COVID-19 and Diabetes: A Comprehensive Review of Angiotensin Converting Enzyme 2, Mutual Effects and Pharmacotherapy.

The potential relationship between diabetes and COVID-19 has been evaluated. However, new knowledge is rapidly emerging. In this study, we systematically reviewed the relationship between viral cell surface receptors (ACE2, AXL, CD147, DC-SIGN, L-SIGN and DPP4) and SARS-CoV-2 infection risk, and emphasized the implications of ACE2 on SARS-CoV-2 infection and COVID-19 pathogenesis. Besides, we updated on the two-way interactions between diabetes and COVID-19, as well as the treatment options for COVID-19 comorbid patients from the perspective of ACE2. The efficacies of various clinical chemotherapeutic options, including anti-diabetic drugs, renin-angiotensin-aldosterone system inhibitors, lipid-lowering drugs, anticoagulants, and glucocorticoids for COVID-19 positive diabetic patients were discussed. Moreover, we reviewed the significance of two different forms of ACE2 (mACE2 and sACE2) and gender on COVID-19 susceptibility and severity. This review summarizes COVID-19 pathophysiology and the best strategies for clinical management of diabetes patients with COVID-19.

Nebulization of Low-Dose S-Nitrosoglutathione in Diabetic Stroke Enhances Benefits of Reperfusion and Prevents Post-Thrombolysis Hemorrhage.

The COVID-19 pandemic has escalated the occurrence of hypoxia including thrombotic stroke worldwide, for which nitric oxide (NO) therapy seems very promising and translatable. Therefore, various modes/routes of NO-delivery are now being tested in different clinical trials for safer, faster, and more effective interventions against ischemic insults. Intravenous (IV) infusion of S-Nitrosoglutathione (GSNO), the major endogenous molecular pool of NO, has been reported to protect against mechanical cerebral ischemia-reperfusion (IR); however, it has been never tested in any kind of "clinically" relevant thromboembolic stroke models with or without comorbidities and in combination with the thrombolytic reperfusion therapy. Moreover, "IV-effects" of higher dose of GSNO following IR-injury have been contradicted to augment stroke injury. Herein, we tested the hypothesis that nebulization of low-dose GSNO will not alter blood pressure (BP) and will mitigate stroke injury in diabetic mice via enhanced cerebral blood flow (CBF) and brain tissue oxygenation (PbtO2). GSNO-nebulization (200 µg/kgbwt) did not alter BP, but augmented the restoration of CBF, improved behavioral outcomes and reduced stroke injury. Moreover, GSNO-nebulization increased early reoxygenation of brain tissue/PbtO2 as measured at 6.5 h post-stroke following thrombolytic reperfusion, and enervated unwanted effects of late thrombolysis in diabetic stroke. We conclude that the GSNO-nebulization is safe and effective for enhancing collateral microvascular perfusion in the early hours following stroke. Hence, nebulized-GSNO therapy has the potential to be developed and translated into an affordable field therapy against ischemic events including strokes, particularly in developing countries with limited healthcare infrastructure.

A pilot open-label study of aldose reductase inhibition with AT-001 (caficrestat) in patients hospitalized for COVID-19 infection: Results from a registry-based matched-control analysis.

BACKGROUND AND AIMS: Cardiometabolic disease may confer increased risk of adverse outcomes in COVID-19 patients by activation of the aldose reductase pathway. We hypothesized that aldose reductase inhibition with AT-001 might reduce viral inflammation and risk of adverse outcomes in diabetic patients with COVID-19. METHODS: We conducted an open-label prospective phase 2 clinical trial to assess safety, tolerability and efficacy of AT-001 in patients hospitalized with COVID-19 infection, history of diabetes mellitus and chronic heart disease. Eligible participants were prospectively enrolled and treated with AT-001 1500 mg BID for up to 14 days. Safety, tolerability, survival and length of hospital stay (LOS) were collected from the electronic medical record and compared with data from two matched control groups (MC1 and MC2) selected from a deidentified registry of COVID-19 patients at the same institution. RESULTS: AT-001 was safe and well tolerated in the 10 participants who received the study drug. In-hospital mortality observed in the AT-001 group was 20% vs. 31% in MC1 and 27% in MC2. Mean LOS observed in the AT-001 group was 5 days vs. 10 days in MC1 and 25 days in MC2. CONCLUSIONS: In hospitalized patients with COVID-19 and co-morbid diabetes mellitus and heart disease, treatment with AT-001 was safe and well tolerated. Exposure to AT-001 was associated with a trend of reduced mortality and shortened LOS. While the observed trend did not reach statistical significance, the present study provides the rationale for investigating potential benefit of AT-001 in COVID 19 affected patients in future studies.

