US Pharm. 2023;48(11):HS2-HS11.
ABSTRACT: Diabetes is the seventh leading cause of death in the United States and affects 11.3% of the population. Additionally, the number of people affected by diabetes continues to rise. People who have diabetes are more prone to infections, including the coronavirus disease 2019 (COVID-19). Diabetes has a significant impact on outcomes when it comes to COVID-19. This population is found to be at higher risk for severe COVID-19 and worse outcomes. By understanding the pathophysiology and pathways linking diabetes to severe COVID-19, pharmacists can identify new interventions or ways to optimize therapies.
Diabetes plagues a large portion of the population, not only in the United States but also worldwide.1 Diabetes is the seventh leading cause of death in the United States and affects 11.3% of the population.2 Additionally, the number of people affected by diabetes continues to rise.1 People who have diabetes are more prone to infections, including the coronavirus disease 2019 (COVID-19).3,4 This population is found to be at higher risk for severe COVID-19 and worse outcomes. Therefore, understanding how to manage COVID-19 and its complications and promoting preventive care are crucial to optimizing medical therapy for these patients.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a single-stranded, positive-sense, enveloped RNA virus, causes COVID-19, which spread exponentially throughout the world after its initial reports in Wuhan, China.5,6 As of August 2023, there were 769,369,823 confirmed cases worldwide and 6,954,336 deaths cumulatively reported to the World Health Organization.7 In comparison with the beginning of the pandemic, there is now a better understanding of the virus and disease process itself that has led to the identification of several therapies and strategies to treat and prevent COVID-19. Additionally, insight into which populations may be more affected as well as other risk factors for poor COVID-19 outcomes has emerged. Studies have demonstrated that those with underlying medical conditions are more likely to develop severe COVID-19 requiring hospitalization, intensive care management and mechanical ventilation, and are more likely to die.3,8-14 A report from the CDC revealed that hospitalizations and deaths in patients with underlying conditions were six times and 12 times higher, respectively.3 Of those diagnosed with COVID-19, 9.8% to 18% had diabetes.8 Multiple studies have demonstrated that patients with diabetes who acquire COVID-19 are more likely to have severe disease or poor outcomes.9,15-18 The risk is even higher with increased age and concomitant underlying medical conditions.3,16
Risk Factors With COVID-19 and DiabetesDiabetes is a chronic disease that affects 37.3 million people in the U.S.19 Currently, 28.7 million people have been diagnosed with diabetes; however, 8.5 million people who have diabetes are undiagnosed and do not know they have it. It is one of the leading causes of mortality and morbidity worldwide.6,20 Its complications extend beyond insulin impairment, impaired insulin utilization, or glucose dysregulation. Although some concomitant diseases increase mortality with COVID-19, there are other proposed mechanisms at play that can contribute to worse outcomes in diabetics specifically.8 Diabetes is a risk factor for worse outcomes with infections such as influenza, pneumonia, and Middle East respiratory syndrome coronavirus.4-6,21-24 Hyperglycemia increases the virulence of certain pathogens.21 Diabetics already carry a chronic low level of inflammation and experience changes in their innate immunity.4,6,8,21,25,26 For example, phagocytosis and chemotaxis are impaired in diabetes.4,21,23 Proinflammatory macrophages are also increased, natural-killer cells are decreased, and the T-cell activity is altered.
