At the time of this writing, 210 countries and territories have been affected by the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), with two million cases of COVID-19 (the disease caused by the virus) diagnosed and 134,616 deaths recorded¹, though the actual numbers may be considerably higher. Many countries are under lockdown and our day-to-day lives have been changed by this pandemic. There are seven different human coronaviruses. The SARS-CoV-2 belongs to the β-coronavirus and, when compared to Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS), has a higher rate of infectivity². Despite a lower mortality rate than SARS and MERS, due to the infectious nature of SARS-CoV-2, the number of patients afflicted has overwhelmed the health care system in many countries, including the United States, Italy and Spain, which have the highest number of cases. Given the scope of this disease and the large number of patients worldwide diagnosed with diabetes, it is important to understand how this pandemic can affect patients with both conditions.

     Poorly controlled diabetes mellitus not only leads to micro- and macrovascular damage, but due to its effect on the immune system, also increases susceptibility to infection. Reduction in T-cell response and neutrophil function, disorder of the humoral immune response and reduced inflammatory response have been found in individuals with diabetes. Moreover, human and animal studies have shown that in the presence of diabetes, there is a predominance of proinflammatory macrophages from regulatory or anti-inflammatory macrophages and T-cells in adipose tissue³. When compared to an age and gender matched cohort, patients with type 1 and type 2 diabetes were at higher risk for all infections, particularly those affecting the bones and joints, as well as sepsis and cellulitis. Risk of hospitalization following infection was higher for patients with type 1 diabetes compared to those with type 2 diabetes (3.71 versus 1.88)⁴. In terms of respiratory tract infections, patients with diabetes were found to be six times more likely than healthy individuals to be hospitalized during a flu epidemic⁵.

     In past viral pandemics, patients with diabetes were found to have poorer outcomes than the general population. During the 2002-2003 SARS outbreak, diabetes was an independent risk factor for mortality and morbidity^6,7. In 2009, during the H1N1 influenza pandemic, patients with diabetes had three times the risk of being hospitalized and were four times as likely to be admitted to the intensive care unit. The role of hyperglycemia in increasing the severity of influenza infections remains unclear. Possible links include: glycemic variability leading to endothelial dysfunction, increased viral load secondary to raised pulmonary glucose concentration, and immune system dysfunction in patients with diabetes⁸. Three years after the H1N1 influenza outbreak, MERS emerged in Saudi Arabia. The MERS infection had a higher case fatality rate compared to SARS (41.8% versus 9.6%)⁹. Investigators also found that comorbidities such as diabetes, hypertension, renal, cardiac and respiratory disease were clinical predictors of death in patients with MERS¹⁰.

     The prevalence of diabetes amongst patients infected with COVID-19 varies among countries. China reported a prevalence of 8-11%; similarly, the United States reported a prevalence of 11%, while in Italy the prevalence was reported to be higher at 36%^11-14. The global case fatality rate for all patients infected with the virus has been reported to be 3.4%¹⁵. Since the outbreak began in December 2019 in Wuhan China, numerous studies have been conducted to identify risk factors for disease severity and death. In a systemic review of 53,000 patients, older age (>50 years), male gender, smoking, as well as underlying comorbidities (chronic kidney disease, chronic obstructive airway disease, cerebrovascular disease) were predictors for severe COVID-19 disease. The same review identified age greater than 60 years (relative risk [RR]=9.45), cardiovascular disease (RR=6.75), hypertension (RR=4.48), and diabetes (RR=4.43), as factors that are independently associated with COVID-19 mortality¹⁶. Analysis of a case series of 174 individuals with diabetes (and no comorbidities) revealed that patients had a higher risk of severe pneumonia (based on computed tomography imaging score). Patients with diabetes also had an excessive inflammatory response with raised interleukin-6, C-reactive protein and ferritin levels, as well as hypercoagulable state as confirmed by raised coagulation index and D-dimer. This may suggest that patients with diabetes are more susceptible to cytokine storm leading to rapid deterioration¹⁷. 

     Owing to their mechanisms of action, concerns have been raised about some frequently prescribed medications in patients with diabetes. It has been suggested that the use of angiotensin-converting enzyme (ACE) inhibitors may result in an increased expression of the ACE-2 receptor, potentially leading to increased uptake of the virus. The SARS CoV-2 virus enters the cell via ACE-2 receptors, which are expressed by the alveolar cells in the lungs as well as the vascular endothelia, renal and cardiovascular tissue, small intestine and pancreas^18,19. However there is no clinical data to support this phenomenon. Moreover, one study of 112 patients with COVID-19 and cardiovascular disease found that the use of ACE inhibitors or angiotensin II-receptor blockers (ARB) did not increase mortality²⁰. A joint statement by the American Heart Association, the American College of Cardiology, and the Heart Failure Society of America has advised that patients on ACE inhibitors or ARBs should continue taking their medication²¹.

     Because the dipeptidyl peptidase-4 (DPP-4) enzyme is a transmembrane protein expressed in many tissues including the immune cells, it also plays a role in immune regulation particularly by T-cell activation. Animal studies have found that expression of DPP-4 on diabetic mice infected with MERS-CoV had a prolonged infection and delayed recovery ²². How this finding would translate in human studies is uncertain. The use of DPP-4 inhibitors was previously reported to be associated with an increase in upper respiratory infections such as nasopharyngitis and sinusitis while there was no increase in the incidence of pneumonia ²³. However a more recent meta-analysis did not find any increase in the overall risk of infection (including respiratory tract infections) with the use of DPP-4 inhibitors in comparison to placebo and active drug comparators²⁴.

     The care of patients with diabetes during the COVID-19 pandemic is fraught with challenges. Countries worldwide are imposing lockdowns and patients may have difficulty accessing health care facilities or obtaining their medications. Dietary patterns may also differ from the usual –depending on availability of specific foods–and physical activity may be limited. While we await the development of vaccines to slow the spread of the virus and for the decline of new cases, the care of our patients must evolve and adapt to the situation. Virtual health care or telemedicine is now more vital than ever to communicate with patients and ensure continuity of care. With the ongoing pandemic requiring the focused attention of the global health care community, our responsibility to managing patients with diabetes—who are at an elevated risk for virus-related morbidity and mortality—continues to be an important priority. To those on the frontlines worldwide, who have been tirelessly battling this pandemic, thank you and stay safe!

References:

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