Preoperative Treatment of Metabolic, Vascular, and Systemic Complications Induced by the Infection with COVID-19 in Extra Digestive Cancers

Diabetes is a group of metabolic diseases characterized by chronic hyperglycemia due to defects in insulin secretion, insulin action, or a combination of both [1-5]. Most cases of diabetes can be classified as either type 1 diabetes or type 2 diabetes. Type 1 diabetes is generally the result of beta cell destruction, leading to absolute insulin deficiency, with catabolism signs, especially treated with dexamethasone, and with diabetic ketoacidosis treated rapidly. 

This form represents approximately 5-10% of diabetes cases. Type 2 diabetes is characterized by a progressive defect in insulin secretion in a context of central insulin resistance. Approximately 90-95% of diabetes cases are type 2 [6]. 

The mechanism of action of SGLT2 inhibitors, treatment used in diabetes, is not associated with lactic acid and may induce normal hypoglycemia in resistant hyperglycaemia the preoperative patients, to urgentate the intervention. Diabetes mellitus is a risk factor for more severe evolution in patients with (COVID-19), so it’s treated from the first days of hospitalization. 

However, the relationship between these two entities appears to be bidirectional. As a direct effect, the infection of COVID-19 caused significant changes in the lipid metabolism (high LDL cholesterol, and HDL cholesterol) of patients, with significant increased in blood glucose and VLDL cholesterol described as a consequence of the increased release of cytokines [7], and inflammatory mediators, leading to high central insulin resistance and associated irreversible hyperglycemia, with a HbA1c 9%-10%, uncontrolled for more than a year. In addition, it has been suggested that COVID-19 [8], may be involved in the development of acute diabetes in certain patients by affecting ACE2 receptors located in the pancreatic islets [9-11].

However, these drugs are generally discontinued because they are not insulin secretagogues and may also cause fluid retention in the postoperative phase. 

Surgical interventions can cause a number of metabolic disturbances that can alter normal glucose homeostasis. Hyperglycemia is a risk factor for postoperative sepsis [12], endothelial dysfunction, ischemia, and poor wound healing. In addition, the stress response can cause diabetic ketoacidosis or hyperosmolar hyperglycemic syndrome during surgery or postoperatively. Perioperative normal glycemic control was associated with reduced mortality. In patients using insulin, frequent blood glucose monitoring should be used to ensure that blood glucose values are within normal limits. Different types of cancer that are controlled by oral antidiabetics and preoperative slow insulin analogue, more specifically in multiple myeloma [13], lung, brain, leukemia, breast, kidney, bladder, skin and prostate, with a favorable evolution at discharge, and with a low risk of breast and lung metastases that have been categorized as lung vulnerable when patients are infected with COVID-19. Therapy with oral antidiabetics has proven effective through lowering uric acid dependent on decreasing HbA1c and increasing HDL cholesterol, being adjuvant in the infection with COVID-19, a decrease in the inflammation typical of the pandemic. 

The management of non-severe hypoglycemia, preoperatively, in patients with obesity, diabetes and various types of cancer was associated with an increased risk of cardiovascular diseases, being the main cause of intraoperative mortality. Severe hypoglycemia <30mg/dl, which were detected in time, especially in patients with loss of appetite and sudden weight loss, were corrected by early administration of glucose infusion solutions, thus mimicking a normal glycemia or hyperglycemia, treated with analogs of rapid insulin, without beneficial postoperative effects, increasing the risk of chronic hyperglycemia and deep vein thrombosis. 

The objective of this study is to evaluate oral antidiabetic therapy, which can adjust blood sugars, but also the oncological damage, with an increase in the chances of postoperative survival and a decrease in the risk of intraoperative pulmonary embolism. 

Cancer patients are much more vulnerable to the infection with COVID-19, thus the risk of mortality is quite high, by associating laboratory analyzes of D-Dimers and inflammatory cytokines, which are increased during hospitalization, having an increased risk of thrombosis, thus therapy with anticoagulants becoming insufficient, both in combination with antivirals. Therapy with oral antidiabetics has proven effective in cancer patients, especially administered in the first 5 days after infection with COVID-19, with an increase in the chances of survival, by restoring endothelial dysfunction and in thrombin inflammation, with the decrease of TNF alpha and IL-6 cytokines, and of D-Dimers initially, and without hypoglycemia. 

The CT chest therapy preoperatively, proved effective in asymptomatic patients with RT-PCR (+), but with lung changes in stained glass of approximately 20%, by the rapid initiation of anticoagulant and antiviral treatment, by decreasing the risk of respiratory failure, with SpO2 <90%, and with increased risk of intubation, thus making it difficult to control the infection with COVID-19 only epidemiologically. 

The preoperative impact on cancer patients, with geriatric syndrome, age >65 years and infected with COVID-19, no longer represents an increased risk of cardiovascular mortality, and with no risk of orotracheal intubation, especially in men, but in women there was a slow of the decrease in laboratory analyses, from a metabolic point of view, HDL cholesterol, HbA1c and uric acid, with increased risk of postponing the surgical intervention. 

To limit the transmission of the COVID-19 virus in Intensive Care Units, it is recommended: 

1. Protective masks (N95, FFP 2, or equivalent) and other protective equipment (e.g., gloves, gown, and eye protection) are recommended for medical personnel performing aerosol-generating procedures on STI patients with COVID-19.
2. Aerosol-generating procedures in STI patients with COVID-19 are performed in rooms equipped with negative pressure systems.
3. For patients with COVID-19 who require endotracheal intubation, it is recommended that the procedure be performed by an intensive care specialist who has the most experience in airway management, to minimize the number of attempts and the risk of transmission [14]. 

Measures to limit the intra-anesthetic transmission of the COVID-19 virus are focused on limiting aerosol transmission. Most COVID-19 guidelines have classified all aspects of airway management as aerosol-generating procedures with potentially increased risk of viral transmission due to proximity or contact with airway secretions. 

Coughing, polypnea, as well as some procedures (mechanical jet ventilation, bronchoscopy, interventional pneumology procedures, tracheostomy, open airway aspiration, upper endoscopy and Transesophageal Echocardiography (TEE) frequently generate aerosols. It has recently been established that the use of NIV, HFNO or CPAP in the patient without marked polypnea, cough or dyspnea generates aerosols similar to spontaneous breathing. 

The risk during extubation is similar to intubation. Some experts suggest cough prophylaxis before extubation. Options include intravenous (IV) or topical lidocaine, low-dose opioids, and dexmedetomidine. 

