COVID-19 in Diabetics

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Anahita Deylamsalehi, M.D.[2]

Overview

World Health Organization declared the COVID-19 outbreak a pandemic in 2020. Numerous explanations have been developed for this Comorbidity, such as immune system impairment due to abnormal production of adipokines and cytokines (eg, tumor necrosis factor-alpha and interferons), as well as decreased phagocytic activity and chemotaxis among diabetics. These explanations justify the higher prevalence of COVID-19 among diabetic patients. Old age, male sex and some ethnic minority groups, such as Hispanic, Latino and African American, are considered as risk factors and are also related to worse outcome. There are some confirmed risk factors for COVID-19 in diabetics such as glycemic instability, immune deficiency and related comorbidities, like obesity and cardiac and renal disease. There are also some hypothesized risk factors such as reduced ACE2, Increased furin and chronic inflammation. COVID-19 among diabetic patients has been related to higher rate of complications. Acute respiratory distress syndrome (ARDS), septic shock, acute kidney injury, acute heart injury and diabetic ketoacidosis are some of the frequently reported complications. Diabetic patients with COVID-19 have higher rate of hospitalization, intensive care unit admission and death, compared to non-diabetics. These patients are presented with fever, cough, dyspnea, fatigue, chest pain, headache and some gastrointestinal complains. Concurrent COVID-19 and diabetes have been related to lower levels of lymphocytes, red blood cells (RBC), albumin and hemoglobin. Conversely, higher levels of neutrophils, erythrocyte sedimentation rate (ESR), D-dimer, interleukin-6 (IL-6) and interleukin-10 (IL-10) have been reported in these patients. Bilateral consolidation and ground‐glass opacification have been reported based on chest X-ray and CT scan, respectively. Insulin is used for hospitalized patients in order to maintain a desirable glycemic control and higher insulin requirements have been reported among diabetic patients. There are numerous considerations regarding antidiabetics and antihypertensive medications, their possible side effects and their effects on ACE2 expression. Hyperglycemia has been reported with lopinavir, ritonavir and glucocorticoids use. Furthermore, antivirals such as lopinavir and ritonavir should be used with caution with statin therapy due to augmented risk of hepatic and muscle toxicity.

Historical Perspective

• On March 12, 2020, the World Health Organization declared the COVID-19 outbreak a pandemic

Classification

• There is no classification for COVID-19 in diabetes mellitus.

Pathophysiology

• COVID-19 is caused by a virus called severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) that belongs to the order nidovirale, family coronaviridae.
• Abnormal production of adipokines and cytokines such as tumor necrosis factor-alpha and interferons in diabetic patients have been associated with impairment in immune system and increased susceptibility to infections.
• COVID-19 has been related to cytokine storm and beta cell damage. The latter effects added to the own nature of COVID-19 lead to the following conditions:
  • Hyperglycemia at the time of admission
  • New onset diabetes
  • Aggravated metabolic control in a diabetic patient
• The following factors have been demonstrated as responsible mechanisms which increase the risk of infections in diabetes:
  • Reduction of Interleukin production
  • Neutrophil dysfunction
  • Decreased phagocytic activity and chemotaxis
  • Decreased T cell activity
  • Immobilized granulocytes
  • Poor circulation, especially with concurrent peripheral vascular disease (PVD)

Causes

• Coronavrus Disease 2019 (COVID-19) is caused by a virus named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).
• To browse the causes of diabetes, click here.

Differentiating from other Diseases

• Two types of diabetes is better to be differentiated from each other for optimal approach.
• To browse the differential diagnosis of type 2 diabetes, click here.
• To browse the differential diagnosis of COVID-19, click here.

Epidemiology and Demographics

• It has been estimated that 20-25% of patients with COVID-19 had diabetes.
• Based on a Meta-analysis, the prevalence of diabetes among Chinese population with COVID-19 was 9·7%.
• A study done on 1317 participants reported that 88.5% of patients with COVID-19 had concurrent diabetes mellitus type 2.
• Based on a study done in Wuhan, 16.2% of patients who experienced sever COVID-19 were diabetics.

Age

• Diabetic patients of all age groups may develop COVID-19, although older age has higher prevalence and been related to higher mortality rate with exception of Korean population, which reported higher rate of COVID-19 among individuals aged 20–29 years.

