key: cord-0953251-4grscz5h
authors: Samuel, Samson Mathews; Varghese, Elizabeth; Büsselberg, Dietrich
title: Therapeutic Potential of Metformin in COVID-19: Reasoning for its Protective Role
date: 2021-03-14
journal: Trends Microbiol
DOI: 10.1016/j.tim.2021.03.004
sha: 580467e72d99f579a9c501812cb31bce501c277a
doc_id: 953251
cord_uid: 4grscz5h

SARS-CoV-2 infections present with increased disease severity and poor clinical outcomes in diabetic patients compared with their non-diabetic counterparts. Diabetes/hyperglycemia-triggered endothelial dysfunction and hyperactive inflammatory and immune responses are correlated to two- to three-fold higher intensive care hospitalizations and more than twice the mortality among diabetic COVID-19 patients. While comorbidities such as obesity, cardiovascular disease, and hypertension worsen the prognosis of diabetic COVID-19 patients, COVID-19 infections are also associated with new-onset diabetes, severe metabolic complications, and increased thrombotic events in the backdrop of aberrant endothelial function. While several antidiabetic medications are used to manage blood glucose levels, we discuss the multi-faceted ability of metformin to control blood glucose levels, attenuate endothelial dysfunction, inhibit viral entry, and infection and modify inflammatory and immune responses during SARS-CoV-2 infections. These actions make it a viable candidate for drug repurposing and the higher ground against the SARS-CoV-2 induced tsunami in diabetic COVID-19 patients.

On 7 th January 2020, a novel beta-coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified as the causative agent of the 'atypical pneumonia', that surfaced in Wuhan, China, on 30 th December 2019 [1] . After the World Health Organization (WHO) declared the SARS-CoV-2 caused coronavirus disease (COVID- 19) outbreak as a pandemic on 11 th March 2020, to-date (05 th March 2021), over 116 million COVID-19 cases were reported, and more than 2.5 million people have lost their lives globally [1] [a]. Finding an effective way to control the rapid spread of the disease and a cure for COVID-19 remains at the forefront of the battle against this pandemic even as the vaccines, Tozinameran/BNT162b2/Comirnaty (Pfizer/BioNTech), mRNA-1273 (Moderna), AZD1222/Covishield (University of Oxford/AstraZeneca) and Ad26.COV2.S/JNJ-78436735 (Janssen Vaccines and Prevention) are being approved and authorized for emergency use in several countries [2] [3] [4] [5] . However, the emergence of highly transmissible SARS-CoV-2 mutants has raised concerns that these variants could evade the body's immune response, threaten vaccine efficacy and may cause a resurgence of highly transmissible cases of COVID-19 [6] .

The highly contagious SARS-CoV-2 can affect all individuals irrespective of age, gender, and ethnicity, but to varying degrees [7] . Most COVID-19 cases remain asymptomatic or present with relatively mild flu-like symptoms, increasing the risk of transmission and the significant spread of SARS-CoV-2 [8] . Nevertheless, the vulnerability, aggressiveness/severity of the disease, hospitalization rates, and mortality is significantly higher in men, among the elderly, and those with one or more comorbidities/pre-existing conditions such as hypertension, cardiovascular or cerebrovascular diseases, diabetes, cancers, and renal damage [1, 9] . In the face of pre-existing/comorbid conditions, severe COVID-19 cases can rapidly progress into acute respiratory distress syndrome (ARDS), septic shock, and multiple organ dysfunction syndrome (MODS), and organ failure [10] .

