US Pharm. 2020;45(11)9-12.
ABSTRACT: Coronavirus 2019 (COVID-19) has quickly spread, infecting and claiming the lives of many as healthcare professionals around the globe work tirelessly to treat patients who become infected. According to the American Diabetes Association, at this time, there are insufficient data to show if those with diabetes are more likely to become infected with COVID-19; however, those with diabetes have worse outcomes, such as higher rates of serious complications. This article discusses proposed mechanisms associated with increased risk of negative COVID-19 outcomes in patients with diabetes, comorbidities, and management of diabetes in patients with COVID-19.
Coronavirus disease 2019, or COVID-19, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It was first identified in Wuhan, China in 2019 and rapidly spread across the world such that it was declared a pandemic by the World Health Organization on March 11, 2020.1
Since then, it has infected more than 5 million people in the United States, and the death toll continues to rise to more than 219,000 at the time of publication.2 U.S. states that initially emerged as epicenters for COVID-19 were able to decrease community transmission with shelter-in-place orders, mandatory masks, and social distancing measures. COVID-19 can rapidly spread from person to person, through respiratory droplets produced through breathing, singing, talking, coughing, or sneezing. COVID-19 continues to be spread in the community in multiple states, prompting reversal of reopening plans.3 According to the American Diabetes Association (ADA), at this time, there are insufficient data to show if those with diabetes are more likely to become infected with COVID-19; however, those with diabetes have worse outcomes, such as higher rates of serious complications.4
It is known that older adults and those with chronic obstructive pulmonary disease, heart disease, diabetes, chronic kidney disease, and obesity are at increased risk for severe COVID-19 requiring hospitalization.5 With a long incubation time reported to be up to 24 days and both symptomatic and asymptomatic carriers able to transmit the disease, COVID-19 has proven to be highly infectious.6
At this time, there is no effective cure for COVID-19. The most common symptoms of COVID-19 include fever or chills, cough, shortness of breath or difficulty breathing, fatigue, muscle or body aches, headache, new loss of taste or smell, sore throat, congestion or runny nose, nausea or vomiting, and diarrhea.7
A multitude of medications to treat COVID-19 patients have been and continue to be studied in clinical trials around the world. Some medications include remdesivir, lopinavir plus ritonavir, tocilizumab, anakinra, as well as convalescent plasma therapy. Most patients receive supportive care, and those who become severely ill may require mechanical ventilation.6
Pathophysiology of SARS-CoV-2
The SARS-CoV-2 genetic sequence is similar to both SARS-CoV and MERS-CoV, with each originating in bats. Angiotensin-converting enzyme 2 (ACE2) is found in multiple locations, including the upper respiratory system, alveolar epithelial cells in the lungs, the heart, endothelial cells, kidney tubular epithelium, enterocytes, and the pancreas. ACE2 is also the cellular receptor for SARS-CoV-2. Once the virus enters the cytosol, it replicates, forms mature virions, and spreads. As infected cells undergo apoptosis, it activates proinflammatory cytokines or chemokines. SARS-CoV-2 will also infect immune cells and increases apoptosis of lymphocytes, which is associated with subsequent lymphocytopenia. The so-called cytokine storm occurs when high amounts of inflammatory cytokines are released, and it is believed to contribute to hyperinflammation, leading to multiorgan failure.8
Mechanisms for Increased Risk of Negative COVID-19 Outcomes in Diabetes
Approximately 34 million people in the U.S. have diabetes, and 26.9 million of those have been diagnosed.9 Hypertension and severe obesity are common comorbidities in patients with diabetes. It is unclear whether diabetes alone contributes to increased risk of morbidity and mortality related to COVID-19. Studies have indicated that poorer glycemic control is associated with poorer outcomes in people with diabetes.10 Muniyappa and Gubbi identified the following five mechanisms that may increase the ability of COVID-19 to impact patients with diabetes: higher affinity cellular binding and efficient virus entry; decreased viral clearance; diminished T-cell function; increased susceptibility to hyperinflammation and cytokine storm; and the presence of cardiovascular disease.8
Impact of Comorbidities on COVID-19 Outcomes in Patients With Diabetes
Apicella and colleagues reviewed the following comorbidities associated with patients who had COVID-19 with diabetes: hypertension, cardiovascular disease, and obesity. Additional factors that may impact outcomes include inflammation, coagulation, and hyperglycemia.11