It has also been suggested that COVID-19 induces an excessive stress response that results in increased production of catecholamines and glucocorticoids, leading to hyperglycemia.4 Increased blood glucose then leads to increased oxidative stress and production of proinflammatory cytokines but reduced lymphocyte-proliferative responses and functionality of neutrophils and macrophages.4,23 This increased level of inflammation during COVID-19 can be seen with elevated ferritin levels, lactate dehydrogenase, procalcitonin, d-dimer, C-reactive protein (CRP), and interleukin-6.21 This increase could not only damage lung tissue and other tissues but can also potentiate coagulation pathways, causing microemboli in the lungs and large arterial vessels.4,8,27 The damage to other tissues could involve organs important to glucose metabolism.5 Multiorgan-level endothelial dysfunction can cause microvascular complications in patients with diabetes that further contribute to inflammation, vasoconstriction, and vascular lesions, which may result in tissue edema, organ ischemia, and a procoagulant state.4,6,28 To complicate matters, injury to lung tissue can also increase the expression of the angiotensin-converting enzyme 2 receptor, which SARS-CoV-2 uses to bind to host cells.4 Diabetics also seem to have significantly thicker endothelial capillary basal lamina and alveolar epithelia, so they may experience impaired respiratory function.6
In addition to the mechanisms by which diabetes alters the immune system and contributes to poor outcomes with COVID-19, there are other risk factors that can contribute to worse outcomes in diabetics with COVID-19. Hyperglycemia with or without diabetes was linked with increased mortality and worse glycemic control with more severe COVID-19.8,10 Studies suggest that COVID-19 disproportionately impacts men, the elderly, minority populations, and people with comorbidities other than diabetes, such as cardiovascular disease, chronic obstructive lung disease (COPD), microvascular and macrovascular complications, and obesity.16,21,22 Among those, cardiovascular disease and hypertension were more common in diabetics who were hospitalized with COVID-19.28 Chronic kidney disease (CKD) was also found to be an independent risk factor for death.21 Having obesity can also further increase the risk for severe COVID-19 because obesity can alter lung function, produce inflammatory cytokines due to visceral fat, and increase thromboembolic events.29 Longer length of stay and increased hospitalizations have been associated with lower socioeconomic status, older patients, obesity, smoking, physical inactivity, poor glycemic control, insulin use, longer duration of diabetes, or presence of other complications.8
One study demonstrated that lower discharge rates were associated with hypertension, microvascular or macrovascular diabetic complications, heart failure, and COPD, as well as patients who had markers of inflammation such as CRP, high white cell count, lower lymphocyte count, and higher aspartate aminotransferase (AST) or dyspnea or higher plasma creatinine on admission.30 Death was more likely in those who were male, had a longer duration of diabetes, a history of microvascular and macrovascular complications, heart failure, and COPD, or those with COVID-19 symptoms, fever, dyspnea, and biological findings, such as higher plasma glucose, creatinine, AST, white cells, lymphocytes, platelets, CRP, and creatinine phosphokinase on admission. The lack of COVID-19 vaccination seemed to also be linked with increased fatality.31
Treatment Therapies for COVID-19
Current management of adult COVID-19 patients includes using therapies that decrease viral replication, disease progression, and the inflammatory immune response.8 Strategies for pediatric patients are extrapolated mostly from the adult population.32 The current management of hospitalized adult patients per the National Institutes of Health is summarized in TABLE 1. Other supportive care measures to consider include treating bacterial pneumonia if the clinical suspicion is high and providing antipyretics, oxygen therapy as needed, and thromboprophylaxis.8
Managing diabetic patients with COVID-19 extends beyond treatment of the infection alone. Managing hyperglycemia is critical, as insulin resistance seems to be enhanced by COVID-19.26 Hyperglycemia has been associated with increased morbidity, length of stay, ICU needs, and mortality in the inpatient setting.23 Persistently elevated fasting blood glucose seems to promote viral replication, decrease clearance of SARS-CoV-2, and slow recovery.5,26 Therefore, intensive glucose monitoring at least four times daily is important in the management of a diabetic patient with COVID-19.6 Hemoglobin A1C should also be checked.20 Those with preprandial blood glucose persistently above 180 mg/dL should be given antihyperglycemic therapy with a targeted blood glucose of 140 mg/dL to 180 mg/dL.5 This is especially important since some patients may require glucocorticoid therapy in their treatment course for COVID-19, which can cause hyperglycemia. Risk factors for steroid-induced hyperglycemia in those without diabetes include high-dose steroids, long-term steroid use, older age, history of gestational diabetes or impaired fasting blood glucose, family history of diabetes, abdominal obesity, and ethnicity associated with high risk for diabetes.8 Subcutaneous insulin regimens are typically preferred in managing hyperglycemia in hospitalized patients although insulin infusions may be used in the critically ill with appropriate monitoring.6,8,23 Insulin is easily titratable based on renal function and nutritional status.8