SARS-CoV-2's ability to infect and damage multi-organ systems is dependent on the expression/distribution pattern of the host angiotensin-converting enzyme 2 receptor (ACE2;

which binds to the viral spike protein) and the transmembrane serine protease 2 (TMPRSS2;

which cleaves and primes the viral spike protein), in various organs and tissues, facilitating viral activation and entry in the host cell [11, 12] . Comorbidities such as diabetes and obesity upregulate ACE2, leading to an increase in viral load within these tissues [13] . Furthermore, increased ACE2 shedding from the cell surface in diabetic and obese subjects facilitates re-J o u r n a l P r e -p r o o f Journal Pre-proof Figure 1. Diabetes/hyperglycemia and possible outcomes in COVID-19 patients. SARS-CoV-2 infection causes activation of RAAS that can result in a 'cytokine storm' via the AngII/AT1R axis resulting in the synthesis and secretion of pro-inflammatory cytokines/chemokines such as TNF, IL1/2/6, interferon-γ (IFN) and monocyte chemoattractant protein-1 (MCP1). SARS-CoV-2 infection in an individual with pre-existing diabetes, the diabetes-associated pro-inflammatory status and endothelial dysfunction and the incidence of one or more comorbidities such as obesity, hypertension, CVD, NAFLD and CKD and the hyperglycemia-induced DKA and HHS can lead to increase in disease severity, higher rates of ICU admissions and may be responsible for the poor prognosis and higher mortality rates in diabetic COVID-19 patients. Interestingly, reports also suggest that SARS-CoV-2 infects the -islets of the pancreas, causing -cell damage and subsequent new-onset diabetes, J o u r n a l P r e -p r o o f severe hyperglycemia and DKA in COVID-19 patients. Treatment using appropriate glucose-lowering agents and proper management of blood glucose levels aids recovery and survival among affected diabetic COVID-19 patients. Various aspects such as benefits, contra-indications, and limitations of using certain combinations of glucose-lowering agents and anti-viral treatments that could affect the outcome of the disease in a diabetic COVID-19 patient must be carefully analyzed. CKD = Chronic Kidney Disease, COPD = Chronic Obstructive Pulmonary Disorder, CVD = Cardiovascular Disease, DKA = Diabetic Ketoacidosis, HHS = Hyperglycemic Hyperosmolar Syndrome, NAFLD = Non-Alcoholic Fatty Liver Disease. Created with BioRender.com

Diabetic patients have a compromised immune response and are prone to severe bacterial and viral infections/diseases, require more recovery time, and present longer-lasting adverse effects than their non-diabetic counterparts [24] . Proper management and maintenance of controlled blood glucose levels (avoiding consistent hyperglycemia) are closely related to the body's ability to regulate immune and inflammatory responses and fight infections in chronic diabetic patients [10] . An aggravated inflammatory and immune response-related severe course of the disease and higher mortality was observed during various bacterial/viral infections in hyperglycemic/diabetic COVID-19 patients that could be significantly reversed by maintaining controlled blood glucose levels.

Plotting HbA 1c against the risk of SARS-CoV-2 infection/COVID-19 related hospitalization shows a characteristic J-curve, which indicates that diabetes is associated with a higher risk of infections (respiratory infections in particular) [1] . Although pre-existing diabetes did not increase the risk of occurrence of COVID-19; there was a significant increase in the severity of SARS-CoV-2 infection (COVID-19) among diabetic individuals, thereby increasing their risk of hospitalizations and requirement of emergency care [1] . Elderly severely ill diabetic COVID-19 patients exhibited an exaggerated inflammatory response and were more likely to require mechanical ventilation and ICU support with a markedly higher risk of mortality than COVID-19 patients without diabetes [25] . Worldwide studies corroborated severe pneumonia cases, increased risk of ICU admissions, and higher mortality rates in COVID-19 patients with diabetes (Table 1) . 