Hypertension has been the most frequent comorbidity in COVID-19 patients. The use of ACE inhibitors to treat hypertension has been hypothesized to contribute by allowing SARS-CoV-2 to bind to ACE2 and to enter cells. However, further analysis of present data found in multiple studies suggest that ACE inhibitors are unlikely to be responsible for the association between COVID-19 and hypertension.11 In a joint statement from the American College of Cardiology (ACC), the American Heart Association (AHA), and the Heart Failure Society of America (HFSA) on March 17, 2020, there is no clinical data showing beneficial or adverse outcomes in those who use ACE inhibitors, angiotensin receptor blockers, or other renin antiotensin aldosterone system (RAAS) antagonists in COVID-19. The ACC, AHA, and HFSA recommend the continuation of RAAS antagonists for patients who have been prescribed the agents.12
Patients with COVID-19 have been found to have a high prevalence of cardiovascular disease. Acute myocarditis has been reported, myocardial injury has been hypothesized, and stress-induced cardiomyopathy may result from COVID-19. Overall cardiovascular-related problems may occur due to pneumonia, increased cardiac demand, electrolyte imbalance, or adverse drug reactions related to the use of medications for the treatment of COVID-19.11
Obesity has been tied to more severe COVID-19 illness and death. Abdominal fat can have a restrictive ventilatory effect, as it has been reported that mechanical ventilation was needed more for those with a BMI >35 kg/m2 than those with a BMI <25 kg/m2. Patients may develop disseminated intravascular coagulation, as obesity and diabetes are prothrombotic conditions. Myocarditis and cardiac dysfunction could be worsened by adipose tissue, and ACE2 is expressed in the adipose tissue, which could increase virus internalization.11
Other Factors That May Contribute to Negative Outcomes
Inflammation induces the cytokine storm and increases risk for vascular hyperpermeability, multiorgan failure, and death as seen by high blood concentrations of inflammatory markers. The cytokine storm is more likely to occur in patients with diabetes because these patients at baseline carry a risk for low-grade chronic inflammation.11
Diabetes causes an increase in risk of thromboembolic events as it is tied to a prothrombotic state that results from an imbalance of clotting factors and fibrinolysis. COVID-19 increases coagulation activity even further. The endothelial dysfunction linked to hypoxia can cause intravessel coagulation during an infection. Anticoagulation therapy in patients with COVID-19 seems to improve prognosis.11
In past epidemics, hyperglycemia has been found to be a predictor of death and morbidity. At this time, although this likely holds true for COVID-19, additional research is required to analyze the impact of glycemic control before and during hospitalization.11
Effects of Shelter-in-Place Orders
As shelter-in-place orders were implemented across the globe, patients’ lifestyles may have changed drastically. During these stay-at-home orders, people may be more sedentary, eat foods they would not normally eat, and have an increase in mental health concerns.13-15 Additionally, regular follow-up visits and monitoring are being delayed, and some patients have had medication-access issues.15 A study conducted in Italy reviewed continuous glucose monitoring (CGM) data 14 days prior to lockdown and 14 days after the start of the lockdown period in 55 patients. Most patients had type 1 diabetes and needed at least four daily injections of insulin or were on an insulin pump. Their study found no major changes in blood glucose profile, but it found that those who were at risk of hypoglycemia before the lockdown had reductions in time below their blood glucose range. These results may be limited by the small sample size.16
Evidence is lacking on the effectiveness of diabetes self-management education during the COVID-19 pandemic, but pharmacists should consider the use of educational materials that are delivered via smartphones and computers. Patients with diabetes should be educated about the importance of regular exercise, blood glucose monitoring (potentially utilizing remote technologies for the provider to review), and sick-day management.17,18 Typical diabetes self-management education should be provided to inpatients upon discharge, including information on administration of medications, hypoglycemia and hyperglycemia management, and the importance of regular blood glucose monitoring.
Patients with diabetes who are hospitalized for COVID-19 infection may or may not require scheduled insulin doses, which is defined as basal, prandial, and correction doses of insulin. Patients who were well controlled on noninsulin therapies or those with newly identified hyperglycemia may not require scheduled insulin doses. Clinicians may consider discontinuing insulin if the patient’s blood glucose remains lower than 180 mg/dL for 24 to 36 hours.
Choosing noninsulin therapies in admitted patients requires clinicians to take a multifactorial approach. Dipeptidyl peptidase-4 (DPP-4) inhibitors have been shown to be safe and effective in patients with mild hyperglycemia during the recovery phase of COVID-19; however, these studies were all conducted in patients also receiving correction insulin doses. Aloglitpin and saxagliptin are not recommended due to the increased risk of heart failure.18 A multicenter trial conducted in 338 patients found a reduction in mortality and improved clinical outcomes among patients who were given sitagliptin while admitted for the management of COVID-19.19 Glucagon-like peptide receptor antagonists (GLP-1 RAs) are not recommended due to their risk of nausea and vomiting and are generally not used in patients who are acutely ill.