Could Exogenous Insulin Ameliorate the Metabolic Dysfunction Induced by Glucocorticoids and COVID-19?

The finding that high-dose dexamethasone improves survival in those requiring critical care due to COVID-19 will mean much greater usage of glucocorticoids in the subsequent waves of coronavirus infection. Furthermore, the consistent finding of adverse outcomes from COVID-19 in individuals with obesity, hypertension and diabetes has focussed attention on the metabolic dysfunction that may arise with critical illness. The SARS coronavirus itself may promote relative insulin deficiency, ketogenesis and hyperglycaemia in susceptible individuals. In conjunction with prolonged critical care, these components will promote a catabolic state. Insulin infusion is the mainstay of therapy for treatment of hyperglycaemia in acute illness but what is the effect of insulin on the admixture of glucocorticoids and COVID-19? This article reviews the evidence for the effect of insulin on clinical outcomes and intermediary metabolism in critical illness.

Diabetes and coronavirus (SARS-CoV-2): Molecular mechanism of Metformin intervention and the scientific basis of drug repurposing.

Coronavirus Disease 2019 (COVID-19), caused by a new strain of coronavirus called Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), was declared a pandemic by WHO on March 11, 2020. Soon after its emergence in late December 2019, it was noticed that diabetic individuals were at an increased risk of COVID-19-associated complications, ICU admissions, and mortality. Maintaining proper blood glucose levels using insulin and/or other oral antidiabetic drugs (such as Metformin) reduced the detrimental effects of COVID-19. Interestingly, in diabetic COVID-19 patients, while insulin administration was associated with adverse outcomes, Metformin treatment was correlated with a significant reduction in disease severity and mortality rates among affected individuals. Metformin was extensively studied for its antioxidant, anti-inflammatory, immunomodulatory, and antiviral capabilities that would explain its ability to confer cardiopulmonary and vascular protection in COVID-19. Here, we describe the various possible molecular mechanisms that contribute to Metformin therapy's beneficial effects and lay out the scientific basis of repurposing Metformin for use in COVID-19 patients.

Beneficial Effect of Statins in COVID-19-Related Outcomes-Brief Report: A National Population-Based Cohort Study.

OBJECTIVE: Although statins are widely prescribed lipid-lowering drugs, there are concerns about the safety of their use in the context of coronavirus disease 2019 (COVID-19), since statins increase the expression of ACE2 (angiotensin-converting enzyme 2). This study aimed to disclose the association between statins and 60-day COVID-19 mortality. Approach and Results: All patients hospitalized with laboratory-confirmed COVID-19 were enrolled in this study from January 19 to April 16, 2020, in Korea. We evaluated the association between the use of statins and COVID-19-related mortality in the overall and the nested 1:2 propensity score-matched study. Furthermore, a comparison of the hazard ratio for death was performed between COVID-19 patients and a retrospective cohort of patients hospitalized with pneumonia between January and June 2019 in Korea. The median age of the 10 448 COVID-19 patients was 45 years. Statins were prescribed in 533 (5.1%) patients. After adjusting for age, sex, and comorbidities, Cox regression showed a significant decrease in hazard ratio associated with the use of statins (hazard ratio, 0.637 [95% CI, 0.425-0.953]; P=0.0283). Moreover, on comparing the hazard ratio between COVID-19 patients and the retrospective cohort of hospitalized pneumonia patients, the use of statins showed similar benefits. CONCLUSIONS: The use of statins correlates significantly with lower mortality in patients with COVID-19, consistent with the findings in patients with pneumonia. Graphic Abstract: A graphic abstract is available for this article.

The Efficacy and Potential Mechanisms of Metformin in the Treatment of COVID-19 in the Diabetics: A Systematic Review.

