Archives of Medicine and Health Sciences

SHORT COMMUNICATION
Year
: 2020  |  Volume : 8  |  Issue : 1  |  Page : 167--171

The impact of COVID-19 in diabetic patient


Antonio Vitiello, Francesco Ferrara 
 USL Umbria 1, Pharmaceutical Assisance Department, Perugia, Italy

Correspondence Address:
Dr. Francesco Ferrara
USL Umbria 1, Perugia
Italy

Abstract

The global pandemic SARS-CoV-2 (COVID-19) is causing thousands of deaths worldwide and is one of the greatest health challenges ever faced in human history. SARS-CoV-2 infection can cause fatal lung injuries caused by a generalized inflammatory state associated with multi-organ dysfunction. In this context, it is essential to recognize the factors that increase the risk of viral infection. People with pre-existing conditions, such as diabetes, are at greater risk of complications and death caused by COVID-19. Old age, possible chronic drug therapies, kidney failure, hyperglycemia, and heart disease, are predictive factors of a bad outcome for the diabetic patient. The regulation of glycemia and the adoption of appropriate measures are critical aspects to be taken into consideration for the diabetic patient in this pandemic period, especially in the patient with ongoing infection. In the latter, the use of drugs used to fight COVID-19 infection, such as antivirals or immunomodulants, must be well controlled to avoid possible drug interactions and major complications. People with diabetes fall into the category of the fragile and at-risk population, and if a COVID-19 infection is also ongoing, the patient must be managed optimally, trying to fight the virus but also without neglecting homeostasis and glycemic control. This analysis highlights the current knowledge and challenges for the prevention and management of patients with diabetes and COVID-19 infection.



How to cite this article:
Vitiello A, Ferrara F. The impact of COVID-19 in diabetic patient.Arch Med Health Sci 2020;8:167-171


How to cite this URL:
Vitiello A, Ferrara F. The impact of COVID-19 in diabetic patient. Arch Med Health Sci [serial online] 2020 [cited 2020 Nov 28 ];8:167-171
Available from: https://www.amhsjournal.org/text.asp?2020/8/1/167/287344


Full Text



 Introduction



SARS-CoV-2 infection

The viral infection caused by the new SARS-CoV-2 (COVID-19), recorded its first cases in China at the end of 2019, and within a few months, it became a global pandemic. At the time of writing, there were 569 Mln infected cases and 356.000 deaths, with over 250 countries affected.[1] In most cases, COVID-19 infection is a mild disease, and resolves spontaneously with symptoms such as weakness, nausea, fever lines, while some people develop a severe infection characterized by a rapid decline in lung function and breathing difficulties. A minority of patients develop a generalized inflammatory state caused by a cytokine storm responsible for multi-organ dysfunction, which can rapidly cause the death of the patient. To date, there are no direct antivirals and effective vaccines against SARS-CoV-2.[2]

Diabetes patient

Diabetes patients are more at risk than the general population of viral or bacterial infections. The immune system compromised by the metabolic pathology is characterized by a reduced response and effectiveness of neutrophil and T-lymphocyte activity and by the lack of an adequate humoral immune response, which makes the patient with diabetes at high risk of viral or bacterial infection especially in the airways.[3],[4]

People with diabetes are, therefore, at increased risk of both COVID-19 infection and increased complications and mortality. General precautions to prevent COVID-19 infection are essential for people with diabetes. Patients with diabetes need continuous and regular blood glucose monitoring and optimal compliance with ongoing drug treatment, even in the case of COVID-19 infection. For patients with severe COVID-19 diabetes, drugs such as gliptins, incretin mimetics or sodium-glucose co-transporter-2 (SGLT2) inhibitors can safely continue to be taken, and ace inhibitors/angiotensin receptor blocker (ARB) antihypertensives should also continue to be taken, unless contraindications or further evidence against their use develop. In particular, the diabetic patient has a higher risk of pneumonia mortality than the general population. In addition, during the SARS-CoV epidemic in 2003, similar to COVID-19, diabetes was identified as a risk factor for mortality from infection. Similarly, in another similar epidemic, such as Middle East respiratory syndrome (MERS), the presence of diabetes was a risk factor for infection and serious complications.[5],[6] Similarly, among patients with influenza A (H1N1) in 2009, diabetes increased the risk of complications.[7]

