19 with statins, compared with placebo or standard of care, were reviewed. Seven RCTs (enrolling 1830 participants) met the inclusion criteria. There was no statistically significant difference in all-cause mortality (risk ratio [RR]: 0.92, 95% confidence interval [CI]: 0.75-1.13), length of hospital stay (weighted mean difference: -0.21 days, 95% CI: -1.01 to 0.59 days), intensive care unit (ICU) admission (RR: 1.84, 95% CI: 0.45-7.55), and mechanical ventilation (RR: 1.09, 95% CI: 0.70-1.70) between the two groups. Statins failed to reduce mortality, ICU admission, mechanical ventilation, and length of stay in hospitalized patients with COVID-19. Statins probably should not be used routinely in COVID-19 patients.

Optimizing lipid management-impact of the COVID 19 pandemic upon cardiovascular risk in England.

BACKGROUND: We sought to understand the impact of the COVID-19 pandemic on lipid-lowering therapy prescribing as a potential cause of the excess cardiovascular mortality seen post-pandemic in England. We examined temporal changes over 3 years in the prescribing of high-intensity and non-high-intensity statin therapy and ezetimibe. SOURCES OF DATA: We utilized data available via the National Health Service (NHS) Business Services Authority (NHSBSA) Information Services Data Warehouse, extracting 3 monthly data from October 2018 to December 2021 on high- and low-intensity statin and ezetimibe prescribing, (commencement, cessation or continuation) through each time period of study and those before, and after, the period of interest. AREAS OF AGREEMENT: Optimizing lipid management is a key component of the NHS Long Term Plan ambition to reduce deaths from cardiovascular disease, stroke and dementia. AREAS OF CONTROVERSY: The COVID-19 pandemic and associated lockdown have seen a significant reduction in prescribing of lipid-lowering therapies. If cardiovascular risk is not to worsen in the forthcoming years, urgent action is needed to ensure that the impact of the pandemic upon optimization of cholesterol and the historical undertreatment of cholesterol is reversed and improved. AREAS TIMELY FOR DEVELOPING RESEARCH: Prescription data available via NHSBSA can support our understanding of the implications of policy and behaviour and highlight the impact of guidelines in practise. GROWING POINTS: Understanding the impact of the COVID-19 pandemic upon cholesterol management and the opportunities for newer lipid-lowering therapies delivered using a population health approach have the potential to enhance lipid-lowering and improve cardiovascular mortality and morbidity and reduce health inequalities.

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.

Target-agnostic drug prediction integrated with medical record analysis uncovers differential associations of statins with increased survival in COVID-19 patients.

Drug repurposing requires distinguishing established drug class targets from novel molecule-specific mechanisms and rapidly derisking their therapeutic potential in a time-critical manner, particularly in a pandemic scenario. In response to the challenge to rapidly identify treatment options for COVID-19, several studies reported that statins, as a drug class, reduce mortality in these patients. However, it is unknown if different statins exhibit consistent function or may have varying therapeutic benefit. A Bayesian network tool was used to predict drugs that shift the host transcriptomic response to SARS-CoV-2 infection towards a healthy state. Drugs were predicted using 14 RNA-sequencing datasets from 72 autopsy tissues and 465 COVID-19 patient samples or from cultured human cells and organoids infected with SARS-CoV-2. Top drug predictions included statins, which were then assessed using electronic medical records containing over 4,000 COVID-19 patients on statins to determine mortality risk in patients prescribed specific statins versus untreated matched controls. The same drugs were tested in Vero E6 cells infected with SARS-CoV-2 and human endothelial cells infected with a related OC43 coronavirus. Simvastatin was among the most highly predicted compounds (14/14 datasets) and five other statins, including atorvastatin, were predicted to be active in > 50% of analyses. Analysis of the clinical database revealed that reduced mortality risk was only observed in COVID-19 patients prescribed a subset of statins, including simvastatin and atorvastatin. In vitro testing of SARS-CoV-2 infected cells revealed simvastatin to be a potent direct inhibitor whereas most other statins were less effective. Simvastatin also inhibited OC43 infection and reduced cytokine production in endothelial cells. Statins may differ in their ability to sustain the lives of COVID-19 patients despite having a shared drug target and lipid-modifying mechanism of action. These findings highlight the value of target-agnostic drug prediction coupled with patient databases to identify and clinically evaluate non-obvious mechanisms and derisk and accelerate drug repurposing opportunities.