Introduction: Diabetes mellitus (DM) is one of the most common comorbidities among patients with coronavirus disease 2019 (COVID-19) which may exacerbate complications of this new viral infection. Metformin is an anti-hyperglycemic agent with host-directed immune-modulatory effects, which relieve exaggerated inflammation and reduce lung tissue damage. The current systematic review aimed to summarize the available evidence on the potential mechanism of action and the efficacy of metformin in COVID-19 patients with DM. Methods: A systematic search was carried out in PubMed/Medline, EMBASE, the Cochrane Controlled Register of Trials (CENTRAL), and Web of Science up to July 30, 2020. The following keywords were used: "COVID-19", "SARS-CoV-2", "2019-nCoV", "metformin", and "antidiabetic drug". Results: Fourteen studies were included in our systematic review. Three of them were observational with 6,659 participants. Decreasing insulin resistance, reduction of some inflammatory cytokines like IL-6 and TNF-α, modulation of angiotensin-converting enzyme 2 (ACE2) receptor, and improving neutrophil to lymphocyte ratio are some of the potential mechanisms of metformin in COVID-19 patients with DM. Nine out of fourteen articles revealed the positive effect of metformin on the prognosis of COVID-19 in diabetic or even non-diabetic patients. Moreover, different studies have shown that metformin is more effective in women than men. Conclusions: The use of metformin may lead to improve the clinical outcomes of patients with mild to moderate SARS-CoV-2, especially in diabetic women. Further observational studies should be conducted to clarify the effects of metformin as a part of the treatment strategy of COVID-19.

The triumvirate: why hypertension, obesity, and diabetes are risk factors for adverse effects in patients with COVID-19.

The outbreak of coronavirus disease 2019 (COVID-19) caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a pandemic. The cellular receptor for SARS-CoV-2 entry is the angiotensin-converting enzyme 2, a membrane-bound homolog of angiotensin-converting enzyme. Henceforth, this has brought the attention of the scientific community to study the interaction between COVID-19 and the renin-angiotensin system (RAS), as well as RAS inhibitors. However, these inhibitors are commonly used to treat hypertension, chronic kidney disorder, and diabetes. Obesity is a known risk factor for heart disease, diabetes, and hypertension, whereas diabetes and hypertension may be indirectly related to each other through the effects of obesity. Furthermore, people with hypertension, obesity, diabetes, and other related complications like cardiovascular and kidney diseases have a higher risk of severe COVID-19 infection than the general population and usually exhibit poor prognosis. This severity could be due to systemic inflammation and compromised immune response and RAS associated with these comorbid conditions. Therefore, there is an urgent need to develop evidence-based treatment methods that do not affect the severity of COVID-19 infection and effectively manage these chronic diseases in people with COVID-19.

Remote Continuous Glucose Monitoring With a Computerized Insulin Infusion Protocol for Critically Ill Patients in a COVID-19 Medical ICU: Proof of Concept.

OBJECTIVE: The use of remote real-time continuous glucose monitoring (CGM) in the hospital has rapidly emerged to preserve personal protective equipment and reduce potential exposures during coronavirus disease 2019 (COVID-19). RESEARCH DESIGN AND METHODS: We linked a hybrid CGM and point-of-care (POC) glucose testing protocol to a computerized decision support system for continuous insulin infusion and integrated a validation system for sensor glucose values into the electronic health record. We report our proof-of-concept experience in a COVID-19 intensive care unit. RESULTS: All nine patients required mechanical ventilation and corticosteroids. During the protocol, 75.7% of sensor values were within 20% of the reference POC glucose with an associated average reduction in POC of 63%. Mean time in range (70-180 mg/dL) was 71.4 ± 13.9%. Sensor accuracy was impacted by mechanical interferences in four patients. CONCLUSIONS: A hybrid protocol integrating real-time CGM and POC is helpful for managing critically ill patients with COVID-19 requiring insulin infusion.

Efficacy and safety of DPP-4 inhibitor in the treatment of patients with COVID-19 combined with diabetes mellitus: A protocol for systematic review and meta-analysis.