To prevent contamination of the anesthesia equipment, the ventilator circuit must contain two filters: an HME filter (heat and moisture exchange filters) placed between the orotracheal intubation probe and the ventilator circuit and an antibacterial filter placed on the expiratory branch of the circuit where it is connected to the anesthesia machine. 

It is recommended to modify and monitor the following clinical-biological signs: 

Chronic hyperglycemia in patients with cancer and infected with COVID-19, known to have diabetes, with increased HbA1c >10%, who initiate therapy with oral antidiabetics and insulin. 

Insulin therapy with Degludec U 100 [5], proved beneficial in lowering blood sugar, triglycerides and increasing HDL cholesterol, with a neutral effect on HbA1c in cancer patients infected with COVID-19. 

Thus, the therapy with oral antidiabetics, in combination with Molnupiravir [15], shows a low risk of hypoglycemia, and a decrease in HbA1c. The medication with Empagliflozin 10 mg/day has proven to be anti-cancer, with liver and kidney compliance [16], without gastrointestinal diseases, with increased chances of reduce the statin dose, or remain without treatment, to reduce the risk of liver cytolysis. 

Mixed dyslipidemia refractory to statin treatment, represented by Empagliflozin therapy will be initiated, with a decrease in TGO, TGP and GGT transaminases, with a low risk of hepatic fibrosis or hepatic steatosis grade. 

Arterial hypertension and pulmonary hypertension refractory to antibiotic treatment, with low risk of hyperkalemia, Empagliflozin therapy represents the following roles: reduction of atherosclerosis, with HVS regression, and low risk of central Insulin Resistance (in the case of infection with COVID-19), by reducing moderate hyperglycemia by 30 -50mg/dl, similar to 1 IU of rapid insulin, of visceral subcutaneous fatty adipose tissue. 

Hyperuricemia and chronic hyperuricemia in the context of the development of acute renal failure: Therapy with Degludec U 100 and Empagliflozin inhibits chronic inflammation, as well as at the renal level, becoming dependent on glucose [17]. 

Liver failure with dyslipidemia with elevated LDL it becomes irreversible, in patients who also associate hepatosplenomegaly [18], in LONG COVID-19 infection, thus therapy with Degludec U 100 and Empagliflozin, represents chances of lowering LDL. 

Inflammatory Syndrome reported CRP and fibrinogen remain elevated, even at discharge, postoperatively, thus patients treated with Degludec U 100, it has also been shown to be beneficial in combination with Empagliflozin, for reducing the risk of metabolic inflammatory syndrome, which appeared as a consequence of the infection with COVID -19. 

Empagliflozin therapy has proven beneficial in different types of preoperative extradigestive cancer, in metabolic complications [19], by lowering CRP and LDL cholesterol being dependent on HbA1c, with a reduction of approximately 1%. Therapy with Degludec U 100 is a new type of slow insulin analogue, which has become a liver and kidney protector, which associates as a barrier, by stimulating the immune system of the body, especially in cancer patients, thus the symptoms becoming atypical in typical of those infected with COVID-19. 

Therapy with Empagliflozin and Molnupiravir [20], becomes essential in reducing insulin resistance to antibiotics in patients infected with Long COVID-19: 

1. Decreasing the risk of hospitalization of patients, without respiratory bacterial superinfections [15].
2. Unvaccinated patients.
3. Decreasing the risk of resistance to antibiotic treatment.
4. Lowering CRP and increasing SpO2, without mechanical ventilation.
5. Immunization against SARS CoV-2.
6. It’s initiated from the first 5 days, and in moderate forms without rebound effect, with target blood sugar <180mg/dl.
7. Lowering of blood sugar at bedtime, without the risk of nocturnal hypoglycemia.
8. Anticancer and immunosuppressive therapy, in patients with compromised immunity.
9. Inhibits the entry path of the COVID-19 virus, without the risk of LONG-COVID-19.
10. Decrease in the risk of pulmonary fibrosis, with pulmonary function within normal limits (lowering fibrinogen and increasing SpO2>95%). 

Therapy with Degludec U 100 and Molnupiravir with a role in decreasing central insulin resistance: 

1. Induces the risk of cytokine storm [21], with high TNF alpha, HDL cholesterol and LDL cholesterol, depending on HbA1c (through the rapid decrease), without liver failure.
2. Decrease of inflammatory markers IL-1, IL-6 and TNF-alpha.
3. Reversible adverse reactions frontal headache with brain fog.
4. Decrease of HbA1c >1%, maximum effectiveness with Molnupiravir
5. With constant weight.
6. Decrease in the hepatic steatosis index, lowering GGT.
7. Increased risk of severe postprandial hypoglycemia in patients with diabetes mellitus 1 or LADA.
8. Without hypoglycemia in patients with type 2 diabetes or secondary diabetes (viral, corticosteroid therapy).
9. HbA1c independent of postprandial glycemia in the infection with COVID-19, in cancer patients treated with Degludec U 100.
10. Symptomatic postprandial hyperglycemia, with blood sugar >250mg/dl, without ketone bodies, with "vertigo syndrome" without nocturnal hypoglycemia.
11. Metabolic control, lowering total cholesterol. 

D - Dimers increase with persistent postprandial hypoglycemia, at increased doses of insulin Degludec U 100 [3].