Coronary microcirculatory dysfunction in hypercholesterolemic patients with COVID-19: potential benefit from cholesterol-lowering treatment.

Patients with hypercholesterolemia often have coronary microvascular dysfunction (CMD). Viral infections, such as the SARS-CoV-2 infection, may also result in CMD. Three non-randomized studies have shown significant beneficial effects of statins on CMD in non-infected patients. Similarly, in SARS-CoV-2 - infected patients one beneficial mechanism of action of statins may be the amelioration of endothelial dysfunction, which is a major driver of CMD. Apart from statins, lipoprotein apheresis and PCSK9 inhibitors can also improve or even reverse CMD. The potential reversal of CMD by using effective cholesterol-lowering medications during and after COVID-19 infection, especially in hypercholesterolemic COVID-19 patients, is important.KEY MESSAGESCoronary microvascular dysfunction (CMD) is common in patients hospitalized with SARS-CoV-2 infectionThree nonrandomized studies in non-infected patients are showing the beneficial effects of statin treatment on CMDEffective cholesterol-lowering medication during and after SARS-CoV-2 infection, especially in hypercholesterolemic COVID-19 patients, is of great significance.

COVID-19 unemployment and access to statin medications in the United States.

Objective: To quantify the effect of the unemployment created by COVID-19 on access to (sales of) statin drugs in the United States population. Methods: Approximately half a billion transactions for statin drugs in the United States between January 2018 and September 2020 are analyzed. We studied the potential causal relation between abnormal levels of unemployment during the first wave of COVID-19 in the U.S. and abnormal levels of sales of statin products (both variables defined at the state/week level). Variables are analyzed using the Two-Stage Least Squares (2SLS) method, which exploits comparisons of statin sales between states where, given the occupational distribution of their workforce, unemployment was more structurally vulnerable to mobility restrictions derived from COVID-19 against states where it was less structurally vulnerable. Results: While we do not find unemployment effects on statin sales on most of the population, our estimates link COVID-fueled unemployment with a sharp sales reduction among Medicaid-insured populations, particularly those in working age. For the period between March and August of 2020, these estimates imply a 31% drop of statin sales among this population. Discussion: COVID-fueled unemployment may have had a negative and significant effect on access to statin populations among Medicaid-insured populations.

IMPACT OF STATINS ON THE CLINICAL COURSE OF COVID-19-ASSOCIATED PNEUMONIA IN UNVACCINATED PATIENTS WITH ARTERIAL HYPERTENSION.

OBJECTIVE: The aim: To assess the impact of statins on the severity and lethality rate in hypertensive patients with COVID-19-associated pneumonia. PATIENTS AND METHODS: Materials and methods: 106 unvaccinated hypertensive patients were enrolled in the study. 29 (27.4%) patients took statins. RESULTS: Results: Statins were not associated with reduced risks of lethality (relative risk (RR), 0.24; [95%CI, 0.03-1.79], p=0.16), decline in oxygen saturation <92% during the inpatient stay (RR, 0.70 [95%CI, 0.39-1.28], p=0.25) and need for supplemental oxygen (RR, 0.84; [95%CI, 0.51-1.37], p=0.48). There was no significant difference in the median length of in-hospital stay between the patients taking statins (14.0 [10.0-15.0] days) and patients, which didn't take statins (13.0 [9.0-18.0] days) (p=0.76). However, subgroup analysis showed that statins reduced the risk of decline in oxygen saturation <92% in patients aged 65 years and older with body mass index $ 25.0 kg/m2 (RR, 0.33 [95%CI, 0.11-0.92], p=0.03). CONCLUSION: Conclusions: Statins didn't a#ect the severity and lethality rate in hypertensive patients with COVID-19-associated pneumonia. Subgroup analysis showed that statin use was associated with a decrease in morbidity of patients aged 65 years and older with BMI $25.0 kg/m2 hospitalized for COVID-19-associated pneumonia.

