Note: This is the twenty-ninth of a series of clinical briefs on the coronavirus outbreak. The information on this subject is continually evolving. The content within this activity serves as a historical reference to the information that was available at the time of this publication. We continue to add to the collection of activities on this subject as new information becomes available.

Clinical Context

Diabetes is associated with deficits in humoral and cell-mediated immunity. It is linked to a higher risk for infection overall and greater severity of infection. The authors of the current recommendations noted that 20% of patients who develop severe pneumonia after a viral infection have diabetes.

The COVID-19 crisis has highlighted the increased risk for severe infections with diabetes. Diabetes has been associated with worse outcomes of infection, and specific mechanisms under investigation explain this relationship. First, angiotensin-converting enzyme 2 (ACE2) has been identified as the receptor for the coronavirus spike protein. Angiotensin-converting enzyme 2 has anti-inflammatory effects as well as effects in glucose metabolism. How COVID-19 upsets the balance and function of ACE2 remains largely unknown. The authors of the current recommendations noted that insulin resistance among patients with diabetes appears more severe with COVID-19 compared with other causes of critical illness. Patients with COVID-19 also seem to experience a disproportionate burden of diabetic ketoacidosis (DKA).

The dipeptidyl peptidase-4 (DPP4) enzyme, which is a treatment target in type 2 diabetes, was found to be the receptor for another coronavirus, which promoted Middle East respiratory syndrome (MERS). It is unclear if severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) follows this same pattern or how treatment with DPP4 inhibitors might affect infection with SARS-CoV-2.

The current guidelines by Bornstein and colleagues address the management of diabetes in the era of COVID-19.

Synopsis and Perspective

New guidance is available for managing inpatient hyperglycemia and DKA in patients with COVID-19 with diabetes using subcutaneous (SC) insulin. Bornstein and colleagues authored the new recommendations, which were published online April 23 in The Lancet Diabetes & Endocrinology.^[1]

"The glycemic management of many COVID-19 positive patients with diabetes is proving extremely complex, with huge fluctuations in glucose control and the need for very high doses of insulin," according to a statement from Diabetes UK's National Diabetes Inpatient COVID Response Team.

"Intravenous [(IV)] infusion pumps, also required for inotropes, are at a premium and there may be the need to consider the use of [SC] or intramuscular insulin protocols," the team noted.

Updated as of May 20, all of the information of the National Diabetes Inpatient COVID Response Team is available on the Diabetes UK website.^[2]

The new inpatient management graphic^[3] adds more detail to the previous "front-door" guidance,^[4] as reported by Medscape Medical News.

That document stressed that as well as identifying patients with known diabetes, it is imperative that all newly admitted patients with COVID-19 are evaluated for diabetes, as the SARS-CoV-2 infection is known to cause new-onset diabetes.

Subcutaneous Insulin Dosing

The new graphic^[3] gives extensive details on SC insulin dosing in place of variable rate IV insulin when infusion pumps are not available and when the patient has a glucose level > 216 mg/dL but does not have DKA or hyperosmolar hyperglycemic state (HHS); however, the advice is not intended for people with COVID-19 causing severe insulin resistance in the intensive care unit.

The other new guidance graphic^[5] on managing DKA or HHS in people with COVID-19 using SC insulin is also intended for situations where IV infusion isn't available.

Seek Help From Specialist Diabetes Team When Needed

Note: This is not to be used for mixed DKA/HHS or for patients who are pregnant, have severe metabolic derangement, other significant comorbidity, or impaired consciousness.

For those situations, the advice is to seek help from a specialist diabetes team, stated Diabetes UK.

Specialist teams will be available to answer diabetes queries, both by referring to relevant existing local documents and also by providing patient-specific advice.

Indeed, NHS England recommended that such a team be available in every hospital, with a lead consultant -- who must be free of other clinical duties at the time -- designated each day to coordinate these services. The role involves coordination of the whole service from the emergency department through to liaison with other specialties and managers.

Also newly updated is a page with extensive information for patients,^[6] including advice for staying at home, medication use, self-isolating, shielding, hospital and doctor appointments, need for urgent medical guidance, and going to the hospital.

It also covers how COVID-19 can affect people with diabetes, especially with regard to children and school, pregnancy, work situations, and tips for picking up prescriptions.

The JDRF-Beyond Type 1 Alliance posted another shorter document with COVID-19 advice.^[7]

The American Diabetes Association, Harvard Medical School, and the International Society for Pediatric and Adolescent Diabetes, in partnership with many other professional organizations, including the International Diabetes Federation, American Association of Clinical Endocrinologists, and Association of Diabetes Care & Education Specialists have all endorsed the recommendations.

The shorter document covers topics such as personal hygiene, distancing, diabetes management, and seeking treatment, as well as links to other resources on what to do when health insurance is lost and legal rights.

Highlights

• The recommendations were developed by an expert panel from across Europe.
• Outpatients with diabetes should continue to try to optimize glycemic control, with a target plasma glucose concentration of 72 to 144 mg/dL. In general, the target glycated hemoglobin (HbA_1c) level for outpatients is < 7%.
• In general, previous outpatient therapy for diabetes should be continued and refined through remote monitoring of plasma glucose levels and telemedicine.
• Tighter glycemic control may improve patients’ risk of acquiring COVID-19. The recommendations also state that blood pressure and lipid control can reduce the impact of COVID-19.
• Patients diagnosed with COVID-19 should be monitored for new-onset diabetes.
• Although modulation of ACE2 is thought to influence infection rates and the severity of COVID-19, patients should generally continue treatment with ACE inhibitors and angiotensin receptor blockers (ARBs). This recommendation may change as new data emerge.
• Likewise, statins should be continued during infection with SARS-CoV-2. Prompt discontinuation of statins might promote a cytokine storm among these patients.
• Metformin and sodium-glucose cotransporter 2 (SGLT2) inhibitors may be continued among patients with mild COVID-19, but they should be held among patients with severe illness and dehydration because of the risks for lactic acidosis with metformin and DKA with SGLT2 inhibitors.
• DPP4 inhibitors may be continued among patients with COVID-19.
• Insulin therapy may also be continued among outpatients with less severe cases of COVID-19. Insulin needs may increase, so monitoring of blood glucose levels every 2 to 4 hours, or with a continuous glucose monitor, is recommended.
• Patients with diabetes and concomitant fatty liver disease may be at particularly high risk for a cytokine storm and thus patients with COVID-19 should be closely monitored.
• Obesity is a risk factor for ventilatory failure, and patients with diabetes and obesity may have a higher risk for intubation and ventilatory support.
• Previously, severe acute respiratory syndrome coronavirus (SARS) was associated with long-term metabolic alterations among patients with severe infection. Survivors of severe COVID-19 should be monitored for the same.
• Healthcare providers with diabetes should be kept away from frontline clinical duties if possible because of their increased health risks with COVID-19.
• The authors recommended postponing bariatric surgery during the COVID-19 crisis because of potential risk for transmission in the operating room.

Clinical Implications

• ACE2 has been particularly implicated in the pathophysiology of both diabetes and COVID-19.
• The current recommendations state that ACE inhibitors, ARBs, DPP4 inhibitors, and statins can be continued among patients with diabetes and COVID-19; however, patients with severe SARS-CoV-2 infection should have metformin and SGLT2 inhibitors withheld.
• Implications for the Healthcare Team: The current recommendations regarding the care of diabetes among patients with COVID-19 are reasonable, but they may change quickly as new data emerges. The healthcare team should follow a process for routine assessment of new information which might influence patient care.

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