Why have SGLT2 Inhibitors Failed to Achieve the Desired Success in COVID-19?

The SARS-CoV-2 virus emerged towards the end of 2019 and caused a major worldwide pandemic lasting at least 2 years, causing a disease called COVID-19. SARS-CoV-2 caused a severe infection with direct cellular toxicity, stimulation of cytokine release, increased oxidative stress, disruption of endothelial structure, and thromboinflammation, as well as angiotensin-converting enzyme 2 (ACE2) down-regulation-mediated renin-angiotensin system (RAS) activation. In addition to glucosuria and natriuresis, sodium-glucose transport protein 2 (SGLT2) inhibitors (SGLT2i) cause weight loss, a decrease in glucose levels with an insulin-independent mechanism, an increase in erythropoietin levels and erythropoiesis, an increase in autophagy and lysosomal degradation, Na+/H+-changer inhibition, prevention of ischemia/reperfusion injury, oxidative stress and they have many positive effects such as reducing inflammation and improving vascular function. There was great anticipation for SGLT2i in treating patients with diabetes with COVID-19, but current data suggest they are not very effective. Moreover, there has been great confusion in the literature about the effects of SGLT2i on COVID-19 patients with diabetes . Various factors, including increased SGLT1 activity, lack of angiotensin receptor blocker co-administration, the potential for ketoacidosis, kidney injury, and disruptions in fluid and electrolyte levels, may have hindered SGLT2i's effectiveness against COVID-19. In addition, the duration of use of SGLT2i and their impact on erythropoiesis, blood viscosity, cholesterol levels, and vitamin D levels may also have played a role in their failure to treat the virus. This article aims to uncover the reasons for the confusion in the literature and to unravel why SGLT2i failed to succeed in COVID-19 based on some solid evidence as well as speculative and personal perspectives.

Severe acute respiratory syndrome coronavirus 2 may cause liver injury via Na+/H+ exchanger.

The liver has many significant functions, such as detoxification, the urea cycle, gluconeogenesis, and protein synthesis. Systemic diseases, hypoxia, infections, drugs, and toxins can easily affect the liver, which is extremely sensitive to injury. Systemic infection of severe acute respiratory syndrome coronavirus 2 can cause liver damage. The primary regulator of intracellular pH in the liver is the Na+/H+ exchanger (NHE). Physiologically, NHE protects hepatocytes from apoptosis by making the intracellular pH alkaline. Severe acute respiratory syndrome coronavirus 2 increases local angiotensin II levels by binding to angiotensin-converting enzyme 2. In severe cases of coronavirus disease 2019, high angi-otensin II levels may cause NHE overstimulation and lipid accumulation in the liver. NHE overstimulation can lead to hepatocyte death. NHE overstimulation may trigger a cytokine storm by increasing proinflammatory cytokines in the liver. Since the release of proinflammatory cytokines such as interleukin-6 increases with NHE activation, the virus may indirectly cause an increase in fibrinogen and D-dimer levels. NHE overstimulation may cause thrombotic events and systemic damage by increasing fibrinogen levels and cytokine release. Also, NHE overstimulation causes an increase in the urea cycle while inhibiting vitamin D synthesis and gluconeogenesis in the liver. Increasing NHE3 activity leads to Na+ loading, which impairs the containment and fluidity of bile acid. NHE overstimulation can change the gut microbiota composition by disrupting the structure and fluidity of bile acid, thus triggering systemic damage. Unlike other tissues, tumor necrosis factor-alpha and angiotensin II decrease NHE3 activity in the intestine. Thus, increased luminal Na+ leads to diarrhea and cytokine release. Severe acute respiratory syndrome coronavirus 2-induced local and systemic damage can be improved by preventing virus-induced NHE overstimulation in the liver.

Prolonged NHE Activation may be both Cause and Outcome of Cytokine Release Syndrome in COVID-19.