BACKGROUND: DM is a common chronic metabolic disease. COVID-19 is a large-scale infectious disease. Some studies have shown that DM is an independent risk factor that increases COVID-19 mortality or other adverse outcomes. There is currently no specific and effective drug treatment. More and more people realize that DPP-4 inhibitors may play a huge role in fighting COVID-19 combined with diabetes. However, there is no evidence-based medicine to confirm the effectiveness and safety of DPP-4 inhibitors in the treatment of COVID-19 patients with diabetes. Therefore, we will conduct a systematic review and meta-analysis to synthesize the existing clinical evidence. METHODS AND ANALYSIS: Electronic databases include CNKI, Wanfang, VIP, CBM database, Cochrane Library, PubMed, Web of Science, EMBASE, etc. We will retrieve each database from December 2019 to September 2020. At the same time, we will look for clinical trial registration and gray literature. This study only included clinical randomized controlled trials. The reviewers independently conduct literature selection, data analysis, quality analysis, and evaluation. The primary outcomes include mortality rate, morbidity, interleukin-6, tumor necrosis factor-alpha, clinical improvement, symptoms improvement, fasting blood glucose, 2-hour postprandial blood glucose, glycosylated hemoglobin, fasting insulin, adverse reactions, etc. Finally, we will conducted a meta-analysis through Review Manager Software version 5.3. RESULTS: The results will be published in peer-reviewed journals and presented at a relevant conference. CONCLUSION: This study will explore the effectiveness and safety of DPP-4 inhibitors in the treatment of COVID-19 patients with diabetes. It will provide evidence-based medical evidence for DPP-4 inhibitors in the treatment of diabetes with COVID-19. REGISTRATION NUMBER: INPLASY202090015.

Sitagliptin: a potential drug for the treatment of COVID-19?

Recently, an outbreak of a fatal coronavirus, SARS-CoV-2, has emerged from China and is rapidly spreading worldwide. Possible interaction of SARS-CoV-2 with DPP4 peptidase may partly contribute to the viral pathogenesis. An integrative bioinformatics approach starting with mining the biomedical literature for high confidence DPP4-protein/gene associations followed by functional analysis using network analysis and pathway enrichment was adopted. The results indicate that the identified DPP4 networks are highly enriched in viral processes required for viral entry and infection, and as a result, we propose DPP4 as an important putative target for the treatment of COVID-19. Additionally, our protein-chemical interaction networks identified important interactions between DPP4 and sitagliptin. We conclude that sitagliptin may be beneficial for the treatment of COVID-19 disease, either as monotherapy or in combination with other therapies, especially for diabetic patients and patients with pre-existing cardiovascular conditions who are already at higher risk of COVID-19 mortality.

[Diabetes and COVID-19: analysis of the clinical outcomes according to the data of the russian diabetes registry].

BACKGROUND: Data on the national level and worldwide show a higher rate of mortality in patients with diabetes mellitus (DM) due to COVID-19, which determines the high relevance of risk factor analysis for outcomes in DM patients to substantiate the strategy for this category of patients. AIM: To assess the effect of clinical and demographic parameters (age, gender, body mass index (BMI), glycemic control (HbA1c), and antidiabetic and antihypertensive drugs, including ACE inhibitors and ARBs) on clinical outcomes (recovery or death) in patients with type 2 DM. MATERIALS AND METHODS: A retrospective analysis of the Russian Register of Diabetes database was performed, including patients with type 2 DM (n=309) who suffered pneumonia/COVID-19 in the period from 01.02.2020 to 27.04.2020 and the indicated outcome of the disease (recovery or death) RESULTS: The percentage of lethality was determined to be 15.2% (47 of 309 people). The degree of lethality was found to be significantly higher in males (OR=2.08; 95% CI 1.1–3.9; p=0.022) and in patients on insulin therapy (OR=2.67; 95% CI; 1.42–5.02; p=0.002), while it was significantly lower in patients with an age <65 years (OR=0.34; 95% CI 0.18–0.67; p=0.001) and in patients receiving metformin (OR=0.26; 95% CI 0.14–0,5; p<0.0001), antihypertensive therapy (OR=0.43; 95% CI 0.22–0.82; p=0.009), β-blockers (OR=0.26; 95% CI 0.08–0.86; p=0.018), diuretics (OR=0.4; 95% CI 0.17–0.93; p=0.028) and renin-angiotensin system blockers (ACE inhibitors or ARBs) (OR=0.36; 95% CI 0.18–0.74; p=0.004). A tendency to an increase in lethality at higher rates of HbA1c and BMI was present, but it did not reach a statistical significance. Differences between patients receiving insulin therapy and those who were not receiving the insulin therapy were observed as follows: a significantly longer duration of type 2 DM (13.4 vs. 6.8 years, respectively; p<0.0001), worse overall glyacemic control (HbA1c: 8.1% vs. 7.0%, resp.; p<0.0001), and three times more frequent failure to achieve the HbA1c goal by more than 2.5% (14.7% vs. 5.9%, resp.; p=0.04). CONCLUSION: The identified risk factors for lethality in patients with type 2 DM indicate that good glycemic control and previous treatment with metformin and antihypertensive drugs (including RAS blockers) could reduce the frequency of deaths. In patients on insulin therapy, a higher lethality degree was associated with worse glycemic control.