 Sars-CoV-2 Infection and Diabetic Patient



In light of currently available data, people with diabetes seem to be more susceptible to SARS-CoV-2 infection. This is because, in general, people with all forms of diabetes are at increased risk of infection because there is a defect in innate immunity affecting phagocytosis, neutrophil chemotaxis, and cell-mediated immunity.[8] Predisposing risk factors are also related to secondary diseases caused by diabetes, such as coagulation dysfunction, inflammatory tissue status, nephropathy, and cardiovascular diseases. An extensive epidemiological study of 72,314 patients with COVID-19 in China indicated that patients with diabetes have a mortality rate three times higher than all patients with COVID-19.[9] Diabetes is known to cause homeostasis dysfunction of the coagulation system and fibrinolytic cascade and overactive inflammation. These two components also manifest themselves in the more severe stages of SARS-CoV-2 infection. In the most severe stages of infection, the main complications are caused by a generalized hyperactive inflammatory state and coagulative dysfunction with the risk of thrombosis and lung injury. In a study of 174 patients with COVID-19 in Wuhan, China, people with diabetes had a higher concentration of inflammatory markers and a higher incidence of coagulopathy associated with higher mortality than those without diabetes.[10] Another key aspect to highlight is that during the SARS-CoV epidemic, it was noted that patients with viral infection had higher blood sugar levels than patients with infections caused by other viral agents.[11] Today it is known that SARS-CoV and SARS-CoV-2 use ACE-2 membrane glycoprotein to penetrate cells. In vitro and animal studies have shown that SARS-CoV binds ACE-2 even on pancreatic islands, damaging their function and causing a lack of adequate insulin production,[12] this biological mechanism is probably the cause of the hyperglycemia noticed in patients with SARS-CoV. Considering that SARS-CoV and SARS-CoV-2 share a high percentage of genomic similarity and that SARS-CoV-2 also binds ACE-2, a risk of hyperglycemia could also be hypothesized in patients with COVID-19, as happened in the SARS-CoV epidemic. It should also be noted that hyperglycemia is known to downregulate ACE2 expression that makes cells vulnerable to inflammation and the damaging effect of the virus. It should also be added that diabetes may not only be a risk factor for a severe viral form COVID-19, but also that the infection could worsen the pathology of diabetes creating a glycemic normalization more difficult to control and manage,[12],[13] also the potential damage to β cells caused by the virus, as described above, is reinforced by cases of severe diabetic ketoacidosis in hospitalized COVID-19 positive patients. In addition, it appears that COVID-19 infection may cause tissue resistance to the action of insulin, but as the COVID-19 plays a direct role in this high insulin resistance, it is not clear. In vitro studies have identified that DPP-4 is functional receptor for the virus responsible for MERS, and it could also be the case for SARS-CoV-2, currently there is no evidence of this, but the DPP-4 protein is also responsible for increased inflammation in type 2 diabetes.

 Telemedicine for Diabetes Care during COVID19 Pandemic



The control of glycemic homeostasis and the pathology of diabetes must always be practiced. During the COVID-19 pandemic period, due to lockdown in many countries, it may be complicated for the patient with diabetes to receive all the medical assistance necessary to better manage the disease. During this period, telemedicine can be useful for the management of patients with chronic diseases such as diabetes. The literal meaning of the term “Telemedicine” is “healing at a distance.”[14] The WHO has defined it as “the delivery of health care services, where distance is a critical factor, by all health care professionals using information and communication technologies for the exchange of valid information for the diagnosis, treatment, and prevention of disease and injuries, research and evaluation, and for the continuing education of health care providers, all in the interests of advancing the health of individuals and their communities.” Scientific studies support the use of telemedicine in patients of diabetes, especially in this time of the global pandemic. A meta-analysis of 35 randomized controlled trials telemedicine (video, phone, and E-mail) from China [involving a common population (n, 3514) to which telemedicine has been administered on 3and 60 months] has been done. This study showed a reduction of HbA1c 0.37% (P < 0.001) in the telemedicine group compared to checks.[15] In a recently published review of 46 studies, which including patients with diabetes mellitus type 2 (T2DM, n, 24,000) and T1DM n, 2052, different modalities of telemedicine have been studied. The average overall reduction of HbA1c was equal to that of HbA1c in the telemedicine intervention group in both T1DM (from 0.12% to 0.86%) and T2DM patients (0.01%–1.13%).[16] This evidence shows that every national health system must implement guidelines to be followed to improve health care for patients with diabetes in this period of a global pandemic.