The release of cytokines and chemokines such as IL-1ß, IL-2, IL-6, IL-7, IL-10, TNF-α, IFN-γ, CCL2, CCL3, and CXCL10 is increased in critically ill patients with COVID-19. Excessive cytokine release during COVID-19 is related to increased morbidity and mortality. Several mechanisms are put forward for cytokine release syndrome during COVID-19. Here we have mentioned novel pathways. SARS-CoV-2 increases angiotensin II levels by rendering ACE2 nonfunctional. Angiotensin II causes cytokine release via AT1 and AT2 receptors. Moreover, angiotensin II potently stimulates the Na+/H+ exchanger (NHE). It is a pump found in the membranes of many cells that pumps Na+ inward and H+ outward. NHE has nine isoforms. NHE1 is the most common isoform found in endothelial cells and many cells. NHE is involved in keeping the intracellular pH within physiological limits. When the intracellular pH is acidic, NHE is activated, bringing the intracellular pH to physiological levels, ending its activity. Sustained NHE activity is highly pathological and causes many problems. Prolonged NHE activation in COVID-19 may cause a decrease in intracellular pH through H+ ion accumulation in the extracellular area and subsequent redox reactions. The activation reduces the intracellular K+ concentration and leads to Na+ and Ca2+ overload. Increased ROS can cause intense cytokine release by stimulating NF-κB and NLRP3 inflammasomes. Cytokines also cause overstimulation of NHE. As the intracellular pH decreases, SARS-CoV-2 rapidly infects new cells, increasing the viral load. This vicious circle increases morbidity and mortality in patients with COVID-19. On the other hand, SARS-CoV-2 interaction with NHE3 in intestinal tissue is different from other tissues. SARS-CoV-2 can trigger CRS via NHE3 inhibition by disrupting the intestinal microbiota. This review aimed to help develop new treatment models against SARS-CoV-2- induced CRS by revealing the possible effects of SARS-CoV-2 on the NHE.

Proprotein convertase subtilisin/kexin type 9 is associated with atherosclerosis in patients with Behcet's disease.

OBJECTIVES: The incidence of cardiovascular disease is increased in patients with Behcet's disease (BD). Proprotein convertase subtilisin/kexin type 9 (PCSK9) causes the acceleration of atherosclerosis. We aimed to investigate whether there is a relationship between PCSK9 with carotid artery intima-media thickness (cIMT), a marker of subclinical atherosclerosis, and BD disease activity. METHODS: Fifty-eight patients with BD and 58 age-, gender-, and body mass index (BMI)-matched healthy control subjects were included in the study. The disease activity of the patients was estimated. Individuals' cIMT values were measured, and PCSK9 levels were studied. RESULTS: Patients with BD' cIMT (0.51 ± 0.1 vs 0.41 ± 0.1 mm, p < .001) and PCSK9 (623.2 ± 101.7 ± 10.1 vs 528.3 ± 242.7 ng/ml, p = .007), values were significantly higher than the control group. In stepwise regression analysis, there was an independent relationship between cIMT with PCSK9 (ß = 0.179, p < .050). There was no independent relationship between disease activities with PCSK9. Based on the ROC curve analysis, the PCSK9 optimal cutoff value for cIMT was 595.1 ng/ml, sensitivity 66.7%, specificity 64.7% (AUC = 0.672; 95% CI: 0.530-0.815, p = .040). CONCLUSION: There is a strong independent association between subclinical atherosclerosis and PCSK9 in patients with BD. There may be no independent association between PCSK9 and disease activity.

The effects of TNF-α inhibitors on carbon tetrachloride-induced nephrotoxicity.