Sulfonylureas and meglitinides should be used with extreme caution due to their hypoglycemia risk. They should not be used at all in patients who are on insulin, are elderly, or have acute renal insufficiency. Metformin should not be used, as it is contraindicated in patients who have an increased risk of acidosis. Thiazolidinediones, such as pioglitazone, can cause fluid retention and new or worsening heart failure, and delays in onset of action make these medications nonideal choices for inpatient use. Sodium-glucose cotransporter-2 (SGLT2) inhibitors have no data associated with their use in inpatients, and they may increase the risk of volume depletion and diabetic ketoacidosis (DKA). These agents should be discontinued upon admission.
Patients with type 1 diabetes, type 2 diabetes managed with insulin, or type 2 diabetes not managed at home with insulin who have elevated blood sugar in the hospital should have scheduled insulin while inpatients. Prior to the COVID-19 epidemic, most patients in the critical-care setting were treated with IV insulin infusions, but due to staffing concerns, many institutions have revised and implemented strategies such as scheduled insulin doses or the use of premixed insulin to manage critically ill patients. It is extremely important to ensure that the patient is receiving regular blood glucose monitoring while on insulin therapy. Patients with COVID-19 will have varying degrees of insulin requirements during their admission due to factors such as concomitant medications (e.g., steroids, vasopressors, hydroxychloroquine) and changing pathophysiologic conditions (such as acute on chronic kidney injury).
Patients should have their blood glucose monitored regularly via a glucometer or CGM device while inpatient. Although there is no FDA-approved CGM for inpatient use, the FDA stated that they would allow their use during the pandemic—although some CGMs require confirmatory blood glucose readings to make treatment decisions.18
Outpatient Management of Diabetes in Patients With COVID-19
Although it is extremely important to ensure that patients control their blood glucose at home to prevent severe COVID-19 infection, there are also considerations with medication use in the outpatient setting.19,20 It is recommended to consider discontinuation of metformin, especially if the patient is experiencing more severe symptoms and is at risk of dehydration, as this may increase the possibility of lactic acidosis or liver injury.20 SGLT2 inhibitors are also recommended to be discontinued due to risk of volume depletion and DKA in COVID-19–positive patients.18,20 The risk of euglycemic DKA with SGLT2 inhibitors is present, even a couple days after discontinuation of the drug.18 Patients should be monitored for early signs and symptoms of DKA, such as nausea, vomiting, or abdominal pain, as this may present in patients with normal blood glucose values. Some of the most common triggering events of euglycemic DKA in patients taking SGLT2 inhibitors include vomiting, dehydration, discontinuing or reducing doses of insulin or insulin secretagogues, surgery, viral or bacterial infection, or reduction of caloric intake.21
GLP-1 RAs and DPP-4 inhibitors can be continued. Patients should be encouraged to stay hydrated and eat regular meals to prevent serious illness related to dehydration. Insulin therapy should not be discontinued, and the patient should monitor their blood glucose more regularly (every 2 to 4 hours). Insulin dose adjustments may be needed.20
Role of the Pharmacist
Under normal circumstances, patients diagnosed with diabetes often struggle to manage the disease. With the added stresses caused by the COVID-19 pandemic, pharmacists can play a vital role in helping patients continue to manage their diabetes. Pharmacists are able to provide telehealth visits when face-to-face office visits may not be possible. Telehealth appointments provide a degree of flexibility for patients to receive care, serve as a reminder for them to follow up on necessary laboratory work for monitoring, and may encourage patients to maintain continuity of care. The CDC has also emphasized that pharmacists can continue to educate these high-risk patients on how to prevent COVID-19.22 The following are recommendations from the CDC on education pharmacists can reinforce to prevent the spread of COVID-19: know how it spreads; wash your hands often; avoid close contact; cover your mouth and nose with a mask when around others; cover coughs and sneezes; clean and disinfect; monitor your health daily; and protect your health this flu season with the flu vaccine.23
Pharmacists can also refer patients to diabetes self-management education and support (DSMES) services. Providing information to the healthcare teams and people with diabetes about the benefits of DSMES can help to improve care. Pharmacists can screen those at high risk for type 2 diabetes using a screening tool developed by the CDC and the ADA and then refer patients to other healthcare providers for services and treatment. Patients can also be referred to the National Diabetes Prevention Program, which provides a multitude of resources.22 In the inpatient setting, pharmacists can ensure that patients receive safe and effective medication therapy and recommend appropriate monitoring to the healthcare team.
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21. Diaz-Ramos A, Eilbert W, Marquez D. Euglycemic diabetic ketoacidosis associated with sodium-glucose cotransporter-2 inhibitor use: a case report and review of the literature. Int J Emerg Med. 2019;12(27).
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23. CDC. How to Protect Yourself and Others. Centers for Disease Control and Prevention. www.cdc.gov/coronavirus/2019-ncov/prevent-getting-sick/prevention.html. Updated September 11, 2020. Accessed October 20, 2020.
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