The impact of statin therapy on in-hospital prognosis and endothelial function of patients at high-to-very high cardiovascular risk admitted for COVID-19.

Statins may protect against adverse outcomes from Coronavirus disease 2019 (COVID-19) through their pleiotropic effects. Endothelial dysfunction seems to be implicated in the pathophysiology of COVID-19, and can be attenuated by statins. This study assessed the role of preadmission statin therapy and its interaction with endothelial function, measured using flow-mediated dilation (FMD) at hospital admission, in predicting in-hospital outcomes among patients with COVID-19 having high-to-very high cardiovascular (CV) risk. We conducted a retrospective cohort study of hospitalized patients with COVID-19 having high-to-very high CV risk, including a subgroup of patients who underwent FMD assessment. Among 342 patients, 119 (35%) were treated with statins at study baseline. Preadmission statin therapy was independently associated with a 75% risk reduction of intensive care unit admission/in-hospital death (adjusted hazard ratio 0.252, 95% confidence interval 0.122-0.521, p < 0.001). In the subgroup of patients with an FMD assessment (245 patients, 40% statin-treated), preadmission statin therapy was independently associated with higher FMD values (ß = 0.159, p = 0.013). However, preadmission statin therapy × FMD interaction was not associated with in-hospital outcomes (F = 0.002, pinteraction = 0.960). Preadmission statin therapy is associated with better in-hospital outcomes among patients with COVID-19 having high-to-very high CV risk, independent of the endothelium-protective effects of these drugs.

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.).

Prevalence of Statin Use for Primary Prevention of Atherosclerotic Cardiovascular Disease by Race, Ethnicity, and 10-Year Disease Risk in the US: National Health and Nutrition Examination Surveys, 2013 to March 2020.

Importance: The burden of atherosclerotic cardiovascular disease (ASCVD) in the US is higher among Black and Hispanic vs White adults. Inclusion of race in guidance for statin indication may lead to decreased disparities in statin use. Objective: To evaluate prevalence of primary prevention statin use by race and ethnicity according to 10-year ASCVD risk. Design, Setting, and Participants: This serial, cross-sectional analysis performed in May 2022 used data from the National Health and Nutrition Examination Survey, a nationally representative sample of health status in the US, from 2013 to March 2020 (limited cycle due to the COVID-19 pandemic), to evaluate statin use for primary prevention of ASCVD and to estimate 10-year ASCVD risk. Participants aged 40 to 75 years without ASCVD, diabetes, low-density lipoprotein cholesterol levels 190 mg/dL or greater, and with data on medication use were included. Exposures: Self-identified race and ethnicity (Asian, Black, Hispanic, and White) and 10-year ASCVD risk category (5%-<7.5%, 7.5%-<20%, ≥20%). Main Outcomes and Measures: Prevalence of statin use, defined as identification of statin use on pill bottle review. Results: A total of 3417 participants representing 39.4 million US adults after applying sampling weights (mean [SD] age, 61.8 [8.0] years; 1289 women [weighted percentage, 37.8%] and 2128 men [weighted percentage, 62.2%]; 329 Asian [weighted percentage, 4.2%], 1032 Black [weighted percentage, 12.7%], 786 Hispanic [weighted percentage, 10.1%], and 1270 White [weighted percentage, 73.0%]) were included. Compared with White participants, statin use was lower in Black and Hispanic participants and comparable among Asian participants in the overall cohort (Asian, 25.5%; Black, 20.0%; Hispanic, 15.4%; White, 27.9%) and within ASCVD risk strata. Within each race and ethnicity group, a graded increase in statin use was observed across increasing ASCVD risk strata. Statin use was low in the highest risk stratum overall with significantly lower rates of use among Black (23.8%; prevalence ratio [PR], 0.90; 95% CI, 0.82-0.98 vs White) and Hispanic participants (23.9%; PR, 0.90; 95% CI, 0.81-0.99 vs White). Among other factors, routine health care access and health insurance were significantly associated with higher statin use in Black, Hispanic, and White adults. Prevalence of statin use did not meaningfully change over time by race and ethnicity or by ASCVD risk stratum. Conclusions and Relevance: In this study, statin use for primary prevention of ASCVD was low among all race and ethnicity groups regardless of ASCVD risk, with the lowest use occurring among Black and Hispanic adults. Improvements in access to care may promote equitable use of primary prevention statins in Black and Hispanic adults.

