Can dapagliflozin have a protective effect against COVID-19 infection? A hypothesis

Abstract

It has been reported that frequent occurrence of COVID-19 infection in these patients is associated with low cytosolic pH. During virus infection, serum lactate dehydrogenase (LDH) level excessively rises. LDH is a cytosolic enzyme and the serum level increases as the cell break down. When anaerobic conditions develop, lactate formation increases from pyruvate. Cell pH is regulated by very complex mechanisms. When lactate increases in the extracellular area, this symporter carries lactate and H⁺ ion into the cell, and the intracellular pH quickly becomes acidic. Paradoxically, Na⁺/H⁺ exchanger activation takes place. While H⁺ ion is thrown out of the cell, Na⁺ and Ca⁺² enter the cell. When Na⁺ and Ca⁺² increase in the cell, the cells swell and die. Dapagliflozin is a sodium-glucose cotransporter-2 inhibitor. Dapagliflozin has been reported to reduce lactate levels by various mechanisms. Also, it reduces oxygen consumption in tissues and causes the use of glucose in the aerobic pathway, thereby reducing lactate production. A lactate decrease in the environment reduces the activation of lactate/H⁺ symporter. Thus, the H ion pumping into the cell by this symporter is reduced and the cytosolic pH is maintained. Dapagliflozin also directly inhibits NHE. Thus, Na⁺ and Ca⁺² flow to the cell are inhibited. Dapagliflozin provides the continuation of the structure and functions of the cells. Dapagliflozin can prevent the severe course of COVID-19 infection by preventing the lowering of cytosolic pH and reducing the viral load.

Dear Sir,

The novel coronavirus disease 2019 (COVID-19) infection is common in patients with diabetes, hypertension, and heart failure [1]. It has been reported that frequent occurrence of COVID-19 infection in these patients is associated with low cytosolic pH [1]. It shows angiotensin-converting enzyme 2 (ACE2) activity in an acidic environment [2]. Hydroxychloroquine, used in the treatment of COVID-19, increases the cytosolic pH and alters the glycoprotein structure of ACE2 and prevents virus binding the cells [1], [2], [3]. During virus infection, serum lactate dehydrogenase (LDH) level excessively rises. LDH is a cytosolic enzyme and the serum level increases as the cell break down. ACE2 is in the lung, kidney, brain, pancreas, testicles, and vessels [1,4]. A recent study claimed that COVID-19 infects erythrocytes and causes immune hemolysis [3]. Presumably, the virus can be transported through the blood or vascular endothelium and penetrate all tissues containing ACE2 in its structure. The virus may cause the LDH to enter the bloodstream by disrupting the organs and cells. LDH is a two-way enzyme. It causes lactate formation from pyruvate and pyruvate from lactate. In aerobic conditions, lactate converts into pyruvate with lactate dehydrogenase enzyme and enters the TCA cycle. Since tissue oxygenation is disturbed, the hypoxic environment is formed [5,6]. When anaerobic conditions develop, lactate formation increases from pyruvate. The virus can create such a high anaerobic environment by disrupting tissue oxygenation. [5,6]. Energy production in the hypoxic environment is achieved through anaerobic glycolysis and 2 lactate and 2 H⁺ ions are obtained. H⁺ ion also forms during the hydrolysis of ADP to AMP. A vicious cycle continues and lactate production continues to increment as the hypoxic and acidic environment increases [6]. Besides, elevated lactate levels increase the release of proinflammatory cytokines and oxidative stress.

Cell pH is regulated by very complex mechanisms. Na⁺/H⁺ exchanger (NHE) and lactate/H⁺ symporter (also called monocarboxylate transporter) have important tasks in regulating cell pH. NHE extractions one H⁺ ion outside the cell in return of one Na⁺ ion. The lactate/H⁺ symporter works by transporting lactate and hydrogen ions jointly in the same aspect [7,8]. NHE activation plays an important role in the etiology of insulin resistance, diabetes, and heart failure [9]. When lactate increases in the extracellular area, this symporter carries lactate and H⁺ ion into the cell, and the intracellular pH quickly becomes acidic. Paradoxically, NHE activation takes place. While H⁺ ion is thrown out of the cell, Na⁺ and Ca⁺² enter the cell. When Na⁺ and Ca⁺² increase in the cell, the cells swell and die [7,8].