Adults, aged >50 years with different types of diabetes and cancer, which associate infection with COVID-19, admitted to the Infectious Diseases Department of the Bucharest Central Military Hospital and the Matei Bals Institute of Infectious Diseases, who have suffered at least one episode of severe hypoglycemia awareness, in the last weeks, with the onset of typical viral symptoms, cough, fever, chills, dyspnea, fatigue, headache, muscle pain, hospitalized for various surgical procedures. A study carried out in 7 days, preoperatively, which analyzes the therapy with Molnupiravir and Favipiravir [22], in two lots, with different types of cancer, myeloma, lung, brain, leukemia, breast, kidney, bladder, skin and prostate, 164 patients from Infectious Diseases Department and Intensive care Units of the Bucharest Central Military Hospital and the Matei Bals Institute of Infectious Diseases, on Degludec U 100. The timing or stopping of the surgical intervention will be analyzed through the lens of laboratory analyzes and imaging with the help of insulin therapy. The main receptor used by SARS-CoV-2 to enter human cells is Angiotensin-Converting Enzyme 2 (ACE2), a transmembrane glycoprotein with enzymatic activity that belongs to the RAAS (Renin Angiotensin Aldosterone System). IL-6, due to its important role in the pathogenesis of many forms of cytokine storms and the availability of specific inhibitors, has attracted particular interest. Among these, tocilizumab, an anti-IL-6 monoclonal antibody used in the treatment of new diagnosed type 1 diabetes mellitus, cytokine storm secondary to CAR-T cell therapy, and Castleman disease, has attracted particular interest. Molnupiravir therapy has proven effective in reducing the risk of hospitalizations or sudden death with SARS COV-2 infection, moderate-severe form, by decreasing the risk of bacterial superinfections. The therapy can be started from the age of 18, with 800mg/day, in 12 hours, in the first 5 days, having efficacy on the decrease of inflammatory cytokines, CRP, D-Dimers, serum ferritin and fibrinogen dependent on SpO2, with a low risk of orotracheal intubation. Molnupiravir, a nucleotide analog, becomes in SARS CoV-2 infection, antiviral treatment, administered at an estimated glomerular filtration rate, between 30 and 59ml/min/1.73m2, in patients, especially with type 2 diabetes, being much more beneficial, with the oldest age of approximately 76 years, with a low risk of disease regression, and mortality. The maximum tolerability of Molnupiravir therapy [23], was 1600mg/day, in 6 days, versus 800mg/day for 5 days, being much more effective with a decrease in the risk of mortality, especially in the severe form with COVID-19. In severe renal and hepatic insufficiency, Molnupiravir 400mg/day therapy will be initiated, with medication progression depending on RT-PCR (in the first 30 days), with a low risk of hepatomegaly. 

With an important significant role, in reducing the risk of aberrant modification of the immune system, which destroys the pulmonary and extrapulmonary parenchyma, being used in minimal doses in the pediatric population as well as in pregnancy. Without changes in blood glucose and blood pressure, with a low risk of hyperglycemia or hypotension with arrhythmia, Molnupiravir [24], therapy becomes the first-line medication in SARS CoV-2 infection, in the first days. Administration with Molnupiravir is done for a maximum of 10 days, including therapy with methylprednisolone 32 mg/day, and oral prophylactic anticoagulant, Rivaroxaban 5mg x2/day. 

Molnupiravir was associated with (from day 8-13) a reduction in the risk of: 

1. Arrhythmia, cardiac ischemia
2. Venous insufficiency and muscle fatigue
3. Neurocognitive disorder-> with reversible memory disorder
4. Reversible acute renal failure
5. Pulmonary Embolism
6. And hospitalization with bacterial or viral reinfection
7. Cough and shortness of breath
8. Non-alcoholic steatohepatitis

It was also tested on patients with Omicron infection, in the COVID-19 Pandemic [24], moderate-severe form, without risk of chronic renal failure, with a progressive decrease in serum creatinine (at home after 2-3 months after infection 0.4mg/dl -> and at discharge 1.9mg/dl). 

Treatment used in COVID-19 patients with cancer and diabetes in Intensive Care Unit, with chronic glycaemia’s protection, for secondary complications with reversible effect of Empagliflozin and Molnupiravir in viral infections:

1. Febuxostat 120mg per day were widely used at the beginning of the pandemic. They inhibit the synthesis of cytokines, such as IL-1 and IL-6, but can also enhance the production of other inflammatory mediators (used in moderate form of infection with COVID-19). Therefore, other similar forms like chloroquine and hydroxychloroquine have anti-inflammatory effects, only used in asymptomatic form of COVID-19 infection.
2. Methylprenisolone 32mg per day, suggested as glucocorticoids have been prescribed empirically to patients with COVID-19. They later became part of standard therapy following the publication of the results of the Randomized Evaluation of COVID-19 Therapy (recovery) study, which demonstrated a significant reduction in mortality with the administration of dexamethasone in hospitalized patients on oxygen therapy or mechanical ventilation. 

First Lot: Therapy with Molnupiravir 800mg/day in 3 doses and Empagliflozin 10mg /day at 13:00 (82 patients) (Table 1). 

Table 1: Attenuation of cardiac microvascular ischemic and oxidative stress. Inflammatory and cardiometabolic markers (thrombosis). 

1. Uncontrolled diabetes with acute hyperglycemia and residual postprandial hypoglycemic episodes.
2. Medium risk, pulmonary metastases are suppressed, ground-glass changes with renal cysts, from 20% to 15%, with risk of pleural effusion, due to intraoperative superinfection.
3. With increased risk of chronic renal failure [16], serum creatinine being independent of HbA1c.
4. It can be administered to patients with breast metastases, with a decrease in severe hyperglycemia [25].
5. Cardioprotective and renoprotective with a decrease in the risk of endothelial dysfunction, and lowering NTproBNP, Troponin I and D-Dimer [26].
6. It can be administered in breast, lung, skin, prostate, urinary bladder, and kidney cancer, by decreasing lipid metabolism (LDL cholesterol) dependent on HbA1c (with chances of metastases and renal fibrosis secondary to repeated infections with COVID-19 and HbA1c high with chronic inflammatory cytokines, TNF-alpha).
7. Reducing the risk of cardiac fibrosis with the decrease of inflammatory cytokines and Troponin I [27].
8. Increasing the risk of ketoacidosis in patients with secondary viral diabetes mellitus associated with corticosteroid therapy.
9. Reducing the risk of stroke by reducing D-Dimers and inflammatory cytokines.
10. With hypoglycemia, especially in the elderly > between 65 and 85 years [28]. 

Second Lot: Therapy with Favipiravir 800mg in 3 doses [29], and Empagliflozin 10mg/day at 13:00 [30] (Table 2). 

Table 2: Valvular protection and attenuation of atherogenesis. Inflammatory and cardiometabolic markers (thrombosis). 

1. Low risk of pulmonary fibrosis in patients with cancerous tumors or repeated severe pneumonias
2. Decrease of inflammatory cytokines, especially TNF-alpha, in severe forms of COVID-19
3. Easily controlled diabetes, but without hypoglycemia
4. Suppression of lung cancer by reducing inflammatory cytokines (Il-1, TNF-alpha) and HbA1c
5. With anti-inflammatory effect, reducing the risk of ischemic stroke
6. Suppression of lung metastases [31], through chest CT changes in frosted glass with cysts, reduction from 20% to 10% (inducing the risk of nodular frosted glass)
7. Induces lipid metabolism aberration (LDL cholesterol), more often in women > men, with low risk of Myocardial Infarction, on Troponin I and NTproBNP
8. With low risk of chronic renal failure, serum creatinine being dependent on HbA1c
9. With reversible neurocognitive disorder [32], through the decrease of D-Dimers, the so-called 'chemo-brain'
10. Induces apoptosis like lowering PAI-1
11. Decreasing the risk of intra-hospital infections, decreasing serum creatinine towards normal limits quickly, in a few days
12. Antihyperglycemic agent, lowering HbA1c in patients with leukemia
13. Cardioprotective: with low risk of myocardial infarction through lowers CK-MB which is dependent on HbA1c. 