Risk Factors

• Some possible factors that lead to more severe COVID-19 in diabetic patient have been summarized in the table below:

Confirmed factors	hypothesized factors
1- Glycemic instability 2- Immune deficiency (especially T-cell response) 3- Related comorbidities, like obesity and cardiac and renal disease	1- Chronic inflammation (elevated interleukin-6) 2- Elevated plasmin 3- Reduced ACE2 4- Increased furin (involved in virus entry into cell)

Natural History, Complications and Prognosis

Complications

• Diabetic patients with SARS-CoV-2 infection had higher rate of the following complications:
  • Acute Respiratory Distress Syndrome (ARDS)
  • Septic Shock
  • Acute kidney injury
  • Acute heart injury
  • Requirement of oxygen inhalation
  • Multi-organ failure
  • Both non-invasive and invasive ventilation (eg, extracorporeal membrane oxygenation (ECMO))
  • Diabetic ketoacidosis:
    • Associate to higher mortality rate
  • Hyperosmolar hyperglycemic state
• Optimal metabolic control reduces the chance of complications in concurrent diabetes mellitus and COVID-19 in outpatients.
• COVID-19 has been related to high coagulation activity, probably due to endothelial dysfunction caused by hypoxia. The latter COVID-19 consequence will be more augmented by the prothrombotic state in diabetic patients, which can lead to more thrombosis related complications.

Prognosis

• SARS-CoV-2 infection has been linked with higher rate of hospitalization and mortality in diabetic patients compared to non-diabetics.
• Records from the Centers for Disease Control and Prevention (CDC) and other national health centers and hospitals state that diabetic patients with COVID-19 have up to 50% higher chance of death compared to non diabetics with this infection.
• Based on a study done in Wuhan, 53.8% of patients who died of COVID-19 were diabetics.
• Based on a study done in Italy, 35.5% of COVID-19 death had concurrent diabetes.
• Another study done in the US reports more than fourfold mortality rate elevation in COVID-19 in diabetic patients.
• Study on COVID-19 patients in intensive care unit demonstrated a twofold increase in incidence of diabetes, compared to non-intensive care patients.
• Another study done among 1561 patients with COVID-19 in Wuhan demonstrated that diabetic patients had higher rate of intensive care unit (ICU) admission and death, compared to nondiabetics.
• A cohort study done on 5693 patients in England demonstrated higher chance of death among patients with uncontrolled diabetes.
• Complications of diabetes and higher prevalence of comorbidities such as hypertension, cardiovascular disease, cerebrovascular disease, pulmonary disease and chronic kidney disease.
• Estimated GFR less than 60 mL/min per 1·73 m2 at the time of admission is correlated to higher rate of early death in diabetic patients with COVID-19.
• HbA1C more than 86 mmol/mol (10%) has been related to worst outcome and higher chance of death, compared to HbA1C less than 48 mmol/mol (6·5%), which further confirms the importance of desirable glycemic control.
• Elevation in the followings are related to poor prognosis among diabetic patients with COVID-19:
  • C-reactive protein
  • Erythrocyte sedimentation rate (ESR)
  • Ferritin
  • Procalcitonin

Diagnosis

History and Symptoms

• Symptoms of COVID-19 may include the following:
  • fever
  • Cough
  • Shortness of breath
  • Fatigue
  • Chest pain
  • Chest tightness
  • Headache
  • Mild gastrointestinal disease (diarrhea, nausea and vomiting)
• For explore further about symptoms of COVID-19, click here
• To browse the Symptoms of type 2 diabetes, click here.

Physical Examination

• To browse the physical examination of COVID-19, click here.
• To browse the physical examination of type 2 diabetes, click here.

Laboratory Findings

• Diabetic patients with SARS-CoV-2 infection have lower levels of the following, compared to non-diabetics:
  • Lymphocytes
  • Red blood cells (RBC)
  • Albumin
  • Hemoglobin
• Diabetic patients with SARS-CoV-2 infection have higher levels of the following, compared to non-diabetics:
  • Neutrophils
  • Erythrocyte sedimentation rate (ESR)
  • D-dimer
  • A-hydroxybutyrate dehydrogenase
  • Lactic dehydrogenase
  • Alanine aminotransferase (ALT)
  • Fibrinogen
  • C reactive protein
  • Ferritin
  • Interleukin-6 (IL-6)
  • Interleukin-10 (IL-10)
  • γ-glutamyl transferase
  • Procalcitonin
• High C-reactive protein (CPR) level is one of the risk factors that increase mortality rate in diabetic patients who become infected with SARS-CoV-2. Therefore, A study suggests usage of C-reactive protein (CRP) as a tool to identify patients with higher chance of dying during hospitalization. Based on a prospective cohort study, C-reactive protein higher than 200 mg/L and Ferritin more than 2500 ng/mL at the time of admission have been related to more severe COVID-19.
• Sever COVID-19 in diabetic patients were related to higher levels of serum amyloid A (SAA) and low CD4+ T lymphocyte counts.
• There is a J-curve association between HbA1c and risk of infections in general, particularly respiratory tract infections.
• Increased concentrations of N-terminal prohormone of brain natriuretic peptide (N-terminal prohormone of brain natriuretic peptide) and cardiac troponin I have been related to myocardial infarction. Since diabetic patients may already suffer from cardiac complications, checking these lab values could be helpful.