OBJECTIVES: Carbon tetrachloride (CCl4), employed in various industrial fields, can cause acute damage in renal tissues. This study investigated the therapeutic effect of the TNF-alpha inhibitor Infliximab on TGF-ß and apoptosis caused by acute kidney image induced by CCl4. METHODS: Twenty-four male Sprague-Dawley rats were assigned into control, CCl4, and CCl4+ Infliximab groups. The control group received an isotonic saline solution, and the CCl4 group 2 mL/kg CCl4 intraperitoneally (i.p). The CCl4+ Infliximab group was given 7 mg/kg Infliximab 24 hours after administration of 2 mL/kg CCl4. Kidney tissues were removed at the end of the experiment and subjected to histopathological and biochemical analysis. RESULTS: The application of CCl4 led to tubular necrosis, inflammation, vascular congestion, and increased Serum BUN and creatinine values. An increase in caspase-3 activity also occurred in the CCl4 group. However, Infliximab exhibited an ameliorating effect on kidney injury by causing a decrease in the number of apoptotic cells. Tissue ADA and TGF-ß values of the CCL4 group were significantly higher than the values of the control group (p = .001, p < .001 respectively) and CCL4+ Inf group (p = .004, p = .015, respectively). CONCLUSIONS: This study shows that Infliximab ameliorates nephrotoxicity by reducing lipid peroxidation, oxidative stress, and apoptosis in acute kidney damage developing in association with CCl4 administration. These findings are promising in terms of the ameliorating role of TNF-alpha inhibitors in acute kidney injury.

Strong relationship between cholesterol, low-density lipoprotein receptor, Na+/H+ exchanger, and SARS-COV-2: this association may be the cause of death in the patient with COVID-19.

Lipids have a wide variety and vital functions. Lipids play roles in energy metabolism, intracellular and extracellular signal traffic, and transport of fat-soluble vitamins. Also, they form the structure of the cell membrane. SARS-CoV-2 interacts with lipids since its genetic material contains lipid-enveloped ribonucleic acid (RNA). Previous studies have shown that total cholesterol, high-density lipoprotein, and low-density lipoprotein (LDL) levels are lower in patients with severe novel coronavirus disease 2019 (COVID-19) compared to patients with non-severe COVID-19.Na+/H+ Exchanger (NHE) is an important antiport that keeps the intracellular pH value within physiological limits. When the intracellular pH falls, NHE is activated and pumps H+ ions outward. However, prolonged NHE activation causes cell damage and atherosclerosis. Prolonged NHE activation may increase susceptibility to SARS-CoV-2 infection and severity of COVID-19.In COVID-19, increased angiotensin II (Ang II) due to angiotensin-converting enzyme-2 (ACE2) dysfunction stimulates NHE. Lipids are in close association with the NHE pump. Prolonged NHE activity increases the influx of H+ ions and free fatty acid (FFA) inward. Ang II also causes increased low-density lipoprotein receptor (LDLR) levels by inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9). Thus, intracellular atheroma plaque formation is accelerated.Besides, SARS-CoV-2 may replicate more rapidly as intracellular cholesterol increases. SARS-CoV-2 swiftly infects the cell whose intracellular pH decreases with NHE activation and FFA movement. Novel treatment regimens based on NHE and lipids should be explored for the treatment of COVID-19.

Restless Leg Syndrome and Sleep Disorders in Patients with Rheumatoid Arthritis and Its Relation with Anemia Parameters.

OBJECTIVES: We aimed to investigate the prevalence of restless legs syndrome (RLS) and sleep disorders in patients with rheumatoid arthritis (RA), and the association of iron deficiency with them. MATERIALS AND METHODS: The study included 72 patients with RA (59 females, 13 males), and 50 healthy control subjects (57 females, 15 males). Assessments were made using the International RLS Rating Scale, Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale, Fatigue Severity Scale (FSS), Beck anxiety and depression index and the SF-36 quality of life scores. RESULTS: We found that the frequency of RLS in RA patients was 29.1% and 13.8% in healthy control (p = 0.021). RA patients had 44.4% iron deficiency and 5.5% anemia of chronic disease. We found that 52.3% of patients with iron deficiency had RLS. There was an independent relationship between present of RLS and FSS (Beta [ß] = 0.317, p = 0.005) and total iron binding capacity (TIBC) (ß = 0.244, p = 0.031). There was an independent relationship between RLS severity score and PSQI (ß = 0.264, p = 0.025) and social functionality (ß = 0.302, p = 0.009). CONCLUSION: The prevalence of iron deficiency is high in RA in the developing countries. Analysis obtained in patients with RA is suggestive of an association between iron deficiency and increased frequency of RLS. The presence of RLS in patients with RA negatively affects sleep quality, psychiatric status, and quality of life of patients with RA. TIBC value may be a predictive marker for early detection of RLS in patients with RA.