Recently, sodium-glucose cotransporter-2 (SGLT2) inhibitor have been very popular in the treatment of diabetes and heart failure. They inhibit renal glucose absorption and provides glucose excretion from the body. SGLT2 inhibitors also cause the excretion of water and salt from the body. They prevent albuminuria and have a renoprotective effect. It has been reported that SGLT2 inhibitors may prevent the release of proinflammatory cytokines such as interleukin-6 [10]. Dapagliflozin is a sodium-glucose cotransporter-2 (SGLT2) inhibitor. In addition to these positive effects, dapagliflozin has been reported to reduce lactate levels by various mechanisms. The lactate-lowering effect of dapagliflozin may not be a class effect and other SGLT2 inhibitors may not have a lactate-lowering effect [11]. Dapagliflozin reduces lactate release from epicardial adipose tissue [12]. It reduces oxygen consumption in tissues and causes the use of glucose in the aerobic pathway, thereby reducing lactate production [6]. Also, it increases urinary lactate excretion [13]. It has been reported that the combination of dapagliflozin with drugs that increase the lactate level, such as metformin, prevents hyperlactatemia [12]. A lactate decrease in the environment reduces the activation of lactate/H⁺ symporter. Thus, the H ion pumping into the cell by this symporter is reduced and the cytosolic pH is maintained [7,8]. Dapagliflozin also directly inhibits NHE [14]. Thus, Na⁺ and Ca⁺² flow to the cell are inhibited. Dapagliflozin provides the continuation of the structure and functions of the cells. Dapagliflozin will lower the increased lactate level as a result of increased LDH due to cell destruction in COVID-19 infection. Unlike the binding of the virus to hemoglobin and leaving the tissues to deoxygenated will further increase lactate production, dapagliflozin may prevent damage and die of the cells, both by increasing tissue oxygenation and by decreasing the lactate level. Dapagliflozin inhibits NHE and prevents the pH of the cells from decreasing and shows a cytoprotective effect. Also, SGLT2 inhibitors increase the ACE2 level [15,16]. ACE2 forms angiotensin 1-7 from angiotensin II. Angiotensin 1-7 is a potent vasodilator. It has been reported that angiotensin 1–7 may be protective against acute respiratory distress syndrome (ARDS). Increased ACE2 increases the angiotensin 1-7 level, however, increased ACE2 can also be harmful by causing an increase in viral load [1,4,17]. Dapagliflozin can prevent the severe course of COVID-19 infection by preventing the lowering of cytosolic pH and reducing the viral load. Therefore, an increase in ACE2 may be useful in preventing ARDS by increasing the angiotensin 1-7 level. It may also alleviate the cytokine storms due to the virus.

SGLT2 inhibitors can lead to euglycemic (E) diabetic ketoacidosis (DK). Causes such as insulin lack, infection, and dehydration can lead to DK. Patients using SGLT2 inhibitors may reduce insulin doses. Decreasing the insulin dose, and lowering the lactate level by dapagliflozin can lead to EDK. Contrary to popular belief, the EDK rate is quite low in patients using SGLT2 inhibitors (only 1%) [12]. Since dapagliflozin inhibits the development of lactic acidosis in EDK, lower mortality may occur [12]. In one study, 2 of 24 patients with diabetes with COVID-19 infection developed DK. One of the patients who developed DK died [18]. In severe infections like COVID-19, insulin and water need of patients with diabetes increase. Since COVID-19 is a serious infection, the risk of DK in patients with diabetes will increase. Careful use of dapagliflozin together with insulin in COVID-19 infection by avoiding dehydration may be useful in treatment.

Declaration of competing interest

We declare that there is no conflict of interest.