Patients with diabetes are at higher risk of cardiovascular diseases and cognitive impairment. SGLT2 inhibitors (Empagliflozin, Canagliflozin, Dapagliflozin, Ertugliflozin, Sotagliflozin) are newer hypoglycemic agents with many pleiotropic effects. In this review, we discuss their neuroprotective potential. SGLT2 inhibitors (SGLT2i) are lipid-soluble and reach the brain/serum ratio from 0.3 to 0.5. SGLT receptors are present in the central nervous system (CNS). Flozins are not fully SGLT2-selective and have an affinity for the SGLT1 receptor, which is associated with protection against ischemia/reperfusion brain damage. SGLT2i show an anti-inflammatory and anti-atherosclerotic effect, including reduction of proinflammatory cytokines, M2 macrophage polarization, JAK2/STAT1 and NLRP3 inflammasome inhibition, as well as cIMT regression. They also mitigate oxidative stress. SGLT2i improve endothelial function, prevent remodeling and exert a protective effect on the neurovascular unit, blood-brain barrier, pericytes, astrocytes, microglia, and oligodendrocytes. Flozins are also able to inhibit AChE, which contributes to cognitive improvement. Empagliflozin significantly increases the level of cerebral BDNF, which modulates neurotransmission and ensures growth, survival, and plasticity of neurons. Moreover, they may be able to restore the circadian rhythm of mTOR activation, which is quite a novel finding in the field of research on metabolic diseases and cognitive impairment. SGLT2i have a great potential to protect against atherosclerosis and cognitive impairment in patients with type 2 diabetes mellitus.

The virus responsible for the current COVID-19 pandemic is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): a new virus with high infectivity and moderate mortality. The major clinical manifestation of COVID-19 is interstitial pneumonia, which may progress to acute respiratory distress syndrome (ARDS). However, the disease causes a potent systemic hyperin-flammatory response, i.e., a cytokine storm or macrophage activation syndrome (MAS), which is associated with thrombotic complications. The complexity of the disease requires appropriate intensive treatment. One of promising treatment is statin administration, these being 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors that exert pleiotropic anti-inflammatory effects. Recent studies indicate that statin therapy is associated with decreased mortality in COVID-19, which may be caused by direct and indirect mechanisms. According to literature data, statins can limit SARS-CoV-2 cell entry and replication by inhibiting the main protease (Mpro) and RNA-dependent RNA polymerase (RdRp). The cytokine storm can be ameliorated by lowering serum IL-6 levels; this can be achieved by inhibiting Toll-like receptor 4 (TLR4) and modulating macrophage activity. Statins can also reduce the complications of COVID-19, such as thrombosis and pulmonary fibrosis, by reducing serum PAI-1 levels, attenuating TGF-β and VEGF in lung tissue, and improving endothelial function. Despite these benefits, statin therapy may have side effects that should be considered, such as elevated creatinine kinase (CK), liver enzyme and serum glucose levels, which are already elevated in severe COVID-19 infection. The present study analyzes the latest findings regarding the benefits and limitations of statin therapy in patients with COVID-19.

SGLT2 (Sodium-glucose Cotransporter-2) inhibitors are newer glucose-lowering drugs with many cardiovascular benefits that are not fully understood yet. Endothelial integrity plays a key role in cardiovascular homeostasis. 25-hydroxycholesterol (25-OHC), which is a proatherogenic stimuli that impairs endothelial barrier functions. VE-cadherin is an endothelial-specific protein crucial in maintaining endothelial integrity. The aim of this study was to assess the influence of SGLT2i on the integrity of endothelial cells interrupted by 25-OHC. We also aimed to evaluate whether this effect is associated with changes in the levels of VE-cadherin. We pre-incubated HUVECs with 10 μg/mL of 25-hydroxycholesterol (25-OHC) for 4 h and then removed it and incubated endothelial cells with 1 μM of empagliflozin, 1 μM canagliflozin, or 1 μM dapagliflozin for 24 h. The control group included HUVECs cultured with the medium or with 25-OHC 10 μg/mL. The integrity of endothelial cells was measured by the RTCA-DP xCELLigence system, and VE-cadherin was assessed in confocal microscopy. Our results show that SGLT2 inhibitors significantly increase endothelial integrity in comparison to medium controls, and they improve endothelial cell integrity interrupted by 25-OHC. This effect is associated with significant improvements in VE-cadherin levels. SGLT2i: empagliflozin, canagliflozin, and dapagliflozin have a beneficial effect on the endothelial cell integrity and VE-cadherin levels reduced by 25-OHC.

