Practical Recommendations for Diabetes Management during COVID-19: Expert Consensus

Since January 2020, we have been facing an unprecedented outbreak of coronavirus disease 2019 (COVID-19) caused by a new coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has now become in a global catastrophe.

Data from the first months of 2020 suggest that most people with COVID-19 have comorbidities , the most prevalent being diabetes, cardiovascular disease and hypertension. A significant association with worse outcomes is observed in people with these comorbidities. also demonstrated that COVID-19 is associated with hyperglycemia, particularly in the elderly with type 2 diabetes.

In light of many uncertainties with COVID-19, a panel of primary and specialty care representatives has developed a consensus document on diabetes management for people at risk or with confirmed COVID-19 for use in primary and specialty care. The brief practical recommendations written by this group were convened virtually.

The recommendations are based on queries that clinicians have emphasized as important, questions that have been raised by colleagues and social networks, and recommendations guided by the use of a focused literature review.

Clinical decision-making in diabetes management is already complex, and under normal circumstances we recommend physicians follow guidelines for the management of people with diabetes. However, our group’s recommendations add to existing guidelines by considering specific points for the treatment of patients with diabetes and COVID-19 disease or at risk for metabolic disease.

Possible links between diabetes and COVID-19 infection

The risk of a fatal outcome from COVID -19 is up to 50% higher in patients with diabetes than in those without diabetes

Diabetes is a primary risk factor for the development of severe pneumonia and a septic course due to viral infections and occurs in about 20% of patients. Diabetes was identified as a major contributor to disease severity and mortality in Middle East Respiratory Syndrome (MERS-CoV).

Evidence from epidemiological observations in regions heavily affected by SARS-CoV-2 and reports from the Centers for Disease Control and Prevention (CDC) and other national health centers and hospitals showed that the risk of a fatal outcome of COVID -19 is up to 50% higher in patients with diabetes than in those without diabetes. 

There are several hypotheses to explain the higher incidence and severity of COVID-19 infection in people with diabetes. In general, people with all forms of diabetes are at increased risk of infection due to defects in innate immunity that affect phagocytosis, neutrophil chemotaxis, and cellular immunity; However, the high frequency of diabetes in severe cases of COVID-19 could reflect the higher prevalence of type 2 diabetes in older people. Additionally, diabetes in older age is associated with cardiovascular disease , which in itself could help explain the association with fatal COVID-19 outcomes.

There are at least two specific mechanisms that could play a role in COVID-19 infection.

1. First, to enter its target cells, the SARS-CoV-2 virus hijacks an endocrine pathway that plays a crucial role in regulating blood pressure, metabolism, and inflammation. Angiotensin-converting enzyme 2 ( ACE2) has been identified as the receptor for the coronavirus spike protein. ACE2 has protective effects mainly with respect to inflammation. COVID-19 infection reduces the expression of ACE2 which induces cell damage, hyperinflammation and respiratory failure.

Acute hyperglycemia has been shown to upregulate ACE2 expression in cells, which could facilitate viral cell entry. However, chronic hyperglycemia is known to downregulate ACE2 expression making cells vulnerable to the inflammatory and damaging effect of the virus. Furthermore, ACE2 expression in pancreatic β cells may lead to a direct effect on β cell function.

Although these findings have not been verified in humans, they suggest that diabetes may not only be a risk factor for severe COVID-19 disease, but also that the infection could induce new-onset diabetes . Italian colleagues and co-authors’ observation of these recommendations supports the potential β-cell damage caused by the virus leading to insulin deficiency . Severe diabetic ketoacidosis (DKA) was frequently reported at the time of hospital admission.

Another important observation by co-authors from several centers in different countries affected by COVID-19 is the tremendous insulin requirement in patients with a severe course of the infection. To what extent COVID-19 plays a direct role in this high insulin resistance is unclear. Based on the personal experiences of the co-authors of this view, the degree of insulin resistance in patients with diabetes appears disproportionate compared to critical illness caused by other conditions.