Did Australia's COVID-19 Restrictions Impact Statin Incidence, Prevalence or Adherence?

COVID-19 restrictions may have an unintended consequence of limiting access to cardiovascular care. Australia implemented adaptive interventions (eg, telehealth consultations, digital image prescriptions, continued dispensing, medication delivery) to maintain medication access. This study investigated whether COVID-19 restrictions in different jurisdictions coincided with changes in statin incidence, prevalence and adherence. Analysis of a 10% random sample of national medication claims data from January 2018 to December 2020 was conducted across 3 Australian jurisdictions. Weekly incidence and prevalence were estimated by dividing the number statin initiations and any statin dispensing by the Australian population aged 18-99 years. Statin adherence was analyzed across the jurisdictions and years, with adherence categorized as <40%, 40%-79% and ≥80% based on dispensing per calendar year. Overall, 309,123, 315,703 and 324,906 people were dispensed and 39,029, 39,816, and 44,979 initiated statins in 2018, 2019, and 2020 respectively. Two waves of COVID-19 restrictions in 2020 coincided with no meaningful change in statin incidence or prevalence per week when compared to 2018 and 2019. Incidence increased 0.3% from 23.7 to 26.2 per 1000 people across jurisdictions in 2020 compared to 2019. Prevalence increased 0.14% from 158.5 to 159.9 per 1000 people across jurisdictions in 2020 compared to 2019. The proportion of adults with ≥80% adherence increased by 3.3% in Victoria, 1.4% in NSW and 1.8% in other states and territories between 2019 and 2020. COVID-19 restrictions did not coincide with meaningful changes in the incidence, prevalence or adherence to statins suggesting adaptive interventions succeeded in maintaining access to cardiovascular medications.

Beneficial effects of prehospital use of statins in a large United States cohort of hospitalized coronavirus disease 2019 patients.

AIMS: This large cohort study aimed to assess the role of chronic statin use on COVID-19 disease severity. METHODS: An observational retrospective study from electronic medical records of hospitalized patients (n = 43 950) with COVID-19 between January and September 2020 in 185 hospitals in the United States. A total of 38 875 patients met inclusion criteria; 23 066 were included in the propensity-matched sampling with replacement cohort; 11 533 were prehospital statin users. The primary outcome was all-cause death; secondary outcomes were death from COVID-19 and serious complications. Mean, standard deviation, chi-square test, Student's t-test, linear regression, and binary and multinomial logistic regressions were used for statistical analysis. RESULTS: Among 38 875 patients, 30% were chronic statin users [mean age, 70.82 (±12.25); 47.1% women] and 70% were statin nonusers [mean age, 58.44 (±18.27); 48.5% women]. Key propensity-matched outcomes among 11 533 chronic statin users showed 20% lower risk of all-cause mortality (OR 0.80, 95% CI 0.74-0.86, P < 0.001), 23% lower risk of mortality from COVID-19 (OR 0.77, 95% CI 0.71-0.84, P < 0.001), 16% lower risk of ICU admission (OR 0.84, 95% CI 0.79-0.89, P < 0.001), 24% lower risk of critical acute respiratory distress syndrome with COVID-19 (OR 0.76, 95% CI 0.70-0.83, P < 0.001), 23% lower risk of mechanical ventilation (OR 0.77, 95% CI 0.71-0.82, P < 0.001), 20% lower risk of severe sepsis with septic shock (OR 0.80, 95% CI 0.67-0.93, P = 0.004), shorter hospital length of stay [9.87 (±8.94), P < 0.001] and brief duration of mechanical ventilation [8.90 (±8.94), P < 0.001]. CONCLUSION: Chronic use of statins is associated with reduced mortality and improved clinical outcomes in patients hospitalized for COVID-19.

Severe COVID-19-A Review of Suggested Mechanisms Based on the Role of Extracellular Matrix Stiffness.