Viral infections, including enterovirus, rotavirus, and mumps, could lead to acute type 1 diabetes [37] . Individuals with no previous diagnosis or history of diabetes developed acute hyperglycemia, upon SARS-CoV-1 infection, an independent indicator for higher mortality among such individuals [38] . This was associated with the ability of the SARS-CoV-1 virus to bind to the pancreatic islet ACE2 receptors causing acute islet damage [38] .

downregulates ACE2 activity and creates an imbalance in the RAAS [40] . The subsequent accumulation of AngII and the over-activation of AngII/AT1R-axis triggers macrophage activation and triggers NF-κB signaling. This, in turn, leads to the excessive synthesis and secretion of several inflammatory cytokines (hyper-cytokinemia/cytokine storm), resulting in pancreatic damage, and partially explains new-onset diabetes in COVID-19 patients [17, 40, 41] . Significant increase in the levels of several pro-inflammatory cytokines/markers (IL-1, IL-6, IL-10, and TNF) were reported in severely ill COVID-19 patients and COVID-19

patients admitted in the ICU, while higher levels of IL-6 were correlated with higher mortality rates [41, 42] . An in vitro model that studied virus tropism using pseudo-viruses for SARS-CoV-2 entry in human pancreatic α-and β-cells showed that the pancreatic cells are highly permissive to SARS-CoV-2 entry and mimicked the chemokine induction that is typical of COVID-19 patients [37] .

A study involving 33 children (who were previously exposed to SARS-CoV-2 or had active SARS-CoV-2 infection) reported the occurrence of new-onset type 1 diabetes in thirty of them (aged 23 months to 16.8 years) [43] . Twenty-one children (70%) developed diabetic ketoacidosis (DKA), while 11 of the 21 children reported severe DKA [43] . Despite a direct link, the study postulated that SARS-CoV-2 exposure caused an increase in new-onset type 1 diabetes in children [43] . A single-case study reported high blood glucose concentration (552 mg/dl) and HbA 1c (16.8%) levels in a 19-year old male who presented with DKA and tested positive for antibodies against SARS-CoV-2, indicating a possible COVID-19 infection 5-7 weeks before hospitalization [44] . Interestingly, autoimmune factors that could lead to the development of a type-1-diabetic condition were ruled out, suggesting a causal link between COVID-19 and the development of diabetes possibly due to SARS-CoV-2 infection of the cells via the ACE2 receptors and a direct cytolytic effect of the virus on the cells [44] .

Remarkably, reports suggest a significant increase in mortality among COVID-19 patients diagnosed with new-onset hyperglycemia (without diabetes) compared to patients with preexisting diabetes [45, 46] .

Health authorities must make general health recommendations that require the COVID-19

patients to monitor their blood glucose levels frequently and remain vigilant regarding possible signs/symptoms of hyperglycemia. Therapeutic recommendations must be made based on initial and continuously monitored blood glucose measurements and the patient's medical history. Evaluation of markers of inflammation, coagulation factors, acute phase reactants, hepatic and renal function will help identify hyper-cytokinemia and predict J o u r n a l P r e -p r o o f prothrombotic events. Thus, necessary adjustments in the treatment plan will improve the prognosis and survival of high-risk diabetic COVID-19 patients.

The vasculature is most vulnerable to SARS-CoV-2 infections [18]. Endothelial cells (ECs) express ACE2 receptors through which SARS-CoV-2 enters the cells [19] . SARS-CoV-2 particles and host inflammatory cells found inside ECs with evidence of endothelial and inflammatory cell death suggest that the endothelium and alterations in its function may contribute to disease progression and outcome among COVID-19 patients [19, 20] . COVID-19 is associated with endothelial dysfunction (ED), hyper-viscosity/coagulation, higher incidence of thrombotic events, and microvascular complications as evidenced by elevated levels of D-dimer, VWF, fibrinogen and soluble P-selectin and increase in activity of VWF and factor VIII activity in critically ill COVID-19 ICU patients when compared with their non-ICU counterparts [18, 47, 48 ]. An increase in the incidence of venous thromboembolism, microvascular lung thrombosis, arterial events, and disseminated intravascular damage was linked to higher ICU admissions, the occurrence of terminal events, and mortality among severe COVID-19 patients [1, 18, 48, 49] .