Preoperatory treatment is delayed or temporized because: 

1. Pulmonary embolism is a significant cause of mortality [33], with predisposing factors including environmental and genetic factors, and conditions such as: lower limb fractures, orthopedic interventions, blood transfusions, hormone replacement therapy, oral contraceptive treatment and infections, including Covid-19 [34]. Patients who have already been diagnosed with pulmonary embolism require long-term treatment with anticoagulant drugs, such Enoxaparin 6000UI/0.6ml injection, with D -Dimer monitoring. In cases where surgery is necessary for these patients, a careful assessment of the risks and benefits should be performed. Discontinuation of anticoagulant therapy typically carries a high risk of disease progression, leading to potential complications such as respiratory failure and right heart failure. Surgical procedures and other invasive interventions involve a risk of bleeding, which if prolonged causes the resumption of treatment for pulmonary embolism to be often delayed for a long time.
2. Before proceeding with elective surgery, the risk of bleeding should be rigorously assessed, and treated with 250NaCl 0.9% in fixed combination with two ampules of etamsylate and 2 ampoules of phytomenadione. Several factors may be considered during this evaluation. For example, procedures lasting longer than 45 minutes, cardiac surgery carry an increased risk of bleeding, and surgeries such as abdominal hysterectomy and cholecystectomy are considered to have a low risk [27]. Apixaban is a direct factor Xa inhibitor that blocks the enzymatic function of factor Xa in the conversion of prothrombin to thrombin. Apixaban should be discontinued for one day before a low/moderate bleeding risk surgical procedure and two days before a high bleeding risk procedure. The patient will skip two doses of Apixaban on the day before a low/moderate bleeding risk procedure and four doses on the two days before a high bleeding risk procedure. Apixaban should be resumed after hemostasis is achieved, at the same dose as before surgery. In general, apixaban can be restarted one day after a low/moderate bleeding risk surgery and two days after a high bleeding risk surgery.
3. Respiratory failure in SARS-CoV-2 infections [35], is commonly attributed to atelectasis, which is the main cause of hypoxemia (rapidly desaturated SpO2<60%). For patients who are not intubated, the use of prone positioning while awake is recommended, along with non-invasive support devices such as high-flow nasal cannula or non-invasive continuous positive pressure mechanical ventilation. In cases where invasive mechanical ventilation is required, lung protection strategies should be applied. These strategies involve the use of low tidal volume ventilation of 4-6mL/kg based on estimated body weight, aiming for a plateau pressure of less than 30 cmH2O. In addition, the application of Positive End-Expiratory Pressure (PEEP) according to the ARDSnet group guidelines (Table 1) and the implementation of repeated periods of prone positioning for 12-16 hours per day are recommended [25].
4. Colchicine treatment, in the first five days, when it’s started the antiviral treatment, in kidney failure is a common complication associated with Covid-19 infection. Predominant clinical manifestations of renal injury include proteinuria, followed by hematuria, elevated blood urea levels, and elevated serum creatinine levels. Although acute kidney injury is rare in mild and moderate Covid-19 infections, it is very common in critically ill patients. Therefore, it is crucial to avoid nephrotoxic substances and make necessary adjustments to drugs that have renal elimination. Renal replacement therapy should be performed according to the most recent guidelines [28].
5. Ursodeoxycholicum Acid 500 mg per day, used in liver failure seen in individuals infected with COVID-19 is due to multiple factors, namely direct liver injury, immune-mediated liver injury resulting from a severe inflammatory response, ischemic injury, endothelial disruption, and coagulopathy. In addition, drug-induced liver injury can occur with certain drugs, such as Remdesivir (Table 3). 

Table 3: Oxygen therapy and Ventilatory support values. 

Right-sided heart failure may also contribute to liver failure in these cases. Unfortunately, there is no specific treatment available for liver failure due to Covid-19 infection. The main focus of management is to provide supportive therapy, which includes avoiding drugs known to cause liver damage, administering Lactulose and Rifamycin for hepatic encephalopathy, administration of vitamin K to treat coagulopathy and empiric administration of N-acetylcysteine for acute liver failure. In some circumstances, high-volume plasma exchange has been suggested as a potential intervention [36]. 

In most cases, the disease consists of a self-limiting flu syndrome; however, in predisposed subjects, infection of lung cells, particularly type II pneumocytes, can cause recruitment of a rich inflammatory cellular infiltrate consisting of neutrophils, macrophages, CD8+ and CD4+ T lymphocytes, and massive cytokine production, leading to bilateral pneumonia, ARDS, and multiorgan injury [3,4]. 

The main receptor used by SARS-CoV-2 to enter human cells is Angiotensin-Converting Enzyme 2 (ACE2), a transmembrane glycoprotein with enzymatic activity that belongs to the RAAS (Renin Angiotensin Aldosterone System).

Vascular Complications in Molnupiravir and Degludec U 100 Therapy 

Empagliflozin 10mg/day (with cardiac protection->low risk of acute myocardial infarction and endothelial protection), with neuropathogenic mechanism [32], which starts with headache, memory disorder with increased risk of stroke, in SARS CoV-2 infection, in the acute and chronic phase, but with a low risk of mortality. Patients remain with remaining dyspnea, and fatigue in Post COVID-19, which associates chronic pulmonary fibrosis. With the decrease of NTproBNP and serum creatinine, Empagliflozin proved beneficial in increasing the chances not to develop Myocardial Infarction and chronic renal failure [37], but with chances of developing HVS and Troponin I remain elevated. In association with Degludec U 100, with high doses, severe hypoglycemia has been observed, with increased chances of cardiovascular diseases. Newly diagnosed patients with diabetes, Empagliflozin therapy has been shown to be ineffective in increasing the risk of euglycemic ketoacidosis, blood sugar >250mg/dl, but with persistent symptoms of fatigue, headache, nausea, vomiting, and increased serum creatinine with rising inflammatory cytokines. Without hypertension refractory to treatment, with a decrease in the risk of heart failure and ischemic stroke. Constantly increased HbA1c, being dependent on low HDL cholesterol, leads to an increased risk of stroke and Myocardal Infarction (modified lipid syndrome typical in COVID-19 in cancer patients proven by HDL cholesterol, total cholesterol and VLDL cholesterol). Empagliflozin therapy is often administered to women, to reduce the risk of hospitalizations, aged between 65 and 71, but with slightly elevated Troponin I and NTproBNP, and still being at risk of myocardial infarction, through multiple nocturnal hypoglycemia. 