Oral antihyperglycemic agents are generally not recommended for in-hospital use, although there has been some evidence demonstrating their effects when used to manage hyperglycemia in diabetics with COVID-19.23 Metformin seems to be linked with reduction in mortality, hospitalization, and need for ICU care; however, metformin use in-hospital is limited by potentially life-threatening adverse effects such as lactic acidosis and acute kidney injury and should be avoided in the critically ill, severe respiratory distress, renal impairment, or heart failure.5,16,20,23 When it comes to dipeptidyl peptidase-4 inhibitors, the evidence did not demonstrate benefit or harm from their use in diabetics with COVID-19.5 Glucagon-like peptide-1 receptor agonists could potentially provide improved outcomes and decreased mortality, hospitalizations, and respiratory complications, but their use is often limited due to the time needed to titrate the medication before their benefits are realized and associated side effects such as dehydration, nausea, vomiting, and aspiration pneumonia.5,6 Sodium-glucose cotransporter 2 inhibitors are generally avoided for hospital use due to the hypoglycemia and volume depletion that could cause diabetic ketoacidosis.5 Sulfonylureas are not typically recommended due to the risk of hypoglycemia.5,6 Thiazolidinediones are generally not recommended due to the risk of fluid retention or weight gain that could aggravate heart failure.5,6
Hyperglycemic emergencies such as diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state are also of concern in COVID-19 patients, as they tend to have higher mortality compared with patients without COVID-19.23 Although the data on DKA in COVID-19 are limited, the mortality rates have been reported as high as 40% to 50%.8 The standard management consisting of continuous insulin and isotonic fluids and electrolyte repletion is used to replete intravascular volume, improve renal perfusion, and decrease hyperglycemia, counterregulatory hormones, hepatic gluconeogenesis, lipolysis, and ketogenesis.8,20 There are some protocols now where SC insulin is used in mild and moderate DKA in patients without major comorbidities and who are not pregnant.
Diabetics are also at increased risk for acute kidney injury.8 Diabetic foot ulcers can worsen due to the inflammation and prothrombotic state from COVID-19. Diabetics with COVID-19 seem to experience long-term symptoms compared with their nondiabetic comparators.33 These symptoms include fatigue, neurocognitive dysfunction, shortness of breath, and chest pain. The elderly and obese tend to have worse outcomes and persistent symptoms.
Preventive methods are a vital part to managing COVID-19 and protecting the community.8 Preventive measures include wearing well-fitted masks in areas of high community transmission, social distancing (especially in crowded and poorly ventilated areas), and practicing general hygiene measures, such as frequent hand washing. Vaccinations are encouraged.8,34 Although it has been shown that immunity wanes in the months following vaccination, the likelihood of experiencing severe disease after vaccination is less compared with those who are unvaccinated. In those who developed severe disease, at least one of the following risk factors was present: aged 65 years and older; immunocompromised state; chronic cardiac, pulmonary, renal, neurologic, or liver disease; or diabetes. Because of the waning immunity, booster vaccinations are recommended.8
Despite the recommendations for vaccines, vaccine hesitancy and barriers to vaccination remain. The speed of vaccine production has raised skepticism around its efficacy. An infodemic—where too much information, including that which is false or misleading—can create confusion and generate mistrust in the healthcare system and towards healthcare authorities. Limited healthcare literacy can also contribute to vaccine hesitancy. Fear of deportation due to immigration status, previous experience with exploitative treatment and experimentation on certain communities, and racial discrimination further the mistrust of the medical community. Inadequate access to resources and healthcare information also contributes to the lack of information or prohibits much-needed groups from being informed. Other possible contributors to vaccine hesitancy include religious reasons, perception that COVID-19 is not a dangerous or serious disease, use of traditional remedies, fear of injection, and other cultural reasons.
ConclusionDiabetes has a significant impact on outcomes when it comes to COVID-19. By understanding the pathophysiology and pathways linking diabetes to severe COVID-19, pharmacists can identify new interventions or ways to optimize therapies. Awareness of the differences in COVID-19 outcomes in diabetics can serve as additional motivation to not only improve understanding of risk factors but also advocate for diabetics to optimize outcomes, encourage appropriate therapies, and support vaccinations to prevent infection.
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