In diabetic COVID-19 patients, it is still too early to precisely state whether diabetesassociated ED exacerbates COVID-19 infection or whether COVID-19 infection accentuates diabetes-associated ED. In diabetes, the endothelium is exposed to hyperinsulinemia, hyperglycemia, and an excess of free fatty acids, and a consequent array of adverse molecular events -in response to various triggers such as increased ROS and decreased endothelial nitric oxide (NO) levels -causing ED [50] . Diabetes-associated ED and consequent prothrombotic state likely increases the risk of thromboembolic events in diabetic COVID-19

patients [1, 25, 51] . Furthermore, an increase in the levels of advanced glycation end products (AGEs) and subsequent activation of the receptors of AGEs (RAGEs) contribute to ED and chronic vascular complications that promote coagulation, supported by an increase in vascular hyper-permeability, increased leukocyte adhesion, and extravasation in diabetes [52, 53] . While the lungs' type- Constant clinical evaluation of ED and markers of thrombotic events, radiological assessment, and thromboprophylaxis/anticoagulant therapy is recommended and encouraged as a part of standard care for all COVID-19 patients, especially those with diabetes [48, 56] .

Therapeutic intervention(s) that support restoration and stabilization of the normal endothelial apparatus and function and target inflammation may improve prognosis and survival of COVID-19 patients [57] . Currently, several studies investigate the possible beneficial effects of anticoagulant therapy and potential interventions that improve endothelial function, such as RAS inhibitors, statins, and antioxidants, to decrease disease severity and mortality among COVID-19 patients [57] .

Irrespective of whether a COVID-19 patient has pre-existing diabetes, was diagnosed with new-onset diabetes, or is non-diabetic, the available evidence points to the fact that the blood glucose level is a crucial factor that would determine 1) susceptibility to a COVID-19

infection in the event of an exposure, 2) severity of the disease, 3) treatment strategies, 4) recovery and 5) outcomes (measured in terms of disease severity/ARDS/ICU admissions/cardiac injury/renal damage/survival/mortality) among COVID-19 patients [10, 46, 58, 59] . Hyperglycemia and higher fasting blood/plasma glucose (FBG/FPG) levels (Table 2) unarguably increased disease severity, the incidence of ARDS, cardiac and renal damage and was correlated with higher ICU admissions and mortality among COVID-19

patients. Hence, blood glucose measurements are crucial and must be frequently monitored and managed efficiently under strictly supervised treatment. 

Several anti-hyperglycemic drugs are routinely used to manage blood glucose levels in Meta-analysis studies reported significant metformin treatment-associated reduction in COVID-19 infection-related mortality [68, 69] . Reports from retrospective studies suggest a significant metformin treatment-associated reduction in mortality among high-risk diabetic COVID-19 patients [23] . Interestingly, a retrospective cohort study, involving 6256 type 2 diabetic or obese (BMI at least 30 kg/m 2 ) COVID-19 participants, among whom 2333 patients were on a metformin treatment plan before their COVID-19 diagnosis, found a gender-dependent effect in which metformin treatment was associated with a reduction in disease severity and mortality among women, but not in men [70] . A retrospective study, among 1213 COVID-19 patients (678 were using metformin), showed that metformin treatment was associated with an increased incidence of acidosis (but not mortality) in type 2 diabetic COVID-19 participants, which was correlated to high metformin dosage, compromised renal function and severe COVID-19 illness [71] . However, owing to the ability of metformin to reduce inflammation and confer cardio-protection among type 2 diabetic COVID-19 patients, the researchers recommended the continuation of metformin therapy while continuously monitoring the patients for acidosis and deterioration of renal function [71] . Crouse et al. reaffirmed the role of diabetes as a prominent independent risk factor that contributed to a higher mortality rate among diabetic COVID-19 patients when compared non-diabetic COVID-19 patients [72] . They reported a three-fold decrease in J o u r n a l P r e -p r o o f mortality among diabetic COVID-19 patients on a metformin treatment regimen before their COVID-19 diagnosis, while prior insulin use did not affect mortality [72] . This beneficial effect of metformin was observed even after correcting for other COVID-19 risk factors such as age, sex, race, obesity, and hypertension, or chronic kidney disease and heart failure [72] .