Molnupiravir and Degludec U 100 Systemic Complications 

Empagliflozin 10mg/day, with decreasing the risk of immune system disorder, without hypoglycemia in association with Degludec U 100, on increased doses, and without persistent increased inflammatory syndrome, with low inflammatory cytokines, with low risk of infection, excessive bleeding and thrombosis intraoperative deep vein. Empagliflozin therapy, with anti-inflammatory effect, in cancer patients, with a low risk of pancreatitis in combination with Degludec U 100 [2], and a low risk of intraoperative pulmonary embolism, (having a role in the suppression of lung metastases), and the induction of nodular opacities in ground glass, with minimal risk of intraoperative infection. 

Patients with recurrent venous thromboembolic [38], events and treated with anticoagulants, with SpO2 <90% at admission, elevated Troponin I and inflammatory cytokines, even if oral antiviral and antidiabetic therapy is initiated, was associated with a low risk of mortality by suspending surgical therapy, at least until the decrease of HbA1c and the increase of HDL cholesterol. 

The adjustment of D-Dimers lowered dependent on HDL cholesterol increasing, has become mandatory, having chest CT with sequelae changes in 20% frosted glass, and Empagliflozin therapy is reconsidered by gradually increasing it to 25mg together with Degludec U 100, thus being beneficial and lowering HbA1c, to reduce the chances of intraoperative pulmonary embolism and postoperative deep vein thrombosis. 

Cancer patients, diagnosed for approximately 1 year, have chances of developing pulmonary embolism, and mortality of: 1.9% hospitalized, 9.9% >30 days, 20.9% incidence of pulmonary embolism, 22.1% >90 days mortality rate, 27.1% incidence of central pulmonary embolism, without postoperative treatment with Empagliflozin.

Preoperatory types of cancer with complications [39], treated urgently, for only 82 patients with Favipiravir: 

• Prostate cancer, high risk >66 years (20 cases): multitherapeutic approach -> prostatectomy, a laparoscopic procedure, with lowering the risk of skin metastases, a differential diagnosis was put with COVID -19 skin infection, very common in patients unvaccinated with BCG, with creatine levels significantly increased in infected COVID-19 patients, post operatory.

Seric cretinine levels from 2mg/dl preoperatory to 2.4mg/dl post operatory.

One case with colorectal anastomotic leakage requiring covering ileostomy, and two cases of vesicoureteral anastomotic leakage requiring Foley catheter reinsertion (with urinary incontinence 6-12 months).

Six cases with radiotherapy, in prostate cancer, after nephrectomy. Rare complications intra operatory, pneumoperitoneum, and partial nephrectomy (immunohistopathological with renal cell carcinoma). Recurrence occurred after 12 months. 

• Breast cancer (30 cases), high risk, between 40-49 years old, post operatory:

A case with, intraductal multicentric right breast cancer with bilateral axillary nodal metastases, with COVID-19 recurrences post operatory after 6-12 months.

A case with peritoneal metastases, of breast cancer, occurring after 5 years, diagnosed with right mammary neoplasm (histopathological type of the tumor was invasive lobular mammary carcinoma.

All 28 cases, with lymph nodes (over 10 lymph nodes), treated surgically (morphological -> primary tumor and axillary lymph nodes).

All 28 cases can cause Venous thrombosis during anticoagulant treatment, intra operatory. 

• Pulmonary cancer (32 cases), with average age 71 years:

Almost 20 patients, with pulmonary open lobectomy (video assisted thoracic surgery, and robotic lobectomy, can cause pulmonary thromboembolism post operatory.

About of 2 patients, with lobectomy in both lungs, can cause post operatory, pulmonary edema with respiratory failure, <SpO2<80 %, treated with Furosemid 60mg/2ml in 100ml Glycose 10% PEV, in 60 minutes and oxygen therapy.

And 10 patients, with recurrent or second primary lung cancer, underwent limited surgery, and with D-Dimer 8110ug/ml, lowered till 1136ug/ml post operatory. Now underwent completion pneumonectomy at second operation.

Preoperatory types of cancer with complications [34], treated urgently, for 82 patients with Molnupiravir: 

• Prostate cancer with minimal invasive prostate cancer surgery (30 cases) -> Radical Prostatectomy (ORP) and Robotic - Assisted Laparoscopic (RACP).

Seric Creatinine levels from 2mg/dl preoperatory to Seric Creatinine 0.9 mg/dl post operatory. 

• Breast cancer (30 cases):

Included post operatory local, hematoma, wound dehiscence, persistent postsurgical pain, fat necrosis, reduced tactile sensation.

Venous Thromboembolism treated with Empagliflozin.

With no postmastectomy radiation.

Treated scars post operatory with Betamethasone 0.5mg, Acid Fusidic 2% 15g, Gentamicin 15g/grams and Zinc Oxide 3g. 

• Pulmonary cancer (22 cases):

All 22 cases with Thoracotomy, had post operatory persistent pain.

Comparing Molnupiravir with Favipiravir, with the SGLT-2 inhibitors influence:

Rare neoplasm, with distinct histological types of carcinomas, with different origins, separated by normal tissue, ( and no mixed areas), are described in only three organs prostate, pulmonar and breast, treated with Molnupiravir, when patients are infected with COVID-19, and identified with a low risk of metastases, with a discharge from the hospital, presented in the decreased biological inflammatory markers, IL-1,IL-6, PAI-1 and TNF -Alpha, with the same immunity at different ages in male and women.

Hypokalemia, in kidney inflammation, was observed in Favipiravir [40], treated cancer and infected COVID-19 patients and chronic hyperglycemias, with irreversible renal status, has been reported pattern malignancies, signs of a very aggressive profile with rapid evolution on Favipiravir. Creatinine seric, lowered very fast, with hypokalemia, in COVID-19 patients, with cancer, can be fatal intra operatory, and post operatory, with a high risk of angina pectoris, predicting obstructive coronary diseases (Table 4). 