Effects of the Na+/H+ Ion Exchanger on Susceptibility to COVID-19 and the Course of the Disease.

The Na+/H+ ion exchanger (NHE) pumps Na+ inward the cell and H+ ion outside the cell. NHE activity increases in response to a decrease in intracellular pH, and it maintains intracellular pH in a narrow range. Patients with obesity, diabetes, and hypertension and the elderly are prone to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. The angiotensin II (Ang II) level is high in chronic diseases such as diabetes, hypertension, and obesity. Ang II is the main stimulator of NHE, and an increased Ang II level causes prolonged NHE activation in these patients. The long-term increase in NHE activity causes H+ ions to leave the cell in patients with diabetes, hypertension, and obesity. Increasing H+ ions outside the cell lead to an increase in oxidative stress and reactive oxygen species. H+ ion flows into the cell due to the increased oxidative stress. This vicious circle causes intracellular pH to drop. Although NHE is activated when intracellular pH decreases, there is prolonged NHE activation in chronic diseases such as aforementioned. Novel coronavirus disease 2019 (COVID-19) progression may be more severe and mortal in these patients. SARS-CoV-2 readily invades the cell at low intracellular pH and causes infection. The renin-angiotensin system and NHE play a vital role in regulating intracellular pH. The reduction of NHE activity or its prolonged activation may cause susceptibility to SARS-CoV-2 infection by lowering intracellular pH in patients with diabetes, hypertension, and obesity. Prolonged NHE activation in these patients with COVID-19 may worsen the course of the disease. Scientists continue to investigate the mechanism of the disease and the factors that affect its clinical progression.

Can emapalumab be life saving for refractory, recurrent, and progressive cytokine storm caused by COVID-19, which is resistant to anakinra, tocilizumab, and Janus kinase inhibitors.

Although many potent drugs have been used for cytokine storm, mortality is high for patients with coronavirus disease-2019 (COVID-19), which is followed up in the intensive care unit. Interferons (IFNs) are the major cytokines of the antiviral defense system released from many cell types. However, IFN-γ plays a key role in both primary and secondary cytokine storms. If the cytokine storm is not treated urgently, it will be fatal; therefore, it should be treated immediately. Anakinra, an interleukin-1 (IL-1) antagonist, tocilizumab, an IL-6 antagonist, and Janus kinase (JAK) inhibitors are successfully used in cytokine storm caused by COVID-19. However, sometimes, despite these treatments, the patient's clinical course does not improve. Emapalumab (Eb) is the human immunoglobulin G1 monoclonal antibody and is a potent and noncompetitive antagonist of IFN-γ. Eb can be life saving for cytokine storm caused by COVID-19, which is resistant to anakinra, tocilizumab, and JAK inhibitors.

Could ferritin, vitamin B12, and vitamin D play a role in the etiopathogenesis of fibromyalgia syndrome?