 Clinical Pharmacological Aspects in the Management of the Diabetic Patient during the COVID-19 Pandemic



Antidiabetes agents

The continuous control and monitoring of blood glucose are of fundamental importance for the diabetes patient, even more so during the COVID-19 pandemic. Patients with diabetes can safely continue to take routine drug therapies; to date, there is no evidence that any anti-diabetes therapeutic agent can increase the risk of COVID-19 infection. Even if the patient with diabetes is affected by SARS-CoV-2, one should continue to monitor blood sugar levels and take the usual drug therapy. Probably, in the case of SARS-CoV-2 infection leads the patient into serious complications, possible changes in dosage or medication could be considered, but should always be considered on a case-by-case basis. Several factors, including blood glucose, hemodynamic stability, nutritional status, kidney function, risk of hypoglycemia, and drug interactions, should be carefully assessed. However, the most commonly used antidiabetes medications in therapy may need to be modified or even discontinued in specific cases. Metformin is among the most commonly used medications for type 2 diabetes and is predominantly eliminated renal, in a COVID-19 patient, careful monitoring of renal function should be performed to avoid the risk of lactic acidosis caused by increased drug concentrations. Hypoxia may also increase the risk of lactic acidosis.[17] In addition, some antivirals used to fight COVID-19 are inhibitors of the organic cation transporter (OCT), metformin is a substrate of this transporter, inhibiting OCT may increase metformin concentrations in plasma, careful monitoring should be carried out to avoid this interaction. Some nonsteroidal anti-inflammatory drugs that can be used in the COVID-19 patient may decrease renal function and increase plasma metformin concentration. However, glucocorticoids may increase blood glucose, in which case a change in metformin dose may be considered, although at present, the use of glucocorticoids does not seem to be recommended in the COVID-19 patient. Metformin may be discontinued in hospitalized and seriously ill patients due to the risk of lactic acidosis. Agonist glucagon peptide-1 receptor therapy (GLP-1RA) should probably be temporarily discontinued in patients with hemodynamic instability (which impairs absorption from subcutaneous sites), renal dysfunction, and gastrointestinal dysfunction. GLP-1RA may cause a slowdown in gastric emptying and may result in clinically significant reductions in the rate and degree of absorption of certain oral drugs administered simultaneously, such as darunavir or remdesivir antivirals.[18] Common side effects of GLP-1RA include nausea, vomiting, and diarrhea, which is a COVID-19 patient with similar gastrointestinal symptoms may lead to electrolyte depletion, careful evaluation should be made, GLP-1RA are excreted predominantly renal, in a COVID-19 patient with renal dysfunction an increase in drug concentrations may occur. No particular interactions with anticoagulants such as Low-molecular-weight heparin (LHMW) or interleukin-1 (IL1) and 6 inhibitors are known.

Dipeptidyl peptidase-4 (DPP4) inhibitors are associated with a low risk of hypoglycemia and are relatively safe in a wide range of renal functions, which is a strength in the COVID-19 patient. Although the renal function is severely impaired, dose modification of drugs in this class should be considered.[19] Another strength of these drugs is that there are no particular interactions with CYP inhibitors, and this is a very important aspect in a COVID-19 patient with diabetes, who is a complex patient and can use highly interacting drugs such as antivirals. Furthermore, there are no particular interactions with anticoagulants. Probably, the use of SGLT-2 inhibitors is more complex in the COVID-19 patient, due to the risk of diabetic ketoacidosis, which can lead to potentially fatal cases.[20] The clinical condition of the patient, the concentration of ketone bodies, hyperglycemia, renal function are aspects to be taken into account for a possible suspension of treatment with SGLT-2. In addition, this category of drug data suggests that the primary route of metabolism in humans is uridine 5′-diphosphorus glucuronidation glucuronyltransferase 1A3, 1A8, 1A9 and 2B7, and they are also OCT substrates. Interaction with antivirals such as darunavir and remdesivir should be carefully considered. There are no particular interactions with LHMW or IL-1 and 6 inhibitors. Insulin use should be carefully monitored due to the risk of hypoglycemia, and a dose change should be considered if the patient is on glucocorticoid therapy. In addition, a possible hypoglycemic additive effect due to hydroxychloroquine should be carefully evaluated. In patients with COVID-19 on sulfonylurea therapy, a change to insulin therapy should be considered because of the risk of high hypoglycemia in patients with SARS-CoV-2 infection. Caution with sulfonylureas should also be exercised in consideration of chloroquine, due to the risk of hypoglycemia with both and if renal dysfunction is present.[21]

Thiazolidinediones such as pioglitazone should be carefully questioned for use in the COVID-19 patient, as this class of drugs is contraindicated in patients with hemodynamic instability, liver or cardiac dysfunction, which may be present in a severe COVID-19 infection. Currently, existing evidence suggests that insulin is used compared to agents such as sulfonylureas or thiazolidinediones [Figure 1].{Figure 1}