Table 4: Predictive value for coronary stenosis. Cardio-Renal Markers. 

Ionic Calcium/Total Calcium with CK/CK-MB, mixed, showed a significant main predictor of myocardial infarction and chronic kidney disease, impact on the arterial lumen, occlusion, in post operatory surgery. 

All 164 patients with prostate, breast, and pulmonary cancer, with severe atherosclerotic coronary disease, have been delayed intraoperative surgery, with a high risk of chronic renal disease post operatory. 

Surgical treatment, with median age of 66 years, (from 59 years to 74 years), with BMI> 26kg/m2 at high risk of secondary determination intraoperatory: 

1. Intraoperative ultrasonography
2. Laparoscopic ultrasonography
3. Partial nephrectomy - secondary sepsis with viral infection COVID-19
4. Epileptic attacks
5. Respiratory and circulatory complications
6. Local anesthesia toxicity (desaturation rapidly SpO2< 80%)
7. Hypertension episodes with increased risk of sudden death
8. Hypoglycemia unawareness
9. Cardiogenic shock [41], (with severe cardiac and pulmonary failure) -> initial laparoscopic exploratory laparotomy under VA-ECMO (extracorporeal membrane oxygenation) support. ICG -FA (indocyanine green fluorescent angiography reveals segment of ischemic small bowel-associated MI - mesenteric ischemia. Intraoperative improvement with human immunoglobulin therapy. 

Study Objectives: Different laboratory analyses, which represent the intraoperative complications: pneumonia with sepsis, deep vein thrombosis and pulmonary embolism, with postoperative consequences: 

1. Metabolic complications showed: lower HDL cholesterol and increased HbA1c: chronic hyperglycemia with irreversible postoperative hyperuricemia.
2. Vascular complications diagnosis increased thrombotic markers D-dimer and VSH inclusion endothelial dysfunction with risk of postoperative thrombosis, and significant high risk of coronary events.
3. Systemic complications inflammatory cytokines and LDH increased: with chronic postoperative respiratory failure (SpO2<90% at discharge). 

Cytokine Storm Induced, Preoperatory, with a total of 82 Patients Treated With Favipiravir [42]: 

• Acute intercurrent disease, antibiotic use at home Rifamycin (Rifampicin 150mg x 3 per day).
• Cancer progression -> pulmonary fibrosis ->SpO2<90 % with oxygen therapy
• Geriatric age with polly pill > 65 years.
• Acute kidney disease: IL-6, IL-1↑ and creatinine seric ↑ increased with glomerulopathy and with thrombosis.
• The spectrum of liver injury with, immunodeficiency and systemic inflammation with focal lobular inflammation, and elevated D-Dimer, ALT and AST, resulting microvascular and macrovascular steatosis with cell death.
• Cardiac injury -> causes acute myocardial injuries, as well as chronic damage -> NT-proBNP/Troponin I ↑ (>5611/1015)=>5.5 dependent of IL-6 ↑, with high risk of thrombosis, with coronary artery aneurysms.
• Interrupted treatment with Molnupiravir, in patients with elevated IL-1, IL-6, PAI-1, TNF-Alpha and D -Dimer, initiating anticoagulant and antibiotic treatment (CT chest remains 20 %).
• Administrating Rifampicin 150mg per day with [43], beneficial results on FiO2 and delaying cytokine storm, with low risk of sepsis intra operatory.
• Stopping the treatment with Molnupiravir, is important when the patient is still symptomatic after 5-6 days, with persistence of somatic symptoms, a positive SARS CoV-2 alpha, with difficulties breathing, pain when breathing, painful muscles, ageusia or anosmia, lump in throat, feeling hot, and cold alternately, heavy arms and legs, ang general tiredness. 

Degludec U 100 with Molnupiravir lowering the Risk Preoperatory [15]: 

• Low risk of hypoglycemic shock.
• Longer duration of action > 48 hours, allowing flexibility in daily administration.
• With no risk of flatness.
• Obtain rapid acting prandial glycaemia and toward the goal of enhanced basal glycemic.
• Uncontrolled glycaemia on antivirals (HbA1c ↑).
• With no adverse cardiovascular events, confirmed in lowering glycaemia slowly in the first 5-6 days.
• Lowering creatinine levels at the same time with the glycaemia, with potassium levels, remaining still lower for the first 2 weeks, in acute kidney injury.
• Reduces microvascular acute events -> polyneuropathy in LONG COVID-19. 

Empagliflozin Treatment with Molnupiravir Action in lowering the Intra Operatory Risk: 

• Blood coagulation
• Pulmonary thromboembolism
• Pulmonary vascular damage 

Cardiovascular System: 

• Myocardial Hypertrophy
• Coronary Artery Atherosclerosis
• Focal Myocardial fibrosis
• Acute Myocardial infarction
• Cardiac Hypertrophy 

Mental Health: 

• Stress 

Microvascular thrombosis and multiple organ failure post operatory, are treated with Tocilizumab, if Molnupiravir and Rifampicin treatment is uncontrollable, in critical illness. 