The severity of COVID-19 commonly depends on age-related tissue stiffness. The aim was to review publications that explain the effect of microenvironmental extracellular matrix stiffness on cellular processes. Platelets and endothelial cells are mechanosensitive. Increased tissue stiffness can trigger cytokine storm with the upregulated expression of pro-inflammatory cytokines, such as tumor necrosis factor alpha and interleukin IL-6, and tissue integrity disruption, leading to enhanced virus entry and disease severity. Increased tissue stiffness in critically ill COVID-19 patients triggers platelet activation and initiates plague formation and thrombosis development. Cholesterol content in cell membrane increases with aging and further enhances tissue stiffness. Membrane cholesterol depletion decreases virus entry to host cells. Membrane cholesterol lowering drugs, such as statins or novel chitosan derivatives, have to be further developed for application in COVID-19 treatment. Statins are also known to decrease arterial stiffness mitigating cardiovascular diseases. Sulfated chitosan derivatives can be further developed for potential use in future as anticoagulants in prevention of severe COVID-19. Anti-TNF-α therapies as well as destiffening therapies have been suggested to combat severe COVID-19. The inhibition of the nuclear factor kappa-light-chain-enhancer of activated B cells pathway must be considered as a therapeutic target in the treatment of severe COVID-19 patients. The activation of mechanosensitive platelets by higher matrix stiffness increases their adhesion and the risk of thrombus formation, thus enhancing the severity of COVID-19.

Study protocol of the PROUD48 study comparing the effects of pemafibrate and omega-3 fatty acid ethyl esters on ApoB-48 in statin-treated patients with dyslipidaemia: a prospective, multicentre, open-label, randomised, parallel group trial in Japan.

INTRODUCTION: This study will compare the lowering effects of pemafibrate and omega-3 fatty acid ethyl esters on fasting apolipoprotein B-48 (apoB-48), a surrogate marker reflecting postprandial hypertriglyceridaemia, which is a residual risk for atherosclerotic cardiovascular disease with statin treatment. METHODS AND ANALYSIS: This is a prospective, multicentre, open-label, randomised, parallel group, comparative trial. Adult Japanese patients with dyslipidaemia receiving statin treatment for more than 4 weeks with a fasting triglyceride level ≥177 mg/dL will be randomly assigned in a 1:1 ratio to receive pemafibrate (0.4 mg orally per day) or omega-3 fatty acid ethyl esters (4 g orally per day) for 16 weeks. The primary endpoint is the percentage change in fasting apoB-48 from baseline to 16 weeks. The key secondary endpoints include the change in fasting apoB-48 from baseline to 16 weeks, the percentage changes in clinical variables from baseline to 16 weeks and the incidence of adverse events. A total sample size of 128 was set by considering the increased drop-out rate due to the COVID-19 pandemic, in addition to estimation based on a two-sided alpha of 0.05 and a power of 0.8 for apoB-48. ETHICS AND DISSEMINATION: The study protocol has been approved by the Certified Review Board of the University of the Ryukyus for Clinical Research Ethics (No. CRB7200001) and will be performed in accordance with the Declaration of Helsinki. Written informed consent will be obtained from all participants. The results of the study will be disseminated through publications and conference presentations to participants, healthcare professionals and the public. TRIAL REGISTRATION NUMBER: jRCTs071200011.

Phenotypical and Functional Alteration of γδ T Lymphocytes in COVID-19 Patients: Reversal by Statins.

(1) Background: statins have been considered an attractive class of drugs in the pharmacological setting of COVID-19 due to their pleiotropic properties and their use correlates with decreased mortality in hospitalized COVID-19 patients. Furthermore, it is well known that statins, which block the mevalonate pathway, affect γδ T lymphocyte activation. As γδ T cells participate in the inflammatory process of COVID-19, we have investigated the therapeutical potential of statins as a tool to inhibit γδ T cell pro-inflammatory activities; (2) Methods: we harvested peripheral blood mononuclear cells (PBMCs) from COVID-19 patients with mild clinical manifestations, COVID-19 recovered patients, and healthy controls. We performed ex vivo flow cytometry analysis to study γδ T cell frequency, phenotype, and exhaustion status. PBMCs were treated with Atorvastatin followed by non-specific and specific stimulation, to evaluate the expression of pro-inflammatory cytokines; (3) Results: COVID-19 patients had a lower frequency of circulating Vδ2+ T lymphocytes but showed a pronounced pro-inflammatory profile, which was inhibited by in vitro treatment with statins; (4) Conclusions: the in vitro capacity of statins to inhibit Vδ2+ T lymphocytes in COVID-19 patients highlights a new potential biological function of these drugs and supports their therapeutical use in these patients.