Introduction. Fibromyalgia syndrome (FS) comprises general body pain, sleep disturbances, and fatigue. Vitamin B12 (VB), vitamin D (VD), and iron deficiencies lead to similar complaints. First, this study aimed to evaluate the VB, VD, and ferritin levels of patients with FS. Second, it aimed to investigate whether there was a relationship between these parameters and FS severity. Material and methods. The study included 58 female patients with FS and 58 healthy females as a control group. The patients completed the Fibromyalgia Impact Questionnaire (FIQ), Visual Analog Scale (VAS), fatigue questionnaire, Pittsburgh sleep quality scale, and the Short Form-36 (SF-36). This study examined the VD, VB, and ferritin levels of the patient and control groups. Results. The VB (240.0 [110.0-394.0] vs 291.0 [210.0-609.0] pg/ml, p<0.001), VD (12.5 [3.0-45.0] vs 20.0 [5.0-54.0] ng/ml, p=0.013), and ferritin levels (21.2 [4.0-86.0] vs 32.0 [7.1-120.0], ng/ml, p=0.009) of the FS patients were determined to be significantly lower than those of the control group. A negative correlation was determined between the number of tender points and VB, VD, and ferritin levels. In the regression analysis, we found low ferritin levels (odds ratio [OR] 1.036, 95% confidence interval [CI] 1.015-1.058, p<0.001) and VB (OR 1.010, CI 1.002-1.018, p=0.010) to be an independent risk factor for FS. Conclusions. There may be a relationship between VB, VD, and ferritin levels and the number of tender points in patients with FS. Levels of iron and VB may play a vital role in FS etiopathogenesis. However, VD levels may not be a risk factor for FS etiopathogenesis.

The relationship of serum visfatin levels with clinical parameters, flow-mediated dilation, and carotid intima-media thickness in patients with ankylosing spondylitis

Background/aim: Atherosclerotic heart diseases can occur at an early age in patients with ankylosing spondylitis (AS). Flow-mediated dilation (FMD) and carotid intima-media thickness (cIMT) values are reliable markers for early detection of subclinical atherosclerosis in patients with AS. We aimed to investigate the relationship between visfatin levels and indirect markers of subclinical atherosclerosis and endothelial dysfunction in patients with AS. Materials and methods: Forty-two patients diagnosed with AS and 42 age, sex, and body mass index (BMI)-matched controls were included in the study. Visfatin levels, FMD, and cIMT were measured using appropriate methods. Results: Visfatin levels of the patients were significantly higher than controls (p < 0.001). FMD values in patients with AS were significantly lower (p = 0.007) whereas cIMT were significantly higher than the controls (p = 0.003). There was a negative relationship between FMD with visfatin levels (p = 0.004), BASDAI (p = 0.010), and BASFI (p = 0.007). There was a positive relationship between cIMT with visfatin (p = 0.005), BASDAI (p < 0.001), and BASFI (p < 0.001). There was a positive relationship between visfatin with BASDAI (p < 0.001), and BASFI (p < 0.001). Conclusion: Visfatin levels are increased and associated with impaired FMD and increased cIMT in patients with AS. Increased visfatin levels may be associated with subclinical atherosclerosis in AS.

Effects of the COVID-19 pandemic on psychology and disease activity in patients with ankylosing spondylitis and rheumatoid arthritis

Background/aim: The COVID-19 outbreak is known to increase stress levels of most patients with chronic diseases. Patients with ankylosing spondylitis (AS) and rheumatoid arthritis (RA) are highly susceptible to environmental stress. In the current study, we aimed to determine how the COVID-19 pandemic psychologically affected patients with chronic progressive diseases such as AS and RA and the effects of these psychological factors on disease activity. Materials and methods: Age and sex-matched patients with AS (n = 80), RA (n = 80), and healthy controls (n = 80) were included in the study. All participants were evaluated with the "Perceived COVID-19 Threat Form (PCTF)", "Suicide-Ideation Scale (SIS)", "Hospital Anxiety and Depression Scale (HADS)", "The Ability to Cope with Trauma (PACT)", and "Psychological General Well-Being Index (PGWB)" scales. BASDAI was used in patients with AS, and DAS28 was used in patients with RA to assess disease severity. Results: Compared to healthy individuals, patients with RA and AS had lower PGWB scores and higher HADS depression and anxiety subscale scores. Almost all psychometric assessment test scores were worse in AS patients with high-disease activity compared to those in low-disease activity. PACT scores were higher in patients with moderate RA compared to patients with mild RA (p = 0.006). While a positive correlation was identified between BASDAI and most of the psychometric assessment test scores (r = 0 .36 for PCTF, r = 0.53 for depressive scores, r = 0.54 for anxiety scores, r = 0.57 for suicidal ideation), DAS28 scores were found to be associated only with PACT total and PACT perceived forward-focused subscale scores (r = ­.26 and r = .33, respectively). Conclusion: Psychologically, AS and RA patients were found to be worse off compared to healthy controls. The perceived COVID threat and psychological status were associated with disease activity in AS, but not RA patients. Patients with chronic illnesses may be more vulnerable to the psychological effects of the pandemic, which can worsen disease activity.