1. Patients with type 1 diabetes are prone to postprandial hypoglycemia, on therapy with Empagliflozin 10mg and Degludec U 100.
2. Therapy with Empagliflozin 10mg and Degludec U 100 has proven to be effective, maintaining pre- and postprandial blood sugar levels in a plateau effect, without nocturnal hypoglycemia.
3. Infection with COVID-19 increases the risk of lung and breast metastases, with chronically elevated inflammatory cytokines (Il-6 and TNF-alpha) and chronically elevated HbA1c metabolic memory.
4. Acute and subacute effects, in patients treated with Degludec U 100 and Empagliflozin 10mg, by gradually reducing glycemic levels, in the first 5 days, at the same time with inflammatory cytokines, with vasculoprotection [44], focused on atherogenesis, with increasing HDL cholesterol and lowering systolic/diastolic BP with Favipiravir, the sudden drop in blood sugar in the first days, with increased inflammatory cytokines [45], but with lowering triglycerides , BP, TA systolic/diastolic, with nocturnal hypoglycemia.
5. Delayed effects on therapy with Degludec U 100 and Molnupiravir, without hypoglycemia and chronic cardiovascular complications, versus Favipiravir, including antibiotic resistance, with repeated pulmonary superinfections, postoperatively, and chronic glycemic excursions.
6. Contouring of the lipid and glycosylic effects, on Empagliflozin 10mg therapy, the decrease of HbA1c dependent on the decrease of inflammatory cytokines, with a role in decreasing the risk of intraoperative myocardial infarction, and the mitigation of asymptomatic hyperuricemia.
7. Empagliflozin, often used to lower blood sugar levels and the risk of decompensated heart failure, has been shown to be inferior to Dapagliflozin, in Degludec u 100 therapy in cancer patients and infected with COVID-19, by reducing serum creatinine, rapidly, with an increase in HbA1c, thus concluding that HbA1c is not dependent on glucose.
8. Therapy with Empagliflozin 10mg/day proved beneficial in lowering NTproBNP [46], in the first 4-5 days, with a reduction in the risk of mortality, cardio-renal, but with the risk of renal acidosis.
9. Therapy with Empagliflozin 10mg/day, lowering TGO, TGP and GGT (by decreasing hepatic steatofibrosis) and restoring endothelial dysfunction, lowering Troponin I [47], with a neutral effect on weight, in combination with Degludec U 100, the risk of subarachnoid hemorrhage is reduced intraoperatively, and the induction of acute pulmonary insufficiency postoperatively.
10. Oxygen therapy in suspected TEP patients, it’s unnecessary, complicating the view of CT chest preoperatory.
11. Pulmonary cancers, have always inflammatory cytokines high in severe forms only on TNF-alpha and develop a new metabolic syndrome, with high LDL cholesterol levels, in severe forms of infection in COVID-19, in diabetes patients.
12. Breast cancers, have inflammatory citokines like IL-6 high, with a new metabolic syndrome, with high HDL cholesterol levels, in mild form of infection with COVID-19 in diabetes patients.

This research received no external funding.

Not applicable.

Not applicable.

The authors declare no conflicts of interest.