COVID-19 outcomes in patients taking cardioprotective medications.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) caused a worldwide pandemic and has led to over five million deaths. Many cardiovascular risk factors (e.g. obesity or diabetes) are associated with an increased risk of adverse outcomes in COVID-19. On the other hand, it has been suggested that medications used to treat cardiometabolic conditions may have protective effects for patients with COVID-19. OBJECTIVES: To determine whether patients taking four classes of cardioprotective medications-aspirin, metformin, renin angiotensin aldosterone system inhibitors (RAASi) and statins-have a lower risk of adverse outcomes of COVID-19. METHODS: We conducted a retrospective cohort study of primary care patients at a large integrated healthcare delivery system who had a positive COVID-19 test between March 2020 and March 2021. We compared outcomes of patients who were taking one of the study medications at the time of the COVID-19 test to patients who took a medication from the same class in the past (to minimize bias by indication). The following outcomes were compared: a) hospitalization; b) ICU admission; c) intubation; and d) death. Multivariable analysis was used to adjust for patient demographics and comorbidities. RESULTS: Among 13,585 study patients, 1,970 (14.5%) were hospitalized; 763 (5.6%) were admitted to an ICU; 373 (2.8%) were intubated and 720 (5.3%) died. In bivariate analyses, patients taking metformin, RAASi and statins had lower risk of hospitalization, ICU admission and death. However, in multivariable analysis, only the lower risk of death remained statistically significant. Patients taking aspirin had a significantly higher risk of hospitalization in both bivariate and multivariable analyses. CONCLUSIONS: Cardioprotective medications were not associated with a consistent benefit in COVID-19. As vaccination and effective treatments are not yet universally accessible worldwide, research should continue to determine whether affordable and widely available medications could be utilized to decrease the risks of this disease.

Global, regional and national trends in statin utilisation in high-income and low/middle-income countries, 2015-2020.

OBJECTIVE: Prior studies have reported inequitable global access to essential medicines for cardiovascular disease (CVD) prevention, especially statins. Here we examine recent trends and disparities in statin utilisation at the income group, regional and country levels. DESIGN: Ecological study. Pharmaceutical sales data were used to examine statin utilisation in high-income counties (HICs) and low/middle-income countries (LMICs) from 2015 to 2020. Population estimates were obtained from the Global Burden of Disease. Fixed-effects panel regression analysis was used to examine associations between statin utilisation and country-level factors. SETTING: Global, including 41 HICs and 50 LMICs. PARTICIPANTS: Population older than 40 years of age. PRIMARY AND SECONDARY OUTCOME MEASURES: Statin utilisation was measured using defined daily doses (DDDs) per 1000 population ≥40 years per day (TPD). RESULTS: Globally, statin utilisation increased 24.7% from 54.7 DDDs/TPD in 2015 to 68.3 DDDs/TPD in 2020. However, regional and income group disparities persisted during this period. In 2020, statin utilisation was more than six times higher in HICs than LMICs (192.4 vs 28.4 DDDs/TPD, p<0.01). Substantial disparities were also observed between LMICs, ranging from 3.1 DDDs/TPD in West African nations to 225.0 DDDs/TPD in Lebanon in 2020. While statin utilisation increased in most LMICs between 2015 and 2020, several experienced declines in utilisation, most notably Venezuela (-85.1%, from 92.3 to 14.0 DDDs/TPD). In LMICs, every $100 increase in per capita health spending was associated with a 17% increase in statin utilisation, while every 10% increase in out-of-pocket health spending was associated with a 11% decline (both p<0.05). CONCLUSIONS: Despite global increases in statin utilisation, there are substantial regional and country-level disparities between HICs and LMICs. To address global CVD disparities, policymakers should promote increased and equitable access to statins in LMICs.