Clinical Characteristics of Diabetic Patients with COVID-19.

BACKGROUND: Since December 2019, novel coronavirus- (SARS-CoV-2) infected pneumonia (COVID-19) has rapidly spread throughout China. This study is aimed at describing the characteristics of COVID-19 patients in Wuhan. METHODS: 199 COVID-19 patients were admitted to Wuhan Red Cross Hospital in China from January 24th to March 15th. The cases were divided into diabetic and nondiabetic groups according to the history of taking antidiabetic drugs or by plasma fasting blood glucose level at admission, and the difference between groups were compared. RESULTS: Among 199 COVID-19 patients, 76 were diabetic and 123 were nondiabetic. Compared with nondiabetics, patients with diabetes had an older age, high levels of fasting plasma glucose (FPG), D-dimer, white blood cell, blood urea nitrogen (BUN) and total bilirubin (TBIL), lower levels of lymphocyte, albumin and oxygen saturation (SaO2), and higher mortality (P < 0.05). The two groups showed no difference in clinical symptoms. Diabetes, higher level of D-dimer at admission, and lymphocyte count less than 0.6 × 109/L at admission were associated with increasing odds of death. Antidiabetic drugs were associated with decreasing odds of death. Treatment with low molecular weight heparin was not related to odds of death. CONCLUSION: The mortality rate of COVID-19 patients with diabetes was significantly higher than those without diabetes. Diabetes, higher level of D-dimer, and lymphocyte count less than 0.6 × 109/L at admission were the risk factors associated with in-hospital death.

Dissecting the interaction between COVID-19 and diabetes mellitus.

Coronavirus disease 2019 (COVID-19) is a global pandemic that is caused by a novel coronavirus, severe acute respiratory syndrome coronavirus-2. Data from several countries have shown higher morbidity and mortality among individuals with chronic metabolic diseases, such as diabetes mellitus. In this review, we explore the contributing factors for poorer prognosis in these individuals. As a significant proportion of patients with COVID-19 also have diabetes mellitus, this adds another layer of complexity to their management. We explore potential interactions between antidiabetic medications and renin-angiotensin-aldosterone system inhibitors with COVID-19. Suggested recommendations for the use of antidiabetic medications for COVID-19 patients with diabetes mellitus are provided. We also review pertinent clinical considerations in the management of diabetic ketoacidosis in COVID-19 patients. In addition, we aim to increase clinicians' awareness of the metabolic effects of promising drug therapies for COVID-19. Finally, we highlight the importance of timely vaccinations for patients with diabetes mellitus.

A potential therapeutic combination for treatment of COVID-19: Synergistic effect of DPP4 and RAAS suppression.

COVID-19, caused by the novel coronavirus SARS-CoV-2, is an abbreviated name for coronavirus disease 2019. COVID-19 became a global pandemic in early 2020. It predominantly affects not only the upper and lower respiratory tract, but also multiple organs, including the kidney, heart, and brain. The mortality of COVID-19 patients is high in men and in elderly patients with age-related diseases such as hypertension and diabetes. The angiotensin converting enzyme-2 (ACE-2), a component in the renin-angiotensin-aldosterone system (RAAS), plays as cell surface receptors for SARS-CoV-2. A recent study proved that coronavirus SARS-CoV-2 also uses dipeptidyl peptidase-4 (DPP4, also known as adenosine deaminase complexing protein 2, CD26) as a co-receptor when entering cells. In addition, DPP4 is also implicated in the regulation of the immune response. Thus, the combination of DPP4 inhibition and suppression of ACE-2/RAAS may be a novel therapeutic strategy for combating this pandemic.