2. A second potential mechanism that could explain the link between COVID-19 and diabetes involves the enzyme dipeptidyl peptidase-4 (DPP-4) , which is commonly targeted pharmacologically in people with type 2 diabetes. In cellular studies, DPP-4 was identified as a functional receptor for the human coronavirus -Erasmus Medical Center (hCoV-EMC), the virus responsible for MERS.

Antibodies directed against DPP-4 inhibited hCoV-EMC infection of primary cells. The DPP-4 enzyme is a ubiquitously expressed type II transmembrane glycoprotein. It plays an important role in glucose and insulin metabolism, but also increases inflammation in type 2 diabetes. Currently, it is unknown whether these mechanisms also apply to COVID-19 and whether treating diabetes with DPP inhibitors -4 in clinical practice influences the course of infection, but, if these mechanisms translate into SARS-CoV-2, the use of these agents could reduce DPP-4 concentrations and provide therapeutic opportunities for the treatment of COVID -19.12 
Implications in the management of diabetes.

The clinical relevance of the aforementioned mechanisms is currently uncertain, but healthcare professionals should be aware of their implications for patients with diabetes. We have compiled a simple diagram for metabolic screening and management of patients with COVID-19 and diabetes or at risk of metabolic disease. This includes recommendations regarding both the need for primary prevention of diabetes and the avoidance of serious sequelae of diabetes triggered by unrecognized or poorly managed diabetes. Additionally, the panel presents special considerations for diabetes medications commonly used in patients with type 2 diabetes in light of COVID-19.

Metabolic and glycemic control

People with diabetes who have not yet been infected with the SARS-CoV-2 virus should intensify their metabolic control as necessary as a means of primary prevention of COVID-19 disease. This includes continuation and strict counseling with adequate blood pressure and lipid control.

Where possible, remote consultations using Connected Health models should be used to reduce exposure. They should also be encouraged to follow general advice from the WHO, CDC, and state and local governments on handwashing and physical distancing .

• All patients without diabetes and particularly when they are at high risk of metabolic disease who have contracted the viral infection should be monitored for new-onset diabetes that may be triggered by the virus.
   
• All patients with diabetes and COVID-19 disease require continuous and reliable glycemic control.

Management of hyperglycemia and associated metabolic conditions

Most patients with type 2 diabetes have other components of the metabolic syndrome , such as hypertension and dyslipidemia. Therefore, continuation of an appropriate antihypertensive and lipid-lowering regimen in all these patients is of crucial importance.

Treatment with ACE inhibitors and angiotensin 2 receptor blockers could increase ACE2 expression, which could accelerate virus entry into cells. However, as SARS-CoV-2 could affect the protective ACE2/Mas receptor pathway and increase harmful angiotensin 2 activity, the use of ACE inhibitors and angiotensin 2 receptor blockers could protect against lung injury. serious after infection.

Based on currently available evidence, we recommend that patients continue their antihypertensive regimens, including ACE inhibitors and angiotensin 2 receptors.

This view is supported by a recent position statement from the European Society of Cardiology and the Heart Failure Society of America, the American College of Cardiology, the American Heart Association, which strongly recommended continued treatment with ACE inhibitors and angiotensin 2 receptor blockers.

Statins have been shown to restore the reduction in ACE2 induced by high lipids, such as low-density lipoprotein or lipoprotein (a). The pleiotropic anti-inflammatory effects of statins have been attributed to the upregulation of ACE2. However, although we believe that modulation of ACE2 expression is associated with infection and mortality rates in COVID-19, statins should not be discontinued due to the long-term benefits and the possibility of tipping the balance towards a storm of cytokines due to rebound increases in interleukin (IL)-6 and IL-1ß whether they should be discontinued.

Given the close links between diabetes and cardiovascular disease, we recommend monitoring lipid concentrations in all patients with COVID-19.

There are certain subgroups of people with diabetes that may require specific consideration.

Elevated hemoglobin A1c in people with type 1 diabetes compromises immune function, making them more susceptible to any infectious disease. These individuals will require more intensive monitoring and supportive therapy to reduce the risk of metabolic decompensation, including diabetic ketoacidosis (DKA), particularly for those taking sodium glucose cotransporter 2 (SGLT2) inhibitors.