Therapeutic agents for comorbidities

The therapy of the diabetic patient is complex and should aim not only at controlling glycemic homeostasis but also at a series of comorbidities that can worsen the clinical picture. The medical antihypertensive therapy of choice for the diabetic patient involves the use of ACE inhibitors or angiotensin 2 antagonists. These drugs not only reduce blood pressure and proteinuria but also slow the progression of diabetic nephropathy. To date, there are conflicting and as yet inconclusive results on their use in this period of the COVID-19 pandemic, causing an increase in the risk of infection that they could cause by raising ACE-2 concentrations. It remains to be emphasized that there is currently no clear evidence for or against the use of ACEI/ARB in people with diabetes at risk or infected with SARS-CoV-2.[22] Currently, most international organizations recommend the continuation of ACEI/ARB therapy, unless there are explicit contraindications such as uncontrolled kalaemia or renal stenosis [23],[24] Patients with diabetes undergoing treatment with antiaggregants such as 100 mg acetylsalicylic acid should continue to take them. There is currently no evidence of a possible suspension unless there are clear contraindications such as a risk of gastrointestinal bleeding or severe renal impairment. However, in severe COVID-19 patients co-administration of acetylsalicylic acid and corticosteroids or acetylsalicylic acid and heparin may lead to an increased risk of ulcer and gastrointestinal bleeding. In addition, there is currently no direct evidence for statin suspension in patients with diabetes and COVID-19. However, it is of great importance to consider that if the viral infection leads to renal damage (e.g., creatinine clearance <60 ml/min) or liver damage with increased transaminases,[25],[26] the statin concentration may increase causing a worsening of the clinical picture with the risk of myopathy and liver damage. In addition, antiviral protease inhibitors such as lopinavir in association with statins should not be used because of drug interaction and the risk of increased statin concentrations.[27] Therefore for the use of statins, we suggest individualized decisions on a case by case basis.

Anti-diabetes agent as a potential therapeutic treatment for COVID-19

Some therapeutic agents used to treat diabetes have shown evidence of effectiveness against SARS-CoV and MERS, epidemics similar to SARS-CoV-2. It is now known that in the most severe stages of COVID-19 infection, an overactive and uncontrolled inflammatory host system caused by a cytokinic cascade is responsible for multi-organ dysfunction and serious fatal lung lesions. The use of metformin has shown a decrease in inflammatory markers in patients with SARS-CoV and MERS, and appears to have additional benefits on viral infections, particularly hepatitis C virus (HCV).[28],[29] HCV, like SARS-CoV-2, is a ribonucleic acid virus, which leads to liver lesions. Overall, it appears that metformin may be useful to reduce insulin resistance in individuals infected with the virus, thereby influencing cellular response to infection but also reduces liver fibrosis in HCV patients.[30],[31] In addition, some studies have also shown that it may have a protective role on the liver in the more severe stages caused by SARS-CoV-2 infection; therefore, a role of metformin could be hypothesized to protect the liver in patients with diabetes and COVID-19.[32] However, its use in the severe COVID-19 patient should be carefully assessed in view of the risks described above.[33],[34] The use of DPP IV inhibitors (glyptine) is being studied in the COVID-19 patient. The DPP4 protein is expressed in many cells, including alveolar epithelium and inflammatory cells. MERS-CoV uses DPP4 to enter host cells,[35] but it is not known whether SARS-CoV-2 also uses the same protein to enter the cell, in addition to ACE-2. If this is demonstrated, the use of gliptins could decrease the risk of SARS-CoV-2 infection, but this has not been demonstrated so far. The potential benefit in the treatment of SARS-CoV-2 infection with DPP IV inhibitors remains to be further investigated.[36] Similar to metformin, the effects of reducing inflammatory markers are also known for GLP-1RA and have also demonstrated a potential therapeutic benefit in acute lung lesions.[37] However, the available data are limited to experimental models, and their benefit still remains to be studied. There is also evidence that Thiazolidinediones such as pioglitazone has anti-inflammatory properties. In particular, pioglitazone (30–45 mg/day) can significantly reduce inflammatory mediators such as IL-6, IL-2. IL-8 and tumor necrosis factor-α.[38] It has also been reported that pioglitazone inhibits the secretion of pro-inflammatory cytokines and may increase the anti-inflammatory ones (e.g., IL-4 and IL-10).[39] Finally, there is evidence that pioglitazone can exert a direct effect on inflammation in lung tissue and a reduction in the fibrotic state.[40],[41]

 Conclusion



The global pandemic from COVID-19 represents one of the greatest health challenges in human history. Pending the discovery of an effective vaccine and antivirals directed against SARS-CoV-2, it is essential to recognize factors that may increase the risk of infection or worsen complications from COVID-19. The identification of effective preventive and therapeutic strategies is urgently needed, especially for patients with chronic diseases such as diabetes. Patients with diabetes are at greater risk in this pandemic period, and even diabetes therapy can be complex to manage during a COVID-19 infection. Clinical data and EBM to be translated into guidelines by scientific societies and countries are needed to better guide clinicians in the complex management of a diabetes patient who is COVID-19 positive.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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