Effects of statins on outcomes in Hispanic patients with COVID-19.

The Hispanic population is regarded among those who are at greater risk of adverse prognoses due to higher rates of diabetes and obesity in the USA during the COVID-19 pandemic. Statin medications are speculated to help treat the infection by decreasing inflammation caused by COVID-19. In this retrospective, observational study, outcomes of statin use were assessed among Hispanic patients with COVID-19 by screening all patients hospitalized between March, 2020 and March, 2021 at a tertiary care hospital in El Paso, Texas, resulting in a total of 1039 patients. The patients were categorized into a group of either being on statins or not. The considered outcomes were mechanical ventilation, intensive care unit (ICU) hospitalization, oxygen supplementation at discharge, hospital length of stay, and mortality. Patients receiving statins were observed to be older with more comorbidities. In the propensity-scores adjusted analysis, no association was found between statin use and: mortality (adjusted risk ratio (aRR)=0.96, p=0.754), mechanical ventilation (aRR=0.91, p=0.503), ICU transfer (aRR=0.96, p=0.395), and O2 supplementation at discharge (aRR=1.03, p=0.729). These outcomes were also evaluated in patients who had myocardial infarction and stroke with COVID-19. Among these patients, association was found between statin use and: a reduced risk of mortality (aRR=0.61, p=0.005), mechanical ventilation (aRR=0.53, p=0.012) and ICU transfers (aRR=0.81, p=0.005). These results may not give us a reason to start patients on statins for the specific treatment of COVID-19, but it may be sufficient evidence to suggest statins should not be discontinued during hospitalization due to COVID-19.

Co-Application of Statin and Flavonoids as an Effective Strategy to Reduce the Activity of Voltage-Gated Potassium Channels Kv1.3 and Induce Apoptosis in Human Leukemic T Cell Line Jurkat.

Voltage-gated potassium channels of the Kv1.3 type are considered a potential new molecular target in several pathologies, including some cancer disorders and COVID-19. Lipophilic non-toxic organic inhibitors of Kv1.3 channels, such as statins and flavonoids, may have clinical applications in supporting the therapy of some cancer diseases, such as breast, pancreas, and lung cancer; melanoma; or chronic lymphocytic leukemia. This study focuses on the influence of the co-application of statins-simvastatin (SIM) or mevastatin (MEV)-with flavonoids 8-prenylnaringenin (8-PN), 6-prenylnarigenin (6-PN), xanthohumol (XANT), acacetin (ACAC), or chrysin on the activity of Kv1.3 channels, viability, and the apoptosis of cancer cells in the human T cell line Jurkat. We showed that the inhibitory effect of co-application of the statins with flavonoids was significantly more potent than the effects exerted by each compound applied alone. Combinations of simvastatin with chrysin, as well as mevastatin with 8-prenylnaringenin, seem to be the most promising. We also found that these results correlate with an increased ability of the statin-flavonoid combination to reduce viability and induce apoptosis in cancer cells compared to single compounds. Our findings suggest that the co-application of statins and flavonoids at low concentrations may increase the effectiveness and safety of cancer therapy. Thus, the simultaneous application of statins and flavonoids may be a new and promising anticancer strategy.

Multiplex Testing of the Effect of Statins on Disease Severity Risk in COVID-19 Cases.

Statins have pleiotropic effects on inflammatory responses in addition to their lipid-lowering action, which contributes to their favorable effect on cardiovascular disorders. Statins affect adhesion, migration, antigen presentation, and cytokine generation of immune cells. Pre-clinical and clinical studies suggest that statin intervention targeted early in the infection might help COVID-19 patients to reduce the effects of acute respiratory distress syndrome (ARDS), the cytokine storm, and vascular collapse by modulating harmful pathogenic mechanisms. This chapter presents a protocol for measuring blood-based biomarkers predictive of these responses in COVID-19 patients using two specific multiplex immunoassays that target proteins that differ widely in concentration.