In the co-authors’ experience, an increase in the prevalence of severe DKA has been observed in COVID-19 positive patients with established type 1 diabetes, but this could be partly due to late hospital admission. Therefore, make patients with type 1 diabetes aware of this complication and re-educate them about typical symptoms, home measurement of urine or blood ketones, acute behavioral guidelines, and liberal and early consultation. of professional medical advice and sick day rules is crucial.

Patients who have undergone islet, pancreas, or kidney transplantation , or those on immunosuppressive therapy will be at particularly increased risk; Furthermore, the possible effect of coronavirus infection on pancreatic function in this group is unknown and it is important to monitor the recurrence of insulin requirement in those who are insulin independent after their transplant.

Surgical treatment of type 2 diabetes: metabolic surgery

The provision of elective surgical procedures, including metabolic surgery, is being postponed in many hospitals around the world to increase inpatient and acute care bed capacity. However, postponing elective metabolic surgery during the COVID-19 outbreak is advisable regardless of hospital capacity issues.

Patients with type 2 diabetes and obesity are at increased risk of COVID-19 complications, compounding the potential negative influence of surgical stress on the recovery period. Additionally, although specific data are not available, there are plausible concerns that pneumoperitoneum and the use of hemostatic instruments during laparoscopy (by far the most common approach used in metabolic surgery due to its ability to reduce morbidity and mortality ) could lead to viral aerosolization  thus increasing the risk of virus transmission to patients and staff.

Whether patients with type 2 diabetes who have undergone metabolic surgery will be protected from the adverse outcomes of COVID-19 relative to their peers who have not undergone surgical treatment simply due to better glycemic control remains unclear. However, metabolic surgery could induce nutritional deficiencies , including reduced absorption of vitamins and micronutrients, which play an important role in regulating the immune and stress response.

Although there is still no data to suggest that patients who have undergone metabolic surgery are at increased risk of infection or complications from COVID-19, these patients should receive particular attention and close monitoring.

Special considerations regarding the use of diabetes medications

Although it is important to optimize glycemic control to reduce the risk of severe illness from COVID-19, specific considerations should be made regarding treatment modality (see panel). Lactic acidosis associated with metformin, or hyperglycemic or euglycemic or moderate diabetic ketoacidosis associated with SGLT-2 inhibitors are rare events; however, we recommend that these medications be discontinued for patients with severe COVID-19 symptoms to reduce the risk of acute metabolic decompensation.

Importantly, it is not recommended to discontinue these medications prophylactically for outpatients with diabetes without any symptoms of infection or in the absence of evidence of a severe course of COVID-19. Furthermore, at present, there is no compelling evidence to suggest that DPP-4 inhibitors should be discontinued. Additional analyzes in patients affected with various treatments for diabetes and COVID-19 could allow elucidation of the effects of DPP-4 inhibitors. 

It is important to note that, if medications are discontinued, the alternative treatment of choice, in cases where this option is feasible, is insulin.

Given the multiple stresses associated with COVID-19, including but not limited to respiratory failure, defects in insulin secretion, and the frequent occurrence of diarrhea and sepsis, most patients will require insulin and, especially as many cases are They report very high insulin consumption, this should be administered by intravenous infusion.

Considerable care is required in fluid balance as there is a risk that excess fluid may exacerbate pulmonary edema in the severely inflamed lung. Furthermore, potassium balance should be carefully considered in the context of insulin treatment, as hypokalemia is a common feature in COVID-19 (possibly associated with hyperaldosteronism induced by high concentrations of angiotensin 2) and could be exacerbated after the onset of insulin. insulin.

We realize that all our recommendations and reflections are based on our expert opinion , awaiting the result of randomized clinical trials. Running clinical trials under difficult circumstances during the COVID-19 pandemic has been proven, and trial networks are emerging to provide evidence-based therapies.

Investigating subgroups with diabetes and how these relate to COVID-19 outcomes will be important, particularly investigating whether some of the various management approaches would be particularly effective in managing diabetes in a COVID-19 context.