Electrocardiogram

• There are no ECG findings associated with COVID-19 in diabetics.

X-ray

• Chest X-ray could be normal in early stages of COVID-19 or in mild disease.
• Bilateral consolidation or airspace opacities is one the findings of Chest X-ray.

Echocardiography or Ultrasound

• There are no echocardiography/ultrasound findings associated with COVID-19 in diabetics.

CT scan

• Ground‐glass opacification

MRI

• There are no MRI findings associated with COVID-19 in diabetics.

Other Imaging Findings

• There are no other imaging findings associated with COVID-19 in diabetics.

Other Diagnostic Studies

• There are no other diagnostic studies associated with COVID-19 in diabetics.

Treatment

Medical Therapy

• Even though some studies reported that insulin was associated with poor prognosis in diabetic patients with COVID-19, Insulin is still the choice agent to control blood glucose in hospitalized diabetic patients with COVID-19.
  • Possible β cell damage caused by SARS-CoV-2 can cause to insulin deficiency, which explain increased insulin requirement in these patients. Due to elevated insulin consumption, intravenous infusion must be considered.
  • The following table is a summary of some insulin regimens and their effects in management of diabetic patients infected with COVID-19, who are receiving nutritional therapy:

Insulin Regimen	Glycemic Control	Glycemic Variability	Hypoglycemia Rate ¶
Insulin Infusion	++++	+	-
Basal Insulin (Every 12 Hours) + Regular Insulin (Every 6 Hours)	+++	++	++++
NPH Insulin (Every 8 hours) + Regular Insulin (Every 8 Hours)	++	+++	+++
Regular Insulin (Every 6 Hours)	+	++++	++

_{¶ Upon discontinuation of medical nutritional therapy.}

• Although angiotensin-converting enzyme II (ACE) expression has been reduced in COVID-19, treatment with ACE inhibitors (ACEI) or angiotensin II type-I receptor blockers (ARB) in diabetic patient with hypertension had no significant difference compared to other anti-hypertensive treatments based on one study. On the other hand, another study done on diabetic patients showed higher risk of SARS-CoV-2 infection with ACE2-increasing drugs. Elevated ACE2 level can ease the entry of virus. Therefore It is hypothesized that medications such as Angiotensin-converting-enzyme inhibitors (ACEI), angiotensin II type-I receptor blockers (ARB), thiazolidinediones and ibuprofen augment the risk of a severe and lethal SARS-CoV-2 infection.
• Due to increased risk of chronic kidney disease and acute kidney injury, renal function should be monitored in patients who take metformin. There is also a recommendation to stop Metformin use in a patient with poor oral intake and vomiting. There are other data that suggest metformin as a possibly helpful anti-diabetic agent in concurrent SARS-CoV-2 infection. Metformin leads to less elevation in interleukin-6 level, compared to other anti-diabetic agents. These data also assert an association between metformin use and albumin level elevation and a lower COVID-19 related death in patients who took metformin.
• Based on a study done in china on 1200 hospitalized diabetic patients with COVID-19 infection metformin use has been related to significantly high lactic acidosis incidence.
• A hypothesis state that since Sodium glucose cotransporter 2 (SGLT-2) inhibitors decrease lactate production and subsequently increase the cytosolic pH, they interfere with virus entry into the cells. Conversely, based on another study Sodium glucose cotransporter 2 (SGLT-2) inhibitors are also indirectly responsible for high ACE2 level, which is attributed as a risk factor for SARS-CoV-2 infection. High ACE2 level can be further elevated by concurrent Angiotensin-converting-enzyme inhibitors (ACEI) use. Current database suggests benefit from discontinuation of Sodium glucose cotransporter 2 (SGLT-2) inhibitors in diabetic patient with COVID-19.
• Initiation of Sodium-glucose-co-transporter 2 inhibitors should be avoided in respiratory illnesses.
• Although lactic acidosis due to metformin use and euglycaemic or moderate hyperglycaemic diabetic ketoacidosis associated with Sodium-glucose-co-transporter 2 inhibitors are rare, their usage has not been recommended. Nevertheless, there is no need to stop these medications prophylactically in diabetic patients with no sign of COVID-19.
• Dipeptidyl peptidase-4 inhibitors has been well tolerated in some diabetic patients with concurrent SARS-CoV-2 infection. It can be continue in mild to moderate COVID-19, nevertheless it is better to be discontinued in sever cases.
• Use of thiazolidinediones has been linked with increased fluid retention and congestive heart failure in diabetic patients with SARS-CoV-2 infection. Pioglitazone use can be continued in mild or moderate COVID-19.
• Dehydration in diabetic patients with COVID-19 should be avoided. Based on a practical recommendation, medications with possible dehydration side effect like Metformin, Sodium-glucose-co-transporter 2 inhibitors and Glucagon-like peptide-1 receptor agonists should be avoided to prevent further complications.
• A summary of anti-diabetic medications in diabetic patients with SARS-CoV-2 infection:

Anti-diabetic medication	Relation to ACE2 expression	Advantage	Disadvantage
Metformin	None	Lower level of IL-6 Higher albumin level Lower COVID-19 related death Potential cardiovascular benefits	Higher chance of lactic acidosis and renal dysfunction higher chance of dehydration
Pioglitazone	Increased ACE2 production in animal models	Reduction in proinflammatory cytokines Lower chance of lung injury	Increased chance of SARS-CoV-2 infection due to ACE2 overexpression
Sulfonylurea	None	No specific advantage has been found in patients with COVID-19	Higher chance of hypoglycemia
Dipeptidyl peptidase-4 inhibitors	None	Some anti-inflammatory properties are reported *There are some evidences about possible effectiveness of sitagliptin in survival of diabetic patients who are infected with COVID-19.	No specific disadvantage has been found in patients with COVID-19 Due to limitted data more study is required.
Sodium-glucose-co-transporter 2 inhibitors	Increased ACE2 production by kidney in human studies	Decreased oxidative stress Anti-inflammatory effects	Higher chance of hypovolemia
Glucagon-like peptide-1 receptor agonists	Liraglutide has been linked with elevated ACE2 production in lung and heart in animal models	Potential cardiovascular benefits	Higher chance of dehydration higher chance of gastrointestinal side effects
Insulin	Increased Renal ACE2 production in animal models	Anti-inflammatory effects	No specific disadvantage has been found in patients with COVID-19

• The following table is a summary of COVID-19 treatment and possible effects on diabetes:

COVID-19 treatment	Advantages in diabetics	disadvantages in diabetics	Explanation
Chloroquine/Hydroxychloroquine	None	Hypoglycemia (specially in patients on insulin or sulfonylureas)	These medications interfere with insulin metabolism and action
Lopinavir/Ritonavir	None	hyperglycaemia Hepatic toxicity Muscle toxicity Possible drug interaction with anti-diabetic treatments	Due to the hepatic and muscle toxicity, should be used under caution in patients with statin therapy or history of fatty liver disease
Glucocorticoids	None	Resistance to Insulin Hyperglycemia	Glucocorticoids interfere with insulin metabolism and action Glucocorticoids can worsen glycaemic control by enhancing production of glucagon due to interfering with GLP-1 effects.

Management Considerations:

• Evaluation of electrolytes, blood glucose, blood PH, blood ketones or beta-hydroxybutyrate should be considered in patients in intensive care unit (ICU). Since hypokalemia is a feature of COVID-19 (possibly as a result of high angiotensin 2 concentration and consequent hyperaldosteronism), potassium level should be checked. Specially in concurrent insulin treatment.
• Plasma glucose concentration goal for diabetic outpatients infected with SARS-CoV-2 is 72-144 mg/dl, while plasma glucose concentration of patients in intensive care unit is recommended to be maintained between 72 and 180 mg/dl.
• The glycemic control during hospital stay plays an important role in the overall outcome of diabetic patients with COVID-19. Based on a study done on 1122 patients with COVID-19 in the US, hyperglycaemia during the hospitalization has been associated with four time increase in mortality rate, compared to normoglycemia.
• The importance of a careful glycemic control is further supported by a study done in china, which demonstrated that patients with blood glucose concentration median less than 6·4 mmol/L during their hospital stay had lower rate of lymphopenia. These patients also had lower chance of neutrophilia, high C-reactive protein and procalcitonin levels.

Surgery

• Surgical intervention is not recommended for the management of COVID-19 in diabetic patients.

Prevention

• Here is a list of precautions that can prevent COVID-19 infection in diabetic patients:
  • Continue to take medications regularly.
  • Check the blood sugar regularly and adjust the dose of medications based on activity level and diet.
  • Consider checking the ketone level in patients with insulin-dependent diabetes (type 1 or 2) who are persistently hyperglycemic.
  • Follow a healthy diet composed of green vegetables, fruits, nuts, and green leaves.
  • Follow routine vaccination plan.
  • Stay physically active and consider indoor exercise and walking.
  • Manage the stress.
  • Avoid smoking and drinking alcohol.
• To browse the prevention of COVID-19, click here.
• To browse the prevention of type 2 diabetes, click here.