Background: Lipoprotein (a)–Lp(a) has proinflammatory, prothrombotic and proatherogenic properties and may theoretically influence the course of COVID-19.Objectives: The aim of the study was to explore whether patients hospitalized due to COVID-19 with Lp(a) ≥30mg/dl may develop a worse course of the disease, increased incidence of thromboembolic complications, intubation and ICU hospitalization or death.Patients and methods: A retrospective analysis was performed of 124 patients hospitalized due to COVID-19 in the Department of Internal Diseases and Clinical Pharmacology between 29 November 2020 and 15 April 2021. The only exclusion criterion was age≥80 years. Patients were divided into two groups: 1. COVID-19 patients with Lp(a) <30mg/dl regarded as not elevated n = 80; 2. COVID-19 patients with Lp(a) ≥30 regarded as elevated n = 44.Results: A total of 124 COVID-19 patients were included in the study (66 men and 58 women) with a mean age of 62.8±11 years. COVID-19 patients with elevated Lp(a) level had significantly longer hospitalization time (11 vs. 9.5 days; p = 0.0362), more extensive radiological changes in CT scan (35 vs. 30%; p = 0.0301) and higher oxygen demand on admission (8 vs. 5L/min; p = 0.0428). Elevated Lp(a) was also associated with significantly higher OR for High Flow Nasal Oxygen Therapy (HFNOT) OR = 3.5 95%CI(1.2;8.9), p = 0.0140, Intubation and ICU OR = 4.1 95%CI(1.1;15.2) p = 0.0423, Death OR = 2.8 95%CI(0.9;8.5), p = 0.0409.Conclusions: Elevated Lp(a) might be one of the factors which contribute to a more severe course of COVID-19; however, further studies including larger groups of patients are needed.

Refractory hypercholesterolemia (RH) is characterized by the failure of patients to achieve therapeutic targets for low-density lipoprotein-cholesterol (LDL-C) despite receiving maximal tolerable doses of standard lipid-lowering treatments. It predominantly impacts individuals with familial hypercholesterolemia (FH), thereby elevating the risk of cardiovascular complications. The prevalence of RH is now recognized to be substantially greater than previously thought. This review provides a comprehensive insight into current and emerging therapies for RH patients, including groundbreaking genetic-based therapeutic approaches. The review places emphasis on the dependency of therapies on low-density lipoprotein receptors (LDLRs) and highlights the critical role of considering LDLR activity in RH patients for individualization of the treatment. Refractory hypercholesterolemia (RH) is a condition where patients are unable to get below target levels of 'bad' cholesterol despite receiving maximum doses of standard treatments. It is commonly present in those with a genetic disorder, called familial hypercholesterolemia (FH), known to increase the risk of heart complications. RH's prevalence is now understood to be higher than previously believed and this review offers insights into current and emerging therapies for RH, including genetic-based treatments. It stresses the importance of the mechanistic pathways behind cholesterol clearance, particularly low-density lipoprotein receptor (LDLR) activity, in RH treatment customization. Article highlightsRefractory hypercholesterolemia - definition, epidemiological data.Therapeutic targets for the treatment of refractory hypercholesterolemiaLow-density lipoprotein receptor (LDLR)-dependent therapies targeting cholesterol production and upregulating LDLRThe efficacy of lipid-lowering treatments that depend on low-density lipoprotein receptor (LDLR) activity may be limited in patients with importantly reduced LDLR function, particularly among homozygous familial hypercholesterolemia (HoFH) patients with very low or no residual LDLR activity.3-Hydroxy-3-Methylglutaryl-Coenzyme A (HMG-CoA) inhibitors (statins)Statins as first-line lipid-lowering drugs, mechanism, efficacy, side effects.Adenosine triphosphate (ATP)-citrate lyase inhibitorBempedoic acid is a good therapeutic option for statin-intolerant patients. Mechanism of action, efficacy, side effects.PCSK9 inhibitorsReview of therapeutic options aimed at PCSK9 inhibition including monoclonal antibodies, siRNA, and therapeutic genome editing.LDLR gene replacement therapy and gene editing strategiesClinical trial of LDLR gene replacement therapy in HoFH, potential of clustered regularly interspaced short palindromic repeats (CRISPR)-based methods.LDLR-independent therapiesAngiopoietin-like 3 inhibitionAngiopoietin-like 3 (ANGPTL3) inhibition as a therapeutic target which is LDLR independent. Efficacy of monoclonal antibodies, siRNA, and therapeutic genome editing.MTP inhibitionMechanism of action, efficacy, and side effects of lomitapide.CETP inhibitionDrug development history, efficacy, and limitations of use.Inhibition of apolipoprotein B (apoB) formationMechanism of action, efficacy, and side effects leading to Mipomersen cessation.Cholesterol absorption inhibition: ezetimibeMechanism of action, efficacy, and side effects of ezetimibe.Agents targeting Lipoprotein (a) (Lp[a])Atherogenic mechanisms of Lipoprotein (a) (Lp[a]). Lp(a) lowering the potential of currently available drugs. Novel therapies aimed at Lp(a) reduction are available within clinical trials.Combination of therapiesSummary of lipid-lowering potential of drug combinations.LDL and Lp(a) apheresisTypes of aphereses, indications, limitations of use.High-density lipoprotein (HDL) autotransfusionThe efficacy of plasma delipidation system (PDS-2TM) in patients with atherosclerosis, who do not respond adequately to available pharmacological options.Refractory hypercholesterolemia beyond LDL-cholesterol: residual cardiovascular risk associated with remnant cholesterolThe role of remnant cholesterol in triglyceride-rich lipoproteins in residual cardiovascular risk and potential therapeutic role of anti-apolipoprotein C-III (APOC3) therapy.Refractory hypercholesterolemia in the pediatric populationSummary of available therapeutic options for pediatric population with severe hypercholesterolemia.ConclusionRefractory hypercholesterolemia appears to be a more prevalent condition than might be initially perceived. In terms of its management, it is of particular importance to custom-tailor the appropriate treatment regimen depending on the underlying etiology. The principal determinant for therapy selection should be based on LDL receptor activity.

The clinical manifestations of COVID-19 which mainly involve the respiratory system may however affect also cardiovascular system. There are a lot and still increasing numbers of reports revealing c