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.

Relationship Between Serum Endocan Levels and Other Predictors of Endothelial Dysfunction in Obese Women.

Endocan, or endothelial cell-specific molecule-1 (ESM-1), is a potential inflammatory marker implicated in endothelial dysfunction. The purpose of this study was to determine the correlation between serum endocan levels and the presence and severity of endothelial dysfunction, and the relationships with serum intracellular adhesion molecule-1 (ICAM-1), adiponectin (a marker of inflammation), high sensitivity C-reactive protein (hsCRP) levels, and carotid intima-media thickness (cIMT) in obese subjects. Serum endocan, ICAM-1, adiponectin, hsCRP levels, and cIMT were evaluated in 76 obese women (BMI > 30 kg/m2) and 53 controls (BMI < 25 kg/m2). ICAM-1 (P = .01), hs-CRP (p < 0.001), and cIMT (p < .001) were significantly higher, while adiponectin (P = .006) was significantly lower, in obese women compared with the controls. Serum endocan levels were similar between the obese (470.5 ± 171.3 pg/mL) and controls (471.9 ± 146.3 pg/mL) (P = .732). There was no correlation between serum endocan values and the endothelial dysfunction markers, hsCRP (r = -.021), ICAM-1 (r = -.054), adiponectin (r = .113), or cIMT (r = -.060) in obesity. Endocan is not a suitable marker of endothelial dysfunction in the context of obesity. More research is required to evaluate the role of endocan in the regulation of inflammatory processes in obesity.

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.

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.

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.