Alpha-lipoic acid may protect patients with diabetes against COVID-19 infection.

COVID-19 pandemic is spreading rapidly worldwide, and drug selection can affect the morbidity and mortality of the disease positively or negatively. Alpha-lipoic acid (ALA) is a potent antioxidant and reduces oxidative stress and inhibits activation of nuclear factor-kappa B (NF-kB). ALA reduces ADAM17 activity and ACE2 upregulation. ALA is known to have antiviral effects against some viruses. ALA may show antiviral effect by reducing NF-kB activation and alleviating redox reactions. ALA increases the intracellular glutathione strengthens the human host defense. ALA activates ATP dependent K+ channels (Na+, K+-ATPase). Increased K+ in the cell raises the intracellular pH. As the intracellular pH increases, the entry of the virus into the cell decreases. ALA can increase human host defense against SARS-CoV-2 by increasing intracellular pH. ALA treatment increases antioxidant levels and reduces oxidative stress. Thus, ALA may strengthen the human host defense against SARS-CoV-2 and can play a vital role in the treatment of patients with critically ill COVID-19. It can prevent cell damage by decreasing lactate production in patients with COVID-19. Using ALA with insulin in patients with diabetes can show a synergistic effect against SARS-CoV-2. We think ALA treatment will be beneficial against COVID-19 in patients with diabetes.

COVID-19 infection can cause chemotherapy resistance development in patients with breast cancer and tamoxifen may cause susceptibility to COVID-19 infection.

Breast cancer is the most common cancer in women and is the second most common cause of death in women. Estrogen plays an important role in breast tumor etiopathogenesis. Tamoxifen and other anti-estrogen drugs are used in breast cancer patients who have a positive estrogen receptor (ER). While angiotensin II plays a key role in breast cancer etiology and causes tamoxifen resistance, angiotensin 1-7 has been reported to may reduce the spread and invasion of breast cancer. During the COVID-19 infection, the virus blocks ACE2, and angiotensin 1-7 production discontinued. Angiotensin III production may increase as angiotensin II destruction is reduced. Thus, aminopeptidase upregulation may occur. Increased aminopeptidase may develop resistance to chemotherapy in breast cancer patients receiving chemotherapy. Estrogen can have a protective effect against COVID-19. Estrogen increase causes ER-α upregulation in T lymphocytes. Thus, estrogen increases the release of interferon I and III from T lymphocytes. Increasing interferon I and III alleviates COVID-19 infection. Tamoxifen treatment causes down-regulation, mutation, or loss in estrogen receptors. In the long-term use of tamoxifen, its effects on estrogen receptors can be permanent. Thus, since estrogen receptors are damaged or downregulated, estrogen may not act by binding to these receptors. Tamoxifen is a P-glycoprotein inhibitor, independent of its effect on estrogen receptors. It suppresses T cell functions and interferon release. We think tamoxifen may increase the COVID-19 risk due to its antiestrogen and P-glycoprotein inhibitory effects.