1. Galindo RJ, Pasquel FJ, Vellanki P, Alicic R, Lam DW, et al. (2021) Degludec hospital trial: A randomized controlled trial comparing insulin degludec U100 and glargine U100 for the inpatient management of patients with type 2 diabetes. Diabetes Obes Metab 24: 42-49.
2. Insulin Degludec (2016) (Tresiba®, Novo Nordisk A/S) for the Treatment of Diabetes: Effectiveness, Value, and Value-Based Price Benchmarks Final Report Institute for Clinical and Economic Review.
3. Katakura Y, Tatsumi F, Kusano T, Shimoda M, Kohara K, et al. (2022) Persistent hypoglycemia induced by long-acting insulin Degludec. Intern Med 61: 861-864.
4. Lane WS, Weinrib SL, Lawrence MJ, Lane BC, Jarrett RT (2022) Basal Insulin Degludec and Glycemic Control Compared to Aspart via Insulin Pump in Type 1 Diabetes (BIGLEAP): A single-center, open-label, randomized, crossover trial. Endocr Pract 28: 165-172.
5. Nassar M, Daoud A, Nso N, Medina L, Ghernautan V, et al. (2021) Diabetes mellitus and COVID-19: Review article. Diabetes Metab Syndr 15: 102268.
6. Zanza C, Romenskaya T, Manetti AC, Franceschi F, Russa RL, et al. (2022) Cytokine Storm in COVID-19: Immunopathogenesis and Therapy. Medicina (Kaunas) 58: 144.
7. Caricchio R, Gallucci M, Dass C, Zhang X, Gallucci S, et al. (2021) Preliminary predictive criteria for COVID-19 cytokine storm. Ann Rheum Dis 80: 88-95.
8. Rayman G, Lumb A, Kennon B, Cottrell C, Nagi D, et al. (2020) Guidance on the management of diabetic ketoacidosis in the exceptional circumstances of the COVID-19 pandemic. Diabet Med 37: 1214-1216.
9. Arora K, Panda PK (2021) Steroid harms if given early in COVID-19 viraemia. BMJ Case Rep 14: 241105.
10. Montazersaheb S, Khatibi, SMH, Hejazi MS, Tarhriz V, Farjami A, et al. (2022) COVID-19 infection: An overview on cytokine storm and related interventions. Virol J 19: 92.
11. Sun X, Wang T, Cai D, Hu Z, Chen J, et al. (2020) Cytokine storm intervention in the early stages of COVID-19 pneumonia. Cytokine Growth Factor Rev 53: 38-42.
12. Alhazzani W, Evans L, Alshamsi F, Møller MH, Ostermann M, et al. (2021) Surviving sepsis campaign guidelines on the management of adults with coronavirus disease 2019 (COVID-19) in the ICU: First update. Crit Care Med 49: 219-234.
13. Passamonti F, Nicastri E, Rocco AD, Guarini A, Ibatici A, et al. (2023) Management of patients with lymphoma and COVID-19: Narrative review and evidence-based practical recommendations. Hematol Oncol 41: 3-15.
14. Goldenberg RM, Aroda VR, Billings LK, Christiansen ASL, Donatsky AM, et al. (2021) Effect of insulin degludec versus insulin glargine U100 on time in range: SWITCH PRO, a crossover study of basal insulin-treated adults with type 2 diabetes and risk factors for hypoglycaemia. Diabetes Obes Metab 23: 2572-2581.
15. Johnson MG, Puenpatom A, Moncada PA, Burgess L, Duke ER, et al. (2022) Effect of molnupiravir on biomarkers, respiratory interventions, and medical services in COVID-19 a randomized, placebo-controlled trial. Ann Intern Med 175: 1126-1134.
16. Faour WH, Choaib A, Issa E, Choueiry FEl, Shbaklo K, et al. (2022) Mechanisms of COVID-19-induced kidney injury and current pharmacotherapies. Inflamm Res 71: 39-56.
17. Tamaki S, Yamada T, Watanabe T, Morita T, Furukawa Y, et al. (2021) Effect of empagliflozin as an add-on therapy on decongestion and renal function in patients with diabetes hospitalized for acute decompensated heart failure: A prospective randomized controlled study. Circ Heart Fail 14: 7048.
18. Khawaja J, Bawa A, Omer H, Ashraf F, Zulfiqar P (2022) COVID-19 infection presenting as an isolated severe acute liver failure. Cureus 14: 24873.
19. Zhang Z, Ni L, Zhang L, Zha D, Hu C, et al. (2021) Empagliflozin Regulates the AdipoR1/p-AMPK/p-ACC pathway to alleviate lipid deposition in diabetic nephropathy. Diabetes Metab Syndr Obes 14: 227-240.
20. Xie Y, Choi T, Al-Aly Z (2023) Molnupiravir and risk of post-acute sequelae of Covid-19: Cohort study. BMJ 381: 74572.
21. Tang Y, Liu J, Zhang D, Xu Z, Ji J, et al. (2020) Cytokine storm in COVID-19: The current evidence and treatment strategies. Front Immunol 11: 1708.
22. Shiraki K, Sato N, Sakai K, Matsumoto S, Kaszynski RH, et al. (2022) Antiviral therapy for COVID-19: Derivation of optimal strategy based on past antiviral and favipiravir experiences. Pharmacol Ther 235: 108121.
23. Lui DTW, Chung MSH, Lau EHY, Lau KTK, Au ICH, et al. (2023) Analysis of All-Cause Hospitalization and Death Among Nonhospitalized Patients With Type 2 Diabetes and SARS-CoV-2 Infection Treated With Molnupiravir or Nirmatrelvir-Ritonavir During the Omicron Wave in Hong Kong. JAMA Netw Open 6: 2314393.
24. Pagliano P, Sellitto C, Ascione T, Scarpati G, Folliero V, et al. (2022) The preclinical discovery and development of molnupiravir for the treatment of SARS-CoV-2 (COVID-19). Expert Opin Drug Discov 17: 1299-1311.
25. Coursin DB, Connery LE, Ketzler JT (2004) Perioperative diabetic and hyperglycemic management issues. Crit Care Med 32: 116-125.
26. Tentolouris A, Vlachakis P, Tzeravini E, Eleftheriadou I, Tentolouris N (2019) SGLT2 Inhibitors: A review of their antidiabetic and cardioprotective effects. Int J Environ Res Public Health 16: 2965.
27. Galway U, Chahar P, Schmidt MT, Araujo-Duran JA, Shivakumar J, et al. (2021) Perioperative challenges in management of diabetic patients undergoing non-cardiac surgery. World J Diabetes 12: 1255-1266.
28. Dhatariya K, Levy N, Kilvert A, Watson B, Cousins D, et al. (2012) NHS diabetes guideline for the perioperative management of the adult patient with diabetes. Diabet Med 29: 420-433.
29. Joshi S, Parkar J, Ansari A, Vora A, Talwar D, et al. (2021) Role of Favipiravir in the Treatment of COVID-19. Int J Infect Dis 2021, 102: 501-508.
30. Pelletier R, Ng K, Alkabbani W, Labib Y, Mourad N, et al. (2020) The association of sodium-glucose cotransporter 2 inhibitors with cancer: An overview of quantitative systematic reviews. Endocrinol Diabetes Metab 3: 145.
31. Mangalmurti N, Hunter CA (2020) Cytokine storms: Understanding COVID-19. Immunity 53: 19-25.
32. De Gennaro R, Gastaldo E, Tamborino C, Baraldo M, Casula N, et al. (2021) Selective cranial multineuritis in severe COVID-19 pneumonia: Two cases and literature review. Neurol Sci 42: 1643-1648.
33. Qdaisat A, Kamal M, Al-Breiki A, Goswami B, Wu CC, et al. (2020) Clinical characteristics, management, and outcome of incidental pulmonary embolism in cancer patients. Blood Adv 4: 1606-1614.
34. Sudhakaran S, Surani SR (2015) Guidelines for perioperative management of the diabetic patient. Surg Res Pract.
35. Fujishima S (2023) Guideline-based management of acute respiratory failure and acute respiratory distress syndrome. J Intensive Care 11: 10.
36. Rayman G, Lumb AN, Kennon B, Cottrell C, Nagi D, et al. (2021) Dexamethasone Therapy in COVID-19 Patients: Implications and Guidance for the Management of Blood Glucose in People with and without Diabetes. Diabet Med 38: 14378.
37. Lu QY, Yang LJ, Xiao JJ, Liu Q, Ni LH, et al. (2023) Empagliflozin Attenuates the Renal Tubular Ferroptosis in Diabetic Kidney Disease through AMPK/NRF2 Pathway. Free Radic Biol Med 195: 89-102.
38. Konstantinides SV, Meyer G, Bueno H, Galié N, Gibbs JSR, et al. (2020) 2019 ESC guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J 41: 543-603.
39. Wagner J, Lock JF, Kastner C, Klein I, Krajinovic K, et al. (2019) Perioperative management of anticoagulant therapy. Innov Surg Sci 4: 144-151.
40. Hashemian SMR, Farhadi T, Velayati, AA (2021) A review on Favipiravir: The properties, function, and usefulness to treat COVID-19. Expert Rev Anti Infect Ther 19: 1029-1037.
41. Aleman R, Labkovski M, Patel S, Zadneulitca N, Frieder JS, et al. (2022) Shifting Surgical Archetypes of ICG Fluorescent-Angiography for Bowel Perfusion Assessment in Cardiogenic Shock under ECMO Support. J Card Surg 37: 2187-2190.
42. Manabe T, Kambayashi D, Akatsu H, Kudo K (2021) Favipiravir for the treatment of patients with COVID-19: A systematic review and meta-analysis. BMC Infect Dis 21: 489.
43. Surette MD, Spanogiannopoulos P, Wright GD (2021) The Enzymes of the Rifamycin Antibiotic Resistome. Acc Chem Res 54: 2065-2075.
44. Quagliariello V, De Laurentiis M, Rea D, Barbieri A, Monti MG, et al. (2021) The SGLT-2 Inhibitor Empagliflozin Improves Myocardial Strain, Reduces Cardiac Fibrosis and pro-Inflammatory Cytokines in Non-Diabetic Mice Treated with Doxorubicin. Cardiovasc Diabetol 20: 150.
45. Hu B, Huang S, Yin L (2021) The cytokine storm and COVID-19. J Med Virol 93: 250-256.
46. Januzzi JL, Zannad F, Anker SD, Butler J, Filippatos G, et al. (2021) Prognostic importance of NT-ProBNP and effect of Empagliflozin in the EMPEROR-reduced trial. J Am Coll Cardiol 78: 1321-1332.
47. Rubina SKS, Anuba PA, Swetha B, Kalala KP, Pm A, et al. (2022) Drug interaction risk between cardioprotective drugs and drugs used in treatment of COVID-19: A evidence-based review from six databases. Diabetes Metab Syndr 16: 102451.