Inflammation: A bridge between diabetes and COVID-19, and possible management with sitagliptin.

Patients with SARS-CoV-2 infections experience lymphopenia and inflammatory cytokine storms in the severe stage of the disease, leading to multi-organ damage. The exact pattern of immune system changes and their condition during the disease process is unclear. The available knowledge has indicated that the NF-kappa-B pathway, which is induced by several mediators, has a significant role in cytokine storm through the various mechanisms. Therefore, identifying the state of the immune cells and the dominant mechanisms for the production of cytokines incorporated in the cytokine storm can be a critical step in the therapeutic approach. On the other hand, some studies identified a higher risk for diabetic patients. Diabetes mellitus exhibits a close association with inflammation and increases the chance of developing COVID-19. Patients with diabetes mellitus have shown to have more virus entry, impaired immunity response, less viral elimination, and dysregulated inflammatory cytokines. The parallel analysis of COVID-19 and diabetes mellitus pathogenesis has proposed that the control of the inflammation through the interfering with the critical points of major signaling pathways may provide the new therapeutic approaches. In recent years, the role of Dipeptidyl Peptidase 4 (DPP4) in chronic inflammation has been proved. Numerous immune cells express the DPP4 protein. DPP4 regulates antibody production, cytokine secretion, and immunoglobulin class switching. DPP4 inhibitors like sitagliptin reduce inflammation intensity in different states. Following the accumulating data, we hypothesize that sitagliptin might reduce COVID-19 severity. Sitagliptin, an available DPP4 inhibitor drug, showed multidimensional anti-inflammatory effects among diabetic patients. It reduces the inflammation mostly by affecting on NF-kappa-B signaling pathway. Under the fact that inflammatory mediators are active in individuals with COVID-19, blocking the predominant pathway could be helpful.

Hydroxychloroquine, COVID-19 and diabetes. Why it is a different story.

Hydroxychloroquine has been proposed for the cure of the COVID-19 due to its anti-inflammatory and anti-viral action. People with diabetes are more prone to severe outcome if affected by COVID-19 and the use of Hydroxychloroquine might have some benefit in this setting. However, the use of Hydroxychloroquine in diabetes deserves particular attention for its documented hypoglycemic action.

Antihyperglycemic properties of hydroxychloroquine in patients with diabetes: Risks and benefits at the time of COVID-19 pandemic.

The antimalarial drug hydroxychloroquine (HCQ) has long been used as a disease-modifying antirheumatic drug for the treatment of several inflammatory rheumatic diseases. Over the last three decades, various studies have shown that HCQ also plays a role in the regulation of glucose homeostasis. Although the mechanisms of action underlying the glucose-lowering properties of HCQ are still not entirely clear, evidence suggests that this drug may exert multifaceted effects on glucose regulation, including improvement of insulin sensitivity, increase of insulin secretion, reduction of hepatic insulin clearance, and reduction of systemic inflammation. Preliminary studies have shown the safety and efficacy of HCQ (at a dose ranging from 400 to 600 mg/day) in patients with type 2 diabetes over a short-term period. In 2014, HCQ has been approved in India as an add-on hypoglycemic agent for patients with uncontrolled type 2 diabetes. However, large randomized controlled trials are needed to establish the safety and efficacy profile of HCQ in patients with type 2 diabetes over a long-term period. With regard to the COVID-19 pandemic, several medications (including HCQ) have been used as off-label drugs because of the lack of proven effective therapies. However, emerging evidence shows limited benefit from HCQ use in COVID-19 in general. The aim of this manuscript is to comprehensively summarize the current knowledge on the antihyperglycemic properties of HCQ and to critically evaluate the potential risks and benefits related to HCQ use in patients with diabetes, even in light of the current pandemic scenario.