In addition to lowering blood glucose levels and increasing insulin sensitivity, metformin has documented molecular effects that suggest its therapeutic efficacy against COVID-19 (Please refer to Figure 2 for details).

The use of metformin in type 2 diabetic patients is associated with a reduced risk of deep vein thrombosis, as reported by a non-randomized, pair-matched cohort study [73] . Other studies suggest that metformin prevents platelet activation and extracellular mitochondrial DNA release, thereby preventing venous and arterial thrombosis without a significantly prolonged of bleeding time [74] . Metformin confers multiple protective effects on the endothelium, improves endothelium-dependent vascular response, and attenuates ED in diabetes through several well-studied mechanisms such as the activation of AMPK, Sirt1, and eNOS [75] .

Besides, metformin can protect the endothelium by reducing oxidative stress, inhibiting endothelial inflammation, and suppressing leukocyte-endothelium interactions while also attenuating endothelial cell senescence and apoptosis and preserving the endothelial glycocalyx that shields against ED [75, 76] . [79] . The AMPK dependent increase in (A) ACE2 receptor phosphorylation (Ser680) causes a conformational change that inhibits ACE2 binding -viral spike protein binding and reduction of viral entry into the cell [15, 16] . AMPK J o u r n a l P r e -p r o o f mediated increase in (B) ACE2 phosphorylation (ACE2 phosphorylation prevents poly-ubiquitination and subsequent 26-proteasome mediated degradation of ACE2) and (C) ACE2 expression, increases its halflife/stability, and offers cardio-pulmonary protection via the RAAS regulation [14] [15] [16] . The ability of metformin to reduce blood glucose levels and improve insulin stability (D) reduces the risk of SARS-CoV-2 infections [15] . Metformin treatment-associated increase in ACE2 levels and stability, in turn, regulates the ACE2/AngII/AT1R axis and suppresses (E) inflammatory response and release of pro-inflammatory cytokines by inhibiting macrophage activation and NF-B signaling [16] . Metformin targets complex I of the mitochondrial electron transport chain (ETC), inhibits the generation of reactive oxygen species (ROS), and (F) suppresses the oxidative stress-mediated release of pro-inflammatory cytokines and attenuates inflammatory immune response [15, 80] . Inhibition of ETC and mTORC1 signalling (via AMPK or PI3K/Akt) by metformin (G1 and G2) contributes to the suppression of host-viral protein interactions, such as NDUF (human)-Nsp7 (viral) and LARP/FKBP7 (human): N/ORF8 (viral) interactions [81] . The suppression of the host-virus protein interactions inhibits host-dependent viral replication, synthesis of viral proteins, virion maturation, and release. Metformin, a strong base, targets the vacuolar ATPase (V-ATPase) and endosomal Na + /H + exchangers (eNHEs) (H), increasing the cellular and endosomal pH and suppressing the endocytotic cycle and virion assembly and maturation [15, 82] . The anti-hyperglycemic, antioxidant, immunomodulatory, and anti-inflammatory effects of metformin attenuate endothelial dysfunction and confer vascular protection, thus (I) reducing microvascular complications and thrombotic events during SARS-CoV-2 infection. Created with BioRender.com

Available data support the repurposing and use of metformin benefits as an effective therapeutic in the treatment of COVID-19. Data from ClincalTrials.gov 

Most studies have outlined the beneficial effects of metformin in COVID-19 patients, while some studies have reported an increased risk of acidosis (but not mortality) and disease severity in COVID-19 patients using metformin [71, 83] . This suggests that metformin is not an appropriate choice in patients with severe respiratory distress, renal impairment, or heart failure [1] , shedding light on the importance of paying attention to pre-existing conditions and comorbidities in drug selection. Furthermore, metformin-drug contraindications must be addressed before administration.

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